Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:30](=[O:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:33]=[C:34](Br)[C:35]([Cl:37])=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+].[CH3:79][NH:80][CH3:81]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:30]([N:14]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1)[CH:10]1[CH2:11][CH2:12][CH2:13][N:7]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])[C:8]2[CH:36]=[C:35]([Cl:37])[C:34]([N:80]([CH3:81])[CH3:79])=[CH:33][C:9]1=2)(=[O:32])[CH3:31]
Reactant: CNC
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Cl)c(Br)cc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Cl)c(N(C)C)cc21
Yield: 52.3 %

Procedure:
Combine isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-bromo-8-chloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (0.075 g, 0.119 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.003 g, 0.0029 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.006 g, 0.012 mmol), sodium tert-butoxide (0.029 g, 0.298 mmol) and dimethylamine (0.071 mL, 0.143 mmol, 2.0 M in THF) in toluene (0.5 mL) in a 10 mL microwave vessel and irradiate at 110° C. for 20 min (50 W). Add a large excess of dimethylamine (2 mL, 4 mmol, 2.0 M in THF) and irradiate at 110° C. for 20 min. Dilute the cooled mixture with ethyl acetate (25 mL) and filter through Celite. Remove the filtrate solvent under reduced pressure and purify the residue using chromatography on silica gel, eluting with hexanes/ethyl acetate (60:40), to provide the title compound as an off-white solid (0.037 g, 52%): ESI MS 594 (M+H).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:22]([C@H:24]([C@@H:26]([OH:42])[C@@H:27]([CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([OH:38])[C:32]=1[C:39]([OH:41])=[O:40])[CH3:28])[CH3:25])=[O:23])[C@H:4]1[O:8][C@@:7]([C@@H:11]2[O:16][C@@H:15]([CH3:17])[C@@:14]([OH:20])([CH2:18][CH3:19])[CH2:13][CH2:12]2)([CH2:9][CH3:10])[CH2:6][C@@H:5]1[CH3:21].[BH4-].[Na+]>C(O)C>[CH3:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH2:29][CH:27]([CH3:28])[CH:26]([OH:42])[CH:24]([CH3:25])[CH:22]([OH:23])[CH:3]([CH2:2][CH3:1])[CH:4]2[CH:5]([CH3:21])[CH2:6][C:7]([CH2:9][CH3:10])([CH:11]3[CH2:12][CH2:13][C:14]([CH2:18][CH3:19])([OH:20])[CH:15]([CH3:17])[O:16]3)[O:8]2)=[C:32]([C:39]([OH:41])=[O:40])[C:33]=1[OH:38]
Reactant: CC[C@@H](C(=O)[C@@H](C)[C@@H](O)[C@H](C)CCc1ccc(C)c(O)c1C(=O)O)[C@H]1O[C@](CC)([C@H]2CC[C@](O)(CC)[C@H](C)O2)C[C@@H]1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCC(C(O)C(C)C(O)C(C)CCc1ccc(C)c(O)c1C(=O)O)C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C
Reaction time: 8 h

