Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([CH2:13][OH:14])[C@H:10]([CH2:15][OH:16])[O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[CH2:1]([NH:8][CH2:12][CH:11]([CH2:13][OH:14])[CH:10]([OH:9])[CH2:15][OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@@H]1CN(Cc2ccccc2)O[C@H]1CO
Agent: [Zn]
Solvent: CC(=O)O
Product: OCC(O)C(CO)CNCc1ccccc1
Reaction time: 1.5 h

Procedure:
Zinc dust (0.47 g, 7.2 mmol) was added to a solution of N-benzyl trans-4,5-bis(hydroxymethyl)isoxazolidine (0.32 g, 1.43 mmol) in acetic acid (6 ml) and the mixture stirred vigorously for 1.5 hrs after which time the starting material had been consumed. The mixture was filtered through a plug of celite and the filtrate concentrated to dryness before being redissolved in DCM, preabsorbed onto silica and then fractionated by chromatography, eluting isocratically with M/7M NH3-MeOH, (4:1) to give the aminotriol (0.26 g, 81%) as an immobile syrup. 1H NMR (CDCl3) δ 3.90 (q, J=4.0 Hz, 1H), 3.80 (s, 2H), 3.75 (d, J=5.1 Hz, 2H), 3.66 (dq, J=11.7, 3.9 Hz, 2H), 2.94 (d, J=6.9 Hz, 2H), 1.78 (m, 1H). 13C NMR 138.9, 129.1, 128.7, 127.9, 73.7, 65.4, 65.3, 54.4, 48.9, 43.9. −ESMS—clean spectrum shows only MH+ (226) and MNa+ (248), C12H19NO3.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[C:15]2=[O:21])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][C:25]=1[O:33][C:34]([F:37])([F:36])[F:35]>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][C:10]([N:8]3[CH2:7][CH2:6][C:3]4([CH2:5][CH2:4]4)[C@H:2]([OH:1])[CH2:9]3)=[O:22])[C:15](=[O:21])[C@@H:16]2[CH3:20])=[O:32])=[CH:26][C:25]=1[O:33][C:34]([F:35])([F:37])[F:36]
Reactant: O=C=Nc1ccc(Cl)c(OC(F)(F)F)c1
Reactant: C[C@@H]1NCCN(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Product: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(Cl)c(OC(F)(F)F)c1
Yield: 67 %

Procedure:
In analogy to the procedure described in Example 30, (S)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (intermediate 13) and 1-chloro-4-isocyanato-2-trifluoromethoxy-benzene (intermediate 18) gave the titled compound in 67% yield as light brown foam. MS: 547.19 (MH+, 1Cl).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20](=[CH2:23])[CH2:21][OH:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([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>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Si:1]([O:18][CH2:19][C:20](=[CH2:23])[CH:21]=[O:22])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(CO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Product: C=C(C=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 20 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
A mixture of 2-t-butyldiphenylsilyloxymethyl-2-propene-1-ol (25.5 g, 86.7 mmol), molecular sieves in powder (26 g), N-methylmorpholine-N-oxyde (15.3 g, 130 mmol) and tetrapropylammoniumperruthenate (1.5 g, 4 mmol) in anhydrous dichloromethane (400 ml) is stirred overnight at 20° C. Then the reaction mixture is concentrated in vacuo and purified by flash chromatography on silica gel to give the title product (21 g, 83%).
Reaction SMILES: O1CCCC1.B.CO[N:9]=[C:10]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH:11]1[CH2:13][CH2:12]1.O.[OH-].[Na+]>C1COCC1>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([CH:10]([CH:11]2[CH2:12][CH2:13]2)[NH2:9])=[CH:19][CH:18]=1
Reactant: CON=C(c1ccc(Cl)cc1)C1CC1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(c1ccc(Cl)cc1)C1CC1
Temperature: 0 °C
Yield: 92.5 %

