Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=2)[N:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:62]1[CH2:67][CH2:66][O:65][CH2:64][CH2:63]1>CN(C=O)C>[N:62]1([C:26]([C:25]2[CH:24]=[CH:23][C:22]([C:19]3[N:18]=[C:17]([C@H:12]4[CH2:13][CH2:14][CH2:15][CH2:16][N:11]4[C:9](=[O:10])[CH2:8][O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[O:21][N:20]=3)=[CH:30][CH:29]=2)=[O:27])[CH2:67][CH2:66][O:65][CH2:64][CH2:63]1
Reactant: O=C(O)c1ccc(-c2noc([C@H]3CCCCN3C(=O)COc3ccccc3)n2)cc1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(-c2noc([C@H]3CCCCN3C(=O)COc3ccccc3)n2)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.07 mmol of (R)-4-{5-[1-(2-Phenoxy-acetyl)-piperidin-2-yl]-[1,2,4]oxadiazol-3-yl}-benzoic acid were treated with 1 eq. of TBTU/DIPEA in 1 ml DMF for 10 min and 2 eq. of Morpholine added. Ther reaction is stirred overnight at room temperature and the product isolated via preperative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=1)[O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])[C:5]2=O.O.[NH2:28][NH2:29]>>[Cl:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]([OH:8])=[C:4]([C:5]2[C:6]([C:13]3[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=3)[O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])=[CH:7][NH:29][N:28]=2)[CH:3]=1
Reactant: N#CCCCCOc1cccc(-c2coc3cc(O)c(Cl)cc3c2=O)c1
Reactant: NN
Solvent: O
Product: N#CCCCCOc1cccc(-c2c[nH]nc2-c2cc(Cl)c(O)cc2O)c1
Yield: 87 %

Procedure:
This compound was synthesised in the same manner as described above. 5-[3-(6-Chloro-7-hydroxy-4-oxo-4H-chromen-3-yl)-phenoxy]-pentanenitrile (0.1 g, 0.27 mmol), Hydrazine hydrate (5 ml). The precipitate formed on quenching was filtered to give 5-{3-[3-(5-Chloro-2,4-dihydroxy-phenyl)-1H-pyrazol-4-yl]-phenoxy}-pentanenitrile as a white solid (0.09 g, 87.0%); Rf 0.6 ethyl acetate/hexane (70/30)].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br>CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([O:14][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([Cl:22])[CH:24]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: Clc1cccc(CBr)c1
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCc2cccc(Cl)c2)c1C(=O)OC
Yield: 90.1 %

Procedure:
To a stirred suspension of 3-hydroxyphthalic acid dimethyl ester (1.3 g, 6.3 mmol) in acetone (20 mL) and potassium carbonate (2.1 g, 15.2 mmol) was added 3-chlorobenzyl bromide (1.0 mL, 7.6 mmol) and refluxed overnight. The solvent was evaporated and the residue was partitioned between water (100 mL) and ethyl acetate (150 mL), and washed with water (2×100 mL). The combined organic phases was dried, concentrated and purified by flash column chromatography (EtOAc/Hexane) to give 3-(3-chloro-benzyloxy)-phthalic acid dimethyl ester (1.9 g, 92% yield). The product was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[O:4][CH2:5][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.Br[CH2:16][CH:17]1[CH2:20][CH2:19][CH2:18]1>>[CH:17]1([CH2:16][C@@:2]2([CH3:1])[C:3](=[O:14])[O:4][CH2:5][C@H:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[NH:7]2)[CH2:20][CH2:19][CH2:18]1
Reactant: BrCC1CCC1
Reactant: CC1=N[C@@H](c2ccccc2)COC1=O
Product: C[C@@]1(CC2CCC2)N[C@@H](c2ccccc2)COC1=O

