Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[C:4]([O:8][C:9]([CH2:11][C:12](=[O:24])[C:13](=[N+:22]=[N-:23])[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15])=[O:10])([CH3:7])([CH3:6])[CH3:5].Cl[C@@H:26]1[N:29](C(=O)C(OCOC(=O)C(C)(C)C)=O)[C:28](=[O:43])[C@H:27]1[C:44]([OH:47])([CH3:46])[CH3:45].C(O)(=O)C>ClCCl>[C:4]([O:8][C:9]([CH:11]([C@H:26]1[NH:29][C:28](=[O:43])[C@@H:27]1[C:44]([OH:47])([CH3:46])[CH3:45])[C:12](=[O:24])[C:13](=[N+:22]=[N-:23])[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15])=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)CC(=O)C(=[N+]=[N-])C(=O)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)C(=O)OCOC(=O)C(=O)N1C(=O)[C@@H](C(C)(C)O)[C@@H]1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C(C(=O)C(=[N+]=[N-])C(=O)OCC(Cl)(Cl)Cl)[C@H]1NC(=O)[C@@H]1C(C)(C)O
Temperature: -78 °C

Procedure:
To 50 ml of 0.2 M methanolic sodium methoxide solution stirred and cooled at -78° C., are successively added 3.43 g of 2,2,2-trichloroethyl 4-t-butyloxycarbonyl-2-diazo-3-oxobutyrate in 30 ml of dichloromethane and 10 mMol equivalent of pivaloyloxymethyl [3R,4S]-2-[4-chloro-3-(1-hydroxyisopropyl)-2-oxoazetidin-1-yl]-2-oxoacetate, which is prepared according to the procedure of Example 1, in 30 ml of dichloromethane. After a few minutes, 0.6 ml of acetic acid is added to the solution and the solution is evaporated to dryness under reduced pressure. The residue is taken into 50 ml of ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure to give the crude product. The product is subjected to silica-gel column chromatography by use of n-hexane-ethyl acetate=1:2 for elution. The fractions containing the desired compound are combined and concentrated to give 2.6 g of the titled compound.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:22])[C:9]([N:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]=[CH:12]1)=[O:10])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42](=S)=[S:43]>C1(C)C=CC=CC=1>[N:1]([CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:22])[C:9]([N:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]=[CH:12]1)=[O:10])=[C:42]=[S:43]
Reactant: S=C=S
Reactant: CN(CCCCN=[N+]=[N-])C(=O)n1cnc(-c2ccccc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CN(CCCCN=C=S)C(=O)n1cnc(-c2ccccc2)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a compound 48 (0.85 mmol) in anhydrous toluene (20 mL) was added triphenylphosphine (1 mmol) and reaction mixture was stirred at 50° C. for 2 h. Carbondisulfide (10 mmol) was added and the stirring continued at 50° C. for 4 h. Reaction was cooled to r.t. and solvent was evaporated on Rotavapor to give a crude compound which on purification by Biotage SP1 gave a pure isothiocyante 49.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12]([NH2:13])=[N:11][C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:9]2)[CH:3]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.O>CN1C(=O)CCC1>[C:15]1([NH:14][C:10]2[N:11]=[C:12]([NH2:13])[N:8]([C:4]3[CH:3]=[C:2]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[N:7]=[CH:6][N:5]=3)[N:9]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C1CNCCN1
Reactant: Nc1nc(Nc2ccccc2)nn1-c1cc(Cl)ncn1
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1nc(Nc2ccccc2)nn1-c1cc(N2CCNCC2)ncn1
Temperature: 220 °C

Procedure:
To a solution of 200 mg of 1-(6-chloro-pyrimidin-4-yl)-N3-phenyl-1H-[1,2,4]triazole-3,5-diamine (0.69 mMol, 1 equiv) in 5 mL of NMP was added 200 mg of piperazine (2.32 mMol, 3.3 equiv). The reaction vessel was sealed and warmed to 220° C. via microwave irradiation for 6 min and allowed to cool. The resulting solution was poured into 50 mL of water and the precipitate was filtered and washed with water (3×20 mL). The resulting waxy solid (150 mg) was used without further purification.
Reaction SMILES: [C:1]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.Br[CH2:17][CH2:18][CH2:19][Cl:20].C(=O)([O-])[O-].[K+].[K+]>>[CH2:14]([O:13][C:1](=[O:12])[CH2:2][C:3]1[CH:11]=[CH:10][C:8]([O:9][CH2:17][CH2:18][CH2:19][Cl:20])=[C:5]([O:6][CH3:7])[CH:4]=1)[CH3:15]
Reactant: ClCCCBr
Reactant: CCOC(=O)Cc1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)Cc1ccc(OCCCCl)c(OC)c1
Yield: 65.1 %

