Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](F)=[O:26])[CH:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1.[CH3:32][N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1.CN1CCOCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([NH:39][CH:36]4[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]4)=[O:26])[CH:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1
Reactant: CN1CCC(N)CC1
Reactant: C=C(C)C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C=C(C)C1N(CC(=O)NC2CCN(C)CC2)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 31.2 %

Procedure:
In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.2 g, 0.433 mmol) prepared in example 116d was reacted with 1-methyl-piperidin-4-ylamine (0.134 mg, 0.95 mmol), N-methylmorpholine (99 mg, 0.95 mmol) and 4-dimethylaminopyridine (5 mg) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-1′-[(1-methyl-piperidin-4-yl)aminocarbonyl-methyl]spiro[3H-indole-3,3′ piperidine]-2,6′(1H)-dione as an off-white solid (Yield: 75 mg, 31.2%).
Reaction SMILES: [CH3:1][C:2]([NH2:12])([CH3:11])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:13]1[O:15][CH:14]1[CH2:16][OH:17]>CC(O)C>[CH3:11][C:2]([NH:12][CH2:13][CH:14]([OH:15])[CH2:16][OH:17])([CH3:1])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(N)CCc1ccccc1
Reactant: OCC1CO1
Solvent: CC(C)O
Product: CC(C)(CCc1ccccc1)NCC(O)CO
Temperature: 75 °C

Procedure:
To 1,1-dimethyl-3-phenylpropylamine (3.6 g., 22 mmole) in 20 ml. 2-propanol at 50° C. in an oil bath was added glycidol (1.7 g., 23 mmole) in 10 ml. 2-propanol dropwise over 5-10 min. The mixture was heated at 75° C. for 2 hours. After evaporation of the solvent, vacuum distillation provided 3.9 g. (75%) of 3-(1,1-dimethyl-3-phenylpropylamino)-1,2-dihydroxypropane (bp 160°-180°/0.5 mm which crystallized upon standing (mp 74°-77° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][NH:19][CH:20]=3)[S:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][OH:31]>CN(C=O)C>[CH3:1][C:2]1([CH3:21])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:29][CH2:30][OH:31])[CH:20]=3)[S:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1
Reactant: CC1(C)CCCN(C(=O)c2csc(-c3cn[nH]c3)c2)CC1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)CCCN(C(=O)c2csc(-c3cnn(CCO)c3)c2)CC1
Temperature: 100 °C
Yield: 23 %

Procedure:
(4,4-Dimethyl-azepan-1-yl)-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanone (0.075 g, 0.25 mmol) was dissolved in DMF (1 mL) and potassium carbonate (44 mg, 0.32 mmol) was added followed by 2-bromoethanol (27 μL, 0.38 mmol). The reaction mixture was heated at 100° C. overnight then quenched by addition of ammonium chloride. The mixture was extracted with ethyl acetate (×2) then the organics were washed with lithium chloride (15% aqueous solution) and evaporated. The crude material was purified by chromatography on a silica II cartridge, eluting with 10-66% ethyl acetate in cyclohexane. The residue was purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid) over 20 minutes. The fractions containing the desired product were concentrated under vacuum and freeze-dried to give the title compound as a colourless oil (0.020 g). LCMS m/z 348.29 [M+H]+ R.T.=8.62 min (Analytical Method 2).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1>>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:12][CH:13]=1
Reactant: COc1ccc(I)cc1
Reactant: c1ccc2[nH]ccc2c1
Product: COc1ccc(-n2ccc3ccccc32)cc1

Procedure:
Prepared by Procedure C and Scheme O using 1H-indole and 1-iodo-4-methoxybenzene: ESMS m/e: 224.0 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([Br:9])[N:3]=1.[C:10]([N:13]=[C:14]=[S:15])(=[O:12])[CH3:11].O>CC(C)=O>[Br:9][C:4]1[N:3]=[C:2]2[S:15][C:14]([NH:13][C:10](=[O:12])[CH3:11])=[N:8][C:7]2=[CH:6][CH:5]=1
Reactant: Nc1ccc(Br)nc1Br
Reactant: CC(=O)N=C=S
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)Nc1nc2ccc(Br)nc2s1
Temperature: 67.5 °C
Reaction time: 2.5 h
Yield: 121.2 %