Procedure:
To a solution of 10 g of crystalline antibiotic X-537A in 500 ml of absolute ethanol was added 1.36 g of NaBH4. The reaction was followed by assaying with thin layer chromatography (silica gel - CHCl3 /acetone 8:2) and the reaction was continued overnight after adding an additional 1.0 g. of NaBH4. The following morning the solvent was removed under reduced pressure and the heavy oil diluted with methylene chloride, washed with dilute HCl, dried (Na2SO4), and concentrated to a solid foam. The slightly pink solid was chromatographed on a 500 g silica gel column eluting with 2 l. hexane-methylene chloride (1:1), 2 l. methylene chloride 2 l. methylene chloride ether (1:1), The 250 ml fractions were assayed by TLC and fractions 13-17 pooled, concentrated to a yellow solid and rechromatographed on a 150 g florisil column eluting with a gradient from hexane to acetone. The fractions containing 3-methyl-6-{4,6-dihydroxy-3,5-dimethyl-7-ethyl-7-]5-ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl 2-tetrahydrofuryl]heptyl}salicylic acid were pooled and concentrated to a small volume from which pure 3-methyl-6-{4,6-dihydroxy-3,5-dimethyl-7-ethyl-7 -[5-ethyl-3-methyl-5-(5-ethyl-6-methyl-2-tetrahydropyranyl) 2-tetrahydrofuryl]heptyl}salicylic acid crystals were recovered, m.p. 151°-153°. From the mother liquor, additional material was crystallized, [α]D25 + 0.83 (C=.60%, CH3OH).
Reaction SMILES: [CH2:1]([NH:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:11]([OH:15])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6]1)[CH2:2][CH3:3].CC1C=CC(S(O[CH2:27][CH2:28][C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)(=O)=O)=CC=1.S([O-])([O-])=O.[Na+].[Na+]>C1(C)C(C)=CC=CC=1>[CH2:1]([N:4]([CH2:27][CH2:28][C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)[C@H:5]1[CH2:14][CH2:13][C:12]2[C:11]([OH:15])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCN[C@H]1CCc2c(O)cccc2C1
Reactant: Cc1ccc(S(=O)(=O)OCCc2cccs2)cc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCCN(CCc1cccs1)[C@H]1CCc2c(O)cccc2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.4 %

Procedure:
2.00 kg (9.74 mol) of (S)-5,6,7,8-tetrahydro-6-propylamino-1-naphthol, 4.12 kg (14.62 mol) of 2-(2-thienyl)ethyl 4-methylbenzenesulfonate (with a sulfonate/starting material mole ratio of 1.5/1), 3.69 kg (29.25 mol) of sodium sulfite (with a sodium sulfite/starting material mole ratio of 3.0/1) and 25 L of xylene were mixed to form a mixture, and the mixture was refluxed. After 48 hours, the reaction was stopped. The mixture was cooled to room temperature, and washed with an appropriate amount of water. Active carbon was added to decolorize the mixture. The mixture was filtered and left standing. An organic phase was reserved and concentrated under vacuum to obtain a residue. The residue was separated by silica gel column chromatography, and eluted with ethyl acetate and hexane (1:19), to obtain 1.64 kg of (S)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-1-naphthol, which was converted into a hydrochlorate thereof. The yield was 47.8%.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[S:6][CH:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4](=O)[CH2:3]1.[CH2:14]([C:19]1[CH:20]=C(O)C=[C:23]([CH:25]=1)[OH:24])[CH2:15][CH2:16][CH2:17][CH3:18]>>[CH3:1][C:2]1([CH3:13])[S:6][C:5]2[C:7](=[O:8])[O:9][C:10]3[CH:20]=[C:19]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:25]=[C:23]([OH:24])[C:11]=3[C:4]=2[CH2:3]1
Reactant: CCOC(=O)C1SC(C)(C)CC1=O
Reactant: CCCCCc1cc(O)cc(O)c1
Product: CCCCCc1cc(O)c2c3c(c(=O)oc2c1)SC(C)(C)C3
Yield: 72.5 %

Procedure:
Ethyl 5,5-dimethyl-3-oxo-tetrahydrothiophene-2-carboxylate was reacted with 5-n-pentyl resorcinol following a procedure similar to that of Example 3-C to produce 1,2-dihydro-2,2-dimethyl-9-hydroxy-7-n-pentyl-4-oxo-4H-thieno-[2,3-c][1] benzopyran in a 72.5% yield, m.p. 203°-206°C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][CH2:15][C:14]([CH3:18])([CH3:17])[S:13]1.[CH2:19](Br)[CH:20]([CH3:22])[CH3:21]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:16]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:15][C:14]([CH3:18])([CH3:17])[S:13]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NCC(C)(C)S1
Reactant: CC(C)CBr
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SC(C)(C)CN1CC(C)C

