Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([N:13]1[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][S:2]([O:18][C@H:15]1[CH2:16][CH2:17][N:13]([CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:14]1)(=[O:4])=[O:3]
Reactant: O[C@H]1CCN(Cc2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CS(=O)(=O)O[C@H]1CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Methanesulfonyl chloride (15 mL, 0.19 mol) is added to a cooled (0° C.) solution of toluene (300 mL) containing (S)-1-benzylpyrrolidin-3-ol (24.5 g, 0.14 mol) and triethylamine (80 mL, 0.57 mol). The resulting mixture is stirred at 0° C. for 15 min, and allowed to warm to room temperature with stirring for 2 h. The mixture is quenched with a 5% aqueous solution of sodium bicarbonate (250 mL). The organic layer is washed with a 5% aqueous solution of sodium bicarbonate (2×250 mL), washed with water (1×250 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give N (35.1 g, 99%) as an orange oil. 1H NMR (300 MHz, CDCl3): δ2.07 (m, 1H), 2.30 (m, 1H), 2.49 (m, 1H), 2.75-2.90 (m, 3H), 2.98 (s, 3H), 3.61 (d, J=13.0 Hz, 1H), 3.68 (d, J=13.0 Hz, 1H), 5.18 (m, 1H), 7.15-7.30 (m, 5H). LCMS m/z calcd for C12H17NO3S 255 ([M+]); found 256 ([M+H]+, 100%), 160 (40%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=4)[NH:27][N:26]=3)=[CH:23][N:24]=[C:19]2[N:18]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:17]=1)=[O:15])([CH3:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[CH2:55][CH2:56][C:57](=[O:59])[CH3:58].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Si:1]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=4)[N:27]([CH2:55][CH2:56][C:57](=[O:59])[CH3:58])[N:26]=3)=[CH:23][N:24]=[C:19]2[N:18]([C:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:17]=1)=[O:15])([CH3:11])[CH3:12])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Reactant: CC(=O)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)CCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(F)cc21
Temperature: 65 °C
Yield: 60.6 %

Procedure:
To a solution of N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-fluoro-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (60 mg, 0.083 mmol) in DMF (4 mL) was added 4-chlorobutan-2-one (11 mg, 0.1 mmol) followed by K2CO3 (34 mg, 0.25 mmol). The mixture was heated at 65° C. for 1.5 hours. After cooling to room temperature, the mixture was poured into water and filtered to give N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-fluoro-1-(3-oxobutyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (40 mg, 61%). After drying, the crude was used into the next step without further purification. LCMS: (M+H)+=795.
Reaction SMILES: Cl.FC1C=CC2NC3C=CC(C)=CC=3C(N)=NC=2C=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]2[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:32][C:29]=2[C:30]#[N:31])=[C:23]([N+:39]([O-])=O)[CH:22]=1.[Sn](Cl)[Cl:43]>>[ClH:43].[F:20][C:21]1[CH:26]=[CH:25][C:24]2[NH:27][C:28]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:32][C:29]=3[C:30]([NH2:31])=[N:39][C:23]=2[CH:22]=1
Reactant: Cl[Sn]Cl
Reactant: CC(C)c1ccc(Nc2ccc(F)cc2[N+](=O)[O-])c(C#N)c1
Agent: Cc1ccc2c(c1)C(N)=Nc1cc(F)ccc1N2
Agent: Cl
Product: CC(C)c1ccc2c(c1)C(N)=Nc1cc(F)ccc1N2
Yield: 73.8 %

Procedure:
Using a similar procedure as found for 8-fluoro-2-methyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride, using 2-(4-fluoro-2-nitro-phenylamino)-5-isopropyl-benzonitrile (0.559 g, 1.87 mmol), tin (II) chloride(1.06 g, 5.60 mmol) to obtain the title compound (0.422 g, 1.38 mmol, 74% yield) as a yellow amorphous solid: Mass Spectrum (m/e): 270(M+1).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][C:14]=1[F:21]>C1COCC1>[Si:1]([O:8][CH2:9][CH:10]([C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[C:14]([F:21])[CH:15]=1)[OH:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Fc1cc([Mg]Br)ccc1Cl
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC(O)c1ccc(Cl)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A solution of 2-(tert-butyldimethylsilyloxy)acetaldehyde (2.00 g, 10.3 mmol) in dry THF (40 mL) was placed in an ice bath, and (4-chloro-3-fluorophenyl)magnesium bromide (24.8 mL, 12.4 mmol) was added dropwise via a syringe. The reaction mixture was stirred at 0° C. for 1 hour and then carefully quenched by dropwise addition of water. The reaction mixture was concentrated, and the residue was partitioned between EtOAc and saturated aqueous NH4Cl. The organics were dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with hexanes/EtOAc (20:1) to give 2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanol (2.92 g, 9.58 mmol, 92.8% yield) as an oil.
Reaction SMILES: C=O.N[CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:5]1([CH3:18])[CH3:17].[C:19]([BH3-])#[N:20].[Na+].[C:23](O)(=O)C>CO>[CH2:10]([N:7]1[CH2:8][CH2:9][CH:4]([N:20]([CH3:19])[CH3:23])[C:5]([CH3:18])([CH3:17])[CH2:6]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC1(C)CN(Cc2ccccc2)CCC1N
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN(C)C1CCN(Cc2ccccc2)CC1(C)C
Reaction time: 24 h

Procedure:
Formaldehyde solution (47%, 10 g) was added to the stirred solution of 4-amino-1-benzyl-3,3-dimethylpiperidine (2.0 g, 9.2 mmol) in methanol (20 ml) at 0° C. and sodium cyanoborohydride (0.5 g, 9.2 mmol) was added to it. Then, acetic acid (2 ml) was added to the resulting mixture and stirring was continued for 24 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to give 1-benzyl-4-dimethylamino-3,3-dimethylpiperidine. Yield 1.9 g (84%), C16H26N2, m/z 247 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](O)[N:5]2[CH:9]=[CH:10][N:11]=[C:4]2[CH:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:6]1[N:5]2[CH:9]=[CH:10][N:11]=[C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: Oc1nc(Cl)cc2nccn12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cc2nccn2c(Cl)n1
Temperature: 120 °C

Procedure:
38.3 g (225.86 mmol) of 7-chloroimidazo[1,2-c]pyrimidin-5-ol are suspended in 450.2 g (2936 mmol) of phosphoryl chloride under argon and heated at 120° C. for 4 h. After this time, the excess phosphoryl chloride is removed in vacuo, and the residue is distilled together with toluene. The residue is suspended in water, the pH is brought to 7 with saturated aqueous sodium bicarbonate solution, and the precipitated solid is filtered off with suction. The latter is washed with water and dried over phosphorus pentoxide for 18 h. 33.5 g (67% of theory) of the product are obtained as a solid.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH:47]3[CH2:51][CH2:50][CH2:49][C@H:48]3[OH:52])=[CH:42][CH:41]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:26]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1)[CH3:14]>O>[CH2:13]([C:15]1[N:16]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH:47]3[CH2:51][CH2:50][CH2:49][C@H:48]3[OH:52])=[CH:42][CH:41]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:3][C:4](=[O:7])[O:5][N:38]=3)=[CH:29][CH:30]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1)[CH3:14]
Reactant: CCCc1nc(CC)n(-c2ccc(OC3CCC[C@H]3O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(CC)n(-c2ccc(OC3CCC[C@H]3O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 44.3 %

Procedure:
A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogen carbonate (1.9 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[2-ethyl-1-(4-{[(2R)-2-hydroxycyclopentyl]oxy}phenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.59 g) was added, and the mixture was stirred at 90° C. for 24 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.18 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.17 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.29 g, 44%).
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][O:3]1)=O.[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCCCCC.C(OCC)(=O)C>[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:1][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:3])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCCCCc1ccccc1
Reactant: O=C1OCc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1c2ccccc2CN1CCCCc1ccccc1
Temperature: 150 °C
Reaction time: 16 h
Yield: 10.4 %

