Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=2)[C:43](OC)=[O:44])=[N:8]1.O.[OH-].[Li+].[C:53]([NH2:62])([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)([CH3:55])[CH3:54].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.O1CCCC1.O>[NH:17]1[C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([C:43]([NH:62][C:53]([CH3:55])([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[CH3:54])=[O:44])[CH:47]=[CH:48][CH:49]=2)=[N:20][CH:19]=[N:18]1
Reactant: CC(C)(N)c1ccccc1
Reactant: COC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(NC(=O)c1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1)c1ccccc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 143.8 %

Procedure:
To a stirred solution of methyl 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl) (1,2,4-triazol-3-yl)]-1H-indazol-3-yl}benzoate (0.400 g, 0.619 mmol) in a tetrahydrofuran/water mixture (2.50 mL/1.00 mL) was added lithium hydroxide monohydrate (0.0780 g, 1.86 mmol) and the mixture heated at 60° C. for 21 h. To this mixture was added tetrahydrofuran (2.00 mL), cumylamine (0.270 mL, 1.86 mmol), 1-hydroxybenzotriazole hydrate (0.251 g, 1.86 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.356 g, 1.86 mmol). This mixture was stirred for 18 h at ambient temperature. After the mixture was extracted with ethyl acetate (2×), the combined organic extracts were washed with aqueous saturated sodium bicarbonate, followed by brine, dried over anhydrous sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography with 40–100% ethyl acetate/hexanes gave the title compound (0.376 g, 81% yield). ES-MS (m/z) 507 [M+1(−Tr)]+
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C@:5]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:6]1[C@@H:7]1[C@@:20]([CH3:23])([CH2:21][CH2:22]2)[C@@:19]2([CH3:24])[C@@H:10]([C@:11]3([CH3:37])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][CH:28]=2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1.[OH-].[Na+]>O1CCOCC1.CO>[F:1][CH2:2][CH2:3][NH:4][C@:5]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:6]1[C@@H:7]1[C@@:20]([CH3:23])([CH2:21][CH2:22]2)[C@@:19]2([CH3:24])[C@@H:10]([C@:11]3([CH3:37])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]2[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:35][CH:36]=2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCF)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(NCCF)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 85 °C
Yield: 48 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-fluoroethyl)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)benzoate (0.059 g, 0.100 mmol) in 1,4-dioxane (2 mL) was added NaOH (1N) (0.5 mL, 0.500 mmol). The mixture was heated to 85° C. for 15.25 h, was cooled to rt, then was diluted with methanol and 1,4-dioxane and was purified by prep HPLC. The fractions containing the expected product were combined and concentrated under reduced pressure to give 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-fluoroethyl)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)benzoic acid (29.2 mg, 0.048 mmol, 48.2% yield) as a white solid. LCMS: m/e 576.6 (M+H)+, 1.74 min (method 2). 1H NMR (400 MHz, Acetic acid d4) δ 7.99 (d, J=8.53 Hz, 2H), 7.26 (d, J=8.28 Hz, 2H), 5.33 (d, J=4.77 Hz, 1H), 4.73-4.99 (m, 3H), 4.70 (s, 1H), 3.41-3.73 (m, 2H), 2.83-2.94 (m, 1H), 1.73 (s, 3H), 1.19 (s, 3H), 1.11 (s, 3H), 1.05 (s, 3H), 0.98 (s, 3H), 0.96 (s, 3H), 0.82-2.27 (m, 22H).
Reaction SMILES: Br[C:2]1[C:3]([F:21])=[C:4]([C:8]([NH:10][C:11]2[O:12][C:13]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)=[N:14][N:15]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)[CH3:23]>>[CH2:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([NH:10][C:11]4[O:12][C:13]([C:16]5[O:17][CH:18]=[CH:19][CH:20]=5)=[N:14][N:15]=4)=[O:9])[C:3]=3[F:21])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)[CH3:23]
Reactant: CCc1ccc(-c2ccc(B(O)O)cc2)cc1
Reactant: O=C(Nc1nnc(-c2ccco2)o1)c1cccc(Br)c1F
Product: CCc1ccc(-c2ccc(-c3cccc(C(=O)Nc4nnc(-c5ccco5)o4)c3F)cc2)cc1

