Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]2[CH2:16][CH2:17][OH:18])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:32]([N:37]([CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:38](Cl)=[O:39])[CH2:33][CH2:34][CH2:35][CH3:36]>O1CCCC1>[C:19]1([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:38](=[O:39])[N:37]([CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:12][CH:11]2[CH2:16][CH2:17][OH:18])=[O:9])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCCCCN(CCCCC)C(=O)Cl
Reactant: O=C(N(c1ccccc1)c1ccccc1)N1CCNCC1CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2ccccc2)C(CCO)C1
Temperature: 60 °C
Reaction time: 48 h
Yield: 64.2 %

Procedure:
To a solution of 174 mg (0.53 mmol) of (RS)-1-(N,N-diphenylcarbamoyl)-2-(2-hydroxyethyl) piperazine in 10 mL of dry tetrahydrofuran was added 450ml (3.23 mmol) of triethylamine in one portion and 176 mg (0.80 mmol) of dipentylcarbamyl chloride (dissolved in 2 mL of dry tetrahydrofuran) and the mixture was stirred under nitrogen at 60° C. for two days. The solution was cooled and concentrated in vacuo. Flash chromatography on 25 g of silica gel using 75:25 v/v ethyl acetate/hexane as the eluant afforded 173 mg (64%) of a yellow oil.
Reaction SMILES: S(Cl)(Cl)(=O)=O.C1C2C(=CC=CC=2)C=CC=1.[C:16]1([CH2:26][O:27][CH2:28]SC)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.CS[Cl:33]>ClCCl>[Cl:33][CH2:28][O:27][CH2:26][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CSCOCc1cccc2ccccc12
Reactant: CSCl
Solvent: c1ccc2ccccc2c1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: ClCOCc1cccc2ccccc12

Procedure:
1-Chloromethyloxymethyl)naphthalene Sulfuryl chloride (12 mmol) in dry dichloromethane (20 mmol) was added dropwise with stirring to a solution of methylthiomethyl 1-naphthylmethyl ether (12 mmol) in dry dichloromethane (40 ml) at room temperature. After stirring for 30 min the solvent and methanesulfenyl chloride formed in the reaction were distilled off at reduced pressure. The residual material was used for alkylation without further purification. 1H NMR (CDCl3): δ5.13 (CH2), 5.47 (CH2Cl), 7.2-8.3 (Naph).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:39]1[CH2:43][CH2:42][NH:41][CH2:40]1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11](=[O:12])[N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:27])([F:28])[F:26])=[N:20][C:21]([C:22]([N:41]3[CH2:42][CH2:43][S:39][CH2:40]3)=[O:23])=[C:15]2[CH2:14]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: C1CSCN1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCSC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 89.4 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.15 g, 0.27 mmol), thiazolidine (57 mg, 0.6 mmol), triethylamine (0.275 g, 2.72 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.138 g, 0.544 mmol) were dissolved in 10 mL of dichloromethane under stirring. The reaction mixture was stirred at room temperature for 2 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concen-trated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-oxo-3-[1-(thiazolidine-3-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 20a (0.15 g, yield 89%) as a white solid.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.[CH:19]([C:21]1[CH:31]=[CH:30][C:24]([CH:25]=[CH:26][C:27]([OH:29])=[O:28])=[CH:23][CH:22]=1)=O.[OH-].[K+].Cl>CCO>[ClH:1].[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16](=[O:18])/[CH:17]=[CH:19]/[C:21]3[CH:22]=[CH:23][C:24](/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])=[CH:30][CH:31]=3)=[CH:14][CH:15]=2)[CH2:5][CH2:4]1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Reactant: CC(=O)c1ccc(CC2CCN(C)CC2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCC(Cc2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
A mixture of 1-[4-(1-methyl-piperidin-4-ylmethyl)-phenyl]-ethanone hydrochloride (prepared as described in Preparation 2, 426 mg, 1.59 mmol), 4-formylcinnamic acid (280 mg, 1.59 mmol) and 1.7 M KOH (2.8 ml) in EtOH (7 ml) was stirred at room temperature overnight. The mixture was acidified with 10% HCl and the resulting precipitate was filtered off to give 388 mg of (E)-3-(4-{(E)-3-[4-(1-methyl-piperidin-4-ylmethyl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid hydrochloride.
Reaction SMILES: CS(O[CH:6]([CH:17]([CH3:19])[CH3:18])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=1)(=O)=O.[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:18][CH:17]([CH3:19])[CH:6]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=1)[N:20]1[CH:24]=[N:23][CH:22]=[N:21]1
Reactant: CC(=O)Nc1ccc(C(OS(C)(=O)=O)C(C)C)cc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)Nc1ccc(C(C(C)C)n2cncn2)cc1
Yield: 25.1 %

