Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@H:4]1[CH2:8][N:7]([C@@H:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH3:10])[C:6](=[O:19])[CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.C(O)=O.Cl>CC#N.[Cl-].[Na+].O.CCOC(C)=O>[OH:3][C@@H:1]([C@H:4]1[CH2:8][N:7]([C@@H:9]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH3:10])[C:6](=[O:19])[CH2:5]1)[CH3:2]
Reactant: COc1ccc([C@@H](C)N2C[C@H](C(C)=O)CC2=O)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O=CO
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)O)CC2=O)cc1
Temperature: -10 °C
Reaction time: 18 h

Procedure:
In a separate flask, a solution of (R)-4-acetyl-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.03 (1.8 g, 6.9 mmol) in MeCN (34 mL) was cooled to an internal temperature of −10° C. under Ar in a jacketed 3-neck flask equipped with a thermocouple. Triethylamine (5.1 mL, 36 mmol) was added during the cooling ramp at 0° C. Formic acid (0.525 mL, 13.9 mmol) was added once the internal temperature reached −10° C. The aforementioned catalyst mixture was then added in one portion, washing with additional MeCN (2×1 mL). The resulting orange solution was stirred for 18 h at −10° C. and was then warmed to 0° C. After an additional 4.5 h, hydrochloric acid (3 M, 13 mL, 39 mmol) was added followed by EtOAc (50 mL) and brine (30 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (50 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated. The product was purified by silica gel chromatography (35% to 50% acetone in hexanes) to afford (R)-4-((R)-1-hydroxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.04.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.[NH2:15][C@H:16]([CH3:33])[C@:17]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32])([OH:24])[CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1.C([BH3-])#N.[Na+]>C(O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[C@:17]([OH:24])([C@H:16]([NH:15][CH:11]1[CH2:12][CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:9][CH2:10]1)[CH3:33])[CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1
Reactant: C[C@@H](N)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C1CCN(c2ccccc2F)CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CCO
Product: C[C@@H](NC1CCN(c2ccccc2F)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 44 %

Procedure:
To a solution of 1-(2-fluorophenyl)piperidin-4-one (36.0 mg, 0.19 mmol) in anhydrous ethanol (1 mL) was added (2R,3R)-3-amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (50.0 mg, 0.19 mmol). While being stirred, the reaction solution was mixed at room temperature for four hrs with titanium (IV) isopropoxide (0.06 mL, 0.21 mmol) and then at room temperature for 18 hrs with sodium cyanoborohydride (35.0 mg, 0.56 mmol). The reaction was terminated by adding distilled water, after which the reaction mixture was concentrated by evaporation at reduced pressure and extracted with ethyl acetate to give an organic solvent layer. This organic layer was dried over anhydrous magnesium sulfate and purified by silica gel chromatography to afford the title compound (yield 44%).
Reaction SMILES: [O:1]=[C:2]1[CH:6]([N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]3[C:15]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:16][N:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=34)=[N:8]2)[CH2:5][CH2:4][NH:3]1.[H-].[Na+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].O>CN(C)C=O>[CH2:36]([O:35][C:33]([CH2:32][N:3]1[CH2:4][CH2:5][CH:6]([N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]3[C:15]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:16][N:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=34)=[N:8]2)[C:2]1=[O:1])=[O:34])[CH3:37]
Reactant: O=C1NCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCC(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)C1=O
Reaction time: 0.5 h

Procedure:
To a solution of 3-[2-(2-oxopyrrolidin-3-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (740 mg) in N,N-dimethylformamide (5 ml) was added 60% sodium hydride in mineral oil (120 mg) at 0° C. After the mixture was stirred for 30 minutes, to this was added ethyl 2-bromoacetate (0.22 ml). After the reaction mixture was stirred at 0° C. for 1 hour, it was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (CHCl3—CHCl3:MeOH (30:1)) to give 3-[2-(1-ethoxycarbonylmethyl-2-oxopyrrolidin-3-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.7 g) (yellow oil).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]([O:21][CH2:22][CH3:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=CC=2)=[CH:8][C:7]=1[CH3:20]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:24])[C@@H:4]([O:21][CH2:22][CH3:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:20]
Reactant: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1C)C(=O)OC
Agent: [Pd]
Solvent: CO
Product: CCO[C@@H](Cc1ccc(O)cc1C)C(=O)OC
Yield: 76.4 %