Procedure:
The title compound was prepared from (5S)-3-methyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one (1 g, 5.28 mmol, see WO-A-02/051983) and (bromomethyl)cyclobutane according to the procedure outlined in Preparation 1. The total amount of compound synthesised was 0.445 g.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:3]1.C([Li])CCC.[F:18][C:19]1[CH:26]=[CH:25][C:24]([C:27]2([CH3:32])[O:31][CH2:30][CH2:29][O:28]2)=[CH:23][C:20]=1[CH:21]=[O:22]>C1COCC1>[F:18][C:19]1[CH:26]=[CH:25][C:24]([C:27]2([CH3:32])[O:28][CH2:29][CH2:30][O:31]2)=[CH:23][C:20]=1[CH:21]([C:6]1[N:2]([CH3:1])[N:3]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=1)[OH:22]
Reactant: Cn1cnc(-c2ccccc2)n1
Reactant: CC1(c2ccc(F)c(C=O)c2)OCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nc(-c2ccccc2)nc1C(O)c1cc(C2(C)OCCO2)ccc1F
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
To a solution of 1-methyl-3-phenyl-1H-1,2,4-triazole (1.56 g, 9.83 mmol) in THF (50 mL) cooled to −78° C. was added 1.6 M n-butyl lithium (6.76 ml, 10.8 mmol) drop-wise and stirred for 30 min. Next a solution of Intermediate 416.2 (2.46 g, 11.8 mmol) in THF (15 mL) was added drop-wise and stirred for 5 min before allowing the mixture to warm to 23° C. The reaction mixture was quenched with aqueous NH4Cl and extracted with EtOAc (3×50 mL). The organic layer was washed with H2O, brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 100% EtOAc/hexanes gradient) to afford 3.6 g of Intermediate 416.3. 1H NMR (400 MHz, CDCl3) δ ppm 1.59 (s, 3H) 3.62 (s, 3H) 3.66-3.78 (m, 2H) 3.91-4.04 (m, 2H) 6.22 (s, 1H) 6.94-7.07 (m, 1H) 7.32-7.49 (m, 5H) 7.70 (dd, J=7.25, 2.42 Hz, 1H) 7.97-8.05 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]([OH:9])[C:6]2[S:10][C:11]([CH3:13])=[CH:12][C:5]=2[CH2:4]1)[CH3:2].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1F>>[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:9][CH:7]1[CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][C:5]2[CH:12]=[C:11]([CH3:13])[S:10][C:6]1=2
Reactant: Fc1ccccc1Br
Reactant: CCN1Cc2cc(C)sc2C(O)C1
Product: CCN1Cc2cc(C)sc2C(Oc2ccccc2Br)C1

Procedure:
The same method as in Example 1 was conducted using 5-ethyl-2-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 32) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2-bromo-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [C:1](/[N:3]=[C:4](\[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1)#[N:2].Br[CH2:22][CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1](/[N:3]=[C:4](\[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[N:5]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1)[CH2:22][CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1)#[N:2]
Reactant: BrCCCOC1CCCCO1
Reactant: N#C/N=C(/Nc1ccc(F)c(F)c1)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#C/N=C(\Oc1ccccc1)N(CCCOC1CCCCO1)c1ccc(F)c(F)c1
Temperature: 85 °C

Procedure:
To a solution of (Z)-phenyl N′-cyano-N-(3,4-difluorophenyl)carbamimidate (286 mg, 1.05 mmol) and 2-(3-bromopropoxy)tetrahydro-2H-pyran (369 mg, 277 μL, 1.57 mmol) in DMF (10.5 mL) was added at room temperature under an atmosphere of nitrogen potassium carbonate (289 mg, 2.09 mmol). The suspension was heated to 85° C. over night. Additional 2-(3-bromopropoxy)tetrahydro-2H-pyran (140 μL, 0.8 mmol) and potassium carbonate (145 mg, 1.05 mmol) were added and the reaction was heated for 5 hours to 85° C. Water was added and the reaction was extracted twice with diethyl ether. The combined organic layers were washed with water and with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The title compound was obtained as a light yellow viscous oil (202 mg, 46%) after column chromatography on silica gel using a gradient of heptane/ethyl acetate 4:1 to 1:1 (v/v) as eluent.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8](Br)=[CH:7][N:6]=1)=[O:4].[CH2:13]([O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[C:14]#[CH:15]>>[Cl:11][C:10]1[C:5]([C:3]([OH:2])=[O:4])=[N:6][CH:7]=[C:8]([C:15]#[C:14][CH2:13][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH:9]=1
Reactant: C#CCOC1CCCCO1
Reactant: COC(=O)c1ncc(Br)cc1Cl
Product: O=C(O)c1ncc(C#CCOC2CCCCO2)cc1Cl

Procedure:
The title compound was prepared by an analogous procedure to Acid-xx using 5-bromo-3-chloro-pyridine-2-carboxylic acid methyl ester instead of 3-amino-5-bromo-pyridine-2-carboxylic acid methyl ester and 2-prop-2-ynyloxy-tetrahydro-pyran instead of 3-methoxy-propyne [Acid-xx step a)].
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1)([CH3:27])[CH3:26]
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)nc1
Reactant: CC(C)N
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 92 %

