Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11](=[O:13])[CH3:12].[OH-].[Na+]>O>[F:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:10]/[C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)/C=C/c1ccc(F)cc1
Temperature: 65 °C
Yield: 100 %

Procedure:
To a mixture of 4-fluorobenzaldehyde (5 mL, 45.2 mmol), propan-2-one (9.13 mL, 124 mmol), and water (9.5 mL) was added 12 mL of a 1% solution of NaOH in water. The reaction mixture was heated at 65° C. for 2 h. The mixture was then partitioned between EtOAc and ice water, the organic layer separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried with MgSO4 and concentrated under vacuum. The product was obtained as a yellow oil and was used in the next step without further purification (7.93 g, 48.3 mmol, 100% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.54-7.51 (m, 2H), 7.47 (d, 1H), 7.08 (t, 2H), 6.64 (d, 1H), 2.37 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH3:12])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1)[NH2:17]>CN1CCCC1=O>[CH2:11]([N:10]1[C:3]2[C:2]([NH:17][C:16]3[CH:18]=[CH:19][C:20]([O:21][C:22]4[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=4)=[C:14]([CH3:13])[CH:15]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)[CH3:12]
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Reactant: CCn1ccc2ncnc(Cl)c21
Solvent: CN1CCCC1=O
Product: CCn1ccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c21
Yield: 39.8 %

Procedure:
To a solution of 4-chloro-5-ethyl-5H-pyrrolo[3,2-d]pyrimidine (85 mg) in 1-methyl-2-pyrrolidone (0.94 mL) was added 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (150 mg). The title compound (67 mg) was obtained as white powder crystals by the reaction in the same manner as in Example 29.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)=[O:5])C.[Li+].[OH-].Cl>C1COCC1>[CH2:11]([N:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1cnn(Cc2ccccc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cnn(Cc2ccccc2)c1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
This known compound [CAS Reg. No. 401647-24-3] was made from 1-benzyl-1 H-pyrazole-4-carboxylic acid ethyl ester by saponification: 1-benzyl-1H-pyrazole-4-carboxylic acid ethyl ester (2.35 g) was dissolved in dry THF (25 mL) and then a 1M aqueous solution of LiOH (15.31 mL) was added. The mixture was stirred at 60° C. for 2.5 hours and analyzed by TLC: starting material was still visible. Another batch of LiOH monohydrate (1.29 g) was added and the mixture was allowed to stir at room temperature for 48 hours. The mixture was poured into ice water and acidified with 2M aqueous HCl (20 mL). The aqueous phase was extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2SO4 and evaporated to give the title compound as a colorless solid (1.55 g). MS (m/e, ISP neg. ion)=201.6 [(M−H+)−].
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:17]([C:21]#[N:22])=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.[NH2:24][OH:25].C(=O)([O-])[O-].[Na+].[Na+]>CCO.O>[OH:25][NH:24][C:21]([C:17]1[C:18]2[CH:19]=[CH:20][C:11]([NH:10][C@H:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]3)=[N:12][C:13]=2[CH:14]=[CH:15][CH:16]=1)=[NH:22]
Reactant: NO
Reactant: N#Cc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(NO)c1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Yield: 78.5 %

Procedure:
A stirred suspension of 2-((R)-indan-1-ylamino)-quinoline-5-carbonitrile (example 80, step A) (571 mg, 2.0 mmol), hydroxylamine hydrochloride (514 mg, 7.4 mmol), sodium carbonate (424 mg, 4.0 mmol) in EtOH (7.5 ml) and water (7.5 ml) was heated under reflux conditions for 24 hours, water (40 ml) was added, and the mixture was extracted with ethyl acetate (3×75 ml). The combined organic layers were washed with brine (30 ml), dried (MgSO4) and evaporated to yield the crude product as solid which was further purified by crystallization (dichloromethane/MeOH) to yield N-hydroxy-2-((R)-indan-1-ylamino)-quinoline-5-carboxamidine as white solid (500 mg, 79%).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][NH:11][CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH2:15]([NH:22][C:23](=[O:26])[CH:24]=[CH2:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>>[CH2:15]([NH:22][C:23](=[O:26])[CH2:24][CH2:25][N:11]1[CH2:12][CH2:13][C:14]2=[C:2]([CH3:1])[C:3]3[C:8]([CH:9]2[CH2:10]1)=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=CC(=O)NCc1ccccc1
Reactant: CC1=C2CCNCC2c2ccccc21
Agent: Cl
Product: CC1=C2CCN(CCC(=O)NCc3ccccc3)CC2c2ccccc21

