Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1)([CH3:4])[CH3:3].N1C=CN=C1.[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22].S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[C:21]([Si:24]([CH3:26])([CH3:25])[O:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]#[C:5][Si:2]([CH3:3])([CH3:4])[CH3:1])=[CH:12][CH:11]=1)([CH3:23])([CH3:22])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[Si](C)(C)C#Cc1ccc(CO)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C#C[Si](C)(C)C)cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 95.2 %

Procedure:
Under argon condition, (4-((trimethylsilyl)ethynyl)phenyl) methanol (258 mg, 1.26 mmol) was dissolved in 5 mL of dry THF and then cooled to 0° C., and imidazole (103 mg, 1.52 mmol) and TBSCl (228 mg, 1.52 mmol) dissolved in 3 mL of dry THF were added thereto. Thereafter, the temperature was raised to room temperature, and the reaction mixture was stirred for 15 hours at room temperature. Upon completion of the reaction, the reaction was terminated by adding 10 mL of aqueous saturated ammonium chloride solution. The reaction mixture was extracted with ethyl acetate (10 mL×4), and the organic layer thus obtained was treated with anhydrous magnesium sulfate to remove water. The precipitate was filtered out and the resulting solution was concentrated by distillation under reduced pressure, and purified by column chromatography to obtain 383 mg (1.20 mmol, 95%) of the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([OH:11])[CH:3]=1.[Cl-].[C:13]([C:15]1[N:19]([CH3:20])[N:18]=[C:17]([CH2:21][NH2+:22][CH3:23])[CH:16]=1)#[N:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:13]([C:15]1[N:19]([CH3:20])[N:18]=[C:17]([CH2:21][N:22]([CH3:23])[C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=2[OH:11])[CH:16]=1)#[N:14]
Reactant: O=C(O)c1ccc(F)cc1O
Reactant: C[NH2+]Cc1cc(C#N)n(C)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1cc(C#N)n(C)n1)C(=O)c1ccc(F)cc1O
Temperature: 25 °C
Reaction time: 14 h
Yield: 40.1 %

Procedure:
To a solution of 4-fluoro-2-hydroxybenzoic acid 136 (500 mg, 3.2 mmol), (5-cyano-1-methyl-1H-pyrazol-3-yl)-N-methylmethanaminium chloride 137 (600 mg, 3.2 mmol), and HATU (1.4 g, 3.5 mmol) in DMF (21 mL) was added DIEA (2.8 mL, 16 mmol). After stirring at room temperature for 14 hours, the solution was concentrated and purified by column chromatography over silica gel eluting with heptane/ethyl acetate(0-75%) to afford compound 138 (370 mg, 40%) as a semi-solid. 1H NMR (400 MHz, 80° C., DMSO-d6) δ 10.08 (s, 1 H) 7.19 (m, 1 H) 6.94 (s, 1 H) 6.70-6.59 (m, 2 H) 4.52 (s, 2 H) 3.98 (d, J=0.8 Hz, 3 H) 2.86 (s, 3 H). LCMS APCI m/z 298 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[C:5]([N+:19]([O-])=O)[CH:4]=1>C(O)C.O1CCCC1.[Ni]>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[O:7][CH2:8][CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:19][C:5]=2[CH:4]=1
Reactant: COc1ccc(OCC(=O)c2ccccc2)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)NC(c1ccccc1)CO2
Reaction time: 48 h

Procedure:
The compound obtained in Step A (3 g; 10.44 mmol) is dissolved in a Parr reactor with an ethanol/tetrahydrofuran mixture (1/1). Raney nickel (30% by weight, 900 mg) is then added. The mixture is left for 48 hours at 50° C. under a hydrogen pressure of 50 psi. After returning to ambient temperature, the solution is filtered over Celite and the filtrate is evaporated. The crude reaction product is purified by flash chromatography on silica gel (eluant: PE/AcOEt (85/15)). The title product is obtained in the form of a yellow solid.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:22][C:20]([F:21])([F:23])[C:17]1[CH:18]=[CH:19][C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)=[N:15][CH:16]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1ccc(C(F)(F)F)cn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2ccc(C(F)(F)F)cn2)sc2ccccc12
Yield: 22.5 %

Procedure:
A mixture of methyl thiosalicylate (0.43 g, 2.6 mmol), 2-cyano-5-trifluoromethylpyridine (0.44 g, 2.6 mmol), triethylamine (0.60 ml, 3.8 mmol) and toluene (30 ml) was refluxed for 48 hrs as described in Example 1. The solvent was concentrated under reduced pressure. The residue was recrystallized from ethanol to give the titled compound (0.18 g, 23%) as crystals.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH:8]([CH3:10])[CH3:9])[C:4]([O:6][CH3:7])=[O:5].[C:11](=[O:14])(O)[O-:12].[Na+]>C1COCC1.CO>[C:8]([O:12][C:11]([NH:2][C@H:3]([CH:8]([CH3:10])[CH3:9])[C:4]([O:6][CH3:7])=[O:5])=[O:14])([CH3:10])([CH3:9])[CH3:3]
Reactant: COC(=O)[C@H](N)C(C)C
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 190.8 %

Procedure:
(R)-methyl 2-amino-3-methylbutanoate hydrochloride (4.0 g, 23.86 mmol) was dissolved in THF (60 mL) and methanol (15 mL). The colorless solution was chilled to 0° C., followed by the addition of sodium bicarbonate (6.01 g, 71.6 mmol) in one portion, immediately followed by addition of solid BOC-anhydride (7.81 g, 35.8 mmol). The reaction mixture was allowed to warm to ambient temperature and left stirring overnight, quenched with 200 mL water, and extracted twice with 200 mL MTBE. The organic phase was washed with 200 mL saturated NaHCO3 solution and 200 mL brine, dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on a Grace Reveleris 120 g column, eluted with 0-30% EtOAc in Hexanes (35 mL/min) to obtain the title compound (5.265 g, 22.76 mmol, 95% yield) as a colorless oil. MS (DCI+) m/z 249.2 (M+NH4); 1H NMR (300 MHz, DMSO-d6) δ 7.15 (d, J=8.1, 1H), 3.83 (dd, J=8.0, 6.8, 1H), 3.62 (s, 3H), 2.06-1.91 (m, 1H), 1.38 (s, 9H), 0.86 (dd, J=6.8, 3.2, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH3:17][O:18][C:19]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:19]=2[O:18][CH3:17])[N:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(Cl)nc3c2ncn3C2CCCC2)c(OC)c1

Procedure:
2-Chloro-6-[(2,4-dimethoxybenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2,4-dimethoxybenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:12][C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CO.CC(C)=O>[CH2:17]([O:16][C:14](=[O:15])[C:13](=[O:19])[CH2:12][S:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1)[CH3:18]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Sc1nc2ccccc2[nH]1
Solvent: CO
Solvent: CC(C)=O
Product: CCOC(=O)C(=O)CSc1nc2ccccc2[nH]1
Yield: 92.7 %

Procedure:
A solution of 2-mercaptobenzimidazole (200 mg, 1.33 mmol) and ethyl 3-bromopyruvate (0.20 mL, 1.43 mmol) in methanol (2.5 mL) and acetone (2 mL) was shaken at 20° C. for 4 hours. The solvents were removed under the reduced pressure on a rotary evaporator. The residue was triturated with ethyl acetate. Solvent was decanted and the residue was dissolved in methylene chloride. The solution was washed with diluted aqueous sodium bicarbonate solution and water, and then dried over magnesium sulfate. Removal of the solvent gave the expected product, 3-(1H-Benzoimidazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester (326 mg, 93%). 1H-NMR (CDCl3, 300 MHz) δ (ppm): 7.31 (br. s, 1H), 7.24 (br. s, 1H), 7.15-7.05 (m, 2H), 4.32 (q, J=7.1 Hz, 2H), 4.29 br. s, 1H), 3.90 (br. s, 1H), 1.24 (t, J=7.1 Hz, 3H). MS (ESI): m/z 265 (M+1, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH:11]=O)[S:10][C:3]=12.[NH2:13][OH:14].Cl>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH:11]=[N:13][OH:14])[S:10][C:3]=12
Reactant: O=Cc1cc2nccc(Cl)c2s1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CO
Product: ON=Cc1cc2nccc(Cl)c2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of aldehyde 14 (scheme 3) in MeOH was added NH2OH×HCl (227 mg, 3.26 mmol) in water (0.5 mL) and the mixture was stirred at room temperature for 0.5 h. The solvents were removed by under reduced pressure and the residue was partitioned between EtOAc and water. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness to afford the title compound 125 (458 mg, 85% yield) as a white solid. MS (m/z) 213.1/215.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=O)=O)[CH:6]=[CH:7][CH:8]=1.[NH:21]([C:25]1[NH:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=1)[C:22]([NH2:24])=[NH:23].[OH-].[Na+]>CO.O>[N:29]1[C:28]2[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=2[NH:26][C:25]=1[N:21]=[C:22]1[NH:24][C:9]2([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:24][C:22](=[N:21][C:25]3[NH:29][C:28]4[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=4[N:26]=3)[NH:23][C:11]2([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[NH:23]1
Reactant: N=C(N)Nc1nc2ccccc2[nH]1
Reactant: COc1cccc(C(=O)C(=O)c2cccc(OC)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cccc(C23NC(=Nc4nc5ccccc5[nH]4)NC2(c2cccc(OC)c2)NC(=Nc2nc4ccccc4[nH]2)N3)c1

Procedure:
Following the procedure of Example 1, 3,3'-dimethoxybenzil (1.0 g, 3.69 mmol) and 2-guanidinobenzimidazole (540 mg, 3.08 mmol) in methanol (40 mL) was treated with a solution of sodium hydroxide (200 mg, 5 mmol) in 5 mL of water. The title compound was isolated as pale yellow crystals (655 mg, 73% yield). mp: 276-278 ° C. (dec);MS (ESI) m/z 585 [M+H]+.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([Mg]Br)=[CH:3][CH:2]=1.[C:10]1([P:16]([O-])[O:17]CC)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.S(=O)(=O)(O)O>CCOCC>[C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([PH2:16]=[O:17])=[CH:11][CH:12]=1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: CCOP([O-])c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: Cc1ccccc1-c1ccc([PH2]=O)cc1
Yield: 80.9 %

Procedure:
A solution of p-tolylmagnesium bromide [prepared from p-bromotoluene (29.1 g, 0.16 mol) and magnesium (4.38 g, 0.18 g-atom)] in ether (100 mL) was treated with a solution of ethyl phenylphosphonite (13,6 g, 0.08 mol) in ether (50 mL) with vigorous mechanical stirring. The mixture was heated at reflux for 1/2 hr., then 100 mL of 25% sulfuric acid was added cautiously. Three layers formed; the bottom (aqueous) layer was extracted with toluene. Addition of NaHCO3 to the combined upper layers produced a vigorous reaction and a single organic phase. The organic phase was washed with water and with saturated NaCl, dried and evaporated to give an oil (14 g). Kugelrohr distillation at 120°-160° C. (0.1 mmHg) followed by chromatography on silica gel (CHCl3), then 10% MeOH--CHCl3) gave 7.1 g of an oil. This was distilled in the Kugelrohr again (150° C., 0.1 mmHg) to give 6.2 g of product which appears to be pure by NMR and crystallized on standing. 1H NMR (CDCl3) δ8.0-7.2 (m, 9H), 8.08 (d, J=480 Hz, 1H), 2.42 (s, 3H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[N:13][N:12]=3)[CH:9]=2)[N:4]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:3]=1.[Cl:30][C:31]1[N:36]=[C:35]([Sn](CCCC)(CCCC)CCCC)[CH:34]=[CH:33][N:32]=1>CN(C=O)C.C(Cl)Cl.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.[Cu]I>[Cl:30][C:31]1[N:36]=[C:35]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[O:15][C:14]([NH:16][CH:17]([CH3:18])[CH3:19])=[N:13][N:12]=4)[CH:9]=3)[N:4]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=3)(=[O:22])=[O:21])[CH:3]=2)[CH:34]=[CH:33][N:32]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(Cl)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccnc(Cl)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Temperature: 100 °C
Yield: 69 %

Procedure:
A glass microwave reaction vessel was charged with 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (1.00 g, 1.914 mmol) and 2-chloro-4-(tributylstannyl)pyrimidine (0.966 g, 2.393 mmol) in DMF (5 mL) followed by tetrakis(triphenylphosphine)palladium (0.111 g, 0.096 mmol) and CuI (0.016 mL, 0.479 mmol). The reaction mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 1 h. The mixture was diluted with DCM and washed with water (3×50 mL) and brine. The organic layer was dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 5-40% EtOAc in Hexanes) to give 5-(3-(2-chloropyrimidin-4-yl)-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (672 mg, 1.320 mmol, 69.0% yield) as a brown solid. MS (ESI, pos. ion) m/z: 509.0 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.Cl[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][O:33][CH2:34][CH3:35])=[CH:28][N:27]=1>>[CH2:34]([O:33][CH2:32][C:29]1[CH:30]=[CH:31][C:26]([N:7]2[C:8]3[C:13](=[CH:12][C:11]([C:15]4[CH:16]=[CH:17][C:18]([O:21][CH:22]([CH3:23])[CH3:24])=[CH:19][CH:20]=4)=[CH:10][CH:9]=3)[CH:14]=[C:6]2[C:4]([OH:3])=[O:5])=[N:27][CH:28]=1)[CH3:35]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(OC(C)C)cc3)ccc2[nH]1
Reactant: CCOCc1ccc(Cl)nc1
Product: CCOCc1ccc(-n2c(C(=O)O)cc3cc(-c4ccc(OC(C)C)cc4)ccc32)nc1

Procedure:
The title compound was prepared in accordance with Example 10 using 5-(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester and 2-chloro-5-(ethoxymethyl)pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][C:10]=2[CH3:18])=[CH:5][C:4]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=1[CH2:29][N:30]1[C@@H:34]([CH3:35])[C@@H:33]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)[O:32][C:31]1=[O:43].C(Cl)(=O)C(Cl)=O.[OH-].[NH4+].C([N:55](C(C)C)CC)(C)C>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([NH2:55])=[O:17])=[CH:11][C:10]=2[CH3:18])=[CH:5][C:4]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][C:20]=1[CH2:29][N:30]1[C@@H:34]([CH3:35])[C@@H:33]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)[O:32][C:31]1=[O:43]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2ccnc(C)c2)[C@@H]1C
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(-c2ccc(C(N)=O)cc2C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2ccnc(C)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4′-methoxy-2-methyl-2″-{[(4S,5R)-4-methyl-5-(2-methylpyridin-4-yl)-2-oxo-1,3-oxazolidin-3-yl]methyl}-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid (15 mg, 0.025 mmol) in CH2Cl2 (2 mL), was added 2M oxalyl chloride in CH2Cl2 (0.038 mL, 0.076 mmol) and 2 drops of DMF. The mixture was stirred at room temperature under N2 for 30 min. The reaction mixture was concentrated in vacuo. The residue was re-dissolved in THF (2 mL), then ammonium hydroxide (0.035 mL, 0.254 mmol) and diisopropylethylamine (0.013 mL, 0.076 mmol) were added. The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC reverse phase (C-18), eluting with MeCN/water. The fractions were collected and lyophilized to give 4′-methoxy-2-methyl-2″-{[(4S,5R)-4-methyl-5-(2-methylpyridin-4-yl)-2-oxo-1,3-oxazolidin-3-yl]methyl}-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxamide as a white powder. LCMS calc.=590.2; found=590.0 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers) δ 8.49 (t, J=4.3 Hz, 1H); 7.77 (br s, 1H); 7.72 (s, 0.5H); 7.66 (br s, 1.5H); 7.46-7.38 (m, 3H); 7.33-7.29 (m, 1H); 7.14 (dd, J=2.2, 7.7 Hz, 1H); 7.09 (dd, J=6.2, 8.5 Hz, 1H); 7.06 (s, 0.5H); 7.01 (s, 0.5H); 6.95 (d, J=4.3 Hz, 0.5H); 6.90 (d, J=4.4 Hz, 0.5H); 6.17 (br s, 1H); 5.79 (br s, 1H); 5.43 (d, J=8.1 Hz, 0.5H); 5.20 (d, J=8.0 Hz, 0.5H); 4.92 (d, J=15.9 Hz, 0.5H); 4.86 (d, J=15.8 Hz, 0.5H); 4.22 (d, J=15.8 Hz, 0.5H); 4.00 (d, J=15.8 Hz, 0.5H); 3.88 (s, 1.5H); 3.87 (s, 1.5H); 3.80-3.75 (m, 1H); 2.57 (s, 1.5H); 2.56 (s, 1.5H); 2.39 (s, 1.5H); 2.35 (s, 1.5H); 0.58 (d, J=6.5 Hz, 1.5H); 0.47 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.Cl.[OH:18][NH3+:19].O>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:19][OH:18])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: [NH3+]O
Agent: Cl
Solvent: CCO
Solvent: O
Product: ON=C(Cn1cncn1)c1ccc(Cl)cc1Cl
Yield: 42.8 %

Procedure:
106.8 g (0.44 mole) of 1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-1-ethanone are dissolved in 780 ml of ethanol, 48 g of hydroxylammonium hydrochloride are added and the mixture is heated under reflux for 5 hours. 1,000 ml of water are then added to the reaction mixture, and the mixture is filtered. 51 g (45% of theory) of 1-(2,4-dichlorophenyl)-1-oximino-2-(1,2,4-triazol-1-yl)-ethane of melting point 165°-170° C. are obtained. ##STR8##
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[O:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][NH2:28])[CH2:22][CH2:21]1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:28][CH2:27][CH2:26][CH:23]2[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2F)cn1
Reactant: NCCC1CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1cnc(Oc2ccc(CNCCC3CCOCC3)cc2F)cn1
Reaction time: 8 h
Yield: 67.2 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737, Part E) (0.400 g, 1.53 mmol), 2-(tetrahydropyran-4-yl)ethylamine (0.217 g, 1.68 mmol) and 3 Å molecular sieves in a vial. Add methanol (7.7 mL), cap and stir overnight. Add NaBH4 (0.058 g, 1.53 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 30% (2.0 M NH3 in methanol) in 80% (ethyl acetate in hexanes) to give the title compound (0.385 g, 67%): TOF MS ES+ 375.2 (M+H)+, HRMS calcd for C19H24N4O3F 375.1832 (M+H)+, found 375.1847, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR 8.6 min, 95.4% purity.
Reaction SMILES: [CH2:1]([C:8]1[NH:16][C:15]2[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=3)[C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.[H][H]>[Pd]>[NH2:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][CH2:22][N:11]2[C:10]3[N:9]=[C:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[NH:16][C:15]=3[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12]2=[O:21])=[CH:29][CH:28]=1
Reactant: CCCn1c(=O)c2[nH]c(Cc3ccccc3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Reactant: [H][H]
Agent: [Pd]
Agent: NN
Solvent: O
Product: CCCn1c(=O)c2[nH]c(Cc3ccccc3)nc2n(CCc2ccc(N)cc2)c1=O

Procedure:
By methods well known in the art, 8-benzyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine (9) is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-8-benzyl-1-propylxanthine.
Reaction SMILES: [C:1]([O:6][CH:7]([O:9][C:10]([NH:12][CH2:13][C:14]1([CH2:20][C:21]([O:23]CC2C=CC=CC=2)=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:6][CH:7]([O:9][C:10]([NH:12][CH2:13][C:14]1([CH2:20][C:21]([OH:23])=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(OC(=O)NCC1(CC(=O)OCc2ccccc2)CCCCC1)OC(=O)C(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(OC(=O)NCC1(CC(=O)O)CCCCC1)OC(=O)C(C)C

Procedure:
Compound (10) (113 g) was dissolved in ethyl acetate (700 mL) and 10 g of 10% Pd-C was added. The reaction mixture was subjected to 50 psi of hydrogen gas in a Parr reactor for 40 min. Filtration through a sintered glass funnel and a hydrophobic membrane filtration cartridge (Millipore Opticap) removed the catalyst. The supernatant was concentrated to afford the product (11) as a white, crystalline solid (78 g, quantitative yield). Crystals formed in the freezer, then at room temperature over several days. 1H NMR (CDCl3, 400 MHz): 1.15 (d, 6H), 1.40–1.55 (m, 10H), 1.45 (d, 3H), 2.32 (s, 2H), 2.49–2.56 (m, 1H), 3.23 (d, 2H), 5.41 (t, 1H), 6.75 (q, 1H). MS(ESI) m/z 330.29 (M+H+).
Reaction SMILES: CN1C2C(C(F)(F)F)=CC(NC3C=NC=CC=3)=CC=2C2CNCCC12.[CH3:26][N:27]1[C:35]2[C:30](=[CH:31][C:32]([NH:38][C:39]3[CH:40]=[N:41][CH:42]=[CH:43][C:44]=3C(F)(F)F)=[CH:33][C:34]=2[C:36]#[N:37])[C@@H:29]2[CH2:49][NH:50][CH2:51][CH2:52][C@H:28]12.BrC1C([O:60][CH:61]([CH3:63])[CH3:62])=NC=CC=1.CC([O-])(C)C.[Na+]>>[CH:61]([O:60][C:40]1[C:39]([NH:38][C:32]2[CH:31]=[C:30]3[C:35](=[C:34]([C:36]#[N:37])[CH:33]=2)[N:27]([CH3:26])[C@H:28]2[CH2:52][CH2:51][NH:50][CH2:49][C@@H:29]32)=[CH:44][CH:43]=[CH:42][N:41]=1)([CH3:63])[CH3:62]
Reactant: CN1c2c(C#N)cc(Nc3cnccc3C(F)(F)F)cc2[C@@H]2CNCC[C@@H]21
Reactant: CC(C)Oc1ncccc1Br
Agent: CC(C)(C)[O-]
Agent: CN1c2c(cc(Nc3cccnc3)cc2C(F)(F)F)C2CNCCC21
Agent: [Na+]
Product: CC(C)Oc1ncccc1Nc1cc(C#N)c2c(c1)[C@@H]1CNCC[C@@H]1N2C

Procedure:
The title compound was prepared by following the general method for (5-methyl-6-trifluoromethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indol-8-yl)-pyridin-3-yl-amine (Method B) as a tan solid (32 mg, 21%) from (4aS,9bR)-8-amino-6-cyano-3,4,4a,9b-tetrahydro-1H-pyrido[4,3-b]indole-2,5-dicarboxylic acid tert-butyl ester (Example 162, 150 mg, 0.46 mmol), 3-bromo-2-iso-propoxypyridine (91 mg, 0.42 mmol) and NaOt-Bu (66 mg, 0.69 mmol). 1H NMR (300 MHz, CDCl3) δ 7.58 (dd, J=5.0, 1.4 Hz, 1H), 7.18–6.97 (m, 3H), 6.71 (dd, J=7.6, 5.0 Hz, 1H), 5.83 (br s, 1H), 5.41 (sept, J=6.2 Hz, 1H), 3.53–3.48 (m, 1H), 3.33–3.01 (m, 4H), 2.99–2.80 (m, 2H), 2.79–2.61 (m, 1H), 2.59–2.01 (m, 1H), 2.00–1.80 (m, 2H), 1.39 (d, J=6.2 Hz, 6H); APCI MS m/z 364 [C21H25N5O+H]+.