Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.[Li]CCCC.[CH2:13]([CH:15]([CH:21]([CH2:27][CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:14].IC(C)C.CN(C)P(N(C)C)(N(C)C)=O>O1CCCC1>[CH2:13]([C:15]([CH:5]([CH3:6])[CH3:7])([CH:21]([CH2:27][CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:14]
Reactant: CC(C)NC(C)C
Reactant: CCOC(=O)C(CC)C(CC)C(=O)OCC
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)I
Solvent: C1CCOC1
Product: CCOC(=O)C(CC)C(CC)(C(=O)OCC)C(C)C
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 10 mL (72 mmol) of diisopropylamine in 250 mL of tetrahydrofuran (THF) was added 28.6 mL (72 mmol) of BuLi (2.5 molar in cyclohexanes) at −20° C. After 20 minutes stirring, 9.2 g (83% pure) (28.3 mmol) of diethyl 2,3-diethylsuccinate was added at −40° C. and after addition the mixture was stirred for 2 h at room temperature. Then this mixture was cooled to −70° C. and a mixture of 4.3 mL (43 mmol) of 2-iodopropane and 7.4 mL (43 mmol) of hexamethylphosphoramide (HMPA) was added. After addition the cooling was removed and the mixture was stirred for four days. The volatiles were removed and 250 mL of ether was added. The organic layer was washed twice with 100 mL of water. The organic layer was isolated, dried over MgSO4, filtered and concentrated in vacuo yielding an orange oil. This oil was chromatographed over silica with CH2Cl2 yielding 2.3 g (30%) of a 96% pure product. According to gaschromatography (GC) only one isomer was present.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[C:8]([CH3:27])=[N:9][C:10]3[C:15]([C:16]=2[CH3:17])=[C:14](OS(C(F)(F)F)(=O)=O)[CH:13]=[C:12]([CH3:26])[CH:11]=3)=[CH:4][CH:3]=1.[Si]([O:37][C:38]([O:40][CH3:41])=[CH2:39])(C(C)(C)C)(C)C.C([O-])(=O)C.[Na+]>CN(C)C=O.[Cl-].[NH4+].[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:41][O:40][C:38](=[O:37])[CH2:39][C:14]1[CH:13]=[C:12]([CH3:26])[CH:11]=[C:10]2[C:15]=1[C:16]([CH3:17])=[C:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:29][CH:28]=1)[C:8]([CH3:27])=[N:9]2
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)c2c(C)c(Cc3ccc(Cl)cc3)c(C)nc2c1
Reactant: C=C(OC)O[Si](C)(C)C(C)(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cc(C)cc2nc(C)c(Cc3ccc(Cl)cc3)c(C)c12
Temperature: 120 °C

Procedure:
A mixture of trifluoromethanesulfonic acid 3-(4-chlorobenzyl)-2,4,7-trimethylquinolin-5-yl ester (0.39), 1-(tert-butyldimethylsilyloxy)-1-methoxyethene (0.95 mL), sodium acetate (0.086 g), tris(dibenzylideneacetone) dipalladium (0) (0.080 g) and 1,1′-bis(diphenylphospino) ferrocene (0) (0.048 g) in N,N-dimethylformamide (3.0 mL) was heated by microwave irradiation at 120° C. for 10 minutes. The mixture was diluted with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and the solvent removed under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:1 by volume) gave title compound, 0.11 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([O:18]CC)=[O:17])[C:13](=[O:21])[C:12]([CH3:23])([CH3:22])[O:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[Li+].[OH-]>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([OH:18])=[O:17])[C:13](=[O:21])[C:12]([CH3:23])([CH3:22])[O:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)CN1C(=O)C(C)(C)OC[C@H]1c1cc(F)cc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OC[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl [(5R)-5-(3,5-difluorophenyl)-2,2-dimethyl-3-oxomorpholin-4-yl]acetate from Step H (150 mg, 0.46 mmol) in THF (3 mL) and H2O (3 mL) was added 1 N aqueous LiOH (0.55 mL, 0.55 mmol) and the resulting mixture was stirred at ambient temperature for 18 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=300 (M+1).