Procedure:
A mixture of (±)-4-(acetylamino)-α-(1-methylethyl)benzenemethanol methane sulfonate (ester) (0.1541 mol), 1H-1,2,4-triazole (0.308 mol) and K2CO3 (0.308 mol) in CH3CN (500 ml) was stirred and refluxed for 12 hours. The solvent was evaporated and the residue was taken up in water/CH2Cl2. The organic layer was dried, filtered off and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent : CH2Cl2/CH3OH 97/3). The pure fractions were collected and evaporated, yielding 10 g (25%) of (±)-N-[4-[2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]-phenyl]acetamide (compound 153).
Reaction SMILES: [CH3:1][C:2](=[CH2:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7](O)=[O:8].C(Cl)(=O)C([Cl:14])=O>C1C=CC=CC=1>[CH3:1][C:2](=[CH2:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([Cl:14])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=C(C)CCCCC(=O)O
Solvent: c1ccccc1
Product: C=C(C)CCCCC(=O)Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the carboxylic acid 7 (2.2 g, 15.5 mmol) in benzene (30 ml), was added oxalyl chloride (3 ml, 34.4 mmol, 2.22 equiv). A drying tube was placed on the flask and the reaction mixture was stirred for 90 min at room temperature before it was concentrated in vacuo. The crude acid chloride 8 was used in the next step without further purification: TLC Rf=0.37 (silica gel, 25% EtOAc/hexanes); 1H NMR (600 MHz, CDCl3) δ 4.69 (s, 1H), 4.67 (s, 1H), 2.88 (t, J=7.8 Hz, 2H), 2.02 (t, J=7.8 Hz, 2H), 1.74-1.66 (m, 2H), 1.69 (s, 3H), 1.58-1.46 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 173.9, 145.1, 110.7, 46.7, 37.3, 26.4, 24.8, 22.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[N+:20]([O-])=O.C(O)C.[H][H]>[Pd]>[CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20]
Reactant: [H][H]
Reactant: COc1c([N+](=O)[O-])ccc2c1CCC(N1CCOCC1)CC2
Agent: [Pd]
Solvent: CCO
Product: COc1c(N)ccc2c1CCC(N1CCOCC1)CC2
Reaction time: 8 h
Yield: 97.4 %

Procedure:
4-(1-Methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-morpholine (0.24 g, 0.00078 mol) was dissolved in ethanol (40 mL, 0.7 mol) and placed in a Parr bottle. To this solution was added palladium on carbon (10 mg). The reaction mixture was placed under 50 psi of hydrogen and shaken overnight. The mixture was filtered through celite and washed with additional ethanol (40 mL). The filtrate was concentrated in vacuo. The film was triturated with diethyl ether to provide 1-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine as a solid (0.21 g, 97%). 1H NMR (400 MHz, CDCl3) δ 6.71 (d, 1H, J=7.84 Hz), 6.51 (d, 1H, J=7.83 Hz), 3.70 (s, 7H), 3.31 (m, 1H), 2.75 (m, 1H), 2.60 (m, 2H), 2.55 (s, 4H), 2.31 (m, 1H), 2.0-2.16 (m, 2H), 1.37 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].N#N>O.C(Cl)Cl>[C:17](=[O:18])([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[O:19][CH2:20][CH3:21]
Reactant: CCOC(=O)Cl
Reactant: O=Cc1ccc(O)cc1
Agent: N#N
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)Oc1ccc(C=O)cc1
Temperature: 25 °C
Yield: 91.9 %

