Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5](Cl)[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>>[F:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH:23][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Nc1cccc(F)c1
Reactant: COc1ccc(C(=O)O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C(=O)O)c(Nc2cccc(F)c2)c1

Procedure:
4-methoxy-2-chloro-benzoic acid (2.0 g), potassium carbonate (1.78 g), 3-fluoroaniline (6.7 mL) and Cu powder (100 mg) were combined and heated at 125 C for 1 h. The reaction was cooled and partitioned between saturated aqueous sodium carbonate and ethyl ether. The aqueous solution was extracted once with ether, then the combined organic solutions were washed with saturated aqueous sodium carbonate (2×). The combined aqueous solutions were acidified to pH 3.5 with conc HCl and extracted with EtOAc (4×). The combined organic solutions were dried (MgSO4) and concentrated. Flash chromatography (0 to 10% MeOH in CH2Cl2) provided a solid, which was recrystallized from CH2Cl2/hexanes to give 1.9 g of 2-(3-fluoro-anilino)-4-methoxybenzoic acid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.Cl.[C:14]([OH:18])(=[O:17])[CH:15]=O.C(OCC)(=O)C>O>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][N:10]=[CH:15][C:14]([OH:18])=[O:17])=[CH:7][CH:8]=1
Reactant: NNc1ccc(C(F)(F)F)cc1
Reactant: O=CC(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)C=NNc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
4-Trifluoromethylphenyl hydrazine (4.1 g, 23 mmol) was gradually added to a solution of concentrated hydrochloric acid (5 ml) in water (120 ml). 40% aqueous solution (4.3 g, 23 mmol) of glyoxylic acid was gradually added, and stirred at room temperature for 5 hours. After leaving it overnight, the mixture was extracted with ethyl acetate. The organic phase was washed with a saturated brine, and dried on anhydrous sodium sulfate. The solvent was distilled off, and the resulting crystals were washed with hexane and a little amount of ethyl acetate to obtain (4-trifluoromethylphenyl hydrazono) acetic acid (4.7 g, 20 mmol, 88%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18](Cl)[N:17]=2)[CH2:10][CH2:9]1)(C)(C)C.[CH:27]1([CH2:33][NH2:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(Cl)Cl>[NH2:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:34][CH2:33][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[N:17]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCC(CNc2nc(Cl)ncc2[N+](=O)[O-])CC1
Reactant: NCC1CCCCC1
Solvent: ClCCl
Product: N[C@H]1CC[C@H](CNc2nc(NCC3CCCCC3)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
To a solution of the above {4-[(2-chloro-5-nitro-pyrimidin-4-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester (50.2 mg, 0.13 mmol) in CH2Cl2 (0.8 mL) was added cyclohexylmethylamine (44.1 mg, 0.39 mmol). The reaction mixture was stirred at room temperature for 3 h and then purified by silica gel column chromatography using 50:1 CH2Cl2;MeOH as an eluent to afford 32 mg (54%) of the desired product as a pale yellow solid.
Reaction SMILES: N1C=CC=CC=1.[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])[CH:8]=1.[N:22]1([C:28]2[N:29]=[C:30]([CH2:35][C:36]([O-])=[O:37])[NH:31][C:32](=[O:34])[CH:33]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[Na+]>CN(C)C=O>[N:22]1([C:28]2[N:29]=[C:30]([CH2:35][C:36]([NH:21][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][CH2:13][C:9]3[CH:8]=[N:7][CH:12]=[CH:11][CH:10]=3)=[O:37])[NH:31][C:32](=[O:34])[CH:33]=2)[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: Nc1ccccc1OCc1cccnc1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccccc1OCc1cccnc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 37.2 %