Procedure:
As described for example 272, 6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (97.6 mg, 0.3 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (97 mg, 92%) which was obtained as a white solid. MS: m/e=353.4 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:27]3[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=3[O:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17].[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:35]=1[NH2:41]>>[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:35]=1[NH:41][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:27]3[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=3[O:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17]
Reactant: Cc1ccc(C)c(N)c1
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(CC3)COc3c(F)cccc34)cnc12
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC4(CC3)COc3c(F)cccc34)cnc12
Yield: 60.7 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(7-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.145 g, 0.318 mmol) obtained in Example 145, step 2 and 2,5-dimethylphenylamine (0.046 mL, 0.372 mmol), the title compound (0.105 g, 61%) was obtained.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:17])=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][NH:6][CH2:7][CH:8]([O:11][CH3:12])[O:9][CH3:10].N1C=CC=CC=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl>[F:1][C:2]1[C:3]([CH3:17])=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][N:6]([S:30]([C:27]1[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=1)(=[O:32])=[O:31])[CH2:7][CH:8]([O:9][CH3:10])[O:11][CH3:12]
Reactant: COC(CNCc1ccc(F)c(F)c1C)OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(CN(Cc1ccc(F)c(F)c1C)S(=O)(=O)c1ccc(C)cc1)OC
Temperature: 25 °C
Yield: 110.9 %

Procedure:
3,4-Difluoro-2-methylbenzyl-2,2-dimethoxyethylamine (23, 37.8 g) was dissolved in dichloromethane (100 mL). Pyridine (42 mL) was added. At 0° C. a solution of p-toluenesulphonyl chloride (36.8 g, 193 mmol) in dichloromethane was added dropwise. The reaction was allowed to warm to room temperature and stirring continued until the conversion was complete. For workup, the reaction mixture was diluted with dichloromethane (100 mL) and extracted twice with 1.5M hydrochloric acid, twice with sodium bicarbonate solution and once with brine. The organic layer was dried over magnesium sulphate, evaporated to dryness to give crude product as an orange oil (68.3 g). This was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][C@H:15]([CH2:28][CH2:29][OH:30])[C:14]3=[O:31])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:34][S:35]([O:30][CH2:29][CH2:28][C@H:15]1[CH2:16][C@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=2)[N:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:33][CH:32]=3)=[CH:12][CH:11]=2)[C:14]1=[O:31])(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1[C@@H](CCO)C[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)OCC[C@H]1C[C@H](c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 93 %

Procedure:
To a solution of (3R,5R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]-3-(2-hydroxyethyl)pyrrolidin-2-one (50 mg, 0.105 mmol) in DCM (2 mL) at 0° C. is added MsCl (26 μL) and TEA (50 μL). The reaction mixture is stirred at room temperature for 45 min before removal of the solvent. The residue is purified on silica gel (0-50% ethyl acetate in hexane) to give 2-{(3R,5R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]-2-oxopyrrolidin-3-yl}ethyl methanesulfonate (54.3 mg, 93%) as a colorless oil.
Reaction SMILES: C(Cl)Cl.[CH2:4]([O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([F:16])[C:8]=1[F:17])[CH3:5].[F:18][CH:19]1[C:24]([F:26])([F:25])[C:23]2([CH2:29][CH2:30][CH3:31])[CH2:27][CH2:28][C:20]1(O)[CH2:21][CH2:22]2.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.O>[F:18][CH:19]1[C:24]([F:25])([F:26])[C:23]2([CH2:29][CH2:30][CH3:31])[CH2:22][CH2:21][C:20]1([O:12][C:11]([C:10]1[CH:14]=[CH:15][C:7]([O:6][CH2:4][CH3:5])=[C:8]([F:17])[C:9]=1[F:16])=[O:13])[CH2:28][CH2:27]2
Reactant: CCCC12CCC(O)(CC1)C(F)C2(F)F
Reactant: CCOc1ccc(C(=O)O)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCCC12CCC(OC(=O)c3ccc(OCC)c(F)c3F)(CC1)C(F)C2(F)F

