Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])C)=[CH:4][N:3]=1.[CH3:11][C:12]([S@@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>ClC(Cl)C.CCOCC.O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[N:3]=[CH:4][C:5](/[C:8](=[N:17]/[S:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])/[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(Br)nc1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: CC(Cl)Cl
Solvent: CCOCC
Solvent: O
Product: C/C(=N\S(=O)C(C)(C)C)c1ccc(Br)nc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To a solution of 2-bromo-5-isopropyl-pyridine (2.0 g, 9.99 mmol) in dichloroethane (15 mL) was added (S)-(−)-2-methyl-propane-2-sulfinic acid amide (1.45 g, 11.72 mmol) and titanium(IV) ethoxide (4.15 mL, 19.99 mmol). The mixture was heated at 110° C. in a microwave. After 2 h, the mixture was diluted with ether (20 mL) and water (6 mL). The mixture was stirred for 10 minutes. The layers were separated and the organic layer was dried over magnesium sulfate, filtered and concentrated to afford a residue. The crude residue was purified by normal phase flash chromatography on silica gel using ethyl acetate-dichloromethane (0-40%) to afford 2-methyl-propane-2-sulfinic acid[1-(6-bromo-pyridin-3-yl)-eth-(E)-ylidene]-amide (2.0 g, 66%).
Reaction SMILES: C([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C:16]=3[C:17](=[O:37])[CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].O.CCCCCCC>CO>[OH:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C:16]=3[C:17](=[O:37])[CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC(=O)C2=C3CC[C@H]4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCCC
Solvent: CO
Product: CC(C)CCC[C@@H](C)[C@H]1CC(=O)C2=C3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@@]21C
Yield: 91.6 %

Procedure:
A stirred mixture of 29.3 kg of crude (3β,5α)-3-(benzoyloxy)cholest-8(14)en-15-one (6) (Example 3) in 190 liters of methanol in a 100-gallon glass-lined reactor was treated with 8 5 kg of potassium carbonate, the mixture was heated to gentle reflux and held at reflux for 3 hours. The methanol solution was cooled, then was treated with 130 liters of water and 80 liters of heptane with vigorous stirring. The agitation was stopped and the mixture was chilled to 0° C. to -5° C. for 16 hours The crystalline mass was broken up by agitation and the solid was filtered, washed with 100 liters of methanol at 15° C, then air-dried to yield 21.3 kg of the desired crude product. The crude product was recrystallized as follows: A solution of the crude product, 21.3 kg, in 180 liters of methanol at about 45° C. was filtered through a pad of diatomaceous earth using nitrogen pressure. The filtrate was added to 200 liters of heptane at 45°-50° C. Then the solution was treated by vigorous agitation with 100 liters of water preheated to 60° C. The mixture was agitated for 10 minutes, then cooled to 35° C. over a 3-hour period, followed by standing at 25° C. for 24 hours and finally the mixture was chilled to 3° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH2:12]P(=O)(OCC)OCC)[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].O>C1COCC1.O1CCOCCOCCOCCOCC1>[CH3:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH:12]=[C:36]2[CH2:37][CH2:38][N:33]([C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[CH2:34][CH2:35]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(=O)(Cc1cccc(Oc2cccc(C)n2)c1)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(Oc2cccc(C=C3CCN(C(=O)OC(C)(C)C)CC3)c2)n1
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
Diethyl 3-(6-methylpyridin-2-yloxy)benzylphosphonate (4.7 g, 14 mmol) from Step 3 and 1,4,7,10,13-pentaoxacyclopentadecane (15-Crown-5, 0.05 mL, 0.28 mmol) were combined in THF (150 mL). Sodium hydride (617 mg, 60% dispersion in mineral oil, 15.4 mmol) was added. The reaction was stirred for 30 min and then a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (3.07 g, 15.4 mmol) in THF (15 mL) was added. After 16 h, water was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×200 mL) and the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10-30%, EtOAc:heptane) to afford the title compound (4.4 g, 83% yield) as a thick oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[NH2:8].C([O-])([O-])=O.[K+].[K+].[C:18](Cl)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].CC(O)=O.CC#N.O>O>[CH2:21]([O:20][C:18]([NH:8][CH:7]([C:9]([OH:11])=[O:10])[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC(Cc1cccs1)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CC(=O)O
Product: O=C(NC(Cc1cccs1)C(=O)O)OCc1ccccc1
Reaction time: 1 h
Yield: 98 %

