Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.I[C:31]1[S:32][CH:33]=[CH:34][CH:35]=1>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: Ic1cccs1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccs2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 34, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 2-iodothiophene. The title compound was obtained in 51% yield as light brown foam. MS (m/e): 488.4 (MH+, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH:18][C:19](=[O:31])[C:20]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)=[O:21])[N:13](CC3C=CC(OC)=CC=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH:41][C:42](=[O:50])[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.[Ni]>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH:18][C:19](=[O:31])[C:20]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)=[O:21])[NH:13][CH2:12][C:11]=2[S:10][C:9]=1[NH:41][C:42](=[O:50])[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(CN2Cc3sc(NC(=O)C(=O)OC(C)(C)C)c(C(=O)OC(C)(C)C)c3CC2CNC(=O)C(=O)c2c[nH]c3ccccc23)cc1
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(=O)Nc1sc2c(c1C(=O)OC(C)(C)C)CC(CNC(=O)C(=O)c1c[nH]c3ccccc13)NC2
Reaction time: 18 h

Procedure:
2-(tert-Butyoxyoxalyl-amino)-5-((2-(1H-indol-3-yl)-2-oxo-acetylamino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (101 mg, 0.143 mmol) was dissolved in dry tetrahydrofuran (6 ml) and passed through a pipette, plugged with cotton containing Raney 2800 Nickel (0.38 g). The pipette was flushed with dry tetrahydrofuran (6 ml) and the filtrate was concentrated in vacuo. Pd on carbon (10%, 102 mg, source: Avocado) and formic acid (10% in methanol, 5 ml) were added to the flask containing 2-(tert-Butyoxyoxalyl-amino)-5-((2-(1H-indol-3-yl)-2-oxo-acetylamino) methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester. After stirring for 18 hours, the solution was filtered through a pad of celite and concentrated in vacuo. The residue was diluted in ethyl acetate, washed with saturated sodium bicarbonate (2×25 ml), brine (2×25 ml), dried (MgSO4), filtered and concentrated in vacuo. The residue was subjected to flash chromatography using a mixture of 10% methanol/dichloromethane as eluent, which afforded 2-(tert-butyoxyoxalyl-amino)-5-((2-(1H-indol-3-yl)-2-oxo-acetylamino)methyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[C:9]([CH3:17])=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11](O)=[O:12])=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[C:9]([CH3:17])=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([Cl:22])=[O:12])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Product: Cc1c(C(=O)Cl)cccc1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 29.9 g of 3-p-chlorobenzoyl-2-methyl-benzoic acid and 300 cc of thionyl chloride was refluxed for 3 hours and then stirred at room temperature overnight. Excess thionyl chloride was removed under reduced pressure and the last traces were eliminated by adding benzene and distilling the benzene off under reduced pressure to obtain 3-p-chlorobenzoyl-2-methyl-benzoyl chloride.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][C:6]([F:10])([F:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([CH2:36][C:37](O)=[O:38])[CH:30]=2)=[CH:25][CH:24]=1.P(Cl)(Cl)(Cl)=O>O1CCCC1>[F:9][C:6]1([F:10])[CH2:7][CH2:8][C:3]([NH:2][C:37](=[O:38])[CH2:36][C:31]2[CH:30]=[C:29]([C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)[CH:34]=[CH:33][C:32]=2[CH3:35])([C:11]([O:13][CH3:14])=[O:12])[CH2:4][CH2:5]1
Reactant: COC(=O)C1(N)CCC(F)(F)CC1
Reactant: Cc1ccc(-c2ccc(F)cc2)cc1CC(=O)O
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C1(NC(=O)Cc2cc(-c3ccc(F)cc3)ccc2C)CCC(F)(F)CC1
Reaction time: 0.08 h