Procedure:
Borane tetrahydrofuran complex (1N in THF, 65.6 mL) was added to (4-chlorophenyl)(cyclopropyl)methanone O-methyl oxime (Intermediate 2) (2.75 g) in THF (100 mL) at 25° C. under nitrogen. The resulting solution was stirred at reflux for 3 hours, then cooled to 0° C. Water was carefully added, followed by aqueous NaOH (20%, 100 mL). The resulting mixture was stirred at reflux overnight, then allowed to cool to room temperature. The product was extracted into hexane, then dried over sodium sulfate, filtered and evaporated to afford (4-chlorophenyl)(cyclopropyl)methanamine as a clear oil (2.205 g, 93%).
Reaction SMILES: [ClH:1].Cl.[CH:3]([C@H:16]1[N:21]2[CH2:22][CH2:23][CH2:24][C@H:20]2[CH2:19][N:18]([CH2:25][C:26]2[CH:31]=[C:30](Br)[CH:29]=[CH:28][C:27]=2[O:33][CH3:34])[CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].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>[ClH:1].[ClH:1].[CH:3]([C@H:16]1[N:21]2[CH2:22][CH2:23][CH2:24][C@H:20]2[CH2:19][N:18]([CH2:25][C:26]2[CH:31]=[C:30]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:29]=[CH:28][C:27]=2[O:33][CH3:34])[CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc(Br)cc1CN1C[C@@H]2CCCN2[C@H](C(c2ccccc2)c2ccccc2)C1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2ccccc2)cc1CN1C[C@@H]2CCCN2[C@H](C(c2ccccc2)c2ccccc2)C1
Temperature: 85 °C
Reaction time: 2 h
Yield: 164.6 %

Procedure:
(4R,8aS)-4-Benzhydryl-2-(2-methoxy-5-bromobenzyl)octahydropyrrolo[1,2-a]pyrazine dihydrochloride (29.8 mg) was dissolved in a mixture of 1,2-dimethoxyethane (0.5 ml) and 2M aqueous sodium carbonate (0.16 ml). Then phenylboronic acid (9.01 mg) and tetrakis(triphenylphosphine)palladium (6.1 mg) were added to the solution at room temperature. The whole was stirred for 2 hours at 85° C. The reaction mixture was poured into water, extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by preparative TLC (0.5 mm) with a mixture of dichloromethane and methanol (15:1) as an eluent, and treated with 4N hydrogen chloride in ethyl acetate to give (4R,8aS)-4-benzhydryl-2-[(4-methoxy-[1,1′-biphenyl]-3-yl)methyl]octahydropyrrolo[1,2-a]pyrazine dihydrochloride (24.4 mg) as a brownish power.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]5[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH:27]=5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH:12]=2)[CH:8]=[N:7]1>C(N1C=C(B2OC(C)(C)C(C)(C)O2)C=N1)C1C=CC=CC=1.[OH-].[Pd+2].[OH-]>[F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([CH:26]5[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])[CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: [Pd+2]
Agent: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
Agent: [OH-]
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Reaction time: 18 h
Yield: 81 %

Procedure:
To a solution of tert-butyl 4-(4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (235 mg, 0.334 mmol) in ethyl acetate/ethanol 15/15 mL was added palladium hydroxide (60 mg) and stirred under hydrogen atmosphere for 18 hours. The catalyst was filtered through celite and the solvent was distilled off to get 191 mg (81.0% yield) of the titled compound. MS: m/z=706.3 (M+1).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH:16]3[C:20]3[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([N:27]4[CH:31]=[CH:30][N:29]=[CH:28]4)[N:21]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C=O.[C:34](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH:16]3[C:20]3[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([N:27]4[CH:31]=[CH:30][N:29]=[CH:28]4)[N:21]=3)[CH3:34])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(=O)O
Reactant: Cc1cc(C2CCCN2CCNCc2ccc3c(c2)OCCO3)nc(-n2ccnc2)n1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C2CCCN2CCN(C)Cc2ccc3c(c2)OCCO3)nc(-n2ccnc2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.5 %

