Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6](=[O:23])[O:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([N:15]1[N:19]=[C:18]([CH2:20][CH3:21])[C:17]([CH3:22])=[N:16]1)[CH:9]=2)(=O)C.P(Cl)(Cl)(Cl)=O.[CH3:29][N:30](C)[CH:31]=O>>[CH3:29][N:30]([CH:1]=[N:4][C:5]1[C:6](=[O:23])[O:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([N:15]1[N:19]=[C:18]([CH2:20][CH3:21])[C:17]([CH3:22])=[N:16]1)[CH:9]=2)[CH3:31]
Reactant: CN(C)C=O
Reactant: CCc1nn(-c2ccc3cc(NC(C)=O)c(=O)oc3c2)nc1C
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nn(-c2ccc3cc(N=CN(C)C)c(=O)oc3c2)nc1C
Temperature: 25 °C
Reaction time: 22 h
Yield: 80 %

Procedure:
15.6 g (50.0 mmols) of 3-acetylamino-7-(4-ethyl-5-methyl-2H-1,2,3-triazol-2-yl)-coumarin are suspended in 100 ml of anhydrous dimethylformamide. 11.5 g (75.0 mmols) of phosphorus oxychloride are added dropwise to the suspension at 10°-15° C., and the mixture is stirred for 22 hours at room temperature. The slurry is introduced into 500 ml of ice water, and the mixture is filtered and brought to a pH of 8 with sodium carbonate. The yellow crystals are filtered off under suction, washed with water and dried: 15.5 g (95.5%). Recrystallisation from ethanol yields 12.9 g (80%) of 3-(dimethylaminomethyleneamino)-7-(4-ethyl-5-methyl-2H-1,2,3-triazol-2-yl)-coumarin in the form of small pale yellow crystals of melting point 158°-159° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][C:3]=1[NH2:4].Cl[CH2:12][CH:13]=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][C:3]=1[NH:4][CH2:12][CH:13]=[O:14]
Reactant: Cc1ccc(C#N)cc1N
Reactant: O=CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccc(C#N)cc1NCC=O
Temperature: 150 °C

Procedure:
2-Methyl-5-cyanoaniline (0.3 mole), the dimethyl acetal of 2-chloroacetaldehyde (0.3 mole) and sodium carbonate (20 grams) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated to about 150°C for a period of about 8 hours. After this time the mixture is filtered and the filtrate is distilled to yield the desired product the dimethyl acetal of 2-(2-methyl-5-cyanoanilino)acetaldehyde.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13]>C(O)CO>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[Cl:10])[C:7]=1[NH2:8]
Reactant: Nc1ccccc1Cl
Reactant: Nc1c(Cl)ncnc1Cl
Solvent: OCCO
Product: Nc1c(Cl)ncnc1Nc1ccccc1Cl
Temperature: 100 °C
Yield: 85 %

Procedure:
4,6-Dichloropyrimidin-5-amine (CAS no. 5413-85-4) (2 g, 12.20 mmol) and 2-chloroaniline (CAS no. 95-51-2) (1.556 g, 12.20 mmol) were dissolved in ethylene glycol (12 mL) and sealed into a microwave tube. The reaction was heated to 100° C. for 1 hour in the microwave reactor and cooled to room temperature. The reaction mixture was quenched with water (50 mL), extracted with EtOAc (3×50 mL), the organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, eluting with 0 to 60% EtOAc in isohexane to afford the product (2.65 g, 85%). 1H NMR (400 MHz, DMSO) 65.38 (s, 2H), 7.19-7.25 (m, 1H), 7.32-7.38 (m, 1H), 7.49-7.54 (m, 1H), 7.57-7.62 (m, 1H), 7.73 (s, 2H), 7.19-7.25 (s, 1H); m/z (ES+), (M+H)+=255.25; HPLC tR=1.82 min.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH:8]([CH3:14])[N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=1[O:31][CH3:32].C(O)C>Cl.O>[CH:15]1([N:7]2[CH:8]([CH3:14])[CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC1CC(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)C(C)CC(=O)N2C
Yield: 72.9 %