Procedure:
2.53 g (11 mmol) of the compound from Example 4A were initially charged in 50 ml of absolute tetrahydrofuran (THF). At 20° C., 3.07 ml of triethylamine were added dropwise, the mixture was stirred for 5 min and 2.44 g (10 mmol) of (4′-fluoro-4-methylbiphenyl-3-yl)acetic acid were added. After 15 min, a further 2.3 ml of triethylamine were added, followed immediately by the dropwise addition of 0.58 ml (6.2 mmol) of phosphorus oxychloride, and the mixture was stirred under reflux for 30 min. The mixture was concentrated under reduced pressure and the residue was purified by means of flash chromatography on silica gel using the mobile phase n-hexane/ethyl acetate 1:1. This gave 2.84 g (60% of theory) of the title compound of melting point 187° C.
Reaction SMILES: C[O:2][C:3](=[O:48])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][C@H:15]([N:19]([CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([Cl:37])[CH:28]=3)[C:20]3[N:21]=[N:22][N:23]([CH3:25])[N:24]=3)[C:14]3[CH:38]=[C:39]([CH3:47])[C:40]([C:43]([F:46])([F:45])[F:44])=[C:41]([CH3:42])[C:13]2=3)[CH2:7][CH2:6]1.[OH-].[Na+]>CO.O.Cl>[Cl:37][C:29]1[CH:28]=[C:27]([CH:32]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:30]=1)[CH2:26][N:19]([C:20]1[N:21]=[N:22][N:23]([CH3:25])[N:24]=1)[C@H:15]1[CH2:16][CH2:17][CH2:18][N:12]([CH2:11][CH:8]2[CH2:9][CH2:10][CH:5]([CH2:4][C:3]([OH:48])=[O:2])[CH2:6][CH2:7]2)[C:13]2[C:41]([CH3:42])=[C:40]([C:43]([F:44])([F:45])[F:46])[C:39]([CH3:47])=[CH:38][C:14]1=2
Reactant: COC(=O)CC1CCC(CN2CCC[C@H](N(Cc3cc(Cl)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)c(C)c32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc2c(c(C)c1C(F)(F)F)N(CC1CCC(CC(=O)O)CC1)CCC[C@@H]2N(Cc1cc(Cl)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 60 °C

Procedure:
To a solution of (S)-(4-{5-[(3-Chloro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-cyclohexyl)-acetic acid methyl ester (0.1 mmol) in methanol (1 mL), add 4N sodium hydroxide (0.5 mL). Heat the mixture at 60° C. for 3 h. Dilute the cooled mixture with water and 1N HCl to bring the pH to 6-7 and extract with CH2Cl2 (3×15 mL). Combine the organic layers, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by chromatography (elution with 5%-10% methanol in EtOAc) to afford the title compound. MS (ES+): 687 (M+H).
Reaction SMILES: [CH2:1]([Li])CCC.O=[C:7]([CH3:15])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].O.Cl>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O.C1COCC1>[CH3:1][C:7](=[CH2:15])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: CC(=O)CCCCC(=O)O
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: CS(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)CCCCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
n-Butyllithium (10.8 ml of 2.5 M in hexanes, 27 mmol, 1.3 equiv) was added to a solution of methyltriphenylphosphonium bromide (9.7 g, 27 mmol, 1.3 equiv) in dimethyl sulfoxide (50 ml) at 0° C., and the mixture was stirred at room temperature for 1 h. It was added to a solution of 6-oxo-heptanoic acid 6 (3 g, 20.82 mmol, 1 equiv) and n-butyllithium (8.33 ml of 2.5 M in hexanes, 20.82 mmol, 1 equiv) in THF (30 ml). The mixture was stirred at room temperature for 48 hr. Water was added and the mixture was acidified with 2 N HCl and extracted with methylene chloride (3×50 ml). The organic layer was washed with 10% sodium hydroxide solution. The aqueous layer was acidified with 2 N HCl and extracted with ethyl acetate (3×60 ml). The organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (10% EtOAc/hexanes) gave pure acid 7 (2.32 g, 78%) as a colorless oil: TLC Rf=0.47 (silica gel, 25% EtOAc/hexanes); 1H NMR (600 MHz, CDCl3) δ 4.69 (s, 1H), 4.65 (s, 1H), 2.34 (t, J=7.8 Hz, 2H), 2.01 (t, J=7.8 Hz, 2H), 1.69 (s, 3H), 1.64-1.58 (m, 2H), 1.50-1.44 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 180.7, 145.6, 110.4; 37.5, 34.2, 27.1, 24.4, 22.5.
Reaction SMILES: [O:1]=[C:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[CH2:3][P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6].[H-].[Na+].C([Li])CCC.C1(S([Cl:38])(=O)=O)C=CC=CC=1>CCCCCC.C(O)(=O)C.O1CCCC1>[O:1]=[C:2]([CH:10]([Cl:38])[CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[CH2:3][P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COP(=O)(CC(=O)CCCCCOC1CCCCO1)OC
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)C(Cl)CCCCOC1CCCCO1)OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under an atmosphere of nitrogen, a solution of 4.2 g. of dimethyl 2-oxo-7-(2-tetrahydropyranyloxy)-heptylphosphonate (prepared as described above) in 15 ml. of tetrahydrofuran was added to a suspension of 596 mg. of sodium hydride (63% content) in 20 ml. of tetrahydrofuran at room temperature, and the mixture was stirred at the same temperature for 30 minutes. After cooling to 0° C., 14 ml. of a 1.3M solution of n-butyllithium in n-hexane were added to the solution and the mixture was stirred at 0° C. for 30 minutes. After cooling the solution to -78° C., there was added a solution of 3.23 g. of benzenesulphonyl chloride in 10 ml. of tetrahydrofuran. The mixture was stirred at -78° C. for one hour and then at room temperature for one hour. The reaction mixture was acidified to pH 3 with acetic acid and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and benzene (5:1) as eluent to give 2.97 g. of the title compound having the following physical characteristics:-
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:13]([Mg]Br)[CH:14]=[CH2:15]>>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([OH:12])[CH2:15][CH:14]=[CH2:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=CC1CCC2(CC1)OCCO2
Reactant: C=CC[Mg]Br
Product: C=CCC(O)C1CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 8 h

