Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:19]([C:20]2[CH:21]=[N:22][C:23]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:25]=2[C:26]#[N:27])=[CH:18][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH3:9])=[O:7])=[C:4]([OH:32])[CH:3]=1.[O:33]1[CH:37]=[C:36]([CH2:38][CH2:39][CH2:40]O)[CH:35]=[N:34]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:19]([C:20]2[CH:21]=[N:22][C:23]([C:28]([F:29])([F:30])[F:31])=[CH:24][C:25]=2[C:26]#[N:27])=[CH:18][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH3:9])=[O:7])=[C:4]([O:32][CH2:40][CH2:39][CH2:38][C:36]2[CH:35]=[N:34][O:33][CH:37]=2)[CH:3]=1
Reactant: COc1ccccc1N(C)C(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1O
Reactant: OCCCc1cnoc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccccc1N(C)C(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OCCCc1cnoc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-hydroxy-N-(2-methoxy-phenyl)-N-methyl-benzamide (30 mg, 0.065 mmol) in THF (700 μL), 3-isoxazol-4-yl-propan-1-ol (9 mg, 0.071 mmol), triphenylphosphine (26 mg, 0.089 mmol) and DIAD (20 μL, 0.098 mmol) were added. The mixture was stirred at rt overnight, concentrated, diluted with 1 mL MeOH and purified by prep HPLC to give 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(3-isoxazol-4-yl-propoxy)-N-(2-methoxyphenyl)-N-methyl-benzamide 46-1. MS: 571.2 (M+H)+, tR=6.12 min (method 3).
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[N:17]=[C:16]([NH:18][CH3:19])[N:15]=[C:14]([CH3:20])[N:13]=2)[CH2:4]1)[CH3:2].C1(OC2C=CC=CC=2)C=CC=CC=1.CO>[Pd].C(Cl)Cl>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[N:17]=[C:16]([NH:18][CH3:19])[N:15]=[C:14]([CH3:20])[N:13]=2)[CH:4]=1)[CH3:2]
Reactant: CCC1CN(c2nc(C)nc(NC)n2)c2ccccc21
Agent: [Pd]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: CCc1cn(-c2nc(C)nc(NC)n2)c2ccccc12
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A mixture 4-(3-ethylindolin-1-yl)-2-methyl-6-methylamino-1,3,5-triazine (1.5 g, 5.6 mM), 30% w/w palladium on charcoal (0.15 g) and diphenyl ether (10 ml) was heated under reflux in an argon atmosphere for 45 minutes. The mixture was cooled to ambient temperature and methanol (10 ml) and methylene chloride (20 ml) were added. The catalyst was removed by filtration through diatomaceous earth. The filtrate was evaporated to low volume by distillation in vacuo and then diluted with hexane (50 ml) to give 4-(3-ethylindol-1-yl)-2-methyl-6-methylamino-1,3,5-triazine as a white solid (1.3 g, 87% yield), m.p. 174°-175° C.; microanalysis, found: C,67.3; H,5.9; N,26.2%; C15H17N5 requires C,67.42; H,6.3; N,26.21%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=2)[C:10]([Br:20])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+].[I-].[Na+]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:18])[CH:15]=2)[C:10]([Br:20])=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)n1nc(Br)c2ccc(C(=O)O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)n1nc(Br)c2ccc(C(=O)OCc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution containing 3-bromo-indazole-1,6-dicarboxylic acid 1-tert-butyl ester (1.80 g, 5.28 mmol), benzylbromide (0.753 mL, 6.33 mmol), Cs2CO3 (1.89 g, 5.80 mmol) and sodium iodide (0.095 g, 0.633 mmol) in DMF (30 mL) was stirred 16 h at RT. The mixture was diluted with water and extracted with EtOAc (×3). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc/c-hexane 1:4). MS (UPLC/MS): 431.2/433.2 [M+H]+; tR (UPLC conditions f): 2.77 min.
