Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:10][C:11](=[O:26])[NH:12][C@H:13]1[C@H:19]([CH3:20])[NH:18][C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[NH:15][C:14]1=[O:25])([CH3:9])([CH3:8])[CH3:7].[C:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)(=[O:29])[CH3:28]>N1C=CC=CC=1.O>[C:6]([O:10][C:11](=[O:26])[NH:12][C@H:13]1[C@H:19]([CH3:20])[N:18]([C:34](=[O:35])[C:33]2[CH:32]=[CH:31][C:30]([C:27](=[O:29])[CH3:28])=[CH:38][CH:37]=2)[C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[NH:15][C:14]1=[O:25])([CH3:7])([CH3:8])[CH3:9]
Reactant: C[C@@H]1Nc2ccccc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)c1ccc(C(=O)N2c3ccccc3NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H]2C)cc1
Reaction time: 2 h
Yield: 66.8 %

Procedure:
Phosphoryl chloride (0.16 ml, 1.72 mmol) was added to a solution of ((2S,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester (0.5 g, 1.72 mmol) and 4-acetyl-benzoic acid (0.25 g, 1.54 mmol) in pyridine (15 ml) at 0° C., stirring continued for 2 h. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (2×60 mL). The organic layers were combined, washed with 10% aqueous citric acid (1×15 mL), water (1×15 mL) and a saturated aqueous solution of sodium hydrogen carbonate (1×15 mL) and brine. The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography over silica gel gradient eluted with 10 to 60% v/v ethyl acetate hexanes to give [(2S,3S)-1-(4-acetyl-benzoyl)-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-carbamic acid tert-butyl ester (0.45 g, 60%).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:21][C:22]([C:24]2[C:33]([NH:34]C(=O)OCC3C=CC=CC=3)=[CH:32][C:31]3[C:26](=[CH:27][C:28]([CH:45]=O)=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:10]1)=O)(C)(C)C.[NH:47]1[CH2:51][CH2:50][CH2:49][CH2:48]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Br.CC(O)=O>C(Cl)Cl>[NH2:34][C:33]1[C:24]([C:22]([NH:21][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[N:11]2[CH2:12][CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10]2)=[O:23])=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[C:28]([CH2:45][N:47]1[CH2:51][CH2:50][CH2:49][CH2:48]1)[CH:27]=2
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2NC(=O)c2nc3cc(C=O)ccc3cc2NC(=O)OCc2ccccc2)C1
Reactant: C1CCNC1
Agent: Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1cc2ccc(CN3CCCC3)cc2nc1C(=O)Nc1cnccc1N1CCC[C@H](N)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzyl (2-{[(4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}pyridin-3-yl)amino]carbonyl}-7-formylquinolin-3-yl)carbamate (0.008 g, 0.01 mmol) (from Example 15, step 5) was mixed with pyrrolidine, DCM (0.20 mL) and sodium triacetoxyborohydride (0.020 g, 0.094 mmol). The reaction mixture was stirred at room temperature for 2 h. HBr in AcOH (8.0 M; 0.20 mL, 1.6 mmol) was added and the reaction mixture was stirred at room temperature for 30 min. After concentration to remove the solvent, the crude product was diluted with MeOH and neutralized with a small amount of NH4OH. The mixture was filtered and purified by preparative LC-MS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with NH4OH) to give the title compound. LCMS calc. for C25H32N7O (M+H)+: m/z=446.2. Found: 446.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@H:5]1[NH:10][C:9](=[O:11])[C@@H:8]([CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:22])[CH:14]=2)[NH:7][C:6]1=[O:23].[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([NH:1][CH2:2][CH2:3][CH2:4][C@H:5]1[NH:10][C:9](=[O:11])[C@@H:8]([CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:22])[CH:14]=2)[NH:7][C:6]1=[O:23])(=[O:26])[CH3:25]