Procedure:
The title compound was synthesized in accordance with the synthesis method of compound Ia-50, using 3-bromo-2-fluoro-N-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]benzenecarboxamide prepared in Reference Example 5 instead of compound Ia-50 and using commercially available 4′-ethyl-4-biphenylboronic acid instead of 1-methyl-5-indoleboronic acid pinacol ester.
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1.[Cl:12][CH2:13][C:14](Cl)=[O:15].C>C1C=CC=CC=1>[Cl:12][CH2:13][C:14]([N:6]1[CH2:7][C@H:3]([OH:2])[CH2:4][C@H:5]1[C:8]([O:10][CH3:11])=[O:9])=[O:15]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: c1ccccc1
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)CCl
Reaction time: 0.5 h

Procedure:
To a suspension of Example 54A (130 g, 0.72 mol, 1 equivalent) in benzene (3.9 L), chloroacetylchloride (81.1 g, 0.72 mol, 1 equivalent) was added dropwise at 20-25° C. The reaction mixture was refluxed for 5 hours. Then, charcoal (500 mg) was added, and the reaction mixture was hot filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure. To this crude material, methyl tert-butyl ether (650 mL) was added, and the mixture was stirred for 30 minutes. The solid was collected by filtration, and the wet cake was dried in a vacuum tray dryer for 5 hours at about 50° C. to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.9-1.96 (m, 1H), 2.08-2.19 (m, 1H), 3.36 (d, 1H, J=14.4 Hz), 3.65 (s, 3H), 3.66 (m, 2H), 4.33 (s, 2H), 4.35 (m, 1H), 5.25 (bs, 1H); MS (ESI) m/z 222 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C@H:11]([C:17](O)=[O:18])[CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])(=[O:9])=[O:8])=[CH:4][CH:3]=1>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C@H:11]([CH2:17][OH:18])[CH:12]([CH2:13][CH3:14])[CH2:15][CH3:16])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: CCC(CC)[C@H](NS(=O)(=O)c1ccc(Cl)s1)C(=O)O
Solvent: C1CCOC1
Product: CCC(CC)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To N-[(5-Chloro-2-thienyl)sulfonyl]-3-ethyl-L-norvaline (5.6 g, 17.2 mmol) in THF (150 mL) at 0° C. was added a solution of 1 M borane tetrahydrofuran complex in THF (69 mL, 69 mmol) dropwise via addition funnel. After 15 min, the reaction mixture was warmed to 25° C. and stirred for 18 h. It was then quenched with 90 mL of 10% AcOH in MeOH slowly. Volatiles were removed in vacuo. The residue was then dissolved in EtOAc (300 mL) and washed with sat. aqueous NaHCO3 (3×200 mL), dried (Na2SO4), and concentrated to a white precipitate (5.1 g, 96% yield, 96% chiral purity). The precipitate was recrystallized with heptane/EtOAc, 4:1, to give optically pure 5-chloro-N-[(S)-2-ethyl-1-(hydroxymethyl)butyl]-2-thiophenesulfonamide as white needles (4.4 g, 81% yield). [α]D25=+4.5° (c=1% SOLUTION, DMSO). Mass Spectrum (−ESI): 310 (M−H)−. Anal. Calc'd for C11H18ClNO3S2: C, 42.37; H, 5.82; N, 4.49. Found: C, 42.37; H, 5.79; N, 4.38.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[S:9][CH:10]=1)=[O:5])C.O1CCCC1.[OH-].[Na+].[Na+].[Cl-]>CO.C(OCC)(=O)C>[C:4]([C:6]1[N:7]=[C:8]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]2)[S:9][CH:10]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1,1-dimethylethyl 4-[4-(ethoxycarbonyl)-2-thiazolyl]-1-piperidinecarboxylate (i.e. the product of Example 1, Step A) (3.4 g, 10 mmol) in 20 mL of methanol and 20 mL of tetrahydrofuran was added 1 N aqueous NaOH solution (15 mL), and the resulting mixture was stirred at ambient temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure, diluted with water and acidified with excess 20% aqueous citric acid solution to give a gummy precipitate. Ethyl acetate (30 mL) was added to dissolve the precipitate, the aqueous layer was saturated with NaCl, and the reaction mixture was extracted with ethyl acetate. The extract was dried over MgSO4 and concentrated under reduced pressure to give 3.09 g of the title compound as a tan solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:28]3[CH2:33]COC[CH2:29]3)[CH:22]=2)[C:9]2[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].C(OC(C1C=C(C2C=CC=C(CCl)C=2)C2N(C3C=CC=CC=3)C=NC=2C=1)=O)C.CNC>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:28]([CH3:29])[CH3:33])[CH:22]=2)[C:9]2[N:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:11]=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2cccc(CN3CCOCC3)c2)c2c(c1)ncn2-c1ccccc1
Agent: CCOC(=O)c1cc(-c2cccc(CCl)c2)c2c(c1)ncn2-c1ccccc1
Agent: CNC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2cccc(CN(C)C)c2)c2c(c1)ncn2-c1ccccc1
Yield: 25 %

