Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH2:31]([O:38][C@H:39]1[C@H:44]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C@@H:43]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C@H:42]([C:61]2[CH:66]=[CH:65][C:64]([CH2:67][CH3:68])=[C:63]([CH2:69][C:70]3[CH:79]=[CH:78][C:73]4[O:74][CH2:75][CH2:76][O:77][C:72]=4[CH:71]=3)[CH:62]=2)[O:41][C@@H:40]1[CH2:80]O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:31]([O:38][C@H:39]1[C@H:44]([O:45][CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C@@H:43]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C@H:42]([C:61]2[CH:66]=[CH:65][C:64]([CH2:67][CH3:68])=[C:63]([CH2:69][C:70]3[CH:79]=[CH:78][C:73]4[O:74][CH2:75][CH2:76][O:77][C:72]=4[CH:71]=3)[CH:62]=2)[O:41][C@@H:40]1[CH2:80][O:11][C:10](=[O:12])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:13]([CH3:15])[CH3:14])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCc1ccc([C@@H]2O[C@H](CO)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc2c(c1)OCCO2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCc1ccc([C@@H]2O[C@H](COC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
To a stirred solution of (R)-2-tert-butoxycarbonylamino-3-methyl-butyric acid (6.3 g, 29.1 mmol) in DMF (40 ml) was added N,N′-dicyclohexylcarbodiimide (6.0 g, 29.1 mmol). After stirring for 30 min at room temperature, reaction mixture was cooled to 0° C., added a solution of {(2R,3R,4R,5S,6S)-3,4,5-tris-benzyloxy-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-yl}-methanol (4.0 g, 5.8 mmol) in DMF (20 ml) followed by DMAP (360 mg, 2.9 mmol) and stirred at ambient temperature for overnight. Reaction was quenched by the addition of water (150 ml) and extracted with ethyl acetate (2×80 ml). Combined organic layers were washed with water (100 ml), brine (100 ml), dried over sodium sulfate, concentrated and purified by silica gel column chromatography to give 4.5 g of (R)-2-tert-butoxycarbonylamino-3-methyl-butyric acid (2R,3R,4R,5S,65)-3,4,5-tris-benzyloxy-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-ylmethyl ester as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7](=[O:9])[N:6]([CH3:10])[C:5]=1[CH3:11])(=[O:3])[CH3:2].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[CH3:14][N:15]([CH3:17])[CH:16]=[CH:2][C:1]([C:4]1[S:8][C:7](=[O:9])[N:6]([CH3:10])[C:5]=1[CH3:11])=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1sc(=O)n(C)c1C
Product: Cc1c(C(=O)C=CN(C)C)sc(=O)n1C
Temperature: 100 °C
Yield: 44.5 %

Procedure:
5-Acetyl-3,4-dimethyl-3H-thiazol-2-one (4.64 g, 27.10 mmol) and dimethylformamide dimethyl acetal (8.4 mL, 59.62 mmol) were mixed in a dry, argon-flushed flask, and heated at 100° C. for 3 h. The mixture was cooled, producing some precipitation, which was enhanced by the addition of an equal volume of Et2O. The resulting orange solid was filtered and washed with Et2O to give 2.73 g of the title product. 1H-NMR (d6-DMSO): δ2.52 (s, 3H), 2.82 (bs, 3H), 3.11 (bs, 3H), 3.22 (s, 3H), 5.10 (d, 1H, J=12.2 Hz), 7.61 (d, 1H, J=11.7 Hz). IR (ATR): 1669 and 1630 cm−1 (CO str).
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[C:16]([O:17][CH3:18])=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:19])[CH:13]=2)[N:8]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:6][C:7]1[C:16]([O:17][CH3:18])=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:19])[CH:13]=2)[N:8]=1
Reactant: COc1ccc(CNc2nc3ccc(F)cc3nc2OC)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1nc2cc(F)ccc2nc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.6 %