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decane-8-carbaldehyde (627 mg, 3.68 mmol, prepared as described in Pearson, et al. in J. Org. Chem. 1997, 62(16), 5284-5292) cooled to −78° C. under argon was added a allylmagnesium bromide (5 mL, 5 mmol, 1 M in THF) dropwise. After the complete addition, the reaction mixture was allowed to reach room temperature overnight. It was then re-cooled to −78° C. and quenched with saturated NaHCO3 solution and warmed to room temperature. After extraction with ether, the organic layer was concentrated in vacuo and the residue purified by flash chromatography (silica gel, 0-100% ether/hexanes) to afford the product.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:5]=2[S:4](=[O:14])(=[O:13])[N:3]=1.[CH2:15]([N:22]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([N:22]1[CH2:26][CH2:25][CH:24]([NH:27][C:2]2[NH:7][C:6]3[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:5]=3[S:4](=[O:14])(=[O:13])[N:3]=2)[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=S1(=O)N=C(Cl)Nc2ccc(Cl)cc21
Reactant: NC1CCN(Cc2ccccc2)C1
Product: O=S1(=O)N=C(NC2CCN(Cc3ccccc3)C2)Nc2ccc(Cl)cc21
Temperature: 110 °C
Reaction time: 72 h
Yield: 72.9 %

Procedure:
A suspension of 3,7-dichloro-4H-1,2,4-benzothiadiazine 1,1-dioxide (100 mg; 0.4 mmol) 1-benzyl-3-aminopyrrolidine (0.35 ml; 2.0 mmol) was stirred at 110° C. for 72 h. The reaction mixture was concentrated in vacu and the residue was purified by flash chromatography using ethyl acetate/methanol 10:1 to give oily crystals (114 mg). These were recrystallised from ethyl acetate to give the title compound as white crystals (83 mg, 53%); m.p. 208.5-209.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([CH2:10][CH3:11])[CH:3]=1.[CH3:12][C:13]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:16]([C:13]([CH3:15])([CH3:14])[CH3:12])([CH3:18])[CH3:17])=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCc1cc(Br)ccc1CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(Br)ccc1CO[Si](C)(C)C(C)(C)C
Reaction time: 12 h
Yield: 93 %

Procedure:
To a solution of (4-bromo-2-ethyl-phenyl)-methanol in anhydrous DMF was added TBSCl (1.5 eq.) and imidazole (1.5 eq). The mixture was stirred at that temperature for 12 hours before it was diluted with water. The mixture was extracted with Et2O and the combined organic layers were washed with H2O, brine, dried over MgSO4. The solvent was removed in vacuo to give the desired product. (93% yield). 1H NMR (300 MHz, CDCl3): δ 0.09 (s, 6H), 0.92 (s, 9H), 1.20 (t, J=7.5 Hz, 3H), 2.57 (q, J=7.5 Hz, 2H), 4.67 (s, 2H), 7.29 (s, 3H).
Reaction SMILES: [C:1]1([N:7]([C:18]2[CH:23]=[CH:22][C:21](B3OC(C)(C)C(C)(C)O3)=[CH:20][CH:19]=2)[C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:34]1[CH:39]=[N:38][C:37]([Br:40])=[CH:36][N:35]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[Br:40][C:37]1[N:38]=[CH:39][C:34]([C:4]2[CH:3]=[CH:2][C:1]([N:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:11]=[CH:10][CH:9]=3)=[CH:6][CH:5]=2)=[N:35][CH:36]=1
Reactant: Brc1cnc(Br)cn1
Reactant: CC1(C)OB(c2ccc(N(c3ccccc3)c3cccc4ccccc34)cc2)OC1(C)C
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Brc1cnc(-c2ccc(N(c3ccccc3)c3cccc4ccccc34)cc2)cn1
Temperature: 85 °C
Yield: 70.4 %

