Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:21])[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)=[CH:9][C:10]=2[F:12])[CH:5]=[CH:4][C:3]=1[OH:22].B(Br)(Br)Br>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:21])[C:8]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)=[CH:9][C:10]=2[F:12])[CH:5]=[CH:4][C:3]=1[OH:22]
Reactant: COc1ccc(-c2cc(F)c3c(Cl)c(O)ccc3c2Cl)cc1
Agent: BrB(Br)Br
Product: Oc1ccc(-c2cc(F)c3c(Cl)c(O)ccc3c2Cl)cc1

Procedure:
The title compound was prepared by reacting 1,5-dichloro-8-fluoro-6-(4-methoxyphenyl)-2-naphthol (0.15 g, 0.445 mmol) with boron tribromide (0.67 mL of 1N solution, 0.67 mmol) according to method D to yield 0.12 g (83%) of a light yellow solid mp 206–216° C.; 1H NMR (DMSO-d6): δ 6.88 (2H, d, J=8.55 Hz), 7.34–7.39 (3H, m), 7.51 (1H, d, J=9.34 Hz), 8.21 (1H, dd, J=1.66 Hz, J=9.34 Hz), 9.74 (1H, bs), 10.99 (1H, bs); MS (ESI) m/z 321/323/326 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:20])[N:16]=3)[NH:11][CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:23].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:20])[N:16]=3)[N:11]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=3)[CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:23]
Reactant: Cc1cccc(CBr)n1
Reactant: COc1ccc(C(=O)c2c[nH]c3ccc(C)nc3c2=O)cc1C
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2cn(Cc3cccc(C)n3)c3ccc(C)nc3c2=O)cc1C
Yield: 26 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1 were used with 100 mg (0.324 mmol) of 3-(4-Methoxy-3-methyl-benzoyl)-6-methyl-1H-[1,5]naphthyridin-4-one, 72.4 mg (0.389 mmol) of 2-Bromomethyl-6-methyl-pyridine, 15.6 mg (0.389 mmol, 60% dispersion in oil), and 1 mL of N,N-dimethylformamide. The crude product was purified by flash column chromatography using a gradient of 20-100% ethyl acetate in hexane and further purified on the reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 34.8 mg of 3-(4-Methoxy-3-methyl-benzoyl)-6-methyl-1-(6-methyl-pyridin-2-ylmethyl)-1H-[1,5]naphthyridin-4-one. LC-MSD, m/z for C25H23N3O3 [M+H]: 414.17 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 1.8 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](O)[N:5]2[N:9]=[N:10][N:11]=[C:4]2[N:3]=1.P(Cl)(Cl)([Cl:14])=O>C(Cl)(Cl)Cl>[Cl:14][C:6]1[N:5]2[N:9]=[N:10][N:11]=[C:4]2[N:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)n2nnnc2n1
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cl)n2nnnc2n1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
A mixture of 67.88 g (0.45 mole) of 5-methyl-7-hydroxytetrazolo[1,5-a]pyrimidine and 300 ml of phosphorus oxychloride was stirred for 1.5 hours in a bath of 100° C. and then concentrated. The residue obtained was dissolved in 600 ml of chloroform, ice-cooled and then washed with water, followed by drying over anhydrous magnesium sulfate to evaporate the solvent. The set residue was collected by filtration with addition of n-hexane and dried to obtain 70.2 g of the title compound (Yield: 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:25]([C:26](=[O:29])[NH:27][CH3:28])=[C:11]3[CH:12]=[C:13]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19](O)=[O:20])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.Cl.[C:31]1([C:37]2([NH2:40])[CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:25]([C:26]([NH:27][CH3:28])=[O:29])=[C:11]3[CH:12]=[C:13]([C:16]4[CH:24]=[CH:23][CH:22]=[C:18]([C:19](=[O:20])[NH:40][C:37]5([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=6)[CH2:39][CH2:38]5)[CH:17]=4)[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(-c3cccc(C(=O)O)c3)cc12
Reactant: NC1(c2ccccc2)CC1
Agent: Cl
Product: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(-c3cccc(C(=O)NC4(c5ccccc5)CC4)c3)cc12