Procedure:
2-Methyl-2-hydroxypropylamine was reacted with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to afford 2-(2-methyl-4-nitrophenylimino)-5,5-dimethyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2g to afford 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-5,5-dimethyl-1,3-thiazolidine.
Reaction SMILES: [C:1]([NH:20][C@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[OH:27])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:28][C:29]1([CH3:45])[O:34][CH:33]([C:35]([NH:37][CH2:38][CH2:39][C:40](O)=[O:41])=[O:36])[C:32]([CH3:44])([CH3:43])[CH2:31][O:30]1>>[CH3:28][C:29]1([CH3:45])[O:34][CH:33]([C:35]([NH:37][CH2:38][CH2:39][C:40]([O:27][C@H:22]2[CH2:23][CH2:24][CH2:25][CH2:26][C@@H:21]2[NH:20][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:41])=[O:36])[C:32]([CH3:44])([CH3:43])[CH2:31][O:30]1
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)N[C@H]1CCCC[C@@H]1O
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)N[C@H]1CCCC[C@@H]1OC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 44 %

Procedure:
(1S,2S)-2-(N-Linoleoylamino)cyclohexanol (3.77 g) and 2.59 g of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid were reacted in the same manner as in Example 15 to obtain 2.72 g of the title compound (yield: 44%)
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:18][C:2]1([F:1])[CH2:6][NH:5][C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1
Reactant: COC(=O)[C@@H]1CC(F)(F)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CC(F)(F)CN1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(S)-1-tert-butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate (0.472 g) in CH2Cl2 (1 mL) was treated with trifluoroacetic acid (1.4 mL), stirred at ambient temperature for 4 hours, and concentrated. The product was free-based using a MEGA BE-SCX column with 1:1 CH2Cl2/methanol as eluent for the trifluoroacetic acid. The product was released from the column with 5% (7 M ammonia in methanol) in CH2Cl2 as eluent.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH:15]=[CH:16][C:17]2[S:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[N:19][C:18]=2[CH3:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]>[Pd].C(O)C.O1CCOCC1>[CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]2[S:21][C:20]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)=[N:19][C:18]=2[CH3:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)COc1ccc(C=Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)COc1ccc(CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Reaction time: 6 h

