Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:13]([CH3:49])([CH3:48])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:47])([C@@:18]4([CH3:46])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([NH:37][CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl>O1CCOCC1>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:13]([CH3:49])([CH3:48])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:47])([C@@:18]4([CH3:46])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([NH:37][CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCOCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCOCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 75 °C
Yield: 38.7 %

Procedure:
To a solution of methyl 2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-morpholinoethylamino)-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 (0.075 g, 0.111 mmol) in 1,4-Dioxane (1 mL) was added NaOH (1M) (0.5 mL, 0.500 mmol). The mixture was heated to 75° C. for 15 h then was cooled to rt. The mixture was acidified with 1N HCl (3 mL) and was concentrated under reduced pressure. The residue was diluted with 15 mL of water and the solids that remained were collected by filtration and were washed with water then with ether. The compound was dissolved in DMF and methanol and was purified by prep HPLC. Fractions containing the expected product were combined and concentrated under reduced pressure to give 2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-morpholinoethylamino)-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 (30 mg, 0.043 mmol, 38.8% yield) as a white solid. LCMS: m/e 661.5 (M+H)+, 1.67 min (method 2). 1H NMR (500 MHz, Acetic acid d4) ppm 7.96 (1H, t, J=7.9 Hz), 7.09 (1H, dd, J=8.2, 1.2 Hz), 7.03 (1H, d, J=11.6 Hz), 5.42 (1H, d, J=4.6 Hz), 4.86 (1H, s), 4.74 (1H, s), 3.89-3.99 (4H, m), 3.53-3.69 (4H, m), 3.29 (4H, br. s.), 2.81-2.90 (1H, m), 1.77 (3H, s), 1.23 (3H, s), 1.13 (3H, s), 1.08 (3H, s), 1.04 (3H, s), 1.01 (3H, s), 0.85-2.26 (22H, m).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[N:17][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([NH:26]C(=O)OC(C)(C)C)[CH2:22]3)=[N:19][CH:20]=1)=[N:11][C:10]([C:34]1[CH:39]=[C:38]([Cl:40])[C:37]([OH:41])=[C:36]([Cl:42])[CH:35]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[ClH:43]>>[ClH:40].[ClH:43].[ClH:40].[NH2:26][CH:23]1[CH2:24][CH2:25][N:21]([C:18]2[N:19]=[CH:20][C:15]([NH:14][C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([C:34]5[CH:39]=[C:38]([Cl:40])[C:37]([OH:41])=[C:36]([Cl:42])[CH:35]=5)[N:11]=4)[N:6]=[CH:5][C:4]=3[C:1](=[O:3])[CH3:2])=[CH:16][N:17]=2)[CH2:22]1
Reactant: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1cnc(N2CCC(NC(=O)OC(C)(C)C)C2)nc1
Agent: Cl
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1cnc(N2CCC(N)C2)nc1
Yield: 50 %

Procedure:
Following general procedure IV-1, tert-butyl 1-{5-[3-acetyl-6-(3,5-dichloro-4-hydroxyphenyl)-1,5-naphthyridin-4-ylamino]pyrimidin-2-yl}pyrrolidin-3-ylcarbamate (123 mg, 0.20 mmol) was reacted with 6 N HCl (2 mL) followed by formation of the trihydrochloride salt to afford the desired product (62 mg, 50%) as a light orange solid: 1H NMR (500 MHz, CD3OD) δ 9.36 (br s, 1H), 8.51-8.35 (m, 3H), 7.51 (br s, 2H), 4.12-3.97 (m, 2H), 3.89-3.84 (m, 1H), 3.80-3.69 (m, 2H), 2.84 (br s, 3H), 2.58-2.48 (m, 1H), 2.28-2.17 (m, 1H); ESI MS m/z 510 [M+H]+; HPLC 95.6% (AUC), tR=9.18 min.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.NC(N)=[S:23].[OH-].[Na+]>>[CH3:20][C:16]1[CH:15]=[C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[N:4]=[N:3][C:2]([SH:23])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cccc(N2CCN(c3ccc(Cl)nn3)CC2)c1
Reactant: NC(N)=S
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(N2CCN(c3ccc(S)nn3)CC2)c1
Temperature: 165 °C
Reaction time: 3 h
Yield: 22.7 %