Procedure:
2-(4-fluorophenyl)-N-methyl-5-(3-(1-phenylcyclopropylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide was prepared from 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-5-yl)benzoic acid (0.070 g, 0.14 mmol) and 1-phenylcyclopropanamine hydrochloride (0.040 g, 0.20 mmol). 1H NMR (500 MHz, DMSO-D6) δ ppm 9.40 (s, 1H), 8.90 (d, J=7.32 Hz, 1H), 8.35 (s, 1H), 8.11 (d, J=1.22 Hz, 1H), 8.03 (d, J=7.93 Hz, 1H), 7.98 (d, J=7.63 Hz, 2H), 7.90 (dd, J=8.70, 5.65 Hz, 2H), 7.65 (t, J=7.78 Hz, 1H), 7.49 (dd, J=7.32, 1.83 Hz, 1H), 7.28-7.35 (m, 4H), 7.23-7.26 (m, 2H), 7.15-7.20 (m, 1H), 2.81 (d, J=4.58 Hz, 3H), 1.32 (d, J=9.16 Hz, 4H). LCMS: retention time: 3.053 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 u, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3OH/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 505 (MH+).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:14][C@H:13]2[CH2:15][C@@H:10]1[CH2:11][C@@H:12]2[OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([Si:21](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])([CH3:19])[CH3:18].N1C=CN=C1>CN(C=O)C>[CH2:1]([O:8][C@H:9]1[CH2:14][C@H:13]2[CH2:15][C@@H:10]1[CH2:11][C@@H:12]2[O:16][Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O[C@H]1C[C@H]2C[C@@H]1C[C@@H]2OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](O[C@H]1C[C@H]2C[C@@H]1C[C@@H]2OCc1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of (1R,2S,4R,5S)-5-(benzyloxy)bicyclo[2.2.1]heptan-2-ol (4.20 g, 19.2 mmol) in DMF (10 mL) was added tert-butylchlorodiphenylsilane (6.00 mL, 23.1 mmol) and imidazole (3.27 g, 48.1 mmol). The resulting mixture was stirred at ambient temp. overnight. The mixture was partitioned between diethyl ether and water. The organic portion was separated, washed with brine, and concentrated in vacuo. The residue was purified by flash column chromatography (0 to 5% of EtOAc in hexanes) to give the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[NH2:10][C:11]([NH2:13])=[NH:12]>O>[NH2:1][C:2]1[N:3]=[C:4]([NH:12][C:11]([NH2:13])=[NH:10])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: N=C(N)N
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: O
Product: N=C(N)Nc1cc(Cl)nc(N)n1
Temperature: 25 °C
Yield: 52.9 %

Procedure:
A mixture of 12.0 g (0.0732 m) of 2-amino-4,6-dichloropyrimidine and 55.0 g (0.931 mole) of guanidine was heated at 80° for 1.5 hours. The mixture was cooled to room temperature and diluted with water; the white crystalline precipitate was filtered, washed with water then air dried giving 7.22 g (53%) of 2-amino-6-chloro-4-guanidinopyrimidine, mp 220° (dec.).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[F:13][C:14]([F:40])([F:39])[C:15]1[CH:16]=[C:17]([C:25]#[C:26][CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])[CH2:30][CH2:29]2)[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1>O1CCCC1>[F:22][C:21]([F:24])([F:23])[C:19]1[CH:18]=[C:17]([C:25]#[C:26][CH2:27][N:28]2[CH2:29][CH2:30][CH:31]([C:34]([CH3:37])([CH3:38])[CH2:35][O:36][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:32][CH2:33]2)[CH:16]=[C:15]([C:14]([F:39])([F:13])[F:40])[CH:20]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CO)C1CCN(CC#Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(COS(C)(=O)=O)C1CCN(CC#Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reaction time: 5 h
Yield: 67.1 %

