Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)=[O:3].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:20][CH:19]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]([CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[C:2]([N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)=[O:3])=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Reactant: CCN(CC)CCNc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CCN(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 18.2 %

Procedure:
tert-Butyl 4-chlorocarbonyl-piperazine-1-carboxylate (0.97 g, 3.9 mmol) was added to a solution of 4-chloro-N-(2-(diethylamino)ethyl)benzenamine (884 mg, 3.9 mmol) and N,N-diisopropylethylamine (1.9 mL, 11.7 mmol) in DCM (8 mL). The reaction mixture was heated at reflux for 20 hours. The mixture was cooled to room temperature, quenched with saturated NH4Cl (10 mL), and extracted with DCM (2×20 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel chromatography to give tert-butyl 4-(N-(4-chlorophenyl)-N-(2-(diethylamino)ethyl)carbamoyl)piperazine-1-carboxylate (311 mg, 18%). MS (APCI+) [M+H]+439.4. 1H NMR (CDCl3, 400 MHz) 7.29 (d, J=8.8 Hz, 2H), 7.09 (d, J=8.8 Hz, 2H), 3.70-3.66 (m, 2H), 3.45-3.42 (m, 2H), 3.24-3.21 (m, 4H), 3.15-3.12 (m, 2H), 2.61-2.57 (m, 2H), 2.52 (q, J=7.2 Hz, 4H), 1.42 (s, 9H), 0.99 (t, J=7.2 Hz, 6H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:33]1[CH:37]=[CH:36][CH2:35][CH2:34]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH:34]3[CH2:35][CH2:36][CH2:37][O:33]3)[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=COCC1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OC3CCCO3)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 39 mg, 0.090 mmol) in CH2Cl2 (2.0 ml) was added 2,3-dihydrofuran (68 μl, 0.90 mmol) and catalytic amount of PPTS. The reaction was stirred at room temperature for 4 h, and was purified directly by PTLC on silica gel (30% EtOAc-hexanes) to yield the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CO>C1COCC1>[CH2:14]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24 %

Procedure:
To a solution of 75 g of methyl 4-hydroxybenzoate in 700 ml THF at 22° C. were added 19.7 g of a 60% dispersion of sodium hydride in mineral oil. After the mixture was stirred for 90 minutes, 84.3 g of benzyl bromide was added dropwise. The reaction was heated at reflux for 18 hours, cooled to room temperature and 50 ml methanol was added. The mixture was evaporated and the resulting residue extracted with three portions of ethyl acetate. The combined organic extracts were washed with water and brine, dried over magnesium sulfate and evaporated to a solid. Recrystallization from cold methanol gave 28.7 g of the title compound: 300 MHz 1H NMR (CDCl3) δ53.96 (s, 3H), 5.19 (s, 2H), 7.05 (d, J=9 Hz, 2H), 7.42 (s, 5H), 8.05 (d, J=9 Hz, 2H).
Reaction SMILES: C[O-].[Na+].[C:4]([C:14]([C:17]([C:20]([C:23]([C:26]([C:29]([CH2:32][CH2:33][SH:34])([F:31])[F:30])([F:28])[F:27])([F:25])[F:24])([F:22])[F:21])([F:19])[F:18])([F:16])[F:15])([C:10]([F:13])([F:12])[F:11])([C:6]([F:9])([F:8])[F:7])[F:5].[CH2:35]1[O:37][CH2:36]1.Cl>O.CO>[C:4]([C:14]([C:17]([C:20]([C:23]([C:26]([C:29]([CH2:32][CH2:33][S:34][CH2:35][CH2:36][OH:37])([F:30])[F:31])([F:27])[F:28])([F:24])[F:25])([F:22])[F:21])([F:19])[F:18])([F:16])[F:15])([C:10]([F:13])([F:12])[F:11])([C:6]([F:9])([F:8])[F:7])[F:5]
Reactant: FC(F)(F)C(F)(C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCS
Reactant: C1CO1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCCSCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(C(F)(F)F)C(F)(F)F
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A 500 ml flask is charged with 100 ml of methanol, 5.4 g (0.1 mole) of sodium methoxide, and 53 g (0.1 mole) of (CF3)2CF(CF2)6C2H4SH and the mixture stirred for 30 minutes at 5°C. To this is added 4.6 g (0.105 mole) of liquid ethylene oxide keeping the temperature below 5°. After stirring for 1 hour, 100 ml of water is added and the product acidified to litmus with conc. hydrochloric acid. Extraction with 1,1,2-trichloro-1,2,2-trifluoroethane and solvent evaporation affords 41 g of (CF3)2CF(CF2)6C2H4SC2H4OH, m.p., 69°-71°.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=2)[CH2:3][CH2:2]1.[Br:16]N1C(=O)CCC1=O>C(OCC)(=O)C.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:16][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:7][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(OCC2CC2)cc1[N+](=O)[O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(OCC2CC2)ccc1CBr
Temperature: 90 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To a mixture of 4-(cyclopropylmethoxy)-1-methyl-2-nitrobenzene (66.4 g) and a solution of N-bromosuccinimide (68.4 g) in ethyl acetate (1.0 L) was added 2,2′-azobis(2-methylpropionitrile) (2.63 g) in 5 portions at 90° C. The reaction mixture was stirred at 90° C. overnight. To the reaction mixture were added N-bromosuccinimide (34.2 g) and 2,2′-azobis(2-methylpropionitrile) (1.32 g) at 90° C. The mixture was allowed to cool to room temperature, concentrated under reduced pressure and left standing overnight. The resulting crystals were collected by filtration, washed with methanol, and dried under reduced pressure to give the title compound (49.9 g).
Reaction SMILES: [C:1]([C:3]1[C:12]([NH:13][CH:14]([CH3:16])[CH3:15])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:17])[CH:4]=1)#[N:2].OO.C(=O)([O-])[O-:21].[K+].[K+]>CS(C)=O>[NH2:2][C:1]([C:3]1[C:12]([NH:13][CH:14]([CH3:15])[CH3:16])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:17])[CH:4]=1)=[O:21]
Reactant: COC(=O)c1cc(NC(C)C)c(C#N)cc1C
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cc(NC(C)C)c(C(N)=O)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 261.3 %

Procedure:
Methyl 4-cyano-5-(isopropylamino)-2-methylbenzoate (224 mg, 0.96 mmol) was dissolved in DMSO (2 mL) and cooled in a cold water bath. 30% Aqueous hydrogen peroxide (0.2 mL) and potassium carbonate (42.6 mg, 0.31 mmol) was added, and the mixture was stirred at ambient temperature for 1 h. The reaction mixture was partitioned between ethyl acetate and 10% aqueous lithium chloride. The aqueous portion was extracted with ethyl acetate. The combined organic portion was dried over sodium sulfate, then filtered and concentrated to a yellow oil which was purified by column chromatography (silica gel, 15-30% ethyl acetate in hexanes to afford methyl 4-aminocarbonyl-5-(isopropylamino)-2-methylbenzoate (202 mg, 0.81 mmol, 83% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.35 (d, 1H), 7.26 (d, 1H), 7.24-7.22 (m, 2H), 5.70 (br s, 1H), 3.90 (s, 3H), 3.75-3.68 (m, 1H), 2.42 (s, 3H), 1.26-1.24 (m, 6H); MS (EI) for C13H18N2O3: 251 (MH+).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[S:10]([CH2:13][CH:14]([CH3:16])[CH3:15])(=[O:12])=[O:11])[CH2:3][CH2:2]1.[NH2:20][C@@H:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:22]([NH:24][CH3:25])=[O:23]>>[CH3:27][C:26]([CH3:29])([CH3:28])[C@H:21]([NH:20][C:17]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([S:10]([CH2:13][CH:14]([CH3:15])[CH3:16])(=[O:11])=[O:12])[N:8]=1)=[O:19])[C:22](=[O:23])[NH:24][CH3:25]
Reactant: CC(C)CS(=O)(=O)c1nc(C(=O)O)ccc1C1CC1
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Product: CNC(=O)[C@@H](NC(=O)c1ccc(C2CC2)c(S(=O)(=O)CC(C)C)n1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid (Example 351 b) and (2S)-2-amino-N,3,3-trimethyl-butanamide (CAN 89226-12-0) as starting materials. MS (EI): m/e=410.6 [M+H]+.
Reaction SMILES: O[C:2]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C(N(S(F)(F)[F:19])CC)C>ClCCl.O>[F:19][C:2]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(O)c1ccc(C#N)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(F)c1ccc(C#N)cc1
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To a solution of 4-(2-hydroxypropan-2-yl)benzonitrile (1.00 g, 6.20 mmol; obtained from 4-(propan-2-yl)benzonitrile according to literature procedure: Synth. Comm. 2006, 36, 2145-2155) in dichloromethane (20 mL) was added diethylamino sulfur trifluoride (DAST; 1.20 g, 7.44 mmol) at a temperature of 0° C. The reaction mixture was allowed to stirr at rt for 2 h, whereupon it was diluted with water and extracted with dichloromethane. The organic extract was washed with water, dried with anhydrous magnesium sulfate and filtered. After evaporation of the solvent, the crude product was purified by MPLC (silica, cyclohexane/ethyl acetate 95:5) to afford the title compound (675 mg, 67%): 1H NMR (400 MHz, CDCl3) δ 7.57 (d, 2H), 7.48 (d, 2H), 1.72 (s, 3H), 1.68 (s, 3H); ES-MS m/z 163, HPLC RT (Method F) 2.12 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:16][CH2:15][CH:10]([C:11](OC)=[O:12])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][CH:10]([CH2:11][OH:12])[CH2:15][CH2:16]2)=[CH:3][CH:2]=1
Reactant: COC(=O)C1CCN(c2ccncc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCN(c2ccncc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.3 %

Procedure:
1-(4-Pyridyl)piperidine-4-methanol was prepared using a procedure similar to the following: A solution of methyl N-(4-pyridyl)isonipecotate (600 mg, 2.72 mmol) in tetrahydrofuran was added to a solution of lithium aluminum hydride (100 mg) in tetrahydrofuran (14 mL) cooled to 0° C. Upon consumption of the starting material (0.5-2 h), the mixture was treated with water (0.10 mL), 15% aqueous sodium hydroxide (0.10 mL), and water (0.30 mL). After 0.25 h, the mixture was sonicated for 0.25 h, then poured into a mixture of ethyl acetate, water, sodium tartrate, and potassium tartrate. The aqueous layer was extracted twice with ethyl acetate and the combined extracts were dried (magnesium sulfate), filtered, and concentrated in vacuo to yield 357 mg (68%) of 1-(4-pyridyl)piperidine-4-methanol, which was used without further purification.
Reaction SMILES: [O:1]1[CH2:4][C:3](=O)[CH2:2]1.C1(P(=[CH:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[O:1]1[CH2:2][C:3](=[CH:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:4]1
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Reactant: O=C1COC1
Solvent: ClCCl
Product: O=C(C=C1COC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under argon and at 0° C., 3.0 g (41.63 mmol) of oxetan-3-one (CAS Reg.-No. 6704-31-0) were dissolved in 50 ml of dichloromethane, and 18.8 g (45.79 mmol) of benzyl (triphenyl-λ5-phosphanylidene)acetate were then added. The reaction mixture was then slowly warmed to room temperature and stirred for another 15 minutes. The reaction solution was then concentrated to dryness. The residue was taken up in 25 ml of diethyl ether and stirred, and the mixture was kept at 4° C. for 12 h. The precipitated triphenylphosphine oxide was filtered off and the filtrate was concentrated to dryness. The crude product obtained was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 4:1→1:1). This gave 4.2 g (20.57 mmol, 49% of theory) of the title compound.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:8]([OH:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1.COC1C=CC([Br:30])=CC=1C=O>>[Br:30][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:8]([OH:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Reactant: COc1ccc(Br)cc1C=O
Product: COc1ccc(Br)cc1C(O)C#Cc1ccccc1
Yield: 69 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 2-methoxy-5-bromobenzaldehyde was reacted to give the title compound as a colourless oil (440 mg, 69%). LCMS (Method B): RT=4.47 min, [M−OH+H]+=299/301.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[CH2:30]([SH:34])[CH2:31][CH2:32][CH3:33]>O1CCOCC1.CN(C=O)C>[CH2:30]([S:34][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6])[CH2:31][CH2:32][CH3:33]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CCCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCCCSc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and butanethiol in dioxane and DMF. ES-MS m/e (%): 459 (M+H+, 100).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].Cl[CH2:6][C:7]([NH:9][C:10]([CH3:17])([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:8]>O.CO.[Pd]>[NH2:1][CH2:6][C:7]([NH:9][C:10]([CH3:17])([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:8]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCC(C)(C)NC(=O)CCl
Agent: [Pd]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCC(C)(C)NC(=O)CN

Procedure:
A solution of sodium azide (6.7 g, 103 m mol) in water (56 ml) and methanol(104 ml) was treated with 2-chloro-N-(1,1-dimethylhexyl)acetamide (16.5 g, 80 m mol) and the mixture was refluxed for 5 hours. After cooling, the mixture was extracted with 40-60 petrol (3×200 ml), the extracts were dried over magnesium sulphate and evaporated under reduced pressure to give crude 2-azido-N-(1,1-dimethylhexyl)acetamide as a pale yellow oil.This oil was dissolved in methanol (200 ml) and hydrogenated over 10% palladium on charcoal (3.2 g) at atmospheric pressure and room temperaturefor 24 hours. The mixture was filtered and the filtrate evaporated to give a crude oil (13.6 g) which was distilled to give 2-amino-N-(1,1-dimethylhexyl)acetamide as a colourless oil, b.p. 88°-90° C. at 0.05 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+].[C:12]1([S:18]([C:21]2[CH:26]=[CH:25][C:24](F)=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CS(C)=O>[C:12]1([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:9][C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(F)cc1
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=S(=O)(c1ccccc1)c1ccc(Oc2ccc(Cl)c(Cl)c2)cc1
Temperature: 60 °C
Yield: 84.2 %

Procedure:
To a solution of 9.0 g (0.0550 mole) of 3,4-dichlorophenol dissolved in 150 ml of DMSO was added 2.20 g (0.0550 mole) of NaOH. The mixture was heated to 60° C. and 12.5 g (0.0529 mole) of 4-fluorophenyl phenyl sulfone was added. The reaction mixture was heated at 125° C. for 3.25 hrs and cooled. The mixture was poured into a solution of 100 ml of 20% aqueous NaOH and 600 ml of water. The crystalline product was collected by filtration, washed well with water and partially dried. Recrystallization from ethanol afforded 16.9 g (84.5% yield) of purified 4-(4-(phenylsulfonyl)phenoxy)-1,2-dichlorobenzene, mp 145°-146° C.
Reaction SMILES: C[O-].[Na+].CO[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[SH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7].[NH2:26][C@H:27]([C:29]([OH:31])=[O:30])[CH3:28].Cl>CO.O>[SH:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9][C:8]=1[C:6]([NH:26][C@@H:27]([CH3:28])[C:29]([OH:31])=[O:30])=[O:7]
Reactant: C[C@H](N)C(=O)O
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1S
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@H](NC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1S)C(=O)O
Temperature: 150 °C

Procedure:
To a solution of 6.0 ml of 0.5 M sodium methoxide in methanol was added 100 mg of 4-Mercapto-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester and 286 mg of L-alanine. The mixture was heated to 150° C. for 15 minutes using a CEM Discover microwave reactor. The resultant solution was acidified to pH 3 with 1 N HCl, diluted with 10 ml water, and extracted with 20 ml of ethyl acetate. The organic fraction was washed with brine, dried over anhydrous sodium sulfate, and concentrated to 114 mg of product; MS (−): m/z 369.07 (M−1).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:16]([OH:18])=O)=[N:8][C:9]=2[O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH2:3][CH2:2]1.[CH3:19][C:20]([CH3:27])([C:22]1[S:23][CH:24]=[CH:25][N:26]=1)[NH2:21]>>[CH3:19][C:20]([NH:21][C:16]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])[N:8]=1)=[O:18])([C:22]1[S:23][CH:24]=[CH:25][N:26]=1)[CH3:27]
Reactant: CC(C)(N)c1nccs1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC(F)(F)F)n1
Product: CC(C)(NC(=O)c1ccc(C2CC2)c(OCC(F)(F)F)n1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 280c, using 5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 301a) and α,α-dimethyl-2-thiazolemethanamine (Example 12c) as starting materials, MS (EI): m/e=386.3 [M+H]+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[N:9]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=2)[CH:11]=[CH:10]1.[CH3:29][Sn:30](Cl)([CH3:32])[CH3:31]>C1COCC1>[CH3:29][Sn:30]([CH3:32])([CH3:31])[C:10]1[N:9]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]2[C:12]([CH:11]=1)=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=2
Reactant: COC(=O)c1ccc2ccn(C(=O)OC(C)(C)C)c2c1
Reactant: C[Sn](C)(C)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cc([Sn](C)(C)C)n(C(=O)OC(C)(C)C)c2c1
Temperature: 0 °C

Procedure:
A solution of lithium diisopropylamide (0.50 M, 72.6 mL, 36.2 mmol, 1.6 equiv) was added via cannula to a solution of 1-tert-butyl 6-methyl 1H-indole-1,6-dicarboxylate (1-5, 6.23 g, 22.6 mmol) in THF (100 mL) at −78° C. The resulting mixture was stirred for 2 hours at −78° C. before a solution of trimethyltin chloride in THF (2.3 M, 19.7 ml, 45.3 mmol, 2.00 equiv) was added. The resulting solution was warmed to 0° C. for 15 minutes, then partitioned between EtOAc (2×150 mL) and aqueous half-saturated NH4Cl solution (200 mL). The combined organics layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (100% hexanes initially, grading to 20% EtOAc in hexanes) to afford 1-tert-butyl 6-methyl 2-(trimethylstannyl)-1H-indole-1,6-dicarboxylate (1-6) as an orange oil. 1H NMR (300 MHz, CDCl3) δ 8.74 (s, 1H), 7.88 (dd, 1H, J=8.2, 1.8 Hz), 7.53 (d, 1H, J=8.2 Hz), 6.77 (br s, 1H), 3.95 (s, 3H), 1.74 (s, 9H), 0.33 (s, 9H).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([C:19]([OH:21])=[O:20])=[C:13]2[CH2:22][CH2:23][CH2:24][NH:25]C(OC(C)(C)C)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:33]>O1CCOCC1.C(Cl)Cl>[ClH:33].[C:1]([NH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([C:19]([OH:21])=[O:20])=[C:13]2[CH2:22][CH2:23][CH2:24][NH2:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCCc1c(C(=O)O)[nH]c2ccc(NC(=O)c3ccccc3)cc12
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCCCc1c(C(=O)O)[nH]c2ccc(NC(=O)c3ccccc3)cc12
Reaction time: 0.75 h

Procedure:
The above carboxylic acid (31 mg) was dissolved in 5 mL of 4N HCl in dioxane. Within 2 min a white precipitate had formed. The mixture was stirred for 45 min and then diluted with 10 mL of methylene chloride. The solid was filtered with a filter-tipped cannula and washed with 2×10 mL of methylene chloride. The solid was dried under vacuum to provide the title compound; MS, electrospray, 339 (M+H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:13][C:14]1[CH:15]=[C:16]2[C:20]3=[C:21]([CH2:23][S:24][CH2:25][CH2:26][N:19]3[C@H:18]3[CH2:27][CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][C@@H:17]23)[CH:22]=1>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]([F:12])([F:11])[F:10])=[CH:3][C:2]=1[NH:13][C:14]1[CH:15]=[C:16]2[C:20]3=[C:21]([CH2:23][S:24][CH2:25][CH2:26][N:19]3[C@H:18]3[CH2:27][CH2:28][NH:29][CH2:30][C@@H:17]23)[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Reactant: FC(F)(F)c1ccc(Cl)c(Br)c1
Product: FC(F)(F)c1ccc(Cl)c(Nc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c1

Procedure:
Using 3-bromo-4-chlorobenzotrifluoride and following the procedures described in EXAMPLE 33, Parts C and D, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 38 as a powder. 1H NMR(CDCl3, 300 MHz) δ 1.82-1.87 (m, 4H), 2.58-2.65 (m, 1H), 2.82-3.28 (m, 6H), 3.46-3.51 (m, 1H), 3.62-3.65 (m, 1H), 3.76 (s, 2H), 6.04 (s, 1H), 6.73 (s, 1H), 6.83 (s, 1H), 6.91 (d, 1H, J=8 Hz), 7.14 (s, 1H), 7.37 (d, 1H, J=8 Hz). LRMS (ES)+: 440 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.I[CH2:30][CH2:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH2:30][CH2:31][CH3:32]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CCC)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), 1-iodopropane (0.16 mL), potassium carbonate (0.38 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.5 g, 90%).