Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH3:5][O:6][C:7](=[O:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:22][OH:23])[C:16]=1[CH3:24]>O.O1CCOCC1.O>[CH3:5][O:6][C:7](=[O:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([OH:23])[C:3]([NH:2][CH3:1])=[O:4])[C:16]=1[CH3:24]
Reactant: CN=C=O
Reactant: COC(=O)c1ccccc1Nc1cccc(CNO)c1C
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)N(O)Cc1cccc(Nc2ccccc2C(=O)OC)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.1 %

Procedure:
Methyl isocyanate (0.33 g, 5.8 mmol) is added dropwise to 2-[[3-(N-hydroxyamino)methyl-2-methylphenyl]amino]benzoic acid methyl ester (1.5 g, 5.2 mmol) in 33% water/dioxane (60 mL) with ice bath cooling. The reaction mixture is stirred at 0° C. for 30 minutes and then at room temperature for 1 hour. It is then diluted with water (100 mL) and extracted with ethyl acetate (200 mL). The organic layer is washed with water (50 mL) and dried over magnesium sulfate. Evaporation of the ethyl acetate gives the crude product which is purified by recrystallization first from ether and then from ethyl acetate to give 2-[[3-[[hydroxy[(methylamino)carbonyl]amino]methyl]2-methylphenyl]amino]benzoic acid methyl ester (0.68 g, 38%). mp=173-175° C.
Reaction SMILES: [CH2:1]([C:3]1[S:17][C:6]2=[N:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([OH:11])=[C:5]2[CH:4]=1)[CH3:2].[C:18]([O:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([C:3]1[S:17][C:6]2[N:7]([CH2:35][C:34]3[CH:37]=[CH:38][C:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])=[CH:32][CH:33]=3)[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCOC(=O)c1cnc2sc(CC)cc2c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2sc(CC)cc2c1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 62.3 %

Procedure:
A mixture of ethyl 2-ethyl-4-hydroxythieno[2,3-b]pyridine-5-carboxylate (200 mg, 0.8 mmol), 4-(2-t-butoxycarbonylphenyl)benzyl bromide (300 mg, 0.9 mmol) and cesium carbonate (650 mg, 2.0 mmol) in DMF (10 ml) was stirred at 60° C. for 3 hours and further at 100° C. for an additional hour. After cooling, the reaction mixture was poured into water followed by extraction with ethyl acetate. The organic layer was washed with water, dried (MgSO4), and evaporated to dryness. The resulting residue was purified by flash column chromatography on silica gel to give 258 mg (62%) of the title compound as crystals.
Reaction SMILES: C(SCC1CS[C@@H]2C(NC(=O)C(C3N=C(N[C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)SC=3)=NOC)C(=O)N2C=1C(O)=O)(=O)C.C(O)=[O:51]>>[C:30]1([C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[OH:51])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=CO
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Product: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 55 °C

Procedure:
A mixture of 4.58 g of the product of Example 16 and 30 ml of 50% aqueous formic acid was heated at 55° C. for 20 minutes and crystallization occured. The mixture was cooled and was diluted and stirred. The mixture was vacuum filtered and the product was rinsed and dried to obtain 1.257 g of triphenyl carbinol. The filtrate was evaporated to dryness under reduced pressure and the residue was taken up in water. Crystallization occured and the mixture was stirred for 30 minutes and was vacuum filtered. The solid was rinsed and dried to obtain 1.68 g of raw product. The latter was dissolved in 4 ml of a molar solution of sodium bicarbonate and the insolubles were ground up. The mixture was vacuum filtered and the filtrate was rinsed with water. 0.24 ml of acetic acid were added to the filtrate and the mixture was vacuum filtered. The precipitate was rinsed with water and dried to obtain 426 mg of purified product. 0.15 ml of formic acid were added to the filtrate and crystallization occurred. The mixture was vacuum filtered and the product was rinsed with water and dried to obtain 505 mg of more pure anti isomer of 3-acetylthiomethyl-7-[{2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl}amino]-ceph-3-eme-4-carboxylic acid melting at 190° C.
Reaction SMILES: [CH:1]([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)=[CH:13][C:8]=2[CH:7]=[C:6]([C:26]([O:28]C)=[O:27])[CH2:5][CH2:4]1)=[O:2].[OH-].[Na+]>CO.C1COCC1>[CH:1]([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:18][CH:19]=3)=[CH:13][C:8]=2[CH:7]=[C:6]([C:26]([OH:28])=[O:27])[CH2:5][CH2:4]1)=[O:2]
Reactant: COC(=O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2N(C=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=CN1CCC(C(=O)O)=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
In methanol (250 ml) and THF (250 ml) was dissolved methyl 1-formyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (3.54 g). To the solution was added 1N sodium hydroxide solution (90 ml), and the mixture was stirred at room temperature overnight and concentrated. To the mixture was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 1-formyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (3.30 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[CH:32]1([CH2:38][N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:30])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:42]4[CH2:43][CH2:44][N:39]([CH2:38][CH:32]5[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]5)[CH2:40][CH2:41]4)=[O:23])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: C1CCC(CN2CCNCC2)CC1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(CC2CCCCC2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(cyclohexylmethyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=611.96 (M+H+); retention time=0.65 minutes.
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[CH3:22])[N:13]=[C:12]([NH:23][CH3:24])[N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:25][NH2:26].CCN(C(C)C)C(C)C>C(O)C>[CH3:24][NH:23][C:12]1[N:11]=[C:10]([C:8]2[CH:7]=[C:6]3[C:3]([C:4]([NH2:5])=[N:25][NH:26]3)=[CH:2][CH:9]=2)[CH:15]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@H:17]2[CH3:22])[N:13]=1
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2CCOC[C@H]2C)n1
Reactant: NN
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCOC[C@H]2C)n1
Temperature: 150 °C
Yield: 41.8 %

