Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1.C(OCC)(OCC)OCC.C([BH3-])#N.[Na+].[C:32]([C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33].[Cl-].[Na+]>CN(C=O)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:40][C:39]2[CH:41]=[CH:42][C:36]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:37][CH:38]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C=O)cc1
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(OCC)OCC
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)CCNC(=O)c1ccc(CNc2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.8 %

Procedure:
The above 3-(4-formylbenzoylamino)propionic acid methyl ester (2.0 g, 8.5 mmol) was dissolved in DMF (20 mL). Triethyl orthoformate (10 mL), glacial acetic acid (1 mL), sodium cyanoborohydride (0.81 g, 12.8 mmol) and 4-tert-butylaniline 1.27 g, 8.5 mmol) were added and the resulting mixture was stirred at room temperature for 16 hours. The mixture was added saturated aqueous sodium chloride (100 mL) and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (3×100 mL). The organic phase was dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of ethyl acetate and heptane (1:1) to afford 0.87 g (30%) of 3-{4-[(4-tert-butylphenylamino)methyl]benzoylamino}propionic acid methyl ester as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:4][C:3]=1[CH3:13].[H-].[Na+].I[CH3:17]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:17])[CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:13]
Reactant: CI
Reactant: Cc1cc(-c2ncc[nH]2)ccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(-c2nccn2C)ccc1Br
Reaction time: 0.5 h

Procedure:
2-(4-Bromo-3-methylphenyl)imidazole (D88, 900 mg; 3.8 mmol) was dissolved in dry THF (30 ml) under argon and treated with sodium hydride (114 mg of an 80% dispersion in mineral oil; 3.8 mmol). After stirring for 30 minutes, iodomethane (237 μl; 3.8 mmol) was added and stirring continued for 18 hours. Evaporated in vacuo, the residue partitioned between water and CHCl3, the organic phase then dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by flash silica gel chromatography using CHCl3 as eluant to yield the title compound as a clear, colourless gum (600 mg; 63%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:41][C:42](=[O:51])[O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:8]([C:12]([NH:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[N:21]3[CH2:26][C@H:25]([CH3:27])[C@H:24]([N:28]4[CH:32]=[CH:31][N:30]=[N:29]4)[C@H:23]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:22]3)=[O:13])=[N:9]2)=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1.[CH3:66][N:67]1[CH2:72][CH:71]=[C:70](B2OC(C)(C)C(C)(C)O2)[CH2:69][CH2:68]1>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl.O>[C:37]([O:36][C:34]([NH:33][C@H:23]1[C@@H:24]([N:28]2[CH:32]=[CH:31][N:30]=[N:29]2)[C@@H:25]([CH3:27])[CH2:26][N:21]([C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[NH:14][C:12]([C:8]2[C:7]([NH:41][C:42](=[O:51])[O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:6][C:5]3[C:10](=[CH:11][C:2]([C:70]4[CH2:71][CH2:72][N:67]([CH3:66])[CH2:68][CH:69]=4)=[CH:3][CH:4]=3)[N:9]=2)=[O:13])[CH2:22]1)=[O:35])([CH3:38])([CH3:39])[CH3:40]
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(Br)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1ccnn1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(C4=CCN(C)CC4)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1ccnn1
Temperature: 90 °C
Yield: 30.4 %

Procedure:
A pressure tube was charged with benzyl {7-bromo-2-[({4-[(3R,4S,5S)-3-[(tert-butoxycarbonyl)amino]-5-methyl-4-(1H-1,2,3-triazol-1-yl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]quinolin-3-yl}carbamate (15 mg, 0.020 mmol), K3PO4 (8.4 mg, 0.034 mmol), 1,4-dioxane (0.3 mL), water (0.04 mL) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (6.6 mg, 0.03 mmol). The reaction mixture was purged with nitrogen for 5 min., then dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (1.6 mg, 0.002 mmol) was added. The reaction mixture was sealed and heated at 90° C. for 30 min., then allowed to cool to room temperature. The crude mixture was filtered and purified by preparative LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the title compound as a light yellow powder (4.7 mg, 33%). LCMS calc. for C42H49N10O5 (M+H)+: m/z=773.4. Found: 773.4.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[O:13][CH2:12][CH:11]([NH:14][C:15](=[O:18])[CH2:16][CH3:17])[CH2:10][C:7]2=[N:8][CH:9]=1)([O-])=O.O.O.Cl[Sn]Cl>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[O:13][CH2:12][CH:11]([NH:14][C:15](=[O:18])[CH2:16][CH3:17])[CH2:10][C:7]2=[N:8][CH:9]=1
Reactant: CCC(=O)NC1COc2cc([N+](=O)[O-])cnc2C1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CCC(=O)NC1COc2cc(N)cnc2C1
Yield: 100.2 %