Procedure:
This was prepared analogously to 5-Ethoxycarbonyl-7-(3-(morpholin-4-yl-methyl)phenyl)-1-phenylbenzimidazole from 5-ethoxycarbonyl-7-(3-(chloromethyl)phenyl)-1-phenylbenzimidazole (0.50 g, 1.28 mmol) and dimethylamine (approximately 2 ml) in anhydrous dimethylformamide (5 ml). The crude product was triturated in diethyl ether to afford the title product as an off-white solid (0.139, 25%) m/z, 400.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:14])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH2:12].[CH:15](=O)[CH2:16][CH3:17].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:1][O:2][N:3]([CH3:14])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH:12][CH2:15][CH2:16][CH3:17]
Reactant: CCC=O
Reactant: CON(C)C(=O)c1ccc(F)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCNc1cc(F)ccc1C(=O)N(C)OC
Reaction time: 1.5 h

Procedure:
To a solution of N-methoxy-N-methyl-2-amino-4-fluoro-benzamide (0.27 g, 1.36 mmol), propionaldehyde (0.15 mL, 2.08 mmol), and AcOH (0.12 mL, 2.1 mmol) in dichloromethane (20 mL) was added sodium triacetoxyborohydride (576 mg, 2.72 mmol) at 5° C. The mixture was stirred for 90 minutes at the same temperature and then 40 minutes at room temperature. The reaction was quenched by adding water. The organic layer was washed with saturated aqueous NaHCO3 solution and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give N-methoxy-N-methyl-4-fluoro-2-propylamino-benzamide quantitatively.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[NH2:17][C:18]1[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=[C:22]([Br:24])[CH:23]=1.[Na]>CN(C)C=O>[Br:24][C:22]1[CH:23]=[C:18]([NH:17][C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)=[O:9])=[CH:6][N:7]=2)[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=1
Reactant: CN1CCN(C(=O)c2ccc(Cl)nc2)CC1
Reactant: Cn1cc(Br)cc(N)c1=O
Agent: [Na]
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Reaction time: 18 h
Yield: 26 %