Procedure:
Triethylamine (0.75 g), followed by methylsulphonyl chloride (0.85 g) were added to a solution of 1-(3,5-bistrifluoromethylphenyl)-3-[4-(1,1-dimethyl-2-hydroxyethyl)piperidino]-prop-1-yne (3.0 g) in tetrahydrofuran (50 ml). After stirring for 5 hours, the precipitate of triethylamine hydrochloride was filtered off, and the filtrate was evaporated in vacuo to give a brown gum. This gum was purified by medium pressure chromatography using a mixture of dichloromethane and ethyl acetate (85:15) as eluent to give 1-(3,5-bistrifluoromethylphenyl)-3-[4-(1,1-dimethyl-2-methylsulphonyloxyethyl)piperidino]prop-1-yne (2.4 g) as a colourless gum.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:10]([O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[CH:11]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCCCC.[C:33]([O:36][CH2:37]C)(=[O:35])[CH3:34]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@@H:10]([O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)/[CH:11]=[CH:34]/[C:33]([O:36][CH3:37])=[O:35])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](C=O)OC1CCCCO1
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)/C=C/[C@H](OC1CCCCO1)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 69 %

Procedure:
Using the procedure of Example 5 with the resultant compound of Example 11 provided, after silica gel chromatography using 6:1 hexane:ethyl acetate, the desired compound (Rf 0.55, 7:3 hexane:ethyl acetate) in 69% yield. 1H NMR spectrum showed a 1:1 mixture of diastereomers. Mass spectrum: (M+H)+ =420.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[OH:37]>CN(C)C=O.C(OCC)(=O)C.ON1C2C=CC=CC=2N=N1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15](=[O:17])[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[OH:37])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Reactant: Nc1ccccc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCCC1CC(=O)Nc1ccccc1O
Reaction time: 2 h
Yield: 97.9 %

Procedure:
A mixture of 2-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (0.97 g), (Peschke, Bernd; Ankersen, Michael; Hansen, Birgit Sehested; Hansen, Thomas Kruse; Johansen, Nils Langeland; Lau, Jesper; Madsen, Kjeld; Petersen, Hans; Thogersen, Henning; Watson, Brett. Eur. J. Med. Chem. (1999), 34(5), 363-380) in dimethylformamide (8.0 ml) was treated sequentially with EDC.HCl (0.76 g), 2-aminophenol (0.43 g) and 1-hydroxybenzotriazole (0.05 g). The mixture was stirred for 2 h, diluted with ethyl acetate and washed with water, dried (MgSO4) and solvent removed at reduced pressure to give the title compound (1.29 g) as a gum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:35])=[C:14]([C:30](OCC)=[O:31])[C:15](=[O:29])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:36][C@@H:37]([CH3:40])[CH2:38][OH:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:35])=[C:14]([C:30]([NH:36][C@@H:37]([CH3:40])[CH2:38][OH:39])=[O:31])[C:15](=[O:29])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: C[C@H](N)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCC2=O)c1=O
Product: C[C@@H](CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxo-1-piperidinyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2S)-2-amino-1-propanol using methods similar to Example 563 to provide a tan solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.19 (d, J=6.74 Hz, 3 H), 1.65-1.80 (m, 6 H), 2.19 (t, J=5.79 Hz, 2 H), 3.21 (t, J=5.16 Hz, 2 H), 3.37 (t, J=7.79 Hz, 2 H), 3.48 (t, J=5.16 Hz, 2 H), 4.00-4.12 (m, 1 H), 4.16-4.28 (m, 4 H), 5.00 (t, J=5.16 Hz, 1 H), 7.11-7.18 (m, 2 H), 7.41 (dd, J=8.74, 5.58 Hz, 2 H), 7.99 (s, 1 H), 8.56 (d, J=1.47 Hz, 1 H), 10.37 (d, J=8.63 Hz, 1 H), 17.26 (s, 1 H); ES+ MS: 511 (M+H+).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28]N>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Reactant: NNc1ccccc1F
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1ccccc1F

