Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:11](=[O:44])[NH:12][C@H:13]([CH2:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)[C:14]([N:16]1[CH2:33][CH2:32][CH2:31][C:18]2([C:22](=[O:23])[N:21]([CH3:24])[CH2:20][CH:19]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:17]1)=[O:15])([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]([CH3:10])([CH3:9])[C:11]([NH:12][C@H:13]([CH2:34][O:35][CH2:36][C:37]1[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=1)[C:14]([N:16]1[CH2:33][CH2:32][CH2:31][C:18]2([C:22](=[O:23])[N:21]([CH3:24])[CH2:20][CH:19]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:17]1)=[O:15])=[O:44]
Reactant: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccc(F)cc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccc(F)cc3)NC(=O)C(C)(C)N)C2)C1=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of {1-[(R)-1-(4-Fluoro-benzyloxymethyl)-2-(2-methyl-1-oxo-4-phenyl-2,7-diaza-spiro[4.5]dec-7-yl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamic acid tert-butyl ester (Intermediate from step 3) (154 mg, 0.24 mmol) in DCM (2.5 ml) was cooled with an ice bath and TFA (0.57 ml, 7.4 mmol) was added. The resulting solution was stirred for 3 h at 0° C. The reaction mixture was diluted with DCM (20 ml) and quenched at 0° C. with 2M NaOH aqueous solution (10 ml). The organic phase was separated, washed with brine (5 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 0-2.5% MeOH in DCM to afford the title compound.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12][CH2:13]2)=[C:9]([S:16](Cl)(=[O:18])=[O:17])[C:8]=1[OH:20])=[O:4].[NH3:21]>CC(C)=O.O>[Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12][CH2:13]2)=[C:9]([S:16](=[O:18])(=[O:17])[NH2:21])[C:8]=1[OH:20])=[O:4]
Reactant: O=C(CCl)NCc1cc2c(c(S(=O)(=O)Cl)c1O)CCC2
Reactant: N
Solvent: CC(C)=O
Solvent: O
Product: NS(=O)(=O)c1c(O)c(CNC(=O)CCl)cc2c1CCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
33.8 g (0.1 mole) of 6-(N-chloroacetylaminomethyl)-5-hydroxy-4-chlorosulfonylindane are dissolved in a little acetone, and the solution is added dropwise to 50 ml of concentrated ammonia solution. The mixture is stirred for 30 minutes at room temperature and is diluted with water. The precipitate which is deposited is filtered off with suction and dissolved in acetone, and the solution is filtered and stirred into water again.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:3]=1[C:4]#[N:5]>C(O)C.[Pd]>[NH2:10][C:7]1[CH:8]=[CH:9][C:2]([Cl:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [Pd]
Solvent: CCO
Product: N#Cc1cc(N)ccc1Cl
Yield: 43.1 %

Procedure:
A solution of 10.0 g (54.8 mmol) 2-chloro-5-nitrobenzonitril in 500 ml ethanol was hydrogenated at 40 psi by using 0.5 g 5% Pd-C as a catalyst. The catalyst was filtered off and the filtrate was evaporated in vacuo. Recrystallization (ethanol-water) gave 3.6 g (43%) 5-amino-2-chlorobenzonitril. M.p. 129-130° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].C1(C2[NH:24][CH2:23][CH:22]([CH2:25][Cl:26])[O:21]2)C=CC=CC=1.Cl>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([NH:24][CH2:23][CH:22]([OH:21])[CH2:25][Cl:26])=[O:7]
Reactant: ClCC1CNC(c2ccccc2)O1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)NCC(O)CCl)cc1OC
Temperature: 25 °C
Yield: 72.3 %

