Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:30])[C@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].N1C=CC=CC=1>C(Cl)Cl>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:14](=[O:30])[C:13]=1[C:8]1[NH:7][C:6]2[CH:31]=[CH:32][C:3]([NH:2][C:33](=[O:35])[CH3:34])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3[C@@](C)(CCC(C)C)C1=O)N2
Yield: 91 %

Procedure:
A solution of Example 39H (0.050 g, 0.105 mmol), acetic anhydride (0.011 mL, 0.116 mmol), and pyridine (0.068 mL, 0.840 mmol) in methylene chloride (2 mL) was stirred at 25° C. for 4 hours. The solution was concentrated in vacuo and the residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (0.046 g, 90%). 1H NMR (300 MHz, DMSO-d6): 5 ppm 0.43 (m, 1H) 0.77 (m, 7H) 1.33 (m, 1H) 1.56 (m, 3H) 2.06 (m, 4H) 2.23 (m, 1H) 7.53 (m, 1H) 7.66 (m, 1H) 7.77 (m, 3H) 8.16 (m, 1H) 8.29 (m, 1H) 10.38 (m, 1H) 13.84 (m, 1H).
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([C@:25]1([CH3:31])[CH2:29][O:28][C:27](=[O:30])[NH:26]1)[CH:19]=[CH:18]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[C:1]1([C@H:7]2[CH2:8][CH2:9][C@H:10]([O:13][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[CH:21]=[C:20]([C@:25]3([CH3:31])[CH2:29][O:28][C:27](=[O:30])[NH:26]3)[CH:19]=[CH:18]4)[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O[C@H]1CC[C@H](c2ccccc2)CC1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@@]1(c2ccc3cc(O[C@H]4CC[C@H](c5ccccc5)CC4)ccc3c2)COC(=O)N1

Procedure:
The mixture of trans-4-phenyl-cyclohexanol (86.9 mg, 0.000493 mol), (R)-4-(6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one (Example 4, 100.0 mg, 0.0004111 mol) and triphenylphosphine (129 mg, 0.000493 mol) in tetrahydrofuran (4 mL, 0.05 mol) was heated to reflux, and diisopropyl azodicarboxylate (0.0971 mL, 0.000493 mol) was added dropwise and was stirred and refluxed for 3 hours. TLC monitoring showed the reaction to be complete. The mixture was taken up into DCM and subjected to chromatographic purification with EtOAc/hexane (10:90 to 80:20) to give (R)-4-(6-(trans-4-phenyl-cyclohexyloxy)naphthalen-2-yl)-4-methyloxazolidin-2-one (160 mg, 97% yield). LCMS 402.28 ([M+1]+, 100%).
Reaction SMILES: [CH:1](OCC)=[O:2].[CH3:6][C:7]([CH3:23])([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1)[C:8](=[O:10])[CH3:9].C[O-].[Na+]>C(OCC)C>[CH3:6][C:7]([CH3:23])([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:19]([F:21])([F:22])[F:20])=[CH:14][CH:13]=1)[C:8](=[O:10])[CH:9]=[CH:1][OH:2]
Reactant: CCOC=O
Reactant: CC(=O)C(C)(C)Cc1ccc(SC(F)(F)F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(Cc1ccc(SC(F)(F)F)cc1)C(=O)C=CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.4 %