Procedure:
A mixture of 0.059 g (0.0002 mole) of (rac)-2-chloro-9-cyclopentyl-5,8-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-3), 0.033 g (0.0002 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated to 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.062 g of (rac)-4-(9-cyclopentyl-5,8-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-3-methoxy-benzoic acid (I-3) as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[CH2:14](Br)[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:16]([O:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[C:4]([OH:6])=[O:5])[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: CCOC(=O)c1cc(C)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(C)cc1C(=O)O

Procedure:
The reaction of ethyl 2-hydroxy-5-methyl-benzoate and allyl bromide in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 2-Allyloxy-5-methyl-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.52 (s, —CO2H); 7.43 (m, 1 arom. H); 7.26 (m, 1 arom. H); 6.98 (m, 1 arom. H); 5.99 (m, —CH═CH2); 5.46, 5.22 (2 d-like, CH═CH2); 4.56 (d-like, CH2—CH═CH2); 2.23 (s, —CH3). 13C-NMR (100 MHz, d6-DMSO): 167.39 (C═O); 154.91; 133.52; 133.20; 130.91; 129.05; 121.34; 116.83; 113.79; 68.69; 19.78.
Reaction SMILES: [Cl-].[Cl-].[CH-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Zr+2:13].[CH:14]1[C:27]2[C:18](=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:16][CH:15]=1.[Mg]>C1COCC1>[CH:14]1[C:27]2[C:18](=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:16][CH:15]=1.[CH:3]1([Zr:13][CH:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)[CH:7]=[CH:6][CH:5]=[CH:4]1
Reactant: [Zr+2]
Reactant: c1cc[cH-]c1
Agent: [Cl-]
Agent: [Mg]
Agent: c1ccc2nc3ccccc3cc2c1
Solvent: C1CCOC1
Product: C1=CC([Zr]C2C=CC=C2)C=C1
Temperature: 25 °C
Yield: 62.6 %

Procedure:
To a solution of 5.00 g (17.10 mmol) zirconocene dichloride in 100 ml THF were added 3.06 g (17.10 mmol) acridine and 0.41 g magnesium and the mixture was stirred at room temperature until the metal was fully reacted. The solvent was then removed to dryness in vacuo and the residue was extracted with 80 ml toluene. 4.29 g bis(cyclopentadienyl)zirconium acridine were isolated from the toluene extract as a red solid.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9](=[O:23])[CH2:10][CH2:11][C:12]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[NH:14][C:13]=2[CH:21]=O)[CH2:3]1.[CH2:24]([S:26]([C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33](=[O:38])[CH2:32]2)(=[O:28])=[O:27])[CH3:25]>>[CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9](=[O:23])[CH2:10][CH2:11][C:12]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[NH:14][C:13]=2/[CH:21]=[C:32]2\[C:33](=[O:38])[NH:34][C:35]3[C:31]\2=[CH:30][C:29]([S:26]([CH2:24][CH3:25])(=[O:27])=[O:28])=[CH:37][CH:36]=3)[CH2:3]1
Reactant: CC1CN(C(=O)CCc2c(C=O)[nH]c3c2CCCC3)CC(C)N1
Reactant: CCS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CCS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCC(=O)N1CC(C)NC(C)C1)CCCC3)C(=O)N2
Yield: 46 %

Procedure:
3-[3-(3,5-Dimethylpiperazin-1-yl)-3-oxo-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde, prepared as described in Example 3 above, was condensed with 5-ethylsulfonyloxindole following the same procedure used in example 1 to give the desired product (72 mg, 46% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].CC1(C)C(C)(C)OB([C:29]2[CH:30]=[CH:31][C:32]([NH2:35])=[N:33][CH:34]=2)O1>>[NH2:35][C:32]1[N:33]=[CH:34][C:29]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:30][CH:31]=1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N)nc3)ccn2c1=O
Yield: 113.6 %