Procedure:
Into a 500 ml flask was placed 3.0 g of 3-(2-Thienyl)-D,L-alanine (optically active material in the L-form is available 4from Aldrich or SIGMA and could be used to obtain an optically active product) in 75 ml H2O/60 ml dioxane, and 5.6 g K2CO3 was added, followed by 2.85 ml of carbobenzyloxy chloride. The mixture was stirred rapidly for 1 hour. TLC (21/7/7/9, EtoAc/AcOH/CH3CN/H2O) showed that the starting material was gone. A new higher Rf product was seen. The dioxane was concentrated off and the aqueous layer was washed with Et2O (75 ml). The aqueous layer was mixed with CH2Cl2 (150 ml) and acidified to pH=2.0 with 5N HCl. The desired N-(Benzyloxycarbonyl)-3-(2-thienyl)-D,L-alanine was extracted with CH2Cl2. The organic layer was separated and dried with Na2SO4, filtered, and concentrated to give 5.05 g of desired N-(Benzyloxycarbonyl)-3-(2-thienyl)-D,L-alanine (98% yield).
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH2:23][N:21]2[CH2:22][C@@H:5]([CH2:6][C@:7]([C:57]([O:59][CH3:60])=[O:58])([C:24]3[CH:25]=[C:26]4[C@:34]56[C@@H:38]7[C@:39]([CH2:54][CH3:55])([C@@H:43]([O:50][C:51]([CH3:53])=[O:52])[C@:44]([OH:49])([C:45]([O:47][CH3:48])=[O:46])[C@@H:33]5[N:32]([CH3:56])[C:27]4=[CH:28][C:29]=3[O:30][CH3:31])[CH:40]=[CH:41][CH2:42][N:37]7[CH2:36][CH2:35]6)[C:8]3[NH:16][C:15]4[CH:14]=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=4[C:9]=3[CH2:19][CH2:20]2)[CH:4]=1.Cl.C(C[OH:67])(F)(F)F.[BH4-].[Na+]>O.O.O.O.O.O.O.C([O-])(=O)C([O-])=O.[Fe+3].C([O-])(=O)C([O-])=O.C([O-])(=O)C([O-])=O.[Fe+3].CCOC(C)=O.CO.CCN(CC)CC>[CH3:1][CH2:2][C@@:3]1([OH:67])[CH2:23][N:21]2[CH2:22][C@@H:5]([CH2:6][C@:7]([C:57]([O:59][CH3:60])=[O:58])([C:24]3[CH:25]=[C:26]4[C@:34]56[C@@H:38]7[C@:39]([CH2:54][CH3:55])([C@@H:43]([O:50][C:51]([CH3:53])=[O:52])[C@:44]([OH:49])([C:45]([O:47][CH3:48])=[O:46])[C@@H:33]5[N:32]([CH3:56])[C:27]4=[CH:28][C:29]=3[O:30][CH3:31])[CH:40]=[CH:41][CH2:42][N:37]7[CH2:36][CH2:35]6)[C:8]3[NH:16][C:15]4[CH:14]=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=4[C:9]=3[CH2:19][CH2:20]2)[CH2:4]1
Reactant: CCC1=C[C@H]2CN(CCc3c([nH]c4ccc(OC)cc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@H]3[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]5(CC)C=CCN6CC[C@]43[C@@H]65)C2)C1
Reactant: OCC(F)(F)F
Agent: [Fe+3]
Agent: Cl
Agent: O=C([O-])C(=O)[O-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC[C@]1(O)C[C@H]2CN(CCc3c([nH]c4ccc(OC)cc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@H]3[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]5(CC)C=CCN6CC[C@]43[C@@H]65)C2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A mixture of iron(III) oxalate hexahydrate (79.4 mg, 0.13 mmol, 30 equiv) in H2O (22 mL) was cooled to 0° C. and air was bubbled through the mixture for 10 minutes. A solution of 10′-methoxyanhydro-vinblastine (22a, 4.5 mg, 0.0055 mmol, 1 equiv) in H2O (0.5 mL), aqueous 0.1 N HCl (0.5 mL), and CF3CH2OH (0.1 mL) was transferred by pipette to the mixture and NaBH4 (4.1 mg, 0.11 mmol, 20 equiv) in H2O (1 mL) was added to the mixture at 0° C. The resulting mixture was stirred for 30 min before being quenched by addition of 28-30% aqueous NH4OH (10 mL). The mixture was extracted with 10% MeOH in CH2Cl2 and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. PTLC (SiO2, Et3N:MeOH:EtOAc=3:3:97) provided 10′-methoxyvinblastine (22b, 2.2 mg, 0.0026 mmol, 48%) as a white solid and 10′-methoxyleurosidine (1.3 mg, 0.0015 mmol, 28%).
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([NH2:22])[C:18]=1[C:19]([OH:21])=[O:20]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.ClC1C=CC=CC=1Cl>[Cl:12][C:13]1[C:18]2[C:19](=[O:21])[O:20][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:22][C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cccc(Cl)c1C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Clc1ccccc1Cl
Product: O=c1oc(-c2ccccc2)nc2cccc(Cl)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.9 %