Procedure:
To 2-(2,4-dimethoxybenzylamino)-6-fluoro-3-methoxyquinoxaline (2.70 g, 7.86 mmol), 60 ml of 50% trifluoroacetic acid in dichloromethane was added at room temperature. The resulting mixture was stirred at room temperature for 24 hours and concentrated under the reduced pressure to remove the solvent. The residue was neutralized with saturated sodium bicarbonate solution and then NaCl solution was added thereto. The product was extracted with dichloromethanee and the organic layer was dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (4:1) mixture and concentration gave 1.27 g of the titled compound (yield, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[NH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(Cl)Cl>[C:43]1([NH:42][C:8]([C:5]2[C:4]([N:11]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:27])([F:28])[F:26])[CH:19]=3)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:9])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: COCN(c1cc(Cl)cnc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCN(c1cc(Cl)cnc1C(=O)Nc1ccccc1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
To a magnetically stirred solution of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid (229 mg, 0.50 mmol) in anhydrous methylene chloride (5 mL) was added oxalyl chloride (0.5 mL) at room temperature. The reaction was heated at reflux for 1 h, then concentrated to dryness. The residue was dissolved in methylene chloride (4 mL) and this solution was added dropwise to a magnetically stirred solution of triethylamine (1.0 mL) and aniline (93 mg, 1.00 mmol) in methylene chloride (2 mL). The reaction mixture was stirred 1 h (the reaction was monitored by LCMS), quenched with saturated aqueous NH4Cl (50 mL), and the aqueous layer was extracted with EtOAc (3×75 mL). The combined extracts were washed with 0.5 M HCl (50 mL) and water (50 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by chromatography on silica gel using a gradient of ethyl acetate-hexane (0:100 to 100:0) to afford pure 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid phenylamide. MS m/z 556.1 (M+Na); 502.1 (M+H−MeOH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:19])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([CH3:20])[CH:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[C:23]([CH:30]=O)=[CH:22]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:21]1[C:29]2=[N:28][CH:27]=[CH:26][CH:25]=[C:24]2[C:23]([CH:30]=[C:11]2[O:10][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[CH3:20])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]2=[O:19])=[CH:22]1
Reactant: CCOC(=O)C1=C(Nc2ccc(F)cc2C)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc(F)cc2C)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 55.8 %

Procedure:
To a solution of ethyl 2-[(4-fluoro-2-methylphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.30 g, 1.1 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.16 g, 1.1 mmol) in ethanol (7.0 mL), L-proline (0.013 g, 0.10 mmol) was added at ambient temperature. The mixture was refluxed for 3 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with methanol then dried to afford the titled compound as solid (0.25 g, y. 58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][N:7]=[C:6]2[C:14]([O:16][CH2:17][CH3:18])=[O:15].C[O-].[Li+].Cl[CH2:23][C:24]1[N:25]=[CH:26][N:27]([C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=1>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:23][C:24]1[N:25]=[CH:26][N:27]([C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:28]=1)[N:7]=[C:6]2[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCOC(=O)c1n[nH]c2cc(OC)c(OC)cc12
Agent: C[O-]
Agent: [Li+]
Solvent: CS(C)=O
Product: CCOC(=O)c1nn(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
In 5000 ml of dimethyl sulfoxide was suspended 250.2 g of ethyl 5,6-dimethoxyindazole-3-carboxylate, and 40.2 g of lithium methoxide was added to the suspension, followed by stirring at room temperature for 1 hour. A solution of 447.8 g of 4-chloromethyl-1-tritylimidazole in 2000 ml of dimethyl sulfoxide was added dropwise thereto at room temperature over 10 minutes. After stirring at room temperature for 2 hours, 4.2 g of lithium methoxide and 44.8 g of 4-chloromethyl-1-tritylimidazole were further added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into 30000 ml of ice-water while stirring. A precipitated crystal was collected, washed with three 2000 ml portions of water, and dried. The solid was dissolved in 10000 ml of chloroform, and the solution was dried over sodium sulfate, filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform:ethanol=50:1) and recrystallized from chloroform/isopropyl alcohol to yield 222.0 g of the title compound as a colorless prism crystal.
Reaction SMILES: [N:1]([CH2:4][CH3:5])=[C:2]=[O:3].[F:6][C:7]([F:25])([F:24])[C:8]1[CH:9]=[C:10]([S:14]([N:17]2[CH2:21][CH2:20][C@H:19]([O:22][NH2:23])[CH2:18]2)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:4]([NH:1][C:2]([NH:23][O:22][C@H:19]1[CH2:20][CH2:21][N:17]([S:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:7]([F:25])([F:6])[F:24])[CH:9]=2)(=[O:15])=[O:16])[CH2:18]1)=[O:3])[CH3:5]
Reactant: NO[C@H]1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)C1
Reactant: CCN=C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCNC(=O)NO[C@H]1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 78.7 %