Procedure:
34.7 g (0.469 mole) of ethyl formate are added dropwise with stirring to 129.4 g (0.469 mole) of 3,3-dimethyl-4-(4-trifluoromethylthiophenyl)-butan-2-one and 25.3 g (0.469 mole) of sodium methylate in 1 liter of diethyl ether at room temperature, and the mixture is stirred at room temperature for 4 hours after the addition is complete. For work-up, the mixture is extracted with 1 liter of water, and the combined aqueous extracts are washed once with diethyl ether, acidified to pH 1-2 with dilute aqueous hydrochloric acid and extracted with dichloromethane. The dichloromethane phase is dried over sodium sulphate and concentrated in vacuo. 90.5 g of 4,4-dimethyl-5-(4-trifluoromethylthiophenyl)-penten-1-ol-3-one are obtained; these are dissolved in 200 ml of methanol and 17.0 g (0.315 mol) of sodium methylate are added. Concentrating the solution in vacuo gives 97.1 g (75% of theory) of the sodium salt of 4,4-dimethyl-5-(4-trifluoromethylthiophenyl)-1 -penten-1-ol-3-one as a resin, which is further reacted without purification. ##STR875##
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[C:12]2[NH:11][C@H:10]3[CH2:13][CH2:14][NH:15][CH2:16][C@H:9]3[C:8]=2[CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C1COCC1>[Br:3][C:4]1[C:12]2[NH:11][C@H:10]3[CH2:13][CH2:14][N:15]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:16][C@H:9]3[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc2c1N[C@H]1CCNC[C@@H]21
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)N1CC[C@@H]2Nc3c(Br)cccc3[C@@H]2C1
Temperature: 25 °C

Procedure:
(4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate may be prepared by first obtaining [4aS,9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (36.0 g, 0.142 mol)) as a free base by using 50% aqueous sodium hydroxide solution and extracting the product into MTBE. The conversion to (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate may then be done by cooling a suspension of compounds of [4aS,9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (36.0 g, 0.142 mol)) in THF (300 ml) and triethylamine (24 ml) in an ice-water bath. Ethyl chloroformate is added dropwise (13.5 ml, 0.142 mol) via a syringe pump over 1 hour. The ice-water bath is removed and the reaction mixture is stirred at room temperature for another hour. The reaction mixture is passed through a pad of celite and the solvent is evaporated to give (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate). 1H NMR (CDCl3, 300 MHz): 1.20-1.35 (m, 3H), 1.73-1.85 (m, 1H), 1.85-1.99 (m, 1H), 3.22-3.52 (m, 3H), 3.52-3.66 (m, 1H), 3.66-3.95 (Br, 1H), 3.95-4.21 (m, 4H), 6.60 (t, J=7.7 Hz, 1H), 7.04 (d, J=7.2 Hz, 1H), 7.20 (d, J=8.1 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:10]=1[N+:18]([O-])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[NH2:18][C:10]1[CH:11]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[S:13][C:9]=1[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(NC(=O)OC(C)(C)C)s1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)c(NC(=O)OC(C)(C)C)s1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A solution of methyl 5-(tert-butoxycarbonylamino)-4-nitrothiophene-2-carboxylate 88 (0.165 mmol, 50 mg) and palladium on activated carbon (0.083 mmol, 9.79 mg) in methanol (5 mL) was stirred for 1 h at rt with hydrogen gas bubbling through. Additional (0.2 eq) of Pd/C was added and stirred for 1 h. Reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give methyl 4-amino-5-(tert-butoxycarbonylamino)thiophene-2-carboxylate 89 (45 mg, 100%). NMR (400 MHz, CDCl3) 1.52 (s, 9H), 3.83 (s, 3H), 6.85 (br s, 1H), 7.30 (s, 1H). (m/z)=273 (M+H)+.
Reaction SMILES: [C:1]([C@@H:3]([NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[NH:17][C:18]([C:20]1[N:21]([CH2:29][CH2:30][CH2:31]Cl)[C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6])#[N:2].[I-].[Na+].C(#N)C.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>O>[C:1]([C@@H:3]([NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[NH:17][C:18]([C:20]1[N:21]([CH2:29][CH2:30][CH2:31][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6])#[N:2]
Reactant: CC(C)C[C@@H](C#N)NC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1cc2ccccc2n1CCCCl
Reactant: C1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)C[C@@H](C#N)NC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1cc2ccccc2n1CCCN1CCCCC1
Temperature: 50 °C
Reaction time: 24 h
Yield: 67.4 %