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and 2-fluoro-phenylhydrazine according to the method described for example 1. MS: M=333.2 (M+H)+
Reaction SMILES: [Cl:1]Cl.C(O)(=O)C.[CH3:7][O:8][C:9]1[CH:32]=[CH:31][C:12]([O:13][C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH:21]([C:23]([F:26])([F:25])[F:24])[C:20]([C:27]([OH:29])=[O:28])=[CH:19][C:18]=3[CH:30]=2)=[CH:11][CH:10]=1>>[Cl:1][C:32]1[CH:31]=[C:12]([CH:11]=[CH:10][C:9]=1[O:8][CH3:7])[O:13][C:14]1[CH:15]=[CH:16][C:17]2[O:22][CH:21]([C:23]([F:26])([F:25])[F:24])[C:20]([C:27]([OH:29])=[O:28])=[CH:19][C:18]=2[CH:30]=1
Reactant: ClCl
Reactant: COc1ccc(Oc2ccc3c(c2)C=C(C(=O)O)C(C(F)(F)F)O3)cc1
Solvent: CC(=O)O
Product: COc1ccc(Oc2ccc3c(c2)C=C(C(=O)O)C(C(F)(F)F)O3)cc1Cl
Yield: 53 %

Procedure:
To a stirred solution of chlorine in acetic acid (3.5 mL of 0.24 M solution, 0.84 mmol) was added 6-(4-methoxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid (0.31 g, 0.85 mmol) (Example 7). After 1 hour additional chlorine in acetic acid (1.5 mL of 0.24 M solution, 0.36 mmol) was added. After three additional hours additional chlorine in acetic acid (0.25 ml of 0.25 M solution, 0.06 mmol) was added. After 2.5 hours the reaction was quenched with aqueous 10% sodium bisulfite solution and the resulting mixture extracted with ethyl acetate. The organic phase was washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo yielding a brown oil. The oil was dissolved in a minimum of hexanes which induced crystallization. Vacuum filtration of the mixture provided the title compound as yellow crystals (0.18 g, 53%): mp 205-207° C. 1H NMR (acetone-d6/300 MHz) 7.89 (s, 1H), 6.97-7.18 (m, 6H), 5.83 (q, 1H, J=7.0 Hz), 3.90 (s, 3H). FABLRMS m/z 400 (M+). FABHRMS m/z 399.0249 (M−H, Calc'd 399.0247). Anal. Calc'd for C18H12ClF3O5: C, 53.95; H, 3.02; Cl, 8.85. Found: C, 53.78; H, 3.08; Cl, 8.98.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH:8]=[O:9])[C:5]([CH3:10])=[N:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[N:23]=C(Cl)C=[CH:20][N:19]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:17][C:18]1[N:23]=[C:1]([N:3]2[CH:7]=[C:6]([CH:8]=[O:9])[C:5]([CH3:10])=[N:4]2)[CH:2]=[CH:20][N:19]=1
Reactant: CCn1cc(C=O)c(C)n1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nn(-c2ccnc(Cl)n2)cc1C=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 42.4 %