Reactant: Cn1cc(C[C@H]2NC(=O)[C@@H](CCCN)NC2=O)c2ccccc21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NCCC[C@H]1NC(=O)[C@@H](Cc2cn(C)c3ccccc23)NC1=O
Temperature: 100 °C
Yield: 88.2 %

Procedure:
A mixture of (3R,6R)-3-(3-aminopropyl)-6-(1-methylindol-3-ylmethyl)piperazine-2,5-dione (0.1 g) and acetic anhydride (0.08 g) in pyridine (1.0 ml) was heated at 100° C. for 1 hour. After the mixture was cooled to ambient temperature, the precipitated solid was collected by filtration and washed with pyridine (2 ml) and ethanol (5 ml) to give (3R,6R)-3-(3-acetamidopropyl)-6-(1-methylindol-3-ylmethyl)piperazine-2,5-dione (0.1 g).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:8]1[O:12][N:11]=[C:10]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)[CH:9]=1)([CH2:6][OH:7])[CH2:4][OH:5].[N:23]1([CH2:29][CH2:30][O:31][C:32]2[CH:50]=[CH:49][C:35]3[N:36]4[CH:41]=[C:40]([C:42]5[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=5)[N:39]=[C:37]4[S:38][C:34]=3[CH:33]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CN(C)C1C=CN=CC=1.C1COCC1>[OH:7][CH2:6][C:3]([C:8]1[O:12][N:11]=[C:10]([NH:13][C:14]([NH:48][C:45]2[CH:44]=[CH:43][C:42]([C:40]3[N:39]=[C:37]4[N:36]([CH:41]=3)[C:35]3[CH:49]=[CH:50][C:32]([O:31][CH2:30][CH2:29][N:23]5[CH2:24][CH2:25][O:26][CH2:27][CH2:28]5)=[CH:33][C:34]=3[S:38]4)=[CH:47][CH:46]=2)=[O:22])[CH:9]=1)([CH2:2][OH:1])[CH2:4][OH:5]
Reactant: Nc1ccc(-c2cn3c(n2)sc2cc(OCCN4CCOCC4)ccc23)cc1
Reactant: O=C(Nc1cc(C(CO)(CO)CO)on1)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-c2cn3c(n2)sc2cc(OCCN4CCOCC4)ccc23)cc1)Nc1cc(C(CO)(CO)CO)on1

Procedure:
A mixture of phenyl 5-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)isoxazol-3-ylcarbamate (1 equivalent), 7-(2-morpholin-4-yl-ethoxy)-2-(4-aminophenyl)imidazo[2,1-b]benzothiazole (4) (1 equivalent) and 4-(dimethylamino)pyridine (0.05-0.5 equivalents) in anhydrous THF is stirred at a temperature between rt and 50° C. until the reaction is substantially complete as monitored by LCMS or TLC. The reaction mixture is concentrated under reduced pressure and the residue is purified by either preparative reverse-phase HPLC or silica gel flash chromatography to afford 1-[5-(2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-isoxazol-3-yl]-3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea (I-1b).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12](=[O:21])[CH:13]([P:15]([O:19][CH3:20])([O:17][CH3:18])=[O:16])[OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].N1C=CN=C1>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12](=[O:21])[CH:13]([P:15]([O:19][CH3:20])([O:17][CH3:18])=[O:16])[O:14][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COP(=O)(OC)C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: COP(=O)(OC)C(O[Si](C)(C)C(C)(C)C)C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
To a mixture of 3.48 g of product from Example 97 and 12 ml of dimethylformide is added 1.86 of t-butyldimethylsilyl chloride and 1.86 g of imidazole. After stirring the reaction at room temperature for 2 hours, the mixture is diluted with 50% ethyl acetate/diethyl ester, washed 5 times water, once with saturated solid bicarbonate and once with saturated solid chloride. The organic layer is dried, filtered and concentrated in vacuo to give 3.90 g of the desired silylated product.