Procedure:
To a 250 mL dry round bottom flask were added 4-hydroxybenzaldehyde (6.11 g, 50.0 mmol), anhydrous CH2Cl2 (150 mL). The solution was cooled in an ice-water bath, then pyridine (4.86 mL, 60.0 mmol) was added. To the resulting solution, ethyl chloroformate (4.78 mL, 50.0 mmol) was added slowly under stirring and N2. The mixture was stirred and warmed to room temperature, then stirred at room temperature overnight. To the reaction mixture, water (100 mL) was added and the CH2Cl2 layer was separated. The aqueous layer was extracted continually with CH2Cl2 (100 mL×2). The combined CH2Cl2 solution was dried over Na2SO4. After removal of the solvent, the residue was purified with a silica gel chromatography (heptane/ethyl acetate, gradient eluting) to give ethyl 4-formylphenyl carbonate (8.92 g) as colorless oil. Yield: 92%. 1H NMR (CDCl3, 300 MHz): δ=10.07 (s, 1H), 8.00 (d, J=8.7 Hz, 2H), 7.45 (d, J=8.7 Hz, 2H), 4.42 (q, J=7.2 Hz, 2H), 1.47 (t, J=7.2 Hz, 3H). 13C NMR (CDCl3, 75.5 MHz): δ=191.0, 155.7, 152.9, 134.2, 131.4, 121.9, 65.4, 14.3.
Reaction SMILES: [CH3:1][C:2]1([C:8](Cl)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[NH2:17][C:18]1[C:19]([CH3:24])=[CH:20][CH:21]=[CH:22][CH:23]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([C:8]([NH:17][C:18]2[C:19]([CH3:24])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cc1ccccc1N
Reactant: CC1(C(=O)Cl)CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1ccccc1NC(=O)C1(C)CCCCC1

Procedure:
A mixture of 32.7 grams (0.203 moles) of 1-methyl-1-cyclohexanecarboxylic acid chloride, 15.2 grams (0.11 mole) of anhydrous potassium carbonate and 21.8 grams (0.203 mole) of o-toluidine in 260 ml. of dry toluene is stirred and refluxed for 2.5 hours. The inorganic salts are removed by filtration and the filtrate is concentrated in vacuuo. The residue yields from diethyl ether-pentane 40.5 grams (87%) of N-(1-methylcyclohexyl carbonyl)-o-toluidine; m.p. 138° C.
Reaction SMILES: [C:1]([C:4]12[CH2:11][N:8]([CH2:9][CH2:10]1)[CH2:7][CH2:6][CH2:5]2)(=[O:3])[CH3:2].[Br:12]Br>CO.O>[BrH:12].[Br:12][CH2:2][C:1]([C:4]12[CH2:11][N:8]([CH2:9][CH2:10]1)[CH2:7][CH2:6][CH2:5]2)=[O:3]
Reactant: BrBr
Reactant: CC(=O)C12CCCN(CC1)C2
Solvent: CO
Solvent: O
Product: Br
Product: O=C(CBr)C12CCCN(CC1)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 225.5 %

Procedure:
A solution of the hydrobromide salt of (±) 5-acetyl-1-azabicyclo[3.2.1]octane (D4) (2.0g; 8.5 mmole) in dry methanol (35ml) was cooled to -10° C. and treated with a solution of bromine (0.44ml; 8.5 mmole) in dry methanol (5ml). The reaction was maintained at 0° C. for 18h. A further quantity of bromine (0.44 ml) was added and after 5h at room temperature the reaction was diluted with water and stirred for 1h. Evaporation of solvent and excess reagent in vacuo afforded a yellow foam (3.0 g) consisting mainly of the title compound (D5). This material was used in the next stage without purification.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.[Br:8][C:9]1[S:10][C:11]2[CH2:12][NH:13][CH2:14][CH2:15][C:16]=2[N:17]=1.[CH2:18](N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl.CC(C)=O.C(O)(=O)C>[Br:8][C:9]1[S:10][C:11]2[CH2:12][N:13]([CH:3]([CH3:2])[CH3:18])[CH2:14][CH2:15][C:16]=2[N:17]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Brc1nc2c(s1)CNCC2
Reactant: CCN(CC)CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)N1CCc2nc(Br)sc2C1
Temperature: 25 °C