Procedure:
N-(3,4-Dihydro-7-nitro-2H-pyrano[3,2-b]pyridin-3-yl)propionamide (445 mg, 1.76 mmol) was dissolved in ethanol (80 ml) and SnCl2.2H2O (2 g, 8.82 mmol) was added. The resulting mixture was refluxed for 8 h and then the solvent was removed under vacuum. The raw material was dissolved in ethyl acetate and washed successively with 2 N aqueous NaOH (2×) and water. The organic layer was dried (Na2SO4), filtered through a pad of celite and evaporated to afford the crude N-(7-amino-3,4-dihydro-2H-pyrano[3,2-b]pyridin-3-yl)-propionamide (390 mg, 99%) as a pale yellow powder.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:19][CH2:18][CH:17](OS(C)(=O)=O)[CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH2:25]([NH:32][CH:17]1[CH2:18][CH2:19][N:15]([S:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][CH:8]=2)(=[O:14])=[O:13])[CH2:16]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1ccccc1
Reactant: CCCCOc1ccc(S(=O)(=O)N2CCC(OS(C)(=O)=O)C2)cc1
Solvent: C1CCOC1
Product: CCCCOc1ccc(S(=O)(=O)N2CCC(NCc3ccccc3)C2)cc1
Temperature: 100 °C
Reaction time: 48 h
Yield: 95.9 %

Procedure:
A solution of methanesulfonic acid 1-(4-butoxy-benzenesulfonyl)-pyrrolidin-3-yl ester (1.51 g, 4 mmol) in tetrahydrofuran (8 ml) was added benzylamine (3.46 g, 32 mmol) and the mixture was stirred at 100° C. for 2 days. After cooling to room temperature the tetrahydrofuran was evaporated, and the residue washed with hexanes. The solid was stirred with 10% sodium carbonate solution (30 ml) and ethyl acetate (40 ml), and the organic solution was washed brine, dried over anhydrous sodium sulfate, and filtered through Magnolsol. The filtrate was evaporated, and the residue was washed with hexanes to give 1.49 g of a white solid; m.p. 99-100° C.; MS (ES) m/z 389.0 (MH+); HRMS (EI) Calcd. for C21H28N2O3S (M+): 388.1820, Found: 388.1826.
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:19]([NH:29]C(=O)OC(C)(C)C)[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)=[N:4][CH:5]=[C:6]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH:7]=1.[ClH:37].O1CCOCC1>CO>[ClH:37].[NH2:29][C@H:19]([C:3]1[N:4]=[CH:5][C:6]([N:8]2[C:9](=[O:18])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]2=[O:17])=[CH:7][C:2]=1[Br:1])[CH2:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1ncc(N2C(=O)c3ccccc3C2=O)cc1Br
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N[C@@H](Cc1cc(F)cc(F)c1)c1ncc(N2C(=O)c3ccccc3C2=O)cc1Br
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Compound 30E (260 mg, 0.047 mmol) was dissolved in 10 mL of methanol and cooled to 0° C. To it was added 4N HCl/1,4-dioxane (2 ml). The reaction mixture was stirred at room temperature for overnight and concentrated to afford the title product. MS (m/z) 458.00 [M+H]+
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([OH:38])=O)[C:31]2=[O:39])=[CH:26][CH:25]=1.[NH2:40][C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1.C(N(CC)CC)C>CN(C=O)C>[C:44]1([CH3:47])[CH:45]=[CH:46][C:41]([NH:40][C:36]([C:32]2[C:31](=[O:39])[N:30]([C:27]3[CH:26]=[CH:25][C:24]([F:23])=[CH:29][CH:28]=3)[CH:35]=[CH:34][CH:33]=2)=[O:38])=[CH:42][CH:43]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccn(-c3ccc(F)cc3)c2=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 273.6 %

Procedure:
TBTU (276 mg, 0.851 mmol) was added to the mixture of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (147 mg, 0.567 mmol), p-toluidine (73.7 mg, 0.681 mmol), and triethylamine (120 μl, 0.851 mmol) in DMF (3 ml) at rt. The combined mixture was stirred at rt for 16 h. After that time, the solvent was removed to give a black solid (500 mg). It was purified by chromatography on silica gel (15 g) eluting with 40% (100 ml), 50% (100 ml), 60% (100 ml) and 70% (100 ml) EtOAc/hexane to give the title compound as a light-brown solid. 1H NMR (400 MHz, CDCl3): δ=2.31 (s, 3H), 6.58 (dd, J=6.8 & 7.2 Hz, 1H), 7.13 (d, J=8.4 Hz, 2H), 7.23-7.29 (m, 2H), 7.38-7.42 (m, 2H), 7.56-7.63 (m, 3H), 8.74 (dd, J=2.0 & 6.8 Hz, 1H), 11.69 (brs, 1H). MS (ES+): m/z 323.09 [MH+]. HPLC: tR=3.69 min (polar—5 min, ZQ3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=3)[N:13]=[C:12]2[CH3:27])[CH:5]=1.[Br:29]N1C(=O)CCC1=O>ClCCl>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Br:29])=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=3)[N:13]=[C:12]2[CH3:27])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C)n3)cc2=O)c1
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C)n3)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.9 %

Procedure:
To a solution of 4-methyl-3-[2-methyl-4-(6-methyl-pyridin-2-ylmethoxy)-6-oxo-6H-pyrimidin-1-yl]-benzoic acid methyl ester from Step A (122 mg, 0.32 mmol) in dichloromethane (2 mL) was added N-bromosuccinimide (57 mg, 0.32 mmol). The solution was stirred at ambient temperature for two hours. The solution was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated to provide the brominated product as colorless oil (148 mg, quantitative yield). MS (M, M+2): 458, 460
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.[C:16]1([C@@H:22]2[CH2:24][C@H:23]2[NH2:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:25][CH:23]2[CH2:24][CH:22]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:7]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ncnc(NC2CC2c2ccccc2)n1
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
A mixture of 2,4-dichloro-1,3,5-triazine (0.5 g, 3.34 mmol) and solid K2CO3 (2.3 g, 16.7 mmol) was suspended in ACCN (20 mL) under nitrogen at 0° C. followed by addition of trans-2-phenylcyclopropylamine hydrochloride (566 mg, 3.34 mmol). The mixture was stirred at 0° C. for 1.25 h. The reaction was quenched by pouring onto ice/water. The white solid formed was collected by suction filtration. The solid was dissolved into EtOAc (100 mL), washed with brine, dried over Na2SO4, concentrated under reduced pressure then purified by column chromatography (elution with 1:1 EtOAc/hexanes followed by EtOAc) to give (4-chloro-[1,3,5]triazin-2-yl)-(2-phenyl-cyclopropyl)amine.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][C:14]=2[F:21])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[N-]1C=CN=C1.[NH2:39][O:40][CH2:41][CH2:42][OH:43]>C1COCC1>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:3]2[C:2]([F:1])=[C:10]([F:11])[CH:9]=[CH:8][C:4]=2[C:5]([NH:39][O:40][CH2:41][CH2:42][OH:43])=[O:7])=[C:14]([F:21])[CH:15]=1)#[CH:20]
Reactant: NOCCO
Reactant: C#Cc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[n-]cn1
Solvent: C1CCOC1
Product: C#Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.2 %

Procedure:
The product of Example 1, Step C, 3,4-difluoro-2-[(4-ethynyl-2-fluorophenyl)amino]benzoic acid (349 mg, 1.20 mmol) was dissolved in dry THF (15 mL), to which was added carbonyldiimidazole (CDI) (389 mg, 2.40 mmol). Within 10 minutes, a bright yellow solution was obtained and conversion to the imidazolide was confirmed by TLC (50% EtOAc/hexanes). A solution of 2-(aminooxy)ethanol (370 mg, 4.80 mmol) in THF (5 mL) was then added and the mixture stirred for 15 hours at room temperature. The reaction solvent was removed under reduced pressure and the residue partitioned between 1 M HCl (100 mL) and EtOAc (100 nL). The EtOAc layer was then washed with water (100 mL) and saturated NaCl solution (100 mL), dried (Na2SO4), and the solvent removed under reduced pressure to afford an oil which was purified by flash column chromatography on silica gel (50% EtOAc/hexanes) to give 2-[(4-ethynyl-2-fluorophenyl)amino]-3,4-difluoro-N-(2-hydroxyethoxy)benzamide as a pale yellow solid (232 mg, 55%); m.p. (EtOAc/hexanes) 158–161° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.80 (br s, 1 H), 8.84 (br s, 1 H), 7.43 (ddd, J=8.8, 5.9, 1.9 Hz, 1 H), 7.34 (dd, J=12.2, 1.9 Hz, 1 H), 7.25 (ddd, J=9.9, 9.0, 7.3 Hz, 1 H), 7.16 (ddd, J=8.3, 1.9, 0.9 Hz, 1 H), 6.79 (ddd, J=9.1, 8.3, 4.9 Hz, 1 H), 4.71 (br s, 1 H), 4.10 (s, 1 H), 3.84 (t, J=5.0 Hz, 2 H), 3.56 (t, J=5.0 Hz, 2 H). Anal. Calcd for C17H13F3N2O3: C, 58.5; H, 4.1; N, 8.0. Found: C, 58.3; H, 3.7; N, 8.0.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:6].[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.Cl>ClC(Cl)C(Cl)Cl>[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](=[O:20])[C:9]2[CH:8]=[C:7]([CH2:5][CH3:6])[CH:12]=[CH:11][C:10]=2[OH:13])=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCc1ccc(O)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)C(Cl)Cl
Product: CCc1ccc(O)c(C(=O)c2ccc(Cl)cc2)c1
Temperature: 105 °C

