Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C@H:10]([OH:15])[C@@H:9]([NH:16][C:17](=[O:25])[C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:8]=2[CH:26]=1)(=[O:3])[CH3:2].O.FC(F)(F)C(O)=[O:31].FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O>C(#N)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]([NH:16][C@H:9]2[C:8]3[CH:26]=[C:4]([C:1](=[O:3])[CH2:2][OH:31])[CH:5]=[CH:6][C:7]=3[O:12][C:11]([CH3:14])([CH3:13])[C@@H:10]2[OH:15])=[O:25])=[CH:19][CH:20]=1
Reactant: CC(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccc(F)cc1)[C@@H](O)C(C)(C)O2
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: CC1(C)Oc2ccc(C(=O)CO)cc2[C@H](NC(=O)c2ccc(F)cc2)[C@H]1O
Yield: 23.6 %

Procedure:
(3R,4S)-6-Acetyl-4-(4-fluorobenzamido)-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran D5 (1.83 g, 5.0 mmol) (Example 20 of WO92/22293) was dissolved in acetonitrile (25 ml), water (5 ml) and trifluoroacetic acid (0.77 ml, 10.0 mmol). [Bis(trifluoroacetoxy)iodo]benzene (4.30 g, 10.0 mmol) was added and the reaction stirred under reflux for three hours. The reaction mixture was allowed to cool and the acetonitrile was removed in vacuo, the resulting material being partitioned between water (50 ml) and dichloromethane (125 ml). The aqueous layer was extracted with further portions of dichloromethane (3×25 ml) and the combined organic extracts were dried over magnesium sulphate, filtered and the solvent removed in vacuo. The resulting yellow foam was purified by column chromatography on silica, eluting with 20% to 50% ethyl acetate in hexane to afford the title compound as a white solid (0.44 g, 24%), m.p. 216° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][CH:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:15][CH3:16])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1CC[CH2:39][CH2:38]1.C(I)C>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][C:14]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])([CH2:38][CH3:39])[CH2:15][CH3:16])=[CH:11][CH:12]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(Cc1ccc(C(=O)OC(C)(C)C)s1)C(=O)OCc1ccccc1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCI
Product: CCC(CC)(Cc1ccc(C(=O)OC(C)(C)C)s1)C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 78.6 %

Procedure:
5-(2-Benzyloxycarbonylbutyl)thiophene-2-carboxylic acid tert-butyl ester (29.5 g, 78.8 mmol) was dissolved in tetrahydrofuran (200 mL), 1.09 M lithium bis(trimethylsilyl)azanide/tetrahydrofuran solution (94 mL, 102 mmol) was added dropwise at −78° C., and the mixture was stirred for 2 hours. To the reaction mixture was added ethyl iodide (12.3 g, 156 mmol) at −78° C., and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was added to ethyl acetate and 0.5 N-hydrochloric acid solution, the organic layer was extracted, and the aqueous layer was extracted two times with ethyl acetate. The organic layers were collected, washed with sodium thiosulfate solution and brine, and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (24.9 g, 61.9 mmol, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:14]2[C:22]3[C:17](=[C:18]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)([CH2:12][CH3:13])[C:9](=O)[CH3:10])=[CH:4][CH:3]=1.Cl.[NH2:29][OH:30].C([O-])([O-])=O.[K+].[K+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:14]2[C:22]3[C:17](=[C:18]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)([CH2:12][CH3:13])[C:9](=[N:29][OH:30])[CH3:10])=[CH:4][CH:3]=1
Reactant: CCC(C(C)=O)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCC(C(C)=NO)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 130 °C
Reaction time: 2 h