Procedure:
A mixture of 5.8 parts of 3-chloro-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine and 3 parts of thiourea was stirred for 3 hours in an oil bath at 165° C. After cooling, there were added 150 parts of a sodium hydroxide solution 0.5N. The whole was stirred and refluxed for 15 minutes. It was filtered while hot and the filtrate was neutralized with acetic acid. The product was filtered off, washed with water and separated by column chromatography over silica gel using a mixture of trichloromethane and methanol (98.5:1.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of ethanol and tetrahydrofuran. The product was filtered off and dried, yielding 1.3 parts (22.7%) of 6-[4-(3-methylphenyl)-1-piperazinyl]-3-pyridazinethiol; mp. 174.2° C. (compound 273).
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][NH:6][C:5](=[O:9])[CH2:4]1)=[O:2].[H-].[Na+].[CH3:12]I>CN(C)C=O>[CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH3:12])[C:5](=[O:9])[CH2:4]1)=[O:2]
Reactant: CI
Reactant: O=CN1CCNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(C=O)CC1=O

Procedure:
To a solution of 6.4 g of 1-formyl-3-oxo-piperazine in 10 ml of anhydrous dimethylformamide was added 2.7 g of a sodium hydride (purity 53%) with ice-cooling, and the resulting mixture was reacted at room temperature for 1 hour. Subsequently, the mixture was incorporated with 7.1 g of methyl iodide and reacted for 10 hours. After the reaction, the dimethylformamide was removed by reduced pressure distillation to obtain 1-formyl-4-methyl-3-oxo-piperazine. This piperazine was dissolved in 70 ml of a 50% aqueous acetone solution containing 2.2 g of sodium hydroxide, and the resulting solution was reacted at room temperature for 3 hours. Thereafter, the solvent was removed by distillation under reduced pressure, and the residue was charged into acetone to deposit insolubles. The insolubles were separated by filtration, and the acetone was removed from the filtrate by distillation under reduced pressure. Subsequently, the residue was subjected to reduced pressure distillation to obtain 5.2 g of 1-methyl-2-oxo-piperazine, b.p. 104° C/4 mmHg, yield 91%.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6](Cl)[CH:5]=1.[Cl:12][C:13]1[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=1.Cl>CS(C)=O>[Cl:12][C:13]1[N:14]=[N:15][C:16]([O:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:3])=[CH:5][CH:6]=2)=[CH:17][CH:18]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: Nc1ccc(O)c(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ccc(Cl)nn2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
12 g of sodium hydride was added in portions to a stirred solution of 71.8 g of 1A and 25 g of 3,6-dichloropyridazine in 300 ml of dimethyl sulfoxide, the temperature of the mixture being held at 50° C. The mixture then was stirred for one hour and poured into ice water. The mixture was slightly acidified with dilute hydrochloric acid, and was extracted with methylene chloride. The extract was washed with water, dried (magnesium sulfate) and the solvent was evaporated to give 4-(6-chloro-3-pyridazinyloxy)benzeneamine (1B), as a tan solid, mp: 126°-129° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH2:24]([NH2:26])[CH3:25]>>[CH2:24]([NH:26][C:20]([C:17]1[S:16][C:15]([CH2:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:23])=[N:19][CH:18]=1)=[O:22])[CH3:25]
Reactant: Cc1onc(-c2ccc(F)cn2)c1CCc1ncc(C(=O)O)s1
Reactant: CCN
Product: CCNC(=O)c1cnc(CCc2c(-c3ccc(F)cn3)noc2C)s1
Yield: 58 %