Procedure:
To a 5-mL microwave vial was added 2-fluoro-4-{2-(methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}benzonitrile (270 mg, 0.824 mmol), hydrazine (0.31 mL, 9.9 mmol), Hunig's base (0.576 mL, 3.30 mmol), and ethanol (3 mL). The reaction mixture was heated at 150° C. for 70 minutes in a microwave reactor. LCMS analysis indicated good conversion, so the reaction mixture was concentrated, dissolved in DMSO and purified by RP-HPLC (8-32% CH3CN in water, 0.1% TFA). The product fractions were pooled, then basified with NaHCO3 and extracted with EtOAc. The organic layer was dried and concentrated to afford the title compound (117 mg). LC-MS (ES) m/z=340 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.17-1.23 (m, 3H), 2.84 (d, J=4.0 Hz, 3H), 3.02-3.20 (m, 1H), 3.38-3.51 (m, 1H), 3.56-3.66 (m, 1H), 3.67-3.78 (m, 1H), 3.87-3.98 (m, 1H), 4.07-4.19 (m, 1H), 4.45-4.57 (m, 1H), 5.38 (s, 2H), 6.55 (bs, 2H), 7.61 (s, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.98 (bs, 1H), 11.51 (s, 1H).
Reaction SMILES: [CH3:1][C@@H:2]([N:9]1[CH2:13][CH2:12][C:11]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)([CH2:14][CH2:15]OS(C)(=O)=O)[C:10]1=[O:29])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:30]([O:32][CH2:33][CH2:34][N:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)[CH3:31]>>[CH3:1][C@@H:2]([N:9]1[CH2:13][CH2:12][C:11]([CH2:14][CH2:15][N:48]2[CH2:47][CH2:46][CH:45]([NH:44][C:36]3[N:35]([CH2:34][CH2:33][O:32][CH2:30][CH3:31])[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[N:37]=3)[CH2:50][CH2:49]2)([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:10]1=[O:29])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@H](c1ccccc1)N1CCC(CCOS(C)(=O)=O)(Cc2ccc(F)cc2)C1=O
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Product: CCOCCn1c(NC2CCN(CCC3(Cc4ccc(F)cc4)CCN([C@H](C)c4ccccc4)C3=O)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-((R)-α-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine (Rf=0.75 silica gel, ethyl acetate) and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give a diastereomer of the title compound.
Reaction SMILES: [Br:1][CH2:2][CH:3]([CH:7]([CH3:9])[CH3:8])[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:15][C:16](=[CH2:18])[CH3:17].C(=O)([O-])O.[Na+]>ClCCl>[C:16]([O:5][C:4](=[O:6])[CH:3]([CH2:2][Br:1])[CH:7]([CH3:9])[CH3:8])([CH3:18])([CH3:17])[CH3:15]
Reactant: CC(C)C(CBr)C(=O)O
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C(CBr)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
To a solution of 2-bromomethyl-3-methyl-butyric acid (52.1 g, 0.267 mol) in dichloromethane (150 ml) was added concentrated sulphuric acid (2.85 ml) and isobutylene (150 ml). The mixture was stirred in a Parr vessel at room temperature for 24 hours. The mixture was slowly added to a saturated solution of sodium hydrogencarbonate (300 ml) and extracted with dichloromethane (50 ml). The organic layer was washed with brine (100 ml), separated, dried over magnesium sulphate, filtered and the solvent removed in vacuo to afford the title compound as a pale yellow oil (66.4 g, 99%).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:19]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[S:26][C:16]=3[N:17]=2)[CH:21]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3cccnc3)nc2s1
Product: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-methylenedioxyphenethylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][N:2]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[C:3]1[N:8]=[CH:7][CH:6]=[C:5]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:4]=1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[CH3:1][N:2]([CH2:20][C:21]([OH:23])=[O:22])[C:3]1[N:8]=[CH:7][CH:6]=[C:5]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:4]=1
Reactant: CN(CC(=O)OC(C)(C)C)c1nccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: CN(CC(=O)O)c1nccc(-c2nc(=O)c3ccccc3s2)n1
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
tert-Butyl {methyl[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyrimidinyl]amino}acetate (0.20 g, 0.52 mmol) was dissolved in trifluoroacetic acid (5 ml), and the mixture was stirred for 0.5 hr. Diisopropyl ether was added thereto. The obtained crystals were recrystallized from ethanol to give the titled compound (0.15 g, 87%) as pale yellow crystals.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[O:14][CH2:15][O:16][CH3:17].C[O:19][B:20](OC)[O:21]C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH3:17][O:16][CH2:15][O:14][C:8]1[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:7]=1[B:20]([OH:21])[OH:19]
Reactant: COB(OC)OC
Reactant: COCOc1ccc(F)cc1Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1ccc(F)cc1B(O)O
Temperature: -78 °C
Yield: 72.7 %