Procedure:
To a solution of N-(1-(3-(4-chlorophenyl)-2-oxopentan-3-yl)-1H-indol-4-yl)methanesulfonamide (200 mg, 0.49 mmol), as described in Example 23 Step A, in EtOH (5 mL) was added hydroxylamine hydrochloride (68 mg, 0.99 mmol) and K2CO3 (137 mg, 0.99 mmol). The mixture was stirred at 130° C. under microwave for 2 h. After removing the solvent, the residue was dissolved in ethyl acetate (30 mL). The organic layer was washed with saturated sodium bicarbonate solution (10 mL) and brine (10 mL), dried over sodium sulfate, and then filtered. After removing the organic solvent, the residue was purified by silica gel chromatography eluting with PE/EA (10/1 to 5/1, v/v) to afford the title compound as a white solid. LC/MS m/z=441.9 [M+Na]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12](O)[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.CS(Cl)(=O)=O.[CH2:21]([N:23](CC)CC)C.[C-]#N.[Na+]>C1COCC1.CN1CCCC1=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12]([C:21]#[N:23])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(N2CCC(O)C2)cc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: N#CC1CCN(c2ccc(N)cc2)C1

Procedure:
1-(4-Nitrophenyl)pyrroidin-3-ol and methanesulfonyl chloride were allowed to undergo the reaction in THF in the presence of triethylamine. The resulting compound and sodium cyanide were allowed to undergo the reaction in 1-methyl-2-pyrrolidone under heating. The resulting compound was subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 to obtain 1-(4-aminophenyl)pyrrolidine-3-carbonitrile. NMR2: 1.48 (9H, s), 3.12-3.19 (2H, m), 6.46-6.50 (2H, m).
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[C@@H:16]([OH:17])[C@@H:15]2[C@H:10]([CH2:11][CH2:12][C@:13]3([CH3:28])[C@@H:20]([C@@H:21]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH3:22])[CH2:19][CH2:18][C@H:14]32)[C@:9]2([CH3:29])[C@H:4]1[CH2:5][C@H:6]([OH:30])[CH2:7][CH2:8]2.[CH3:31]C=O>>[CH3:31][O:26][C:25](=[O:27])[CH2:24][CH2:23][C@H:21]([C@@H:20]1[C@:13]2([CH3:28])[C@H:14]([C@H:15]3[C@H:10]([CH2:11][CH2:12]2)[C@:9]2([CH3:29])[C@@H:4]([CH2:5][C@H:6]([OH:30])[CH2:7][CH2:8]2)/[C:3](=[CH:2]/[CH3:1])/[C:16]3=[O:17])[CH2:18][CH2:19]1)[CH3:22]
Reactant: CC[C@H]1[C@@H](O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12
Reactant: CC=O
Product: C/C=C1\C(=O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)OC)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12

Procedure:
The present invention relates to a process for preparing obeticholic acid Form 1, wherein reacting 3α,7-ditrimethylsilyloxy-5β-chol-6-en-24-oic acid methyl ester with CH3CHO to form E- or E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid methyl ester is carried out in a polar aprotic solvent at a temperature at about −50° C. to about −70° C. in the presence of BF3.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Brc1cccc(CN2CCCCC2)n1
Reaction time: 20 h