Procedure:
As described for example 40c, 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-thiazole-5-carboxylic acid (67 mg, 0.20 mmol) was converted, using ethylamine (2M solution in THF) instead of 4-aminotetrahydropyran, to the title compound (42 mg, 58%) which was obtained as a white solid. MS: m/e=361.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Cl.[NH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]1.C(N(CC)CC)C.[OH-].[Na+]>CN1CCCC1=O.O>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:14][C@H:15]3[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: O[C@H]1CC[C@H](Nc2ccnc3cc(Cl)ccc23)CC1

Procedure:
414.2 g of 4,7-dichloroquinoline, 380 g of trans-4-amino-cyclohexanol hydrochloride and 255 9 of triethylamine were heated to reflux overnight in 1.05 l of 1-methyl-2-pyrrolidone under an argon atmosphere. After cooling the reaction mixture 3.8 l of water and 380 ml of 28% sodium hydroxide solution were added thereto while stirring and cooling. The separated reaction product was filtered off under suction, washed with water until the wash water was neutral and dried at 100° C./12 mbar. Yield 491 g (84.9%) of trans-N-(7-chloro-quinolin-4-yl)-4-aminocyclohexanol.
Reaction SMILES: C(Cl)(=O)C.[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH2:13][CH2:14][C@@H:15]1[O:20][C:19](=[O:21])[CH2:18][C@@H:17](O)[CH2:16]1.C(Cl)(Cl)Cl.C(N(CC)CC)C>O.C(OCC)C>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH2:13][CH2:14][CH:15]1[O:20][C:19](=[O:21])[CH:18]=[CH:17][CH2:16]1
Reactant: O=C1C[C@@H](O)C[C@H](CCc2ccc(Cl)cc2Cl)O1
Solvent: O
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: O=C1C=CCC(CCc2ccc(Cl)cc2Cl)O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Acetyl chloride (8.6 ml) was added slowly to a vigorously stirred solution of trans-6-[2-(2,4-dichlorophenyl)ethyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (19.3 g, 66.8 mmol), CHCl3 (200 ml), triethylamine (35 ml) and 4-(dimethylasmino)pyridine (100 mg) at 20° C. The cloudy Pale amber mixture was stirred at ambient temperature for 16 hours and then distributed between diethyl ether (300 ml) and H2O (300 ml). The organic layer was separated and washed with IN HCl 200 ml) and H2O (2×200 ml), then dried and evaporated. The pale amber residual oil slowly solidified. Crystallization from n-butyl chloride:hexane; 1:5(v:V) provided the title compound as small pale amber needles. m.p. 69°-70° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].C1C(=O)N([Br:20])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][Br:20]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(Br)c(CBr)c1

Procedure:
Into a 500-mL round-bottom flask, was placed a solution of methyl 4-bromo-3-methylbenzoate (10 g, 43.65 mmol, 1.00 equiv) in CCl4 (150 ml), NBS (8.12 g, 45.62 mmol, 1.05 equiv). The resulting solution was heated to reflux overnight under 100 w incandescent bulb. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:30-1:10). This resulted in 6 g (47%) of methyl 4-bromo-3-(bromomethyl)benzoate as a off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9]C(OC)=O)=[CH:4][C:3]=1[N:14]1[C:22](=[O:23])[C:17]2=[CH:18][CH2:19][CH2:20][CH2:21][N:16]2[C:15]1=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl>CO>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:14]1[C:22](=[O:23])[C:17]2=[CH:18][CH2:19][CH2:20][CH2:21][N:16]2[C:15]1=[O:24]
Reactant: COC(=O)Oc1cc(N2C(=O)C3=CCCCN3C2=O)c(Cl)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1cc(Cl)c(N2C(=O)C3=CCCCN3C2=O)cc1O
Yield: 97.8 %

Procedure:
A methanol (45 mL) solution of 2-(2-chloro-4-methyl-5-methoxycarbonyloxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (2.22 g, 6.08 mmol) and potassium carbonate (0.84 g, 6.08 mmol) was stirred at 50°-60° C. for 7 hours. 1N Hydrochloric acid (60 mL) was added to the resulting mixture, and the organic layer was separated and the aqueous layer was extracted with ethyl acetate (30 mL×2 times). The organic layer combined was washed with a saturated sodium chloride solution (100 mL) and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give a white solid of 2-(2-chloro-4-methyl-5-hydroxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (1.74 g, yield:93.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[C:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[OH-].[Na+].Cl>CCO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[C:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCOC(=O)/C=C/c1ccc(C(=C2CCCCCC2)c2ccc(O)c(Cl)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)/C=C/c1ccc(C(=C2CCCCCC2)c2ccc(O)c(Cl)c2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
To a solution of ethyl (2E)-3-{4-[(3-chloro-4-hydroxyphenyl)(cycloheptylidene) methyl]phenyl}-2-propenoate (125) (0.23 g, 0.56 mmol) in a mixture of EtOH (6 mL) and THF (6 mL) was added an aqueous solution of 1 N NaOH (7 mL). The mixture was stirred at 60° C. for 2 h. Upon cooling, the mixture was acidified to pH=2 with an aqueous solution of 2 N HCl. The mixture was extracted with EtOAc (2×50 mL). The combined organic extract was washed with brine and dried over Na2SO4. Upon concentration, light brown foam was obtained. Trituration with hexanes (containing 1% MeOH) afforded compound 126 as a white solid (0.175 g, 82%). mp 155-156° C. 1H NMR (400 MHz, DMSO-d6): δ 1.51 (br s, 8H), 2.10-2.30 (m, 4H), 6.45 (d, J=15.9 Hz, 1H), 6.80-6.95 (m, 2H), 7.02 (s, 1H), 7.14 (d, J=7.8 Hz, 2H), 7.52 (d, J=16.1 Hz, 1H), 7.58 (d, J=7.8 Hz, 2H), 10.08 (s, 1H), 12.33 (s, 1H). LCMS (ESI): m/z 383 (M+H)+, m/z 381 (M−H)−. Anal. Calcd for C23H23ClO3.0.25H2O: C, 71.31; H, 6.11. Found: C, 71.26; H, 6.05.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[N:9](S(C3C=CC(C)=CC=3)(=O)=O)[C:10]([C:12]3[C:16]4=[N:17][C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=[C:15]4[NH:14][CH:13]=3)=[CH:11][C:3]=12.[OH-].[K+]>CO>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][C:10]([C:12]3[C:16]4=[N:17][C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=[C:15]4[NH:14][CH:13]=3)=[CH:11][C:3]=12
Reactant: COc1cc2[nH]cc(-c3cc4c(Cl)c(F)cnc4n3S(=O)(=O)c3ccc(C)cc3)c2nc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2[nH]cc(-c3cc4c(Cl)c(F)cnc4[nH]3)c2nc1OC
Yield: 79.5 %

Procedure:
A suspension of 0.2 g of 3-[4-chloro-5-fluoro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-5,6-dimethoxy-1H-pyrrolo[3,2-b]pyridine and 0.580 g of potassium hydroxide in 40 cm3 of methanol is refluxed for about 5 hours. After concentrating under reduced pressure (13 kPa), the solid is taken up in 50 cm3 of water, filtered off by suction and washed with 10 cm3 of water. After recrystallization from 40 cm3 of acetonitrile, 0.110 g of 3-[4-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl]-5,6-dimethoxy-1H-pyrrolo[3,2-b]pyridine is obtained as a solid with the following characteristics:
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][C:7]#[C:8][CH2:9][OH:10].[CH3:16]C(C)([O-])C.[K+].CI>O1CCCC1>[F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][C:7]#[C:8][CH2:9][O:10][CH3:16]
Reactant: OCC#CCOCc1cc(Br)ccc1F
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COCC#CCOCc1cc(Br)ccc1F
Temperature: -78 °C

Procedure:
A solution of 4-(2-fluoro-5-bromobenzyloxy)-but-2-ynyl alcohol (1.07 g, 3.92 mmol) in tetrahydrofuran (26 ml) was cooled to −40° C. and then treated with potassium t-butoxide (4.31 ml of a 1 M solution in tetrahydrofuran, 4.31 mmol). The resulting dark orange solution was stirred for thirty minutes, cooled to −78° C. and treated with methyl iodide (0.49 ml, 7.84 mmol). The reaction was warmed to 0° C. and stirred for 1.5 hours. The reaction mixture was then partitioned between methylene chloride and saturated sodium bicarbonate. The organic fraction was dried over sodium sulfate, and the solvents were removed in vacuo. The desired title intermediate was further purified by high performance liquid chromatography to yield 790 mg (70%) as a clear oil.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8](SC)=[N:7][C:6]=2[C:5]([O:13][CH3:14])=[CH:4][CH:3]=1.[NH:15]1[CH2:18][CH2:17][CH2:16]1>>[N:15]1([C:8]2[O:9][C:10]3[C:2]([Br:1])=[CH:3][CH:4]=[C:5]([O:13][CH3:14])[C:6]=3[N:7]=2)[CH2:18][CH2:17][CH2:16]1
Reactant: COc1ccc(Br)c2oc(SC)nc12
Reactant: C1CNC1
Product: COc1ccc(Br)c2oc(N3CCC3)nc12
Yield: 59.5 %

Procedure:
Starting from 7-bromo-4-methoxy-2-methylsulfanylbenzooxazole (4.8 g) and azetidine (1.0 g). Purification by chromatography on silica eluting with 50% ethyl acetate in heptane afforded the title compound as a pink solid (2.95 g).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19]>C(OCC)(=O)C>[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19]
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1)Nc1ccc(F)c([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 52 %

Procedure:
Phenylisocyanate (12.0 g, 0.1 mol) was added to 4-fluoro-3-nitroaniline (15.6 g, 0.1 mol) in ethyl acetate (400 mL) at room temperature. The reaction mixture was stirred overnight, then the volume was reduced to approximately 200 mL and the resulting suspension filtered to afford the product (14.3 g); m.p. 200-202° C. Concentration of the filtrate followed by filtration afforded an additional crop of product (5.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][O:19][CH2:20][CH2:21][C:22](O)=[O:23].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:22](=[O:23])[CH2:21][CH2:20][O:19][CH3:18])=[CH:3][CH:4]=3)[N:9]=[CH:10][C:11]=12
Reactant: COCCC(=O)O
Reactant: Nc1ccc(-n2ncc3c(N)ncnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Product: COCCC(=O)Nc1ccc(-n2ncc3c(N)ncnc32)cc1
Reaction time: 0.17 h
Yield: 20 %