Procedure:
To a solution of (6-Chloro-pyridin-3-yl)-(4-methyl-piperazin-1-yl)-methanone (2.00 g, 7.46 mmol) in 10 mL dimethylformamide was added 3-Amino-5-bromo-1-methyl-1H-pyridin-2-one (1.80 g, 8.95 mmol) and sodium hydiride (537 mg, 22.4 mmol). After stirring for 18 hours, this was quenched with water. This was extracted with ethylacetate. The ethylacetate layer was dired over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 0 to 5% methanol/dichloromethane) to yield 5-Bromo-1-methyl-3-[5-(4-methyl-piperazine-1-carbonyl)-pyridin-2-ylamino]-1H-pyridin-2-one (900 mg, 1.94 mmol). MS (ESI) 406.0 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[N:10][C:9]([NH2:12])=[N:8]1)#[N:2].[F:13][C:14]([F:20])([F:19])[CH2:15][N:16]=[C:17]=[S:18]>C(#N)C>[F:13][C:14]([F:20])([F:19])[CH2:15][NH:16][C:17](=[S:18])[NH:12][C:9]1[N:10]=[CH:11][N:7]([CH2:6][CH2:5][CH2:4][CH2:3][C:1]#[N:2])[N:8]=1
Reactant: FC(F)(F)CN=C=S
Reactant: N#CCCCCn1cnc(N)n1
Solvent: CC#N
Product: N#CCCCCn1cnc(NC(=S)NCC(F)(F)F)n1
Yield: 42.3 %

Procedure:
The crude 1-(4-cyanobutyl)-3-amino-1,2,4-triazole (5.45 g.) in acetonitrile (80 ml.) was treated with 2,2,2-trifluoroethylisothiocyanate (4.4 g.) and the solution heated under reflux for 3.5 hours. Evaporation gave a white sticky solid which was triturated with ether/EtOH to give 5-(3-[3-(2,2,2-trifluoroethyl)thioureido]-1,2,4-triazol-1-yl)valeronitrile (4.04 g.) as a white solid, m.p. 136°-138°.
Reaction SMILES: [N:1]1([C:6]2[S:7][C:8]([C:12]#[N:13])=[C:9]([NH2:11])[N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[SH2:14].CN(C)C=O>C(N(CC)CC)C>[N:1]1([C:6]2[S:7][C:8]([C:12](=[S:14])[NH2:13])=[C:9]([NH2:11])[N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1sc(N2CCCC2)nc1N
Reactant: S
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=S)c1sc(N2CCCC2)nc1N
Yield: 53 %