Procedure:
2,6-dibromopyridin-3-amine (4.235 g, 16.8 mmol) was dissolved in acetone and acetyl isothiocyanate (1.85 ml, 21.0 mmol) was added. The flask was fit with a reflux condensor and placed in a preheated oil bath (65-70° C.) and stirred under nitrogen for 2.5 hours. Then, the reaction was cooled to room temperature, poured into water, and filtered. The solid was washed with water, saturated sodium bicarbonate, and water again, and then collected and dried under high vacuum to afford N-(5-bromothiazolo[5,4-b]pyridin-2-yl)acetamide (5.54 g, Yield >100%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:21]3[S:22][C:23]([CH2:25][CH3:26])=[CH:24][C:20]=3[C:19](=[O:27])[N:18]([CH:28]([CH3:33])[C:29](OC)=[O:30])[C:17]2=[O:34])=[CH:11][CH:10]=1)#[N:2].CN1CCOCC1.C(Cl)(=O)OCC.[BH4-].[Na+]>CO.O1CCCC1>[CH2:25]([C:23]1[S:22][C:21]2[N:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)[C:17](=[O:34])[N:18]([CH:28]([CH3:33])[CH2:29][OH:30])[C:19](=[O:27])[C:20]=2[CH:24]=1)[CH3:26]
Reactant: CCc1cc2c(=O)n(C(C)C(=O)OC)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc2c(=O)n(C(C)CO)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: -15 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
To a mixture of methyl 2-[1-[(2′-cyanobiphenyl-4-yl)methyl]-6-ethyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl]propanoate (3 g), N-methylmorpholine (0.86 mL) and tetrahydrofuran (50 mL) was added ethyl chlorocarbonate (0.75 mL) at 0° C., and the mixture was stirred at the same temperature for 2 hr. The reaction mixture was cooled to −15° C., sodium borohydride (0.74 g) and methanol (12 mL) were added, and the mixture was allowed to gradually warm to room temperature. The reaction mixture was extracted with saturated aqueous ammonium chloride solution and ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (2 g, 69%).
Reaction SMILES: C([O-])=O.[NH4+].[NH2:5][CH2:6][CH:7]([N:20](CC1C=CC=CC=1)[C@@H](C1C=CC=CC=1)C)[CH2:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([F:19])=[CH:14][CH:15]=2)[CH2:10]1>CO.[Pd]>[F:19][C:13]1[CH:12]=[C:11]2[C:16]([CH2:17][CH2:18][CH:9]([CH2:8][CH:7]([NH2:20])[CH2:6][NH2:5])[CH2:10]2)=[CH:15][CH:14]=1
Reactant: C[C@H](c1ccccc1)N(Cc1ccccc1)C(CN)CC1CCc2ccc(F)cc2C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: NCC(N)CC1CCc2ccc(F)cc2C1
Reaction time: 1 h

Procedure:
0.45 g of ammonium formate is added to a vigorously stirred suspension of 0.35 g (0.84 mmol) of the compound obtained in Step 4 and 0.25 g of Pd/C 10% in 25 ml of CH3OH. After stirring for 1 hour under reflux, the mixture is cooled and filtered; the catalyst is washed with CH3OH and the combined filtrates are concentrated in vacuo to yield the title compound in the form of an oil, which is used without purification in the following reaction.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:21]=[CH:20][C:8]([C:9]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)=[O:10])=[CH:7][CH:6]=1.[Cl:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.Cl>CCCCCC.CN(C=O)C.COC(C)(C)C.C(=O)(O)[O-].[Na+].C(OCC)(=O)C.O>[ClH:22].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][N:15]3[CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:10])=[CH:20][CH:21]=1
Reactant: ClCCN1CCOCC1
Reactant: COc1ccc(C(=O)c2cccc3[nH]ccc23)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CCCCCC
Solvent: O
Solvent: COC(C)(C)C
Product: COc1ccc(C(=O)c2cccc3c2ccn3CCN2CCOCC2)cc1
Yield: 70.2 %