Procedure:
A mixture of ethyl [2-methyl-4-(2-{4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}ethenyl)phenoxy]acetate (intermediate 19, 0.23 g) and 10% palladium on carbon (0.2 g) in ethanol:1,4-dioxan (1:1, 20 ml) was stirred under a hydrogen atmosphere for 6 hours. The reaction mixture was filtered through Celite™ and the filtrate evaporated. The residue was purified by Biotage™ chromatography using a mixture of petroleum ether:ethyl acetate (4:1) as eluent to give the title compound as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[N:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.Cl[P:17]([O:23][CH3:24])[N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>C1COCC1.C(Cl)Cl>[CH3:24][O:23][P:17]([C:7]1[NH:6][N:5]=[C:4]([N+:1]([O-:3])=[O:2])[N:8]=1)[N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=[N+]([O-])c1nc[nH]n1
Reactant: COP(Cl)N1CCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: COP(c1nc([N+](=O)[O-])n[nH]1)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a stirred solution of 3-nitro-1,2,4-triazole (2.70 g, 23.71 mmol) and triethylamine (11.0 mL, 8.0 g, 79.0 mmol) in THF (40 mL) and CH2Cl2 (20 mL) was added dropwise chloro(methoxy)pyrrolidinophosphine (3.31 g, 19.76 mmol) at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was filtered to remove the resulting salt, and the solvent was removed under reduced pressure to give the crude product as a pale yellow oil (3.97 g, 82%). 31P NMR (CDCl3) δ 132.9.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]([CH3:23])[CH3:22])[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.CC1([CH2+])C(C)(C)OB([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[N:39]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[CH:40]=[CH:41][N:42]=3)=[CH:34][CH:33]=2)O1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]([CH3:23])[CH3:22])[C:5]2[C:10]([C:32]3[CH:33]=[CH:34][C:35]([C:38]4[N:39]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[CH:40]=[CH:41][N:42]=4)=[CH:36][CH:37]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: [CH2+]C1(C)OB(c2ccc(-c3nccn3COCC[Si](C)(C)C)cc2)OC1(C)C
Reactant: CC(C)Oc1nc(Cl)nc2c1c(I)cn2COCC[Si](C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Oc1nc(Cl)nc2c1c(-c1ccc(-c3nccn3COCC[Si](C)(C)C)cc1)cn2COCC[Si](C)(C)C
Temperature: 100 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a degassed mixture of 2-chloro-5-iodo-4-isopropoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), (4,5,5-trimethyl-2-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)-1,3,2-dioxaborolan-4-yl)methylium (1.2 equiv) and tripotassium phosphate trihydrate (3 equiv) in a 9:1 mixture of 1,4-dioxane and water (0.09 M) was added palladium 1,1-bis(diphenylphosphion)-ferrocene dichloride (0.2 equiv). The reaction mixture was stirred at 100° C. for 2 h. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (0-20% ethyl acetate in petroleum ether) to afford the title compound (82% yield) as a red solid. MS (ESI) m/z 614.2 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](Br)=[CH:24][CH:23]=[C:22]([Cl:27])[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40]([O:42][CH3:43])=[O:41])=[CH:35][C:34]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+].C1COCC1>CCOC(C)=O.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:38]4[CH:37]=[C:36]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH:35]=[CH:34][C:33]=4[O:32][CH3:31])=[CH:24][CH:23]=[C:22]([Cl:27])[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br
Reactant: COC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(Cl)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Reaction time: 0.25 h

Procedure:
A flask was charged with (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (265 mg, 0.511 mmol), methyl [4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (156.6 mg, 0.511 mmol), 1M K2CO3 (4 mL, 4 mmol), and THF (4 mL). The reaction was degassed with N2 and then 1,1′-bis(di-t-butylphosphino)ferrocene palladium dichloride (16.7 mg, 0.026 mmol) was added while the reaction was stirred vigorously. Vigorous stirring was continued for 15 min at room temperature, and then the reaction was diluted with EtOAc (40 mL) and washed with water and brine (20 mL each). The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0 to 70% EtOAc/hexanes) to afford methyl {3-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-chloropyridin-3-yl]-4-methoxyphenyl}acetate. Rf=0.21 (25% EtOAc/hexanes). LCMS=617.4 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 6.92-7.83 (m, 8H), 4.88-5.68 (m, 2H), 3.58-4.19 (m, 10H), 0.63 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([N:10]2[C:14]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[S:21](=[O:24])(=[O:23])[CH2:22][C:13]=3[C:12]([C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])=[N:11]2)[CH2:5]1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.[I-].[Na+].C([O-])([O-])=O.[K+].[K+]>C(#N)C.C(Cl)Cl>[N:27]1([C:25]([C:12]2[C:13]3[CH2:22][S:21](=[O:23])(=[O:24])[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:14]=3[N:10]([CH:6]3[CH2:7][CH2:8][CH2:9][N:4]([CH2:3][CH2:2][N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH2:5]3)[N:11]=2)=[O:26])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: C1COCCN1
Reactant: O=C(c1nn(C2CCCN(CCCl)C2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: O=C(c1nn(C2CCCN(CCN3CCOCC3)C2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Enantiomer A of 1- [1-(2-chloroethyl)piperidin-3-yl]-3-(morpholin-4-ylcarbonyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide (274 mg; 0.57 mmol; 1.00 eq.), morpholine (199 μl; 2.29 mmol; 4.00 eq.), sodium iodide (85 mg; 0.57 mmol; 1.00 eq.) and K2CO3 (237 mg; 1.72 mmol; 3.00 eq.) are taken up in ACN (6 mL). The reaction mixture is stirred at 60° C. overnight. The reaction mixture is diluted in DCM and washed with water, brine, then dried over MgSO4 and evaporated. Purification by flash chromatography (DCM/MeOH 0 to 5%) followed by dissolution in ACN : water and freeze drying gives the title compound as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 8.05 (dd, J =1.2, 7.8 Hz, 1H), 7.94 (td, J =1.3, 7.8 Hz, 1H), 7.88-7.81 (m, 11-1), 7.80-7.70 (m, 1H), 5.05-4.62 (m, 3H), 4.05-3.79 (m, 2H), 3.79-3.58 (m, 6H), 3.56-3.42 (m, 4H), 3.32-3.08 (m, 3I-1), 2.91 (d, J =10.8 Hz, 1H), 2.46-2.22 (m, 8H), 2.20-1.60 (m, 6H). MS (ESI+): 530.46. HPLC (max plot) 99.4%; Rt 1.56 min. [α]25D+4.20 (c 1.09, DCM).
Reaction SMILES: C(OC([N:8]1[CH:16]([CH3:17])[C:15]2[C:14]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28](=[O:40])[NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH:23]=[CH:22]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:39][C:36]([F:37])([F:38])[C:32]1[CH:31]=[C:30]([NH:29][C:28]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:18][C:14]4[C:15]5[CH:16]([CH3:17])[NH:8][CH2:9][C:10]=5[N:11]=[CH:12][N:13]=4)=[CH:27][CH:26]=3)[CH:22]=[CH:23]2)=[O:40])[CH:35]=[CH:34][CH:33]=1
Reactant: CC1c2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1NCc2ncnc(Oc3ccc4c(ccn4C(=O)Nc4cccc(C(F)(F)F)c4)c3)c21
Temperature: 25 °C