Procedure:
25 parts of 2-pyrrolidino-4-amino-5-cyanothiazole are reacted with 8 parts of hydrogen sulfide in 150 parts of dimethylformamide and 2 parts of triethylamine, by the method described in Example 1(a). 15.6 parts of 2-pyrrolidino-4-amino-5-thiocarbamoyl-thiazole (53% of theory) of melting point 264°-265° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[C:4]([CH3:10])[N:3]=1.C(Cl)Cl.[N:14]([S:17]([C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23])(=[O:19])=[O:18])=[C:15]=[O:16]>C(Cl)CCC>[CH3:10][C:4]1[C:5]([CH3:9])=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:15]([NH:14][S:17]([C:20]2[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=2[C:22]([O:24][CH3:25])=[O:23])(=[O:19])=[O:18])=[O:16])[N:3]=1
Reactant: Cc1nc(N)nc(C)c1C
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Solvent: CCCCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)c(C)c(C)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 1.0 gram (0.0073 mole) of 2-amino-4,5,6-trimethylpyrimidine and 5.0 ml of dried methylene chloride stirring magnetically in a 50 ml RB single neck flask, 2.1 grams of methyl 2-(isocyanatosulfonyl)benzoate was added at room temperature and the mixture stirred at room temperature for 24 hours. Butyl chloride (4 ml) was added with constant stirring and the insoluble product filtered, washed immediately with butyl chloride and dried. (Yield 1.3 grams, m.p. 152°-161°). IR (Nujol): 5.60, 5.75 (C=O), 11.25 11.90 microns; NMR (TFA-d): δ 2.30 (s, 3H, CH3), 2.65 (s, 6H, 2CH3), 4.00 (s, 3H, CO2CH3), 7.60-8.60 (m, ArH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:17][NH:18][CH:19]1[CH2:28][CH2:27][CH2:26][C:25]2[N:24]=[C:23]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:22]=[CH:21][C:20]1=2.I[CH2:45][CH2:46][C:47]1[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:48]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:34]2[CH:35]=[CH:36][C:37]([C:40]([F:43])([F:41])[F:42])=[CH:38][CH:39]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:17][N:18]([CH2:45][CH2:46][C:47]1[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:48]=1)[CH:19]1[CH2:28][CH2:27][CH2:26][C:25]2[N:24]=[C:23]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:22]=[CH:21][C:20]1=2
Reactant: COC(=O)c1ccc(CCI)cc1
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2NCCc1ccccc1OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccc(C(=O)OC)cc1)CCc1ccccc1OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1Cl
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A suspension of 69 g (111.24 mmol) of ethyl 5-{[2-(2-{[3-chloro-4′-(trifluoromethyl)biphenyl-4-yl]methoxy}-phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 2, Example 86A), 129 g (444.98 mmol) of methyl 4-(2-iodoethyl)benzoate and 17.68 g (166.87 mmol) of anhydrous sodium carbonate in 1500 ml of dry acetonitrile was stirred at a bath temperature of 110° C. overnight. A further 65.54 g of methyl 4-(2-iodoethyl)benzoate and 23.06 g (166.87 mmol) of powdered potassium carbonate were then added, and the mixture was heated under reflux for another 48 h. After cooling of the reaction mixture, the inorganic salts were filtered off and the filtrate obtained was evaporated to dryness. The resulting residue was taken up in ethyl acetate, washed twice with 10% strength aqueous sodium chloride solution, dried over magnesium sulphate, filtered and then once more evaporated to dryness. The residue obtained was purified chromatographically on silica gel (3 kg) (mobile phase: petroleum ether/ethyl acetate 8:2→7:3). This gave 42 g (54.45 mmol, 49% of theory) of the target compound.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([F:25])=[CH:19][C:18]=3[OH:26])[C:9]2=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:35]I.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1>[C:28]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[CH:22]=[C:21]([O:23][CH3:24])[C:20]([F:25])=[CH:19][C:18]=4[O:26][CH2:35]3)[C:9]2=[O:27])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1cc(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)c(O)cc1F
Reactant: ClCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COc1cc2c(cc1F)OCC21C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 43.4 %

Procedure:
A suspended mixture of 1-(diphenylmethyl)-3-(4-fluoro-2-hydroxy-5-methoxyphenyl)-1,3-dihydro-2H-indol-2-one (1.10 g, 2.5 mmol), chloroiodomethane (0.70 g, 4.0 mmol) and cesium carbonate (2.60 g, 8.0 mmol) in tetrahydrofuran (50 mL) was stirred at ambient temperature for 24 h. The reaction mixture was filtered. The solid was washed with acetone (50 mL). The filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography with a 20% to 70% gradient of ethyl acetate in hexanes to afford 1′-(diphenylmethyl)-6-fluoro-5-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.49 g, 43%) as a colorless solid: MS (ES+) m/z 452.0 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.[F:19][C:20]([F:34])([F:33])[CH2:21][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:23][OH:24]>CCOCC>[CH3:15][C:10]1[N:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[C:8](=[O:16])[N:7]([CH3:17])[C:6]1[CH:18]=[C:2]([O:24][CH2:23][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21][C:20]([F:34])([F:33])[F:19])[CH:3]=[CH:4][C:5]2=1
Reactant: CC(C)(C)OC(=O)NC(CO)CC(F)(F)F
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(Cl)ccc21
Solvent: CCOCC
Product: Cc1nccc2c1c(=O)n(C)c1cc(OCC(CC(F)(F)F)NC(=O)OC(C)(C)C)ccc21
Yield: 49 %