Reaction SMILES: [C:1]([NH:4][CH:5](C(OCC)=O)[C:6]([O:8]CC)=[O:7])(=[O:3])[CH3:2].CC(C)([O-])C.[K+].[C:22]1([C:28](Br)(Br)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[Na+]>CN1CCCC1=O.C1(C)C=CC=CC=1>[C:1]([NH:4][CH:5]([CH:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: BrC(Br)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: CC(=O)NC(C(=O)O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
To a solution (1.25 M) of diethyl acetamidomalonate (10.94 g, 50.57 mmol) in N-methyl-2-pyrrolidone (40 mL) was added potassium t-butoxide (5.90 g, 52.60 mmol), and the mixture was stirred at room temperature for 1 hr. Diphenylmethylene bromide (10.0 g, 46.46 mmol) was added, and the mixture was stirred at 70° C. for 5 hrs. After completion of the reaction, 2M aqueous sodium hydroxide solution (45 mL) was added to the reaction mixture, and the mixture was stirred at 70° C. for 3 hrs. The reaction mixture was allowed to cool to room temperature, toluene (19 mL) was added, and the mixture was partitioned. The aqueous layer was adjusted to pH 7.0 with concentrated hydrochloric acid (8.8 mL). Ethyl acetate (80 mL) was added, and then concentrated hydrochloric acid (13.0 mL) was added. The mixture was partitioned, and the aqueous layer was extracted with ethyl acetate (40 mL). The organic layers were combined, successively washed with 2M hydrochloric acid (40 mL, three times) and saturated brine (10 mL), and concentrated. Toluene (30 mL) was added to the concentrated solution and the mixture was concentrated at 50° C. Toluene (30 mL) was added again, and the mixture was stirred for 30 min and cooled to 0° C. over 5 hrs, which resulted in the precipitation of white crystals. The crystals were collected by filtration and dried under reduced pressure to give the title compound (9.18 g).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][NH:4][N:3]=1.[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH:19]=O)[CH2:14][CH2:13][CH2:12][CH2:11]1.C([BH3-])#N.[Na+]>CO>[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:19][NH:1][C:2]2[C:6]([C:7]([OH:9])=[O:8])=[CH:5][NH:4][N:3]=2)[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: Nc1n[nH]cc1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNc2n[nH]cc2C(=O)O)cc1OC1CCCC1
Yield: 48.5 %

Procedure:
A suspension of 3-amino-4-pyrazole carboxylic acid (3.56 g, 28 mmol) in 400 ml of methanol and 3-cyclopentyloxy-4-methoxybenzaldehyde (5.06 g, 23 mmol) was stirred at room temperature for 16 hours with sodium cyanoborohydride, 1.85 g (95% pure, 28 mmol). The methanol was evaporated under reduced pressure and the residue was taken up in 100 ml of 15% sodium hydroxide and extracted twice with 100 ml portions of ether. The aqueous layer was acidified to pH 5 with 5N hydrochloric acid and extracted twice with 100 ml portions of ethyl acetate. The ethyl acetate was dried over sodium sulfate and evaporated. The residue was triturated with ether to give 3.7 g of 3-(3-cyclopentyloxy-4-methoxybenzylamino)-4-pyrazolecarboxylic acid (48.7%). Pure 3-(3-cyclopentyloxy-4-methoxybenzylamino)pyrazole carboxylic acid shows mp. 134-136° C. after crystallization from methanol.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[N:10][CH:9]=[CH:8][C:7]=3[C:6]=2[C:5]2[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:4]=2[N:3]=1.[CH2:21](Br)[CH:22]=[CH2:23]>>[CH2:23]([O:20][C:18]1[CH:17]=[CH:16][C:5]2[C:6]3[C:7]4[CH:8]=[CH:9][N:10]=[CH:11][C:12]=4[C:13](=[O:15])[C:14]=3[C:2]([Cl:1])=[N:3][C:4]=2[CH:19]=1)[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: O=C1c2cnccc2-c2c1c(Cl)nc1cc(O)ccc21
Product: C=CCOc1ccc2c3c(c(Cl)nc2c1)C(=O)c1cnccc1-3

Procedure:
This compound was prepared from 6-chloro-3-hydroxy-5,9-diaza-benzo[c]fluoren-7-one (Example 34a) and allyl bromide in a similar manner to Example 34b. The desired product was obtained as a yellow powder. ESI−MS: m/z 323 (MH+); 1H-NMR (CDCl3): δ4.75 (2H, dt, J=5 Hz, 1 Hz), 5.41 (1H, dq, J=11 Hz, 1 Hz), 5.52 (1H, dq, J=17 Hz, 1 Hz), 6.12 (1H, ddt, J=17 Hz, 11 Hz, 5 Hz), 7.43 (1H, dd, J=8 Hz, 1.5 Hz), 7.45 (1H, s), 8.01 (1H, dd, J=5 Hz, 1 Hz), 8.36 (1H, dd, J=8 Hz, 1.5 Hz), 8.96 (1H, d, J=5 Hz), 9.04 (1H, d, J=1 Hz).