Procedure:
Methylene chloride solution containing 4-ethoxy-2,3-difluorobenzoic acid (7) (52.6 mg) and 2,3,3-trifluoro-1-hydroxy-4-n-propylbicyclo[2.2.2]octane (4) (39.0 mg) was added with N,N′-dicyclohexyl carbodiimide (53.0 mg) and 4-dimethylamino pyridine (7.0 mg), and the mixture was refluxed under heating for 11 hours. The mixture was then added with water to terminate the reaction, the organic layer was extracted three times with ethyl acetate, the organic layers were combined, and the combined organic layer was washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then vaporized off under reduced pressure to thereby obtain a crude product. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate=8:2), to thereby obtain 2,3,3-trifluoro-1-(4′-ethoxy-2′,3′-difluorophenyl)carbonyloxy-4-n-propylbicyclo[2.2.2]octane (8) (yield=20.0 mg, yield ratio=28%) as a colorless clear crystal.
Reaction SMILES: FC(F)(F)C([O-])=O.[CH:8]1[C:20]2[C:19]3[CH2:18][CH2:17][NH2+:16][CH2:15][C:14]=3[CH:13]=[N:12][C:11]=2[NH:10][N:9]=1.[N:21]([C:24]1[CH:25]=[C:26]([CH:35]=[CH:36][CH:37]=1)[O:27][C:28]1[CH:33]=[N:32][CH:31]=[C:30]([CH3:34])[N:29]=1)=[C:22]=[O:23]>>[CH3:34][C:30]1[N:29]=[C:28]([O:27][C:26]2[CH:25]=[C:24]([NH:21][C:22]([N:16]3[CH2:15][C:14]4[CH:13]=[N:12][C:11]5[NH:10][N:9]=[CH:8][C:20]=5[C:19]=4[CH2:18][CH2:17]3)=[O:23])[CH:37]=[CH:36][CH:35]=2)[CH:33]=[N:32][CH:31]=1
Reactant: c1nc2[nH]ncc2c2c1C[NH2+]CC2
Reactant: Cc1cncc(Oc2cccc(N=C=O)c2)n1
Agent: O=C([O-])C(F)(F)F
Product: Cc1cncc(Oc2cccc(NC(=O)N3CCc4c(cnc5[nH]ncc45)C3)c2)n1

Procedure:
The compound, N-{3-[(6-methylpyrazin-2-yl)oxy]phenyl}-3,6,8,9-tetrahydro-7H-pyrazolo[3,4-c][2,7]naphthyridine-7-carboxamide was prepared using 6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7-ium 2,2,2-trifluoroacetate and 2-(3-isocyanatophenoxy)-6-methylpyrazine as described in general procedure M. The product was obtained as a white solid; 400 MHz 1H NMR (DMSO-d6) δ: 13.59 (s, 1H), 8.86 (s, 2H), 8.34 (s, 1H), 8.3-8.25 (m, 2H), 8.17 (s, 1H), 7.4-7.26 (m, 3H), 6.8-6.74 (m, 1H), 4.77 (s, 2H), 3.82 (t, J=5.6 Hz, 2H), 3.14 (t, J=5.6 Hz, 2H), 2.35 (s, 3H); LCMS [M+H]: 402.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[SH:16].C(N(CC)CC)C>C(Cl)Cl>[C:1]([S:16][C:7]1[CH:8]=[CH:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: Sc1ccc2ccccc2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Sc1ccc2ccccc2n1
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
480 mg (1.2 equivalents) of propionyl chloride were added, whilst ice-cooling, to a solution of 1 g of 2-quinolinethiol and 0.83 ml (1.2 equivalents) of triethylamine in 20 ml of anhydrous methylene chloride, and the resulting mixture was stirred for 30 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was mixed with ethyl acetate. This mixture was washed twice with a dilute aqueous solution of sodium hydrogencarbonate and was then washed with water. The organic layer was separated and dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by flash chromatography through silica gel, using a 1:1 by volume mixture of cyclohexane and ethyl acetate as the eluent, to give 600 mg of the title compound having an Rf value of 0.4.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH2:15]O)=[CH:13][C:12]([C:17]([F:20])([F:19])[F:18])=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(S(F)(F)[F:27])CC)C>C(Cl)Cl>[F:27][CH2:15][C:14]1[N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:11]=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:13]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=[N+]([O-])c1ccc(-n2nc(C(F)(F)F)cc2CO)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(-n2nc(C(F)(F)F)cc2CF)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
Intermediate 19 (0.5 g, 1.75 mmol) was dissolved in DCM (10 ml) and reaction mixture cooled to 0° C. To this (Diethylamino)sulphur trifluoride (0.46 ml, 3.5 mmol) was added drop-wise and allowed the reaction mixture to stir at rt for 30 mins. After completion of the reaction, reaction mixture diluted with DCM and washed with water. DCM removed on rotavapour to obtain the crude. Crude was purified by column chromatography using EA and petether (7:97) as eluent to afford the title compound (0.41 g) as an yellow solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.42 (d, J 9, 2H), 7.86 (d, J 9, 2H), 6.94 (d, J 3.4, 1H), 5.42 (d, J 48.4, 2H).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12](S(C)(=O)=O)[N:11]=2)=[CH:8][C:7]([C:20]([NH2:22])=[O:21])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[N:23]1([C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:35][C:32]3[CH:31]=[CH:30][C:29]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:34][CH:33]=3)[N:11]=2)=[CH:8][C:7]([C:20]([NH2:22])=[O:21])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)n1nc(C(N)=O)cc1-c1ccnc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)n1nc(C(N)=O)cc1-c1ccnc(Oc2ccc(N3CCNCC3)cc2)n1
Yield: 20 %