Procedure:
A 500 mL round bottom flask was charged with a 1.6 M solution of n-butyllithium in hexanes (100 mL, 0.16 mol) and flushed with nitrogen. The solution was cooled to −78° C. and a solution of 2-bromo-4-fluoro-1-methoxymethoxy-benzene (30.1 g, 0.13 mol) in dry tetrahydrofuran (50 mL) was added dropwise over one hour. The mixture was stirred at −78° C. and then trimethylborate (20 mL, 0.175 mol) was added very slowly via syringe. The reaction was allowed to gradually warm to room temperature and after two hours the mixture was poured into ice. The mixture was acidified to pH 4 with 5% aqueous citric acid and extracted with ethyl acetate (×3). The combined organic extracts were washed with water and brine, dried over MgSO4 and filtered. The solvent was evaporation under reduced pressure and the residue was recrystallized from hexanes give 2-methoxymethoxy-5-fluorophenylboronic acid (18.9 g).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[CH3:15][O:16][C:17]1[CH:23]=[C:22]([S:24]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:21]=[CH:20][C:18]=1[NH2:19]>CN(C)C(=O)C>[F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4]([NH:19][C:18]1[CH:20]=[CH:21][C:22]([S:24]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)(=[O:25])=[O:26])=[CH:23][C:17]=1[O:16][CH3:15])=[O:5]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: COc1cc(S(=O)(=O)c2ccncc2)ccc1N
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: COc1cc(S(=O)(=O)c2ccncc2)ccc1NC(=O)C(C)(O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.35 g) in N,N-dimethylacetamide (20 mL) was rapidly added thionyl chloride (1.01 g) and the mixture (a precipitate formed after a few minutes) was stirred at -15° to -5° C. for 1 hour. 2-Methoxy-4-(4-pyridylsulfonyl)aniline (1.50 g) was then added in one portion and the mixture allowed to stir at room temperature overnight. The solution was poured into ice water (200 mL) and the resulting tan solid was collected and recrystallized from absolute ethanol to yield the title compound as a white solid (1.58 g); mp 220°-222° C.; MS: 405(M+1); NMR (250 MHz): 1.53 (s,3,), 4.02 (s,3), 7.62 (d,1, J=1.9), 7.68 (dd,1, J=1.9, J=8.5), 7.92-7.95 (m,2,), 8.02 (s, 1,), 8.46 (d,1, J=10) 8.80-8.89 (m,2,), 9.90 (s,1,). Analysis for C16H15F3N2O5S: Calculated: C, 47.53; H, 3.74; N, 6.93; Found: C, 47.56; H, 3.77; N, 6.76.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=3[O:30][CH3:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COc1ccccc1C=O
Product: COc1ccccc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2 methoxybenzaldehyde. MS (ESI) m/z 499.
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][CH:6]([CH3:8])[CH:5]([CH3:9])[O:4]1.[CH3:10][NH2:11]>>[CH3:9][CH:5]1[CH:6]([CH3:8])[O:7][CH:3]([CH2:2][NH:11][CH3:10])[O:4]1
Reactant: CC1OC(CBr)OC1C
Reactant: CN
Product: CNCC1OC(C)C(C)O1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2-Bromomethyl-4,5-dimethyl-1,3-dioxolane (100 grams) and 40% aqueous methylamine (300 ml) were charged into a glass reaction vessel fitted with a mechanical stirrer and thermometer and were stirred at room temperature for a period of about 14 hours. The reaction mixture was then extracted with diethyl ether. The extract was dried and the ether stripped off using a rotary evaporator to yield the desired product N-(4,5-dimethyl-1,3-dioxolan-2-ylmethyl)methylamine as the residue.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[Li]CCCC.[B:17](OC)([O:20]C)[O:18]C>C1COCC1>[B:17]([C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])([OH:20])[OH:18]
Reactant: COB(OC)OC
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)O)cc1B(O)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
3-Bromo-4-methylbenzoic acid (11.00 g, 51.2 mmol) was dissolved in anhydrous THF (150 ml) under argon in a 500 ml 3-necked round bottom flask fitted with two dropping funnels and argon inlet. The stirred solution was cooled to −78° C. and n-BuLi (1.6M in hexane, 60.7 ml, 97.0 mmol) was added drop wise from a dropping funnel (during 1 h). After completion of the addition, the solution was stirred at −78° C. for another 1 h. To this, B(OMe)3 (17.7 ml, 159.0 mmol) was added slowly from a second dropping funnel. The mixture was stirred 1 h at −78° C. and then warmed up to room temperature overnight. The solvent was evaporated under reduced pressure. The crude product was dissolved in ether and poured into aqueous HCl (1N). The mixture was extracted with ether (3×150 ml), and the combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and evaporated to dryness. The crude product was purified using an ISCO system (220 g silica column, hexane/EtOAc gradient and later DCM/MeOH gradient). The impurities washed off in hexane/EtOAc and the pure product eluted in MeOH/DCM (5:95) solvent mixture to give 3.3 g (33% yield) of pure SKC-01-126. 1H NMR (400 MHz, Acetone-d6) δ 12.10 (br s, 1H), 8.16 (s, 1H), 7.90-7.63 (m, 1H), 7.11 (d, J=7.9 Hz, 1H), 2.42 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:25]1[O:29][C:28]2[CH:30]=[C:31]([Cl:36])[C:32]([CH2:34]Cl)=[CH:33][C:27]=2[O:26]1>CN(C=O)C>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:34][C:32]1[CH:33]=[C:27]3[O:26][CH2:25][O:29][C:28]3=[CH:30][C:31]=1[Cl:36])[C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: ClCc1cc2c(cc1Cl)OCO2
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2n1Cc1cc2c(cc1Cl)OCO2
Reaction time: 1 h
Yield: 49.6 %