Procedure:
A solution of (2S)-3-(4-benzyloxy-2-methyl-phenyl)-2-ethoxy-propionic acid methyl ester (3.6 g, 11 mmol) in methanol (300 ml) was hydrogenated over 10% palladium on charcoal (1 g) at ambient temperature for 2 h. The catalyst was filtered off and the solvent evaporated under reduced pressure to give 2 g (8.4 mmol, 77%) of the title compound as yellow liquid which was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)C(=O)OCC1C=CC=CC=1>C(O)C.[C].[Pd]>[CH3:1][NH:2][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CN(CCCCC=CCCCCCCCCCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CNCCCCCCCCCCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 65.4 %

Procedure:
Compound 15 (2.6 g) was dissolved in ethanol (20 mL) and 5% palladium carbon (260 mg) was added thereto, followed by stirring at room temperature for 3.5 hours under hydrogen atmosphere. The reaction solution was replaced with argon atmosphere, filtered with Celite (brand name) and concentrated under reduced pressure to obtain the title compound (1.2 g) having the following physical property values.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7](O)=[O:8])(=[O:3])[CH3:2].S(Cl)([Cl:16])=O>>[C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([Cl:16])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(CC(C)C)C(=O)O
Reactant: O=S(Cl)Cl
Product: CC(=O)SCC(CC(C)C)C(=O)Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-[(Acetylthio)methyl]-4-methylpentanoic acid (6.0 g) is combined with thionyl chloride (5 ml). The reaction mixture is allowed to exotherm to 45° C. It is stirred at room temperature for about 16 hours and the acid chloride product is then vacuum distilled yielding 5.1 g, boiling point 80°-90° C. at 10 mm of Hg.
Reaction SMILES: C[C:2]1[C:3]([CH2:11][CH2:12][CH2:13][CH:14]([C:20]#[N:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:4]([CH:8]=[CH:9][CH:10]=1)C([O-])=O.OCCCC1C=CC([C:30]([O:32][CH3:33])=[O:31])=CC=1.C(CC(OCC)=O)#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:20]([CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:12][CH2:11][C:3]1[CH:2]=[CH:10][C:9]([C:30]([O:32][CH3:33])=[O:31])=[CH:8][CH:4]=1)#[N:21]
Reactant: COC(=O)c1ccc(CCCO)cc1
Reactant: CCOC(=O)C(C#N)CCCc1c(C)cccc1C(=O)[O-]
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(=O)CC#N
Product: CCOC(=O)C(C#N)CCCc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 40 %