Procedure:
Aluminum chloride (267g) was added in portions over 30 minutes to a stirred solution of 4-ethylphenol (122.1g.) and 4-chloro-benzoyl chloride (140ml.) in dry 1,1,2,2-tetrachloroethane (800ml.). The mixture was heated at 105°C. for 22 hours with stirring, and on cooling a mixture of ice (600g) and concentrated hydrochloric acid was added slowly, A vigorous reaction occurred and some material was lost. The remaining material was separated and the aqueous fraction extracted twice with chloroform (200ml.), and the combined organic layers evaporated to a dark oil which was distilled in vacuo giving two main fractions: B (17.4g) 150°-160°C at 0.3mmHg; C (110.8g) 160°-168°C at 0.3mmHg. Both remained liquid on cooling.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=3)[C:11]=2[CH2:12][OH:13])=[O:6])[CH2:3][CH2:2]1.[Br:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1.C1(C)C=CC=CC=1>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([O:13][CH2:12][C:11]2[N:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=3)[N:9]=[N:8][C:7]=2[C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[O:6])=[CH:28][CH:27]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CO)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.2 %

Procedure:
To a suspension of N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-(hydroxymethyl)-1H-1,2,3-triazole-4-carboxamide (0.10 g) obtained in Example 112 in THF (3 ml)—toluene (3 ml) were added 4-bromophenol (0.053 g), tributylphosphine (0.15 ml) and ADDP (0.15 g). The reaction mixture was stirred at room temperature for 15 min, the insoluble material was filtered off, and the solvent was evaporated. The residue was purified by silica gel column (hexane/ethyl acetate=1/2 to ethyl acetate). The resultant product was recrystallized from ethyl acetate/hexane to give the title compound as a colorless powder (0.14 g, 95%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH2:17][S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:14]=2)[NH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:29](I)[CH3:30]>CN(C)C=O>[CH2:29]([N:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH2:17][S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:14]=2)[NH:9][CH:8]=1)[CH3:30]
Reactant: CCS(=O)(=O)CCc1ccc2[nH]cc(C[C@H]3CCCN3)c2c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCC[C@@H]1Cc1c[nH]c2ccc(CCS(=O)(=O)CC)cc12
Temperature: 120 °C
Yield: 35.9 %

Procedure:
To a solution of (R)-3-(pyrrolidin-2-ylmethyl)-5-(2-ethylsulphonylethyl)-1H-indole (0.27 g, 0.8 mmol) in dimethylformamide (dried over 4A sieves) (5 mls), was added sodium carbonate (90 mgs) and ethyl iodide (0.07 mls, 0.88 mmol) at room temperature. The mixture was heated at 120° C. under nitrogen for 16 hours. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate and water. The separated organic phase was washed with water (3×), dried (Na2SO4) and evaporated in vacuo to give an oil. Purification by column chromatography on silica gel, eluting with CH2Cl2 :EtOH:NH4OH (90:10:0.5) gave the title compound as a gum (100 mgs). Anal. Calcd for C19H28N2O2S· 1/4CH2Cl2. 1/2H2O: C,61.04; H,7.85; N,7.40. Found: C,60.80; H,7.69; N,7.48⟦alpha⟧sup.25D =+60° (c=0.1, MeOH).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)[CH2:11][CH2:12][CH3:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:10]([C:14]1[CH:15]=[CH:16][C:17]([CH:18]=[N:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:20][CH:21]=1)[CH2:11][CH2:12][CH3:13]
Reactant: N#Cc1ccc(N)cc1
Reactant: CCCCc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCc1ccc(C=Nc2ccc(C#N)cc2)cc1

Procedure:
A mixture of 11.8 g. of p-aminobenzonitrile and 16.2 g. of p-n-butylbenzaldehyde in 200 ml. of benzene is treated with 300 mg. of p-toluenesulfonic acid and reacted as described in Example 1. After the addition of 3 g. of solid potassium carbonate, the mixture is filtered and evaporated, whereby there are obtained 27.0 g. of a yellow oil which crystallizes with cooling. Purification is carried out by several recrystallizations from isopropanol as described in Example 1. The p-[(p-n-butylbenzyliden)amino]benzonitrile which is obtained has a melting point of 38.1°-38.7°C. and a clearing point of 62.6°C. UV (ethanol): ε280 = 24900 (shoulder at 314 nm). The nuclear magnetic resonance, mass spectrum, infrared and microanalysis data confirm the structure.
Reaction SMILES: [C:1](=[O:21])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[CH:5]=1.C(N(C(C)C)C(C)C)C.Cl.[NH2:32][CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>C(Cl)Cl>[Br:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[CH2:3][O:2][C:1]([NH:32][CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:21]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: O=C(OCc1cccc(Br)c1)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCNC(=O)OCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To a solution of 3-bromobenzyl 4-nitrophenyl carbonate (8 g, 21.58 mmol) in DCM (50 mL) was added N-ethyl-N-isopropylpropan-2-amine (7.47 mL, 43.2 mmol) and tert-butyl 3-aminopropanoate hydrochloride (3.92 g, 21.58 mmol). Upon the completion of addition, the reaction mixture was stirred at room temperature for 1 h and then quenched with water. The resulting mixture was extracted with CH2Cl2 and the combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was purified by flash chromatography (0-50% ethyl acetate:hexanes) to afford the title compound (7.10 g, 89% yield) as a light brown oil. LCMS, [M-tBu+2H]+=302.1. 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.44 (d, J=7.7 Hz, 1H), 7.29-7.19 (m, 2H), 5.31 (br. s, 1H), 5.06 (s, 2H), 3.43 (dd, J=12.1, 6.1 Hz, 2H), 2.46 (t, J=6.0 Hz, 2H), 1.45 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[C:18]([C:20]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][C:21]=1[NH2:22])#[N:19]>>[C:18]([C:20]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1)#[N:19]
Reactant: COc1cc(N)c(C#N)cc1OC
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: COc1cc(C#N)c(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)cc1OC

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol) and 2-cyano-4,5-dimethoxyaniline (48 mg, 0.288 mmol) similar to Example 185 and isolated as a solid (8 mg, 10%). 1H NMR (CDCl3): 9.62 (d, J=1.4 Hz, 1H), 8.69 (m, 2H), 7.43 (dd, J=5.4, 1.5 Hz, 1H), 7.07 (s, 1H), 6.93 (s, 1H), 6.70 (s, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[OH-].[K+:11]>O>[NH2:1][CH:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([O-:9])=[O:8].[K+:11]
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)CC(N)C(=O)[O-]

Procedure:
Separately, in a single-necked, round bottomed flask, equipped with a magnetic stirrer, 7.87 g (60 mmol) of Leucine is dissolved in 300 ml of water. To this is added 72 ml of 1 M potassium hydroxide with vigorous stirring, until heat production ceases. At this point the water is removed by evaporation to yield the carboxylate salt, potassium 2-amino-4-methylpentanoate, shown below.
Reaction SMILES: N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:13]N1C(=O)CCC1=O.C(=[N:28][C:29]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:30]=1[C:31]#[N:32])C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[NH2:28][C:29]1[CH:36]=[C:35]([CH2:37][Br:13])[CH:34]=[CH:33][C:30]=1[C:31]#[N:32]
Reactant: Cc1ccc(C#N)c(N=Cc2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)cc1N
Yield: 47.2 %

Procedure:
2.2′-Azobisisobutyronitrile (AIBN) (1.31 g, 8 mmol) is added to a solution of N-bromosuccinimide (6.87 g, 38 mmol) and 2-benzylideneamino-4-methylbenzonitrile (7 g, 31.8 mmol) in carbon tetrachloride (250 mL), and the reaction mixture refluxed under nitrogen overnight. The reaction mixture is cooled and filtered through a plug of celite, and the celite washed with carbon tetrachloride (100 mL). The combined filtrate is washed with 1N HCl, saturated aqueous NaHCO3, dried over MgSO4 and concentrated in vacuo. The crude product is purified by column chromatography on silica with 10-20% ethyl acetate/hexanes. The combined product fractions are concentrated, and the resulting sticky solid is washed with ethyl ether/hexanes to give the product as a pale yellow solid (3.26 g, 15 mmol).