Procedure:
To a stirred solution of 6-bromo-2-pyridine carboxaldehyde (5.05 g, 27 mmol) in anhydrous CH2Cl2 (200 mL) at RT, under N2, piperidine (2.95 mL, 29 mmol) was added, followed by NaBH(OAc)3 (11.51 g, 54 mmol) and AcOH (6.2 mL, 108 mmol) 30 min later. After 20 h, a 2M solution of Na2CO3(aq) (20 mL) was added. The mixture was vigorously stirred for an additional 30 min, washed successively with a saturated solution of NaHCO3(aq) until the pH of the aqueous layer reached 7 (2×100 mL), H2O (100 mL) and brine (100 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure to yield the title compound as a yellow oil. This was used crude in the next step. MS m/z: 255 (M+H), 257 (M+3).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[C:22]([Cl:29])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:6]=1>C(O)C.CCOC(C)=O.[Pd]>[NH2:26][C:24]1[CH:25]=[C:2]([Cl:1])[C:3]([O:4][C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([S:12]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)(=[O:14])=[O:13])[CH:6]=2)=[C:22]([Cl:29])[CH:23]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Oc2ccc(O)c(S(=O)(=O)c3ccc(F)cc3)c2)c(Cl)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)c(Oc2ccc(O)c(S(=O)(=O)c3ccc(F)cc3)c2)c(Cl)c1
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a solution of 4-(2,6-dichloro-4-nitro-phenoxy)-2-(4-fluoro-benzenesulfonyl)-phenol (454 mg, 0.99 mmol) in a mixture of ethanol (10 mL) and EtOAc (20 mL) was added catalyst 10% Pd/C (100 mg). The mixture was hydrogenated under 45 psi at RT for 2 h. The mixture was filtered through Celite and concentrated to give the title compound of Step C (405 mg) as a solid. The title product of Step C was used in the next step without further purification. MS (APCl−) Calc.: 427.0. Found: 426.1 (M−1).
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[CH2:34]([O:36][C:37](=[O:55])[C:38]1[CH:43]=[C:42]([C:44](=[O:46])[CH3:45])[CH:41]=[CH:40][C:39]=1[O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)C.O>O1CCCC1>[CH3:34][O:36][C:37](=[O:55])[C:38]1[CH:43]=[C:42]([C:44](=[O:46])[CH2:45][Br:1])[CH:41]=[CH:40][C:39]=1[O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: CCOC(=O)c1cc(C(C)=O)ccc1OCc1ccccc1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(C(=O)CBr)ccc1OCc1ccccc1
Reaction time: 18 h
Yield: 72 %

Procedure:
Phenyltrimethyl ammonium tribromide (10.60 g, 28.20 mmol) was added in 7 portions to a stirring solution of acetophenone 44 (8.00 g, 28.10 mmol) in anhydrous tetrahydrofuran (50 mL). After 18 h, the reaction mixture was poured into water (250 mL) and stirred for 1 h. The formed precipitate was collected by vacuum filtration. Re-crystallization of the collected solid from ethanol gave the α-bromide 45 (7.35 g, 72%) as a white, needle solid: 1H NMR (500 MHz, DMSO-d6) δ 3.85 (s, 3H), 4.89 (s, 1H), 5.38 (s, 2H), 7.22 (d, 1H), 7.31-7.51 (m, 6H), 8.17-8.31 (m, 2H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[C:12]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:11]=[CH:10][C:9]=1[NH:26][C:27](=[O:35])[C@:28]([OH:34])([CH3:33])[C:29]([F:32])([F:31])[F:30].[CH3:36][NH:37][CH3:38]>C(Cl)Cl.CN(C=O)C>[Cl:7][C:8]1[CH:13]=[C:12]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:24])[N:37]([CH3:38])[CH3:36])=[CH:19][CH:18]=2)(=[O:15])=[O:16])[CH:11]=[CH:10][C:9]=1[NH:26][C:27](=[O:35])[C@:28]([OH:34])([CH3:33])[C:29]([F:30])([F:31])[F:32]
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)c2ccc(C(=O)O)cc2)cc1Cl)C(F)(F)F
Reactant: CNC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(S(=O)(=O)c2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2)cc1
Reaction time: 5 h

Procedure:
Oxalyl chloride (0.45 ml) was added to a stirred suspension of (R)-N-[2-chloro-4-(4-carboxyphenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 121) (1.81 g) in DCM (100 ml) containing DMF (10 drops). The mixture was stirred for 5 hours and then a solution of dimethylamine (4.2 ml, 2M solution in methanol) was added, and the solution was stirred overnight. The reaction mixture was washed with dilute hydrochloric acid solution (2×25 ml) then dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-10% methanol/DCM to yield the title compound (0.68 g) as a solid. M.p. 120.5° C. (Mettler FP62 apparatus); NMR: (CDCl3): 1.70 (s, 3H), 2.90 (s, 3H), 3.10 (s, 3H), 5.20 (s, 1H), 7.5 (d, 2H), 7.85 (d, 1H), 7.90-8.00 (m, 3H), 8.60 (d, 1H), 9.40 (s, 1H); MS (ESP−): 477.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N:9]([O-])=O.[Na+].O.O.[Sn](Cl)Cl>Cl.O>[I:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:9])[CH:6]=[CH:7][CH:8]=1
Reactant: O=N[O-]
Reactant: Nc1cccc(I)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cccc(I)c1
Reaction time: 0.67 h
Yield: 169.9 %