Procedure:
Preparation of methyl-(4-cyano-4-ethoxycarbonylbutyl)benzoate ##STR21## To a 250 mL flame dried round bottom flask were charged 10.0 g (51.5 mmol) of methyl 4-(-hydroxypropyl)benzoate and 5.48 mL (51.5 mmol) of ethyl cyanoacetate dissolved in 40 mL of anhydrous tetrahydrofuran (THF). To this solution was then added dropwise to a solution of 20.2 g (77 mmol) of triphenylphosphine and 12.1 mL (77 mmol) of diethyl azodicarboxylate dissolved in 60 mL of anhydrous THF. After the addition, the reaction was stirred at ambient temperature for 1.5 hours. The volatiles were removed in vacuo and the crude oil was dissolved in 300 mL of EtOAc, washed with brine, dried over Na2SO4, and removed in vacuo. This crude oil was then purified on silica gel using a Waters Prep LC 2000 eluting with a gradient of 1:1 MeCl2 /Hex to 100% MeCl2 to give 6.0 g (40%) of methyl 4-(4-cyano-4-ethoxycarbonylbutyl)benzoate as a pale yellow oil.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([C:21]1[C:26](=[O:27])[CH2:25][CH2:24][CH2:23][C:22]=1[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1)[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[S:19][CH3:20].[C:39](N1C=CN=C1)(N1C=CN=C1)=[O:40]>C(#N)C>[O:40]=[C:39]1[NH:9][CH:10]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=2[S:19][CH3:20])[C:21]2[C:26](=[O:27])[CH2:25][CH2:24][CH2:23][C:22]=2[N:28]1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CSc1cc(C#N)ccc1C(N)C1=C(Nc2cccc(C(F)(F)F)c2)CCCC1=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CSc1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Triethylamine (89 μL, 0.634 mmol) is added to a mixture of 4-{amino-[6-oxo-2-(3-trifluoromethyl-phenylamino)-cyclohex-1-enyl]-methyl}-3-methylsulfanyl-benzonitrile hydrochloride (INTERMEDIATE 5, 1.19 g, 2.54 mmol) and 1,1′-carbonyldiimidazole (480 mg, 2.96 mmol) in acetonitrile (4 mL) and the mixture is stirred at room temperature for 15 min. The reaction mixture is evaporated. Water is added, the precipitate is filtered and washed with water. The residue is dissolved in dichloromethane and evaporated. Yield: 1.02 g. ESI mass spectrum: [M+H]+=458; Retention time HPLC: 1.05 min (Z018_S04).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]2[CH2:16][N:15]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:14](=[O:25])[CH2:13][NH:12]2)=[CH:2]1.N1C=CC=CC=1.[F:32][C:33]([F:48])([F:47])[C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[C:37](Cl)=[O:38]>ClCCl>[F:32][C:33]([F:47])([F:48])[C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([C:43]([F:46])([F:44])[F:45])[CH:42]=1)[C:37]([N:12]1[C@H:11]([CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:16][N:15]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:14](=[O:25])[CH2:13]1)=[O:38]
Reactant: CCOC(=O)CCCN1C[C@@H](Cc2c[nH]c3ccccc23)NCC1=O
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CCCN1C[C@@H](Cc2c[nH]c3ccccc23)N(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1=O
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 35.8 %

Procedure:
To an ice-cooled solution of (5R)-5-(1H-indol-3-ylmethyl)-1-[3-(ethoxycarbonyl)propyl]piperazin-2-one (0.56 g) and pyridine (0.26 ml) in dichloromethane (10 ml) was added a solution of 3,5-bis(trifluoromethyl)benzoyl chloride (0.45 g) in dichloromethane (1 ml). The solution was stirred for 40 minutes at the same temperature. After concentration, the residue was extracted with ethyl acetate. The organic layer was washed successively with aqueous sodium bicarbonate solution, water, 0.5N hydrochloric acid and brine, and dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (20 g) eluting with a mixture of dichloromethane-methanol (from 0% to 5% gradient solution) to give (5R)-4-[3,5-bis(trifluoromethyl)benzoyl]-1-[3-(ethoxycarbonyl)propyl]-5-(1H-indol-3-ylmethyl)piperazin-2-one (0.34 g) as an amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([O:38][Si](C(C)(C)C)(C)C)[CH2:10][C:11]([C:14]1[N:15]=[C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:37])[CH2:26][N:27]3[C:31]([CH3:32])=[CH:30][C:29]([C:33]([F:36])([F:35])[F:34])=[N:28]3)[CH2:21][CH2:20]2)[S:17][CH:18]=1)=[N:12][OH:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([OH:38])[CH2:10][C:11]([C:14]1[N:15]=[C:16]([CH:19]2[CH2:20][CH2:21][N:22]([C:25](=[O:37])[CH2:26][N:27]3[C:31]([CH3:32])=[CH:30][C:29]([C:33]([F:36])([F:35])[F:34])=[N:28]3)[CH2:23][CH2:24]2)[S:17][CH:18]=1)=[N:12][OH:13]
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(CC(O[Si](C)(C)C(C)(C)C)c3c(F)cccc3F)=NO)cs2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(CC(O)c3c(F)cccc3F)=NO)cs2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(2,6-difluorophenyl)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-[2-[1-[2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolyl]-1-propanone 1-oxime (i.e. the product of Example 6, Step B) (0.25 g, 0.37 mmol) in tetrahydrofuran (5 mL) was added a 1 M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (0.55 mL). The resulting solution was stirred at room temperature for 2 h, concentrated under reduced pressure and treated with minimal dichloromethane and water. The resulting mixture was eluted on a Celite® extraction tube (ChemElute® diatomaceous earth-based liquid-liquid exchange cartridge) with dichloromethane and concentrated to provide 0.225 g of the title compound.
Reaction SMILES: [Cl:1]/[CH:2]=[CH:3]\[CH2:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[Cl:1]/[CH:2]=[CH:3]\[CH2:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(C/C=C\Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1ccc(C/C=C\Cl)cc1
Reaction time: 1 h