Procedure:
To a solution of 5-methyl-4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester in DCM (20 mL), TFA (20 ml, 134 mmol) is added at 0° C. After 30 min the reaction is warmed to rt. At this point, the reaction is evaporated and the crude product is dissolved in EtOAc. A Few drops of NH4OH are added to freebase the amine and the whole mixture is then evaporated. The crude product is added to a silica gel column and is eluted with DCM/MeOH/NH4OH (100:0:0 to 93:6:1) to give racemic 5-(5-Methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 454.9 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.50 (s, 1 H) 8.33 (s, 1 H) 8.06 (s, 1 H) 7.94 (br. S., 2 H) 7.57 (s, 1 H) 7.42 (br. S., 2 H) 7.12 (d, J=9.09 Hz, 1 H) 6.75 (d, J=3.03 Hz, 1 H) 4.70 (br. S., 1 H) 4.10-4.22 (m, 2 H) 1.60 (d, J=6.57 Hz, 3 H). Racemate is then separated using chiral HPLC (IA column; 40% heptane, 60% Ethanol) to give the corresponding enantiomers D-1 and D-2.
Reaction SMILES: [N:1]1([C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[ClH:18].[OH-].[Na+]>C1COCC1>[ClH:18].[N:1]1([C:10]2[CH:11]=[C:12]([CH2:13][NH2:14])[CH:15]=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1cccc(N2CCc3ccccc32)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NCc1cccc(N2CCc3ccccc32)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
A solution of 7.1 g (32.3 mmole) of 3-(1-indolinyl)benzonitrile of Example 3a in 44 ml THF was added dropwise over 30 minutes to an ice cold solution of 129 ml (129 mmole, 4 equivalents) of 1 M BH3.THF complex under nitrogen. After heating at reflux for 1 hour, the reaction mixture was cooled to 0°-5° C. and treated dropwise with 50 ml concentrated HCl. The resulting suspension was heated at reflux for 1 hour, permitted to stand at room temperature overnight (about 16 hours) and then made basic using 50% NaOH (60 ml). The reaction mixture was partitioned between water--CH2Cl2 (300 ml each) and the organic phase was washed with brine (300 ml), dried over MgSO4 and concentrated to give 8.9 g of crude free base. Conversion as in Example 1 to the HCl salt (ethanol/ethereal HCl) and recrystallization from hot acetonitrile-methanol afforded 2.86 g (34% overall) of 3-(1-indolinyl)benzenemethanamine hydrochloride, m.p. 170.5°-173.5° C.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C(NB)(C)(C)C.[CH2:11]([N:18]1[CH2:26][CH:25]2[CH:21]([C:22](=O)[C:23]3[S:29][CH:28]=[CH:27][C:24]=32)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Al+3].[Cl-].[Cl-].[Cl-].B.Cl.[OH-].[Na+]>C(Cl)Cl>[CH2:11]([N:18]1[CH2:26][CH:25]2[CH:21]([CH2:22][C:23]3[S:29][CH:28]=[CH:27][C:24]=32)[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1c2sccc2C2CN(Cc3ccccc3)CCC12
Agent: B
Agent: BNC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: c1ccc(CN2CCC3Cc4sccc4C3C2)cc1
Reaction time: 0.5 h