Procedure:
A mixture of N-phenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)naphthalen-1-amine (Compound 7) (2.91 g, 6.91 mmol), 2,5-dibromopyrazine (3.56 g, 13.8 mmol), Pd(PPh3)4 (0.346 g, 0.3 mmol), K2CO3 (1.93 g, 14 mmol) in dioxane/water (80 mL/15 mL), was degassed and heated at about 85° C. overnight. The resulting mixture was diluted with ethyl acetate (250 mL), washed with brine, dried over Na2SO4, loaded on silica gel and purified by flash column using eluents of hexanes to hexanes/dichloromethane 4:1 to 2:1 to 3:2). The desired fraction was collected, after removal of solvent to give a yellow solid (Compound 8) (2.2 g, in 70.4% yield).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH3:11])[C:8](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[CH:23][NH:24]2)=[CH:20][CH:19]=1>>[C:1]([C:5]1[N:10]=[C:9]([CH3:11])[C:8](/[CH:12]=[CH:13]/[C:14]([NH:17][C:18]2[CH:26]=[C:25]3[C:21]([CH:22]=[CH:23][NH:24]3)=[CH:20][CH:19]=2)=[O:16])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc2cc[nH]c2c1
Reactant: Cc1nc(C(C)(C)C)ccc1/C=C/C(=O)O
Product: Cc1nc(C(C)(C)C)ccc1/C=C/C(=O)Nc1ccc2cc[nH]c2c1

Procedure:
Analogous to the procedure used to prepare Example 1, (2E)-3-[6-(tert-butyl)-2-methyl(3-pyridyl)]prop-2-enoic acid, Example 75(c), (220 mg, 1.0 mmol) and 6-aminoindole (130 mg, 1.0 mmol, Lancaster) provided, after purification by silica gel chromatography (55:45 hexane:EtOAc), the title compound as a yellow solid. MP 182° C. MS (ESI, pos. ion) m/z: 334 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:16]3[CH2:18][O:19][CH:20]([CH3:22])[CH2:21][C:15]=3[N:14]=2)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+]>CO.O>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:16]3[CH2:18][O:19][CH:20]([CH3:22])[CH2:21][C:15]=3[N:14]=2)=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(-c2nc3c([nH]2)COC(C)C3)c(C)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C)c(-c2nc3c([nH]2)COC(C)C3)cc1C(=O)O
Reaction time: 4 h
Yield: 63.5 %

Procedure:
Into around-bottom flask, was placed a solution of methyl 2,4-dimethyl-5-(6-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoate (compound 464.7, 100 mg, 0.330 mmol, 1.00 equiv) in methanol (10 mL). A solution of lithium hydroxide (76 mg, 3.17 mmol, 10.0 equiv) in water (10 mL) was added and the resulting solution was stiffed for 4 h at room temperature. The mixture was concentrated in vacuo and then aqueous HCl was added until the pH was 5-6. The mixture was adjusted to pH 5-6 with aqueous HCl and then the resulting mixture was concentrated in vacuo. MeOH (5 mL) was added to the residue and the solids were removed by filtration. The filtrate was concentrated in vacuo to obtain the title compound as a yellow solid (60 mg, 63%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.C([Li])CCC.[CH:12]12[O:17][CH:13]1[CH2:14][CH2:15][CH2:16]2.C(=O)([O-])O.[Na+]>C1COCC1>[CH3:1][N:2]1[C:6]([C@H:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[OH:17])=[CH:5][CH:4]=[N:3]1
Reactant: C1CC2OC2C1
Reactant: Cn1cccn1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1nccc1[C@H]1CCC[C@@H]1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 21.3 %