Procedure:
To a stirred mixture of 3.5 g (0.0887 mole) of a 60% suspension of sodium hydride in hexane in 50 ml of DMF was added 18.1 g (0.0721 mole) of 4-(4-methoxybenzoyl)indole. The mixture was then treated with a solution containing 0.18 mole of 4-(2-chloroethyl)morpholine in t-butyl methyl ether (prepared by extraction of the free base from a suspension of 35.5 g of the corresponding hydrochloride in saturated sodium bicarbonate). When addition was complete, the reaction mixture was heated under reflux for about twelve hours, treated with 1500 ml of water and extracted with 500 ml of ethyl acetate. The combined organic extracts, on drying and evaporation to dryness, afforded an oil which was dissolved in 250 ml of ethyl acetate and treated with 50 ml of ethereal hydrogen chloride. The material which separated was collected and recrystallized from ethanol to give 20.3 g of 4-(4-methoxybenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indole hydrochloride, m.p. 177°-180° C.
Reaction SMILES: N1CCOCC1.C(OC([N:13]1[CH2:19][CH2:18][C:17]2[S:20][C:21]([CH:23]3[CH2:28][CH2:27][N:26]([C:29]([NH:31][C@H:32]4[CH2:37][CH2:36][C@H:35]([C:38]([O:40][CH:41]([O:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH3:42])=[O:39])[CH2:34][CH2:33]4)=[O:30])[CH2:25][CH2:24]3)=[N:22][C:16]=2[CH2:15][CH2:14]1)=O)C=C>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH2:47]([O:46][C:44]([O:43][CH:41]([O:40][C:38]([C@H:35]1[CH2:34][CH2:33][C@H:32]([NH:31][C:29]([N:26]2[CH2:25][CH2:24][CH:23]([C:21]3[S:20][C:17]4[CH2:18][CH2:19][NH:13][CH2:14][CH2:15][C:16]=4[N:22]=3)[CH2:28][CH2:27]2)=[O:30])[CH2:37][CH2:36]1)=[O:39])[CH3:42])=[O:45])[CH3:48]
Reactant: C=CCOC(=O)N1CCc2nc(C3CCN(C(=O)N[C@H]4CC[C@H](C(=O)OC(C)OC(=O)OCC)CC4)CC3)sc2CC1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CCOC(=O)OC(C)OC(=O)[C@H]1CC[C@H](NC(=O)N2CCC(c3nc4c(s3)CCNCC4)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Prepared by dropwise addition of one equivalent of morpholine to 6-allyloxycarbonyl-2-[1-[[trans-4-[[1-(ethoxycarbonyloxy)-ethyl]-oxycarbonyl]-cyclohexyl]aminocarbonyl]-piperid-4-yl]-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepine and 0.1 equivalent of tetrakis-(triphenylphosphine)-palladium(O) in tetrahydrofuran followed by one hours' stirring at ambient temperature. The following compound is obtained analogously to Example 10:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([CH3:31])=[C:25]([NH:27][C:28](=O)[CH3:29])[CH:26]=3)[CH:17]=[C:16]([N:32]([CH3:34])[CH3:33])[N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([CH3:31])=[C:25]([NH:27][CH2:28][CH3:29])[CH:26]=3)[CH:17]=[C:16]([N:32]([CH3:34])[CH3:33])[N:15]=2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1cc(Nc2cc(N(C)C)nc(N3CCN(Cc4ccccc4)CC3)n2)ccc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCNc1cc(Nc2cc(N(C)C)nc(N3CCN(Cc4ccccc4)CC3)n2)ccc1C
Temperature: 90 °C
Yield: 75.7 %

Procedure:
A mixture of N-(5-{[2-(4-benzyl-1-piperazinyl)-6-(dimethylamino)-4-pyrimidinyl]amino}-2-methylphenyl)acetamide (40 mg, 0.08 mmol) and lithium aluminum hydride (76 mg, 2 mmol) in tetrahydrofuran (3 mL) was heated at 90° C. for 12 hours. The crude product was filtered through Celite® and purified by preparative thin-layer chromatography [eluent: EtOAc/hexane (1:1)], giving the desired product (27 mg, 76%).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:8]=1Br.[C:19](=[O:21])=[O:20]>CCOCC>[Cl:6][C:7]1[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:8]=1[C:19]([OH:21])=[O:20]
Reactant: FC(F)(F)Oc1ccc(Br)c(Cl)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(O)c1ccc(OC(F)(F)F)cc1Cl
Temperature: -78 °C
Reaction time: 4 h