Procedure:
At a temperature of -40° C., a solution of 15.2 g 3,4-dimethoxybenzoyl chloride in 40 ml of chloroform is added dropwise to a solution of 15.0 g of 2-phenyl-5-chloromethyloxazolidine in a mixture of 200 ml of chloroform and 6 ml of pyridine. The mixture is heated to room temperature. After a reaction period of 14 hours, 20 ml of concentrated hydrochloric acid are added, the phases are thoroughly mixed for 10 minutes, and then separated. The separated aqueous phase is diluted with water to twice its volume and is saturated with sodium chloride. Then it is extracted with chloroform. After drying the chloroform extract and evaporating the solvent, 15.0 g of N-(3,4-dimethoxybenzoyl)-3-chloro-1-aminopropan-2-ol is obtained as an oil which can be used in the following reaction without any prior purification. After crystallization from ethanol/toluene, the compound melts at 104°-106° C.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:11]1[C:12]([NH2:18])=[N:13][CH:14]=[C:15]([Br:17])[N:16]=1.C(OCC)(=O)C>C1COCC1>[Br:17][C:15]1[N:16]=[C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]([NH2:18])=[N:13][CH:14]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ncc(Br)nc1Oc1ccccc1
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
Added sodium hydride (0.348 g, 8.70 mmol) to a solution of phenol (0.819 g, 8.70 mmol) in THF (50 mL) at 0° C. and stirred 30 minutes. Added 3,5-dibromopyrazin-2-amine (2.00 g, 7.91 mmol) in THF (10 mL). Removed the ice bath and refluxed overnight. Partitioned between ethyl acetate and water, washed with brine, dried, and concentrated. Purified by MPLC (Biotage) eluting with 5:1 hexane:ethyl acetate to afford the title compound (1.36 g, 64.6% yield) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([CH2:13][OH:14])=[CH:8][C:7]=1[F:15].[H-].[Na+].Cl[C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[CH2:31][CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[C:7]([F:15])=[CH:8][C:9]([CH2:13][O:14][C:23]2[CH:24]=[C:25]3[N:32]([CH3:33])[CH2:31][CH2:30][N:26]3[C:27](=[O:29])[N:28]=2)=[CH:10][C:11]=1[F:12]
Reactant: OCc1cc(F)c(Oc2ccc(F)c(F)c2)c(F)c1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1cc(F)c(Oc3ccc(F)c(F)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using (4-(3,4-difluorophenoxy)-3,5-difluorophenyl)methanol (0.073 g, 0.269 mmol) in THF)(4 mL), sodium hydride (0.016 g, 0.404 mmol) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (0.050 g, 0.269 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:19][S:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)/[CH:10]=[CH:11]/[C:12]([O:14]C(C)(C)C)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]>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.[Cl-].[Rh].C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:19][S:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)/C=C/[C@H](CSc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H](CCC(=O)O)CSc1ccccc1
Reaction time: 24 h

Procedure:
A mixture of Example 480A (5 g, 13.2 mmol) and Wilkinson's catalyst (1 g) in toluene (125 mL) was stirred under H2 at 60° C. for 18 hours, cooled, filtered through silica gel, and concentrated. The concentrate was dissolved in 3:1:1 THF/water/MeOH (150 mL), treated with a 10-fold excess of LiOH, and stirred for 24 hrs. The mixture was poured into saturated NaH2PO4 (200 mL) and extracted three times with ethyl acetate (200 mL). The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated to provide the desired product. MS (ESI) m/e 324, 326 (M−H)−, (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:19]=[CH:18][C:12]2[N:13]=[CH:14][N:15]=[C:16](O)[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>CN(C=O)C>[CH2:1]([O:8][C:9]1[N:19]=[CH:18][C:12]2[N:13]=[CH:14][N:15]=[C:16]([Cl:22])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Oc1ncnc2cnc(OCc3ccccc3)cc12
Solvent: CN(C)C=O
Product: Clc1ncnc2cnc(OCc3ccccc3)cc12
Reaction time: 5.5 h

Procedure:
6-Benzyloxy-4-hydroxy-pyrido[3,4-d]pyrimidine (1.033 g, 4.1 mmol) was suspended in thionyl chloride (10 ml) under a nitogen atmosphere. DMF (3 drops) was added and the mixture was heated to reflux with stirring for 5.5 hours to give a dark solution, and then left to stand under nitrogen overnight. The mixture was concentrated in vacuo, azeotroping twice with toluene to remove all traces of thionyl cloride and acidic by-products. The material was further dried for two hours in vacuo to give the title compound as a brown solid, used without further purification; δH [2H6]DMSO 8.77(1H,s), 8.13(1H,s), 7.30-7.52 (6H,m), 5.45 (2H,s).
Reaction SMILES: [CH3:1][S:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]=1[C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1.OS([O-])=O.[Na+]>ClCCl>[CH3:1][S:2]([C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:4]=1[C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)=[O:32]
Reactant: CSc1onc(-c2ccccc2)c1-c1ccc(S(N)(=O)=O)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1onc(-c2ccccc2)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 36.3 %