Procedure:
50 mg (0.155 mmol) of 1-tert-butyl-5-[2-(methylsulfonyl)pyrimidin-4-yl]-1H-pyrazole-3-carboxamide were dissolved in 1.5 mL of dry DMF; then, 30 mg (0.17 mmol) of 4-piperazin-1-yl-phenol and 64 mg (0.464 mmol) of potassium carbonate were added. The final suspension was stirred at 70° C. for 1 h then the final mixture was purified by preparative HPLC/MS to provide the title compound (20%).
Reaction SMILES: [O:1]1[C:6]2=[CH:7][C:8]3[NH:14][C:13](=O)[C:12]4[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=4[S:10][C:9]=3[CH:20]=[C:5]2[O:4][CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[N:21]1([C:13]2[C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[S:10][C:9]3[CH:20]=[C:5]4[O:4][CH2:3][CH2:2][O:1][C:6]4=[CH:7][C:8]=3[N:14]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: C1CNCCN1
Reactant: O=C1Nc2cc3c(cc2Sc2ccccc21)OCCO3
Product: c1ccc2c(c1)Sc1cc3c(cc1N=C2N1CCNCC1)OCCO3
Yield: 5.4 %

Procedure:
2,3-Dihydro-1,4-benzodioxino[6,7-b][1,4]benzothiazepin-11(12H)-one (29 mg, 0.1 mmol) and piperazine (43 mg, 0.5 mmol) were reacted according to GP4 to give 1.9 mg of the title compound (160FE17B). MS (ESI) 354 (MH+). Purity for MH+ (UV/MS) 99/95.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22][C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(C)cc1
Agent: [Pd]
Product: CCOC(=O)C(Cc1ccc(O)cc1)Oc1ccc(C)cc1
Yield: 103.9 %

Procedure:
In a similar manner to that described in Reference example 1(d), a reaction was carried out using ethyl 3-(4-benzyloxyphenyl)-2-(4-methylphenoxy)propionate (2.84 g), which is the product of Reference example 35(b), and palladium on carbon (284 mg) and the reaction mixture was treated to afford the desired compound (2.27 g) as a syrup.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[SH:17].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Sc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=Cc1ccc(Sc2ccccc2Br)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
4-fluorobenzaldehyde (10 mL, 93 mmol), 2-bromobenzenethiol (12 mL, 102 mmol) and potassium carbonate (15.4 g, 111 mmol) were combined in dimethylsulfoxide (50 mL) under nitrogen and heated to 120° C. After 2 hours, the temperature had reached 210° C. so the reaction was stopped. The cooled reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over Na2SO4 and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica, eluting with 10% ethyl acetate/isohexane, to give 4-[(2-bromophenyl)thio]benzaldehyde (23.83 g, 87%). δH (360 MHz, d6 DMSO): 9.97 (1H, s), 7.89–7.82 (3H, m), 7.55–7.33 (5H, m).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:6])[CH3:5].[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>>[CH2:19]([N:21]([CH2:22][CH3:23])[CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:6])[CH3:5])[CH3:20]
Reactant: CC(O)(CCCl)c1ccccc1-c1ccccc1
Reactant: CCNCC
Product: CCN(CC)CCC(C)(O)c1ccccc1-c1ccccc1

Procedure:
2.6 g of 1-chloro-3-p-biphenylyl-butan-3-ol are heated with 30 ml of diethylamine at 150° for 15 hours in an autoclave, and the mixture is cooled and worked up in the customary manner to give 1-diethylamino-3-p-biphenylyl-butan-3-ol.