Reaction SMILES: [O:1]1[C:13]2[C:4](=[CH:5][C:6]3[NH:10][C:9]([SH:11])=[N:8][C:7]=3[CH:12]=2)[O:3][CH2:2]1.[Cl-].Cl[CH2:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[CH:19][NH+:18]=1.[OH-].[Na+]>C(O)C.O>[CH3:24][O:23][C:21]1[C:20]([O:25][CH3:26])=[CH:19][N:18]=[C:17]([CH2:16][S:11][C:9]2[NH:10][C:6]3[CH:5]=[C:4]4[O:3][CH2:2][O:1][C:13]4=[CH:12][C:7]=3[N:8]=2)[CH:22]=1
Reactant: Sc1nc2cc3c(cc2[nH]1)OCO3
Reactant: COc1c[nH+]c(CCl)cc1OC
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cnc(CSc2nc3cc4c(cc3[nH]2)OCO4)cc1OC

Procedure:
A brownish solid is obtained by the procedure described in Example 13 by reaction of 0.85 g of 5H-[1,3]-dioxolo[4,5-f]-benzimidazole-6-thiol with 0.98 g of 2-chloromethyl-4,5-dimethoxypyridinium chloride in 10 ml of ethanol and 10 ml of water, with the addition of 8.5 ml of 1N sodium hydroxide solution, after a reaction time of 20 hours and after concentration, by removing the solvent in vacuo, to a volume of 10 ml. The crude product is dissolved in 30 ml of methylene chloride, the solution is clarified with fuller's earth (for example, Tonsil®), and concentrated. The residue is crystallized by addition of diisopropyl ether and the now pale yellow solid is boiled up in 5 ml of methanol. 0.90 g (60% of theory) of the title compound is obtained as a colorless solid of m.p. 198°-200° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:19])=[C:7]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=2)[C:13]#[N:14])[CH:8]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:31](O)=[O:32])=[CH:25]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:19][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:31]([C:26]2[NH:27][C:28]3[C:24]([CH:25]=2)=[CH:23][C:22]([O:21][CH3:20])=[CH:30][CH:29]=3)=[O:32])=[CH:8][C:7]=1[O:9][C:10]1[CH:11]=[C:12]([C:13]#[N:14])[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: N#Cc1cc(Cl)cc(Oc2cc(CN)ccc2Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3)cc2c1
Yield: 37.8 %

Procedure:
N-({4-Chloro-3-[(3-chloro-5-cyanophenyl)oxy]phenyl}methyl)-5-(methyloxy)-1H-indole-2-carboxamide was prepared in a similar manner as described herein from 3-{[5-(aminomethyl)-2-chlorophenyl]oxy}-5-chlorobenzonitrile (0.025 g, 0.085 mmol), 5-(methyloxy)-1H-indole-2-carboxylic acid, (0.025 g, 0.13 mmol), HATU (0.05 g, 0.13 mmol), DIPEA (0.025 mL, 0.13 mmol) and DMF (1 mL). The crude material was purified by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA). The desired fractions were neutralized and extracted with EtOAc. The organic extracts were combined, dried over Na2SO4, filtered and evaporated to afford the title compound (0.015 g, 36%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.42 (d, 1H), 8.98 (t, 1H), 7.76 (d, 1H), 7.59 (d, 1H), 7.43 (dd, 1H), 7.35 (d, 1H), 7.25-7.28 (m, 2H), 7.23 (d, 1H), 7.03 (dd, 2H), 6.80 (dd, 1H), 4.48 (d, 2H), 3.72 (s, 3H). MS: m/z 466.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=2)(=[O:21])=[O:20])=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Brc1ccc2cn[nH]c2c1
Product: COc1ccc(S(=O)(=O)n2ncc3ccc(Br)cc32)cc1
Yield: 87.9 %

Procedure:
6-Bromo-1H-indazole (500 mg, 2.54 mmol) was treated with 4-methoxybenzene-1-sulfonyl chloride (576 mg, 2.79 mmol) according to the method described in Preparation 15b to give 820 mg (81% yield) of the title compound. Purity 92%.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C:7]1[CH:39]=[CH:38][C:10]2[N:11]([CH2:25][CH2:26][CH2:27][N:28]([CH3:37])[CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[C:12]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=3)=[N:13][C:9]=2[CH:8]=1)=[O:6]>O1CCCC1.O>[CH3:22][O:21][C:19]1[CH:20]=[C:15]([NH:14][C:12]2[N:11]([CH2:25][CH2:26][CH2:27][N:28]([CH3:37])[CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[C:10]3[CH:38]=[CH:39][C:7]([C:5]([OH:6])=[O:4])=[CH:8][C:9]=3[N:13]=2)[CH:16]=[C:17]([O:23][CH3:24])[CH:18]=1
Reactant: COC(=O)c1ccc2c(c1)nc(Nc1cc(OC)cc(OC)c1)n2CCCN(C)CCc1ccccn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Nc2nc3cc(C(=O)O)ccc3n2CCCN(C)CCc2ccccn2)cc(OC)c1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
Lithium hydroxide (0.350 g, 4 eq) is added to a solution of methyl-2-[(3,5-dimethoxyphenyl)amino]-1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-1H-benzimidazole-5-carboxylate (1.05 g, 1 eq) in a mixture of tetrahydrofuran (10 ml) and water (5 ml). The mixture is stirred at 65° C. for 18 hours then cooled down to ambient temperature and concentrated under reduced pressure at 40° C. Ethyl acetate and water are added to the residue. The mixture is acidified by adding acetic acid to pH 5. After decanting and extracting, the combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. Purification by flash chromatography on silica gel (eluent: dichloromethane/ethanol 95/5 to 70/30) produces the expected compound in the form of a white foam (0.93 g, 91% yield).
Reaction SMILES: [Cl:1][C:2]1[C:28]([N:29]([C:31](=[O:49])[CH2:32][NH:33][C:34](=[O:48])/[CH:35]=[CH:36]/[C:37]2[CH:38]=[N:39][C:40]([C:43]([O:45]CC)=[O:44])=[CH:41][CH:42]=2)[CH3:30])=[CH:27][CH:26]=[C:25]([Cl:50])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[C:11]2[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.[OH-].[Na+]>C(O)C>[C:43]([C:40]1[N:39]=[CH:38][C:37](/[CH:36]=[CH:35]/[C:34]([NH:33][CH2:32][C:31]([N:29]([C:28]2[C:2]([Cl:1])=[C:3]([C:25]([Cl:50])=[CH:26][CH:27]=2)[CH2:4][O:5][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:15]=2[N:14]=[C:13]([CH3:16])[CH:12]=[C:11]3[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH3:30])=[O:49])=[O:48])=[CH:42][CH:41]=1)([OH:45])=[O:44]
Reactant: CCOC(=O)c1ccc(/C=C/C(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c(OCc5ccccn5)cc(C)nc34)c2Cl)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OCc2ccccn2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(C(=O)O)nc4)c3Cl)c2n1
Temperature: 50 °C
Reaction time: 6 h
Yield: 97.1 %

Procedure:
To a solution of 8-[2,6-dichloro-3-[N-[(E)-3-(6-ethoxycarbonylpyridin-3-yl)acryloylglycyl]-N-methylamino]benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (30 mg) in ethanol (0.5 ml) was added 1N aqueous sodium hydroxide solution (0.1 ml) at ambient temperature, and the mixture was stirred at 50° C. for 6 hours. The reaction mixture was evaporated in vacuo, and the residue was dissolved in water. The aqueous layer was washed with diethyl ether and adjusted to pH 5 with 1N hydrochloric acid. The precipitate was collected by filtration to give 8-[3-[N-[(E)-3-(6-carboxypyridin-3-yl)acryloylglycyl]-N-methylamino]- 2,6-dichlorobenzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (28 mg) as powder.
