Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][CH:6]=1)[CH3:2].[CH2:16]([O:18][C@H:19]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:20][C:21]1[CH:31]=[CH:30][C:24]([O:25][CH2:26][C:27]([OH:29])=O)=[CH:23][CH:22]=1)[CH3:17].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:16]([O:18][C@@H:19]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:25][CH2:26][C:27]([N:3]([CH2:1][CH3:2])[CH2:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]([F:13])([F:14])[F:15])=[CH:7][CH:6]=2)=[O:29])=[CH:30][CH:31]=1)[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:17]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reactant: CCNCc1ccc(OC(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(CC)Cc2ccc(OC(F)(F)F)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
To a solution of N-ethyl-N-[4-(trifluoromethoxy)benzyl]amine (0.438 g, 2.00 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.593 g, 2.00 mmol) in methylene chloride (20 mL) were added N,N-diisopropylethylamine (0.80 mL, 4.6 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.674 g, 2.10 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (40 mL) and the organic phase was washed with 5% HCl (50 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 50 g/150 mL) with methylene chloride/ethyl acetate 10:1 as the eluent yielded 0.57 g (58%) of a colourless oil.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH3:17])[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C([O:21][CH2:22][C:23]1[C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH:26]=[CH:25][C:24]=1[N:38]1[CH2:46][C:45]2[C:40](=[CH:41][CH:42]=[C:43]([C:47]([CH3:50])([CH3:49])[CH3:48])[CH:44]=2)[C:39]1=[O:51])(=O)C>>[C:47]([C:43]1[CH:44]=[C:45]2[C:40](=[CH:41][CH:42]=1)[C:39](=[O:51])[N:38]([C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([C:2]3[N:3]=[C:4]([NH:10][C:11]4[CH:12]=[N:13][N:14]([CH2:16][CH3:17])[CH:15]=4)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=3)[C:23]=1[CH2:22][OH:21])[CH2:46]2)([CH3:50])([CH3:48])[CH3:49]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Reactant: CCn1cc(Nc2nc(Br)cn(C)c2=O)cn1
Product: CCn1cc(Nc2nc(-c3cccc(N4Cc5cc(C(C)(C)C)ccc5C4=O)c3CO)cn(C)c2=O)cn1
Yield: 48.2 %

Procedure:
Using the same general procedure as Example 105, reaction of 111c (253 mg, 0.85 mmol) and 103f (473 mg, 1.02 mmol) afforded a 48% yield (210 mg) of 111 as an off-white solid: mp 138-140° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.17 (s, 1H), 7.72 (m, 3H), 7.61 (m, 2H), 7.51 (t, 1H, J=7.6 Hz), 7.43 (m, 1H), 7.31 (s, 1H), 4.94 (s, 2H), 4.88 (t, 1H, J=5.0 Hz), 4.49 (d, 2H, J=5.0 Hz), 4.06 (q, 2H, J=7.1 Hz), 3.52 (s, 3H), 1.37 (s, 9H), 1.33 (t, 3H, J=7.2 Hz); MS (ESI+) m/z 513.2 (M+H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1>O1CCOCC1.Cl.O>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCNCC1
Reaction time: 8 h

Procedure:
To a solution of this 1,1-dimethylethyl 4-{[4-(trifluoromethyl)phenyl]sulfonyl}-1-piperazinecarboxylate in 1,4-dioxane (100 ml), 4M HCl in 1,4-dioxane (50 ml) and 3 drops of distilled water was added. The reaction mixture was stirred overnight. Reaction mixture was then reduced to dryness in vacuo.
Reaction SMILES: [C:1]1([O:7][P:8]([O-:16])[O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([O:21][C:22](=[O:25])[CH2:23]Br)([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>ClCCl>[O:9]([P:8]([CH2:23][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:25])([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: [O-]P(Oc1ccccc1)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CP(=O)(Oc1ccccc1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of diphenylphosphite (2.25 mL) in dichloromethane at 0° C. was added t-butylbromoacetate (1.48 mL) followed by triethylamine (1.95 mL). The mixture was stirred at 0° C. for 15 min and then at rt for 1 h before being quenched with water and extracted into ethyl acetate, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate to give the title compound. 1H NMR (500 MHz, CDCl3): δ 7.40-7.18 (m, 10H); 3.22 (s, 1H); 3.18 (s, 1H); 1.50 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N[C:12]([C:14]([NH:16][C:17](=O)[CH3:18])=[O:15])=[O:13])(=O)C>>[C:2]1([NH:1][C:12]([C:14]([NH:16][C:17]2[CH:18]=[CH:4][CH:3]=[CH:2][CH:7]=2)=[O:15])=[O:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CC(=O)NC(=O)C(=O)NC(C)=O
Product: O=C(Nc1ccccc1)C(=O)Nc1ccccc1
Reaction time: 2 h