Procedure:
The aldehyde (0.22 g) of Example 1 in ether (5 ml) is added to lithium aluminum hydride (0.08 g) in ether (5 ml), and the mixture stirred at 20° for 1 hour. After successive dropwise additions of water (80 l), 15% NaOH (80 l) and water (240 l), the resulting clear ether layer (+ washings) is evaporated to a residue of 4(Z-3-chloroallyl)benzyl alcohol yield 0.19 g (86%) nD25 1.5529.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[N:9]([CH3:18])[CH2:8][C:7]=12)#[N:2].Cl.[NH2:20][OH:21].C(O)C.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:18][N:9]1[C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:6]2[CH:5]=[N:4][C:3]([C:1](=[N:20][OH:21])[NH2:2])=[C:7]2[CH2:8]1
Reactant: NO
Reactant: CN1Cc2c(C#N)ncn2-c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CN1Cc2c(C(N)=NO)ncn2-c2ccccc2C1=O
Reaction time: 2 h

Procedure:
A mixture of 0.0125 mole 3-cyano-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine (prepared as in U.S. Pat. No. 4,316,839), 1.1 g of hydroxylamine hydrochloride, 200 ml of 99% ethanol and 5.2 ml of 20% potassium carbonate solution in water was heated with stirring for two hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was treated with 100 ml of water and the crystalline solid was filtered off and washed with water.
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)C=[CH:22][CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl.OC(COC1C=CC(OC)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.OC(COC1C=CC(C(C)(C)C)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:25]([CH2:26][CH2:27][CH3:28])=[CH:24][CH:29]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2cccc3ccccc23)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)cc2)cc1
Agent: Cl
Product: CCCc1ccc(OCC(O)CNC(C)(C)Cc2ccc(OC)cc2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 356 (M−15, 0.8), 251(18), 250 (100), 163 (5), 121 (19), 114 (7), 110 (5), 107 (7), 91 (6).
Reaction SMILES: CI.[F:3][C:4]([F:21])([F:20])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]2)=[N:9][CH:10]=1.[C:22](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:21][C:4]([F:3])([F:20])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH3:22])=[O:18])[CH2:13][CH2:12]2)=[N:9][CH:10]=1
Reactant: O=C(O)C1CCN(c2ccc(C(F)(F)F)cn2)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.9 %

Procedure:
Methyl iodide (0.30 mL, 4.82 mmol) was added to a solution of 1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylic acid (1.00 g, 3.65 mmol) and potassium carbonate (800 mg, 5.79 mmol) in DMF (10 mL), and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction solution, followed by extraction with diethyl ether twice. The obtained organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elute: hexane/ethyl acetate=100/0-60/40 (gradient)] to obtain the title compound (1.03 g, yield: 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[CH:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:12][C@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14].[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:12][C@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14]
Reactant: C[C@H](NC(c1ccccc1)c1cc([N+](=O)[O-])ccc1Cl)c1ccccc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: C[C@H](NC(c1ccccc1)c1cc(N)ccc1Cl)c1ccccc1

Procedure:
In a similar manner to that described in Example (1b), N-[(2-chloro-5-nitrophenyl)phenylmethyl]-N-[(S)-1-phenylethyl]amine (2.58 g) [prepared as described in step (a) above], nickel chloride hexahydrate (3.33 g) and sodium borohydride (1.06 g) were reacted. The crude product was separated and purified by chromatography through a silica gel column using a 1:10 by volume mixture of ethyl acetate and toluene as the eluant, to afford isomer A (771 mg) as a colorless oil and isomer B (659 mg) as a pale yellow oil of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([N:31]2[C:35]3=[N:36][CH:37]=[N:38][C:39]([NH2:40])=[C:34]3[CH:33]=[N:32]2)[CH2:27][CH2:26]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH2:20][N:25]4[CH2:30][CH2:29][CH:28]([N:31]5[C:35]6=[N:36][CH:37]=[N:38][C:39]([NH2:40])=[C:34]6[CH:33]=[N:32]5)[CH2:27][CH2:26]4)=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1
Reactant: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Reactant: Nc1ncnc2c1cnn2C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1nc2nc(-c3ccc(CN4CCC(n5ncc6c(N)ncnc65)CC4)cc3)c(-c3ccccc3)cn2n1
Temperature: 25 °C
Reaction time: 120 h
Yield: 14.5 %