Procedure:
Title compound 11A, 1-(4-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (37 mg, 1.1 eq, 0.16 mmol) was added to a solution of 3-methoxypropionic acid (15.5 mg, 1.0 eq, 0.15 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (25 mg, 1.0 eq, 0.16 mmol), 1-hydroxybenzotriazole (20 mg, 1.0 eq, 0.15 mmol) in DMF (1 ml) which had been stirred for 10 minutes under an inert atmosphere. The reaction was stirred at room temperature for 18 hours, after which methanol (1 ml) was added, and solvent was removed in vacuo. The resultant solid was washed with water and purified by semi-preparative HPLC to yield the title compound as a white solid (9.3 mg, 0.03 mmol, 20%). LCMS: [M+H]+=313, Rt=1.31 min, 100% purity.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:24][CH2:23]2)=[CH:4][C:5]([CH2:20][CH3:21])=[C:6]([CH:19]=1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])=[O:8].[CH:35]1([C:38]2[O:39][CH:40]=[C:41]([C:43](O)=[O:44])[N:42]=2)[CH2:37][CH2:36]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[CH2:20]([C:5]1[C:6]([C:7](=[O:8])[NH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])=[CH:19][C:2]([NH:1][C:43]([C:41]2[N:42]=[C:38]([CH:35]3[CH2:37][CH2:36]3)[O:39][CH:40]=2)=[O:44])=[C:3]([N:22]2[CH2:23][CH2:24][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:26][CH2:27]2)[CH:4]=1)[CH3:21]
Reactant: CCc1cc(N2CCN(c3ccccc3C)CC2)c(N)cc1C(=O)NCCCN1CCCC1=O
Reactant: O=C(O)c1coc(C2CC2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(N2CCN(c3ccccc3C)CC2)c(NC(=O)c2coc(C3CC3)n2)cc1C(=O)NCCCN1CCCC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
5-Amino-2-ethyl-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide 6b (36.0 mg, 0.08 mmol, 100 mol %), 2-cyclopropyl-oxazole-4-carboxylic acid 1 h (17.8 mg, 0.12 mmol, 150 mol %) and N,N-diisopropylethylamine (0.04 ml, 0.23 mmol, 300 mol %) were combined in N,N-dimethylformamide (2.0 ml) and HATU (44.3 mg, 0.12 mmol, mol %) was added and the reaction was stirred at room temperature for 16 h. The reaction was then diluted with water and extracted three times with ethyl acetate. The combined organics were dried over sodium sulfate and then concentrated to a residue that was purified by column chromatography (dichloromethane to 10% methanol/dichloromethane) to afford 2-cyclopropyl-oxazole-4-carboxylic acid [4-ethyl-5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide 6c (23.4 mg; 0.04 mmol, 50.3%) as a white solid.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:8][CH2:9][C:10]([NH2:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N.[OH2:20]>ClCCl>[C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:8]([CH2:9][C:10]([NH2:12])=[O:11])=[O:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O
Reactant: NC(=O)CSC(c1ccccc1)c1ccccc1
Agent: N
Solvent: ClCCl
Product: NC(=O)CS(=O)C(c1ccccc1)c1ccccc1
Yield: 80 %

Procedure:
10 g (38.9 mmoles) of 2-[(diphenylmethyl)thio]acetamide are dissolved in 100 ml of dichloromethane. The solution is added with 15.7 g of 68% w/w ε-phthalimidoperhexanoic acid, keeping the temperature at about 20° C., and after 6 h is diluted with water, adjusting the pH to 8–9 with aqueous ammonia. The resulting phases are separated and the organic one is evaporated to dryness, to obtain 8.5 g of 2-[(diphenylmethyl)sulfinyl]acetamide (modafinil). Molar yield: 80%.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[O:20]1[CH2:24][CH2:23][CH:22]([CH2:25][C:26](O)=[O:27])[CH2:21]1>>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:26](=[O:27])[CH2:25][CH:22]3[CH2:23][CH2:24][O:20][CH2:21]3)[N:11]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Nn1nc(-c2ccnc(Cl)c2)c2ccccc2c1=O
Reactant: O=C(O)CC1CCOC1
Product: O=C(CC1CCOC1)Nn1nc(-c2ccnc(Cl)c2)c2ccccc2c1=O

Procedure:
The product from Example 29B and 2-(tetrahydrofuran-3-yl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 8.60-8.60 (bs, 1H), 8.55-8.59 (m, 1H), 8.54-8.57 (m, 1H), 7.84-7.93 (m, 2H), 7.69-7.73 (m, 1H), 7.62 (s, 1H), 7.50-7.53 (m, 1H), 3.92-4.04 (m, 2H), 3.78-3.85 (m, 1H), 3.64-3.68 (m, 1H), 2.77-2.87 (m, 1H), 2.50-2.67 (m, 2H), 2.21-2.30 (m, 1H), 1.69-1.81 (m, 1H); MS (APCI+) M/Z 385 (M+H)+.