Reaction SMILES: [CH:1]1([C@@H:7]2[CH2:11][N:10]([C:12](=[O:29])[CH2:13][P:14]([O:26]CC)([CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:15])[C@H:9]([C:30]([OH:32])=[O:31])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.Br[Si](C)(C)C.O>ClCCl>[CH:1]1([C@@H:7]2[CH2:11][N:10]([C:12](=[O:29])[CH2:13][P:14]([OH:26])([CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:15])[C@H:9]([C:30]([OH:32])=[O:31])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOP(=O)(CCCCc1ccccc1)CC(=O)N1C[C@@H](C2CCCCC2)C[C@H]1C(=O)O
Agent: C[Si](C)(C)Br
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(O)[C@@H]1C[C@H](C2CCCCC2)CN1C(=O)CP(=O)(O)CCCCc1ccccc1

Procedure:
(cis)-4-Cyclohexyl-1-[[ethoxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline, (0.83 g), bis(trimethylsilyl)acetamide (0.47 ml) and bromotrimethylsilane (0.28 ml) are stirred in 20 ml of dichloromethane for about 16 hours. A small amount of water is added and the mixture is evaporated to an oil residue (0.61 g). This material is crystallized from acetone with a recovery of 0.047 g of solid, melting point 175°-176° C.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:19][C:20]3[CH:33]=[CH:32][C:23]([C:24]([N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[O:25])=[CH:22][CH:21]=3)=[CH:8][C:9](C3C=CC=CC=3)=[N:10]2)=[CH:5][CH:4]=1.[F:36][C:37]([F:49])([F:48])[C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>C(N(CC)CC)C>[F:36][C:37]([F:49])([F:48])[C:38]1[CH:43]=[CH:42][C:41]([S:44]([N:29]2[CH2:30][CH2:31][N:26]([C:24](=[O:25])[C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:1])([F:34])[F:35])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:33][CH:32]=3)[CH2:27][CH2:28]2)(=[O:46])=[O:45])=[CH:40][CH:39]=1
Reactant: O=C(c1ccc(Nc2cc(-c3ccccc3)nc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
In the manner given in Example 15, 4-[4-[[7-(trifluoromethyl)phenyl-4-quinolinyl]amino]benzoyl]piperazine is reacted with p-trifluoromethylphenylsulfonyl chloride in the presence of triethylamine to give 1-[4-(trifluoromethyl)phenylsulfonyl]-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][C:15](O)=[O:16])[O:11][CH:12]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][OH:16])[O:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1nc(-c2ccc(Cl)cc2)co1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCCc1nc(-c2ccc(Cl)cc2)co1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
To a solution of 4-(4-chlorophenyl)-2-oxazoleproponic acid (1.5 g) in THF (20 ml) was added lithium aluminum hydride (0.27 g), followed by stirring for 3 hours at room temperature. Water (3 ml) was added to the reaction mixture. The resultant was extracted with ethyl acetate. The ethyl acetate layer was washed with 2N-HCl and water, dried over MgSO4, and distilled to remove the solvent. The oily residue was subjected to a silica gel chromatography. Crystals of 3-[4-(4-chlorophenyl)-2-oxazolyl]propanol (1.11 g, 78%) were obtained from the fraction eluted with ethyl acetatehexane (2:1, V/V). Recrystallization from ether-hexane gave colorless prism crystals of mp 43°-44° C.