Procedure:
200 mg (0.64 mmol) 4-(2-methyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)benzaldehyde and 194 mg (0.64 mmol) 1-piperidine-4-yl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine were treated as described in example 2. Additional NaBH(OAc)3 has been added after 24 and 26 hours (two equivalents each). After five days stirring at room temperature the solvents have been evaporated and the residue was purified via chromatography. 48 mg of the desired compound were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH:5]([C:36]#[N:37])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[S:26]([NH:29][C:30]([NH:32][CH2:33][CH2:34][CH3:35])=[O:31])(=[O:28])=[O:27])=[CH:16][CH:15]=1)[C:7](=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2].C(N(CC)CC)C.[CH3:46][SH:47]>ClCCl>[NH2:37][C:36]([S:47][CH3:46])=[C:5]([N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[S:26]([NH:29][C:30]([NH:32][CH2:33][CH2:34][CH3:35])=[O:31])(=[O:28])=[O:27])=[CH:16][CH:15]=1)[C:7](=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11])[C:4]([O:3][CH2:1][CH3:2])=[O:38]
Reactant: CS
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)NCCC)cc1)C(C#N)C(=O)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)NCCC)cc1)C(C(=O)OCC)=C(N)SC
Temperature: -20 °C

Procedure:
A solution of 8.5 g of the product of Stage B and 2.4 ml of triethylamine in 100 ml of dichloromethane was saturated with methanethiol by sweeping through the stirred solution cooled to -20° C. The temperature was allowed to rise and then the solution was maintained under a nitrogen pressure of 10 bars at 40° C. for 48 hours. After concentration, the residue was purified by chromatography on silica (eluant: dichloromethane-MeOH 20-1) to obtain 8.0 g of the expected product with an Rf (SiO2, dichloromethane-MeOH20-1)=0.39.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([C:9](=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8])=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3]>[N+](CC)([O-])=O>[Br:1][C:2]1[S:6][C:5]2[C:7](=[O:8])[CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:4]=2[CH:3]=1
Reactant: CCOC(=O)C(=Cc1ccccc1)C(=O)c1ccc(Br)s1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC[N+](=O)[O-]
Product: CCOC(=O)C1C(=O)c2sc(Br)cc2C1c1ccccc1
Yield: 78.8 %

Procedure:
A solution of ethyl 2-(5-bromothiophene-2-carbonyl)-3-phenylacrylate (1.3 g, 3.56 mmol) and aluminum trichloride (0.563 g, 4.27 mmol) in nitroethane (20 ml) was heated at 83° C. for 2.75 hours. The reaction mixture was poured into 1N HCl-ice solution, and extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4) and concentrated to give a brown oil. The crude product was purified by silica gel flash chromatography using 0-5% ethyl acetate in hexanes to give ethyl 2-bromo-6-oxo-4-phenyl-5,6-dihydro-4H-cyclopenta[b]thiophene-5-carboxylate as a viscous foam (1.024 g, 78.8% yield). LCMS m/z 366, 368 (M+1); 388.9, 386.9 (M+23); HPLC: Rt 3.438, 3.718 min.
Reaction SMILES: [Br:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([OH:22])([CH3:21])[CH3:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:30][O:31][CH2:32]Cl>C1COCC1>[Br:1][C:2]1[C:7]([N:8]([CH2:30][O:31][CH3:32])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([OH:22])([CH3:21])[CH3:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1
Reactant: COCCl
Reactant: CC(C)(O)c1cc(S(=O)(=O)Nc2cc(Cl)cnc2Br)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(C)(C)O)c1

Procedure:
Prepared from 285 mg (0.648 mmol) of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-3-(1-hydroxy-1-methyl-ethyl)-benzenesulfonamide, 268 mg of potassium carbonate and 150 μL of methoxymethyl chloride in 2 mL THF using procedure x. Yield: 153 mg of a white solid. LC-MSD, m/z for C16H17BrCl2N2O4S [M+H]+=482.9, 484.9, 486.9