Procedure:
Aniline (50 ml, 0.549 mol) and N,N'-diacetyloxamide (5 g, 0.029 mol) are charged into a three-necked flask equipped with a condenser, a magnetic stirrer, an inlet tube for nitrogen and a thermometer. The temperature is brought to 50° C. while vigorously stirring and after 2 hours the reaction is stopped by removing the heating bath.
Reaction SMILES: [C:1](/[N:9]=[C:10](\SC)/[NH:11][C@:12]([C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([F:37])[CH:28]=1)([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:40][NH2:41]>CC#N.[N+]([O-])([O-])=O.[Ag+]>[F:37][C:29]1[CH:28]=[C:27]([C@@:12]([NH:11][C:10]2[NH:9][C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:41][N:40]=2)([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=1
Reactant: NN
Reactant: CS/C(=N\C(=O)c1ccccc1)N[C@@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC#N
Product: Fc1ccc([C@](Cc2ccccc2)(Nc2nnc(-c3ccccc3)[nH]2)c2cc(F)cc(C(F)(F)F)c2)cc1
Temperature: 60 °C
Yield: 69.2 %

Procedure:
To a solution of (S,Z)-methyl N′-benzoyl-N-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)carbamimidothioate (58 mg, 0.1 mmol) and TEA (28 μL, 0.2 mmol) in CH3CN (1 mL) was added drop wise a solution of AgNO3 (26 mg, 0.15 mmol) in CH3CN (1 mL), followed by the addition of NH2NH2 (10 μL, 0.1 mmol). The reaction mixture was heated at 60° C. for 1 h and allowed to cool to room temperature. The solid was removed by filtration and the filtrate was concentrated. The residue was purified by ISCO chromatography (4 g column) using hexanes/EtOAc (0-30%) over 10 min to give (S)-N-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-5-phenyl-4H-1,2,4-triazol-3-amine as a white solid (36 mg, 69% yield). LCMS: RT=4.25 min [M+H] 520.97 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). NMR: 400 MHz 1H (CDCl3) 7.77 ppm, 2H, dd, J=7.83, 1.52 Hz; 7.37 ppm, 4H, m; 7.26 ppm, 4H, m; 7.10 ppm, 3H, m; 6.98 ppm, 2H, m; 6.63 ppm, 2H, d, J=7.33 Hz; 3.97 ppm, 1H, m; 3.85 ppm, 1H, m.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH:13]=1)[CH:6]=[CH:5]2.[O:18]1[CH2:20][C@H:19]1[CH2:21][O:22][C:23]1[C:31]2[CH:30]=[CH:29][O:28][C:27]=2[CH:26]=[CH:25][CH:24]=1>CO>[O:28]1[CH:29]=[CH:30][C:31]2[C:23]([O:22][CH2:21][C@@H:19]([OH:18])[CH2:20][N:15]3[CH2:16][CH2:17][C:12]([C:7]4[CH:6]=[CH:5][C:4]5[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=5)[CH:8]=4)=[CH:13][CH2:14]3)=[CH:24][CH:25]=[CH:26][C:27]1=2
Reactant: Fc1ccc2cc(C3=CCNCC3)ccc2c1
Reactant: c1cc(OC[C@@H]2CO2)c2ccoc2c1
Solvent: CO
Product: O[C@H](COc1cccc2occc12)CN1CC=C(c2ccc3cc(F)ccc3c2)CC1
Yield: 37.8 %

Procedure:
A solution 4-(6-fluoronaphth-2-yl)-1,2,5,6-tetrahydropyridine (0.101 g, 0.444 mmol) and (S)-(+)-4-(oxiranylmethoxy)-benzo[b]furan (0.085 g, 0.444 mmol) in methanol (5 mL) was heated at reflux for 18 hours and then cooled and evaporated. The residue was purified by silica gel chromatography (dichloromethane/2% methanol in dichloromethane gradient elution) to give the title compound as a clear colorless oil (0.070 g, 38%). FDMS m/e=418 (M++1). C26H24FNO3.0.5H2O.
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[C:13]([CH3:18])=[N:14][O:15][C:16]=2[CH3:17])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN([C:22]([O:26][N:27]1N=NC2C=CC=N[C:28]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CNOC>CN(C=O)C>[NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[C:13]([CH3:18])=[N:14][O:15][C:16]=2[CH3:17])=[CH:7][C:3]=1[C:4]([N:27]([O:26][CH3:22])[CH3:28])=[O:6]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1noc(C)c1-c1cc(N)c(N)c(C(=O)O)c1
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc(-c2c(C)noc2C)cc(N)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)benzoic acid (22 g, 0.089 mol) was dissolved in DMF (C=3.0 M) and HATU (1.3 eq), DIPEA (7 eq), and N,O-dimethylhydroxylamine hydrochloride (2.5 eq) were added in one portion and the reaction was allowed to stir under air at room temperature for 1 hr. The reaction was concentrated in vacuo and the residue was dissolved in ethyl acetate. The solution was washed once with NaHCO3 and three times with brine. The crude was concentrated in vacuo and purified via silica gel chromatography to give 2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)-N-methoxy-N-methylbenzamide as a light brown powder.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][C:5](=O)[CH2:6]2.C(N1CC=[C:18]([Sn:21](C)([CH3:23])[CH3:22])CC1)(C)(C)C>>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH:4]=[C:5]([Sn:21]([CH3:23])([CH3:22])[CH3:18])[CH2:6]2
Reactant: CN1C2CCC1CC(=O)C2
Reactant: CC(C)(C)N1CC=C([Sn](C)(C)C)CC1
Product: CN1C2C=C([Sn](C)(C)C)CC1CC2

Procedure:
The compound was prepared from 8-methyl-8-azabicyclo[3.2.1]octan-3-one as described above for 1-tert-Butyl-1,2,3,6-tetrahydro-4-(trimethylstannyl)pyridine.
Reaction SMILES: CS([Cl:5])(=O)=O.[CH3:6][N:7]([CH2:16][CH:17](O)[CH3:18])[C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:15].C(N(CC)CC)C>ClCCCl>[CH3:6][N:7]([CH2:16][CH:17]([Cl:5])[CH3:18])[C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:15]
Reactant: Cc1cccc(C)c1N(C)CC(C)O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1N(C)CC(C)Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
3.1 ml (4.6 g, 40 mmoles) of methanesulfonyl chloride are added dropwise, at a temperature not exceeding 20° C., to a solution of 7.0 g (36.2 mmoles) of 1-[N-methyl-N-(2,6-dimethylphenyl)-amino]-2-propanol and 5.45 ml (4.0 g, 40 mmoles) of triethyl amine in 50 ml of 1,2-dichloroethane, and the resulting mixture is stirred at room temperature for 3 hours. The mixture is washed then thrice with 30 ml of water, each, dried over anhydrous magnesium sulfate, the solvent is evaporated, and the oily residue is distilled under reduced pressure. 6.9 g (90.2%) of 1-[N-methyl-N-(2,6-dimethylphenyl)-amino]-2-chloro-propane are obtained; b.p.: 116°-118° C./133 Pa.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[F:8][C:9]([F:31])([F:30])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH:18]([CH3:19])[O:17]2)=[CH:12][CH:11]=1.Cl>CN(C)C=O.O>[F:8][C:9]([F:30])([F:31])[C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)([OH:17])[CH:18]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH3:19])=[CH:12][CH:11]=1
Reactant: CC1OC1(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Reactant: c1nc[nH]n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(n1cncn1)C(O)(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
1,2,4-1H-triazole was added to a stirred suspension of sodium hydride (0.86 g, 50% dispersion, washed with petroleum ether to remove oil) in dry dimethylformamide (40 cm3). After stirring for 1.5 hours, the oxirane (formed in (b) above) dissolved in dimethylformamide (5 cm3) was added slowly. The mixture was heated at 100° C. for 2 days, then cooled and poured into water, neutralised with dilute hydrochloric acid and the product extracted into ether, which was dried (MgSO4) and concentrated by evaporation of the solvent.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH:12]3[O:13][CH:11]3[C:10]([CH3:15])([CH3:14])[O:9][C:8]=2[CH:16]=1)([O-:3])=[O:2].Cl.[NH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].[OH-].[Na+]>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C@@H:12]([NH:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C@H:11]([OH:13])[C:10]([CH3:15])([CH3:14])[O:9][C:8]=2[CH:16]=1)([O-:3])=[O:2]
Reactant: CC1(C)Oc2cc([N+](=O)[O-])ccc2C2OC21
Reactant: CCOC(=O)CCCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CCCN[C@@H]1c2ccc([N+](=O)[O-])cc2OC(C)(C)[C@H]1O