Reaction SMILES: Cl.[CH2:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][O:3]1.FC(F)(F)S([O-])(=O)=O.[N:20]1([S:25](N2C=C[NH+](C)C2)(=[O:27])=[O:26])[CH:24]=[CH:23][N:22]=[CH:21]1>>[N:20]1([S:25]([N:9]2[CH2:10][CH2:11][C:6]3([CH2:2][O:3][CH2:4][CH2:5]3)[CH2:7][CH2:8]2)(=[O:27])=[O:26])[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: C[NH+]1C=CN(S(=O)(=O)n2ccnc2)C1
Reactant: C1CC2(CCN1)CCOC2
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)F
Product: O=S(=O)(N1CCC2(CCOC2)CC1)n1ccnc1

Procedure:
8-(Imidazole-1-sulfonyl)-2-oxa-8-aza-spiro[4.5]decane was prepared in accordance with step A of the general method described in example 76 from 2-oxa-8-aza-spiro[4.5]decane hydrochloride and 3-(1H-imidazol-1-ylsulfonyl)-1-methyl-1H-imidazolium trifluoromethanesulfonate; MS: m/e=216.5 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([NH2:9])[N:3]=1.[N:10]1([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[CH3:1][C:2]1[N:3]=[C:4]([NH2:9])[CH:5]=[C:6]([N:13]2[CH2:12][CH2:11][N:10]([CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[CH2:15][CH2:14]2)[N:7]=1
Reactant: Cc1nc(N)cc(Cl)n1
Reactant: C1CN(CCN2CCOCC2)CCN1
Product: Cc1nc(N)cc(N2CCN(CCN3CCOCC3)CC2)n1

Procedure:
210 mg (1.47 mmol) of 2-methyl-4-chloro-6-aminopyrimidine 20-1 and 294 mg (1.47 mmol) of 4-(2-piperazin-1-ylethyl)morpholine 7-3 were used to obtain the desired product 20-2 as a yellow oil/solid. MS M+1=307. H1 NMR (CDCl3): 2.37(s, 3H), 2.53(br m, 4H), 2.57(br m, 4H), 3.57(m, 4H), 3.73(m, 4H), 4.52(br s, 2H), 5.41(s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[C:9]([N+:16]([O-:18])=[O:17])[CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:5]=2[N:4]=1.[CH3:19][NH:20][CH3:21].CO>C(#N)C>[CH3:19][N:20]([CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[C:9]([N+:16]([O-:18])=[O:17])[CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:5]=2[N:4]=1)[CH3:21]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc2[nH]c(CCl)nc12
Reactant: CNC
Solvent: CC#N
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])cc2[nH]c(CN(C)C)nc12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-(chloromethyl)-6-nitro-1H-benzimidazole-4-carboxylate (72 mg) in acetonitrile (3 mL), was added 2M dimethylamine/MeOH solution (1.3 mL), and the mixture was stirred at 80° C. overnight.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([NH2:23])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:24][C:25]1[N:30]=[C:29](Cl)[N:28]=[C:27]([NH:32][C@@H:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]([CH3:43])([CH3:42])[CH2:34]2)[N:26]=1>C1COCC1>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18])[CH2:12][C@@H:11]([NH:23][C:29]2[N:28]=[C:27]([NH:32][C@@H:33]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:35]([CH3:42])([CH3:43])[CH2:34]3)[N:26]=[C:25]([Cl:24])[N:30]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](N)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CC1(C)C[C@H](Nc2nc(Cl)nc(Cl)n2)c2ccccc21
Solvent: C1CCOC1
Product: CC1(C)C[C@H](Nc2nc(Cl)nc(N[C@@H]3C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)C3)n2)c2ccccc21
Reaction time: 3.5 h
Yield: 64.8 %

Procedure:
To a solution of (1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanamine (0.200 g, 0.556 mmol), TEA (0.21 mL, 1.50 mmol) in THF (0.80 mL) was added 4,6-dichloro-N-[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]-1,3,5-triazin-2-amine (0.160 g, 0.500 mol). The reaction was stirred for 3.5 h then concentrated in vacuo. The residue was purified by preparative TLC (10% EtOAc/hexanes) followed by DCM. The relevant band was cut and washed using acetone, filtered, and concentrated in vacuo to afford the title compound (0.228 g, 71%). LC/MS: Rt=2.77 min, ES+ 633 (FA standard).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][N:29]=1>>[F:23][C:22]1[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][N:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)=[C:18]([O:24][CH3:25])[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: Cc1ccnc(Br)c1
Product: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)c3cc(C)ccn3)c2)c1

Procedure:
This compound is prepared by method C using compound 12g and 2-bromo-4-methylpyridine
Reaction SMILES: [NH2:1][C@@H:2]([CH3:20])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=2)=[N:5]1.[C:21]([C:24]1[CH:28]=[C:27]([C:29](O)=[O:30])[NH:26][N:25]=1)(=[O:23])[CH3:22]>>[C:21]([C:24]1[CH:28]=[C:27]([C:29]([NH:1][C@@H:2]([CH3:20])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=3)=[N:5]2)=[O:30])[NH:26][N:25]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c([N+](=O)[O-])c2)n1
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c([N+](=O)[O-])c3)n2)[nH]n1
Yield: 48.9 %

Procedure:
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile (400 mg, 1.48 mmol) was coupled with 3-acetyl-1H-pyrazole-5-carboxylic acid (250 mg, 1.62 mmol) using the method of Example 34(d). Crude product was purified by CombiFlash (column: silica, eluent: 0-10% MeOH in DCM) to yield 295 mg (49%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.18 (d, 3H), 2.49 (s, 3H), 4.26-4.55 (m, 3H), 7.04 (d, 1H), 7.30 (s, 1H), 7.86 (d, 1H), 8.18 (d, 1H), 8.31 (d, 1H), 8.50 (d, 1H), 8.63 (s, 1H), 14.1 (bs, 1H).
Reaction SMILES: [Br:1][C:2](=[CH2:8])[CH2:3][Si](C)(C)C.[F:9][C:10]([F:19])([F:18])[C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:15]([O:14][C:12](=[O:13])[C:11]([OH:17])([C:10]([F:9])([F:18])[F:19])[CH2:3][C:2]([Br:1])=[CH2:8])[CH3:16]
Reactant: CCOC(=O)C(=O)C(F)(F)F
Reactant: C=C(Br)C[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: C=C(Br)CC(O)(C(=O)OCC)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
To a chilled (−78° C.) solution of 5.2 mL (30.18 mmol) of 2-bromoallyltrimethylsilane and 5.3 g (31.16 mmol) of ethyl trifluoropyruvate in 75 mL of dichloromethane was added 30 mL (30 mmol) of a 1 M solution of titanium tetrachloride in dichloromethane over a 10 minute period. The cold bath was then removed and the mixture was warmed to room temperature. After 3 hours, the mixture was cautiously added to 100 mL of saturated aqueous ammonium chloride and filtered through diatomaceous earth, washing with dichloromethane. The dichloromethane was separated and the aqueous layer was extracted with three 50 mL portions of dichloromethane. The combined organic layers were washed with two 50 mL portions of saturated aqueous sodium bicarbonate, 50 mL of brine, dried over magnesium sulfate, filtered, and concentrated to afford 6.7 g (76%) of 4-bromo-2-hydroxy-2-trifluoromethylpent-4-enoic acid ethyl ester as a yellow oil which was used without further purification.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6]C[N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=1.[BH4-].[Na+]>CO>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:1][C@H:2]2[CH2:7][CH2:6][N:4]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:3]2)=[C:18]([C:24]([F:25])([F:26])[F:27])[CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccc(F)cc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1-Dimethylethyl (3S)-3-aminopiperidine-1-carboxylate (5 g) and 4-fluoro-2-(trifluoromethyl)benzaldehyde (5.15 g, 26.8 mmol) were allowed to stir in methanol for 16 h at room temperature. Sodium borohydride (1.62 g, 26.8 mmol) was then added portionwise. The resulting solution was further stirred for 2 h at room temperature. The solvent was evaporated in vacuo, water was added, and the solution extracted with dichloromethane. The organic extracts were absorbed onto a methanol washed cationic ion exchange resin (Isolute™ SCX-2). The basic components were recovered from the column by elution with 7N ammonia in methanol. The resultant solution was concentrated in vacuo to yield the desired compound as an oil. This was further purified by column chromatography on silica gel, eluting with ethyl acetate/iso-hexane (0:100 to 40:60). The title compound was used in subsequent reactions without further purification. 1H NMR (300 MHz, CDCl3) δH: 7.37-7.28 (m, 2H), 7.24-7.20 (m, 1H), 3.80 (s, 2H), 3.52-3.48 (m, 2H), 3.32 (m, 3H), 3.12 (m, 1H), 2.08-2.0 (m, 1H), 1.75 (m, 1H), 1.45 (s, 9H).
Reaction SMILES: [Li]CCCC.CCCCCC.[S:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([C:34]([C:36]4[N:40]([CH3:41])[CH:39]=[N:38][CH:37]=4)=[O:35])[CH:32]=3)[N:27]=[C:26]([O:42][CH3:43])[CH:25]=2)[CH:21]=[CH:22][CH:23]=1>C(OCC)C.C1COCC1>[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([C:34]([C:36]4[N:40]([CH3:41])[CH:39]=[N:38][CH:37]=4)([C:13]4[S:12][CH:16]=[CH:15][N:14]=4)[OH:35])[CH:32]=3)[N:27]=[C:26]([O:42][CH3:43])[CH:25]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: c1cscn1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(C(=O)c3cncn3C)ccc2n1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3nccs3)c3cncn3C)ccc2n1
Temperature: -70 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
BuLi 1.6 M in hexane (0.0111 mol) was added dropwise at −70° C. under N2 flow to a mixture of thiazole (0.0111 mol) in diethyl ether (30 ml). The mixture was stirred at −70° C. for 1 hour. A mixture of intermediate (9) (0.0074 mol) in THF (30 ml) was added dropwise. The mixture was stirred at −70° C. for 1 hour, hydrolyzed and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (4 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.1; 15–40 μm). The pure fractions were collected and the solvent was evaporated, yielding 3.1 g (91.1%) of 4-(3-chlorophenyl)-2-methoxy-α-(1-methyl-1H-imidazol-5-yl)-α-(2-thiazolyl)-6-quinolinemethanol (intermediate 10).
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:7]2([CH2:12][CH2:11][N:10]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19](C(=O)C)=[CH:18][CH:17]=3)=[O:14])[CH2:9][CH2:8]2)[CH2:6]1)(=[O:4])=[O:3].[BH4-].[Na+].Cl.[CH2:34]([OH:36])[CH3:35].ClCCl>>[CH3:1][S:2]([N:5]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:7]2([CH2:12][CH2:11][N:10]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH2:35][CH2:34][OH:36])=[CH:20][CH:21]=3)=[O:14])[CH2:9][CH2:8]2)[CH2:6]1)(=[O:3])=[O:4]
Reactant: CCO
Reactant: CC(=O)c1ccc(NC(=O)N2CCC3(CC2)CN(S(C)(=O)=O)c2ccccc23)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)N1CC2(CCN(C(=O)Nc3ccc(CCO)cc3)CC2)c2ccccc21
Reaction time: 1 h

Procedure:
To a stirred solution of 1-methylsufonyl-N-(4-acetylphenyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide (400 mg) in ethanol/dichloromethane (5/5 mL) at 0° C., was added sodium borohydride (100 mg). The mixture was stirred for 1 hour, then 3N HCl (0.2 mL) was added to destroy the excess hydride. The mixture was then concentrated and partitioned between water and dichloromethane. The organic layer was dried over MgSO4 and evaporated to give the title compound, 1600 as white powder (386 mg).