Procedure:
2-Bromo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine trifluoroacetate (5.00 g) was suspended in dichloromethane (200 ml), and to the suspension triethylamine (4.16 ml) was added, and the mixture was stirred at room temperature into a solution. Acetic acid (2.55 ml) and acetone (17 ml) were added to the reaction mixture, and the mixture was stirred at room temperature for 2 minutes. Sodium triacetoxyborohydride (19.1 g) was added to the reaction mixture, and the resultant mixture was stirred at room temperature for 5 hours. A 3N aqueous solution (200 ml) of sodium hydroxide was added to the reaction mixture to separate an organic layer. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=100:1) to obtain the title compound (3.45 g) as a yellow oil.
Reaction SMILES: [BH4-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[CH2:13]2)=[CH:4]1.N1C2C(=CC=CC=2)C=C1[C@@H]1C2C(=CC=CC=2)[C@H](O)C1>CO.C1COCC1>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C@H:14]([OH:21])[CH2:13]2)=[CH:4]1
Reactant: O=C1CC(c2c[nH]c3ccccc23)c2ccccc21
Agent: O[C@@H]1C[C@H](c2cc3ccccc3[nH]2)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O[C@@H]1C[C@H](c2c[nH]c3ccccc23)c2ccccc21
Temperature: 25 °C

Procedure:
NaBH4 (6.2 g, 163 mmol, 2 equiv.) was added to 3-(1H-indol-3-yl)-indan-1-one (20 g, 80.9 mmol ) in 200 mL methanol and 100 mL THF at 0° C. The reaction mixture was allowed to warm to room temperature over night. Aqueous work up gave racemic cis-3-indolyl-indan-1-ol (quantitative).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:14][C:15]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:18]=[CH:17][C:16]=1[CH:26]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:3]([N:8]2[CH2:9][CH2:10][N:11]([CH2:26][C:16]3[CH:17]=[N:18][N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:15]=3[CH3:14])[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: Clc1nccnc1N1CCNCC1
Reactant: Cc1c(C=O)cnn1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(CN2CCN(c3nccnc3Cl)CC2)cnn1-c1ccccc1
Yield: 66.9 %

Procedure:
Stir together 3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (1.6 g, 8.43 mmol) and 5-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (2.35 g, 12.6 mmol) in dry tetrahydrofuran (10 mL) at room temperature for 15 min., under nitrogen. Add sodium triacetoxyborohydride (2.68 g, 12.6 mmol) and stir reaction for 1 hr. Quench reaction mixture with saturated aq. sodium bicarbonate (50 mL), then extract with DCM (3×50 mL) and pass through an IST Phase Separator Frit®. Concentrate and purify (silica gel chromatography, eluting with 5:95 methanol:DCM) and concentrate all fractions containing product. Pass the mixture through a CBA column to retain the product, wash with methanol and then elute with 2 M ammonia in methanol. Recrystallize from hot ethanol and dry in vacuum oven to give 3′-chloro-4-(5-methyl-1-phenyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl as white crystals (2.08 g, 65%). MS (ES): m/z=369 [M+H]+.
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH2:34]([O:41][CH2:42][C@H:43]([C:45]1[C:53]2[C:48](=[N:49][CH:50]=[C:51]([C:54]([CH3:59])([CH3:58])[C:55](O)=[O:56])[CH:52]=2)[NH:47][C:46]=1[C:60]1[CH:65]=[C:64]([CH3:66])[CH:63]=[C:62]([CH3:67])[CH:61]=1)[CH3:44])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[CH2:68]([NH:72][CH2:73][CH:74]([CH3:76])[CH3:75])[CH:69]([CH3:71])[CH3:70].C(N(CC)CC)C>C(Cl)Cl>[CH2:68]([N:72]([C:55](=[O:56])[C:54]([C:51]1[CH:52]=[C:53]2[C:45]([C@H:43]([CH3:44])[CH2:42][O:41][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:46]([C:60]3[CH:65]=[C:64]([CH3:66])[CH:63]=[C:62]([CH3:67])[CH:61]=3)[NH:47][C:48]2=[N:49][CH:50]=1)([CH3:59])[CH3:58])[CH2:73][CH:74]([CH3:76])[CH3:75])[CH:69]([CH3:71])[CH3:70]
Reactant: CC(C)CNCC(C)C
Reactant: Cc1cc(C)cc(-c2[nH]c3ncc(C(C)(C)C(=O)O)cc3c2[C@H](C)COCc2ccccc2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2[nH]c3ncc(C(C)(C)C(=O)N(CC(C)C)CC(C)C)cc3c2[C@H](C)COCc2ccccc2)c1
Reaction time: 12 h