Procedure:
To a chilled solution (-78° C.) of 4-[5-methylthio-3-phenylisoxazol-4-yl]benzenesulfonamide (Example 58) (0.256 g, 0.814 mmol) in dichloromethane (8 mL) was added MCPBA (0.234 g of 60% reagent, 0.814 mmol). After 1 hour, the reaction was warmed to 0° C. and held there for an additional hour. Dichloromethane (30 mL) and a solution of NaHSO3 were added and mixed for 5 minutes. The resulting mixture was extracted with ethyl acetate (20 mL) and the layers separated. The organic phase was washed with NaHSO3 solution and with NaHCO3 solution, dried over MgSO4, filtered and concentrated in vacuo yielding 4-[5-methylsulfinyl-3-phenylisoxazol-4-yl]benzenesulfonamide (0.107 g, 36%) as a pale yellow powder: mp 194°-204° C. 1H NMR (CDCl3 with DMSO6 /300 MHz) 7.98 (d, 2H, 8.46 Hz), 7.53-7.37 (m, 7H), 6.39 (s, 2H), 3.18 (s, 3H). FABLRMS m/z 363 (M+H). FABHRMS m/z 363.0480 (M+H, C16H15N2O4S2 requires 363.0473). Anal. Calc'd for C16H14N2O4S2 : C, 53.03; H, 3.89; N, 7.73. Found: C, 53.24; H, 3.96; N, 7.50.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:4].[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(#N)C>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([NH:5][C:3](=[O:4])[CH2:2][N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:7][NH:8]2)=[CH:13][CH:12]=1
Reactant: C1CNCCN1
Reactant: O=C(CCl)Nc1n[nH]c2cc(Cl)ccc12
Solvent: CC#N
Product: O=C(CN1CCNCC1)Nc1n[nH]c2cc(Cl)ccc12
Yield: 63.1 %

Procedure:
The process is performed as in Example 75, starting with 500 mg of 2-chloro-N-(6-chloro-1H-indazol-3-yl)acetamide, 15 cm3 of acetonitrile and 528 mg of piperazine. The reaction medium is refluxed for 1 hour and then concentrated to dryness under reduced pressure (2 kPa; 50° C.); the crude product is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a methylene chloride/methanol/aqueous ammonia mixture (90/10/1 by volume). The fractions containing the expected product are combined, concentrated under reduced pressure and then dried (90 Pa; 45° C.) to give 380 mg of N-(6-chloro-1H-indazol-3-yl)-1-piperazineacetamide in the form of a white foam.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH:2]=O.[C:13]([NH:16][CH2:17][CH2:18][NH2:19])(=[O:15])[CH3:14]>O1CCCC1>[C:13]([NH:16][CH2:17][CH2:18][NH:19][CH2:2][C:1]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4])(=[O:15])[CH3:14]
Reactant: O=CC(=O)OCc1ccccc1
Reactant: CC(=O)NCCN
Solvent: C1CCOC1
Product: CC(=O)NCCNCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
Benzyl glyoxylate (3.28 g, 20.0 mmol) in dry tetrahydrofuran (15 ml) was added dropwise in monoacetylethylenediamine (1.53 g, 15 mmol) in dry tetrahydrofuran (60 ml) at room temperature. After 2 hours, the tetrahydrofuran was removed under vacuum, and the residue was dissolved in dry methanol (100 ml). Upon cooling to 0° C., 1.55 g of sodium cyanoborohydride was added, immediately followed by dropwise addition of 1.54 ml of acetic acid. The reaction was allowed to warm to room temperature and stirred for 40 minutes. The volatiles were removed under vacuum, and the residue was extracted from aqueous sodium bicarbonate with ethyl acetate. The combined organic layers were dried with sodium sulfate, and the volatiles were removed. The residue was purified by column chromatography on silica (LPS-1) (loading with 2% methanol/dichloromethane and eluting with 5% methanol/dichloromethane to yield 1.46 g of the title compound.
Reaction SMILES: B.CSC.[C:5]([O:9][C:10]([NH:12][C@@:13]1([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:18]([CH2:19][S:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=2)[C:17](=[O:29])[C@@H:16]2[C@H:14]1[C@H:15]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:11])([CH3:8])([CH3:7])[CH3:6]>C(OCC)C>[C:5]([O:9][C:10]([NH:12][C@@:13]1([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:18]([CH2:19][S:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=2)[C@@H:17]([OH:29])[C@@H:16]2[C@H:14]1[C@H:15]2[C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2C(=O)[C@H]1CSc1ccc(F)c(F)c1
Agent: B
Solvent: CSC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@H](O)[C@H]1CSc1ccc(F)c(F)c1
Temperature: 25 °C
Yield: 60.7 %

Procedure:
Di-tert-butyl (1S,2R,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-methylidene-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylate (1.03 g, 2.43 mmol) in diethyl ether (100 mL) is bubbled with nitrogen gas for 10 minutes. Add 3,4-difluorobenzenethiol (0.36 g, 2.43 mmol) and triethylamine (0.01 mL, 0.05 μmol). The mixture is warmed to 40° C. and stirred for 15 minutes. The mixture is then allowed to cool to ambient temperature, transferred to a separatory funnel, diluted with hexane (40 mL), washed with of 2N aqueous KOH (1×30 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure giving di-tert-butyl (1S,2R,3S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-{[(3,4-difluorophenyl)sulfanyl]methyl}-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylate (1.35 g, 2.37 mmol): MS (m/z): 567.8 (M−H). This material is taken up in 120 mL of diethyl ether and added slowly over 2 hours to a 200 mL ether solution at −10° C. which contains R-(+)-2-methyl-CBS-oxazaborolidine (981.72 mg, 3.54 mmol) and borane-methyl sulfide complex (2M in tetrahydrofuran, 5.02 mL, 10.04 mmol). The mixture is stirred for an additional hour after final addition of di-tert-butyl (1S,2R,3S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-{[(3,4-difluorophenyl)sulfanyl]methyl}-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylate. Silica gel (30 g) is added over 30 minutes and the reaction mixture is gradually warmed to ambient temperature. The suspension is filtered, and washed with 300 mL of diethyl ether. The solvent is concentrated under reduced pressure giving a residue. The residue is purified by flash chromatography, eluting with (0 to 15% ethyl acetate/hexanes) to give the title compound (0.844 g, 1.48 mmol, 60.7% yield): MS (m/z): 569.8 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:13][CH2:12][N:11]3[C:5]2=[C:6]([CH:25]=1)[C:7]([N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)=[N:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=13>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[C:4]2[CH:13]=[CH:12][N:11]3[C:5]2=[C:6]([CH:25]=1)[C:7]([N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)=[N:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=13
Reactant: CN1CCN(C2=Nc3ccccc3N3CCc4cc(Br)cc2c43)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CN1CCN(C2=Nc3ccccc3-n3ccc4cc(Br)cc2c43)CC1
Reaction time: 36 h
Yield: 65.5 %

Procedure:
To a solution of 4-bromo-6-(4-methyl-1-piperazinyl)-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine (5.7 g, 14.3 mmoles) in chloroform (100 ml) was added manganese dioxide (5 g) and the mixture was heated at gentle reflux for 24 hours. Additional manganese dioxide was added and reflux was continued for 36 hours. The mixture was filtered and the solids were washed with dichloromethane. The filtrate was concentrated at reduced pressure. The residue was purified on a silica gel column (160 g), eluted with a mixture of methanol and dichloromethane (1.5% methanol in dichloromethane, 4 1, 2% methanol in dichloromethane, 2 1). The fractions containing pure product were combined and concentrated to give 3.7 g (64%) of product. Recrystallization from toluene (23 ml) yielded the analytical sample, mp 157°-159° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=2)=[CH:12][C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:21][C:17]1[CH:16]=[C:15]([C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:12][C:13]#[N:14])[CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc(C(=CC#N)c2cccc([N+](=O)[O-])c2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(C(=CC#N)c2cccc(N)c2)cc1OC
Yield: 38.8 %

Procedure:
To a solution of 3-(3,4-dimethoxyphenyl)-3-(3′-nitrophenyl)acrylonitrile (0.7 g, 2.3 mmol) in 40 mL of ethyl acetate was added 0.1 g of 10% palladium on carbon catalyst. The mixture was hydrogenated in a Parr-Shaker apparatus at 55–60 psi of hydrogen for 2.5 hours. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford the crude product. The crude product was purified by flash column chromatography (silica gel, 15% ethyl acetate/methylene chloride) to afford 0.25 g (56%) of a mixture of the E and Z isomers as a yellow solid: mp 100–101° C.; 1H NMR (CDCl3) δ 7.30–6.59 (m, 14H); 5.63 (s, 1H), 5.59 (s, 1H), 3.94 (s, 3H), 3.91 (s, 3H), 3.87 (s, 3H), 3.84 (s, 3H); 13C NMR (CDCl3) δ 163.1, 162.9, 151.1, 150.5, 148.8, 148.7, 146.5, 146.4, 140.4, 138.2, 131.5, 129.5, 129.5, 129.4, 123.2, 122.1, 119.9, 119.0, 118.4, 118.2, 116.8, 116.6, 115.9, 115.0, 112.7, 111.0, 110.7, 93.3, 92.7, 56.1, 56.0, 55.9; Anal. Calcd for C17H16N2O3. Theoretical: C, 72.84; H, 5.75; N, 9.99. Found: C, 72.48; H, 6.05; N, 9.58.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:11]=1>>[CH3:36][S:33]([C:12]1[CH:11]=[C:10]([N:4]2[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]2(=[O:8])=[O:7])[CH:15]=[CH:14][C:13]=1[C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=2)[CH2:20][CH2:19]1)=[O:17])(=[O:35])=[O:34]
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)nc1C
Reactant: C[C@H]1CNS(=O)(=O)C1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C[C@H](C)CS4(=O)=O)cc3S(C)(=O)=O)CC2)nc1C
Yield: 53.5 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (110 mg) described in Preparation Example 4 and (4-bromo-2-methanesulfonylphenyl) [4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (253 mg) described in Preparation Example 122 and by the reaction and treatment in the same manner as in Example 4, the title compound (151 mg) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2)#[N:2].[N-:14]=[N+:15]=[N-:16].[Na+].[Cl-].[NH4+].[Cl-].[Li+]>CN(C=O)C.C(OCC)(=O)C>[NH:2]1[C:1]([C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]3)=[N:16][N:15]=[N:14]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)CCCC2=O
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CCCc2cc(-c3nnn[nH]3)ccc21
Temperature: 120 °C