Procedure:
A mixture of phthalide (0.268 g, 2 mmol) and 4-phenyl-butylamine (0.316 mL, 2 mmol) was stirred at 150° C. for 16 h. Workup and silica gel column chromatography (2:1 hexane-ethyl acetate) afforded 2-(4-phenyl-butyl)-2,3-dihydro-isoindol-1-one (0.055 g, 11%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.70 (m, 4H), 2.71 (t, 2H), 3.66 (t, 2H), 4.31 (s, 2H), 7.14-7.56 (m, 8H), 7.82 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.[Br:15][C:16]1[C:17](F)=[C:18]2[C:24]([NH:25][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][NH:22][C:19]2=[N:20][CH:21]=1.CC#N.O>CCCCO>[C:26]([NH:25][C:24]1[C:18]2[C:19](=[N:20][CH:21]=[C:16]([Br:15])[C:17]=2[N:1]2[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]2)[NH:22][CH:23]=1)(=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CC#N
Solvent: CCCCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4ccccc4)c23)C1
Temperature: 160 °C
Reaction time: 24 h
Yield: 43.9 %

Procedure:
(R)-tert-Butyl piperidin-3-ylcarbamate (162 mg, 0.81 mmol) was added to N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (90 mg, 0.27 mmol, Example 7, Step A) in n-BuOH (3 mL), and the reaction was stirred at 160° C. for 24 hours in a sealed tube. The reaction was concentrated to dryness. The residue was then purified by chromatography (SP4, C-18 25M+column, 10-90% CH3CN/water gradient, 30 CV) to yield (R)-tert-butyl 1-(3-benzamido-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (61 mg, 44% yield) as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[C:12]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[OH-].[NH4+]>[NH2:22][C:21]1[CH:20]=[CH:19][C:11]([C:12]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(=O)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: [NH4+]
Agent: [OH-]
Product: Nc1ccc(C(=O)CCC(=O)O)cc1OCc1ccccc1

Procedure:
A solution of 3-(3-benzyloxy-4-nitrobenzoyl) propionic acid in 5N ammonium hydroxide was added to a well stirred boiling aqueous solution of ferrous sulphate. The pH was adjusted to 9 with concentrated ammonium hydroxide and the mixture was refluxed for 15 minutes. The filtrate was concentrated under reduced pressure and then neutralised with glacial acetic acid to give 3-(4-amino-3-benzyloxybenzoyl)propionic acid.
Reaction SMILES: [CH3:1][O:2][SiH](OC)OC.C(C1C(C(C)C)=C(C(C)C)C=CC=1)(C)C.[CH3:23][O:24][Si:25]([O:37][CH3:38])([O:35][CH3:36])[CH2:26][CH2:27][Si:28]([O:33][CH3:34])([O:31][CH3:32])[O:29][CH3:30]>>[CH:26]([Si:25]([O:37][CH3:38])([O:35][CH3:36])[O:24][CH3:23])=[CH2:27].[CH3:1][O:2][Si:28]([O:29][CH3:30])([O:31][CH3:32])[O:33][CH3:34]
Reactant: CO[Si](CC[Si](OC)(OC)OC)(OC)OC
Reactant: CO[SiH](OC)OC
Agent: CC(C)c1cccc(C(C)C)c1C(C)C
Product: C=C[Si](OC)(OC)OC
Product: CO[Si](OC)(OC)OC
Temperature: 120 °C
Reaction time: 1 h
Yield: 22 %
Yield: 2 %

Procedure:
A 50 ml Schlenk tube with a side arm was equipped with a Claisen adapter and stirring bar. A septum was wired to the Claisen adapter and a water condenser was also attached. Into the flask was placed 5 g (0.041 mol.) trimethoxysilane and 1 g triisopropylbenzene. To this solution was also added 30 ppm of H2PtCl6 (10 ml; 15 mg Pt/ml). The reaction mix was heated to only 120° C. in an oil bath and acetylene was bubbled into the reaction mix with a stainless steel needle at a rate of 50 cc/min with a back pressure maintained of 4-5 psig. After one hour the reaction was complete as monitored by GPC. The major product formed was 1,2-bis(trimethoxysilyl)ethane (76%). Vinyltrimethoxysilane (22%) and tetramethoxysilane (2%) were also produced.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:13](Cl)=[O:14].[CH3:22][NH2:23].O>CCOCC>[CH3:22][NH:23][C:13](=[O:14])[C:12]1[CH:16]=[CH:17][C:18]([N+:19]([O-:21])=[O:20])=[C:10]([S:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH:11]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Reactant: CN
Solvent: CCOCC
Solvent: O
Product: CNC(=O)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-(2,4-difluorophenylthio)-4-nitrobenzoyl chloride (1.2 g) in ether (8 ml) was added to a stirred mixture of 40% methylamine (2 ml), water (8 ml) and ether (5 ml) at 0° to 5° C. The mixture was stirred at the same temperature for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, dried and concentrated. The oily residue was crystallized from a mixture of ethyl acetate and hexane to give crystals of N-methyl-3-(2,4-difluorophenylthio)-4-nitrobenzamide (0.7 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([O:10][CH3:11])=[C:7]([CH:9]=1)[NH2:8].FC(F)(F)C1C=CC(OC)=C([N:22]=[C:23]=[O:24])C=1.[C:29]([C:32]1[CH:33]=[C:34]([CH:43]=[CH:44][CH:45]=1)[O:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)([OH:31])=[O:30]>>[C:29]([C:32]1[CH:33]=[C:34]([CH:43]=[CH:44][CH:45]=1)[O:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)([OH:31])=[O:30].[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([O:10][CH3:11])=[C:7]([NH:8][C:23]([NH:22][C:34]2[CH:43]=[CH:44][CH:45]=[C:32]([C:29]([OH:31])=[O:30])[CH:33]=2)=[O:24])[CH:9]=1
Reactant: COc1ccc(C(F)(F)F)cc1N=C=O
Reactant: COc1ccc(C(F)(F)F)cc1N
Agent: Nc1ccc(Oc2cccc(C(=O)O)c2)cc1
Product: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1cccc(C(=O)O)c1

Procedure:
Entry 38: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C1f to afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N′-(3-carboxyphenyl)urea, which was coupled with 5-amino-2-methoxypyridine according to Method D1c.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].Br[CH2:10][CH2:11]Br.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1([C:6]#[N:7])[CH2:11][CH2:10]1)=[O:8])[CH3:2]
Reactant: BrCCBr
Reactant: CCOC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(C#N)CC1
Temperature: 80 °C
Yield: 72 %

Procedure:
A suspension of cyano-acetic acid ethyl ester (11.3 g, 0.1 mol), 1,2-Dibromo-ethane, Na4(n-Bu)4Br and K2CO3 in DMF (100 mL) was heated to 80° C. overnight. The mixture was poured into water (600 mL) and extracted with EtOAc (3×50 mL). The combined organic layer was washed with brine, dried over Na2SO4, concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether: EtOAc=10:1˜5:1) to give 1-cyano-cyclopropanecarboxylic acid ethyl ester (10 g, yield: 72%). 1H NMR (CDCl3 400 MHz): δ4.21 (q, J=7.2 Hz, 2H), 1.65-1.61 (m, 2H), 1.58-1.55 (m, 2H), 1.28 (t, J=7.2 Hz, 3H).
Reaction SMILES: [OH-].[Na+].[C:3]1([S:9]([C:12]2[C:16](S(C3C=CC=CC=3)(=O)=O)=[N:15][O:14][N+:13]=2[O-:26])(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH:27][CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>C1COCC1>[O-:26][N+:13]1[O:14][N:15]=[C:16]([O:27][CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:12]=1[S:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)(=[O:10])=[O:11]
Reactant: CC(C)(C)OC(=O)CCO
Reactant: O=S(=O)(c1ccccc1)c1no[n+]([O-])c1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCOc1no[n+]([O-])c1S(=O)(=O)c1ccccc1
Reaction time: 2 h

Procedure:
Aqueous 50% NaOH solution (6.4 g-80 mmol) is added in the course of 15 minutes to a solution, cooled to 15° C., of 3,4-bis(phenylsulphonyl)-1,2,5-oxadiazole 2-oxide (16 g-44 mmol) and tert-butyl 3-hydroxypropionate (10 g-68 mmol) in 200 ml of anhydrous THF. After stirring for 2 hours, the solvent is removed in vacuo and the residue is taken up in 100 ml of water and 100 ml of ethyl acetate. The organic phase is decanted off, washed with saturated NaCl solution, dried with sodium sulphate and evaporated.
Reaction SMILES: [BH4-].[K+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]([OH:15])[CH2:13][S:12][C:11]2=[S:16])=[N:8][CH:9]=1.Cl>O.C(#N)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[S:16])[S:12][CH2:13][CH2:14][OH:15])=[N:8][CH:9]=1
Reactant: OC1CSC(=S)N1c1ccc(Cl)cn1
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: OCCSC(=S)Nc1ccc(Cl)cn1
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
A solution of potassium borohydride (8.35 g) in distilled water (95 cc) is added, at a maximum of 30° C., to a suspension of 3-(5-chloropyrid-2-yl)-4-hydroxythiazolidine-2-thione (38.0 g) in acetonitrile (380 cc). The reaction is allowed to proceed for 30 minutes at between 25° and 30° C. A 3 N aqueous solution of hydrochloric acid (51 cc) is added at a maximum of 20° C. The acetonitrile is evaporated off under reduced pressure (20 mm Hg) at 45° C. The resulting crystals are filtered off, washed with acetonitrile (B 15 cc) and isopropyl ether (25 cc) and then 4 times with distilled water (250 cc in total) and dried in air at 20° C. The resulting product (23.7 g; m.p.=100° C.) is suspended in chloroform (480 cc). The suspension is chromatographed on silica (0.2-0.5 mm) (240 g) contained in a column of diameter 3.8 cm. Elution is carried out with chloroform (400 cc) and then with a mixture of chloroform (1,380 cc) and methanol (35 cc), this eluate being discarded. Elution is continued with a mixture of chloroform (720 cc) and methanol (80 cc), this eluate being collected and evaporated to dryness under reduced pressure (20 mm Hg) at 45° C. The resulting crystals are washed with isopropyl ether (60 cc) and then with ice-cooled acetonitrile (10 cc) and dried under reduced pressure (0.2 mm Hg) at 45° C. 2-Hydroxyethyl 5-chloropyrid-2-yldithiocarbamate (18.5 g), which melts at 108° C., is thus obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[CH3:23][C:24]1[S:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:4]3[CH:3]=[CH:2][CH:7]=[C:6]([C:27]4[S:28][C:24]([CH3:23])=[CH:25][CH:26]=4)[CH:5]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3ccc(C)s3)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 5-methylthiophene-2-boronic acid pinacol ester (175 mg, 0.784 mmol) and K2CO3 (162 mg, 1.1 mmol) in DME-water (2:1) was added Pd(PPh3)4 (22 mg, 0.019 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(3-(5-methylthiophen-2-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) d (ppm): 7.7 (d, 1H), 7.6 (m, 2H), 7.37 (s, 1H), 7.23 (m, 2H), 7.19 (d, 1H), 7.03 (d, 1H), 6.8 (s, 1H), 4.6 (m, 2H), 3.7 (m, 2H), 3.3 (m, 1H), 3.1-3.2 (m, 4H), 2.5 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4](Cl)[N:3]=1.C(OCC)(=O)C.O.[NH:18]([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([N:18]([CH3:20])[CH3:19])[N:3]=1
Reactant: OCc1cc(Cl)nc(Cl)c1
Reactant: CNC
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)c1cc(CO)cc(Cl)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of crude (2,6-dichloropyridin-4-yl)methanol in 7 mL of (CH3)2NH (40 wt % solution in H2O) was stirred at r.t. for 45 min. The temperature was increased to 50° C., and the solution was stirred at 50° C. for about 24 h. Ethyl acetate and H2O (15 mL) were added, and the aqueous layer was extracted with EtOAc. The combined extracts were washed with brine, and the aqueous layer was extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (40% EtOAc/hexanes) provided 1.01 g of (2-chloro-6-(dimethylamino)pyridin-4-yl)methanol with some impurity (unreacted starting material).