Procedure:
PyBOP is added to a stirred mixture of (S)-2-[3-(2-benzyloxy-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-pyrrolo-[2,3-b]pyridin-5-yl]-2-methylpropanoic acid, diisobutylamine and triethylamine in CH2Cl2 at ambient temperature. After approximately 12 h, the reaction mixture is poured into waterlbrine (1:1) and extracted with ethyl acetate. The combined organic extract is washed with brine, dried (MgSO4) and concentrated in vacuo. The residue is purified by flash chromatography on silica gel (gradient elution; 60-75% ethyl acetate/hexanes as eluent) to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[Na+].[Na+].Br[C:19]1[CH:27]=[C:26]2[C:22]([C:23]([NH:36][C:37](=[O:41])[CH2:38][CH2:39][CH3:40])=[N:24][N:25]2[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[CH:21][CH:20]=1>O1CCOCC1.C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:19]2[CH:27]=[C:26]3[C:22]([C:23]([NH:36][C:37](=[O:41])[CH2:38][CH2:39][CH3:40])=[N:24][N:25]3[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:33])[CH3:34])=[CH:21][CH:20]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Br)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(C#N)cc3)ccc12
Yield: 189.8 %

Procedure:
853 mg of 4-cyanophenylboronic acid, 15 cm3 of water, 1.0 g of sodium carbonate and 314 mg of tetrakis(triphenylphosphine)palladium are added to 500 mg of N-[6-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, prepared as described in Example 51, in 100 cm3 of dioxane. The reaction medium is then refluxed for 4 hours and diluted with 70 cm3 of ethyl acetate and 75 cm3 of water. The organic phase is separated out after settling of the phases has taken place and washed with 50 cm3 of distilled water and then with 2×50 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 45° C.). The residue obtained, 2.0 g, is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); 1.0 g of N-[6-(4-cyanophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide is obtained in the form of a yellow solid melting at 136° C.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([NH:15][CH3:16])[CH2:9]2)(=[O:4])=[O:3].Cl[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[CH:25]=2)[N:20]=1.C(=O)(O)[O-].[Na+]>C(#N)C>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([N:15]([CH2:18][C:19]1[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[CH:25]=3)[N:20]=1)[CH3:16])[CH2:9]2)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Nc1ccc2nc(CCl)ccc2c1
Reactant: CNC1Cc2ccc(NS(C)(=O)=O)cc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN(Cc1ccc2cc(NS(C)(=O)=O)ccc2n1)C1Cc2ccc(NS(C)(=O)=O)cc2C1

Procedure:
5-Methanesulphonamido-2-methylaminoindane (0.09 g), 2-chloromethyl-6-methanesulphonamidoquinoline (0.1 g) and sodium bicarbonate (0.2 g) were heated under reflux in acetonitrile (10 ml) for 11/2 hours. The solvent was then removed by evaporation in vacuo and the residue was taken up in methylene chloride, washed with aqueous sodium bicarbonate, dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography on silica eluting with methylene chloride containing methanol (0% up to 2%) and the product-containing fractions were combined and evaporated to give the title compound as a foam, yield 0.09 g. A sample was crystallised from deuterochloroform, m.p. 189°-191°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:5][C:6]1[NH:10][C:9]([CH3:11])=[N:8][C:7]=1[CH:12]([CH3:14])[CH3:13].[C:19](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:5][C:6]1[N:10]([CH3:19])[C:9]([CH3:11])=[N:8][C:7]=1[CH:12]([CH3:14])[CH3:13]
Reactant: O=C([O-])[O-]
Reactant: Cc1nc(C(C)C)c(Cc2cc(Cl)cc(Cl)c2)[nH]1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cc1nc(C(C)C)c(Cc2cc(Cl)cc(Cl)c2)n1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 22.2 %

Procedure:
In 20 ml of dry acetone was dissolved 930 mg (3.3 mmol) of 5-(3,5-dichlorobenzyl)-4-isopropyl-2-methyl-1H-imidazole (54), followed by addition of 1.4 g (10.1 mmol)of anhydrous potassium carbonate, and the mixture was stirred at room temperature. After 5 minutes, 225 μl (3.6 mmol)of methyl iodide was added at room temperature, and the mixture was heated to 80° C. After 5 hours, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with water, and extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate)to give 218 mg of the target compound (Compound I-100)(yield 22%).