Procedure:
To a solution of ethyl 3-methyl-1H-pyrazole-4-carbaldehyde (6.4 g, 58.0 mmol) in 60 mL of anhydrous N,N-dimethylformamide were added potassium carbonate (10.8 g, 77.8 mmol) and 2,4-dichloropyrimidine (8.64 g, 58.0 mmol) at room temperature. The resulting suspension was stirred for 14 hours at room temperature with monitoring a reaction with LC-MS or thin layer chromatography (TLC). The reaction mixture was diluted with ethyl acetate and washed with brine (×2). The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a mixture of heptanes and ethyl acetate to afford the desired intermediate 1 as a white solid (5.47 g, 42%); MS (ESI) m/z 223 [M+H]+, 1H NMR (300 MHz, CDCl3) δ 10.06 (s, 1H), 9.04 (s, 1H), 8.70 (d, 1H, J=5.4 Hz), 7.87 (1H, d, J=5.4 Hz), 2.59 (s, 3H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22])[CH:2]=[CH2:3].Br[CH2:24][CH2:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:24][CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)=[CH:7][C:6]=1[N:12]1[C:13](=[O:22])[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]1=[O:21])[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(O)cc1N1C(=O)c2ccccc2C1=O
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(OCCOC2CCCCO2)cc1N1C(=O)c2ccccc2C1=O

Procedure:
A mixture of Example 84A (0.69 g, 2.34 mmol), 2-(2-bromoethoxy)tetrahydro-2H-pyran (1.41 mL, 9.34 mmol) and K2CO3 (1.61 g, 11.68 mmol) in acetone (20 mL) was refluxed overnight and cooled. The solution was filtered, dried with silica gel powder (10 g). 20% Ethyl acetate in hexanes (1 L) and 30% ethyl acetate in hexanes (1 L) were used to run flash chromatography. The title compound was obtained (265.3 mg, 27%). MS (APCI) m/z 424 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14](=[O:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)C1C=CC=CC=1.ClCCCl.ClC(OC(Cl)C)=O>CO>[F:22][C:19]1[CH:20]=[CH:21][C:16]([N:15]2[C:11]3([CH2:10][CH2:9][NH:8][CH2:26][CH2:25]3)[C:12](=[O:24])[NH:13][C:14]2=[O:23])=[CH:17][CH:18]=1
Reactant: O=C1NC(=O)C2(CCN(Cc3ccccc3)CC2)N1c1ccc(F)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: ClCCCl
Product: O=C1NC(=O)C2(CCNCC2)N1c1ccc(F)cc1
Temperature: 25 °C

Procedure:
Combine 8-benzyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione (10 mmol) and 1,2-dichloroethane (70 mL). Cool using an ice bath. Add in dropwise fashion, 1-chloroethyl chloroformate (48.6 mmol). Warm to ambient temperature and maintain for 1 h. Extract using saturated NaHCO3 (120 mL). Extract the aqueous phase using dichloromethane (120 mL). Combine the organic layers, extract with saturated NaCl, dry over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Add anhydrous methanol (70 mL) and heat at reflux for 1 h. Concentrate in vacuo to obtain a residue and purify to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([C:11](=[O:21])[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([F:20])[CH:13]=2)[CH:3]=1.[CH:22]([N:25](CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:7])[N:25]([CH3:22])[C:11]2([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([F:20])[CH:13]=1)[OH:21]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(F)cc(C(=O)c2cc(Br)ccc2C(=O)O)c1
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1cc(F)cc(C2(O)c3cc(Br)ccc3C(=O)N2C)c1