Reaction SMILES: [C:1]1([C:7](=[O:17])[CH:8]2[O:10][CH:9]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].O.C(=O)=O>C(O)C>[C:1]1([C:7](=[O:17])[C:8](=[O:10])[CH2:9][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccccc1)C1OC1c1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=C=O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(Cc1ccccc1)C(=O)c1ccccc1
Reaction time: 0.03 h
Yield: 65 %

Procedure:
To a boiling solution of 30 g 1,3-diphenyl-2,3-epoxy-1-propanone in 500 ml ethanol was rapidly added a hot solution of 30 g potassium t-butoxide in 500 ml ethanol. The mixture was kept boiling on a steambath for 2 minutes. It was then diluted with 3 l. water. The aqueous solution was saturated with carbon dioxide by the addition of small pieces of dry ice. The resulting emulsion was extracted with ether. The ether extracts were diluted with benzene, dried over sodium sulfate and evaporated under reduced pressure. The remaining dark oil was distilled in high vacuum to afford 19.5 g 1,3-diphenyl-1,2-propanedione; b.p. 136°-138°/0.1 mm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7]Br.[CH2:11]([O:13][P:14]([O:18]CC)[O:15][CH2:16][CH3:17])[CH3:12]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7][P:14](=[O:18])([O:15][CH2:16][CH3:17])[O:13][CH2:11][CH3:12]
Reactant: CCOP(OCC)OCC
Reactant: Clc1ccc(Br)cc1CBr
Product: CCOP(=O)(Cc1cc(Br)ccc1Cl)OCC
Temperature: 130 °C
Reaction time: 3 h

Procedure:
A mixture of 9.88 g 5-bromo-2-chloro-benzylbromide in 6.10 ml triethylphosphite is stirred for 3 h at 130° C. Then a further 1.50 ml triethylphosphite are added, and the mixture is stirred for a further 3 h at 160° C. After cooling to ambient temperature the mixture is purified on silica gel (dichloromethane/methanol 1:0->9:1).
Reaction SMILES: C(OC([N:8]1[CH2:20][CH:11]2[C:12]3[CH:13]=[C:14]([Br:19])[S:15][C:16]=3[CH:17]([CH3:18])[CH:10]2[CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[Br:19][C:14]1[S:15][C:16]2[CH:17]([CH3:18])[CH:10]3[CH2:9][NH:8][CH2:20][CH:11]3[C:12]=2[CH:13]=1
Reactant: CC1c2sc(Br)cc2C2CN(C(=O)OC(C)(C)C)CC12
Agent: Cl
Solvent: C1COCCO1
Product: CC1c2sc(Br)cc2C2CNCC12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from step b) (50 mg, 0.14 mmol) was dissolved in 2 mL of 4M HCl/dioxane and stirred at room temperature for one hour. The solvent was evaporated leaving a solid that was purified by preparative LC/MS. MS calculated for C10H12BrNS+H: 258, observed: 258 and 260. 1H NMR (CDCl3300 MHz) δ 1.29 (d, 3H), 1.98 (s, 1H), 3.14 (m, 3H), 3.32 (m 2H), 3.50 (m, 1H), 3.70 (m, 1H), 6.74 (s, 1H) ppm.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C@@H:9]([NH:14][S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH2:8]2)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:2][CH2:3][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C@@H:9]([NH:14][S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH2:8]2
Reactant: COC(=O)c1ccc2c(c1)C[C@H](NS(=O)(=O)C(C)C)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(CO)cc2C1
Reaction time: 0.33 h
Yield: 91.6 %

Procedure:
(R)-methyl-2-(1-methylethylsulfonamido)-2,3-dihydro-1H-indene-5-carboxylate (7.13 mmol, 2.12 g) was dissolved in dry THF (100 mL) and the vessel purged with nitrogen. Lithium aluminium hydride (1M, 14.3 mmol, 14.3 mL) was added dropwise and stirring continued for 20 min. The mixture was quenched by addition of methanol followed by water and 1N HCl before concentration to remove organics. The residue was partitioned between EtOAc/1N HCl. and the phases mixed and separated. The aqueous layer was further extracted with EtOAc (×2) Combined organics washed with brine and concentrated before purification on silica eluting with 1% MeOH/DCM to give (R)—N-(5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide as a light coloured solid (1.76 g, 92%). 1H NMR (400 MHz, CDCl3) δ 1.40 (d, 6H) 1.60 (bs, 1H) 2.90 (m, 2H) 3.18 (sept, 1H) 3.32 (m, 2H) 4.19-4.33 (m, 2H) 4.66 (s, 2H) 7.20 (m, 2H) 7.26 (m, 1H)