Procedure:
A sample of 6-cyanotetralone (102 mg, 0.60 mmol) is dissolved in DMF (1 mL) and treated with sodium azide (96.8 mg, 1.5 mmol), ammonium chloride (31.9 mg, 0.60 mmol) and lithium chloride (25.3 mg, 0.60 mmol) and heated to 120° C. overnight. The reaction is diluted with ethyl acetate and extracted with water twice. The residue is purified by UV triggered reverse phase HPLC to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:21]=2)=[CH:9]\[CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:6][CH:7]=1>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:21]=2)=[CH:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(/C(=C\CN2CCCC2)c2ccccn2)cc1
Solvent: O
Product: Cc1ccc(C(=CCN2CCCC2)c2ccccn2)cc1
Reaction time: 3 h
Yield: 74.1 %

Procedure:
15 ml of demineralized water is charged into a round-bottomed flask kept at 25° to 30° C. and then slowly 243 ml of 90% Conc. H2SO4 is added and the temperature is raised to 10° C.-20° C. under stirring. Slowly 50 g of 1-(4-methylphenyl)-1-(2-pyridyl)-3-pyrrolidinopropan-1-ol is charged and the temperature is maintained at 20° C. under stirring. The reaction mass is heated to 100-105° C. and the temperature is maintained for 4 hours under stirring. After completion of the reaction, the reaction mass is cooled to 25°-30° C., and then poured into ice cold water (1 litre) at 5-10° C. under stirring over a period of an hour. 50% NaOH solution (w/w) is added slowly to the reaction mixture by maintaining the temperature at 5° to 20° C. over a period of 2 hours and the contents are stirred for an hour at 25° to 30° C. The reaction mixture is filtered under suction to obtain 51.3 g of wet triprolidine base comprising >92% E-isomer along with <8% Z-isomer. 500 ml of demineralized water and 51.3 g of wet triprolidine base are charged into a round-bottom flask at 25° to 30° C. and the contents are stirred for 3 hours by maintaining the same temperature. The contents are filtered and dried under suction for 2 hours. The process is repeated thrice to obtain 1-(4-methylphenyl)-1-(2-pyridyl)-3-pyrrolidino prop-1-ene (38 g, 81.2%) consisting of >98% E isomer along with <2% Z-isomer.
Reaction SMILES: CN(C)C1C=CC=CC=1.[CH3:10][S:11][C:12]1[NH:17][C:16](=O)[N:15]2[N:19]=[CH:20][CH:21]=[C:14]2[N:13]=1.CCOC1C=CC(N)=CC=1.O=P(Cl)(Cl)[Cl:34]>>[Cl:34][C:16]1[N:15]2[N:19]=[CH:20][CH:21]=[C:14]2[N:13]=[C:12]([S:11][CH3:10])[N:17]=1
Reactant: CSc1nc2ccnn2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: CCOc1ccc(N)cc1
Solvent: CN(C)c1ccccc1
Product: CSc1nc(Cl)n2nccc2n1
Temperature: 25 °C
Yield: 81 %

Procedure:
N,N-Dimethylaniline (601 mg, 4.96 mmol) was added to a suspension of 2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4(3H)-one (1.88 g, 10.33 mmol) from 1c in POCl3 (29 mL). The reaction mixture was heated to reflux for 7 hours, and then cooled to room temperature, concentrated in vacuo, and diluted with cold water (110 mL). The resulting solid was collected by vacuum filtration, washed with cold water and hexane, and then air dried to give 1.68 g (81%) of 4-chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine.