Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].N1C=CC=CC=1.[C:11](Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].[Cl-].[NH4+]>O1CCCC1>[C:11]([O:4][CH2:3][CH2:2][Br:1])(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)C(=O)Cl
Reactant: OCCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCCBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-bromoethanol (0.36 mL) and pyridine (0.61 mL) in tetrahydrofuran (5 mL) was added pivaloyl chloride (0.62 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with diethyl ether. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give (2-bromoethyl) pivalate (1.04 g). A mixture of 4-bromo-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (0.93 g), (2-bromoethyl)pivalate (0.82 g), cesium carbonate (1.27 g) and sodium iodide (0.2 g) in N,N-dimethylformamide (10 mL) was stirred at 65° C. for 6 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1−3/1) to give the title compound (0.73 g).
Reaction SMILES: Cl.[NH:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH2:3].[CH3:10][C:11](=O)[CH:12]=[CH:13][CH3:14].C(=O)(O)[O-].[Na+]>C(O)C>[CH3:10][C:11]1[CH2:12][CH:13]([CH3:14])[N:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:3]=1
Reactant: CCOC(=O)CNN
Reactant: CC=CC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CN1N=C(C)CC1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.1 %

Procedure:
A mixture of ethyl hydrazinoacetate hydrochloride (1.55 g, 10 mmol), 3-pentene-2-one (0.95 mL, 10 mmol) and sodium bicarbonate (1.00 g, 11.9 mmol) in ethanol (10 mL) was stirred at room temperature overnight. The reaction mixture was then filtered and concentrated under reduced pressure. The resulting oil was purified by medium pressure liquid chromatography on silica gel (0 to 100% gradient of ethyl acetate in hexanes as eluant) to provide the title compound as a yellow oil (0.26 g).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5](CC2C=NC(C)=NC=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.C([BH3-])#N.[Na+].[F:35][C:36]([F:46])([F:45])[C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH:39]=O>>[CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:39][C:38]2[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=2[C:36]([F:46])([F:45])[F:35])[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@@H]1CN(Cc2ccccc2C(F)(F)F)C[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting sodium cyanoborohydride and 2-(trifluoromethyl)benzaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 10.58 (brs, 1H), 8.01 (s, 1H), 7.79-7.76 (m, 1H), 7.64-7.58 (m, 2H), 7.37-7.34 (m, 1H), 4.83-4.76 (m, 1H), 4.14-4.08 (m, 2H), 3.88 (m, 2H), 3.62-3.54 (m, 2H), 3.39 (t, J=8.3 Hz, 1H), 3.02-2.97 (m, 1H), 2.85 (m, 1H), 2.66 (m, 1H), 2.44-2.27 (m, 3H), 2.06-2.03 (m, 1H), 1.91-1.83(m,2H), 1.21 (d,J=7.1 Hz, 3H). MS: (M+H m/z 462.1).
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8](=[O:27])[CH2:9][CH2:10][C:11]2([CH3:26])[CH:16]([CH3:17])[CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH:12]2[CH3:25])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C>[Pd].[Pd](Cl)Cl>[CH:1]1([CH2:6][CH2:7][C:8](=[O:27])[CH2:9][CH2:10][C:11]2([CH3:26])[CH:16]([CH3:17])[CH2:15][CH2:14][NH:13][CH:12]2[CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1CCN(Cc2ccccc2)C(C)C1(C)CCC(=O)CCC1CCCC1
Agent: Cl[Pd]Cl
Agent: [Pd]
Agent: Cl
Product: CC1CCNC(C)C1(C)CCC(=O)CCC1CCCC1
Reaction time: 3 h
Yield: 84.2 %

Procedure:
A mixture of 1-cyclopentyl-5-[2,3,4-trimethyl-1-(phenylmethyl)-3-piperidinyl]-3-pentanone (6.3 g, 17 mmol), 5 ethanolic HCl (4 mL, 20 mmol) and 10% palladium on carbon (1.2 g) was placed on a Parr hydrogenator at 50 psi for 3 hours, then palladium (II) chloride (0.6 g) and charcoal (1.0 g) were added and the mixture was hydrogenated at 50 psi for 2.5 hours. The catalysts were removed by filtration and the solvent was removed in vacuo. The residue was partitioned between 10% Na2CO3 (100 mL) and ether (2×150 mL), the organic layers were separated and washed with brine (50 mL). The organic layers were dried over Na2SO4 and the solvent was removed in vacuo to afford 4.0 g (84%) of 1-cyclopentyl-5-(2,3,4-trimethyl-3-piperidinyl)-3-pentanone. 2.1 g of the product was used directly in the next step, while the remaining 1.9 g was purified by column chromatography on silica gel eluting with 1-10% triethylamine/ether to afford 1.1 g of the purified product. Treatment of the purified product with 5N ethereal HCl followed by dilution with ether and recrystallization of the solid thus obtained from ethanol/ether afforded 0.8 g of 1-cyclopentyl-5-(2,3,4-trimethyl-3-piperidinyl)-3-pentanone hydrochloride as a white powder, m.p. 127°-128° C.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH:25]([CH3:28])[C:26]#[N:27])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>N.[Ni]>[C:1]([N:20]1[CH:24]=[C:23]([CH:25]([CH3:28])[CH2:26][NH2:27])[N:22]=[CH:21]1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C#N)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Ni]
Agent: N
Product: CC(CN)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 12 h

Procedure:
3.2 g 2-(1-trityl-1H-imidazol-4-yl)-propionitrile are dissolved in 150 mL methanolic ammonia (7 mol/L) and Raney nickel is added. After 12 h and 4 bar H2 pressure the catalyst is filtered off and the solvent is eliminated in vacuo. This crude product is used in the following reaction step without further purification.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].C(OC(=O)C)(=O)C.O[CH2:13][CH2:14][C:15]1[S:19][C:18]([NH:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=2)=[N:17][C:16]=1[CH3:29].C([O-])(O)=O.[Na+].C(=O)=O>>[CH3:29][C:16]1[N:17]=[C:18]([NH:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=2)[S:19][C:15]=1[CH2:14][CH2:13][O:2][N+:1]([O-:4])=[O:3]
Reactant: Cc1nc(NC(=O)c2cccnc2)sc1CCO
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1nc(NC(=O)c2cccnc2)sc1CCO[N+](=O)[O-]
Temperature: 25 °C

Procedure:
70% nitric acid (1.2 ml) was added to acetic anhydride (5 ml) stirring and maintaining the temperture between 20-30° C. by external cooling. The mixture was cooled to −5° C. while stirring, followed by the addition of 1 gram of N-[5-(2-hydroxy-ethyl)-4-methyl-thiazol-2-yl]-nicotinamide. After 30 minutes at −5° C. the mixture was heated to 10° C. and stirred for one additional hour. The resulting mixture was poured into ice water and stirred for 1 hour. Aliquots of NaHCO3 were added until CO2 evolution ceased. The orange-yellow water solution was extracted with three portions of 15 ml ethyl acetate. The combined extracts are dried over sodium sulfate and concentrated by evaporation.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[NH:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[C:22]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:21]=[CH:20][C:5]([CH2:6][C:7]3[NH:8][CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:11]=3)=[CH:4][CH:3]=2)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: Clc1ccc(-c2c[nH]c(Cc3ccc(Br)cc3)n2)c(Cl)c1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CC(C)(C)c1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)c[nH]3)cc2)cc1

Procedure:
2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-1H-imidazole (3.8 g, 10 mmol) was treated as described in general procedure G using 4-tert-butylphenylboronic acid (3.6 g, 20 mmol) to give 2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-1H-imidazole, which was treated as described in general procedure R using 1,4-diiodobenzene (13.2 g, 40 mmol) to give 2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-1-(4-iodo-phenyl)-1H-imidazole.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[Na+].[Na+].Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14].O.C12(PC34CC(CC3)CC4)CC(CC1)CC2>O1CCOCC1.[OH-].[Na+].C(OCC)C.[Cl-].[Cl-].C(#N)C1C=CC=CC=1.C(#N)C1C=CC=CC=1.[Pd+2]>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:1]([OH:2])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: Fc1ccccc1Br
Agent: [Pd+2]
Agent: C1CC2(PC34CCC(CC3)C4)CCC1C2
Agent: [Cl-]
Solvent: N#Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccccc1F
Temperature: 120 °C
Reaction time: 16 h

Procedure:
Sodium carbonat (3.34 g, 32 mmols), 1-bromo-2-fluorobenzene (3.68 g, 21 mmols), water (1.1 g, 63 mmol) and 40 ml of dioxane are placed in a glass autoclave. The autoclave is rinsed with nitrogen and heated to 120° C. A solution of palladium bis(benzonitrile) dichloride (161 mg, 0.42 mmols) and dinorbornylphosphine (420 mg, 1.90 mmols) in 2 ml of dioxane (prepared under argon) is added, and then 6 bars CO are applied. After 16 hours at 135° C., the mixture is allowed to cool. The reaction mixture is taken up in sodium hydroxide solution and diethyl ether. The aqueous phase is separated and acidified with concentrated hydrochloric acid. The title compound precipitates in the form of colourless crystals. Yield of title compound: 1.6 g (54%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:5]([C:17]#[N:18])=[C:4]([SH:19])[N:3]=1.[CH2:20]([NH:22][C:23](=[O:26])[CH2:24]Br)[CH3:21].C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:19][CH2:24][C:23]([NH:22][CH2:20][CH3:21])=[O:26])[C:5]([C:17]#[N:18])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[C:7]=1[C:8]#[N:9]
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc(O)cc1
Reactant: CCNC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=O)CSc1nc(N)c(C#N)c(-c2ccc(O)cc2)c1C#N

Procedure:
At RT 0.76 g (2 mmol) of 2-amino-4-(4-hydroxyphenyl)-6-sulfanyl-3,5-pyridinedicarbonitrile and 0.5 g (3 mmol) of N-ethylbromoacetamide are stirred in 5 ml of DMF together with 0.34 g (4 mmol) of NaHCO3 for 4 hours. After dilution with water, the mixture is extracted with ethyl acetate and the ethyl acetate phase is dried with MgSO4 and concentrated under reduced pressure. The solid residue obtained after concentration is stirred with methanol. The crystals are filtered off with suction and dried under reduced pressure.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=1)[C:13]([C:35]1[CH:40]=[CH:39][C:38]([O:41]CC3C=CC=CC=3)=[CH:37][CH:36]=1)=[C:12]2[CH3:49])C1C=CC=CC=1>C1COCC1.CCO>[N:28]1([CH2:27][CH2:26][O:25][C:22]2[CH:21]=[CH:20][C:19]([CH2:18][N:14]3[C:15]4[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=4)[C:12]([CH3:49])=[C:13]3[C:35]3[CH:36]=[CH:37][C:38]([OH:41])=[CH:39][CH:40]=3)=[CH:24][CH:23]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cc1c(-c2ccc(OCc3ccccc3)cc2)n(Cc2ccc(OCCN3CCCCCC3)cc2)c2ccc(OCc3ccccc3)cc12
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(-c2ccc(O)cc2)n(Cc2ccc(OCCN3CCCCCC3)cc2)c2ccc(O)cc12

Procedure:
A solution consisting of indole 44 (17.5g, 26.9 mmol) in THF/EtOH (1:1) was hydrogenated under an atmosphere of H2 using 10% Pd/C as a catalyst. Chromatography on silica gel CH2Cl2/MeOH (gradient from 100/0 to 85/15) yields the desired product as 8.5 g of white foam along with 2.5 g of a fraction containing small impurities. Although the free base is the material used in the next step (bis-glucuronidation), for purposes of characterization and enhancing the compounds shelf life an acid addition salt may be made with HCl by dissolving the compound in MeOH and treating with 1.1 eq of a 2 N aq HCl solution. The compound slowly precipitates out as white crystals. Physical data listed below describes the HCl salt of indole 45:
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.[N:14]1([NH:19][CH:20]=[C:21]([C:27]([O:29]CC)=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15]1>>[O:29]=[C:27]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][NH:19][N:14]2[CH:15]=[CH:16][CH:17]=[C:18]12
Reactant: CCOC(=O)C(=CNn1cccc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]n2cccc2c1=O
Temperature: 220 °C
Yield: 71 %

Procedure:
A mixture of N-aminopyrrole (575 mg, 7.0 mmol, commercially available) and diethyl ethoxymethylenemalonate (1.82 g, 8.4 mmol) was heated at 125° C. for 2 hours to give crude diethyl 2-((1H-pyrrol-1-ylamino)methylene)malonate. To this intermediate was added diphenyl ether (2 mL). The reaction was put under nitrogen and heated at 220° C. for 2 hours, while allowing the ethanol formed in the reaction to be distilled off. The reaction was cooled to room temperature and purified by silica gel flash chromatography (eluted with 100% CH2Cl2) to give the title compound (1.03 g, 71%) as a yellow solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:13]2[C:9]([S:10][C:11]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:12]=32)=[N:8][CH:7]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[N:8]1[CH:7]=[C:6]([CH2:4][OH:3])[N:13]2[C:12]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:11]=3[S:10][C:9]=12
Reactant: CCOC(=O)c1cnc2sc3c(n12)CCCCC3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cnc2sc3c(n12)CCCCC3
Yield: 78.3 %

Procedure:
A solution of 6,7,8,9-Tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazole-3-carboxylic acid ethyl ester (Formula G-4)(11.7 g) in THF (50 mL) was treated with LiAlH4 (2.24 g) at 0° and reacted at ambient temperature for 1.5 hours. The reaction was quenched by serial additions of water and 15% sodium hydroxide. The mixture was filtered and the filtrate was evaporated to yield crude 6,7,8,9-Tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazole-3-methanol (Formula G-5). Crystallization of crude 6,7,8,9-Tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazole-3-methanol (Formula G-5) from iso-propanol solution gave pure 6,7,8,9-Tetrahydro-5H-cyclohept [d]imidazo[2,1-b]thiazole-3-methanol (Formula G-5) (7.7 g) m.p. 145-146°.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:20])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH:18][CH3:19])[CH2:12][CH2:11]1.[CH:27]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33])=[O:28].CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>ClCCl.C(OCC)(=O)C>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:20])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:27]([C:29]2[CH:37]=[CH:36][CH:35]=[C:31]([CH:32]=[O:33])[CH:30]=2)=[O:28])[CH3:19])[CH2:12][CH2:11]1
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: CNCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 112.1 %

Procedure:
1-[2-(Methylamino)ethyl]piperidin-4-yl biphenyl-2-ylcarbamate (1.00 g, 2.83 mmol) was dissolved in dichloromethane (20 mL), 3-formylbenzoic acid (425 mg, 2.83 mmol), 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (1.08 g, 2.83 mmol) and diisopropylethylamine (1.48 mL, 8.49 mmol) were added under ice cooling, and the mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added, and ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol, 10:1, v/v) to give the title compound (1.54 g; yield, 100%) as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:16])=[CH:10][C:11]([Cl:15])=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[S:25])=[CH:22][CH:21]=1>>[C:3]([C:2]([NH:1][C:24](=[S:25])[C:23]1[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:29])[F:30])=[CH:28][CH:27]=1)([CH3:17])[CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:16])=[CH:10][C:11]([Cl:15])=[CH:12]2)=[N:7]1)#[N:4]
Reactant: CC(N)(C#N)Cn1cc2cc(Cl)cc(Cl)c2n1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: CC(C#N)(Cn1cc2cc(Cl)cc(Cl)c2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-2-methyl-3-(5,7-dichloro-2H-indazol-2-yl)propionitrile (60 mg, described in Example 98) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (80 mg, 76%). MS (ES): M/Z [M+H]=473. 1H NMR: (400 MHz, DMSO-d6): 1.70 (s, 3H), 5.11 (d, 1H), 5.25 (d, 1H), 7.48 (s, 1H), 7.84-7.91 (m, 3H), 7.95 (d, 2H), 8.54 (s, 1H) and 9.03 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −42.0 (s, 3F).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].ClC1C=CC(S[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]=2)=[O:30])=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29](=[O:30])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:38])[F:40])[N:32]=2)[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: O=C(Sc1ccc(Cl)cc1)c1cccc(C(F)(F)F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#CC(C(=O)c1cccc(C(F)(F)F)n1)c1ccc(F)cc1
Reaction time: 0.17 h
Yield: 66 %