Procedure:
n-Butyllithium (2.5M in hexane, 38 ml) was added to a stirred, cooled solution of 2-chloro-4-trifluoromethoxybromobenzene (25 g) in ether while maintaining the temperature below -70° C. The mixture was stirred at -78° C. for 4 hours then poured onto solid carbon dioxide with stirring. The mixture was allowed to warm to room temperature and acidified to pH1. The layers were separated and the organic layer was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was triturated with cyclohexane and filtered to give 2-chloro-4-trifluoromethoxybenzoic acid as a white solid mp 90.6°-91.2° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](B(O)O)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.Br[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C.[OH-].[Na+]>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][CH:9]=[C:8]3[CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:22]=1
Reactant: Brc1cccnc1
Reactant: CN1CCC(c2c[nH]c3ccc(B(O)O)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccc(-c4cccnc4)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
A mixture of 3-(1-methylpiperidin-4-yl)-1H-indole-5-boronic acid (0.200g, 0.78 mmol), 3-bromopyridine (0.117 g, 0.74 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (Pd(dppf)Cl2.CH2Cl2) (0.03 g, 0.37 mmol), and 2M aqueous sodium carbonate solution (2 mL) in 7 mL of tetrahydrofuran was heated at reflux, with stirring, overnight. The mixture was allowed to cool to room temperature, diluted with ethyl acetate and 2N aqueous sodium hydroxide solution, and the organic phase was separated, washed with brine solution, dried over sodium sulfate, concentrated in vacuo and purified by silica gel (flash) chromatography (solvent gradient: 100% dichloromethane—25:2 dichloromethane: methanol/aqueous ammonium hydroxide) to give 0.114 g (53%) of the title compound as an amorphous pink solid. FDMS m/e=291 (M+). EA calculated for C19H21N3: C, 78.32; H, 7.26; N, 14.42. Found: C, 78.39; H, 7.39; N, 14.36.
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[CH:7]1[C:17]2[C:16](=[O:18])[C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[C:13](=[O:23])[NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.C(Br)C#C.C(O)(=O)C>CN(C)C=O.O>[CH2:3]([N:12]1[C:13](=[O:23])[C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16](=[O:18])[C:17]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]1=2)[C:2]#[CH:1]
Reactant: CC(C)(C)[O-]
Reactant: O=c1[nH]c2ccccc2c(=O)c2ccccc12
Agent: C#CCBr
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: C#CCn1c(=O)c2ccccc2c(=O)c2ccccc21
Reaction time: 0.5 h

Procedure:
potassium tert.-butoxide, 2.5 g, was added to a suspension of 4.5 g of 5H-dibenz[b,e]azepine-6,11-dione in 50 ml of dimethylformamide. After stirring under nitrogen for 30 minutes, 2 ml of propargyl bromide was added and stirring was continued for I hour at room temperature. The reaction mixture was acidified with acetic acid and diluted with water. The precipitate was filtered off and sucked dry. The solids were dissolved in methylene chloride. The solution was dried and evaporated and the residue was chromatographed over 120 g of silica gel using methylene chloride. The combined clean fractions containing product were evaporated and the residue was crystallized from ether/hexane to give colorless crystals of 5-(2-propynyl)-5H-dibenz[b,e]azepine-6,11-dione with m.p. 117°-118°.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:13]1([N:19]=[C:20]=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C1C=CC=CC=1>[C:13]1([NH:19][C:20]([NH:1][C:2]2[N:6]([CH3:7])[N:5]=[CH:4][C:3]=2[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCOC(=O)c1cnn(C)c1N
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn(C)c1NC(=O)Nc1ccccc1

Procedure:
To a solution of 5-amino-4-ethoxycarbonyl-1-methylpyrazole (0.845 g) in benzene (50 ml), were added phenyl isocyanate (0.543 ml) and triethylamine (0.70 ml), and the mixture was refluxed in a sealed tube for 3 h. The reaction mixture was evaporated under reduced pressure followed by repeated addition of ether, and the title compound was obtained as crystals (0.36 g, yield 25%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20](=S)[CH2:21][C:22](=O)[CH3:23])=[O:4].[Cl:26][C:27]1[CH:32]=[C:31]([NH:33][NH2:34])[CH:30]=[CH:29][N:28]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20]1[N:33]([C:31]2[CH:30]=[CH:29][N:28]=[C:27]([Cl:26])[CH:32]=2)[N:34]=[C:22]([CH3:23])[CH:21]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=S)CC(C)=O
Reactant: NNc1ccnc(Cl)c1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1-c1ccnc(Cl)c1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 253c) was reacted with (2-chloro-pyridin-4-yl)-hydrazine (CAS Reg. No. 700811-29-6) to give the title compound as colorless solid. MS (ESI): m/z=495.1 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[S:13][C:12]([CH3:18])([CH3:17])[CH2:11][C:10]2=[O:19])(=O)=O.[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24]>CCN(CC)CC.CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:17][C:12]1([CH3:18])[CH2:11][C:10](=[O:19])[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])[CH:8]=2)[S:13]1
Reactant: CC1(C)CC(=O)c2cc(OS(=O)(=O)C(F)(F)F)ccc2S1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)CC(=O)c2cc(C#C[Si](C)(C)C)ccc2S1
Temperature: 95 °C
Yield: 90.9 %