Procedure:
To a solution of 1-methylpyrazole (13.4 g, 163 mmol) in THF (1 L), n-butyl lithium (1.63 M solution in hexane; 100 mL, 163 mmol) was added dropwise at −78° C. for 40 minutes. To the reaction solution, cyclopentene oxide (15.1 g, 179 mmol) was added at −78° C., and the reaction solution was stirred at room temperature for 20 hours. To the reaction solution, a saturated aqueous solution of sodium hydrogencarbonate (100 mL) was added, followed by extraction with ethyl acetate (500 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (dichloromethane/methanol=97:3) to yield the title compound (5.77 g, 21%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:15]=3[CH:16]=O)[S:10][C:5]=2[C:4](=[O:26])[NH:3]1.[C:28]1([CH2:34][CH2:35][NH2:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO.C1COCC1>[CH3:27][C:2]1([CH3:1])[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:23])[CH3:24])[C:15]=3[CH2:16][NH:36][CH2:35][CH2:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[S:10][C:5]=2[C:4](=[O:26])[NH:3]1
Reactant: CC1(C)NC(=O)c2sc(-c3cnn(COCC[Si](C)(C)C)c3C=O)cc2N1
Reactant: NCCc1ccccc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)NC(=O)c2sc(-c3cnn(COCC[Si](C)(C)C)c3CNCCc3ccccc3)cc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
A mixture of 4-(2,2-dimethyl-4-oxo-1,2,3,4-tetrahydrothieno[3,2-d]pyrimidin-6-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-carbaldehyde (122 mg, 0.30 mmol), 2-phenylethanamine (0.151 mL, 1.20 mmol) and THF (5 mL) was stirred at room temperature overnight. Then, sodium borohydride (0.023 g, 0.60 mmol) and MeOH (2 mL) were added. After 30 min, the mixture was poured into saturated aqueous NaHCO3 and extracted with EtOAc, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, NH, 95:5 hexane/EtOAc to EtOAc then to 80:20 EtOAc/MeOH) to afford 2,2-dimethyl-6-(5-{[(2-phenylethyl)amino]methyl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (140 mg). 2,2-Dimethyl -6-(5-{[(2-phenylethyl)amino]methyl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (140 mg) was dissolved with N,N,N,N-tetrabutylammonium fluoride (1.0 M in THF, 3.0 mL, 3.00 mmol) and the mixture was stirred at 60° C. overnight. The mixture was filtered, and the filtrate was poured into saturated aqueous NaHCO3 and extracted with EtOAc, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, NH, 95:5 hexane/EtOAc to EtOAc then to 80:20 EtOAc/MeOH) to afford the title compound (27.5 mg, 24%) as a colorless oil:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5]([NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22]O)[CH2:17][CH2:16]1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:47]>C(Cl)Cl>[Br:47][CH2:22][CH2:21][CH:18]1[CH2:19][CH2:20][N:15]([C:9]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:8]=2[NH:7][C:5](=[O:6])[C:4]2[CH:24]=[CH:25][CH:26]=[C:2]([Cl:1])[CH:3]=2)[CH2:16][CH2:17]1
Reactant: BrC(Br)(Br)Br
Reactant: O=C(Nc1cc(Cl)ccc1N1CCC(CCO)CC1)c1cccc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1cc(Cl)ccc1N1CCC(CCBr)CC1)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 43.2 %

Procedure:
A mixture of 0.800 g (2.03 mmol) of 3-chloro-N-{5-chloro-2-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-phenyl}-benzamide and 0.533 g (2.03 mmol) of triphenylphosphine in methylene chloride (20 mL), cooled to 0° C., is stirred for 20 minutes. To this is added 0.674 g (2.03 mmol) of carbon tetrabromide and the mixture is warmed to room temperature and stirred overnight. The mixture is concentrated under reduced pressure and the residue is purified by flash silica gel chromatography to provide 0.400 g (70.0%) of N-{2-[4-(2-bromo-ethyl)-piperidin-1-yl]-5-chloro-phenyl}-3-chloro-benzamide as a light red oil.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.[CH2:42]([S-:44])[CH3:43].[Na+].[O-2].[Al+3].[O-2].[O-2].[Al+3]>CN(C=O)C.CCOC(C)=O>[CH2:42]([S:44][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1)[CH3:43]
Reactant: CC[S-]
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [Na+]
Agent: [O-2]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCSc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 100 °C

Procedure:
(R)-1-(3-Bromo-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (Intermediate 14B; 59 mg, 0.098 mmol), sodium ethanethiolate (20.59 mg, 0.245 mmol), and aluminum oxide (100 mg, 0.979 mmol) were dissolved in DMF (2 mL) and heated in a microwave reactor to 100° C. for 2 h. The reaction mixture was diluted with EtOAc, filtered, and concentrated in vacuo while loading onto silica gel. The residue was purified by flash chromatography (7-60% EtOAc/hexane) to give (R)-1-(3-(ethylthio)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. For C36H33N5OS [M+1]+ 584. found 584.