Procedure:
1,3,4,9b-Tetrahydro-5-methyl-2H-indeno[1,2-c]pyridine and N-benzyl acrylamide are reacted in accordance with the process described in Example 6. Reaction period 8 hours. M.P. of the hydrochloride of the title compound 211°-212.5° from ethanol (decomp.).
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH:10](=O)[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[CH:10](=[C:7]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][C:8]1=[O:9])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: O=CC=Cc1ccccc1
Solvent: O
Product: O=C1NC(=O)C(=CC=Cc2ccccc2)C(=O)N1
Yield: 95.3 %

Procedure:
Barbituric acid (10.0 g) was dissolved in water (150 ml) at reflux, and the solution was stirred vigorously and maintained at just below refluxing point while freshly distilled cinnamaldehyde (10.3 g) was added slowly: a yellow precipitate formed almost immediately. After the addition, the mixture was stirred and maintained at just below refluxing point for 1 hour to complete the reaction. The product was filtered off, washed several times with hot water and then with cold ethanol, and then dried to give yellow 5-cinnamylidenebarbituric acid (18 g, 96% theoretical yield) m.p. 268°-70° (decomp).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([OH:22])[CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[CH:23]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH2:24].[H-].[Na+].O>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([O:22][CH2:24][CH2:23][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CC1
Reactant: C=CS(C)(=O)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(OCCS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
A heterogeneous mixture of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopropanol (0.76 g, 2.6 mmol) and methyl vinyl sulfone (0.54 g, 5.11 mmol) in DMF (10 mL) was heated until a solution formed. Sodium hydride (60% dispersion in oil, 10 mg, 0.26 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. Water (50 mL) and a small amount of brine were added and the mixture was extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford an oil that was purified by flash chromatography (silica gel, eluted with 5% methanol in dichloromethane) to provide 0.75 g of 2-(ethoxymethyl)-1-({1-[2-(methylsulfonyl)ethoxy]cyclopropyl}methyl)-1H-imidazo[4,5-c]quinoline as a tan oil.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[OH:37])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH2:40])=[N-]>CO>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[O:37][CH3:40])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Reactant: C=[N+]=[N-]
Solvent: CO
Product: COC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1

Procedure:
The resulting 7β-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester is taken up in methanol and treated, at 0° C., with an excess of an ethereal solution of diazomethane. After a reaction time of 5 minutes, the solution is concentrated completely and the oily residue is chromatographed on silica gel thick layer plates (toluene/ethyl acetate, 3:1). The silica gel in the zone at Rf=0.19 is extracted with ethyl acetate and gives 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester; melting point 120° C. (from ether), IR spectrum (in CHCl3); 3310, 1775, 1700, 1690 and 1600 cm-1.
Reaction SMILES: [Br:1]Br.[BrH:3].[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([CH2:13][C:14]([O:16][CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[O:15])=[N:5]1>C(O)(=O)C>[BrH:1].[Br:3][CH:13]([C:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:4][N:5]=1)[C:14]([O:16][CH:17]1[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]1)=[O:15]
Reactant: BrBr
Reactant: CN1CCC(OC(=O)Cc2noc3ccccc23)CC1
Agent: Br
Solvent: CC(=O)O
Product: CN1CCC(OC(=O)C(Br)c2noc3ccccc23)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
A solution of bromine (1.12 g) in glacial acetic acid (2 ml) was added dropwise at 60° C. with stirring to a solution of 1-methyl-4-piperidyl 1,2-benzisoxazole-3-acetate hydrobromide (2.0 g) in glacial acetic acid (8 ml). The reaction mixture was stirred for 3 hours at 60° C. and then concentrated in vacuo to about a half volume. The residue was dissolved in acetone and thereto was added diethyl ether until it became turbid. After cooling, the resulting crystals were collected by filtration to give 1-methyl-4-piperidyl 2-bromo-2-(1,2-benzisoxazol-3-yl)acetate hydrobromide (1.9 g). An analytical sample was obtained by recrystallization from ethanol, m.p. 169°-171° C.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH:22]([CH3:24])[CH3:23])[N:13]=[C:12]([NH:25][CH3:26])[N:11]=2)[CH:7]=[C:6]([O:27][CH3:28])[C:3]=1[C:4]#[N:5].O.[NH2:30][NH2:31]>C(O)C>[CH3:26][NH:25][C:12]1[N:11]=[C:10]([C:8]2[CH:9]=[C:2]3[C:3]([C:4]([NH2:5])=[N:30][NH:31]3)=[C:6]([O:27][CH3:28])[CH:7]=2)[CH:15]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@H:17]2[CH:22]([CH3:23])[CH3:24])[N:13]=1
Reactant: NN
Reactant: CNc1nc(-c2cc(F)c(C#N)c(OC)c2)cc(N2CCOC[C@H]2C(C)C)n1
Solvent: CCO
Solvent: O
Product: CNc1nc(-c2cc(OC)c3c(N)n[nH]c3c2)cc(N2CCOC[C@H]2C(C)C)n1
Temperature: 100 °C