Procedure:
4-Bromo-2-(3-fluoro-5-methoxy-benzoyl)-benzoic acid (140 mg; 0.39 mmol) is dissolved in 1.4 ml N,N-dimethylformamide, treated with N,N-Diisopropylethylamine (154 μl; 1.19 mmol) and HATU (66 mg; 0.44 mmol). It is stirred at ambient temperature for 5 minutes before 2.0 mol/l methylamine (341 μl; 0.80 mmol) is added. After 16 hours the reaction mixture is purified via reversed phase chromatography under basic conditions.
Reaction SMILES: [CH2:1]([O:3][N:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])[CH3:2].Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21](=[CH:26][O:27][CH3:28])[C:22]([O:24][CH3:25])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][N:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21](=[CH:26][O:27][CH3:28])[C:22]([O:24][CH3:25])=[O:23])[CH3:2]
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Reactant: CCON=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCON=Cc1ccccc1OCc1ccccc1C(=COC)C(=O)OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
6.9 g (42 mmol) of 2-hydroxybenzaldehyde O-ethyloxime and 10.0 g (35 mmol) of methyl α-(2-bromomethylphenyl)-β-methoxyacrylate are dissolved in 100 ml of dimethylformamide, and 7.3 g (53 mmol) of potassium carbonate are added. The mixture is stirred at room temperature for 48 hours and then concentrated, and the residue is taken up in methylene chloride. The organic phase is washed with water, dried over MgSO4 and concentrated. The resulting oil is purified by chromatography on silica gel (cyclohexane/ethyl acetate). 8.4 g (65% of theory) of the title compound are obtained in the form of colorless crystals (melting point 86°-88° C., compound no. 23).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O[N:33]=[C:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][C:43]([F:46])([F:45])[F:44])=[CH:38][CH:37]=1)[NH2:35]>CN(C=O)C.O>[CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:9][N:35]=[C:34]([C:36]3[CH:37]=[CH:38][C:39]([O:42][C:43]([F:44])([F:45])[F:46])=[CH:40][CH:41]=3)[N:33]=2)[CH:3]=1
Reactant: NC(=NO)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1cc(C(=O)O)n[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mechanically stirred solution of 5-methyl-1H-pyrazole-3-carboxylic acid (15.3 g, 0.121 mol) in dry DMF (600 mL) was added EDCl (23.3 g, 0.121 mol), HOBT (16.4 g, 0.121 mol) and N′-hydroxy-4-(trifluoromethoxy)benzenecarboximidamide (26.7 g, 0.121 mol). The mixture was stirred at rt for 2 h, and then warmed to 140° C. and stirred for further 5 h. After being cooled to rt, the mixture was diluted with water (2 L) and extracted with ethyl acetate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[C:26]([CH2:28][CH3:29])[CH:25]=[CH:24][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][CH2:21][NH2:22])=[CH:14][C:13]=1[F:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:37](Cl)([CH3:40])(=[O:39])=[O:38]>ClCCl>[CH3:40][S:37]([N:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10]2[CH:24]=[CH:25][C:26]([CH2:28][CH3:29])=[CH:27][C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:13]([F:23])[CH:14]=1)[CH2:19][CH2:20][CH2:21][NH2:22])(=[O:39])=[O:38]
Reactant: CCc1ccc(Oc2ccc(NCCCN)cc2F)c(OCc2ccccc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccc(Oc2ccc(N(CCCN)S(C)(=O)=O)cc2F)c(OCc2ccccc2)c1
Yield: 82.8 %

Procedure:
To a solution of N1-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]propan-1,3-diamine (90 mg, 0.23 mmol) in 5 ml of dry dichloromethane and 0.08 ml (0.57 mmol) of triethylamine, cooled to 0° C., was added mesyl chloride (26 mg, 0.23 mmol) taken in 0.5 ml of dichloromethane dropwise. The reaction was quenched after 5 minutes as the reaction was complete on TLC. The reaction mixture was diluted with water and the layers separated. The aqueous layer was extracted with dichloromethane and the combined dichloromethane fraction was washed with water, dried over anhydrous Na2SO4 and concentrated. The crude residue obtained was combined with the crude obtained from an earlier 20 mg batch and column purified over silica gel using 2% methanol in dichloromethane as eluant to get 90 mg, 68.3% of title compound.
Reaction SMILES: [NH:1]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[NH2:2].C1(C)C=CC=CC=1.[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12>O>[O:21]=[C:20]1[C:19]2[C:18](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17](=[O:22])[N:2]1[NH:1][C:3](=[O:4])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)NN
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 104.1 %

Procedure:
Tert-butyl hydrazinecarboxylate (250 g) was added to a toluene (3 L) solution of phthalic anhydride (280 g). In a Dean Stark water separator, the reaction mixture was heated under reflux for 3 hours. After cooled to room temperature, the formed solid was collected through filtration to give crude tert-butyl (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)carbamate (516 g).