Procedure:
8-Chloro-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one and tert-butyl (4,4,4-trifluoro-1-hydroxybutan-2-yl)carbamate were used for ether synthesis as described in Example 16, Part H to afford tert-butyl (1-((4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4,4,4-trifluorobutan-2-yl)carbamate (0.22 g, 0.473 mmol, 49% yield) as a semi-solid. LC/MS (ESI) m/e 466.2 [(M+H)+, calcd for C23H27F3N3O4 466.2]; LC/MS retention time (method D): tR=0.82 min.
Reaction SMILES: [C:1]1([C@H:7](NC[C@@H](CCC)CC(O)=O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:22][CH2:23][CH3:24])(=O)C.Cl>CO>[CH:1]1[CH:6]=[C:5]2[CH:4]=[CH:24][C:23]([OH:22])=[C:7]([C:1]3[C:2]4[C:3](=[CH:8][CH:7]=[CH:23][CH:24]=4)[CH:4]=[CH:5][C:6]=3[OH:22])[C:8]2=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: CCC[C@H](CN[C@H](C)c1ccccc1)CC(=O)O
Agent: Cl
Solvent: CO
Product: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
(S,R)-3-[(1-phenyl ethylamino)-methyl]-hexanoic acid (5.0 g) is dissolved in methanol (20 mL) and (RS)-1,1′-bi-2-naphthol (5.75 g) is added to it at room temperature. The mixture is stirred at 50° C. for 1 hour, during which time solid precipitate comes out from the reaction mixture. Reaction mixture is allowed to cool to room temperature and filtered under reduced pressure to obtain 3.6 g of solid complex. Complex is suspended in the biphasic mixture of ethyl acetate (20 mL) and 1N hydrochloric acid (20 mL) and stirred for 30 to 45 min to decompose the complex. Aqueous phase is washed with 10 mL ethyl acetate. Organic phases are mixed together and washed with brine, followed by drying over sodium sulfate. Solvent is evaporated under vacuum to obtain optically pure (R)-1,1′-bi-2-naphthol (1.25 g) having 95% ee.
Reaction SMILES: C1C=CC=CC=1.CI.[OH-:9].[Na+].C([N+:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])CCCC)CCC>O>[N:15]1[C:20]2[C:26]([CH:27]=[CH:23][C:22](=[O:9])[CH:21]=2)=[CH:25][CH:24]=1
Reactant: [OH-]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Solvent: CI
Product: O=C1C=CC2=CC=NC2=C1
Reaction time: 0.5 h

Procedure:
A mixture of 5 g of 3,4-dihydro-1H-cyclohept[c,d] indol-6-one, 50 ml of benzene, 2.5 ml of methyl iodide, 25 ml of 5 N sodium hydroxide solution and 9.2 g of tetra-n-butyl ammonium acid sulfate was stirred for 30 minutes under an inert atmosphere at 40°-45° C. and the mixture was diluted with water. The decanted aqueous phase was extracted with ethyl acetate and the organic phase was washed with N hydrochloride acid, with water, dried and evaporated to dryness. The residue was chromatographed over silica gel and was eluted with a 95-5 chloroform-ethyl acetate mixture to obtain 6.5 g of raw product. The latter was crystallized from isopropanol to obtain 5.15 g of 1-methyl-1,3,4,5-tetrahydro-6H-cyclohept [c,d,] indol-6-one melting at ≃70° C.
Reaction SMILES: [C:1](OC1C(Cl)=CC(Cl)=CC=1Cl)(=O)[CH2:2][C:3]([O:5][C:6]1[C:11](Cl)=[CH:10][C:9](Cl)=[CH:8][C:7]=1Cl)=[O:4]>C1(C)C=CC=CC=1>[O:5]1[C:6]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:1]=[CH:2][C:3]1=[O:4]
Reactant: O=C(CC(=O)Oc1c(Cl)cc(Cl)cc1Cl)Oc1c(Cl)cc(Cl)cc1Cl
Solvent: Cc1ccccc1
Product: O=c1ccc2ccccc2o1
Temperature: 120 °C

Procedure:
A mixture of VB482 (835 mg, 3.0 mmol) and bis(2,4,6-trichlorophenyl) malonate (1389 mg, 3.0 mmol) in dry toluene (9 ml) was heated in a sealed tube at 120° C. for 2 hrs. The resulting suspension was cooled and filtered, the solids were washed with hot hexanes and dried in vacuo to give pure coumarin VB483 (568 mg, 55%).