Procedure:
Isocyanatoethane (36.0 mg, 0.5 mmol) was added to a solution of (S)—O-(1-(3-(trifluoromethyl)phenylsulfonyl)pyrrolidin-3-yl)hydroxyl amine (155 mg, 0.5 mmol) and pyridine (119 mg, 1.5 mmol) in CH2Cl2 (8 ml), and the whole was stirred at room temperature for 17 hours. The reaction mixture was washed with aqueous 0.1 N HCl solution (10 ml), H2O (20 ml×3) and brine (20 ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether: 60/40) to give (S)-1-ethyl-3-(1-(3-(trifluoromethyl)phenylsulfonyl)pyrrolidin-3-yloxy)urea (150 mg, 64%) as pale yellow oil: LCMS: 382 [M+1]+. 1H NMR (DMSO-d6) δ: 0.95-1.00 (3H, t), 1.74-1.84 (1H, M), 2.05-2.06 (1H, m), 2.99-3.04 (2H, m), 3.15-3.31 (3H, m), 3.50-3.54 (1H, d), 4.21 (1H, s), 6.66-6.70 (1H, t), 7.84-7.89 (1H, t), 8.01 (1H, s), 8.07-8.14 (1H, t), 8.92 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[CH:6]([CH2:15][OH:16])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.N1C=CC=CC=1>ClCCl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[CH:6]([CH2:15][O:16][S:25]([C:22]3[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=3)(=[O:27])=[O:26])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1
Reactant: OCC1c2ccccc2C=Cc2cc(Br)ccc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2c3ccccc3C=Cc3cc(Br)ccc32)cc1
Yield: 88.9 %

Procedure:
To a solution of 2-bromo-5-hydroxymethyl-dibenzo [a,d]cycloheptene (6.1 g) in dry dichloromethane (60 ml) was added p-toluenesulphonyl chloride (4.9 g). pyridine (4 g) and 4-dimethylamino pyridine (100 mg). The reaction mixture was refluxed for 14 h, cooled, washed with water (2×50 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue. was purified by flash silica chromatography using 10% ethyl acetate in hexane as eluent to give the title compound as a colourless oil (8.2 g). δ (360 MHz, CDCl3) 2.46 (3H, s, CH3), 4.12 (1H, dd J=6.2 and 3.5 Hz, CH--CH2 --O), 4.24-4.32 (2H, m, CH--CH2 --O), 6.50 (1H, d, J=11.9 Hz, CHA =CHB), 6.73 (1H, d, J=11.9 Hz, CHA =CHB), 7.10-7.40 (11H, m, ArH).
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([NH2:17])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.Cl.C[CH:20]([NH2:35])[C:21]1C=[CH:25][C:24](CCC2C=CC=CC=2)=[CH:23][CH:22]=1>>[ClH:1].[CH3:2][CH:3]([N:17]=[C:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:35]1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:5]=1
Reactant: CC(N)c1ccc(CCc2ccccc2)cc1
Reactant: CC(N)c1ccc(Oc2ccccc2)cc1
Agent: Cl
Product: CC(N=C1CCCCCN1)c1ccc(Oc2ccccc2)cc1

Procedure:
Following essentially the same procedure described in Example 7 above and substituting α-methyl-p-phenoxybenzylamine hydrochloride for the α-methyl-p-phenethylbenzylamine hydrochloride above, results in the formation of 2-(α-methyl-p-phenoxybenzylimino)hexahydroazepine hydrochloride having a M.P. of 210°-2° C., (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:3]=1[C:4]([NH:6][C:7]([N:9]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=1)[NH:10]C(OC(C)(C)C)=O)=[O:8])=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:9]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=2)[N:10]=1
Reactant: COC(=O)c1ccc(N(NC(=O)OC(C)(C)C)C(=O)NC(=O)c2c(F)cccc2Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89.2 %