Procedure:
70.3 g of benzoyl chloride and 40 g of 50% strength aqueous sodium hydroxide solution are added simultaneously via 2 feed apparatuses in the course of 40 minutes at from 20° to 35° C. to a stirred mixture of 85.8 g of 6-chloroanthranilic acid, 1.3 g of tetrabutylammonium iodide, 0.5 g of dimethylformamide and 1,300 g of 1,2-dichlorobenzene. Stirring is continued for 90 minutes at 30° C., the water is separated off at from 75° to 90° C. and under from 20 to 50 mbar and 64 g of phosgene are added via a gas inlet tube in the course of 1 hour at from 100° to 105° C., while stirring. The mixture is cooled to room temperature while nitrogen is passed through, after which insoluble substances are filtered off and the filtrate is evaporated down, in the final stage at 140° C. and under 20 mbar. Distillation at 221°-230° C. and under 4-5 mbar gives 121 g (94%) of 5-chloro-2-phenyl-4H-3,1-benzoxazin-4-one of melting point 155°-157° C. The product is 99.5% pure according to HPLC.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6](=[O:12])[N:5]3[CH2:13][C:14]([OH:18])([C:15]([OH:17])=[O:16])[C:3]=1[C:4]=23.F[C:20]1C(C2(C([O-])=O)CO2)=C2C(=CC=1)N=CC(OC)=N2.S(=O)(=O)(O)O>CO>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6](=[O:12])[N:5]3[CH2:13][C:14]([OH:18])([C:15]([O:17][CH3:20])=[O:16])[C:3]=1[C:4]=23
Reactant: O=C(O)C1(O)Cn2c(=O)cnc3ccc(F)c1c32
Reactant: COc1cnc2ccc(F)c(C3(C(=O)[O-])CO3)c2n1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)C1(O)Cn2c(=O)cnc3ccc(F)c1c32
Reaction time: 17 h

Procedure:
A 3:1 mixture of 7-fluoro-6-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[1,2,3-de]quinoxaline-6-carboxylic acid and 2-[6-fluoro-3-(methyloxy)-5-quinoxalinyl]-2-oxiranecarboxylate (3.05 g) was partially dissolved in methanol (100 mL) and treated with concentrated sulphuric acid (1 mL), added dropwise at room temperature. The reaction mixture was stirred for 17 hours then quenched to pH 7 by addition of MP-carbonate resin. The mixture was filtered and evaporated. The residue was placed directly onto the top of a 100 g silica gel column and chromatographed, eluting with a 0-50% methanol in ethyl acetate gradient to afford the product (0.558 g, 17% (23% based on acid starting material).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]([CH3:28])[O:11][C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([OH:27])[CH:26]=1)[C:15]([NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=1)=[O:16])(C(C)(C)C)(C)C.[Cl:29][C:30]1[CH:31]=[C:32]([CH:39]=[CH:40][C:41]=1F)[C:33]([N:35]1[CH2:38][CH2:37][CH2:36]1)=[O:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:35]1([C:33]([C:32]2[CH:39]=[CH:40][C:41]([O:27][C:25]3[CH:24]=[C:14]([CH:13]=[C:12]([O:11][C@@H:10]([CH3:28])[CH2:9][OH:8])[CH:26]=3)[C:15]([NH:17][C:18]3[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=3)=[O:16])=[C:30]([Cl:29])[CH:31]=2)=[O:34])[CH2:38][CH2:37][CH2:36]1
Reactant: O=C(c1ccc(F)c(Cl)c1)N1CCC1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2Cl)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 160 °C
Yield: 50.6 %