Procedure:
7-Nitro-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-benzo[b]pyran (0.48 g, the preparation of which is described in Example 3 of U.K. Pat. No. 1,548,221), ethyl 4-aminobutyrate hydrochloride (0.34 g) and sodium hydroxide pellets (0.08 g) were refluxed in ethanol (50 ml) for 12 hours. Filtration and evaporation and chromatography on a chromatotron (2 mm silica gel HF254, gradient elution with pentane-ethyl acetate) gave recovered epoxide (0.20 g) and trans-4-(3-carbethoxypropylamino)-7-nitro-2,2-dimethyl-2H-benzo[b]pyran-3-ol (0.21 g) as a gum, which was used as such in Example 10.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.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.[NH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CN(C=O)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([NH:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:14]
Reactant: O=C(O)c1cnc2ccccc2c1O
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccccc1)c1c[nH]c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.4 %

Procedure:
To a solution of 4-hydroxy-quinoline-3-carboxylic acid (A-1) (19 mg, 0.1 mmol), HATU (38 mg, 0.1 mmol) and DIEA (34.9 μL, 0.2 mmol) in DMF (1 mL) was added aniline (18.2 μL, 0.2 mmol) and the reaction mixture was stirred at room temperature for 3 h. The resulting solution was filtered and purified by HPLC (10-99% CH3CN/H2O) to yield 4-oxo-N-phenyl-1H-quinoline-3-carboxamide (215) (12 mg, 45%). 1H NMR (400 MHz, DMSO-d6) δ 12.97 (s, 1H), 12.50 (s, 1H), 8.89 (s, 1H), 8.34 (dd, J=8.1, 1.1 Hz, 1H), 7.83 (t, J=8.3 Hz, 1H), 7.75 (m, 3H), 7.55 (t, J=8.1 Hz, 1H), 7.37 (t, J=7.9 Hz, 2H), 7.10 (t, J=6.8 Hz, 1H); HPLC ret. time 3.02 min, 10-99% CH3CN, 5 min run; ESI-MS 265.1 m/z (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C:8]([O:10]C)=[O:9])=[C:4]([C:14]#[C:15][C:16]2[CH:21]=[C:20]([S:22]([CH2:24][CH2:25][CH3:26])=[O:23])[CH:19]=[CH:18][C:17]=2[CH3:27])[CH:3]=1.[OH-].[Na+].O>CO>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([C:14]#[C:15][C:16]2[CH:21]=[C:20]([S:22]([CH2:24][CH2:25][CH3:26])=[O:23])[CH:19]=[CH:18][C:17]=2[CH3:27])[CH:3]=1
Reactant: CCCS(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OCC(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCS(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OCC(=O)O)c1
Reaction time: 3 h
Yield: 83.4 %

Procedure:
A solution of methyl (4-chloro-2-{[2-methyl-5-(propylsulfinyl)phenyl]ethynyl}phenoxy)acetate (Intermediate 221, 125 mg; 0.31 mmol) in MeOH (5 ml) was treated with a 1M solution of sodium hydroxide in water (0.93 ml; 0.93 mmol). After stirring for 3 hours, the solvent was removed under reduced pressure, the residue was taken up in AcOEt and extracted with 0.1N HCl. The organic phase was dried on MgSO4 and concentrated to give a residue which was triturated in diethyl ether, to afford the title compound as a pale yellow solid (101 mg, 83%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11](=O)[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(OCC)(=O)C.[Pd]>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][CH2:12][CH2:11][C:4]1[CH:5]=[CH:6][C:7]([NH:8][C:20](=[O:22])[CH3:21])=[C:2]([CH3:1])[CH:3]=1)[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CCC(=O)c1ccc([N+](=O)[O-])c(C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCc1ccc(NC(C)=O)c(C)c1
Reaction time: 8 h
Yield: 90 %

Procedure:
The product from Example 101 (18.05 g) was dissolved in ethyl acetate (1 L) and subjected to hydrogenation with 20% Pd/C (dry) in the presence of acetic anhydride (15 ml). The reaction mixture was filtered, and the solvent was evaporated. The residue was dissolved in ethanol (250 ml) and a catalytic amount of sulfuric acid (5 drops) was added. The resulting solution was hydrogenated at room temperature overnight. The catalyst was filtered and the filtrate was washed with 5% sodium bicarbonate dried and the solvent was evaporated to afford the desired compound in 90% yield.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[N:16]1([CH2:20][C@@H:21]([NH2:29])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[CH2:19][CH2:18][CH2:17]1>>[N:16]1([CH2:20][C@@H:21]([NH:29][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: N[C@H](CN1CCC1)c1cccc(F)c1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: NC(=O)c1ccnc2c(N[C@H](CN3CCC3)c3cccc(F)c3)ncnc12

Procedure:
Compound 68 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with (S)-2-azetidin-1-yl-1-(3-fluoro-phenyl)-ethylamine hydrochloride to give the title compound. LC/MS [367 (M+H)]1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.07 (d, 1H), 9.01 (d, 1H), 8.56 (s, 1H), 8.39 (d, 1H), 8.17 (s, 1H), 7.34 (m, 3H), 7.07 (m, 1H), 5.36 (m, 1H), 3.13 (m, 4H), 2.86 (m, 1H), 1.96 (m, 2H).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:9]1[N:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=[N:16]2)[C:12]([Cl:24])=[CH:11][N:10]=1>C1COCC1>[N:15]1([C:13]2[C:12]([Cl:24])=[CH:11][N:10]=[C:9]([NH:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[N:14]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1
Reactant: Clc1ncc(Cl)c(-n2nnc3ccccc32)n1
Reactant: NC1CCCCC1
Solvent: C1CCOC1
Product: Clc1cnc(NC2CCCCC2)nc1-n1nnc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.4 %

Procedure:
Cyclohexylamine (0.21 mL, 1.88 mmol) was added in portions to a solution of 1-(2,5-dichloro-pyrimidin-4-yl)-1H-benzotriazole (250 mg, 0.94 mmol) in THF (30 mL) at RT under nitrogen atmosphere. The resultant colorless solution was stirred at RT for 4 hours. TEA (2.82 mmol) was then added and the reaction mixture was stirred at RT overnight. The mixture was partitioned between water (50 mL) and EtOAc (50 mL). The organic layer was separated, washed twice with water (50 mL) and once with brine (50 mL), then dried over Na2SO4, filtered and evaporated under reduced pressure to give an off-white solid. This crude material was purified via flash chromatography (toluene/EtOAc, 98/2) to afford 162 mg (53% yield) of (4-benzotriazol-1-yl-5-chloro-pyrimidin-2-yl)-cyclohexyl-amine as an off-white solid. MS: 329.14 (M+1)+, 301.14 ((M+1)+−28).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[C:9]1[N:14]=[C:13]([C:15]([OH:48])([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)[C:16]2[C:24]3[N:23]=[C:22]([O:25]CC)[N:21](C(OC(C)(C)C)=O)[C:20]=3[CH:19]=[C:18]([C:35]3[C:36]([CH3:41])=[N:37][O:38][C:39]=3[CH3:40])[CH:17]=2)[CH:12]=[CH:11][CH:10]=1>C1COCC1>[CH3:41][C:36]1[C:35]([C:18]2[CH:17]=[C:16]([C:15]([OH:48])([C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([O:5][CH2:4][CH2:3][O:2][CH3:1])[N:14]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=3)[C:24]3[NH:23][C:22](=[O:25])[NH:21][C:20]=3[CH:19]=2)=[C:39]([CH3:40])[O:38][N:37]=1
Reactant: CCOc1nc2c(C(O)(c3ccccn3)c3cccc(Cl)n3)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1cccc(C(O)(c2ccccn2)c2cc(-c3c(C)noc3C)cc3[nH]c(=O)[nH]c23)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
2-methoxyethanol (25 mg, 0.33 mmol) was dissolved in THF (0.5 mL) and cooled to 0° C. Sodium hydride (8 mg, 0.33 mmol) was added in one portion and the reaction was allowed to come to rt and stir for 10 minutes. The reaction was then cooled back to 0° C. and tert-butyl 4-((6-chloropyridin-2-yl)(hydroxy)(pyridin-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazole-1-carboxylate (24 mg, 0.04 mmol) was added and the reaction was sealed and heated to 80° C. overnight. Reaction was concentrated and the residue was taken up in EtOH (1.5 mL) and 4M HCl/dioxane (0.5 mL) and heated for 2 hours at 60° C. The reaction was cooled to rt and filtered to remove the sodium salt. Filterate was concentrated to afford the desired product as a brown film.
Reaction SMILES: Br[CH2:2][C:3]([F:6])([F:5])[F:4].C(N(CC)CC)C.[Br:14][C:15]1[CH:26]=[CH:25][C:18]([CH2:19][NH:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:17][CH:16]=1>CN(C=O)C>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]([CH2:21][CH2:22][O:23][CH3:24])[CH2:2][C:3]([F:6])([F:5])[F:4])=[CH:25][CH:26]=1
Reactant: FC(F)(F)CBr
Reactant: COCCNCc1ccc(Br)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCN(Cc1ccc(Br)cc1)CC(F)(F)F
Reaction time: 18 h

Procedure:
To a solution of 2-bromo-1,1,1-trifluoroethane (0.74 ml) and triethylamine (1.13 ml) in DMF (30 ml) was added (4-bromobenzyl)-(2-methoxyethyl)amine (2.05 g). The resulting mixture was stirred for 18 h. The mixture was partitioned between ethyl acetate and water, the organic layer was dried and evaporated to an oil, which was purified by column chromatography eluting with a gradient of ethyl acetate (60 to 100%) in isohexane to give (4-bromobenzyl)-(2-methoxyethyl)-(2,2,2-trifluoroethyl) amine (1.84 g). 1H NMR (DMSO-D6) δ 2.1 (bs, 2H), 2.6 (t, 2H), 3.2 (s, 3H), 3.4 (t, 2H), 3.65 (d, 2H), 7.25 (d, 2H), 7.45 (d, 2H). c) (4-Bromobenzyl)-(2-methoxyethyl)amine 2-Methoxyethylamine (16 ml) was added to a solution of 4-bromobenzaldehyde (17.2 g) in THF (150 ml). Glacial acetic acid (5.32 ml) and MgSO4 (0.5 g) were added and the mixture was stirred for 45 min. Sodium triacetoxyborohydride (29.7 g) was added and the resulting mixture was stirred for 4 h. The mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was dried and concentrated to an oil, which was purified by column chromatography, eluting with a gradient of ethyl acetate (10 to 100%) in isohexane, then eluting with methanol/DCM (10:90) to give (4-bromobenzyl)-(2-methoxyethyl)amine (13.0 g) as a yellow oil. MS (ES) 244 (M+H)+. 1H NMR (DMSO-D6) δ 2.05 (bs, 1H), 2.6 (t, 2H), 3.38 (t, 2H), 3.2 (s, 3H), 3.62 (s, 2H), 7.25 (d, 2H), 7.45 (d, 2H).