Procedure:
Methyl 8-(6-amino-pyridin-3-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-amine (113 mg, 0.51 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (135 mg, 100%). ESI-MS m/z: 350 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:13].[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Br)[C:17]=1[CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C>CN1CCCC1=O.[Cu]Cl>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([Br:15])[C:17]=2[CH3:23])=[CH:8][C:7]=1[CH3:13]
Reactant: COC(=O)CCc1ccc(O)cc1C
Reactant: Cc1c(Br)cccc1Br
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: COC(=O)CCc1ccc(Oc2cccc(Br)c2C)cc1C
Temperature: 120 °C
Yield: 78 %

Procedure:
A mixture of 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (2.0 g, 10.3 mmol), 2,6-dibromotoluene (7.72 g, 30.9 mmol), cesium carbonate (4.03 g, 12.4 mmol), and 2,2,6,6-tetramethyl-3,5-heptanedione (0.47 g, 2.55 mmol) in 1-methyl-2-pyrrolidinone (20 mL) is purged with N2, and then copper (I) chloride (0.51 g, 5.15 mmol) is added. The reaction is heated to 120° C. for 17 hours under N2, and then cooled and quenched with 1 N HCl (50 mL). The mixture is diluted with water and extracted with Et2O. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 9/1 hexanes/ethyl acetate to afford 2.92 g (78%) of the title compound. Rf=0.35 (4/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C18H19O3Br 362, found 363 and 365 (M+1 and M+3, 100%).
Reaction SMILES: FC1C=C(CCC2C=C(OC)C=CC=2C2CCC3C(=CC=C(OC)C=3)C2)C=CC=1O.Cl.ClCCN1CCCCCC1.[F:42][C:43]1[CH:58]=[C:57]([CH2:59][CH2:60][C:61]2[CH:66]=[C:65]([O:67]C)[CH:64]=[CH:63][C:62]=2[CH:69]2[CH2:78][CH2:77][C:76]3[C:71](=[CH:72][CH:73]=[C:74]([O:79]C)[CH:75]=3)[CH2:70]2)[CH:56]=[CH:55][C:44]=1[O:45][CH2:46][CH2:47][N:48]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1>>[N:48]1([CH2:47][CH2:46][O:45][C:44]2[CH:55]=[CH:56][C:57]([CH2:59][CH2:60][C:61]3[CH:66]=[C:65]([OH:67])[CH:64]=[CH:63][C:62]=3[CH:69]3[CH2:78][CH2:77][C:76]4[CH:75]=[C:74]([OH:79])[CH:73]=[CH:72][C:71]=4[CH2:70]3)=[CH:58][C:43]=2[F:42])[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1CCc1ccc(OCCN3CCCCCC3)c(F)c1)C2
Agent: COc1ccc2c(c1)CCC(c1ccc(OC)cc1CCc1ccc(O)c(F)c1)C2
Agent: Cl
Agent: ClCCN1CCCCCC1
Product: Oc1ccc2c(c1)CCC(c1ccc(O)cc1CCc1ccc(OCCN3CCCCCC3)c(F)c1)C2
Yield: 61.9 %

Procedure:
Synthesized from 2-fluoro-4-{2-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]ethyl}phenol and 1-(2-chloroethyl)azepane hydrochloride according to an analogous synthetic method to Preparation Example 40, 1-{2-{2-fluoro-4-{2-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]ethyl}phenoxy}ethyl}azepane (203 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (119 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[C:7]([CH:9]=1)N.Cl.N([O-])=O.[Na+].[H+].[B-](F)(F)(F)[F:18]>O>[F:18][C:7]1[CH:9]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[CH3:10]
Reactant: COc1ccc(C)c(N)c1
Reactant: F[B-](F)(F)F
Agent: Cl
Agent: O=N[O-]
Agent: [H+]
Solvent: O
Product: COc1ccc(C)c(F)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 31 %

Procedure:
A mixture of 5-methoxy-2-methyl aniline (5.0 g; 36 mmol), HCl (7.6 mL of a 12 M solution; 91 mmol) and H2O (11 mL) was heated at 60° C. for 15 min until complete dissolution had occurred. The reaction was cooled to 0° C. and an aqueous solution of NaNO2 (2.5 g; 36 mmol) was added dropwise (internal temperature ≦7° C.). The reaction was stirred at 0° C. for 30 min and a 0° C. solution of HBF4 (5.3 mL of a 48% solution; 40 mmol) was added cautiously. The reaction was stirred at 0° C. for 20 min, and the resultant brown solid was filtered, washed with ice water (3×10 mL) and H2O (2×10 mL). The solid was dried under high vacuum for 20 h, then heated (heat gun) until evolution of BF3 (white fumes) had ceased. The resulting brown oil was partitioned between EtOAc and H2O. The organic phase was dried (Na2SO4), concentrated in vacuo and distilled by Kugelrohr to give 3-fluoro-4-methyl anisole (1.6 g; 31%) as a colorless oil.
Reaction SMILES: C(C1C=C(OC(F)(F)F)C=C([N+]([O-])=O)C=1N)#N.[Cl:18]C1C([N+]([O-])=O)=CC(OC(F)(F)F)=CC=1C#N.N[C:36]1[C:41]([C:42]#[N:43])=[CH:40][C:39]([C:44]([F:47])([F:46])[F:45])=[CH:38][C:37]=1[Cl:48].N(OC(C)(C)C)=O>C(#N)C.Cl.[Cu](Cl)Cl>[C:42]([C:41]1[CH:40]=[C:39]([C:44]([F:47])([F:46])[F:45])[CH:38]=[C:37]([Cl:48])[C:36]=1[Cl:18])#[N:43]
Reactant: N#Cc1cc(OC(F)(F)F)cc([N+](=O)[O-])c1Cl
Reactant: N#Cc1cc(C(F)(F)F)cc(Cl)c1N
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CC#N
Product: N#Cc1cc(C(F)(F)F)cc(Cl)c1Cl
Reaction time: 2 h

Procedure:
2-Cyano-6-nitro-4-trifluoromethoxyaniline was converted into 4-chloro-3-cyano-5-nitrotrifluoromethoxybenzene using the general method illustrated in Preparation 5 of EP 0 398 499. In such Preparation, 4-amino-3-chloro-5-cyano-trifluoromethylbenzene (5.1 g) in dry acetonitrile (0.25 ml) was added dropwise to a stirred suspension of copper (II) chloride (3.72 g) and tertiary butyl nitrite (12.24 g) in dry acetonitrile (75 ml) whilst the temperature was maintained between 0° and +5° C. After the addition was complete, stirring was continued for a further 2 hours, whereupon the reaction mixture was diluted with dilute aqueous hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, and after drying over anhydrous magnesium sulphate, evaporation of the solvent under reduced pressure gave an orange oil which crystallised on standing. Kugelrohr distillation gave 3-cyano-4,5-dichloro-trifluoromethylbenzene as a pale yellow oil which crystallised on standing.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[C:11]3=[C:27]([CH3:31])[N:28]=[C:29]([CH3:30])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>ClCCl>[CH3:31][C:27]1[N:28]=[C:29]([CH3:30])[N:10]2[C:11]=1[C:12]([NH:14][C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1)=[N:13][C:8]([C:4]1[CH:3]=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:7]=[CH:6][CH:5]=1)=[N:9]2
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(Nc2nc(-c3cccc(N)c3)nn3c(C)nc(C)c23)cc(OC)c1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Nc2nc(-c3cccc(NS(C)(=O)=O)c3)nn3c(C)nc(C)c23)cc(OC)c1OC