Procedure:
2 ml of pyridine, 300 mg of N-[3-(dimethylamino)propyl]-M′-ethylcarbodiimide hydrochloride and 366 mg of 2-(pyridin-3-ylmethoxy)phenylamine are added to a solution of 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of example 1, in 2 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 20 hours, and then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is thus stirred for 30 minutes. The precipitate formed is filtered off, and rised with water, ethyl ether and petroleum ether. The solid obtained is dried under vacuum. 150 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-[2-(pyridin-3-ylmethoxy)phenyl]acetamide are obtained in the form of a brown solid, the characteristics of which are the following:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][NH:10][C:11]2[CH:16]=[C:15]([NH2:17])[N:14]=[C:13]([CH3:18])[N:12]=2)[CH:5]=[N:6][CH:7]=1.[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:19][C:16]1[C:11]([NH:10][NH:9][CH2:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)=[N:12][C:13]([CH3:18])=[N:14][C:15]=1[NH2:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(N)cc(NNCc2cncc(Br)c2)n1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nc(N)c(Br)c(NNCc2cncc(Br)c2)n1
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 29.7 %

Procedure:
To a mixture of N-[[(5-bromo-3-pyridinyl)methyl]amino]-2-methyl-4,6-pyrimidinediamine (1.00 g, 3.40 mmol) in carbon tetrachloride (50 mL) at 23° C. was added N-bromosuccinimide (0.61 g, 3.90 mmol). The mixture was stirred for 1.5 hours at 23° C. and then filtered. The isolated solid was purified by flash chromatography (silica gel, 1:1 EtOAc:CHCl3 then 20% MeOH in EtOAc as eluants) and two recrystallizations from methanol to provide the title compound (376 mg, 1.01 mmol, 30%): mp 221°-222° C., Rf 0.69 (20% MeOH in EtOAc); 1H NMR (DMSO-D6, 400 MHz)δ8.54 (d, J=2 Hz, 1H), 8.50 (d, J=2 Hz, 1H), 7.93 (m, 1H), 7.09 (t, J=6 Hz, 1H), 6.39 (s, 2H), 4.51 (d, J=6 Hz, 2H), 2.13 (s, 3H); IR (KBr) 3480, 3300 (NH), 2900-3150 (CH), 1650, 1600 (C=C, C=N) cm-1 ; mass spectrum m/e 375 (M+, 45%), 373 (M+, 84%), 371 (M+, 44%), 292 (C11H11BrN5, 54%), 185 (C6H6BrN2, 50%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][C@H:5]([CH2:7][OH:8])[C@@H:4]([OH:9])[C@H:3]1[OH:10].Cl.N[C:13]1[N:18]=[C:17](Cl)[CH:16]=[C:15]([Cl:20])[N:14]=1.CCN(CC)CC>C(O)(C)C>[Cl:20][C:15]1[N:14]=[CH:13][N:18]=[C:17]([NH:1][C@@H:2]2[CH2:6][C@H:5]([CH2:7][OH:8])[C@@H:4]([OH:9])[C@H:3]2[OH:10])[CH:16]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: N[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: OC[C@H]1C[C@@H](Nc2cc(Cl)ncn2)[C@H](O)[C@@H]1O
Temperature: 90 °C
Yield: 99 %

Procedure:
To a solution of (1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diol.HCl (1.00 g, 5.44 mmol) and 2-amino-4,6-dichloropyrimidine (0.982 g, 5.99 mmol) in isopropyl alcohol (8 mL) was added Et3N (1.90 mL, 13.6 mmol). The reaction was heated to 90° C. for 1 h in an oil bath then cooled, filtered and concentrated in vacuo. The residue was dissolved in CH2Cl2 and purified by flash chromatography (20 to 50% MeOH/CH2Cl2) to afford the title compound as an off-white solid (2.025 g, >99%). LC/MS: Rt=0.81 min ES+ 260 (FA standard).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:25][C:26](C)([O-:28])C.[K+].ClCCO>O1CCCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][OH:28])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)[O-]
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Agent: OCCCl
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC(=O)c1cnc2c(OCCO)cccc2c1Nc1ccccc1C
Reaction time: 48 h
Yield: 32.4 %

Procedure:
3-Butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (3.2 g, 10 mmol) was dissolved in tetrahydrofuran (150 ml), potassium t-butoxide (1.83 g, 15 mmol) added, stirred to dissolve, then 2-chloroethanol (1.3 ml, 20 mmol) added and the mixture heated at reflux overnight. A further portion of potassium t-butoxide (1.83 g) and of 2-chloroethanol (1.3 ml) was added and heating continued for 2 days. The tetrahydrofuran was evaporated, the residue taken up in dichloromethane, washed with water and brine, dried and evaporated. Recrystallisation from ethyl acetate/petroleum ether gave 3-butyryl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)quinoline (1.18 g, 32%), m.p. 125°-127°.
Reaction SMILES: [C:1]1([C:7]2([CH:17]=[O:18])[CH2:16][CH2:15][C:10]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]([Mg]Br)=[CH2:20]>>[CH:19]([CH:17]([C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:15][CH2:16]1)[OH:18])=[CH2:20]
Reactant: C=C[Mg]Br
Reactant: O=CC1(c2ccccc2)CCC2(CC1)OCCO2
Product: C=CC(O)C1(c2ccccc2)CCC2(CC1)OCCO2

Procedure:
Prepared from 8-phenyl-1,4-dioxaspiro[4.5]decane-8-carboxaldehyde (J. Med. Chem. 1975, 18, 593-599) and vinylmagnesium bromide according to the method of Description 22. 1H NMR (400 MHz, CDCl3) δ 1.31 (1H, br s), 1.42-1.69 (4H, m), 1.76-1.89 (2H, m), 2.23-2.28 (1H, m), 2.45-2.51 (1H, m), 3.85-3.96 (5H, m), 5.09-5.14 (2H, m), 5.55-5.63 (1H, m), and 7.21-7.39 (5H, m).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:21])=[C:4]([CH3:20])[C:5]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7][C:6]=2[CH:19]=1.[C:22](OC)(OC)(OC)[CH3:23].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CN(C=O)C>[CH3:22][C:23]1[O:21][C:3]2[C:2]([N:1]=1)=[CH:19][C:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:10][CH2:11][C:5]=1[C:4]=2[CH3:20]
Reactant: Cc1c(O)c(N)cc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: COC(C)(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: Cc1nc2cc3c(c(C)c2o1)CCN(C(=O)OC(C)(C)C)CC3
Yield: 94 %

Procedure:
1,1-Dimethylethyl 8-amino-7-hydroxy-6-methyl-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (1.1 g) was treated with trimethyl orthoacetate (0.718 ml) and pyridinium p-toluenesulfonate (94 mg) in dry DMF (19 ml) at 60° C. for 1.5 hours. Volatiles were evaporated under reduced pressure and the residue was purified on silica gel (ethyl acetate/petroleum ether: 1/4) providing the title compound as white solid (1.127 g, 94% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:17]#[N:18])=[C:6]([C:8]2[C:9]([C:15]#[N:16])=[CH:10][NH:11][C:12](=[O:14])[CH:13]=2)[CH:7]=1.Br[CH:20]([CH3:24])[C:21]([OH:23])=[O:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:17]#[N:18])=[C:6]([C:8]2[C:9]([C:15]#[N:16])=[CH:10][N:11]([CH:20]([CH3:24])[C:21]([OH:23])=[O:22])[C:12](=[O:14])[CH:13]=2)[CH:7]=1
Reactant: CC(Br)C(=O)O
Reactant: N#Cc1ccc(Cl)cc1-c1cc(=O)[nH]cc1C#N
Product: CC(C(=O)O)n1cc(C#N)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
312 mg (purity 91%, 1.11 mmol) of 4-(5-chloro-2-cyanophenyl)-6-oxo-1,6-dihydropyridin-3-carbonitrile and 1.5 eq. of 2-bromopropanoic acid (racemate) were reacted according to General Method 4A at 45° C. Yield: 240 mg (purity 85%, 56% of theory)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH3:29][O:30][C:31](=[O:43])[C@@H:32]([NH:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[CH3:33]>O1CCCC1>[CH3:29][O:30][C:31](=[O:43])[C@@H:32]([N:34]([C:10](=[O:12])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:13])[CH2:35][C:36]1[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=1)[CH3:33]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@H](C)NCc1ccc(F)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)[C@H](C)N(Cc1ccc(F)cc1)C(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To a solution of (R)-2-tert-butoxycarbonylamino-propionic acid (37 g, 195 mmol) in dry tetrahydrofuran (250 mL) at 0° C. was added 4-methyl morpholine (21.5 mL, 195 mmol) followed by isobutylchloroformate (25.3 mL, 195 mmol). The reaction was allowed to warm to ambient temperature and stirred for two hours. This was followed by the addition of (S)-2-(4-fluoro-benzylamino)-propionic acid methyl ester (34.4 g, 162 mmol). The resulting mixture was stirred overnight at ambient temperature. The reaction mixture was filtered through a pad of celite and the filter cake was washed with ethyl acetate. The filtrate was concentrated in vacuo, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (43.2 g).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=1)[CH:3]([C:5]1[CH:6]=[N:7][C:8]([F:11])=[CH:9][CH:10]=1)[OH:4].[C:26]1([C:37](O)=[O:38])[CH:27]=[CH:28][CH:29]=[C:30]2[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=12.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[N:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:37]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=23)=[O:38])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:24])([F:25])[CH:21]([F:22])[F:23])[CH:14]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(F)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(F)nc1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(6-fluoropyridin-3-yl)-3-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-propanol (193 mg, 0.53 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (100 mg, 0.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (153 mg, 0.80 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound (232 mg, 82%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:17]=[C:16](O)[CH:15]=[C:14]([CH3:19])[N:13]=2)[CH:5]=1.O=P(Cl)(Cl)[Cl:23]>>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:17]=[C:16]([Cl:23])[CH:15]=[C:14]([CH3:19])[N:13]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(/C=C/c2nc(C)cc(O)n2)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc(/C=C/c2nc(C)cc(Cl)n2)c1
Yield: 45.4 %

Procedure:
In analogy to example 12c), by heating (E)-3-[2-(4-hydroxy-6-methyl-pyrimidin-2-yl)-vinyl]-benzoic acid methyl ester (2 g, 7.4 mmol) in POCl3 (13.6 ml, 0.15 mol) at 130° C. for 4.5 h there was obtained (E)-3-[2-(4-chloro-6-methyl-pyrimidin-2-yl)-vinyl]-benzoic acid methyl ester (0.97 g, 45%) as a light-yellow solid. EI mass spectrum, m/e: 288.1 (M calculated for C15H13ClN2O2: 288).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].C([O-])([O-])=O.[Na+].[Na+].[C:19](OC(Cl)=O)([O:21][CH2:22][CH:23]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20].O>O1CCOCC1>[CH:34]1[C:35]2[CH:23]([CH2:22][O:21][C:19]([N:9]3[C:10]4[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=4)[CH:7]=[CH:8]3)=[O:20])[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]=2[CH:31]=[CH:32][CH:33]=1
Reactant: O=C(Cl)OC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(OCC1c2ccccc2-c2ccccc21)n1ccc2cc([N+](=O)[O-])ccc21
Reaction time: 8 h

Procedure:
5-Nitroindole (2.0 g, 12.3 mmol) was dissolved in dioxane (25 mL) and 10% wt./vol Na2CO3 solution (2.5 g, water 25 mL) was added. FMOC-chloroformate (3.19 g, 12.3 mmol) was added to the mixture and the reaction was stirred overnight. The reaction mixture was transferred into water, filtered as a yellow solid and dried in vacuum oven at 50° C. for 2 hours. Obtained (4.07 g, 86% y). NMR (400 MHz, CDCl3), δ 8.61 (d, J=2.2 Hz, 1H), 8.43 (d, J=2.2 Hz, 1H), 8.12 (dd, J=7.3, 5.1 Hz, 1H), 8.02 (d, J=8.3 Hz, 1H), 7.82 (d, J=7.6 Hz, 2H), 7.76 (d, J=7.6 Hz, 2H), 7.62 (m, 4H), 7.60-7.30 (m, 8H), 6.74-6.69 (m, 2H), 4.94 (d, J=5.4 Hz, 2H), 4.41 (t, J=5.1 Hz, 1H), 4.05 (d, J=5.6 Hz, 2H). MS 384 [M−H] APCI.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[C:21]([CH:22]=O)=[CH:20][C:19]([Cl:24])=[CH:18][N:17]=1.[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])=[O:27].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[C:21]([CH2:22][N:32]2[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]2)=[CH:20][C:19]([Cl:24])=[CH:18][N:17]=1
Reactant: O=Cc1cc(Cl)cnc1Oc1ccc2c(nnn2CC2CC2)c1Br
Reactant: CS(=O)(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CS(=O)(=O)N1CCN(Cc2cc(Cl)cnc2Oc2ccc3c(nnn3CC3CC3)c2Br)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-{[4-bromo-1-(cyclopropylmethyl)-1H-benzotriazol-5-yl]oxy}-5-chloropyridine-3-carbaldehyde (32, 2.60 g, 6.38 mmol) was dissolved in anhydrous dichloroethane (63.8 mL, 0.1M) and treated with 1-(methylsulfonyl)piperazine (2.10 g, 12.8 mmol, 2 equiv.) and acetic acid (3.65 mL, 63.8 mmol, 10 equiv.). After 30 minutes the solution formed a thick suspension and was treated with sodium triacetoxyborohydride (1.76 g, 8.29 mmol, 1.3 equiv) in small portions over 1 hour. After completion of this addition, the reaction was allowed to stir an additional 2 h at ambient temperature. Upon completion as judged by TLC and LCMS, the reaction was quenched by the slow addition of water (20 mL) and NaHCO3. The mixture was extracted 3× with dichloromethane (3×30 mL), and the combined organic layers were dried over MgSO4. The crude mixture was purified using flash column chromatography (Redisep SiO2, 80 g, 0-100% EtOAc/hexanes) to provide pure 198: 1H NMR (300 MHz, CDCl3) δ 7.89 (d, 1H, J=2.5 Hz), 7.84 (d, 1H, J=2.5 Hz), 7.56 (d, 1H, J=8.8 Hz), 7.33 (d, 1H, 8.8 Hz), 4.53 (d, 2H, J=7.1 Hz), 3.82 (s, 2H), 3.33 (m, 4H), 2.83 (s, 3H), 2.74 (m, 4H), 1.41 (m, 1H), 0.69 (m, 2H), 0.52 (dd, 2H, J=10.8, 5.1 Hz, 2H). LRMS m/z (M+H) 556.9 found, 556.9 required.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([C:14]4[CH:18]=[CH:17][NH:16][N:15]=4)[N:11]([CH2:19][C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]#[N:24])[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].[CH3:30]I>CN(C=O)C>[CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([C:14]4[CH:18]=[CH:17][N:16]([CH3:30])[N:15]=4)[N:11]([CH2:19][C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]#[N:24])[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: CI
Reactant: Cc1nnc2ccc3c(cc(-c4cc[nH]n4)n3Cc3cccc(C#N)c3)n12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nnc2ccc3c(cc(-c4ccn(C)n4)n3Cc3cccc(C#N)c3)n12
Reaction time: 0.17 h

Procedure:
3-{[1-Methyl-7-(1H-pyrazol-3-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-6-yl]methyl}benzonitrile (50. mg, 0.14 mmol, from Example 182, Step 4) in DMF (3.0 mL) was treated with NaH (60% in mineral oil, 34 mg, 0.85 mmol). After 10 minutes, MeI (26 μL, 0.42 mmol, Aldrich) was introduced. After 10 minutes, the reaction was quenched by the addition of water. The product was isolated via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (30 mg, 58%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(N(CC)CC)C.Br[CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[N:23][CH:24]=1>C(O)C>[CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[N:23][CH:24]=2)[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: BrCc1cncnc1
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2cncnc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1.5 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (483 mg, 3.4 mmol) was dissolved in absolute ethanol (70 mL), and triethylamine (1.4 mL, 10.2 mmol) and 5-(bromomethyl)pyrimidine (882 mg, 5.1 mmol) were added. The mixture was stirred overnight at room temperature. The solid was filtered. The filtrate was evaporated. The residue was triturated in water, filtered, and washed with water followed with diethyl ether. The solid was dissolved in DCM and purified on silica gel using 10% DCM/MeOH to afford 6-methyl-2-[(pyrimidin-5-ylmethyl)sulfanyl]pyrimidin-4-ol (12 mg, 2% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.19 (s, 3H), 4.34 (s, 2H), 6.02 (bs, 1H), 8.88 (s, 2H), 9.05 (s, 1H); LRMS (ES) m/z 235 (100%, M+1).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[N+:10]([C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1)[C:16](Cl)=[O:17])([O-:12])=[O:11].C1OC1C>O1CCCC1>[N+:10]([C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1)[C:16]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:17])([O-:12])=[O:11]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: CC1CO1
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)C(=O)O

Procedure:
(S)-Leucine (10 g) was suspended in 150 mL dry tetrahydrofuran and chilled in an ice bath while stirring under a nitrogen atmosphere. 3,5-Dinitrobenzoyl chloride (Table 2, Compound 13, 21 g) and propylene oxide (6.6 g) were added; the resulting heterogeneous mixture became clear after several minutes. The mixture was allowed to stir for 5 h, and was evaporated under reduced pressure to afford an oil which crystallized upon addition of 100 mL of cold dichloromethane. Filtration and drying of the resulting crystals afforded 3,5-dinitrobenzoyl-(S)-leucine, 14, as a white solid (20.64 g, 83% yield). 1H NMR (200 MHz, d6DMSO) δ: 0.95 (m,6 H), 1.75 (M,3 H), 4.25 (m,1 H), 9.00 (t,1 H), 9.17 (d,2 H), 9.41 (d,1 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([SH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH:10]([CH3:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13].[C:18]([C:21]1[CH:31]=[CH:30][C:24]([O:25][CH2:26][CH2:27][CH2:28]Br)=[C:23]([CH2:32][CH2:33][CH3:34])[C:22]=1[OH:35])(=[O:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C.C(OCC)(=O)C>[C:18]([C:21]1[CH:31]=[CH:30][C:24]([O:25][CH2:26][CH2:27][CH2:28][S:8][C:6]2[CH:5]=[CH:4][C:3]([C:9](=[O:17])[CH:10]([CH3:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:2]([Br:1])[CH:7]=2)=[C:23]([CH2:32][CH2:33][CH3:34])[C:22]=1[OH:35])(=[O:20])[CH3:19]
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Reactant: COC(=O)CC(C)C(=O)c1ccc(S)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: CCCc1c(OCCCSc2ccc(C(=O)C(C)CC(=O)OC)c(Br)c2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of the thiol from step C (2.9 g) and 3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylbromide (3.74 g) in methyl ethyl ketone (25 c.c.) was added potassium carbonate (3.78 g, milled) and the suspension was refluxed for 21/2 hours, then stirred at R.T. for 12 hours. The mixture was diluted with ethyl acetate (25 c.c.) and the insolubles filtered off. The filtrate was concentrated to dryness in vacuo and the residue purified on silica gel to yield the title compound as an oil.