Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4]([OH:18])=[C:5]([C:13]([O:15]CC)=[O:14])[CH:6]=[N:7]2.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].[OH-].[K+]>>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4]([OH:18])=[C:5]([C:13]([OH:15])=[O:14])[CH:6]=[N:7]2
Reactant: CCOC(=O)c1cnc2cc(Cl)cc(Cl)c2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: O=C(O)c1cnc2cc(Cl)cc(Cl)c2c1O

Procedure:
reacting 5,7-dichloro-3-carboethoxy-4-hydroxyquinoline with a base selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide, to obtain a salt of 5,7-dichloro-4-hydroxyquinoline-3-carboxylic acid,
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([NH:29]C(=O)OC(C)(C)C)([CH2:25][CH2:26][O:27][CH3:28])[CH2:6][NH:7][C:8](=[O:24])[O:9][CH2:10][CH:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:29][C:5]([CH2:4][CH2:3][O:2][CH3:1])([CH2:25][CH2:26][O:27][CH3:28])[CH2:6][NH:7][C:8](=[O:24])[O:9][CH2:10][CH:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2
Reactant: COCCC(CCOC)(CNC(=O)OCC1c2ccccc2-c2ccccc21)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCC(N)(CCOC)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 5 h

Procedure:
To a solution of (9H-fluoren-9-yl)methyl tert-butyl (4-methoxy-2-(2-methoxyethyl)butane-1,2-diyl)dicarbamate (G22, 269 mg) in methylene chloride (2 mL), trifluoroacetic acid (2 mL) was added at room temperature, and the mixture was stirred at the same temperature for 5 hours. The solvent was evaporated under reduced pressure, and then ethyl acetate and saturated aqueous sodium hydrogencarbonate were added to the residue. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain (9H-fluoren-9-yl)methyl (2-amino-4-methoxy-2-(2-methoxyethyl)butyl)carbamate (G23, 186 mg).
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:22])[CH:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[F:21])C(OCC)=O)C>O>[F:21][C:15]1[C:16]([CH3:20])=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][CH2:7][C:6]([OH:22])=[O:5]
Reactant: CCOC(=O)C(Cc1cccc(C)c1F)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc(CCC(=O)O)c1F
Temperature: 0 °C
Reaction time: 18 h
Yield: 69.1 %

Procedure:
Potassium hydroxide (387 mg, 6.9 mmol) was dissolved in water (8 ml) followed by the addition of 2-(2-fluoro-3-methyl-benzyl)-malonic acid diethyl ester (973 mg, 3.44 mmol). The mixture was refluxed for 5 h followed by removal of the ethanol under reduced pressure. Concentrated sulfuric acid (0.59 ml) was added to the remaining aqueous solution and refluxing was continued for 18 h. The reaction mixture was cooled to 0° C. and the precipitated product was filtered off, washed with water and dried at HV to give 433 mg (69%) of 3-(2-fluoro-3-methyl-phenyl)-propionic acid. LC-MS: tR=0.84 min; [M+H]+=183.20.
Reaction SMILES: [Cl:1]C1C=C(Cl)C=C(Cl)C=1S(N(CCOCC(O)=O)C)(=O)=O.N1C=CC=C(C2(O)CCNCC2)C=1.C(=O)(O)[O-].[Na+].[Cl:40][C:41]1[CH:46]=[C:45]([Cl:47])[CH:44]=[C:43]([Cl:48])[C:42]=1[S:49]([N:52]([CH2:54][CH2:55][O:56][CH2:57][C:58]([N:60]1[CH2:65][CH2:64][C:63]([OH:72])([C:66]2[CH:67]=[N:68][CH:69]=[CH:70][CH:71]=2)[CH2:62][CH2:61]1)=[O:59])[CH3:53])(=[O:51])=[O:50].Cl[Si](C)(C)C>C(Cl)Cl.C(OCC)C.C(C(C)=O)C>[ClH:1].[Cl:48][C:43]1[CH:44]=[C:45]([Cl:47])[CH:46]=[C:41]([Cl:40])[C:42]=1[S:49]([N:52]([CH2:54][CH2:55][O:56][CH2:57][C:58]([N:60]1[CH2:61][CH2:62][C:63]([OH:72])([C:66]2[CH:67]=[N:68][CH:69]=[CH:70][CH:71]=2)[CH2:64][CH2:65]1)=[O:59])[CH3:53])(=[O:50])=[O:51]
Reactant: CN(CCOCC(=O)O)S(=O)(=O)c1c(Cl)cc(Cl)cc1Cl
Agent: CN(CCOCC(=O)N1CCC(O)(c2cccnc2)CC1)S(=O)(=O)c1c(Cl)cc(Cl)cc1Cl
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCC(C)=O
Solvent: CCOCC
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N′-Carbonyldiimidazole (68 mg, 0.420 mmol) was added to a solution of 2-(2-(2,4,6-trichloro-N-methylphenylsulfonamido)ethoxy)acetic acid (acid unit S9) (150 mg, 0.400 mmol) in methylene chloride (4.5 ml) and the mixture was stirred for 1 h at room temperature. A solution of 4-(pyridin-3-yl)piperidin-4-ol (A2) (71 mg, 0.400 mmol) in methylene chloride (2 ml) was subsequently added and the reaction mixture was stirred for 15 h at room temperature. Thereafter, saturated sodium bicarbonate solution (10 ml) was added to the reaction mixture and the aqueous phase was subsequently extracted with methylene chloride (20 ml). The combined organic phases were extracted with saturated sodium chloride solution (10 ml), dried with sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography with diethyl ether/methylene chloride/methanol/ammonia solution (25% aq.) (50:50:5:1). 2,4,6-Trichloro-N-(2-(2-(4-hydroxy-4-(pyridin-3-yl)piperidin-1-yl)-2-oxoethoxy)ethyl)-N-methylphenylsulfonamide (200 mg. 0.374 mmol) was dissolved in diethyl ether/methyl ethyl ketone (25:2, 27 ml), and chlorotrimethylsilane (88 μl, 0.692 mmol) was slowly added. The mixture was subsequently stirred for 30 min at 0° C. The precipitate formed was filtered off, washed with diethyl ether/hexane and dried.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12]([O:18][CH2:19][O:20][CH3:21])=[CH:11][C:10]=2[O:22][CH2:23][O:24][CH3:25])=[N:7][NH:6][C:5]1=[S:26])([CH3:3])[CH3:2].[C:27](=O)([O-])[O-].[K+].[K+].CI>C(O)C>[CH:1]([N:4]1[C:5]([S:26][CH3:27])=[N:6][N:7]=[C:8]1[C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12]([O:18][CH2:19][O:20][CH3:21])=[CH:11][C:10]=1[O:22][CH2:23][O:24][CH3:25])([CH3:2])[CH3:3]
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1-c1n[nH]c(=S)n1C(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCO
Product: COCOc1cc(OCOC)c(C(C)C)cc1-c1nnc(SC)n1C(C)C
Temperature: 80 °C
Yield: 94.9 %

Procedure:
4-isopropyl-5-(5-isopropyl-2,4-bis-methoxymethoxy-phenyl)-2,4-dihydro-[1,2,4]triazol-3-thione (F63-03, 1.96 g, 5.14 mmol) and potassium carbonate (710.4 mg, 5.14 mmol) were weighed and placed in a reaction vessel, and ethanol (30 mL) was added and then methyl iodide (0.32 mL, 5.14 mmol) was added. After heating at 80° C. for 1 hour while stirring, the mixture was returned to room temperature, and the solvent was distilled off under reduced pressure. After adding water, the reaction system was extracted with ethyl acetate, and the extract was washed with saturated sodium chloride solution. After drying the extract over anhydrous sodium, sodium sulfate was removed by filtration and the solvent was distilled off under reduced pressure to obtain yellow syrup. After purification by silica gel column chromatography (chloroform, methanol), 4-isopropyl-3-(5-isopropyl-2,4-bis-methoxy methoxyphenyl)-5-methylsulfanyl-4H-[1,2,4]triazole (F63-04, pale yellow syrup, 1.93 g, 95%) was obtained.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]([C:27](Cl)=[O:28])[C:23]([CH3:26])=[N:24][CH:25]=2)=[CH:16][CH:15]=1.CC(C)([O-])C.[K+]>C(Cl)Cl>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]([C:27]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[C:23]([CH3:26])=[N:24][CH:25]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)O
Reactant: Cc1ncc(-c2ccc(Cl)cc2)cc1C(=O)Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ncc(-c2ccc(Cl)cc2)cc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.9 %

Procedure:
Tert-butanol (1.08 g) and dry pyridine (1.31 g) in dry methylene dichloride (20 ml) were added dropwise to the product (2 g) of Stage 1 in dry methylene dichloride (40 ml). After stirring at room temperature for 2 hours, potassium tert-butoxide (1 g) was added and stirring was continued for a further hour. The mixture was washed twice with water, dried and filtered through a bed of activated charcoal and silica. Concentration of the filtrate gave the title product (0.42 g), m.p. 70°-72°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]2[C:22]([CH3:25])([CH3:24])[NH+:10]3[CH2:11][CH2:12][C:13]4[C:18]([CH:9]3[CH:8]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:7]=2[CH:6]=[CH:5][C:4]=1[O:33][CH3:34])=[CH:17][C:16]1[O:19][CH2:20][O:21][C:15]=1[CH:14]=4.[Br-].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:23]2[C:22]([CH3:24])([CH3:25])[N:10]3[CH2:11][CH2:12][C:13]4[C:18]([CH:9]3[CH:8]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:7]=2[CH:6]=[CH:5][C:4]=1[O:33][CH3:34])=[CH:17][C:16]1[O:19][CH2:20][O:21][C:15]=1[CH:14]=4
Reactant: COc1ccc2c(c1OC)C(C)(C)[NH+]1CCc3cc4c(cc3C1C2Cc1ccccn1)OCO4
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1OC)C(C)(C)N1CCc3cc4c(cc3C1C2Cc1ccccn1)OCO4
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 21 %

Procedure:
To a solution of 9,10-dimethoxy-8,8-dimethyl-13-pyridin-2-ylmethyl-5,6,8,13-tetrahydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium; bromide (64 mg, 0.12 mmol) in methanol (10 mL) was added sodium borohydride (9 mg, 0.24 mmol) in small portions at 25° C. After stirring at 25° C. for 20 min, the mixture was concentrated in vacuo. The resulting residue was extracted with diethyl ether (2×50 mL), washed with water (2×25 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 9,10-dimethoxy-8,8-dimethyl-13-pyridin-2-ylmethyl-5,8,13,13a-tetrahydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (12 mg, 21%). LC/MS m/e calcd for C28H30N2O4 (M+H)+: 459.56, observed: 459.3; 1H NMR (400 MHz, MeOD) δ ppm 1.87 (s, 3 H) 2.03 (s, 3 H) 3.00-3.09 (m, 2 H) 3.25-3.30 (m, 1 H) 3.55 (m, 1 H) 3.82 (s, 3 H) 3.89 (s, 3 H) 4.22 (t, J=5.68 Hz, 1 H) 4.26-4.33 (m, 1 H) 5.20 (d, J=5.05 Hz, 1 H) 6.01 (d, J=4.04 Hz, 2 H) 6.75 (s, 1 H) 6.98 (s, 1 H) 7.01-7.04 (m, 2 H) 7.18 (d, J=8.59 Hz, 1 H) 7.24-7.30 (m, 1 H) 7.73 (t, J=7.71 Hz, 1 H) 8.48 (d, J=5.05 Hz, 1 H).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19](Br)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].CCN(CC)CC>C(Cl)Cl.[Cu]I>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cncc(Br)c1
Reactant: C#CCCCCCC
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCC#Cc1cncc(OC[C@H]2CCCN2C(=O)OC(C)(C)C)c1
Yield: 93 %

Procedure:
A mixture of 3-(1-BOC-2-(R)-pyrrolidinylmethoxy)-5-bromopyridine (300 mg, 0.84 mmol), 1-octyne (0.2 mL, 1.4 mmol), Pd(PPh)3Cl2 (12 mg), CuI (catalytic amount) and NEt3 (2.45 mL) in CH2Cl2 (7 mL) was heated at reflux for 16 h. The solvent was removed, and the residue was washed with 10% NaOH then extracted with CH2Cl2. The organic extract was dried (MgSO4) and concentrated. The residue was chromatographed (silica gel; CHCl3/MeOH, 10:1) to afford the title compound (302 mg) that contaminated with starting material.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([OH:24])(=O)[C:14]1[CH:22]=[CH:21][C:20]2[O:19][CH2:18][O:17][C:16]=2[CH:15]=1.[Br:25][C:26]1[C:27]([CH3:43])=[N:28][O:29][C:30]=1[NH:31][S:32]([C:35]1[CH:39]=[CH:38][S:37][C:36]=1[C:40]([NH2:42])=[O:41])(=[O:34])=[O:33].[H-].[Na+]>C1COCC1.O>[Br:25][C:26]1[C:27]([CH3:43])=[N:28][O:29][C:30]=1[NH:31][S:32]([C:35]1[CH:39]=[CH:38][S:37][C:36]=1[C:40]([NH:42][C:13](=[O:24])[C:14]1[CH:22]=[CH:21][C:20]2[O:19][CH2:18][O:17][C:16]=2[CH:15]=1)=[O:41])(=[O:34])=[O:33]
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: Cc1noc(NS(=O)(=O)c2ccsc2C(N)=O)c1Br
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2ccsc2C(=O)NC(=O)c2ccc3c(c2)OCO3)c1Br
Reaction time: 0.25 h
Yield: 3.6 %

Procedure:
Carbonyldiimidazole (213 mg. 1.31 mmol) was added to a solution of piperonylic acid (181.5 mg., 1.09 mmol) in dry THF (10 ml). The resulting mixture was stirred for 15 minutes. N-(4-bromo-3-methyl-5-isoxazolyl)-2-aminocarbonylthiophene-3-sulfonamide (Example 89) (400 mg, 1.09 mmol) and NaH (175 mg, 60% in mineral oil, 4.37 mmol) were added sequentially. The mixture was stirred at room temperature for 8 hours. Water was added to destroy the excess NaH. The solvent was then evaporated and the residue was partitioned between 1N HCl and EtOAc. The organic layer was dried (MgSO4), the solid filtered and the filtrate concentrated. The residue was recrystallized from EtOAc to give N-(4-bromo-3-methyl-5-isoxazolyl)-2-{[(3,4-methylenedioxy)benzoyl]aminocarbonyl}thiophene-3-sulfonamide (20 mg, 3.6% yield) as a yellowish powder (m.p. 90-93° C.).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[N:9]=2)=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:30]1.CS(C)=O>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([N:29]5[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:30]5)=[N:7][CH:6]=4)=[N:9][N:10]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[C:11]3=[CH:12][N:13]=2)[CH:18]=1
Reactant: Fc1ccc(-c2nn(C3CCCCO3)c3cnc(-c4cccnc4)cc23)cn1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(-c3nn(C4CCCCO4)c4cnc(-c5cccnc5)cc34)cn2)C1
Temperature: 95 °C

Procedure:
A solution containing 3-(6-fluoropyridin-3-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (0.070 g, 0.00019 mol) and (R)-tert-butyl piperidin-3-ylcarbamate (0.224 g, 0.00112 mol) in Dimethyl sulfoxide (1.40 mL, 0.0197 mol) was heated at 95° C. for 18 h. The reaction was quenched with water then filtered and washed with water. The crude product was dried under high vacuum overnight to give tert-butyl (3R)-1-(5-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-3-ylcarbamate which was dissolved in Methylene chloride (1.4 mL, 0.022 mol) and treated with trifluoroacetic Acid (0.72 mL, 0.0093 mol). The reaction was stirred at RT 18 h. The reaction was concentrated then submitted for rHPLC to give 191 (50.6 mg, 73% yield). ESI MS m/z=372.1 (M+1). 1H NMR (400 MHz, DMSO) δ 9.40 (d, J=1.7 Hz, 1H), 9.18 (s, 1H), 8.88 (d, J=2.3 Hz, 1H), 8.60-8.53 (m, 3H), 8.21 (dd, J=8.9, 2.4 Hz, 1H), 7.50 (dd, J=7.7, 5.1 Hz, 1H), 6.97 (d, J=9.0 Hz, 1H), 4.27 (dd, J=23.6, 12.1 Hz, 2H), 2.88 (dd, J=17.5, 7.2 Hz, 2H), 2.73-2.56 (m, 2H), 1.89 (d, J=12.0 Hz, 1H), 1.73 (d, J=13.5 Hz, 1H), 1.47 (dd, J=24.5, 12.1 Hz, 1H), 1.25 (ddd, J=16.2, 12.6, 4.0 Hz, 1H)
Reaction SMILES: CC1(C)C[O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH:22]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:23]([O:25]CC)=[O:24])[CH:17]=[CH:16]3)=N1.CI.C1C[O:40]CC1>>[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH:22]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:23]([OH:25])=[O:24])[CH:17]=[CH:16]2)([OH:5])=[O:40]
Reactant: C1CCOC1
Reactant: CCCCCCC(C(=O)OCC)n1ccc2cc(-c3ccccc3C3=NC(C)(C)CO3)ccc21
Solvent: CI
Product: CCCCCCC(C(=O)O)n1ccc2cc(-c3ccccc3C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-[5-[2-(4,4-dimethyloxazolin-2-yl)phenyl]indole-1-yl]octanoate (0.174 mmoles, 80 mg) was dissolved in 1 ml THF. Methyl iodide (0.15 ml, 1.1 mmole) was added. After stirring overnight at room temperature, the solution was concentrated. The residue was dissolved in 7 ml of 2:1 MeOH:2N NaOH and heated at 90° C. for 24 hours. The reaction was cooled to 0° C. and washed with ether. The pH was adjusted to 1.0 using 2N HCL. The product was extracted with 20% EtOH in ethyl acetate. The organic layer dried and concentrated to yield 35 mg of 2-[5-(2-Carboxyphenyl)indol-1-yl]octanoic acid that solidified upon standing. (MS)
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[CH2:25]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17][CH:8]([NH:7][C:6](=[O:18])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1Cc2ccccc2N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
A mixture of (1,2,3,4-tetrahydroquinolin-3-yl)-carbamic acid tert-butyl ester (507 mg, 2.04 mmol) and potassium carbonate (367 mg, 2.65 mmol) in ethanol (15 mL) was treated with benzyl bromide (367 mg, 2.14 mmol)and stirred overnight at ambient temperature. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The isolated organic phase was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated. The resulting oil was chromatographed on silica gel, eluting with 5-to-50% ethyl acetate in hexane to afford the title compound (529 mg, 77%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ:1.38 (s, 9H), 2.65-2.75 (dd, 1H), 2.83-2.92 (dd, 1H), 3.11-3.22 (dd, 1H), 3.35-3.42 (dd, 1H), 3.77-3.90 (m, 1H), 4.39-4.51 (q, 2H), 6.45-6.52 (m, 2H), 6.82-6.94 (m, 3H), 7.20-7.34 (m, 5H). MS (ESI) m/z 222.2, 283.1, 339.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](I)=[C:13]([OH:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1)[CH2:18][CH3:19].CN(C)C(N(C)C)=N>CN(C=O)C.C(OCC)(=O)C.[Cu]I>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:28]=[C:27]([C:24]3[CH:25]=[CH:26][C:21]([O:20][CH2:17][CH2:18][CH3:19])=[CH:22][CH:23]=3)[O:15][C:13]=2[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cc(OCc2ccccc2)ccc1I
Reactant: C#Cc1ccc(OCCC)cc1
Agent: [Cu]I
Agent: CN(C)C(=N)N(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1ccc(-c2cc3ccc(OCc4ccccc4)cc3o2)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
To a solution of 5-(benzyloxy)-2-iodophenol (2.65 g), 4-propoxyphenylacetylene (1.97 g) and 1,1,3,3-tetramethylguanidine (3.08 mL) in DMF (15 mL) were added bistriphenylphosphinedichloropalladium(II) (288 mg) and copper(I) iodide (156 mg) under a nitrogen atmosphere, and the mixture was stirred at 60° C. for 30 min. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.35 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[N:9]/[S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[CH:4][CH:3]=1.Br[Mg][C:18]#[CH:19]>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:9][S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[C:18]#[CH:19])=[CH:6][CH:7]=1
Reactant: CC(C)(C)S(=O)/N=C/c1ccc(Br)cc1
Reactant: C#C[Mg]Br
Solvent: ClCCl
Solvent: C1CCOC1
Product: C#C[C@@H](NS(=O)C(C)(C)C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2.8 g (9.7 mmol) N-[(1E)-(4-bromophenyl)methylidene]-2-methylpropane-2-sulfinamide in 30 ml CH2Cl2 at −78° C. was added 49 mL (24 mmol) 0.5M bromo(ethynyl)magnesium in THF. The reaction mixture was warmed slowly to room temperature. After 24 h at room temperature, the reaction mixture was quenched with saturated ammonium chloride, extracted three times with methylene chloride, and washed with brine. The organic layer was dried over NaSO4, filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, linear gradient 0-100% EtOAc:hexane) afforded N-[(1R)-1-(4-bromophenyl)prop-2-ynyl]-2-methylpropane-2-sulfinamide. 1H NMR (CDCl3, 400 MHz) 7.52-7.45 (m, 2H); 7.41-7.38 (m, 2H); 5.19 (dd, 1H, J=2.38 Hz, 6.05 Hz); 3.66 (br d, 1H, J=6.04 Hz); 2.64 (d, 1H, J=2.38 Hz); 1.20 (s, 9H). ESMS+1=316.0.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([SH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15]([O:19][C:20](=[O:31])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[O:28])=[C:23](F)[C:22]=1[F:30])([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[C:15]([O:19][C:20](=[O:31])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[O:28])=[C:23]([S:14][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:22]=1[F:30])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)c(F)c1F
Reactant: SCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(C=O)c(SCc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
To a solution of potassium tert-butoxide (2.0 g, 17.9 mmol) in anhydrous THF (80 mL) was added benzyl mercaptan (2.1 mL, 17.9 mmol). The reaction mixture was stirred at room temperature for 5 minutes before being cooled to −30° C. A solution of 2,3-difluoro-4-formyl-benzoic acid tert-butyl ester (4.34 g, 17.9 mmol) in anhydrous THF (20 mL) was added dropwise over 15 minutes and the resultant mixture was stirred at −30° C. for 30 minutes before being quenched by addition of water and extracted with ethyl acetate. The organic layer was separated, washed with water followed by brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a yellow oil (6.2 g, 100%). 1H NMR (CDCl3, 400 MHz) 10.20 (1 H, d, J=0.6 Hz), 7.84 (1 H, ddd, J=8.0, 6.8, 0.7 Hz), 7.59 (1 H, dd, J=8.0, 0.9 Hz), 7.19 (3 H, m), 7.05 (2 H, m), 4.07 (2 H, s), 1.63 (9 H, s).
Reaction SMILES: [CH:1]([C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([NH2:18])[C:6]=2[N:5]=1)([CH3:3])[CH3:2].[F:19][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][C@H:28]2[CH2:33]N[CH2:31][CH2:30][NH:29]2)[CH:23]=[CH:24][CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][C@@H:28]2[NH:29][CH2:30][CH2:31][N:18]([C:7]3[C:6]4[N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[S:13][C:12]=4[NH:11][C:10]4[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=4[N:8]=3)[CH2:33]2)[CH:23]=[CH:24][CH:25]=1
Reactant: Fc1cccc(CC[C@H]2CNCCN2)c1
Reactant: CC(C)c1nc2c(s1)Nc1ccccc1N=C2N
Product: CC(C)c1nc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2cccc(F)c2)C1
Yield: 54.7 %

Procedure:
By using a method similar to the method of Example 460, using 2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine (0.566 g, 2.19 mmol) and (S)-2-[2-(3-fluoro-phenyl)-ethyl]-piperazine (0.457 g, 2.19 mmol) to give 0.539 g of the title compound as a solid: mass spectrum (ion spray): m/z=450 (M+1); Analysis for C25H28FN5S(0.2 H2O): calcd: C, 66.26; H, 6.32; N, 15.45; found: C, 65.96; H, 6.11; N, 15.31.
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:13][C:12]([S:14]([CH3:17])(=[O:16])=[O:15])=[N:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[OH:1][C:2]1([C:9]2[S:13][C:12]([S:14]([CH3:17])(=[O:16])=[O:15])=[N:11][CH:10]=2)[CH2:7][CH2:6][CH:5]([N:18]2[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=3)=[O:24])[CH2:19]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: CS(=O)(=O)c1ncc(C2(O)CCC(=O)CC2)s1
Product: CS(=O)(=O)c1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-(2-methanesulfonyl-thiazol-5-yl)-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.