Reaction SMILES: [Li]C(CC)C.[CH2:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[Si:12]([O:19][C@@H:20]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:22]([C:32]2C=CC=CC=2)[CH2:21]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].FC(F)(F)S(OC)(=O)=O>C1COCC1>[Si:12]([O:19][C@@H:20]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@:22]([CH3:32])([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:21]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]1c1ccccc1
Reactant: C1CCCCC1
Agent: COS(=O)(=O)C(F)(F)F
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@]1(C)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of sec-BuLi in cyclohexane (1.4 M, 2.65 mL, 3.71 mmol, 1.40 equiv) was added to a solution of tertramethylethylenediamine (0.880 mL, 5.83 mmol, 2.20 equiv) and tert-butyl(2S,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-phenylpyrrolidine-1-carboxylate (5-1, 1.00 g, 2.65 mmol, 1 equiv) in THF (150 mL) at −78° C. The resulting bright yellow mixture was stirred for 1 hour, then methyl trifluoromethanesulfonate (1.20 mL, 10.6 mmol, 4.00 equiv) was added. The mixture was warmed to 0° C. and stirred for 30 minutes, then partitioned between saturated sodium chloride solution (100 mL) and ethyl acetate (2×75 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (hexanes, grading to 50% ethyl acetate in hexanes) to provide tert-butyl(2S,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-methyl-2-phenylpyrrolidine-1-carboxylate (21-1) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.38-7.18 (m, 5H), 4.39 (m, 1), 3.92 (dd, 1H, J=10.8, 5.1 Hz), 3.65 (br d, 1H, J=10.8 Hz), 2.28 (dd, 1H, J=13.0, 4.5 Hz), 2.13 (br d, 1H, J=12.8 Hz), 1.92 (s, 3H), 1.12 (s, 9H), 0.91 (s, 9H), 0.03 (s, 3H), 0.02 (s, 3H). LRMS m/z (M+H-Boc) 292.2 found, 292.2 required.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14](O)=[O:15])[N:7]=3.CC[N:21]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl-].[NH4+].C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]([NH2:21])=[O:15])[N:7]=3
Reactant: O=C(O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 93.2 %

Procedure:
To a solution of 8-bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid (8.27 g, 26.7 mmol), EDCI (6.66 g, 34.8 mmol), HOBt (4.69 g, 34.8 mmol) and ammonium chloride (4.29 g, 80.2 mmol) in DMF (80 mL) was added triethylamine (7.49 mL, 53.5 mmol) and the reaction mixture stirred at 45° C. for 1.5 h. The reaction mixture was concentrated in vacuo and the residue triturated with water (250 mL). The precipitated product was collected by filtration and dried in vacuo at 45° C. for 16 h to give 8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide as a buff coloured solid (7.67 g, 93%). 1H NMR (400 MHz, d6-DMSO) 8.40 (1H, d, J=8.7 Hz), 7.80 (1H, s), 7.42 (1H, br s), 7.32 (1H, dd, J=8.7, 2.0 Hz), 7.27 (1H, d, J=2.1 Hz), 7.15 (1H, br s), 4.50-4.46 (4H, m). LCMS: RT=3.07 min, M+H+=308/310. 1H NMR showed product to contain 5% 8-iodo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].C1(S(O)(=O)=O)C=CC=CC=1.[CH3:19][C:20](=[CH2:22])[CH3:21].[OH-].[Na+]>C(Cl)Cl>[NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([O:5][C:20]([CH3:22])([CH3:21])[CH3:19])=[O:4]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: C=C(C)C
Agent: O=S(=O)(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1
Temperature: 5 °C
Reaction time: 72 h

Procedure:
To a 12L round-bottomed flask fitted with a mechanical stirrer, high efficiency reflux condenser (≤-10° C.), adJustable diptube inlet, and overhead nitrogen bubbler was charged a slurry of L-proline (600 g, 5.22 mole) in methylene chloride (6.0L, K.F.≤0.01%). The slurry was cooled to 5° C. and maintained at <20° C. as benzenesulfonic acid (1.24 kg, 7.83 mole) was slowly added. The reaction mixture, now homogeneous, was further cooled under nitrogen to 0°-5° C. and liquefied isobutylene (5.86L, 67.8 mole) was added subsurface via the diptube over 2 hours. The batch was then aged for 3 days at 5° C. under nitrogen. Upon completion, the batch was slowly quenched under nitrogen into well-stirred cold (0°-5° C.) aqueous sodium hydroxide (15.6L, 1.0 molar, 15.6 moles). The biphasic mixture was stirred for 10 minutes after which, the layers were allowed to separate. The pH of the aqueous layer measured 12-13. The lower methylene chloride layer was removed and set aside. The upper aqueous layer was then reextracted with methylene chloride (2×2.0L). The methylene chloride extracts were combined and concentrated under vacuum at ≤25° C. to a volume of 6.0L. The batch was then washed with aqueous sodium hydroxide (2×4.0L, 0.3 molar, 2.4 moles). The aqueous wash layers were combined and subsequently extracted with methylene chloride (2L). The methylene chloride extracts were then combined, dried over sodium sulfate (500 g), filtered, and concentrated under vacuum at ≤25° C. to about 1.5L (cf.50% soln K.F.≤0.06%). The batch was stored cold (0°-5° C.) under nitrogen. The concentrated product must be kept at 0°-5° C. to avoid exothermic decomposition.