Procedure:
To a stirred suspension of 3-iodoaniline (2 g, 9.13 mmol) in 37% hydrochloric acid (11 mL) at 0° C. was added a cold solution of sodium nitrite (0.66 g, 9.59 mmol) in water (3.2 mL). The resulting suspension was allowed to stir for 40 min. Then, a cold solution of tin(II) chloride dihydrate (6.18 g, 27.4 mmol) in 37% hydrochloric acid (4.3 mL) was added to the reaction mixture and stirred for another 40 min. The flask was then placed in the refrigerator for 12 h. The precipitate was isolated by filtration and washed with ice-cold brine (25 mL) followed by 2:1 petroleum ether/ether (25 mL) solution. The light pink solid was dried under vacuum for 2 h to give the title compound 61 (3.63 g, 94% yield) as the SnCl2 complex. LRMS (ESI): calc. 234.0; found 235.0 (MH)+ (compound 61 as the free hydrazine was previously reported in Recueil des Travaux Chimiques des Pays-Bas (1961), 80 1348-56).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[C:14](B(O)O)[CH:13]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].Cl[C:23]1[C:24]2[N:31]=[CH:30][N:29]([CH:32]([CH3:34])[CH3:33])[C:25]=2[N:26]=[N:27][CH:28]=1.P([O-])([O-])[O-].[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.O>[CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[C:14]([C:23]3[C:24]4[N:31]=[CH:30][N:29]([CH:32]([CH3:34])[CH3:33])[C:25]=4[N:26]=[N:27][CH:28]=3)[CH:13]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(-c2cc(B(O)O)ccc2F)cc1
Reactant: CC(C)n1cnc2c(Cl)cnnc21
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: [K+]
Agent: [O-]P([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)c1ccc(-c2cc(-c3cnnc4c3ncn4C(C)C)ccc2F)cc1
Temperature: 100 °C
Yield: 27 %

Procedure:
A stirred solution of 4′-ethylsulfonyl-6-fluorobiphenyl-3-yl-boronic acid (Preparation 65, 30 mg, 0.097 mmol), 4-chloro-7-isopropyl-7H-imidazo[4,5-c]pyridazine (Preparation 6, 15 mg, 0.077 mmol) and potassium phosphite (33 mg, 0.154 mmol) in dioxane (3 mL) and water (0.7 mL) was degassed with argon for 10 minutes followed by the addition of tricyclohexylphosphine (1.72 mg, 0.006 mmol) and tris(dibenzylideneacetone)palladium(0) (2.82 mg, 0.003 mmol). The resulting mixture was heated at 100° C. for 16 hours. The reaction mixture was filtered to remove inorganics and the filtrate was concentrated in vacuo to remove the volatiles. Purification of the crude residue by preparative TLC eluting with 2% MeOH in DCM afforded the title compound as off white solid in 27% yield, 9 mg.
Reaction SMILES: NO.[CH:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]1(C)C=CC=CC=1.C[Zn]C>CCCCCCC.CCOCC>[CH3:11][C@@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1ccccc1
Reactant: O=Cc1ccccc1
Agent: C[Zn]C
Agent: NO
Solvent: CCCCCCC
Solvent: CCOCC
Product: C[C@@H](O)c1ccccc1
Reaction time: 72 h
Yield: 73 %

Procedure:
To a vial containing aminoalcohol 1 (0.05 g, 0.17 mmol) prepared as in Example 1 was added a solution containing benzaldehyde (0.32 g, 3.0 mmol), toluene (3.0 mL), and 1 M dimethylzinc in heptane (6.0 mL). After 3 days at room temperature, the mixture was diluted in ether (50 mL) and the reaction was quenched by dropwise addition of half-saturated aqueous ammonium chloride (50 mL). The ether layer was separated and the aqueous layer was further extracted with ether (2×50 mL). The combined ether layers were dried over magnesium sulfate whereupon the solvent was removed at reduced pressure. The residue was purified by flash chromatography on 220-400 mesh silica with 70% hexane and 30% ethyl acetate as eluant. The solvent was distilled to afford (R)-(+)-sec-phenethyl alcohol (0.27 grams, 73%) with spectroscopic properties identical to a commercial sample. [α]D25=+55.3, c=1.96 g/100 mL chloroform indicating enantiomeric excess was 99%.
Reaction SMILES: [CH:1]1([NH:7][S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][OH:18])[CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26]Cl.P([O-])([O-])([O-])=O>CN(C=O)C.O>[CH:1]1([N:7]([CH2:26][O:25][CH2:24][CH2:23][Si:22]([CH3:29])([CH3:28])[CH3:21])[S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][OH:18])[CH:12]=2)(=[O:9])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=S(=O)(NC1CCCCC1)c1cccc(CO)c1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCN(C1CCCCC1)S(=O)(=O)c1cccc(CO)c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A solution of N-cyclohexyl-3-(hydroxymethyl)benzenesulfonamide (1.744 g) in DMF (30 ml) under nitrogen was treated with sodium hydride (60% dispersion in mineral oil, 311 mg) and the mixture stirred at 20° C. for 0.5 h. 2-(Trimethylsilyl)ethoxymethyl chloride (1.15 ml) was added and the mixture was stirred for a further 2 h at 20° C. Phosphate buffer solution (pH 6.5, 50 ml) and water (50 ml) were added and the mixture was extracted with EtOAc. The combined extracts were washed with water and dried (Na2SO4). Solvent evaporation in vacuo gave a residue which was purified by flash chromatography on silica gel. Elution with EtOAc-petroleum ether (3:7) gave the title compound (1.917 g). LCMS RT=3.83 min.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][N:6]2[C:11]=1[CH:10]=[C:9]([C:12](O)=[O:13])[CH:8]=[CH:7]2)#[N:2].CC(C)CC(Cl)=O.CN1CCOCC1>O1CCCC1>[OH:13][CH2:12][C:9]1[CH:8]=[CH:7][N:6]2[C:11]([CH:10]=1)=[C:3]([C:1]#[N:2])[CH:4]=[CH:5]2
Reactant: N#Cc1ccn2ccc(C(=O)O)cc12
Agent: CC(C)CC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: N#Cc1ccn2ccc(CO)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
To a solution of 1-cyanoindolizine-7-carboxylic acid (0.20 g) in tetrahydrofuran (4.0 mL) were added 3-methylbutyrylchloride (0.16 g) and 4-methylmorpholine (0.13 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The insoluble material was removed from the reaction mixture by filtration. To the filtrate was added ethanol (4.0 mL) and sodium borohydride (0.20 g) was added under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 2 mol/L hydrochloric acid (5.0 mL), and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=30/70-100/0) to give the title compound (0.050 g).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:26]=[CH:25][C:14]3[N:15]=[C:16]([NH:18][C@H:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)[S:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>CC(N(C)C)=O>[C:35]([N:21]1[CH2:22][CH2:23][CH2:24][C@H:19]([NH:18][C:16]2[S:17][C:13]3[CH:12]=[C:11]([O:10][C:8]4[CH:7]=[CH:6][N:5]=[C:4]([C:3]([NH:2][CH3:1])=[O:27])[CH:9]=4)[CH:26]=[CH:25][C:14]=3[N:15]=2)[CH2:20]1)(=[O:37])[CH3:36]
Reactant: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4CCCNC4)sc3c2)ccn1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4CCCN(C(C)=O)C4)sc3c2)ccn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 36.7 %

Procedure:
To the solution of (S)—N-methyl-4-(2-(piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)picolinamide (13 mg, 30 μmol) and triethylamine (13 μL, 90 μmol) in 300 μL of DMA was added acetic anhydride (6 μl, 60 μmol). The reaction solution was stirred at room temperature for 1.5 hours. The crude reaction solution was purified on prep HPLC and evaporated in vaccuo to give (S)-4-(2-(1-acetylpiperidin-3-ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (4.8 mg, 11 μmol) as white powder. ES/MS m/z 426.2 (MH+).
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[NH:5]1[C:9]([C:10]2[CH:11]=[C:12]([C:16]3[CH:17]=[CH:18][C:19]4[O:23][C:22]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)=[C:21]([C:31]([NH:33][CH3:34])=[O:32])[C:20]=4[CH:35]=3)[CH:13]=[CH:14][CH:15]=2)=[N:8][N:7]=[N:6]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]2[O:23][C:19]3[CH:18]=[CH:17][C:16]([C:12]4[CH:13]=[CH:14][CH:15]=[C:10]([C:9]5[N:8]=[N:7][N:6]([CH:2]([CH3:4])[CH3:3])[N:5]=5)[CH:11]=4)=[CH:35][C:20]=3[C:21]=2[C:31]([NH:33][CH3:34])=[O:32])=[CH:25][CH:26]=1
Reactant: CC(C)I
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnn[nH]4)c3)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnn(C(C)C)n4)c3)cc12
Reaction time: 8 h
Yield: 31 %

Procedure:
2-iodopropane (29 mg, 0.169 mmol) was added to a stirring solution of 5-(3-(1H-tetrazol-5-yl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (35 mg, 0.085 mmol) and Na2CO3 (18 mg, 0.169 mmol) in DMF (1 mL) at 100° C. It was allowed to stir overnight. The mixture was concentrated and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (12 mg, 30%). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.49-8.57 (1H, m), 8.34 (1H, s), 8.08 (1H, d, J=7.32 Hz), 7.99-8.05 (2H, m), 7.87-7.94 (2H, m), 7.79-7.83 (1H, m), 7.72-7.78 (1H, m), 7.70 (1H, t, J=7.78 Hz), 7.41 (2H, t, J=8.70 Hz), 5.17-5.27 (1H, m), 2.87 (3H, d, J=4.58 Hz), 1.66 (6H, d, J=6.71 Hz). LC-MS retention time: 2.02 min; m/z (MH+): 456. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=15.35 min, purity=96%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 μm, Rt=13.39 min, purity=97%.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:8]([NH2:9])=[CH:7][S:6][CH:5]=1.C(N(CC)CC)C.Cl.[CH:18]1([C:21](=N)OCC)[CH2:20][CH2:19]1.C(=O)([O-])O.[Na+]>C(O)C>[CH:18]1([C:21]2[NH:3][C:4]3=[CH:5][S:6][CH:7]=[C:8]3[N:9]=2)[CH2:20][CH2:19]1
Reactant: CCOC(=N)C1CC1
Reactant: Nc1cscc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: c1scc2[nH]c(C3CC3)nc12
Temperature: 25 °C
Reaction time: 70 h
Yield: 32 %

Procedure:
[step 1] 3,4-Diaminothiophene dihydrochloride (300 mg, 1.60 mmol) was suspended in ethanol (12 mL), triethylamine (0.45 mL, 3.21 mmol) and ethyl cyclopropanecarboimidate monohydrochloride (WO200970485; 528 mg, 3.53 mmol) were added, and the mixture was stirred at room temperature for 70 hr. To the mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 v/v-0/100 v/v) to give 2-cyclopropyl-1H-thieno[3,4-d]imidazole (84 mg, 32%).