Procedure:
To a solution of 2-fluoro-4-{2-(methylamino)-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}-6-(methyloxy)benzonitrile (350 mg, 0.91 mmol) in ethanol (10 mL) was added hydrazine monohydrate (2.5 mL) in one portion. The mixture was heated at 100° C. for 20 hours, cooled to room temperature and concentrated in vacuo. The residue was taken up in water (10 mL) as a suspension. The solids were collected by filtration, washed with water (2×2 mL), and dried under vacuum at room temperature over P2O5 for 20 hours. The solids were washed with hexane (2×3 mL). Drying under vacuum at 65° C. for 20 hours afforded the title compound (302 mg) as a cream-colored solid. LC-MS (ES) m/z=398 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 0.89 (d, J=6.8 Hz, 3H), 1.11 (d, J=6.6 Hz, 3H), 2.45-2.55 (m, 1H), 2.96 (s, 3H), 3.25-3.35 (m, 1H), 3.53-3.61 (m, 2H), 3.94 (dd, J=11.1, 3.5 Hz, 1H), 4.04 (s, 3H), 4.11 (d, J=11.9 Hz, 1H), 6.38 (s, 1H), 6.89 (s, 1H), 7.35 (s, 1H).
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]1[C:22]([CH3:23])=[C:21]([OH:24])[C:20]([CH3:25])=[CH:19][C:17]=1[OH:18].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>ClC(Cl)C>[CH3:25][C:20]1[C:21](=[O:24])[C:22]([CH3:23])=[C:16]([CH3:15])[C:17](=[O:18])[C:19]=1[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: OC(c1ccccc1)c1cccnc1
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC1=C(C)C(=O)C(C(c2ccccc2)c2cccnc2)=C(C)C1=O
Yield: 72.9 %

Procedure:
To a solution of 1.0 g (5.4 mmol) of phenyl-(3-pyridyl) methanol and 823 mg (5.4 mmol) of 2,3,5-trimethylhydroquinone in 15 ml of dichloroethane, 0.5 ml (9.4 mmol) of concentrated sulfuric acid was added, and refluxed by heating for 2 hours. The reaction mixture was made weakly alkaline with a saturated aqueous solution of sodium hydrogen carbonate, from which the organic phase was separated while the aqueous phase was extracted with chloroform and the extract was combined with the organic phase. The organic phase was washed with water, dried, and oxidized with air, from which the solvent was evaporated off. The residue was purified with silica gel column chromatography (isopropyl ether-ethyl acetate (1:1)), to give 1.25 g (72.7%) of 3,5,6-trimethyl-2-[phenyl-(3-pyridyl)methyl]-1,4-benzoquinone. The physical data are shown in Table 1.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:33]([CH3:34])=[CH:32][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]4[CH:28]=[C:27](C)[C:26](=[O:30])[NH:25][C:24]4=[O:31])[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].N1C=CC(=O)NC1=O>>[C:1]([O:5][C@@H:6]([C:10]1[C:33]([CH3:34])=[CH:32][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]4[CH:28]=[CH:27][C:26](=[O:30])[NH:25][C:24]4=[O:31])[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:35]1[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2nc(-c3cccc(-n4cc(C)c(=O)[nH]c4=O)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Agent: O=c1cc[nH]c(=O)[nH]1
Product: Cc1cc2nc(-c3cccc(-n4ccc(=O)[nH]c4=O)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
Prepared in a similar manner as (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)phenyl)benzo[d]thiazol-6-yl)acetic acid, except starting with uracil instead of thymine. LCMS-ESI+: calc'd for C30H279ClN3O5S: 576.1 (M+H+); Found: 576.2 (M+H+). 1H NMR (400 MHz, CD3OD) δ 8.10-8.02 (m, 1H), 7.95 (t, J=1.8 Hz, 1H), 7.83 (s, 1H), 7.72-7.54 (m, 6H), 7.50 (d, J=7.7 Hz, 1H), 7.44-7.37 (m, 1H), 5.81 (d, J=7.7 Hz, 1H), 5.25 (s, 1H), 2.60 (s, 3H), 0.96 (s, 9H).
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=[CH:15][N:14]=1)=[S:11])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].CCO>O>[CH2:20]([O:19][C:18]1[C:13]([NH:12][C:10]([NH2:9])=[S:11])=[N:14][CH:15]=[CH:16][CH:17]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(NC(=S)Nc1ncccc1OCc1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NC(=S)Nc1ncccc1OCc1ccccc1
Yield: 109.4 %

Procedure:
A 1 L round-bottomed flask was charged with 1-benzoyl-3-(3-(benzyloxy)pyridin-2-yl)thiourea (44.4 g, 122 mmol), potassium carbonate (20.3 g, 147 mmol), and EtOH (400 mL). The reaction mixture was heated to reflux overnight, then cooled, poured into water (900 mL) and filtered to afford 1-(3-(benzyloxy)pyridin-2-yl)thiourea (34.6 g) as a yellow solid. 1H NMR (CDCl3) δ 11.01 (s, 1H), 8.69 (s, 1H), 7.78 (d, 1H), 7.44-7.34 (m, 5H), 7.16 (d, 1H), 7.09 (bs, 1H), 6.91 (dd, 1H), 5.16 (s, 2H). LCMS (25 to 95) Rt=2.06 min (apci) m/z=260 (M+H).
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:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH2:25]>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH:25][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Reactant: COc1ccc(C)c(N)c1
Product: COc1ccc(C)c(Nc2cc(C(F)(F)F)nc(-c3cnccn3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.192 mmol), 5-methoxy-2-methylaniline (40 mg, 0.288 mmol) similar to Example 76 and isolated as a yellow solid (40 mg, 58%). 1H NMR (CDCl3): 9.75 (d, J=1.2 Hz, 1H), 8.79 (dd, J=1.5, 2.4 Hz, 1H), 8.73 (d, J=2.4 Hz, 1H), 7.28 (d, J=4.5 Hz, 1H), 7.24 (s, 1H), 6.89 (d, J=2.7 Hz, 1H), 6.86 (dd, J=2.7, 8.4 Hz, 1H), 6.73 (s, 1H), 3.82 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: [CH3:1][S-:2].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([NH:16][CH:17]1[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:27][CH2:28]Cl)[C:18]1=[O:30])=[O:15])=[CH:8]2>CN(C=O)C.CCOC(C)=O>[Cl:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([NH:16][CH:17]1[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:27][CH2:28][S:2][CH3:1])[C:18]1=[O:30])=[O:15])=[CH:8]2
Reactant: O=C(NC1Cc2ccccc2N(CCCl)C1=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSCCN1C(=O)C(NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Temperature: 80 °C
Yield: 37.1 %

Procedure:
Sodium thiomethoxide (280 mg, 4.00 mmol) and KI (10 mg, 0.06 mmol) were added to a soluton of 5-chloro-N-[1-(2-chloroethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-1H-indole-2-carboxamide (Method 3; 1.07 g, 2.67 mmol) in DMF (10 mL) under an inert atmosphere and heated at 80° C. for 2 hours. On cooling the mixture was diluted with EtOAc (100 mL), washed with water (20 mL), dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (DCM to DCM:THF (2:23)) to give a white solid. The solid was triturated with refluxing Et2O (20 mL) and the solid filtered, washed with Et2O (10 mL) then hexane (10 mL) to afford the title compound (410 mg, 37%) as an off white solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([OH:15])=O)[CH:9]=2)[N:4]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[CH3:53][N:54]1[C:58]([CH3:59])=[C:57]([C@H:60]([NH2:62])[CH3:61])[CH:56]=[N:55]1>C(Cl)Cl>[CH3:53][N:54]1[C:58]([CH3:59])=[C:57]([C@H:60]([NH:62][C:13]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]=[C:3]([C:2]([F:1])([F:17])[F:16])[CH:12]=[CH:11]3)=[O:15])[CH3:61])[CH:56]=[N:55]1
Reactant: O=C(O)c1ccc2nc(C(F)(F)F)ccc2c1
Reactant: Cc1c([C@@H](C)N)cnn1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c([C@@H](C)NC(=O)c2ccc3nc(C(F)(F)F)ccc3c2)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
2-Trifluoromethylquinoline-6-carboxylic acid (100 mg, 0.415 mmol) was dissolved in DCM (10 mL) and N,N-di-iso-propylethylamine (Hunig's base, 268 μl, 1.54 mmol) was added. HATU (158 mg, 0.415 mmol) was added followed by (1R)-1-[1,5-dimethyl-1H-pyrazol-4-yl]ethanamine dihydrochloride (88 mg, 0.415 mmol) and the solution was stirred at RT overnight. The reaction mixture was concentrated and the residue was dissolved in EtOAc (65 mL) then partitioned with sat. aq. NaHCO3 (2×20 mL) and then brine (30 mL). The organic layer dried over MgSO4, filtered and solvent removed under reduced pressure to give a golden oil/gum. The product was purified using an ISCO (12 g column), eluting with EtOAc:Heptane (5:95 increasing to 100:0). Fractions containing pure product concentrated under reduced pressure to give a white foamy solid, 150 mg, yield=41%. 1H NMR (400 MHz, CD3OD) δ 8.68 (1H, d), 8.47-8.49 (1H, m), 8.20-8.23 (2H, m), 7.92 (1H, d), 7.48 (1H, s), 5.29 (1H, q) 3.76 (3H, s), 2.33 (3H, s) and 1.61 (3H, d). LCMS (2 min run): UV (1.37 min, 82%); ELSD (1.37 min, 100%). Mass ion: 363=MH+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19].CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(OS(C)(=O)=O)ccc1Cl
Temperature: 25 °C

Procedure:
To a solution of 4-chloro-3-methylphenol (35.0 g, 277 mmol) in 100 mL of methylene chloride at 0° C. was added triethylamine (77.0 mL, 554 mmol), followed by methanesulfonyl chloride (32.2 mL, 416 mmol). The reaction was allowed to warm to room temperature for 1 hr. The solution was poured into EtOAc, washed with H2O and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting yellow solid product was used without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:14]=[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][N:8]2[N:7]=1)=O)C.C1COCC1.[BH4-].[Na+].[NH4+].[Cl-]>ClCCl.O.C(O)C>[N:14]1[C:6]([CH2:4][OH:3])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12
Reactant: CCOC(=O)c1nc2ccccn2n1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: OCc1nc2ccccn2n1
Temperature: 65 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
Under argon atmosphere, ethyl[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (1 g, 5.23 mmol) was combined with THF (10 mL) at RT to give a brown suspension. Sodium borohydride (1.19 g, 31.4 mmol) was added in four portions. The mixture was heated to 65° C. for 15 min. After cooling down to RT, ethanol (10 mL) was added dropwise over a period of 15 min. The mixture was stirred at 65° C. for 4 h. The mixture was cooled down to 0-5° C. and NH4Cl (saturated aqueous solution, 20 mL) was added dropwise over a period of 10 min (foam!). Water (20 mL) was added and the yellow suspension was poured into dichloromethane (100 mL) and extracted with dichloromethane (4×75 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo to give the product as light yellow solid (720 mg, 4.76 mmol, 91%) which was used without further purification for the next step.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[C:15]([F:17])[C:12]([C:13]#[N:14])=[C:11]([F:18])[CH:10]=2)=[N:5]1.[CH:20]([C:23]1[N:27]=[C:26]([C:28](O)=[O:29])[O:25][N:24]=1)([CH3:22])[CH3:21].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[C:13]([C:12]1[C:11]([F:18])=[CH:10][C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:28]([C:26]3[O:25][N:24]=[C:23]([CH:20]([CH3:22])[CH3:21])[N:27]=3)=[O:29])[CH3:19])[N:5]=2)=[CH:16][C:15]=1[F:17])#[N:14]
Reactant: CC(C)c1noc(C(=O)O)n1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(F)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)c1noc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(F)c3)n2)n1
Yield: 2 %

Procedure:
The title compound was synthesized from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile (0.168 g, 0.64 mmol), 3-isopropyl-1,2,4-oxadiazole-5-carboxylic acid (0.1 g, 0.64 mmol), HOBt (0.13 g, 0.96 mmol), DIPEA (0.335 mL, 1.92 mmol) and EDCI (0.184 g, 0.96 mmol) using DMF as solvent using the method of Example 34(d). Yield of the title compound 5 mg. 1H NMR (400 MHz; MeOD): δ 1.27 (d, 3H), 1.36 (d, 6H), 3.16 (m, 1H), 4.39 (m, 2H), 4.58 (m, 1H), 6.80 (d, 1H), 7.62 (m, 2H), 7.72 (d, 1H).