Procedure:
To a solution of tert-butyl 2-[(2-chloro-6-fluorobenzoyl)carbamoyl]-2-[4-(methoxycarbonyl)phenyl]hydrazinecarboxylate (3.0 g, 6.45 mmol) in DCM (30 mL) was added trifluoro acetic acid (2.0 mL). The reaction mass was stirred at RT for 2-3 h. Excess of solvent was removed at low temperature. The reaction mass was quenched in ice and filtered off to afford 2.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.86 (s, 3H), 7.51-7.60 (m, 2H), 7.70 (br s, 1H), 8.09 (br s, 4H), 12.79 (br s, 1H); MS (m/z): 348.55 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([CH3:35])=[O:34].OO.CC[O:40]C(C)=O>C(O)(=O)C>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:18])[CH3:19])=[CH:13][CH:12]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([CH3:35])(=[O:40])=[O:34]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(Cc3ccccc3S(C)=O)cc(OC)c21
Reactant: CCOC(C)=O
Agent: OO
Solvent: CC(=O)O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(Cc3ccccc3S(C)(=O)=O)cc(OC)c21
Temperature: 25 °C

Procedure:
A mixture of 140 mg (0.252 mmol) of 4-Bromo-2-(4-isopropyl-phenyl)-5-(2-methanesulfinyl-benzyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole and 30 μl (0.265 mmol) hydrogen peroxide solution (30%) in 3 ml acetic acid is stirred at reflux temperature for 3 h. After that the reaction mixture is allowed to cool to room temperature and 25 ml EtOAc are added and this solution is washed with 4n NaOH (2×), water and sodiumhydrogensulfite solution, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=1:1) to afford 112 mg of the title compound as pale red crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Cc1ccnc(N)c1
Product: Cc1ccnc(Nc2nc(Cl)ncc2F)c1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 2-amino-4-methylpyridine gave 2-chloro-5-fluoro-N4-(4-methylpyridin-2-yl)-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.22 (s, 1H), 8.16 (d, 1H, J=8.4 Hz), 8.13 (d, 1H, J=2.4 Hz), 6.91 (d, 1H, J=5.4 Hz), 2.42 (s, 3H); LCMS: purity: 87%; MS (m/e): 239 (MH+).
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]O)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[CH2:1]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][Cl:19])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCc1cccc(CCc2ccccc2)c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCc1cccc(CCc2ccccc2)c1
Yield: 99 %

Procedure:
The resulting alcohol (140 mg) was dissolved in 1 ml of chloroform, and 0.3 ml of thionyl chloride was added. The mixture was reacted at room temperature for 30 minutes. The reaction mixture was evaporated under reduced pressure to give 150 mg (yield 99%) of 3-phenethylbenzyl chloride as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:21]1[CH:35]=[CH:34][C:24]([CH2:25][N:26]2[CH2:31][CH2:30][S:29](=[O:33])(=[O:32])[CH2:28][CH2:27]2)=[CH:23][CH:22]=1>>[O:33]=[S:29]1(=[O:32])[CH2:30][CH2:31][N:26]([CH2:25][C:24]2[CH:34]=[CH:35][C:21]([NH:1][C:2]3[S:3][C:4]([C:10]4[CH:11]=[CH:12][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][CH:15]=4)=[CH:5][C:6]=3[C:7]([NH2:9])=[O:8])=[CH:22][CH:23]=2)[CH2:27][CH2:28]1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(N)=O)c(N)s2)cc1
Reactant: O=S1(=O)CCN(Cc2ccc(Br)cc2)CC1
Product: CS(=O)(=O)c1ccc(-c2cc(C(N)=O)c(Nc3ccc(CN4CCS(=O)(=O)CC4)cc3)s2)cc1

Procedure:
2-({4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}amino)-5-[4-(methyl sulfonyl)phenyl]thiophene-3-carboxamide was prepared according to the general procedure in Example 1 using 2-amino-5-[4-(methylsulfonyl)phenyl]thiophene-3-carboxamide (149 mg, 0.503 mmol) and 4-(4-bromobenzyl)thiomorpholine 1,1-dioxide (153 mg, 0.503 mmol) as the starting materials.
Reaction SMILES: [CH2:1]([S:13]([N:16]1[CH2:21][CH2:20][CH2:19][S:18][C:17]1=[CH:22][N+:23]([O-:25])=[O:24])(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Br:26]N1C(=O)CCC1=O>>[CH2:1]([S:13]([N:16]1[CH2:21][CH2:20][CH2:19][S:18][C:17]1=[C:22]([Br:26])[N+:23]([O-:25])=[O:24])(=[O:14])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCCCCCCCS(=O)(=O)N1CCCSC1=C[N+](=O)[O-]
Product: CCCCCCCCCCCCS(=O)(=O)N1CCCSC1=C(Br)[N+](=O)[O-]