Procedure:
To 1-(3-chloro-propyl)-1H-indole-2-carboxylic acid [(1S,2R)-2-((S)-1-cyano-3-methyl-butylcarbamoyl)cyclohexyl]-amide (200 mg, 0.44 mmol) was added sodium iodide (66 mg, 0.44 mmol), acetonitrile (2 mL), and piperidine (0.1 mL, 1.3 mmol). The reaction mixture was heated to 50° C. and stirred for 24 hrs. Water (15 mL) was added to the reaction and extracted with three 20 mL portions of ethyl acetate. The combined organics were washed with saturated NaHCO3 (20 mL), dried on sodium sulfate, and concentrated. Purification by column chromatography (5:95 methanol:chloroform) gave 1-(3-piperidin-1-yl-propyl)-1H-indole-2-carboxylic acid [(1S,2R)-2-((S)-1-cyano-3-methyl-butylcarbamoyl)-cyclohexyl]-amide as a white solid (150 mg, 68%). MS: 506 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.C1(N=C=NC2CCCCC2)CCCCC1.[OH:25][C:26]1[C:27]([N+:35]([O-:37])=[O:36])=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30].ClCCl>CN(C=O)C>[CH3:1][O:2][C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:29](=[O:30])[C:28]1[CH:32]=[CH:33][CH:34]=[C:26]([OH:25])[C:27]=1[N+:35]([O-:37])=[O:36]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(O)c1cccc(O)c1[N+](=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCCN1C(=O)c1cccc(O)c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 82.3 %

Procedure:
12.9 g of L-proline methyl ester and 21.0 g of N,N'-dicyclohexylcarbodiimide were successively added to an ice-cooled and constantly stirred solution of 18.3 g of 3-hydroxy-2-nitrobenzoic acid dissolved in a mixture consisting of 360 ml of dichloromethane and 30 ml of N,N'-dimethylformamide, and then the same treatment as in Example 1 was carried out. Thus, there was obtained 24.2 g of 1-(3-hydroxy-2-nitrobenzoyl)-L-proline methyl ester as a yellow-colored needle-like crystal having a melting point of 114° to 116° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:9]([CH3:11])[CH3:10])[CH:3]=1.C([Li])CCC.[CH2:17]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)[CH3:18].Cl>O1CCCC1.CCCCCC>[CH2:17]([N:19]1[CH2:24][CH2:23][C:22]([OH:25])([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:9]([CH3:11])[CH3:10])[CH:3]=2)[CH2:21][CH2:20]1)[CH3:18]
Reactant: CC(C)Oc1cccc(Br)c1
Reactant: CCN1CCC(=O)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCN1CCC(O)(c2cccc(OC(C)C)c2)CC1
Temperature: -20 °C

Procedure:
To a stirred solution of 1-bromo-3-(1-methylethoxy)benzene (5.0 g, 23 mmol) in anhydrous tetrahydrofuran (50 ml) at −78° C. under an atmosphere of nitrogen was added n-butyllithium (1.6M in hexane, 13.7 ml, 22 mmol) dropwise. The reaction mixture was stirred for 1 h at −78° C., before N-ethyl-4-piperidone (2.95 ml, 22 mmol) was added dropwise at −78° C. over 15 minutes, and the reaction mixture was then warmed to −20° C. over 30 minutes. The solution was poured onto 2N aqueous hydrochloric acid (35 ml) and this was further acidified to pH 1 with concentrated hydrochloric acid. Hexane (50 ml) was added and the two layers were separated. The organic layer was discarded and the pH of the aqueous layer was adjusted to 14 using sodium hydroxide pellets. The basic aqueous layer was extracted with hexane:diethyl ether (1:1, 5×50 ml) and the combined extracts were dried (MgSO4) and concentrated to give the title compound as a crude oil (4.2 g, 73% crude yield) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:17](O)=[O:18].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:17](=[O:18])[C:16]3[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:14]([F:13])[CH:15]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: COc1ccc(C(=O)O)cc1F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)cc1F
Yield: 90.2 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.87 mmol, Example 1, Step H), 3-fluoro-4-methoxybenzoic acid (311 mg, 1.83 mmol), BOP-Cl (0.465 g, 1.83 mmol), and triethylamine (0.606 mL, 4.35 mmol) in DCM (5 mL) was processed as described in Example 62, Step A, to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-fluoro-4-methoxybenzamide (300 mg, 90% yield) as a solid. LCMS (APCI+) m/z 381.9, 383.9 (M+H)+, Retention time=3.23 minutes (Method 2).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:6]([CH3:18])[C:5]([C:19]#[N:20])=[CH:4][CH:3]=1.ClCCl.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N1C=CC=CC=1>[C:19]([C:5]1[C:6]([CH3:18])=[C:7]([C:2]([NH:1][S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])=[CH:3][CH:4]=1)[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])#[N:20]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1c(C#N)ccc(N)c1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(C#N)ccc(NS(=O)(=O)c2ccccc2)c1C(=O)OCc1ccccc1