Procedure:
To a stirring suspension of sodium hydride (2.03grams (hereinafter "g"), (60% in mineral oil), 50.8 millimoles (hereinafter "mmol")) in DMF (100 milliliters (hereinafter "mL")) was added ethyl 5-benzyloxyindole-2-carboxylate (10.0 g, 33.9 mmol). After 10 minutes (hereinafter "min"), 6-chloropiperonyl chloride (10.4 g, 50.8 mmol) was added. After 1 hour, the mixture was partitioned between water and ethyl acetate. The organic layer was washed with water and saturated brine, dried (MgSO4), filtered and concentrated to leave an oily pale yellow solid. The solid was recrystallized from ethanol to provide the title compound as a white solid (7.8 g, 50%). 1HNMR (400 MHz, CDCl3) d 7.49-7.33 (m, 6H), 7.19-7.08 (m, 3H), 6.87 (s, 1H), 5.86 (s, 2H), 5.78 (s, 1H), 5.77 (s, 2H), 5.11 (s, 2H), 4.33 (q, 2H), 1.36 (t, 3H).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:8]=[C:7]([C:14]([O:16]CC)=O)[CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[NH4+:20].CO>>[CH2:1]([C:5]1[N:9]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:8]=[C:7]([C:14]([NH2:20])=[O:16])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [NH4+]
Reactant: CCCCc1cc(C(=O)OCC)nn1C(C)(C)C
Agent: [OH-]
Solvent: CO
Product: CCCCc1cc(C(N)=O)nn1C(C)(C)C
Temperature: 125 °C
Reaction time: 0.5 h

Procedure:
Ethyl 5-butyl-1-tert-butyl-1H-pyrazole-3-carboxylate (60 g, 0.24 mol) in a 1:1 mixture of concentrated ammonium hydroxide/methanol (238 mL) was heated at 125° C. for 37 hours in a pressure vessel. After cooling to ambient temperature, the vessel was placed in an ice bath. The reaction mixture was stirred for 30 minutes, then was concentrated under reduced pressure to a brown oil. The oil was dissolved in dichloromethane and the solution was washed with water and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a wet brown solid. