Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(Cl)(=O)C(Cl)=O.[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:31])[CH3:30])[C:24]=1[OH:32])([CH3:22])[CH3:21].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[OH:32][C:24]1[C:25]([CH:29]([CH3:30])[CH3:31])=[CH:26][C:27]([C:9]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:13][CH:12]=2)=[O:11])=[CH:28][C:23]=1[CH:20]([CH3:22])[CH3:21]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: CC(C)c1cccc(C(C)C)c1O
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1cc(C(=O)c2ccc(S(C)(=O)=O)cc2)cc(C(C)C)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.8 %

Procedure:
To a solution of 4-methylsulfonylbenzoic acid (4.08 g, 24 mmol) and oxalyl chloride (3.9 mL, 44 mmol) in DCM (70 mL), three drops of DMF was added at 0° C. The reaction mixture was stirred at room temperature for 3 hours and concentrated on a rotavapor. The residue was dissolved in 20 mL of DCM and was added into a suspension of 2,6-diisopropylphenol (2.12 g, 11.9 mmol) and aluminum chloride (1.6 g, 12 mmol in 50 mL of DCM. After stirring for 14 hour, the reaction mixture was poured into 100 mL of ice-water and extracted with diisopropyl ether (2×100 mL). The organic layer was washed with 1 N HCl, saturated aqueous NaHCO3, and brine, and was dried over anhydrous MgSO4. After filtration, the solution was condensed on a rotary evaporator. The crude product was suspended in 100 mL of methanol and 30 mL of water. The resultant suspension was treated with an excess amount of solid NaOH for 16 h at room temperature and acidified by 1 N HCl to pH of 4. The reaction mixture was extracted with ethyl acetate (2×100 mL). After washing with saturated aqueous NaHCO3 and brine, the organic layer was dried over anhydrous Na2SO4 and filtered. The solution was concentrated and the residue was purified by flash silica gel chromatography to afford the desired product as a yellow solid (550 mg, Yield 13%). 1H NMR (500 MHz, CDCl3, δ): 1.27 (s, 6H), 1.29 (s, 6H), 3.12 (s, 3H), 3.18 (hept, J=6.9 Hz, 2H), 5.40 (br s, 1H), 7.57 (s, 2H), 7.90 (dd, J=6.6, 1.7 Hz, 2H), 8.06 (dd, J=6.5, 1.7 Hz, 2H); Anal. Calcd for (C19H21FO2+H)+: 361. Found: 361.
Reaction SMILES: [F:1][C:2]1[C:3]([C:18]2[N:19]=[C:20]([S:28]C)[N:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[C:22]=23)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:8]=[CH:7]2.CC(O)=O.Br>>[NH2:27][C:23]1[C:22]2[N:21]([C:20]([SH:28])=[N:19][C:18]=2[C:3]2[C:2]([F:1])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:10]3)=[CH:5][CH:4]=2)[CH:26]=[CH:25][N:24]=1
Reactant: CSc1nc(-c2ccc3ccc(-c4ccccc4)nc3c2F)c2c(N)nccn12
Agent: Br
Solvent: CC(=O)O
Product: Nc1nccn2c(S)nc(-c3ccc4ccc(-c5ccccc5)nc4c3F)c12
Temperature: 118 °C

Procedure:
A solution of 1-(8-fluoro-2-phenyl-quinolin-7-yl)-3-methylsulfanyl-imidazo[1,5-a]pyrazin-8-ylamine (24 mg, 0.000060 mol) in AcOH (1 mL, 0.02 mol) was charged with hydrogen bromide (300 uL, 0.006 mol) and refluxed at 118° C. over weekend. An additional 5 eq of HBr were added and the reaction mixture was heated at 118° C. for 4-5 h. The reaction was stopped and cooled in ice. Orange precipitate formed on cooling in ice. The reaction mixture was concentrated in vacuo and washed with hexanes to obtain the title compound as an orange gummy solid. 1H NMR (400 MHz, CD3OD d4): δ=7.56 (dd, J=7.33, 3.28 Hz, 1H), 7.63-7.68 (m, 4H), 7.84-7.90 (m, 1H), 8.15 (d, J=8.84 Hz, 1H), 8.19-8.25 (m, 2H), 8.37 (d, J=8.59 Hz, 1H), 8.87 (d, J=8.84 Hz, 1H). MS (ES+): m/z 388.21 (100). HPLC: tR=2.42 min (Open Lynx polar—5 min). Note: Precipitate formed on cooling in ice. At rt the compound is oily.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:10])[C:8]#[N:9])=[CH:3][CH:2]=1.N1C=C(C)C=C(C)C=1.[CH3:19][O:20][C:21]1[C:29]([Cl:30])=[CH:28][CH:27]=[C:26]([Cl:31])[C:22]=1[C:23](Cl)=[O:24]>C(Cl)Cl>[Cl:30][C:29]1[C:21]([O:20][CH3:19])=[C:22]([C:26]([Cl:31])=[CH:27][CH:28]=1)[C:23]([O:10][CH:7]([C:8]#[N:9])[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)=[O:24]
Reactant: N#CC(O)c1ccccc1
Reactant: COc1c(Cl)ccc(Cl)c1C(=O)Cl
Agent: Cc1cncc(C)c1
Solvent: ClCCl
Product: COc1c(Cl)ccc(Cl)c1C(=O)OC(C#N)c1ccccc1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
Benzaldehyde cyanohydrin (13.3 grams; 0.100 moles), 3,5-lutidine (11 grams) and methylene chloride (100 ml) were placed in a 500 ml. 3-necked glass reaction flask equipped with a mechanical stirrer, thermometer, condenser and addition funnel. This mixture was cooled to 10° C. by means of an ice bath and 2-methoxy-3,6-dichlorobenzoic acid chloride (23.9 grams; 0.10 moles) was added dropwise with the temperature of the mixture maintained at 5°-10° C. After the addition of the acid chloride was completed, the reaction mixture was stirred for an additional three hours at room temperature. After the reaction was completed, the mixture was washed three times with water, dried over anhydrous magnesium sulfate, filtered and concentrated by distillation. The residue was heated to a temperature of 150° C. under vacuum from a vacuum pump. Then the residue was dissolved in cyclohexane, treated with nuchar, filtered and stripped dry to give an oil.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH:16](=O)[CH2:17][CH2:18][CH3:19].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:16]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCC=O
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCCNc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
To a solution of 4-(4-fluorophenoxy)aniline (Apollo, 500 mg, 2.46 mmol) and butyraldehyde (240 μL, 2.71 mmol) in DCE (5.0 mL) were added 4 Å molecular sieves. The resulting reaction mixture was stirred at room temperature for 1 h. Next, Na(OAc)3BH (782 mg, 3.69 mmol) was added, and the reaction mixture was stirred at room temperature overnight. Concentration in vacuo afforded a crude residue which was purified by flash column chromatography (10% EtOAc/hexanes) to give the title compound (400 mg, 62%). 1H NMR (CDCl3) δ 7.28-7.21 (m, 2H), 7.20-7.13 (m, 4H), 6.91-6.85 (m, 2H), 3.82 (br s, 1H), 3.39 (t, J=7.0 Hz, 2H), 1.96-1.85 (m, 2H), 1.79-1.67 (m, 2H), 1.26 (t, J=7.4 Hz, 3H); MS(ESI+) m/z 260.1 (M+H)+.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:21])[CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][C:15]1=[O:20].Br[C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:21])[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[C:32]=2[N:31]=[CH:30][CH:29]=[CH:28]3)[CH2:16][C:15]1=[O:20]
Reactant: Brc1cccc2cccnc12
Reactant: O=C1CNCCN1CC(O)CN1CCc2ccccc2C1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: O=C1CN(c2cccc3cccnc23)CCN1CC(O)CN1CCc2ccccc2C1
Temperature: 110 °C
Yield: 15.8 %

Procedure:
To a solution of 1-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)piperazin-2-one (100 mg, 0.35 mmol) in 10 mL of dry toluene was added 8-bromoquinoline (108 mg, 0.52 mmol), Pd2(dba)3 (32 mg, 0.035 mmol), NINAP (44 mg, 0.07 mmol) and t-BuONa (101 mg, 1.05 mmol). The flask was degassed and charged with N2, then heated at 110° C. for 16 h. The reaction mixture was cooled, filtered, and concentrated. The residue was purified by preparative HPLC purification. (23 mg, yield 15.8%) MS (ESI+) e/z: 417.2 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 8.96-8.85 (m, 1H), 8.53-8.39 (m, 1H), 8.38-8.29 (m, 1H), 7.70-7.62 (m, 1H), 7.62-7.51 (m, 2H), 7.37-7.24 (m, 4H), 7.24-7.17 (m, 1H), 4.60-4.52 (m, 1H), 4.52-4.41 (m, 2H), 4.08-3.98 (m, 2H), 3.87-3.78 (m, 2H), 3.77-3.69 (m, 1H), 3.69-3.58 (m, 4H), 3.57-3.49 (m, 1H), 3.42-3.34 (m, 1H), 3.32-3.27 (m, 1H), 3.27-3.13 (m, 2H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:11]2=[CH:12][C:13]3[N:14]=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=4)[CH:16]=[N:17][C:18]=3[CH:19]=[C:10]2[CH:9]=[N:8]1)(=O)C.[Li+].[OH-].O>C1COCC1.CO.O>[OH:4][CH2:5][CH2:6][N:7]1[C:11]2=[CH:12][C:13]3[N:14]=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=4)[CH:16]=[N:17][C:18]=3[CH:19]=[C:10]2[CH:9]=[N:8]1
Reactant: COc1ccc(-c2cnc3cc4cnn(CCOC(C)=O)c4cc3n2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2cnc3cc4cnn(CCO)c4cc3n2)cc1F

Procedure:
To a mixture of 0.36 g of 1-(2-acetoxyethyl)-7-(3-fluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-g]quinoxaline in 50 ml of THF:MeOH:H2O (3:1:1) is added 0.39 g of LiOH:H2O and the resulting mixture is stirred at room temperature overnight. The MeOH and THF are removed in vacuo and the yellow crystalline solid precipitates out from the aqueous solution. More water is added to the mixture and cooled in an ice-bath for 1/2 hour. The product is collected by filtration, washed with water and air dried. The product is recrystallized from ethylacetate, collected and air dried to obtain 1-[2-hydroxyethyl]-7-(3-fluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-g]quinoxaline (m.p. 192°-195° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[C:19]([O:22][CH3:23])[C:20]=1[Br:21])[C:12]([NH:14][CH2:15][C:16]#[CH:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:12]2[O:13][C:16]([CH3:17])=[CH:15][N:14]=2)[CH:18]=[C:19]([O:22][CH3:23])[C:20]=1[Br:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCNC(=O)c1cc(OC)c(Br)c(OCc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc(-c2ncc(C)o2)cc(OCc2ccccc2)c1Br
Temperature: 25 °C
Yield: 43.4 %

Procedure:
To a solution of 3-(benzyloxy)-4-bromo-5-methoxy-N-(prop-2-yn-1-yl)benzamide (0.455 g, 1.22 mmol) in dioxane (12 mL) was added sodium hydride (60% wt, 0.146 g, 3.65 mmol) and the mixture heated at reflux for six hours. The mixture was cooled to RT, quenched by slow addition of water and diluted with ethyl acetate. The mixture was washed with water, saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated. Flash column chromatography (12 g silica, 2% ethyl acetate in DCM) provided 2-(3-(benzyloxy)-4-bromo-5-methoxyphenyl)-5-methyloxazole (198 mg) as an off-white solid. MS=374 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.55 (d, J=7.58 Hz, 2H), 7.43 (t, J=7.33 Hz, 2H), 7.32-7.39 (m, 2H), 7.27 (d, J=2.02 Hz, 1H), 6.89 (d, J=1.01 Hz, 1H), 5.27 (s, 2H), 4.02 (s, 3H), 2.44 (d, J=1.52 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH:12]1[CH:17]=[CH:16][C:15]([O:18][C:19](OC2C=CC=CC=2)=[N:20][C:21]#[N:22])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([NH:6][C:19](=[N:20][C:21]#[N:22])[O:18][C:15]2[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CN=C(Nc1cccc(C(F)(F)F)c1)Oc1ccccc1
Reaction time: 23 h
Yield: 46.5 %

Procedure:
To a solution of 3-trifluoromethylaniline (11 mmol, 1.37 ml) in dichloromethane (25 ml), diphenylcyanocarbonimidate (10 mmol, 2.38 g), and triethylamine (11 mmol, 1.53 ml) were added. The mixture was stirred under nitrogen for 23 h. After concentration the residue was stirred with water, the water was decanted followed by concentration. The residue was stirred with toluene and the solid was collected by filtration giving 1.42 g of N-(3-trifluoromethylphenyl)-N'-cyano-O-phenylisourea (50%);
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](Cl)[N:19]=1>C1COCC1>[Cl:17][C:18]1[N:19]=[C:20]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)[CH:21]=[CH:22][CH:23]=1
Reactant: Clc1cccc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(Cl)n2)CC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
To a stirred solution of 4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.63 g, 8.1 mmol) in THF (20 mL), NaH (0.40 g, 10.1 mmol)) was added and stirred at 60° C. for 0.5 h. 2,6-dichloropyridine (1.0 g, 6.75 mmol) was added and stirred at room temperature for 3-4-h. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was concentrated in vacuo and the resultant residue was purified by flash column chromatography to yield tert-butyl 4-((6-chloropyridin-2-yl)oxy)piperidine-1-carboxylate as a pale yellow solid (0.98 g, 48%); MS: 335.1 (M+23)
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7]4=[C:8]([C:17](=[O:21])[NH:18][C:19](=[S:20])[N:6]4[C:5]=2[CH:4]=1)[CH:9]=[CH:10][CH:11]=3.FC(F)(F)C1C=CC2SC3C4=C(C(=O)NC(=[O:43])N4C=2C=1)C=CC=3>>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:16]=[CH:15][C:14]2[S:13](=[O:43])[C:12]3[C:7]4=[C:8]([C:17](=[O:21])[NH:18][C:19](=[S:20])[N:6]4[C:5]=2[CH:4]=1)[CH:9]=[CH:10][CH:11]=3
Reactant: O=c1[nH]c(=S)n2c3c(cccc13)Sc1ccc(C(F)(F)F)cc1-2
Reactant: O=c1[nH]c(=O)n2c3c(cccc13)Sc1ccc(C(F)(F)F)cc1-2
Product: O=c1[nH]c(=S)n2c3c(cccc13)S(=O)c1ccc(C(F)(F)F)cc1-2

Procedure:
When an equivalent amount of 10-trifluoromethyl-1H-pyrimido[5,4,3-kl]phenothiazine-3-one-1(2H)-thione is substituted in the procedure of Example 6 for 10-trifluoromethyl-1H-pyrimido[5,4,3-kl]phenothiazine-1,3(2H)-dione, the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][NH:12][CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1.[C:24]([N:31](C)[CH2:32][C:33](O)=[O:34])(OC(C)(C)C)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:33](=[O:34])[CH2:32][NH:31][CH3:24])[CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Cl)ccc21
Product: CNCC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Examples 19 and 20, with the exceptions that 5-chloro-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide was used instead of 5-bromo-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide, and that N-Boc-N-methyl glycine was used instead of N-Boc glycine.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([O:16]CC)=O)[N:2]=1.[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=1>O>[C:22]1([CH2:25][CH2:26][NH:27][C:14]([C:3]2[N:2]=[CH:1][C:13]3[NH:12][C:11]4[C:6]([C:5]=3[CH:4]=2)=[CH:7][CH:8]=[CH:9][CH:10]=4)=[O:16])[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Reactant: NCCc1ccccc1
Solvent: O
Product: O=C(NCCc1ccccc1)c1cc2c(cn1)[nH]c1ccccc12
Yield: 95.2 %

Procedure:
2 g of ethyl β-carbolin-3-carboxylate and 5 g of β-phenethylamine are heated for 2 hours at 196° C. The cooled, partly crystallized mixture is treated with hot water which is decanted. The residue is recrystallized from xylene to form β-carbolin-3-carboxylic acid (2-phenylethyl)amide (2.5 g) of a melting point of 297°-298° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=O.[NH:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][N:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: Nc1cnccc1C=O
Reactant: CCOC(=O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1CCN(Cc2ccncc2N)CC1
Temperature: 60 °C
Yield: 104.9 %

Procedure:
3-Amino-pyridine-4-carbaldehyde (5.00 g, 40.9 mmol) was dissolved in DCM (60 mL), ethyl 4-piperidinecarboxylate (7.57 mL, 49.1 mmol) and NaBH(OAc)3 (10.4 g, 49.1 mmol) were added and the reaction mixture was heated in a microwave reactor at 60° C. for 5 min. The reaction mixture was diluted with DCM (100 mL) and quenched with sat aq Na2CO3 (50 mL). The organic fraction was washed with sat aq NH4Cl (30 mL). The combined aq fractions were extracted with DCM (2×50 mL) and the combined organic fractions were dried (MgSO4) and concentrated in vacuo to give the crude title compound as a yellow gum (11.3 g). LCMS (ES+): 264.1 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH:22]([CH3:24])[CH3:23])[CH:16]=4)[C:4]=2[C:3]=1[CH3:25])[CH:12]=[CH:11][CH:10]=[CH:9]3.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[CH:22]([C:17]1[CH:16]=[C:15]([C:14]2[C:4]3[C:3]([CH3:25])=[C:2]([CH3:1])[S:6][C:5]=3[CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:20]=[CH:19][C:18]=1[O:21][C:26](=[O:28])[CH3:27])([CH3:23])[CH3:24]
Reactant: Cc1sc2cc3ccccc3c(-c3ccc(O)c(C(C)C)c3)c2c1C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2c3ccccc3cc3sc(C)c(C)c23)cc1C(C)C
Reaction time: 5.5 h
Yield: 68.6 %

Procedure:
At 5° C., to a stirred solution of 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-isopropyl-phenol (0.500 g, 1.44 mmol) in pyridine (3.5 mL) was added acetic anhydride (0.167 mL, 1.78 mmol). After 5.5 h, the reaction was quenched with H2O, acidified and extracted with ether. The combined ethereal extracts were sequentially washed with H2O, brine and concentrated. Purification on silica gel, eluting with 5 & 7% EtOAc/pet. ether, step gradient gave 0.384 g (69%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 8.49 (s, 1 H), 8.00-7.96 (d, 1 H), 7.48-7.31 (m, 4 H), 7.20 (s, 2 H), 3.10 (septet, 1 H), 2.40 (s, 3 H), 2.37 (s, 3 H), 1.56 (s, 3 H), 1.16 (d, 6 H).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[F:15][C:16]([F:30])([F:29])[CH2:17][O:18][C:19]1[N:24]=[CH:23][C:22]([CH:25]([NH2:28])[CH2:26][CH3:27])=[CH:21][CH:20]=1>>[Cl:13][C:12]1[C:3]2[CH2:2][N:28]([CH:25]([C:22]3[CH:23]=[N:24][C:19]([O:18][CH2:17][C:16]([F:30])([F:15])[F:29])=[CH:20][CH:21]=3)[CH2:26][CH3:27])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: CCC(N)c1ccc(OCC(F)(F)F)nc1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: CCC(c1ccc(OCC(F)(F)F)nc1)N1Cc2c(ccnc2Cl)C1=O
Yield: 51 %

Procedure:
The title compound is prepared in 51% yield (112 mg, yellow oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propan-1-amine hydrochloride (154 mg, 0.57 mmol, Amine-18, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [NH:1]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C@H:2]([C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])[CH:3]([CH3:5])[CH3:4].C=O.O.[C:33]1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:4][CH:3]([CH3:5])[CH:2]([NH:1][C:20](=[O:21])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:6]([N:8]1[CH:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17](=[O:19])[O:18][CH2:33]1)=[O:7]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C=O
Solvent: c1ccccc1
Solvent: O
Product: CC(C)C(NC(=O)OCc1ccccc1)C(=O)N1COC(=O)C1Cc1ccccc1
Temperature: 25 °C
Yield: 187.4 %

Procedure:
Cbz-Val-Phe-OH (4.67 g, 11.7 mmol, obtained from Sigma Chemical Company, St. Louis, Mo. 63178) is combined with paraformaldehyde (5 g) and p-toluenesulfonic acid monohydrate (500 mg, 2.6 mmol) in benzene (120 mL). The reaction is heated at reflux for 23 hours with continuous removal of water with a Dean-Stark trap. The reaction then cooled to room temperature and concentrated under vacuum. The residue is dissolved in ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (60 ) is added with mixing. The layers are then separated and the aqueous layer is extracted with ethyl acetate (2×50 mL). The organic layer and organic extracts are combined and dried over anhydrous magnesium sulfate, passed through a short pad of silica gel and the filtrate is concentrated under vacuum. The residue is then purified by flash chromatography (hexane/ethyl acetate, 95:5 to 90:10 to 80:20, silica gel) to provide [S-(R*,R*)]-[2-methyl-1-[[5-oxo-4-(phenylmethyl)-3-oxazolidinyl]carbonyl]propyl]-carbamic acid, phenylmethyl ester (2.00 g, 42%) as a foam; [α]20D +113.95 (c 0.55, CHCl3); IR (CHCl3) 3314, 3032, 2934, 1804, 1714, 1659, 1437, 1233 cm-1 ; MS m/z 411 (M+H+), 367, 268, 234, 206, 178, 162, 91.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[O:12][C:13]1[C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=[C:15]([S:22][CH3:23])[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(CN)=CC=1.CN(C(O[N:45]1N=N[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][C:46]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CC#N.CCOC(C)=O.CCCCCC>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:26]=[CH:25][CH:24]=[C:11]([O:12][C:13]2[C:18]([C:19](=[O:21])[NH:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[CH:17][N:16]=[C:15]([S:22][CH3:23])[N:14]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CSc1ncc(C(=O)O)c(Oc2cccc(NC(=O)OC(C)(C)C)c2)n1
Agent: COc1ccc(CN)cc1
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CSc1ncc(C(=O)Nc2ccccc2)c(Oc2cccc(NC(=O)OC(C)(C)C)c2)n1
Reaction time: 8 h

Procedure:
Acid 4 was directly mixed with 4-methoxybenzylamine (1.55 g, 11.3 mmol), TBTU (5.4 g, 16.8 mmol) and DIEA (2.4 mL, 13.4 mmol) in 100 mL MeCN at room temperature. The reaction mixture was run overnight to give 6 as a white solid (4.2 g, 8.5 mmol) after flash chromatography (EtOAc-hexane).
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[O:8]1[C:12]2([CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[O:11][CH2:10][CH2:9]1.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC.C(#N)C>[O:8]1[C:12]2([CH2:17][CH2:16][C:15](=[N:7][S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[CH2:14][CH2:13]2)[O:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Ti+4]
Agent: CC[O-]
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)S(=O)N=C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.1 %

Procedure:
To a stirred solution of (S)-(−)-2-methyl-2-propanesulfinamide (854 mg, 7 mmol) and 1,4-dioxaspiro[4,5]decan-8-one (1 g, 6.40 mmol) in tetrahydrofuran (13 mL) was added titanium(IV) ethoxide (5.11 mL, 16 mmol). The mixture was stirred for 4 h at room temperature, poured over stirring saturated aqueous sodium bicarbonate (10 mL) and acetonitrile (10 mL), and stirred for 20 minutes. Magnesium sulfate was added and the mixture was stirred for 20 minutes, filtered over celite and concentrated. The residue was purified by column chromatography on silica gel (10:90 to 70:30 ethyl acetate:hexanes gradient) to afford N-(1,4-dioxaspiro[4.5]dec-8-ylidene)-2-methylpropane-2-sulfinamide (466 mg, 1.8 mmol, 28% yield) as a white solid. MS ESI: [M+H]+ m/z 260.