Procedure:
A mixture of Example 108B (576 mg, 2.2 mmol), anhydrous dichloromethane (22 mL), pyridine (0.4 mL) and benzenesulfonyl chloride (0.33 mL) was stirred 18 hours under nitrogen atmosphere. The mixture was concentrated, dissolved in ethyl acetate (100 mL), washed with 0.5M HCl (3×50 mL) and brine, dried (Na2SO4), filtered, concentrated, and purified on silica gel (20 g) with 50% dichloromethane in hexanes to provide the desired product. MS (ESI(+)) m/e 407 (M+H)+, 424 (M+NH4)+, 429 (M+Na)+; (ESI(−)) m/e 405 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 10.59 (br s, 1H), 7.77 (m, 3H), 7.64 (m, 1H), 7.56-7.37 (m, 7H), 7.24 (d, 1H), 5.31 (s, 2H), 2.32 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][S:9]([N:12]1[C:17]2([CH2:19][CH2:18]2)[CH2:16][N:15]([C:20]2[C:21]3[CH:28]=[CH:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:22]=3[N:23]=[CH:24][N:25]=2)[CH2:14][CH2:13]1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:36]([N:43]1[CH2:47][CH2:46][CH2:45][C@H:44]1[CH2:48]O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(/N=N\C(=O)OC(C)C)=O)(C)C>C1COCC1.O>[CH2:36]([N:43]1[CH2:47][CH2:46][CH2:45][C@H:44]1[CH2:48][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[S:9]([N:12]1[C:17]2([CH2:18][CH2:19]2)[CH2:16][N:15]([C:20]2[C:21]3[CH:28]=[CH:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:22]=3[N:23]=[CH:24][N:25]=2)[CH2:14][CH2:13]1)(=[O:11])=[O:10])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)N1CCN(c2ncnc3c2ccn3C(=O)OC(C)(C)C)CC12CC2
Reactant: OC[C@@H]1CCCN1Cc1ccccc1
Agent: CC(C)OC(=O)/N=N\C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(C[C@@H]1CCCN1Cc1ccccc1)S(=O)(=O)N1CCN(c2ncnc3c2ccn3C(=O)OC(C)(C)C)CC12CC2
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Tert-butyl 4-[8-(tert-butoxycarbonylsulfamoyl)-5,8-diazaspiro[2.5]octan-5-yl]pyrrolo[2,3-d]pyrimidine-7-carboxylate (intermediate 47) (0.55 mmol) was dissolved in dry THF (3 mL) and added [(2S)-1-benzylpyrrolidin-2-yl]methanol (0.61 mmol) and triphenylphosphine (0.66 mmol). The reaction mixture was cooled to 0° C. and slowly added isopropyl (NZ)—N-isopropoxycarbonyliminocarbamate (0.66 mmol). The reaction mixture was allowed to warm up freely to rt and stirred at rt for 16 h. The crude mixture was treated with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic phases were washed with H2O (2×50 mL), brine (2×50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica using EtOAc in heptane as eluent.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Br:10]Br.O>C(Cl)(Cl)Cl>[Br:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[OH:1])[CH:6]=[O:7]
Reactant: BrBr
Reactant: O=Cc1ccc(O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-hydroxybenzaldehyde (10.0 g, 81.9 mmol) in chloroform (100 mL) was added with bromine (4.30 mL, 83.5 mmol), followed by stirring at room temperature for 2 hours. The reaction mixture was added with water (100 mL), and the solvent of the organic layer was evaporated under reduced pressure to obtain 3-bromo-4-hydroxybenzaldehyde as a pale yellow solid (quantitative yield).
Reaction SMILES: O=O.[CH3:3][O:4]/[C:5](=[CH:9]\[C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)/[C:6]([OH:8])=[O:7].C1([C@@H](N)C)C=CC=CC=1.[H][H]>O1CCCC1.CO>[CH3:3][O:4][C@@H:5]([CH2:9][C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: CO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Reactant: [H][H]
Agent: C[C@H](N)c1ccccc1
Agent: O=O
Solvent: CO
Solvent: C1CCOC1
Product: CO[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O

Procedure:
In a glove box (O2 content≦2 ppm), a 185-ml stainless steel autoclave was charged with 2.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (4.59 mmol), 5.40 mg of [Ir((Sa,R)-DBT-Bn-SIPHOX)(COD)]BF4 (0.0046 mmol, S/C 1,000), 24 ml of methanol, 16 ml of tetrahydrofuran and 0.12 ml of (S)-1-phenylethylamine (0.92 mmol). The autoclave was sealed and the hydrogenation was run at 60° C. for 20 h and subsequently 80° C. for 2 h under 10 bar of hydrogen. After the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 89.7% (91.1% conversion) and an enantiomeric purity of 99.8%.
Reaction SMILES: [C@@H:1]12[C:10](=[O:11])[O:9][C:7](=[O:8])[C@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.Cl.[NH3:13]>>[C:10]([C@@H:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8])(=[O:11])[NH2:13]
Reactant: O=C1OC(=O)[C@H]2CCCC[C@H]12
Reactant: N
Agent: Cl
Product: NC(=O)[C@@H]1CCCC[C@H]1C(=O)O
Temperature: 25 °C

Procedure:
To 40 ml of aqueous conc. ammonia were added 10.0 g of trans-1,2-cyclohexanedicarboxylic acid anhydride with stirring at room temperature, and the mixture was stirred at room temperature for 4 hours and 15 minutes. The pH of the reaction mixture was adjusted to 1 with conc. hydrochloric acid with stirring under ice-cooling and the precipitated crystalline solid was collected by filtration and washed with water. The crystalline solid was recrystallized from ethanol to obtain 6.93 g of the desired compound as a colorless crystalline solid.
Reaction SMILES: [CH2:1](C1(N2C3C(=CC=CC=3)C(C([O-])=O)C2=O)OCCO1)[CH2:2]CCC.C(C1(C2C=C3C(=CC=2)NC(=O)C3C(OCC)=O)OCCO1)(C)C.[CH2:47]([C:52]1([C:57]2[CH:58]=[C:59]3[C:63](=[CH:64][CH:65]=2)[NH:62][C:61](=[O:66])[CH:60]3[C:67]([O:69][CH2:70][CH3:71])=[O:68])[O:56][CH2:55][CH2:54][O:53]1)C(C)(C)C.C(C1(C2C=C3C(=CC=2)NC(=O)C3C(OCC)=O)OCCO1)C1C=CC=CC=1>>[CH2:1]([N:62]1[C:63]2[C:59](=[CH:58][C:57]([C:52]3([CH3:47])[O:53][CH2:54][CH2:55][O:56]3)=[CH:65][CH:64]=2)[CH:60]([C:67]([O:69][CH2:70][CH3:71])=[O:68])[C:61]1=[O:66])[CH3:2]
Reactant: CCCCCC1(N2C(=O)C(C(=O)[O-])c3ccccc32)OCCO1
Reactant: CCOC(=O)C1C(=O)Nc2ccc(C3(CC(C)(C)C)OCCO3)cc21
Agent: CCOC(=O)C1C(=O)Nc2ccc(C3(C(C)C)OCCO3)cc21
Agent: CCOC(=O)C1C(=O)Nc2ccc(C3(Cc4ccccc4)OCCO3)cc21
Product: CCOC(=O)C1C(=O)N(CC)c2ccc(C3(C)OCCO3)cc21