Procedure:
A mixture of 50 g (0.238 mole) of ethyl homovanillate (98%), 75 g (0.476 mole) of 1-bromo-3-chloropropane and 98.7 g (0.71 mole) of anhydrous potassium carbonate in 1 liter of actone was heated at reflux for 24 hr. The mixture was filtered and the filtrate was concentrated under reduced pressure to give an oil which gradually crystallized to a semi-solid. The solid was recrystallized from ethyl ether-petroleum ether (30°-60° C.) to yield 44.4 g (65%) of the title compound as a white solid, mp 36°-38° C.
Reaction SMILES: [C:1]([NH:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17](C)=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:22])=[O:11])(=[O:8])[C:2]1[CH:7]=CC=C[CH:3]=1.[C:23](NC(N1C2C(=CC(C)=CC=2)CC1=O)=O)(=O)C.C(NC(N1C2C(=CC(C)=CC=2)CC1=O)=O)(=O)C(C)(C)C.C(NC(N1C2C(=CC(C)=CC=2)CC1=O)=O)(=O)CC.C(NC(N1C2C(=CC(OC)=CC=2)CC1=O)=O)(=O)CCC.C(NC(N1C2C(=CC(OC)=CC=2)CC1=O)=O)(=O)C1C=CC=CC=1.C(NC(N1C2C(=CC(OC)=CC=2)CC1=O)=O)(=O)C>>[C:1]([NH:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:22])=[O:11])(=[O:8])[C:2]([CH3:3])([CH3:7])[CH3:23]
Reactant: Cc1ccc2c(c1)CC(=O)N2C(=O)NC(=O)c1ccccc1
Reactant: CC(=O)NC(=O)N1C(=O)Cc2cc(C)ccc21
Agent: CCC(=O)NC(=O)N1C(=O)Cc2cc(C)ccc21
Agent: CCCC(=O)NC(=O)N1C(=O)Cc2cc(OC)ccc21
Agent: COc1ccc2c(c1)CC(=O)N2C(=O)NC(=O)c1ccccc1
Product: CC(C)(C)C(=O)NC(=O)N1C(=O)Cc2ccccc21

Procedure:
Employing the above procedure, 1-(N-benzoylcarbamoyl)-5-methyloxindole, 1-(N-acetylcarbamoyl)-5-methyloxindole, 1-(N-pivaloylcarbamoyl)-5-methyloxindole, 1-(N-propionylcarbamoyl)-5-methyloxindole, 1-(N-butyrylcarbamoyl)-5-methoxyoxindole, 1-(N-benzoylcarbamoyl)-5-methoxyoxindole and 1-(N-acetylcarbamoyl)-5-methoxyoxindole are prepared.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH:5]([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[O:22][CH3:23])[C:6]([O:8]CC)=[O:7])C.[OH-].[Na+]>O>[CH3:23][O:22][C:13]1[CH:14]=[CH:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]=1[CH2:11][CH:5]([C:6]([OH:8])=[O:7])[C:4]([OH:24])=[O:3]
Reactant: CCOC(=O)C(Cc1c(OC)ccc2ccccc12)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2ccccc2c1CC(C(=O)O)C(=O)O

Procedure:
In a 1 litre single-necked flask, the compound obtained in Step B (20 g, 6.05.10−2 mol) is heated at reflux in the presence of sodium hydroxide (20 g, 5.00.10−1 mol) and water (340 ml) for 4 hours 30 minutes. After cooling, the mixture is diluted with 150 ml of water, filtered through filter paper and acidified using concentrated hydrochloric acid in the hot state (80-90° C.); the white microspheres formed in the hot state are filtered off over a frit after complete cooling. The diacid is washed with cold water. After drying in an oven (110° C.) for one night, the title compound is dried in a desiccator in the presence of P2O5.
Reaction SMILES: B(F)(F)F.CSC.C[O:9][C:10]1[CH:11]=[C:12]([C:17]2[N:21]([CH2:22][C:23]#[N:24])[N:20]=[CH:19][C:18]=2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[NH:37][C:38](=[O:40])[CH3:39])[CH:26]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1>ClCCl>[OH:9][C:10]1[CH:11]=[C:12]([C:17]2[N:21]([CH2:22][C:23]#[N:24])[N:20]=[CH:19][C:18]=2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[NH:37][C:38](=[O:40])[CH3:39])[CH:26]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: COc1cc(C)cc(-c2c(-c3ccnc(-c4ccccc4NC(C)=O)c3)cnn2CC#N)c1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CSC
Product: CC(=O)Nc1ccccc1-c1cc(-c2cnn(CC#N)c2-c2cc(C)cc(O)c2)ccn1
Reaction time: 24 h

Procedure:
Borontrifluoride-dimethylsulfide (0.13 mL, 1.2 mmol) was dropwise added to a solution of the methoxy compound (52.5 mg, 0.12 mmol) prepared in Example 38 in dichloromethane (4 mL) at room temperature under nitrogen atmosphere, and stirred for 24 hours. The reaction mixture was concentrated by vacuum distillation. The residue was treated in ethyl acetate (100 mL) and brine (50 mL) and the organic layer was dried over anhydrous magnesium sulfate and distilled under vacuum. Purification through column chromatography (silica gel, ethyl acetate) afforded pure hydroxy products (29 mg, 58%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6]N=O.[CH2:9]=[C:10]=[O:11].[C]=O>ClC1C=CC=CC=1>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:10]([CH3:9])=[O:11]
Reactant: CCCCCON=O
Reactant: C=C=O
Agent: [C]=O
Solvent: Clc1ccccc1
Product: CCCCCOC(C)=O
Reaction time: 3 h
Yield: 28.3 %

Procedure:
To the same reaction vessel as in Example 9 were charged bistriphenylphosphinedibromopalladium (0.791 g, 1 mmole), stannous bromide (0.558 g, 2 mmoles) and tetra-n-ethylammonium bromide (0.420 g, 2 mmoles), together with n-amyl nitrite (50 ml, 356.0 mmoles) and chlorobenzene (200 ml). Then, nitrogen gas containing 10.0 vol.% of ketene and carbon monooxide were introduced to the mixture at the rate of 116.1 ml/min and 200 ml/min, respectively, and the reaction was performed at 90° C. for 3 hours. The reaction mixture was analyzed to reveal that di-n-amyl malonate (63.0 mmoles, 49.4%) and n-amyl acetate (36.5 mmoles, 28.3%) were obtained.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.Cl.Cl.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[C:29]1[NH:33][C:32](=[O:34])[C:31]2([CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[N:30]=1>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:37]2[CH2:36][CH2:35][C:31]3([N:30]=[C:29]([C:23]4[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]=4[Cl:21])[NH:33][C:32]3=[O:34])[CH2:39][CH2:38]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: O=C1NC(c2ccc(Cl)cc2Cl)=NC12CCNCC2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1NC(c2ccc(Cl)cc2Cl)=NC12CCN(S(=O)(=O)c1ccc(Cl)cc1)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.1 %

Procedure:
Triethylamine (88 μl, 0.632 mmol) and 4-chlorobenzenesulfonyl chloride (70 mg, 0.332 mmol) were added to a mixed solution of 2-(2,4-dichloro-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one dihydrochloride (100 mg, 0.299 mmol) in dichloromethane (3 ml). The reaction solution was stirred at room temperature for 16 hours and then diluted with dichloromethane, and the organic layer was washed with water. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane) to give 8-(4-chloro-benzenesulfonyl)-2-(2,4-dichloro-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (70.8 mg, 96%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[NH:11][C:12](=[O:20])[C:13]2[S:18][C:17]([Br:19])=[CH:16][C:14]=2[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]=O>O1CCCC1>[CH2:1]([N:8]1[CH2:9][C:10]2=[N:15][C:14]3[CH:16]=[C:17]([Br:19])[S:18][C:13]=3[C:12](=[O:20])[N:11]2[CH2:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=O
Reactant: O=c1[nH]c(CNCc2ccccc2)nc2cc(Br)sc12
Solvent: C1CCOC1
Product: O=c1c2sc(Br)cc2nc2n1CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of a crude product (185 mg) of 2-[(benzylamino)methyl]-6-bromothieno[3,2-d]pyrimidin-4(3H)-one, 37% aqueous formaldehyde solution (1 mL) and tetrahydrofuran (2 mL) was stirred at room temperature for 1 hr. The precipitate was collected by filtration, and washed successively with water and ethyl acetate to give a crude product (104 mg) of the title compound as a pale-yellow solid.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.[CH2:12]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:10][C:7]1[N:6]=[C:5]([NH2:11])[C:4]([CH2:3][N:23]2[CH2:24][CH2:25][N:20]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:21][CH2:22]2)=[CH:9][N:8]=1
Reactant: c1ccc(CCN2CCNCC2)cc1
Reactant: Cc1ncc(CCl)c(N)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ncc(CN2CCN(CCc3ccccc3)CC2)c(N)n1
Temperature: 25 °C
Reaction time: 36 h
Yield: 79.8 %

Procedure:
A suspension of 0.30 g (0.0019 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride in 20 ml of dimethylformamide was treated with 0.30 g (0.00157 mol) of 1-phenethyl-piperazine and 0.66 ml (0.0047 mol) of triethylamine and the mixture was stirred at room temperature under argon for 36 hours. The mixture was completely freed from the solvents. The residue was partitioned between dichloromethane and water, extracted, chromatographed over silica gel with methanol as the eluent and recrystallized from toluene. 0.39 g (83%) of 2-methyl-5-(4-phenethyl-piperazin-1-ylmethyl)-pyrimidin-4-ylamine was obtained as white crystals; m.p. 162°-165°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:10]=2[CH:11]=[O:12])=[CH:4][CH:3]=1.[CH:18]([Mg]Br)=[CH2:19].[NH4+].[Cl-]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:10]=2[CH:11]([OH:12])[CH:18]=[CH2:19])=[CH:6][CH:7]=1
Reactant: C=C[Mg]Br
Reactant: O=Cc1c(F)cccc1Sc1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1c(F)cccc1Sc1ccc(F)cc1
Temperature: -78 °C

Procedure:
2-(4-fluorophenylthio)-6-fluorobenzaldehyde (2.06 g, 8.23 mmol) is dissolved in 21 ml of dry THF and cooled to -78° C. Vinylmagnesium bromide solution (12.4 ml of a 1.0M solution in THF) is then added dropwise and the reaction mixture is allowed to warm to room temperature. The reaction mixture is then poured into saturated NH4Cl and extracted twice with diethyl ether. The extracts are washed with water and then brine and dried over K2CO3 to afford the subtitle compound.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:10][C:11](=[O:22])[C@@H:12]([OH:21])[C@@H:13]([N:18]=[N+]=[N-])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][C:3]=2[O:2]1>[C].[Pd].CO>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:10][C:11](=[O:22])[C@@H:12]([OH:21])[C@@H:13]([NH2:18])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][C:3]=2[O:2]1
Reactant: CCCC[C@H](N=[N+]=[N-])[C@H](O)C(=O)Nc1ccc2c(c1)OCO2
Agent: [Pd]
Solvent: CO
Product: CCCC[C@H](N)[C@H](O)C(=O)Nc1ccc2c(c1)OCO2
Reaction time: 18 h
Yield: 95.1 %

Procedure:
To 30 ml of a methanol solution containing 395 mg (1.29 mmol) of (2S,3S)-N-[(3,4-methylenedioxy)phenyl]-3-azido-2-hydroxyheptanamide was added 40 mg of 5% palladium carbon, and the resulting mixture was stirred under hydrogen atmosphere for 18 hours. Insoluble materials were filtered off, and the filtrate was distilled under reduced pressure to obtain 344 mg (Yield: 95%) of the title compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:15][CH:16]([CH3:22])[C:17](OCC)=[O:18])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].Cl>C(OCC)C>[CH2:7]([O:15][CH:16]([CH3:22])[CH2:17][OH:18])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCOC(C)C(=O)OCC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CCCCCCCCOC(C)CO
Reaction time: 15 h
Yield: 86.3 %

Procedure:
Then, 7.5 g of LiAlH4 was added to 250 ml of diethyl ether, followed by stirring for a little while. Then, a solution of 56 g of the above ester in 50 ml of diethyl ether was added dropwise in 2 hours at below 5° C. After the addition, the mixture was stirred at room temperature for 2 hours and allowed to stand for 15 hours. After the reaction, 30 ml of 5% hydrochloric acid was added, and 6N-hydrochloric acid was added to provide a pH of about 1, followed by extraction with ether. The product was washed with water, dried and subjected to removal of the solvent by distillation, followed by vacuum distillation to obtain 39.5 g of 2-octyloxypropanol as a fraction of 107° C./3 mmHg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:18][C:19]#[N:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[H][H]>CO.Cl.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:18][CH2:19][NH2:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: N#CC=C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCCC(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Yield: 96.9 %

Procedure:
(c)(d) 3-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-3-phenylacrylonitrile (500 mg; 1.47 mmol) was dissolved in 20 mL MeOH and 4 mL 1 M HCl. 10% Pd on carbon (170 mg) was added and the reaction was hydrogenated in a Parr bottle over an atmosphere of 50 psi hydrogen for 16 h. The catalyst was filtered off and the solvent removed in vacuo to give pure 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenylpropan-1-amine (492 mg, 100%) as a yellow oil. MS found: (M+H)+=376. 28 mg of this product (free base) was coupled to 2,2,2-trifluoroethanesulfonyl chloride using General Coupling Method B to give 20 mg (50%) of 2,2,2-trifluoro-N-(3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenylpropyl)ethanesulfonamide. MS found: (M+H)+=492.
Reaction SMILES: [F:1][C:2]1[C:12]2[N:11]([C:13](=[O:36])[NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:30][CH2:29][CH2:28][CH2:27][C:26]5[CH:31]=[CH:32][CH:33]=[CH:34][C:25]4=5)=[O:23])=[CH:18][C:17]=3[CH3:35])[CH2:10][CH2:9][C:8](=[O:37])[N:7]([CH2:38][C:39](O)=[O:40])[C:6]=2[CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.[BH4-].[Na+].[Cl-].[NH4+]>C1COCC1.O>[CH3:35][C:17]1[CH:18]=[C:19]([C:22]([N:24]2[CH2:30][CH2:29][CH2:28][CH2:27][C:26]3[CH:31]=[CH:32][CH:33]=[CH:34][C:25]2=3)=[O:23])[CH:20]=[CH:21][C:16]=1[CH2:15][NH:14][C:13]([N:11]1[CH2:10][CH2:9][C:8](=[O:37])[N:7]([CH2:38][CH2:39][OH:40])[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:12]1=2)=[O:36]
Reactant: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)N1CCC(=O)N(CC(=O)O)c2cccc(F)c21
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)N1CCC(=O)N(CCO)c2cccc(F)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {6-fluoro-5-[2-methyl-4-(2,3,4,5-tetrahydrobenzo[b]azepine-1-carbonyl)benzylcarbamoyl]-2-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl}acetic acid from Example 2 (170 mg, 0.30 mmol) in THF (6 ml) were added N-methylmorpholine (47 μl, 0.43 mmol) and isobutyl chlroroformate (57 μl, 0.43 mmol) while cooling in an ice/water bath. The mixture was stirred for 1 h, filtered and added to a solution of sodium borohydride (27 mg, 0.70 mmol) in water (1.5 ml) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature slowly and stirred for 2 h. Saturated ammonium chloride solution (2 ml) was added and the mixture evaporated in vacuo. The residue was partitioned between choroform and water and the organic layer was washed with brine, dried over magnesium sulphate and evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant methanol:dichloromethane 6:94) to give a white solid; yield 104 mg, 64%.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[PH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH3:17])[CH3:2].C(N(CC)CC)C.Cl[SiH](Cl)Cl>C(#N)C>[CH2:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[PH:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2])[CH3:17]
Reactant: CCc1ccccc1[PH](=O)c1ccccc1CC
Agent: Cl[SiH](Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCc1ccccc1Pc1ccccc1CC

Procedure:
Into a 1 L Schlenk flask was added the phosphine oxide (3a) (17.21 g, 66.7 mmol). To this was added acetonitrile (400 ml) and triethylamine (27.9 ml, 200.1 mmol). Then trichlorosilane (20.2 ml, 200.1 mmol) was added slowly. The addition of the trichlorosilane gave the formation of some white precipitate. The resultant mixture was then refluxed overnight. The resultant suspension was then cooled to 0° in an ice bath and a solution of potassium hydroxide (40 g) in water (200 ml) which had been degassed with nitrogen gas was added slowly. This gave a bi-phasic mixture. Additional acetonitrile (100 ml) was then added. The upper organic phase was then removed by cannula into a clean Schlenk flask and the solvent removed under vacuum. This gave an off-white solid (3b). Yield=13.60 g, 84%.
Reaction SMILES: Br[C:2]1[C:3](=[O:22])[N:4]([CH3:21])[N:5]=[C:6]([O:8][CH2:9][C@H:10]2[CH2:12][C@@H:11]2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][N:14]=2)[CH:7]=1.[CH2:23]([C:25]1[CH:29]=[C:28]([CH2:30][NH2:31])[N:27]([CH3:32])[N:26]=1)[CH3:24].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH2:23]([C:25]1[CH:29]=[C:28]([CH2:30][NH:31][C:2]2[C:3](=[O:22])[N:4]([CH3:21])[N:5]=[C:6]([O:8][CH2:9][C@H:10]3[CH2:12][C@@H:11]3[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][N:14]=3)[CH:7]=2)[N:27]([CH3:32])[N:26]=1)[CH3:24]
Reactant: CCc1cc(CN)n(C)n1
Reactant: COc1ccc([C@H]2C[C@@H]2COc2cc(Br)c(=O)n(C)n2)nc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cc(CNc2cc(OC[C@H]3C[C@@H]3c3ccc(OC)cn3)nn(C)c2=O)n(C)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-6-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyridazin-3(2H)-one (70 mg, 0.19 mmol) in toluene (5 mL) under N2, ((3-ethyl-1-methyl-1H-pyrazol-5-yl)methanamine (32.2 mg, 0.23 mmol), Pd2(dba)3 (18 mg, 0.019 mmol), BINAP (35 mg, 0.06 mmol) and NaOtBu (27 mg, 0.285 mmol) were added. After the reaction mixture was stirred at 100° C. overnight, 15 mL water was added. The mixture was extracted with EtOAc (2×10 mL). The combined organics were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC to give the title compound as oil. 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.73 (d, 1H), 7.21 (d, 1H), 6.14 (s, 1H), 5.75 (s, 1H), 4.45-4.28 (m, 3H), 4.00 (d, 4H), 3.89 (s, 3H), 3.67 (s, 3H), 2.66 (d, 2H), 2.53 (s, 1H), 1.88 (s, 1H), 1.41 (s, 2H), 1.22 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]([F:14])([F:13])[F:12])[CH2:9][OH:10])=[CH:4][CH:3]=1.O([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br)C1C=CC=CC=1.[F-].[Cs+]>COCCOCCOC>[C:2]1([C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[CH2:25][O:10][CH2:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:11]([F:12])([F:13])[F:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: OCC(c1ccc(F)cc1)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOCCOC
Product: Fc1ccc(C(COCc2cccc(-c3ccccc3)c2)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Under a nitrogen atmosphere, 0.50 g of 2-(4-fluorophenyl)-3,3,3-trifluoropropanol and 0.63 g of 3-phenoxybenzyl bromide was dissolved in 15 ml of dry diethyleneglycol dimethylether. Into the solution, 1.83 g of dry cesium fluoride was added at room temperature, and the reaction solution was stirred at room temperature for 48 hours. Thereafter, the reaction solution was poured into dilute HCl-ice water and extracted twice with diethyl ether. The ether layers were combined, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure, and the residue was subjected to preparative thin-layer chromatography on silica gel to obtain αmg of the desired compound.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3]1.[CH3:10]O>>[CH3:10][O:8][C:7]([CH:5]1[CH2:4][CH2:3][C:2](=[O:1])[NH:6]1)=[O:9]
Reactant: O=C1CCC(C(=O)O)N1
Reactant: CO
Product: COC(=O)C1CCC(=O)N1
Yield: 90 %

Procedure:
A mixture of 5-oxo-pyrrolidine-2-carboxylic acid (5 g, 38.7 mmol) and Amberlyst® 15 (5 g) in MeOH (50 ml) was refluxed for 20 hours. After cooling, the reaction was filtered and the solvent removed under vacuum to afford the title compound (4.9 g, 90% yield) that was used without further purification in the next step.