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][C@@H:25]([CH3:34])[C@H:26]([OH:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[OH-].[Na+]>CO.C1COCC1>[OH:33][C@H:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C@@H:25]([NH:24][CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:35])=[O:2])[CH:6]=1)[CH3:34]
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN[C@@H](C)[C@H](O)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN[C@@H](C)[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
{2′-[((1S,2R)-2-Hydroxy-1-methyl-2-phenyl-ethylamino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester (0.021 g, 0.04 mmol) in MeOH (0.33 mL) and THF (0.4 mL) was treated with 1N aqueous NaOH (0.1 mL) and stirred at room temperature for 4 hours. Analytical LCMS showed that some starting material was still present, so additional 1N aqueous NaOH (0.05 mL) was added, and the reaction was stirred at room temperature overnight. Analytical LCMS showed that starting material still remained, so additional 1N aqueous NaOH (0.1 mL) was added, and the reaction was stirred for 4 hours. After work-up with CH2Cl2 and 1N aqueous HCl, the combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: FC1(C(O)=O)CCC(=CC2C(C)(C)[C@H]3[C@](C)(CC=2)[C@@H]2[C@](C)([C@@]4(C)[C@H](CC2)[C@H]2[C@H](C(C)=C)CC[C@]2(NCCN2CCC(S(C)(=O)=O)CC2)CC4)CC3)CC1.[O:54]=[S:55]1(=[O:101])[CH2:60][CH2:59][N:58]([CH2:61][CH2:62][NH:63][C@:64]23[CH2:97][CH2:96][C@@H:95]([C:98]([CH3:100])=[CH2:99])[C@@H:65]2[C@@H:66]2[C@@:79]([CH3:82])([CH2:80][CH2:81]3)[C@@:78]3([CH3:83])[C@@H:69]([C@:70]4([CH3:94])[C@@H:75]([CH2:76][CH2:77]3)[C:74]([CH3:85])([CH3:84])[C:73]([CH:86]=[CH:87][CH:88]=[CH:89][C:90]([O:92]C)=[O:91])=[CH:72][CH2:71]4)[CH2:68][CH2:67]2)[CH2:57][CH2:56]1>>[O:101]=[S:55]1(=[O:54])[CH2:60][CH2:59][N:58]([CH2:61][CH2:62][NH:63][C@:64]23[CH2:97][CH2:96][C@@H:95]([C:98]([CH3:100])=[CH2:99])[C@@H:65]2[C@@H:66]2[C@@:79]([CH3:82])([CH2:80][CH2:81]3)[C@@:78]3([CH3:83])[C@@H:69]([C@:70]4([CH3:94])[C@@H:75]([CH2:76][CH2:77]3)[C:74]([CH3:84])([CH3:85])[C:73]([CH:86]=[CH:87][CH:88]=[CH:89][C:90]([OH:92])=[O:91])=[CH:72][CH2:71]4)[CH2:68][CH2:67]2)[CH2:57][CH2:56]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C=CC=CC(=O)OC)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C=C6CCC(F)(C(=O)O)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C=CC=CC(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
5-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)penta-2,4-dienoic acid was prepared following the procedure described in step 2 of the preparation of 1-fluoro-4-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperidin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)methylene)cyclohexanecarboxylic acid using the corresponding crude product from step 1 as the reactant. The title compound was obtained as a mixture of 2E,4E- and 2E,4Z-2,4-dienoic acid isomers (solid, 11%). MS: m/e 667.5 (M+H)+, 2.41 min (method 5). For 2E,4E isomer, 1H NMR (400 MHz, CHLOROFORM-d) δ 7.40-7.26 (m, 1H), 6.54 (d, J=15.1 Hz, 1H), 6.18 (dd, J=15.3, 11.0 Hz, 1H), 5.88 (d, J=15.1 Hz, 1H), 5.65 (s., 1H), 4.80 (s, 1H), 4.66 (s, 1H), 3.22-2.63 (m, 12H), 2.21-0.81 (m, 23H), 1.71 (s, 3H), 1.13 (s, 3H), 1.01 (s, 3H), 0.99 (s, 3H), 0.91 (s, 3H), 0.71 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:14]2[N:13]3[C:8]([C:9]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[CH3:23])=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[N:5]=[C:4]([CH3:24])[N:3]=1.[CH2:25]([NH2:28])[CH2:26][NH2:27].CCOC(C)=O>CN1C(=O)CCC1>[NH2:27][CH2:26][CH2:25][NH:28][C:2]1[C:14]2[N:13]3[C:8]([C:9]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[CH3:23])=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[N:5]=[C:4]([CH3:24])[N:3]=1