Procedure:
Similarly, were prepared ethyl 5-(2-n-pentyl-4,5-dihydro-1,3-dioxol-2-yl-oxindole-3-carboxylate, ethyl 5-(2-isopropyl-4,5-dihydro-1,3-dioxol-2-yl)oxindole-3-carboxylate, ethyl 5-(2-neopentyl-4,5-dihydro-1,3-dioxol-2-yl)oxindole-3-carboxylate and ethyl 5-(2-benzyl-4,5-dihydro-1,3-dioxol-2-yl)oxindole-3-carboxylate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)[CH:2]=1.[H][H]>C(O)C.[C].[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)[CH:2]=1
Reactant: CCOC(=O)/C=C/c1ccc(Oc2cccnc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(Oc2cccnc2)cc1
Yield: 99 %

Procedure:
In 20 ml of ethanol was dissolved 2.0 g of ethyl (E)-3-[4-(pyridin-3-yloxy)phenyl]acrylate, and to the resulting solution was added 1.0 g of 5% palladiumcarbon, after which the resulting mixture was stirred in a hydrogen atmosphere at room temperature for 5 hours. The reaction mixture was filtered and the filtrate thus obtained was concentrated under reduced pressure to obtain 2.0 g (yield 99%) of colorless, oily ethyl 3-[4-(pyridin-3-yloxy)phenyl]propionate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:44])=[C:4]([CH3:43])[C:5]2[O:9][C:8]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18](CC4C=CC=CC=4)[CH2:19][CH2:20][CH:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:14][CH2:13]3)([CH3:10])[CH2:7][C:6]=2[C:41]=1[CH3:42].[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[C:3]([CH3:44])=[C:4]([CH3:43])[C:5]2[O:9][C:8]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][CH2:20][CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:14][CH2:13]3)([CH3:10])[CH2:7][C:6]=2[C:41]=1[CH3:42]
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(N(CCC(c3ccccc3)c3ccccc3)Cc3ccccc3)CC1)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(NCCC(c3ccccc3)c3ccccc3)CC1)O2
Yield: 94.5 %

Procedure:
To a solution of 1-[(5-amino-2,3dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl]-N-benzyl-N-(3,3-diphenylpropyl)-4-piperidinamine (1.5 g) in ethanol (50 mL) was added 0.30 g of 5% palladium on carbon (50% hydrous) and the mixture was stirred in a hydrogen atmosphere at 5 atmospheric pressure and 40° C. for 6 hours. This reaction mixture was filtered and the filtrate was concentrated under reduced pressure to provide 1.2 g of 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl]-N-(3,3-diphenylpropyl)-4-piperidinamine. Yield 94%. This product was treated with 4N-HCl solution in ethanol and the resulting trihydrochloride was recrystallized from ethanol/diethyl ether to provide 1.3 g of the title compound. Yield 82%.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[CH2:4]=[O:5].C(N(CC)CC)C.[CH2:13]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[CH2:15][CH2:14]1.Cl>O1CCCC1>[OH:22][C:17]1[C:18]([CH:4]=[O:5])=[CH:19][CH:20]=[C:21]2[C:16]=1[CH2:15][CH2:14][CH2:13]2
Reactant: Oc1cccc2c1CCC2
Reactant: C=O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1O)CCC2
Temperature: 72.5 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a stirred suspension Magnesium chloride (71.0 gm, 0.745 mole) and Para-formaldehyde (33.6 gm, 1.12 mole) in Tetrahydrofuran (200 ml), Triethylamine (104 ml, 0.745 mole) was added at room temperature and stirred for 30 minutes. To the reaction mixture; the solution of Indan-4-ol (50 gm, 0.373) in Tetrahydrofuran (100 ml) was added at room temperature and heated to 70-75° C. for 6 hours. To the reaction mixture, 2N Hydrochloric acid (600 ml) was added and extracted with Ethylacetate (2×500 ml). The Ethylacetate layer was washed with water (300 ml), dried over Sodium sulphate and further it was distilled under vacuum to give viscous oil (52.0 gm) which becomes solid upon keeping.