Reaction SMILES: [OH-].[K+].CC1C=C(C=CC=1)C([O:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=2)=[O:18])[CH2:13][CH2:12]1)=O>C(O)C.O>[CH3:25][C:21]1[CH:20]=[C:19]([C:17]([N:14]2[CH2:13][CH2:12][CH:11]([CH2:10][OH:9])[CH2:16][CH2:15]2)=[O:18])[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cccc(C(=O)OCC2CCN(C(=O)c3cccc(C)c3)CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C(=O)N2CCC(CO)CC2)c1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A solution of 12.76 g (0.23 mol) of potassium hydroxide in 75 ml of ethanol and 75 ml of water is added to a solution of 80 g (0.23 mol) of {1-[(3-methylphenyl)carbonyl]-4-piperidyl}methyl 3-methylbenzoate in 400 ml of ethanol. The mixture is stirred at 20° C. for 3 h, the ethanol is evaporated off under reduced pressure and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water and then with saturated aqueous sodium chloride solution and dried over magnesium sulphate. The solvent is evaporated off under reduced pressure, and 53 g of alcohol are obtained, this alcohol being used without further treatment in the next stage.
Reaction SMILES: O[CH2:2][C:3]([NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([NH:17][C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])=O)=[C:11]([O:23][CH3:24])[C:10]=1[O:25][CH3:26])=[O:8])([CH3:5])[CH3:4].S(Cl)(Cl)=O>CCOCC>[CH3:26][O:25][C:10]1[C:11]([O:23][CH3:24])=[C:12]([C:15]2[O:20][CH2:19][C:18]([CH3:21])([CH3:22])[N:17]=2)[CH:13]=[CH:14][C:9]=1[C:7]1[O:8][CH2:5][C:3]([CH3:2])([CH3:4])[N:6]=1
Reactant: COc1c(C(=O)NC(C)(C)CO)ccc(C(=O)NC(C)(C)CO)c1OC
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: COc1c(C2=NC(C)(C)CO2)ccc(C2=NC(C)(C)CO2)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.5 %

Procedure:
To 6.00 g (16.3-mmol) of N,N'-bis(2-hydroxy-1,1-dimethylethyl)-2,3-dimethoxy-1,4-phenylenedicarboxamide, was added 7.0 mL (96.0 mmol) of thionyl chloride. The mixture was stirred at room temperature for 3 hours. Further thereto, 7.0 mL (96.0 mmol) of thionyl chloride was added, and the mixture was stirred at room temperature for one hour. The reaction solution was poured into 50 mL of ether. The supernatant liquid was removed by decantation. Aqueous 10% sodium hydroxide solution was added to the residue to bring the pH to 8. It was extracted with ether, and was dried over anhydrous sodium sulfate. The solvent was removed by distillation, and the residue was purified by silca gel column chromatography (methylene chloride:ethanol=20:1) to obtain 2.52 g (47%) of 2,2'-(2,3-dimethoxy-1,4-phenylene)-bis (4,4-dimethyl-2-oxazoline) in a colorless crystal state.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:9]=[C:10]([CH2:16][CH3:17])[C:11](=[O:15])[NH:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[CH2:16]([C:10]1[C:11](=[O:15])[NH:12][C:13]([CH3:14])=[C:8]([C:6]2[O:7][C:3]([CH2:2][NH:1][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)=[CH:4][CH:5]=2)[CH:9]=1)[CH3:17]
Reactant: CCc1cc(-c2ccc(CN)o2)c(C)[nH]c1=O
Reactant: COc1ccc(C(=O)Cl)cc1
Product: CCc1cc(-c2ccc(CNC(=O)c3ccc(OC)cc3)o2)c(C)[nH]c1=O

Procedure:
Example 269 is substantially repeated except for utilizing 5-(5-aminomethylfuran-2-yl)-3-ethyl-6-methyl-1H-pyridin-2-one and 4-methoxybenzoyl chloride to afford the title compound. MS: m/e=367 (M+H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH2:9][C:8]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:7]=2[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][N:4]=1.[CH3:21]N>C(O)C>[Cl:14][C:12]1[CH:11]=[CH:10][C:8]2[CH2:9][C:3]([NH:2][CH3:21])=[N:4][CH:5]=[C:6]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:7]=2[CH:13]=1
Reactant: NC1=NC=C(c2ccccc2)c2cc(Cl)ccc2C1
Reactant: CN
Agent: Cl
Solvent: CCO
Product: CNC1=NC=C(c2ccccc2)c2cc(Cl)ccc2C1

Procedure:
2-Amino-7-chloro-5-phenyl-1H-3-benzazepine hydrochloride (8 g; 0.027 mole) [see Example (e)] in 33% w/w methylamine in ethanol (100 ml) was maintained at 40° for 3 days. The solution was then evaporated to dryness and the residual amine was azeotropically removed with toluene. The residue was treated with dry acetone, acidified with a few drops of ethanolic hydrogen chloride, filtered, and washed with acetone to give the title compound as the hydrochloride. Crystallisation of this hydrochloride from absolute ethanol gave a fine white granular powder; m.p. 318°-320°.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[CH3:13][N:14]([CH3:19])[S:15](Cl)(=[O:17])=[O:16]>C1C=CC=CC=1>[CH3:13][N:14]([CH3:19])[S:15]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:17])=[O:16]
Reactant: c1c[nH]cn1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN(C)S(=O)(=O)n1ccnc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Imidazole (1) (20.0 g, 0.29 mol), triethylamine (41.0 mL, 0.29 mol) and N,N-dimethylsulfamoyl chloride (31.6 mL, 0.29 mol) were added to 320 mL of benzene. The reaction was stirred for 48 h at room temperature (rt) and then filtered. The filtrate was collected and concentrated under reduced pressure. Vacuum distillation of the crude product (˜0.5 mmHg, 115°-118° C.) afforded 38.7 g (76%) of a clear and colorless oil. Upon cooling the product solidifies to give white crystals (2). 1-(Dimethylsulfamoyl) imidazole (2) (18.8 g, 0.11 mol) was added to 430 mL of tetrahydrofuran (THF). The solution was cooled to −78° C. A solution of n-butyl lithium (n-BuLi) in hexane (1.6M, 70.9 mL, 0.11 mol) was added dropwise to the reaction flask. Upon completion, the reaction was stirred for 1 h at −78° C. t-Butyldimethylsilylchloride (17.8 g, 0.12 mol) in 50 mL of THF was added via cannula to the reaction. After the addition was completed the reaction mixture was warmed slowly to rt and then stirred for 24 h. The reaction was diluted with water and the organic layer separated. The organic phase was washed with brine and then dried over sodium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure. Column chromatography (20% ethyl acetate/hexane as eluant) afforded a light yellow solid. Recrystallization from pentane gave 30 g (94%) of white crystals (3). 1-Dimethylsulfamoyl-2-t-butyldimethylsilyl imidazole (3) (5.0 g, 17.3 mmol) was added to 100 mL of THF. The solution was cooled to −20° C. A solution of secondary butyl lithium (s-BuLi) in hexane (1.3M, 14.6 mL, 19 mmol) was added dropwise to the reaction flask. Upon completion the reaction was stirred for 1 h at −20° C. 8 mL of dimethylformamide (DMF) was added to the reaction and then stirred at rt for 3.5 h. The reaction was diluted with water and the organic layer separated. The organic phase was washed with brine and then dried over sodium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure. Column chromatography (20% ethyl acetate/hexane) afforded a light yellow oil. Upon cooling the product solidifies to give yellow crystals of 1-dimethylsulfamoyl-2-t-butyldimethylsilyl -5-imidazolecarboxaldehyde (4).