Reactant: NCCN
Reactant: Cc1cc(C)c(-c2cccn3c2cc2nc(C)nc(Cl)c23)c(C)c1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(-c2cccn3c2cc2nc(C)nc(NCCN)c23)c(C)c1

Procedure:
Heat a solution of 4-chloro-2-methyl-9-(2,4,6-trimethylphenyl)pyrimidino[4,5-b]indolizine (0.3 g, 0.89 mmol), and ethylene diamine (0.6 mL, 8.93 mmol) in dry NMP (3 mL) at 100 ° C. for 14 h. Pour the cooled mixture onto water (30 mL) and extracte twice with EtOAc (30 mL). Wash the combined extracts with brine (30 mL), dry, and evaporate in vacuo. Purify by preparative TLC (20% MeOH in CH2Cl2 with 0.5% ammonium hydroxide) to obtain the title compound as a yellow oil.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][CH2:11][C:12]([OH:14])=[O:13].[C:15]([CH2:18][CH2:19][C:20](Cl)=[S:21])(=[O:17])[CH3:16]>>[C:15]([CH2:18][CH2:19][C:20]([N:10]([CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)[CH2:11][C:12]([OH:14])=[O:13])=[S:21])(=[O:17])[CH3:16]
Reactant: CC(=O)CCC(=S)Cl
Reactant: O=C(O)CNC1Cc2ccccc2C1
Product: CC(=O)CCC(=S)N(CC(=O)O)C1Cc2ccccc2C1

Procedure:
By reacting N-(2-indanyl)glycine with 3-acetylthiopropionyl chloride in a similar manner to that of Example 1, there is obtained N-(3-acetylthiopropionyl)-N-(2-indanyl)glycine as colorless scales.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([O-:9])=[O:8])[CH:2]=1.[OH-].[K+]>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:9])=[O:8])[CH:2]=1
Reactant: O=C([O-])c1cccnc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccnc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 267.1 %

Procedure:
A suspension of crude ethyl 6-[3-endo-({[2-methyl-3-methyloxy)phenyl]carbonyl}amino)-8-azabicyclo[3.2.1]oct-8-yl]pyridine-3-carboxylate (4.72 g, max. 9.55 mmol) and potassium hydroxide (1.07 g, 19.10 mmol) in methanol (90 mL) and water (30 mL) was stirred at 60° C. for 2 hours. After cooling to room temperature, some of the methanol was evaporated, water was added to the resulting mixture, and the pH adjusted to 5 with 1N aqueous hydrochloric acid. The precipitate was filtered, washed with water, and dried to afford 6-[3-endo-({[2-methyl-3-methyloxy)phenyl]carbonyl}amino)-8-azabicyclo[3.2.1]oct-8-yl]pyridine-3-carboxylic acid (3.14 g, 83% yield over two steps). 1H NMR (400 MHz, DMSO-d6): 12.45 (s, 1H), 6.83 (br s, 1H), 8.64 (d, 1H), 8.24 (d, 1H), 7.91 (dd, 1H), 7.23 (t, 1H), 7.02 (d, 1H), 6.86 (d, 1H), 6.75 (d, 1H), 4.60 (br s, 2H), 3.86 (m, 1H), 3.80 (s, 3H), 2.21 (m, 2H), 2.14 (s, 3H), 2.07 (m, 2H), 1.97 (m, 2H), 1.87 (d, 2H); MS (EI) for C22H25N3O4: 396 (MH+).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[O:14]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[I:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:26]([CH2:25][C:24]1[CH:27]=[CH:28][C:21]([O:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:22][CH:23]=1)[CH2:11]2
Reactant: NCc1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)c1c(I)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1c2c(I)cccc2CN1Cc1ccc(Oc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.200 g, 0.56 mmol), 4-phenoxy-benzylamine (0.7 mmol), and K2CO3 (0.166 g, 1.2 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.108 g, 44%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.19 (s, 2H), 4.75 (s, 2H), 6.94-7.40 (m, 1H), 7.92 (d, 1H). GC-MS: m/z 441 (M)+.