Procedure:
A solution of 2,2-dimethyl-4-oxo-thiochroman-6-yl trifluoromethanesulfonate (2.88 g, 8.50 mmol) in 10 mL Et3N and 20.0 mL DMF was purged with argon for 10 minutes. To this solution was added trimethylsilylacetylene (4.15 g, 42.0 mmol) and bis(triphenylphosphine)-palladium (II) chloride (298.0 mg, 0.425 mmol). The solution was heated to 95° C. for 5 hours, cooled to room temperature, and diluted with H2O. Extraction with EtOAc was followed by washing the combined organic layers with H2O and saturated aqueous NaCl and drying over MgSO4. Concentration of the dry solution under reduced pressure and isolation of the product by column chromatography (3% EtOAc/hexanes) afforded 2.23 g (91%) of the 2,2-dimethyl-6-trimethylsilanylethynyl-thioc-hroman-4-one as an orange oil. 1H NMR (300 MHz, CDCl3) δ: 8.18 (1H, d, J=1.9 Hz), 7.34 (1H, dd, J=1.9, 8.1 Hz), 7.15 (1H, d, J=8.1 Hz), 2.85 (2H, s), 1.45 (6H, s), 0.23 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:11])=[C:4]([NH2:10])[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].[CH:12]([N:15]=[C:16]=S)([CH3:14])[CH3:13].C1(N=C=NCCN2CCOCC2)CCCCC1.CC1C=CC(S(O)(=O)=O)=CC=1>N1C=CC=CC=1>[CH:12]([NH:15][C:16]1[NH:10][C:4]2[CH:5]=[C:6]([Cl:9])[C:7]([Cl:8])=[C:2]([Cl:1])[C:3]=2[N:11]=1)([CH3:14])[CH3:13]
Reactant: CC(C)N=C=S
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1N
Agent: C(=NCCN1CCOCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Product: CC(C)Nc1nc2c(Cl)c(Cl)c(Cl)cc2[nH]1
Yield: 70.3 %

Procedure:
3,4,5-Trichloro-1,2-phenylenediamine (3.12 g, 14.8 mmol), isopropyl isothiocyanate (1.62 g, 16.0 mmol), cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (8.4 g, 19.9 mmol), and pyridine (50 mL) were used according to general procedure II. The product was crystallize from 1,4-dioxane to give 2.9 g (72%) of a tan solid MS (CI): m/z 276 (M+1). Anal. Calcd for C10H10Cl3N3-(0.10 C4H8O2): C, 43.47; H, 3.79; N, 14.62. Found: C, 43.70; H, 3.89; N, 14.43.
Reaction SMILES: [N:1]1([S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16](O)=[O:17])(=[O:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:33]=[CH:32][C:27]2[N:28]=[C:29]([NH2:31])[S:30][C:26]=2[CH:25]=1>>[N:1]1([S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([NH:31][C:29]2[S:30][C:26]3[CH:25]=[C:24]([O:23][CH3:22])[CH:33]=[CH:32][C:27]=3[N:28]=2)=[O:17])(=[O:11])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCc3ccccc32)c1
Reactant: COc1ccc2nc(N)sc2c1
Product: COc1ccc2nc(NC(=O)c3cccc(S(=O)(=O)N4CCc5ccccc54)c3)sc2c1

Procedure:
3-(indolin-1-ylsulfonyl)benzoic acid (3) (100 mg, 0.33 mmol) was treated with 6-methoxybenzo[d]thiazol-2-amine (46 mg, 0.25 mmol) using method C. The residue was purified using flash chromatography eluting with 0-30% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give 3-(indolin-1-ylsulfonyl)-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide as a white solid. Yield: 30 mg (25%). 1H-NMR: 8.58 (s, 1H), 8.37 (d, J=8.0 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.77-7.59 (m, 3H), 7.53 (d, J=8.0 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H), 7.08 (dd, J=9.0, 2.5 Hz, 1H), 6.99 (dt, J=7.5, 7.5, 1.0 Hz, 1H), 4.02 (t, J=8.0 Hz, 2H), 2.93 (t, J=8.0 Hz, 2H).
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:17]1([CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:23][C:17]1[CH:22]=[CH:21][C:20]([C:1]([C:2]2[CH:10]=[CH:9][C:5]([C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=3)=[CH:4][CH:3]=2)=[O:11])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C(=O)c2ccc(C(=O)c3ccc(C)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 40 g of terephthaloyl chloride and 200 ml of toluene was added in portions 56 g of solid aluminium chloride at such a rate to maintain the reaction temperature at 45°-55°. The thick orange slurry was then heated to 75° for 2 hours, cooled in ice and slowly treated with 200 ml of dilute HCL. The slurry was stirred for 2 hours at room temperature. The solid was collected by filtration, washed with 200 ml of petroleum ether and 2 L of hot water, and dried to constant weight to give 51 g of colorless product, m.p. 178°-187°. This material was used without further purification.