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:14][N:13]([CH2:15][C:16]([F:19])([F:18])[F:17])[C:12]2[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:11]=2[NH:10][C:9]1=[O:25])(C)(C)C.[ClH:27]>O1CCOCC1>[ClH:27].[NH2:7][C@@H:8]1[C:9](=[O:25])[NH:10][C:11]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:12]=2[N:13]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(CC(F)(F)F)c2ccc(F)cc2NC1=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CN(CC(F)(F)F)c2ccc(F)cc2NC1=O

Procedure:
In an analogous procedure to that described in Example 1d), the treatment of the [(S)-7-fluoro-4-oxo-1-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-carbamic acid tert-butyl ester with hydrochlorid acid (37%) in dioxane yielded the title compound as a light brown foam; MS (m/e): 278 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[C:17]([CH2:19][OH:20])[N:18]=2)=[CH:10][CH:9]=1.[OH:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:40]3[C:39](=[O:41])[NH:38][CH:37]=[CH:36][C:35]=3[N:34]=[C:33](SC)[C:32]=2[C:44]#[N:45])=[CH:27][CH:26]=1.O>CN(C=O)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[S:15][CH:16]=[C:17]([CH2:19][O:20][C:33]3[C:32]([C:44]#[N:45])=[C:31]([C:28]4[CH:29]=[CH:30][C:25]([O:24][CH2:23][CH2:22][OH:21])=[CH:26][CH:27]=4)[C:40]4[C:39](=[O:41])[NH:38][CH:37]=[CH:36][C:35]=4[N:34]=3)[N:18]=2)=[CH:12][CH:13]=1
Reactant: OCc1csc(-c2ccc(Cl)cc2)n1
Reactant: CSc1nc2cc[nH]c(=O)c2c(-c2ccc(OCCO)cc2)c1C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(OCc2csc(-c3ccc(Cl)cc3)n2)nc2cc[nH]c(=O)c2c1-c1ccc(OCCO)cc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
64 mg (0.57 mmol) of potassium tert-butoxide were suspended in 3.5 ml of DMF, 96 mg (0.42 mmol) of [2-(4-chlorophenyl)-1,3-thiazol-4-yl]methanol [Simiti, I. et al. Arch. Pharm. 1972, 305, 509-515] and then 100 mg (0.28 mmol) of the compound from Example 21A were added and the mixture was stirred at 60° C. for 16 h. Another 64 mg (0.57 mmol) of potassium tert-butoxide were added, and the reaction was stirred once more at 80° C. overnight. Water was added, and the reaction solution was extracted 3 times with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered off and concentrated on a rotary evaporator, The crude product was and purified by preparative HPLC (Chromasil, water/acetonitrile).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:24])[CH:6]=1)[CH3:2].Br[C:27]1[CH:28]=[N:29][N:30]([CH:32]([CH3:34])[CH3:33])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:27]3[CH:28]=[N:29][N:30]([CH:32]([CH3:34])[CH3:33])[CH:31]=3)[C:14]=2[CH3:24])[CH:6]=1)[CH3:2]
Reactant: CC(C)n1cc(Br)cn1
Reactant: CCOC(=O)c1cc(F)cc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1
Product: CCOC(=O)c1cc(F)cc(Sc2c(C)n(-c3cnn(C(C)C)c3)c3c(F)c(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-Chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-5-fluoro-benzoic acid ethyl ester and 4-bromo-1-isopropyl-1H-pyrazole.