Procedure:
A solution of 80 mg (0.19 mmol) of 3-[5,7-dimethyl-4-(3,4,5-trimethoxyphenoxy)-imidazo[5,1-f][1,2,4]triazin-2-yl]aniline from example 7, 20 mg (0.19 mmol) of methanesulfonyl chloride and 40 mg (0.38 mmol) of triethylamine in dichloromethane is stirred overnight at 20° C. The mixture is washed with aqueous sodium hydrogencarbonate solution, and the organic phase is dried and purified by HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[CH:27]1([N:33]=[C:34]=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>N1C=CC=CC=1>[Cl:25][C:11]1[CH:12]=[C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH:14]=[CH:15][C:10]=1[C:8]([C:6]1[CH:7]=[C:2]([NH:1][C:34]([NH:33][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:35])[CH:3]=[CH:4][C:5]=1[CH3:26])=[O:9]
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: O=C=NC1CCCCC1
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)NC2CCCCC2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound 494 (0.07 g, 0.18 mmol) was dissolved in pyridine (0.5 mL) and cyclohexyl isocyanate (0.036 mL, 0.28 mmol) was added. The solution was stirred at room temperature for 18 h. Work up as described in the preparation of compound 259. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 15:85→60:40 as the eluent. This afforded the title compound as a slightly coloured solid. 13C NMR (CD3OD) δ 198.5, 161.0 (dd), 157.9 (dd), 157.4, 151.1, 141.0, 138.9, 136.1, 135.0, 132.7, 132.0, 128.9, 127.4 (dd), 126.0 (dd), 122.5, 120.8, 116.6, 112.9, 112.6 (dd), 105.8 (dd), 49.8, 34.5, 26.7, 26.0, 19.7
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[CH2:28]([O:30][C:31](=[O:33])[NH2:32])[CH3:29]>>[CH2:28]([O:30][C:31](=[O:33])[NH:32][C:24]1[CH:25]=[CH:26][C:21]([C:19]([N:16]2[CH2:15][CH2:14][N:13]([C:5]3[C:4]([CH:1]4[CH2:3][CH2:2]4)=[CH:9][C:8]([CH:10]4[CH2:11][CH2:12]4)=[CH:7][N:6]=3)[CH2:18][CH2:17]2)=[O:20])=[CH:22][CH:23]=1)[CH3:29]
Reactant: O=C(c1ccc(I)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: CCOC(N)=O
Product: CCOC(=O)Nc1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)cc1
Yield: 48.1 %

Procedure:
Using [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (473 mg) described in Preparation Example 186 and carbamic acid ethyl ester (137 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (209 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C=O.[C:14](O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH3:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(=O)O
Reactant: CCOC(=O)C1CCNCC1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C1CCN(C)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Piperidine-4-carboxylic acid ethyl ester (78 g) was dissolved in MeOH (1.2 L) at RT then formaldehyde (37%, 90 ml) and acetic acid (42 ml) were added and stirred for 2 h. The mixture was cooled to 0° C., NaCNBH3 (70 g) was added, and the mix was stirred for 20 min at 0° C., then overnight at RT. The mixture was cooled to 0° C. then quenched with 6N NaOH. The mixture was concentrated in vacuo to an aqueous layer, which was extracted with EtOAc (4×), brine-washed, dried over Na2SO4, and concentrated in vacuo to provide 1-methylpiperidine-4-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1)=[O:3].N1C=CC=CC=1.[CH2:17]([S:20](Cl)(=[O:22])=[O:21])[CH2:18][CH3:19].O>ClCCl>[C:2]([C:4]1[CH:5]=[C:6]([NH:10][S:20]([CH2:17][CH2:18][CH3:19])(=[O:22])=[O:21])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:1]
Reactant: CCCS(=O)(=O)Cl
Reactant: CC(=O)c1cccc(N)c1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1cccc(C(C)=O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.8 %

