Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:24])[C:10]([C:22]#[N:23])=[CH:11][C:12]2[CH:17]=[C:16]([O:18]C)[C:15]([OH:20])=[C:14]([F:21])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br.C(Cl)Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:24])[C:10]([C:22]#[N:23])=[CH:11][C:12]2[CH:17]=[C:16]([OH:18])[C:15]([OH:20])=[C:14]([F:21])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C=C(C#N)C(=O)Nc2cccc(Cl)c2)cc(F)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#CC(=Cc1cc(O)c(O)c(F)c1)C(=O)Nc1cccc(Cl)c1
Yield: 35.4 %

Procedure:
Demethylation was effected in the same as in Example 2 with N-(3-chlorophenyl)-2-cyano-3-(3-fluoro-4-hydroxy-5-methoxyphenyl) propenamide (470 mg, 1.36 mmol) and 1M solution of boron tribromide in methylene chloride (3.50 ml, 34.50 mmol). The resulting solid was recrystallized from ethanol-water to give the objective N-(3-chlorophenyl)-2-cyano-3-(3-fluoro-4, 5-dihydroxyphenyl) propenamide (160 mg, 35% in yield) as yellow powder.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([Br:20])[CH:13]=1)C.[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[Br:20][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][OH:9])[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: CCOC(=O)Cc1ccc(OC)c(Br)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(CCO)cc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 10.7 g of LAH in THF (600 ml) was added dropwise a solution of 70.0 g of ethyl(3-bromo-4-methoxyphenyl)acetate in THF (200 ml) at an internal temperature of −12 to −3° C. After stirring at an internal of 0° C. or lower for one hour, Na2SO4/10 hydrate was added slowly. After foaming ended, filtration was carried out. The filtrate was concentrated under reduced pressure to obtain 45.0 g of the title compound (light yellow oil).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]([O:16][C:17]2[C:22](C=CC)=[CH:21][CH:20]=[C:19]([Cl:26])[C:18]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH:14]=[CH2:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1>ClCCCl.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH:14]=[CH:15][C:22]3[C:17](=[C:18]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[C:19]([Cl:26])=[CH:20][CH:21]=3)[O:16]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: C=C[C@H](COS(=O)(=O)c1ccc(C)cc1)Oc1c(C=CC)ccc(Cl)c1-c1ccccc1C
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3ccc(Cl)c(-c4ccccc4C)c3O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
To a solution of (2R)-2-(6-chloro-2′-methyl-3-(prop-1-enyl)biphenyl-2-yloxy)but-3-enyl 4-methylbenzenesulfonate (1.4 g, 2.9 mmol) in 1,2-dichloroethane (30 mL) was added benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (0.57 g, 0.69 mmol) and the resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. Purification by ISCO using a solvent gradient of 0 to 20% ethyl acetate in hexanes provided 0.8 g (63%) of ((2R)-7-chloro-8-o-tolyl-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate as a thick dark oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=3[F:18])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:19].C([O-])([O-])=O.[K+].[K+].Br[CH2:27][C:28]([O:30]CC)=[O:29].[OH-].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=3[F:18])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:19][CH2:27][C:28]([OH:30])=[O:29]
Reactant: Oc1ccc2c(-c3cc(F)ccc3F)noc2c1Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)COc1ccc2c(-c3cc(F)ccc3F)noc2c1Cl
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a solution of 9.3 g of 7-chloro-3-(2,5-difluorophenyl)-6-hydroxy-1,2-benzisoxazole in 100 ml of DMF, 4.97 g of K2CO3 and 6.07 g of ethyl bromoacetate is added dropwise. The mixture is heated for two hours at 60° C. To the mixture 200 ml of water and 15 ml of 50% NaOH are added. The mixture is stirred at 90° C. for 90 minutes and then poured into water and acidified. The product is extracted with ethylacetate, dried over Na2SO4 and evaporated to give {[7-chloro-3-(2,5-difluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid.
Reaction SMILES: C(S)C1C=CC=CC=1.C([Li])CCC.[CH:14]([C@@H:17]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([CH3:43])([CH3:42])[CH3:41])=[C:36]([O:44]C(=O)C)[CH:35]=1)[C:18](N1[C@H](CC2C=CC=CC=2)COC1=O)=[O:19])([CH3:16])[CH3:15].[H-].[H-].[H-].[H-].[Li+].[Al+3].OS(O)(=O)=O>O1CCCC1.CCCCCC.O1CCCC1.O.C(OCC)(=O)C>[CH:14]([C@@H:17]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([CH3:41])([CH3:43])[CH3:42])=[C:36]([OH:44])[CH:35]=1)[CH2:18][OH:19])([CH3:16])[CH3:15]
Reactant: CC(=O)Oc1cc(C[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)C(C)C)ccc1C(C)(C)C
Agent: O=S(=O)(O)O
Agent: SCc1ccccc1
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)[C@H](CO)Cc1ccc(C(C)(C)C)c(O)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution, stirred at 0° C., of 12.3 ml of benzyl mercaptan in 100 ml of tetrahydrofuran there are added dropwise 49 ml of a 1.6M solution of butyllithium in hexane and after a further 15 minutes' stirring at 0° C. a solution of 12.1 g of 3-[2(R)-isopropyl-3-(3-acetoxy-4-tert-butyl-phenyl)-propanoyl]-4(R)-benzyl-oxazolidin-2-one in 100 ml of tetrahydrofuran. The reaction solution is stirred at 0° C. for a further 90 minutes and is then added dropwise at 0° C., with stirring, to a suspension of 4.9 g of LiAlH4 in 100 ml of tetrahydrofuran. The reaction mixture is stirred for a further 150 minutes at 0° C. and then, in succession, 26.8 ml of ethyl acetate, 100 ml of tetrahydrofuran/water=1:1 and 400 ml of 2N H2SO4 are added dropwise thereto. The tetrahydrofuran is removed using a rotary evaporator and the suspension that remains is partitioned between diethyl ether and water. The organic phases are concentrated by evaporation and the residue is purified by FC (300 g of silica gel, dichloromethane/ethyl acetate=9:1 and 200 g of silica gel, ethyl acetate/hexane=1:2), yielding the title compound: Rf (ethyl acetate/hexane=1:2)=0.43.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([C@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26](=[O:35])[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Br[CH2:37][C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39].[Cl-].[Na+]>CCCCCC.O1CCCC1>[CH2:13]([C@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26](=[O:35])[C@H:27]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:37][C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(CCc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: O=C(CBr)OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(C[C@@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)OCc1ccccc1
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
2.91 ml (20.8 mmole) of diisopropylamine and 13.40 ml (21.4 mmole) of butyllithium (as a 1.6M solution in hexane) were added, at -78° C. and under an atmosphere of nitrogen, to 50 ml of anhydrous tetrahydrofuran, and the mixture was stirred for 30 minutes. A solution of 5.35 g (17.3 mmole) of (4S)-(-)-4-benzyl-N-(3-phenylpropionyl)-2-oxazolidinone in 20 ml of anhydrous tetrahydrofuran was added to the resulting mixture, and then the mixture was stirred at the same temperature for 1 hour. At the end of this time, a solution of 5.74 ml (36.2 mmole) of benzyl bromoacetate in 10 ml of anhydrous tetrahydrofuran was added dropwise to the mixture, and then the mixture was stirred for 3 hours. At the end of this time, a saturated aqueous solution of sodium chloride was added to the mixture, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated by distillation under reduced pressure. The residue was purified by medium pressure column chromatography through silica gel (using a 1:5 by volume mixture of ethyl acetate and hexane as the eluent) to afford 5.47 g (yield 69%) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C@:2]12[CH2:38][CH2:37][C@@H:36]([C:39]([CH3:41])=[CH2:40])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:35])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([F:34])[CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.[I-].[K+].P(=O)(O)(O)O.[K].FC(F)(F)S(O[CH2:56][CH2:57][CH2:58][N:59]1[CH2:63][CH2:62][CH2:61][C:60]1=[O:64])(=O)=O>C(#N)C>[F:34][C:26]1[CH:25]=[C:24]([C:11]2[C:12]([CH3:22])([CH3:23])[C@H:13]3[C@:8]([CH3:35])([CH2:9][CH:10]=2)[C@@H:7]2[C@:16]([CH3:21])([C@@:17]4([CH3:20])[C@H:4]([CH2:5][CH2:6]2)[C@H:3]2[C@H:36]([C:39]([CH3:41])=[CH2:40])[CH2:37][CH2:38][C@:2]2([NH:1][CH2:56][CH2:57][CH2:58][N:59]2[CH2:63][CH2:62][CH2:61][C:60]2=[O:64])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)[CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C1CCCN1CCCOS(=O)(=O)C(F)(F)F
Agent: O=P(O)(O)O
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(NCCCN3CCCC3=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 120 °C
Yield: 26.2 %

Procedure:
To a sealable flask containing methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-2-fluorobenzoate (50 mg, 0.089 mmol) was added potassium iodide (39.9 mg, 0.240 mmol) and phosphoric acid, potassium salt (83 mg, 0.392 mmol). The mixture was diluted with acetonitrile (1 mL) and 3-(2-oxopyrrolidin-1-yl)propyl trifluoromethanesulfonate (the crude solution prepared above) (1.0 mL, 0.384 mmol) was added. The mixture was flushed with N2, then the vial was sealed and heated to 120° C. After 15.5 h of heating, the mixture was cooled to rt. An additional 0.5 mL of the above crude solution containing the triflate was added and the mixture was again heated to 120° C. After heating the mixture for an additional 70.25 h, the mixture was cooled to rt. The mixture was adsorbed to silica gel and was purified by flash chromatography using a 0-5% MeOH in DCM gradient and a Thomson 12 g silica gel column. The fractions containing the expected product were combined and concentrated under reduced pressure to give methyl 2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-(2-oxopyrrolidin-1-yl)propylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (16 mg, 0.023 mmol, 26.2% yield) as a yellow film. LCMS: m/e 687.5 (M+H)+, 2.04 min (method 2).
Reaction SMILES: [N:1]1([C:7]2[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][OH:21]>CN(C)C=O>[NH2:14][C:8]1[C:7]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[C:12]([NH:13][CH2:18][CH2:19][CH2:20][OH:21])[CH:11]=[CH:10][CH:9]=1
Reactant: Nc1cccc(N)c1N1CCCCC1
Reactant: OCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1cccc(NCCCO)c1N1CCCCC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 5.6 %

Procedure:
To a solution of 2-piperidin-1-yl-benzene-1,3-diamine (300 mg, 1.57 mmol) in N,N-dimethylformamide (4 mL) was added sodium hydride (60% suspension in mineral oil, 63 mg, 1.57 mmol) followed by 3-bromo-1-propanol (0.14 mL, 1.57 mmol) and the reaction mixture was stirred at 60° C. overnight. The resulting mixture was then extracted with ethyl acetate (150 mL) and the organic layer was washed twice with water (80 mL) and once with brine (80 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (hexane/EtOAc, 60/40) to give 22 mg of 3-(3-amino-2-piperidin-1-yl-phenylamino)-propan-1-ol.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16]CC)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CCOC(=O)Cc1ccc(C2=CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1ccc(C2=CCCCC2)cc1

Procedure:
A solution of 2 g of ethyl p-(1-cyclohexenyl)-phenyl-acetate in 50 ml of ethanol is mixed with 15 ml of 2N NaOH and heated for 2 hours to 60° C. After the bulk of the ethanol has been distilled off in vacuo, the residue is mixed with 20 ml of water, acidified with 2N hydrochloric acid and extracted with ether. The ethereal extracts are dried over sodium sulphate, filtered and evaporated. The solid residue is recrystallized from petroleum ether and yields the p-(1-cyclohexenyl)-phenyl-acetic acid of the formula ##SPC25##
Reaction SMILES: Cl.CC(OC([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[N:16]=[CH:17][C:18]([C:21]([O:23][CH3:24])=[O:22])=[N:19][CH:20]=2)[CH2:11][CH2:10]1)=O)(C)C>CO>[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[N:16]=[CH:17][C:18]([C:21]([O:23][CH3:24])=[O:22])=[N:19][CH:20]=2)[CH2:11][CH2:10]1
Reactant: COC(=O)c1cnc(C2CCN(C(=O)OC(C)(C)C)CC2)cn1
Agent: Cl
Solvent: CO
Product: COC(=O)c1cnc(C2CCNCC2)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 101.4 %

Procedure:
Hydrogen chloride (4M in 1,4-dioxane, 0.37 ml, 1.48 mmol) was added to methyl 5-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]pyrazine-2-carboxylate (120 mg, 0.37 mmol) in MeOH (3.70 ml). The resulting solution was stirred at ambient temperature for 24 h. The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford methyl 5-(piperidin-4-yl)pyrazine-2-carboxylate (83 mg, 100%) as a pale yellow solid. This was used directly with no further purification.
Reaction SMILES: [O-:1][N+:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][OH:13])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+].C(OCC)(=O)C>C(#N)C>[N+:2]1([O-:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1
Reactant: [O-][n+]1ccc(CO)c2ccccc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=Cc1cc[n+]([O-])c2ccccc12
Reaction time: 1 h

Procedure:
To a vigorously stirring suspension of (1-oxidoquinolin-4-yl)methanol (0.10 g, 0.57 mmol) in acetonitrile (10 mL) was added Dess-Martin periodinane (0.47 g, 0.63 mmol). After 1 h, 2M NaOH (aq, 2 mL) and ethyl acetate (105 mL) were added and the reaction was stirred for 5 min. The layers were then separated and the organic phase was washed with saturated NaHCO3 (aq), brine, and dried over MgSO4, filtered, and concentrated in vacuo to a light yellow solid. MS (ES+): 174 [MH+].
Reaction SMILES: [CH:1]([C@H:14]1[CH2:20][C@@H:19]2[C@@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH:1]([C@@H:14]1[O:15][CH2:16][C@@H:17]([OH:18])[C@@H:19]([NH:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccccc1
Reactant: c1ccc(C(c2ccccc2)[C@H]2C[C@H]3O[C@H]3CO2)cc1
Product: O[C@@H]1CO[C@@H](C(c2ccccc2)c2ccccc2)C[C@@H]1NCc1ccccc1

Procedure:
(1S,4R,6R)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]heptane 28d (0.019 g, 0.071 mmol) was reacted with benzylamine (0.15 g, 1.43 mmol) (Procedure E) to yield (3S,4S,6R)-6-benzhydryl-4-benzylamino-tetrahydropyran-3-ol, (+)-29h, 0.023 (85%, [α]D=(+)70.1, c=1, MeOH).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=1.[NH3:21]>CCO>[F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:21])[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=1
Reactant: N#CCCCCn1ccc(NC(=S)NCC(F)(F)F)n1
Reactant: N
Solvent: CCO
Product: N#CCCCCn1ccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 0.5 h

Procedure:
The above thiourea (12.5 g.) was dissolved in 8 M ammonia in EtOH (120 ml.). Mercuric oxide (12.8 g.) was added and the mixture was stirred at 20° for 30 minutes. The resulting mixture was filtered and the filtrate was evaporated in vacuo to give 5-[3-(2-[2,2,2-trifluoroethyl]guanidino)pyrazol-1-yl]valeronitrile as an oil. A sample of the oil was dissolved in acetone and 5 molecular equivalents of maleic acid were added. Ether was added to the resulting clear solution to produce the crystalline maleate, m.p. 123°-125°.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([CH2:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f49) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:14][C:13]3[C:12]([C:15]#[N:16])=[CH:11][N:10]=[C:9]([NH:17]CC4C=CC(OC)=CC=4)[C:8]=3[C:6]=2[CH:7]=1.CS(O)(=O)=[O:29]>>[NH2:17][C:9]1[C:8]2[C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[S:14][C:13]=2[C:12]([C:15]([NH2:16])=[O:29])=[CH:11][N:10]=1
Reactant: COc1ccc(CNc2ncc(C#N)c3sc4ccc(Cl)cc4c23)cc1
Reactant: CS(=O)(=O)O
Product: NC(=O)c1cnc(N)c2c1sc1ccc(Cl)cc12
Temperature: 125 °C

Procedure:
A suspension of 8-chloro-1-[(4-methoxybenzyl)amino][1]benzothieno[3,2-c]pyridine-4-carbonitrile in a 1:1 (mass/mass) mixture of PPA/CH3SO3H (0.8 M) was heated at 125° C. for 2 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc and H2O. The H2O was neutralized with NaHCO3 and NaOH followed by separation of the organic phase. The aqueous phase was extracted again with EtOAc and THF. The solvents were evaporated and the mixture purified by flash chromatography (EtOAc to 10% MeOH in EtOAc) to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH:47]([CH3:49])[CH3:48])[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH:47]([CH3:48])[CH3:49])[CH:42]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)c1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Product: CC(C)c1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(2-isopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K39) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as a light brown solid (360 mg, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]2[N:6]([C:15](=[O:33])[C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:31])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])=[CH:18][C:17]=3[CH3:32])[CH2:7][CH2:8][CH2:9][CH:10]([O:11][CH2:12]SC)[C:4]=2[CH:3]=1.S(Cl)(Cl)(=O)=O.[C:41]([O-:44])(=[O:43])[CH3:42].[Na+].[I-].[Na+]>ClCCCl.C(OCC)(=O)C.C(#N)C>[C:41]([O:44][CH2:12][O:11][CH:10]1[CH2:9][CH2:8][CH2:7][N:6]([C:15](=[O:33])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[CH:18][C:17]=2[CH3:32])[C:5]2[CH:34]=[CH:35][C:2]([Cl:1])=[CH:3][C:4]1=2)(=[O:43])[CH3:42]
Reactant: CSCOC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2C)c2ccc(Cl)cc21
Reactant: CC(=O)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=S(=O)(Cl)Cl
Solvent: CC#N
Product: CC(=O)OCOC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2C)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.7 %

Procedure:
7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-5-methylthiomethoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine (509 mg, 1.0 mmol) was dissolved in 1,2-dichloroethane (10 ml). Sulfuric chloride (0.12 ml, 1.5 mmol) was added thereto, and the mixture was stirred at room temperature for 15 minutes. The obtained mixture was concentrated under reduced pressure, and acetonitrile (10 ml), sodium acetate (246 mg, 2.0 mmol), and sodium iodide (450 mg, 3.0 mmol) were added to the residue, and then the mixture was heated under reflux for 1 hour. After cooling to room temperature, ethyl acetate was added thereto, and the insoluble subject was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography (n-hexane:ethyl acetate=65:35→50:50). The purified product was concentrated under reduced pressure, and the residue was dissolved in aqueous acetonitrile. After concentration at room temperature under reduced pressure, the resulted precipitates were collected by filtration, and dried to obtain 280 mg of 5-acetoxymethoxy-7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine as white powder.
Reaction SMILES: [Mg].[CH3:2][C:3]([C-:5]1C=C[CH:7]=[CH:6]1)=O.[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15].C(Br)C=C.C[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1COCC1>[C-:10]1([C:6]([CH3:7])=[CH:5][CH:3]=[CH2:2])[CH:14]=[CH:13][CH:12]=[CH:11]1.[CH-:21]1[CH:22]=[CH:23][CH:24]=[CH:25]1.[Fe+2:15]
Reactant: CC(=O)[c-]1cccc1
Reactant: CCCCCC
Agent: [Fe+2]
Agent: [Mg]
Agent: c1cc[cH-]c1
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CC=C(C)[c-]1cccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
72 mg (3.0 mmole) of magnesium metal was placed in a 50 ml round bottom flask. 228 mg (1.0 mmole) of ferrocenyl methyl ketone and 181.5 mg (1.5 mmole) of allyl bromide were dissolved in 15 ml of THF. The resulting mixture was poured into the round bottom flask containing the magnesium metal while stirring at room temperature for two hours. After two-hour stirring, the cover of the flask was opened, and the liquid portion of the reaction mixture was introduced into a silica gel column, which had been wetted with n-hexane. All the liquid migrated into the silica gel, and the column was placed still for 24 hours. Next, the column was eluated with n-hexane. After evaporating the solvent from the eluate collected from the elution, 230 mg (0.91 mmole) of a purified title product was obtained with a yield of 91%.