Procedure:
A solution of 4-fluorophenylacetonitrile (0.12 mL, 1.0 mmol) in dry tetrahydrofuran (2 mL) is treated dropwise with potassium bis(trimethylsilyl)amide (0.5 M toluene, 3.0 mL, 1.5 mmol) at 0° C. under an atmosphere of nitrogen. The mixture is stirred 10 min then 6-trifluoromethyl-pyridine-2-carbothioic acid S-(4-chloro-phenyl) ester is added all at once. The mixture is allowed to warn to room temperature then warmed to reflux for 10 min, at which time the reaction is complete by TLC (methylene chloride). The mixture is allowed to cool then poured into 10% citric acid and extracted into methylene chloride. The methylene chloride solution is dried over magnesium sulfate and concentrated in vacuo. The residue is purified on a silica gel cartridge prepared with hexane then eluted with methylene chloride to yield 204 mg (66%) 2-(4-fluoro-phenyl)-3-oxo-3-(6-trifluoromethyl-pyridin-2-yl)-propionitrile. MS ES− m/z 307 (M−1).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C@H:7]([CH2:9][CH:10]=[O:11])[CH3:8])[CH3:3]>C(OCC)(=O)C.[Pt]=O>[CH3:8][C@H:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH2:9][CH:10]=[O:11]
Reactant: CC(C)=CCC[C@@H](C)CC=O
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CC(C)CCC[C@@H](C)CC=O
Temperature: 25 °C
Reaction time: 124 h

Procedure:
A 3 L indented flask equipped with a mechanical stirrer and a H2 inlet was charged with 205.7g (1.333 mol) of (R)-citronellal in 7.4L of ethyl acetate. The flask was flushed with 0.1 cu. ft. of H2 and 0.50 g (2.0 mmol) of platinum oxide were added. The reaction was stirred under a slight over-pressure of H2 at ambient temperature for 124 hours. During this time, due to relatively rapid deactivation of the catalyst, an additional 3.50 g (143.mmol) of platinum oxide had to be added in 5 portions (0.5 g at 3.5 hours., 0.5 g at 22.5 hours., 1.0 g at 96.5 hours and 0.5 g at 121 hours). The course of the hydrogenation was monitored by GC analysis. After 124 hours, GC indicated the hydrogenation to be almost complete with 1.4% of starting material remaining. A total of 1.133 cu. ft. of hydrogen (theroetically 1.166 cu. ft.) had been consumed. The catalyst was removed by filtration through a pad of Celite (diatomeaceous earth). The clear filtrate was combined with the filtrate from a previously run, analogous reduction of 10.0 g (64.8 mmol) of (R)-citronellal and concentrated on the rotovapor. Vacuum distillation of the obtained pale yellow liquid through a 30 cm Goodloe column afforded the (R)-3,7-dimethyloctanal in following fractions:
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C@H:19]3[CH2:23][CH2:22][N:21](C(OCC4C=CC=CC=4)=O)[CH2:20]3)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1>C(O)C.[OH-].[Pd+2].[OH-]>[F:1][C:2]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C@H:19]3[CH2:23][CH2:22][NH:21][CH2:20]3)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)N[C@H]1CCNC1

Procedure:
130 mg of benzyl (3S)-3-[({8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}-carbonyl)amino]pyrrolidine-1-carboxylate (Example 115A; 0.250 mmol) were initially charged in 60 ml of ethanol, 17.5 mg 20% palladium-(II) hydroxide (0.025 mmol, 0.1 equivalents) were added and the mixture was hydrogenated under hydrogen standard pressure for two hours. The reaction mixture was filtered and concentrated and the residue was purified by preparative HPLC. This gave 42 mg (44% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:17][NH:18][C:19]([C:21]3[S:25][C:24]([C:26]([O:28]C)=[O:27])=[CH:23][CH:22]=3)=[O:20])[CH3:16])[C:10]=2[OH:30])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:17][NH:18][C:19]([C:21]3[S:25][C:24]([C:26]([OH:28])=[O:27])=[CH:23][CH:22]=3)=[O:20])[CH3:16])[C:10]=2[OH:30])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(Cl)c(Cl)c3)c2O)s1
Agent: [Na+]
Agent: [OH-]
Product: CC(=NNC(=O)c1ccc(C(=O)O)s1)c1nn(C)c(-c2ccc(Cl)c(Cl)c2)c1O
Yield: 78.6 %

Procedure:
From methyl 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]-2-thiophenecarboxylate (200 mg, 0.43 mmol) and 1 M sodium hydroxide aqueous solution (2.13 mL, 2.13 mmol), 153.3 mg of the desired product was obtained in the same manner as in Synthetic Example 58 as a yellow solid (yield 84%).