Procedure:
To a mixture of 3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyloxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (215 mg, 0.53 mmol) and 1-(3-chloro-4-fluorobenzoyl)azetidine (135 mg, 0.63 mmol) in DMF (2.0 mL) was added potassium carbonate (146 mg, 1.06 mmol) and the stirred mixture heated at 160° C. in a ‘Smith Creator Microwave’ for 120 minutes. The mixture was allowed to reach ambient temperature and pressure then reduced in volume. Purification by column chromatography, eluting with 0-20% methanol in DCM, afforded the title compound (130 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5]([OH:10])([CH3:9])[CH2:6][CH2:7]O.[Br-:12].C([P+](OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1)C1C=CC=CC=1>O1CCCC1>[CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5]([OH:10])([CH3:9])[CH2:6][CH2:7][Br:12]
Reactant: COC(=O)CC(C)(O)CCO
Reactant: [Br-]
Agent: c1ccc(C[P+](Oc2ccccc2)(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CC(C)(O)CCBr

Procedure:
To a solution of 3.00 g. (18.5 mmol) 3,5-dihydroxy-3-methylpentanoic acid methyl ester in 15 ml. anhydrous tetrahydrofuran is added a solution of 8.90 g. (18.5 mmol) benzyl triphenoxyphosphonium bromide in 10 ml. tetrahydrofuran and the reaction mixture is stirred for 15 hours at ambient temperature. Thereafter, it is evaporated in a vacuum, the bath temperature thereby being kept below 15° C. The oily residue obtained is chromatographed on 700 g. silica gel 60 with n-hexane/tert.-butanol (6:1 v/v) as elution agent. After removal of the elution agent, there is obtained 1.32 g. (32% of theory) of the desired product in the form of a bright yellow oil; nD20 =1.4734; RF =0.65 (silica gel; n-hexane/tert.-butanol (6:1 v/v)).
Reaction SMILES: [CH:1]1([CH:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([OH:23])[CH:16]=2)[CH:5]2C(=O)OC(C)(C)[O:7][C:6]2=[O:14])[CH2:3][CH2:2]1.O>CN(C=O)C>[CH:1]1([CH:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([OH:23])[CH:16]=2)[CH2:5][C:6]([OH:14])=[O:7])[CH2:3][CH2:2]1
Reactant: COc1ccc(C(C2CC2)C2C(=O)OC(C)(C)OC2=O)cc1O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(CC(=O)O)C2CC2)cc1O
Temperature: 90 °C
Reaction time: 15 h
Yield: 75.3 %

Procedure:
To a solution of 5-(cyclopropyl(3-hydroxy-4-methoxyphenyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (2.70 g) in DMF (20 mL) was added water (2.0 mL), and the mixture was stirred at 90° C. for 15 hr. The reaction mixture was cooled to room temperature, and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.50 g) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([OH:24])=[C:6]([C@@H:8]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:9][CH2:10][N:11]([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:7]=1.[NH:25]1[C:29](=[O:30])[CH2:28][CH2:27][C@H:26]1[C:31]([OH:33])=[O:32]>CC(C)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([OH:24])=[C:6]([C@@H:8]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:9][CH2:10][N:11]([CH:12]([CH3:14])[CH3:13])[CH:15]([CH3:16])[CH3:17])[CH:7]=1.[NH:25]1[C:29](=[O:30])[CH2:28][CH2:27][C@H:26]1[C:31]([O-:33])=[O:32]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: Cc1ccc(O)c([C@H](CCN(C(C)C)C(C)C)c2ccccc2)c1
Solvent: CC(C)=O
Product: O=C1CC[C@@H](C(=O)[O-])N1
Reaction time: 0.17 h