Procedure:
1 g (7.4 mmol) of 3-aminoacetophenone were dissolved in 35 ml of dry dichloromethane. To the resultant solution cooled at 0° C. 0.89 ml (11.09 mmol) of anhydrous pyridine and 1.26 g (8.87 mmol) of 1-propanesulfonic acid chloride were added. After stirring the reaction mixture for 20 h at room temperature and under inert atmosphere, 15 ml of water were added. The two layers were separated, and the aqueous layer was washed with 2×15 ml of dichloromethane. The organic layers were washed with 30 ml of water and dried over anhydrous sodium sulfate. The dichloromethane layer was evaporated to dryness to yield a yellow solid, 1.8 g (yield=100%) of N-(3-acetylphenyl)-1-propane-sulfonamide which was directly used for the following reaction.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]([Cl:25])=[CH:18][N:17]=1>C(#N)C>[Cl:25][C:19]1[CH:20]=[C:21]([N+:22]([O-:24])=[O:23])[C:16]([O:2][C:1]2[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=2)=[N:17][CH:18]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Cl
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cc(Cl)cnc1Oc1ccc(O)cc1
Temperature: 60 °C
Reaction time: 36 h
Yield: 61.9 %

Procedure:
A mixture of 85.9 g (0.78 mole) of hydroquinone, 1200 ml of acetonitrile and 53.9 g (0.39 mole) of potassium carbonate is heated to 60° C., then a solution of 115.8 g (0.60 mole) of 2,5-dichloro-3-nitropyridine in 500 ml of acetonitrile is added dropwise over 6 hours and the mixture is stirred for 36 hours. The solvent is removed by distillation and the residue is poured into a mixture of ice-water and hydrochloric acid. After extraction with methylene chloride, the combined organic phases are dried over magnesium sulfate, treated with activated carbon, filtered and concentrated. The residue is purified by crystallisation in a mixture of hexane and ethyl acetate, affording 99 g (62% of theory) of 4-(5-chloro-3-nitropyridin-2-yloxy)phenol with a melting point of 125°-126° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[C:5]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:6]([OH:8])=[O:7])#[N:2].C([O-])([O-])=O.[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CC(C)=O>[CH2:31]([C:11]1[C:10]([CH3:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C:3]=1[C:1]#[N:2])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1ccc(S(=O)(=O)Nc2c(C#N)cc(C)cc2C(=O)O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(S(=O)(=O)Nc2c(C(=O)O)cc(C)c(Cc3ccccc3)c2C#N)cc1
Yield: 79 %

Procedure:
To a solution of 1.5 g (4.3 mmol) of the product of Example 176 in 200 mL of acetone was added 4 g of K2CO3 and 5 ml of benzylbromide and the mixture was refluxed for 8 hours. The reaction mixture was then filtered and the acetone was removed in vacuo. The residue was dissolved in chloroform and washed well with water. The organic layer was then dried over MgSO4, filtered and concentrated in vacuo. The resulting residue chromatographed on silica gel luting with 30% Ethyl acetateexane to give 1.8 g (79%) of the desired product as a brown oil. Electrospray Mass Spec 527 (M+H).
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9](C(OC(C)(C)C)=O)[C:10](=[O:11])[C:5]2=[N:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[N:6]2[CH2:7][CH2:8][NH:9][C:10](=[O:11])[C:5]2=[N:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(Br)nnc2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCCn2c(Br)nnc21
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
To a solution of tert-butyl 3-bromo-8-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (663 mg, 2.1 mmol) in DCM (21 mL) was added TFA (4.2 mL, 55 mmol). After 30 minutes, the reaction was concentrated and the residue was diluted with EtOAc, sonicated, and filtered to provide the desired product as a white solid (393 mg, 87%). MS (ESI): mass calcd. for C5H5BrN4O, 216.0; m/z found, 217.0 [M+H]+.