Procedure:
was prepared, as a yellow solid, m.p.: 70°-71° C., by treating (3A) with N-bromosuccinimide, according to the procedure described in Example 1.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([I:9])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:10].[C-:11]#[N:12].[K+]>CCO.O>[Cl:10][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([I:9])[C:3]=1[CH2:2][C:11]#[N:12]
Reactant: Clc1cccc(I)c1CBr
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1c(Cl)cccc1I
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A mixture of 2-(bromomethyl)-1-chloro-3-iodobenzene (14 g, 42 mmol) in 100 mL EtOH was treated with a solution of potassium cyanide (3.6 mL, 84 mmol) in 40 mL water. The mixture was refluxed for 2.5 hours. The mixture was cooled to room temperature and then concentrated. The residue was diluted with 200 mL EtOAc, washed with water (2×50 mL), saturated NaCl (50 mL), dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (20% EtOAc/hexane) to give 10.18 g pale yellow solid. MS m/e: (M−1)− 276.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([OH:17])=O)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1.[CH3:18][C:19]([CH3:26])([C:21]1[O:22][CH:23]=[CH:24][N:25]=1)[NH2:20]>>[CH3:18][C:19]([NH:20][C:15]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:6]=1)=[O:17])([C:21]1[O:22][CH:23]=[CH:24][N:25]=1)[CH3:26]
Reactant: CC(C)(N)c1ncco1
Reactant: O=C(O)c1ccc(Cl)c(-c2cccc(Cl)c2)n1
Product: CC(C)(NC(=O)c1ccc(Cl)c(-c2cccc(Cl)c2)n1)c1ncco1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (Example 58 c) and α,α-dimethyl-2-oxazolemethanamine (CAN 1211519-76-4) as starting materials, MS (EI): m/e=376.0 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:37])[CH2:34][O:35][CH3:36])[NH:28][C:27](=[O:38])[CH2:26]2>>[CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14](/[CH:17]=[C:26]3\[C:27](=[O:38])[NH:28][C:29]4[C:25]\3=[CH:24][C:23]([F:22])=[C:31]([NH:32][C:33](=[O:37])[CH2:34][O:35][CH3:36])[CH:30]=4)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2]
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Reactant: COCC(=O)Nc1cc2c(cc1F)CC(=O)N2
Product: CCN(CC)CCN1CCCc2[nH]c(/C=C3\C(=O)Nc4cc(NC(=O)COC)c(F)cc43)c(C)c2C1=O
Yield: 53.6 %

Procedure:
The title compound was prepared under the same conditions as described in step 10 of Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j obtained from step 9 of Example 1 and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxy-acetamide 7a as starting materials to obtain (Z)—N-{3-[5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxy-acetamide 7 (37 mg, yield 53.6%) as a brown solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[CH3:17][N:18]1[N:22]=[N:21][C:20]([NH2:23])=[N:19]1.C(O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH:23][C:20]1[N:21]=[N:22][N:18]([CH3:17])[N:19]=1
Reactant: Cn1nnc(N)n1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cn1nnc(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
A mixture of 3,5-bis(trifluoromethyl)benzaldehyde (4 g, 16.5 mmol), 2-methyl-2H-tetrazol-5-amine (1.96 g, 19.8 mmol) and molecular sieves (5-10 Å beads) in toluene (50 mL) was heated at reflux for 4 hours, after which time the solvent was removed. Ethanol (50 mL) and sodium borohydride (1.25 g, 33 mmol) were added. The resulting mixture was stirred at room temperature for 30 minutes and then partitioned between saturated NH4Cl (50 mL) and ethyl acetate (2×50 mL). The combined organic layers were washed with saturated NaCl (50 mL), dried (MgSO4), filtered and concentrated to yield the title compound as a white solid (4.7 g). 1H NMR (400 MHz, CDCl3) δ 4.2 (s, 3H) 4.7 (s, 1H) 4.7 (s, 1H) 5.0 (t, J=6.0 Hz, 1H) 7.8 (s, 1H) 7.9 (s, 2H). MS (ES+) Calc: 325.08, Found: 325.8 (M+1).