Procedure:
A solution of (2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-{2-[2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidin-1-yl]-ethyl}-amine (65 mg, 156 μmol), formalin (63 μL, 780 μmol), and acetic acid (170 μL, 2.83 mmol) in MeOH (1 mL) was stirred at r.t. for 5 min. Sodium triacetoxyborohydride (99 mg, 470 μmol) was then added. The reaction mixture was stirred at r.t. for 20 min and then concentrated to residue. EtOAc (5 mL) and 1N NaOH (5 mL) were added. The organic layer was isolated, dried (MgSO4), filtered, and concentrated. Silica gel chromatography (0% to 10% MeOH/DCM) afforded 60 mg (89%) of (2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-{2-[2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidin-1-yl]-ethyl}-methyl-amine. [M+H]+ 435.32; 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 7.88 (s, 1H), 7.33 (s, 1H), 7.12 (s, 1H), 6.65-6.79 (m, 3H), 4.21 (s, 4H), 3.54 (t, 1H), 3.24-3.42 (m, 3H), 2.76 (m, 1H), 2.11-2.55 (m, 8H), 2.15 (s, 3H), 1.84 (m, 2H), 1.70 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=O)[CH2:5][CH:4]([CH3:9])[NH:3]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:17].[Na+].Cl>CO>[CH3:1][C:2]1([CH3:10])[CH2:7][CH:6]([NH2:17])[CH2:5][CH:4]([CH3:9])[NH:3]1
Reactant: [BH3-]C#N
Reactant: CC1CC(=O)CC(C)(C)N1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: CC1CC(N)CC(C)(C)N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2,2,6-trimethyl-piperidin-4-one (790 mg, 5.6 mmol) in 23 ml of MeOH was treated with ammonium acetate (4.6 g, 56.0 mmol) and sodium cyanoborohydride (0.27 g, 3.9 mmol). This mixture was stirred at room temperature for 24 hours. Afterwards 5 ml 1N-HCl were added and stirring continued for 20 minutes. For extraction with EtOAc the solution was basified with 40% NaOH. The crude was purified by chromatography on silicagel (DCM/MeOH/ammonia:6/4/0.4). Yield: 0.39 g (49%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:9])=[C:5]([Br:8])[C:6]=1[CH3:7].C([Li])CCC.[CH3:15][S:16]SC>C(OCC)C>[Br:8][C:5]1[C:6]([CH3:7])=[C:2]([S:16][CH3:15])[S:3][C:4]=1[CH3:9]
Reactant: CSSC
Reactant: Cc1sc(Br)c(C)c1Br
Agent: [Li]CCCC
Solvent: CCOCC
Product: CSc1sc(C)c(Br)c1C
Temperature: -70 °C

Procedure:
20.0 G. of 2,4-dibromo-3,5-dimethylthiophene was dissolved in 300 ml. of anhydrous ethyl ether. The resulting solution was cooled to -70° C. With stirring under argon. 32 Ml. of a 2.4 M solution of n-butyl lithium was added slowly and the solution was warmed to -32° C. for 10 minutes and then cooled again to 31 70° C. 7.5 G. of dimethyl disulfide was added slowly while the temperature was maintained at -70° C. The resulting solution was warmed to room termperature and stirred for 2 hours thne poured into ice water, stirred for 15 minutes, and extracted with ethyl ether. The combined ether extracts were washed with water, 5% sodium carbonate, and saturated sodium chloride solution; dried over sodium sulfate, filtered and evaporated to yield 3-bromo-2,4-dimethyl-5-(methylthio)thiophene.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([OH:12])=[CH:7][C:6]=1[CH3:13])=O.[NH2:14][C:15]([NH2:17])=[S:16]>CCO>[NH2:17][C:15]1[S:16][CH:2]=[C:3]([C:5]2[C:10]([CH3:11])=[CH:9][C:8]([OH:12])=[CH:7][C:6]=2[CH3:13])[N:14]=1
Reactant: Cc1cc(O)cc(C)c1C(=O)CBr
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1cc(O)cc(C)c1-c1csc(N)n1
Yield: 79 %