Procedure:
A slurry of AlCl3 (1.32 g, 9.96 mmol) in CH2Cl2 (6 ml) was treated with tert-butylaminoborane (1.73 g, 19.92 mmol) at 0° C. and stirred for 30 minutes. Next, a solution of the product from step f) (941 mg, 3.32 mmol) in CH2Cl2 (3 ml) was added dropwise to the AlCl3/borane solution. After 2 hours at 0° C., the crude reaction mixture was poured into cold 10% HCl, treated with 2 M NaOH to pH 12 and extracted with CH2Cl2 (3×75 ml). The combined organic extracts were washed with brine (75 ml), dried (MgSO4) and solvent evaporated invacuo. The crude product was purified by silica-gel chromatography using a ethyl acetate/hexanes gradient (0% to 75% ethyl acetate) to give the subtitle compound. MS calculated for C17H19NS+H 270, observed 270.
Reaction SMILES: [CH2:1]([N:3]([CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[C:4]1[C:5]([CH3:14])=[C:6]([C:10]([O:12]C)=[O:11])[CH:7]=[N:8][CH:9]=1)[CH3:2].[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([N:3]([CH:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1)[C:4]1[C:5]([CH3:14])=[C:6]([C:10]([OH:12])=[O:11])[CH:7]=[N:8][CH:9]=1)[CH3:2]
Reactant: CCN(c1cncc(C(=O)OC)c1C)C1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(c1cncc(C(=O)O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 77.4 %

Procedure:
To a stirred solution of methyl 5-[ethyl(oxan-4-yl)amino]-4-methylpyridine-3-carboxylate (415 mg, 1.49 mmol) in THF (7 ml) and MeOH (3 ml) was added 4M NaOH solution (932 μl, 3.73 mmol). The reaction was stirred at room temperature for 4.5 h after which the solution was neutralised via the addition of 1M HCl and the solvent was removed under reduced pressure, followed by the addition of saturated brine (10 ml). The aqueous phase was extracted with 1:1 IPA:CHCl3 (3×50 ml), the combined organics washed with brine (30 ml), dried using Na2SO4, filtered and evaporated to afford the title compound as an off-white solid (305 mg, 77%) which was suitable for use in the next stage without any further purification. LC-MS 99%, m/z=265.1, 1H NMR (500 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.46 (s, 1H), 3.82 (d, J=11.6 Hz, 2H), 3.25 (t, J=10.9 Hz, 2H), 3.16-2.99 (m, 3H), 2.45 (s, 3H), 1.64 (d, J=11.0 Hz, 2H), 1.48 (dt, J=11.9, 5.7 Hz, 2H), 0.81 (t, J=7.0 Hz, 3H).