Procedure:
3.25 g of tolterodine dissolved in 50 mL of acetone was mixed at room temperature (25° C.) with 1.29 g of L-pyroglutamic acid, which was suspended in 50 mL of acetone, and then stirred. In 10 minutes, there started to appear a solid precipitate. 50 mL of acetone was added thereto and the mixture was stirred at room temperature (25° C.) for 1 hour. The resulting solid precipitate was filtered and then washed with acetone. The resultant was dried at room temperature (25° C.) for 24 hours and 3.74 g (theoretical yield: 82.3%) of the final product in white solid was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12](O)=[O:13]>O1CCCC1>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH:12]=[O:13])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=CO
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: O=CNc1ccc(O)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
4-Amino-3-nitrophenol (36 g, 234 mmol) was split into 3 batches, approximately 12 g each. Each batch was dissolved in 150 mL of tetrahydrofuran and heated with 10 mL of 96% formic acid at 95 degrees Centigrade for 4 hours. The 3 batches were combined and concentrated. As the reactions had only proceeded ˜10% to completion, the reaction mixture was dissolved in 100 mL of 96% formic acid and heated at 110 degrees Centigrade. After 30 minutes, a precipitate began to form and 150 mL of tetrahydrofuran was added to ensure good stirring. The reaction was heated at 110 degrees Centigrade for 15 hours. The reaction was concentrated and the residue was diluted with water. The resulting solid was collected by filtration. The solid was washed three times with water and then dried in a vacuum oven at 110 degrees Centigrade for approximately 18 hours to give 40.4 g of (4-hydroxy-2-nitrophenyl)formamide. (M-1) 181.0, 1.48 min (LC/MS method B)
Reaction SMILES: C(O[K])(C)(C)C.[CH3:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:14]2[NH:18][N:17]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:15]=2)[CH:9]=1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH:7](/[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:14]2[NH:18][N:17]=[C:16]([C:19]([F:22])([F:20])[F:21])[CH:15]=2)[CH:9]=1)=[CH:23]\[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1ccnc(-c2cc(C(F)(F)F)n[nH]2)c1
Reactant: O=Cc1ccccc1
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(-c2cc(/C=C/c3ccccc3)ccn2)[nH]n1
Reaction time: 6 h

Procedure:
Ligand L1 was synthesized employing a modified literature procedure,[4] in which solid tert-BuOK (1.19 g, 10.56 mmol) was added to a solution of 4-methyl-2-(3-(trifluoromethyl)-1H-pyrazol-5-yl) pyridine (0.30 g, 1.32 mmol) and benzaldehyde (0.4 mL, 3.96 mmol) in anhydrous DMF (100 mL). The resulting mixture was stirred 6 h at 100□ under nitrogen. The solvent was then evaporated, and product was dissolved in water titrated by 2 M HCl until pH 3˜4. The insoluble solid was filtered on a sintered crucible and recrystallized from hot ethylacetate (EA), filtered, and washed with methanol to obtain the desired product L1 as a beige solid (0.22 g, 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[S:13][CH:12]3[N:9]([CH2:10][CH2:11]3)[C:8]=2[C:14]([O:16]CC2C=CC([N+]([O-])=O)=CC=2)=[O:15])=[CH:4][CH:3]=1.C(=O)(O)[O-:30].[Na+:33]>O1CCOCC1.O.[Pd]>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[S:13][CH:12]3[N:9]([C:10](=[O:30])[CH2:11]3)[C:8]=2[C:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.[Na+:33]
Reactant: O=C([O-])O
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)C1=C(Oc2ccc(Cl)cc2)SC2CCN12
Agent: [Pd]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C([O-])C1=C(Oc2ccc(Cl)cc2)SC2CC(=O)N12

Procedure:
A mixture of a solution of 500 mg of 4-nitrobenzyl 3-(4-chlorophenoxy)-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate in dioxan and 97 mg of sodium bicarbonate in water, and 10% palladium/charcoal was hydrogenated at 50 psi at 25° for 60 minutes.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][C:29]4=[O:33])=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.[N+](C1C=CC(OC(=O)[NH:55][C:56]2[CH:61]=[CH:60][C:59]([O:62][CH:63]([CH3:65])[CH3:64])=[CH:58][CH:57]=2)=CC=1)([O-])=O.CCN(C(C)C)C(C)C>CC#N>[CH:63]([O:62][C:59]1[CH:60]=[CH:61][C:56]([NH:55][C:6]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:23]4[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][N:28]5[CH2:32][CH2:31][CH2:30][C:29]5=[O:33])=[CH:21][CH:22]=4)[N:17]=[CH:16][N:15]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:57][CH:58]=1)([CH3:65])[CH3:64]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCN4CCCC4=O)ccc23)CC1
Reactant: CC(C)Oc1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(NC(=O)N2CCC(c3ncnc4cc(OCCCN5CCCC5=O)ccc34)CC2)cc1
Temperature: 95 °C
Yield: 89 %