Procedure:
A mixture of 2-bromo-1-(4-hydroxy-2,6-dimethylphenyl)ethanone (5-1, 2.43 g, 10.0 mmol) and thiourea (1.37 g, 18.0 mmol) in 95% EtOH (30 mL) was heated at reflux for 120 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and washed with a solution of 50% EtOAc in hexanes. The solids were dried under vacuum to give 4-(2-aminothiazol-4-yl)-3,5-dimethylphenol (5-2, 1.74 g) as pale yellow solids in 79% yield: 1H NMR (500 MHz, CDCl3) δ 8.7 (s, 2 H), 6.17 (s, 2 H), 5.97 (s, 1 H), 1.71 (s, 6 H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:8]=[C:9]([C:11](=[O:17])[NH:12][C@@H:13]([CH3:16])[CH2:14][OH:15])[CH:10]=1)=[O:4].[OH-].[Li+].C1COCC1.Cl>O>[OH:15][CH2:14][C@@H:13]([NH:12][C:11]([C:9]1[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:8]=1)=[O:17])[CH3:16]
Reactant: COC(=O)c1cc(C(=O)N[C@@H](C)CO)cc(-c2ccc(C)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N[C@@H](C)CO)c2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of (S)-methyl5-(1-hydroxypropan-2-ylcarbamoyl)-4′-methylbiphenyl-3-carboxylate (105 mg, 0.321 mmol), lithium hydroxide (9.98 mg, 0.417 mmol), THF (3 mL), and water (1 mL) was stirred at room temperature for 12 h. LC-MS indicated completion of the reaction. The reaction mixture was diluted with water (5 mL) and acidified with 1N aq. HCl to pH=3 and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to yield a white solid. LC-MS: 314.4 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[NH2:20][C@@H:21]([CH2:26][CH3:27])[C:22]([O:24][CH3:25])=[O:23]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([NH:20][C@@H:21]([CH2:26][CH3:27])[C:22]([O:24][CH3:25])=[O:23])=[O:18])[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Reactant: CC[C@H](N)C(=O)OC
Agent: Cl
Product: CC[C@H](NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)OC

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (from Example D11 above) and methyl (S)-2-aminobutanoate hydrochloride (prepared from (S)-(+)-2-aminobutyric acid (Aldrich) using General Procedure H), the title compound was prepared as a solid (mp=154-157° C.).
Reaction SMILES: [CH:1]([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1)([CH3:3])[CH3:2].Br[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[I-].[Na+].C(OCC)(=O)C>CN(C)C=O>[C:18]([CH2:17][CH2:16][CH2:15][CH2:14][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=[C:4]1[CH:1]([CH3:3])[CH3:2])([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CCCCBr
Reactant: CC(C)c1nc2ccccc2[nH]1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCn1c(C(C)C)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Part A. Sodium hydride (1.62 g of a 50% slurry, 33.8 mmol) was washed with hexane and dried under vacuum. Dimethylformamide (50 mL) was added, followed by a solution of 2-isopropyl-1H-benzimidazole (5.41 g, 33.8 mmol) in dimethylformamide (15 mL). After stirring at ambient temperature for two hours, the mixture was treated with ethyl 5-bromovalerate (5.50 mL, 34.8 mmol) and sodium iodide (1.19 g, 7.94 mmol). The mixture was heated to 80° C. for 18 hours, then cooled and poured into ethyl acetate (200 mL). This was washed with water (4×200 mL), then brine (200 mL), and dried over anhydrous magnesium sulfate, filtered and evaporated. The product, 1-(4-carboethoxybutyl)-2-(1-methylethyl)-1H-benzimidazole, was obtained as an oil after purification by silica gel chromatography (1:2 ethyl acetate-hexane) (9.54 g, 33.1 mmol, 98%). 1H NMR (CDCl3): 7.75 (1H, dd, J= 5.6, 3.1 Hz); 7.34-7.19 (3H, m); 4.12 (2H, q, J=7.1 Hz); 1.92-1.80 (2H, m); 1.78-1.65 (2H, m); 1.45 (6H, d, J=6.6 Hz); 1.24 (3H, t, J=7.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([OH:27])[CH2:18][CH2:19]2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7].CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C.[Al+3].C(C(C)=O)(C)C.C(OCC)(=O)C.CCCCCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)(C)[O-]
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 120 °C
Yield: 60.8 %

Procedure:
A solution of 3β-hydroxy-5-cholenic acid methyl ester 3001 (24.16 g, 57.11 mmol), aluminum tri-t-butoxide (56.27 g, 228.43 mmol) and isopropylmethylketone (50 ml) in dry toluene (150 ml) was stirred and heated to 120° C. (oil bath) for 6 hours. The reaction mixture was then cooled to room temperature diluted with toluene (100 ml) and acidified with 2NHCl (70 ml). The organic layer was separated, and the aqueous layer extracted with toluene (3×50 ml). The combined organic extracts were washed with water (1×50 ml), saturated NaHCO3 (2×50 ml), water (1×50 ml), brine (1×50 m), dried (MgSO4), filtered and evaporated in vacuo to get the crude product. Flash chromatography of the crude product using toluene followed by a gradient of ethyl acetate/hexane (5, 10, 20 and 40%) solvent systems gave a pure white solid, 3-oxo-4-cholenic acid methyl ester 3002 (13.43 g, 60%). 1H NMR (400 MHz, CDCl3) δ: 0.71 (3H, s, 18-CH3), 0.90 (3H, d, 21-CH3), 1.17 (3H, S, 19-CH3), 3.66 (3H, s, CO2CH3) and 5.71 (1H, s, 4-H).
Reaction SMILES: [C:1](OCC)(=[O:8])[CH2:2][C:3](OCC)=[O:4].CS(O)(=O)=O.[CH2:17]([O:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH2:25])=[NH:24])[CH2:18][CH3:19].[O-]CC.[Na+].Cl>C(O)C.O>[OH:4][C:3]1[CH:2]=[C:1]([OH:8])[N:25]=[C:23]([C:22]2[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=2[O:20][CH2:17][CH2:18][CH3:19])[N:24]=1
Reactant: CCCOc1ccccc1C(=N)N
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCOc1ccccc1-c1nc(O)cc(O)n1

Procedure:
A stirred mixture of diethyl malonate (17.62 g), 2-propoxybenzamidine methanesulfonate (29.03 g) and sodium ethoxide in ethanol (from sodium, 6.9 g, and ethanol, 150 ml) was heated under reflux for 6 hours. The cooled reaction mixture was evaporated under reduced pressure to yield a residue which was dissolved in water. Concentrated hydrochloric acid was added to the aqueous solution to yield the title compound, 21.56 g. A sample (0.5 g) of this material was recrystallized twice from methanol to yield the pure title compound, 0.19 g, m.p. 224°-50°C.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:26])[C:8]([OH:25])=[C:9]([C:13]3[CH:18]=[C:17]([O:19]C)[C:16]([O:21]C)=[C:15]([O:23]C)[CH:14]=3)[O:10]2)=[CH:5][CH:4]=1)[CH3:2].B(Br)(Br)Br.CO.O>ClCCl>[CH2:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:26])[C:8]([OH:25])=[C:9]([C:13]3[CH:14]=[C:15]([OH:23])[C:16]([OH:21])=[C:17]([OH:19])[CH:18]=3)[O:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc2c(=O)c(O)c(-c3cc(OC)c(OC)c(OC)c3)oc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCc1ccc2c(=O)c(O)c(-c3cc(O)c(O)c(O)c3)oc2c1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a stirring solution of 26 (0.504 g, 1.4.mmol) in dichloromethane (50 ml) under Ar at 0° C. was added boron tribromide in dichloromethane (1.0M, 10 ml, 10 mmol, 7 equ). The mixture was warmed to room temperature and then stirred for 21 hours. The reaction was then cooled to 10° C. and methanol (10 ml) added. The reaction was heated to reflux for 3 hours, then concentrated in vacuo to give an orange solid. Water (50 ml) was added and stirred for two hours then left to stand overnight then 9c (0.313 g, 70%) was collected as a black solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:21][NH:22][C:23]1[CH:24]=[N:25][C:26]([N:37]2[CH2:42][CH2:41][S:40][CH2:39][CH2:38]2)=[CH:27][C:28]=1[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[CH3:36].C(N(CC)CC)C.[OH-].[Na+]>ClCCl>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:13]([CH3:18])([CH3:17])[C:14]([N:22]([CH3:21])[C:23]2[CH:24]=[N:25][C:26]([N:37]3[CH2:38][CH2:39][S:40][CH2:41][CH2:42]3)=[CH:27][C:28]=2[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[CH3:36])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnc(N2CCSCC2)cc1-c1ccc(F)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1cc(N2CCSCC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[4-(4-fluoro-2-methyl-phenyl)-6-thiomorpholin-4-yl-pyridin-3-yl]-isobutyramide is produced by adding a solution of 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in dichloromethane dropwise at room temperature to a solution of methyl-[4-(4-fluoro-2-methyl-phenyl)-6-thiomorpholin-4-yl-pyridin-3-yl]-amine and triethylamine in dichloromethane. The reaction mixture is stirred for about 1 hour and poured onto 1 N aqueous sodium hydroxide. After extraction, the phases are separated, the aqueous phase extracted with dichloromethane, and the organic phases washed with water. The combined organic extracts are concentrated under reduced pressure, and the solvent is exchanged for ethanol. The solution is seeded with some crystals, water slowly added, and the system stirred at room temperature and then at about 0° C. The precipitate is filtered off, washed with cold ethanol (0° C.) and dried under high vacuum to yield 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[4-(4-fluoro-2-methyl-phenyl)-6-thiomorpholin-4-yl-pyridin-3 -yl]-isobutyramide as an off-white powder.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=2)[C:8]([O:11][CH:12]2[CH2:15][C:14]([F:17])([F:16])[CH2:13]2)=[CH:9][CH:10]=1)=[O:4].[Li+].[OH-].CO>O>[Cl:26][C:20]1[CH:19]=[C:18]([C:7]2[C:8]([O:11][CH:12]3[CH2:13][C:14]([F:17])([F:16])[CH2:15]3)=[CH:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: COC(=O)c1ccc(OC2CC(F)(F)C2)c(-c2ccc(OC)c(Cl)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2cc(C(=O)O)ccc2OC2CC(F)(F)C2)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.4 %

Procedure:
85 mg of 3′-Chloro-6-(3,3-difluoro-cyclobutoxy)-4′-methoxy-biphenyl-3-carboxylic acid methyl ester and 14 mg of LiOH (monohydrate) were dissolved using 5 ml of methanol and 0.5 ml of water. The mixture was stirred for 15 h at room temperature. Then, 14 mg of LiOH (monohydrate) were added and the reaction mixture stirred for 24 h at room temperature. Then, 10 ml of water were added and the methanol evaporated. The mixture was then acidified to pH=2 using aqueous NaHSO4-solution. The mixture was stirred for 30 minutes at room temperature. The product was then collected by filtration and dried in vacuo to yield 65 mg of the title compound that was used without further purification.