Procedure:
4-{7-[3-(2-Oxo-pyrrolidin-1-yl)-propoxy]-quinazolin-4-yl}-piperidine-1-carboxylic acid tert-butyl ester (as prepared in the previous step, 0.20 mmol) was treated with 50% TFA/CH2Cl2 (4 mL) for 2 h and the solvents were evaporated. To the residue was added (4-isopropoxy-phenyl)-carbamic acid 4-nitro-phenyl ester (70.2 mg, 0.22 mmol), as prepared in Example 1a, followed by DIEA (130.5 mg, 1.01 mmol) in CH3CN (4 mL). The resulting mixture was heated at 95° C. for 1 h and the solvents were evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (5% MeOH/EtOAc as eluent) to afford the product as a white solid (95.5 mg, 89% yield). 1H NMR (300 MHz, CDCl3) δ 9.14 (s, 1H), 8.06 (d, J=9.33 Hz, 1H), 7.33 (d, J=2.46 Hz, 1H), 7.28 (dd, J=9.30 and 2.65 Hz, 1H), 7.25 (m, 2H), 6.84 (d, J=8.93 Hz, 2H), 6.33 (br, 1H), 4.48 (m, 1H), 4.26 (m, 2H), 4.17 (t, J=6.10 Hz, 2H), 3.69 (m, 1H), 3.53 (t, J=6.99 Hz, 2H), 3.45 (t, J=7.02 Hz, 2H), 3.13 (td, J=12.85 and 2.83 Hz, 2H), 2.40 (t, J=7.78 Hz, 2H), 1.94-2.20 (m, 8H), 1.31 (d, J=6.06 Hz, 6H). LC-MS (ESI) calcd for C30H38N5O4 (MH+) 532.3, found 532.2. Anal. Calcd for C30H37N5O4: C, 67.77; H, 7.01; N, 13.17. Found: C, 67.81; H, 6.96; N, 13.16.
Reaction SMILES: Cl.[C:2]([S:5][CH2:6][C:7]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[CH:15][C:16]([Br:18])=[CH:17][C:9]=2[C:8]=1[CH3:19])(=[NH:4])[NH2:3].OS(C(F)(F)F)(=O)=O.[OH-].[Na+].C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(OCC)C>[Br:18][C:16]1[CH:15]=[CH:14][C:10]2[O:11][CH2:12][CH2:13][C@@H:7]3[CH2:6][S:5][C:2]([NH2:3])=[N:4][C@:8]3([CH3:19])[C:9]=2[CH:17]=1
Reactant: CC1=C(CSC(=N)N)CCOc2ccc(Br)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: C[C@]12N=C(N)SC[C@H]1CCOc1ccc(Br)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
To a solution of (7-bromo-5-methyl-2,3-dihydrobenzo[b]oxepin-4-yl)methyl carbamimidothioate hydrochloride from step H8 (2.59 g, 7.12 mmol) in TFA (20 mL) was added triflic acid (5.0 mL). The mixture was stirred at rt for 3 h. The reaction mixture was chilled to 0° C. then diluted with diethyl ether (150 mL). The resulting mixture was slowly neutralized with 50% aqueous NaOH and made basic (pH=12) with saturated aqueous NaHCO3 solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromography (30-100% EtOAc/hexanes) to afford rel-(4aS,11bS)-10-bromo-11b-methyl-4a,5,6,11b-tetrahydro-4H-benzo[2,3]oxepino[4,5-d][1,3]thiazin-2-amine (1.31 g, 4.00 mmol, 56% yield). LCMS (M+H)+=329.0. 1H NMR (500 MHz, methanol-d4) δ 7.50 (dd, J=8.5, 2.4 Hz, 1H), 7.18 (d, J=2.4 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H), 4.38-4.31 (m, 1H), 3.76 (td, J=13.2, 1.5 Hz, 1H), 3.05-2.92 (m, 2H), 2.85 (ddt, J=15.5, 13.4, 4.5 Hz, 1H), 2.55-2.47 (m, 1H), 1.96-1.88 (m, 1H), 1.86 (s, 3H).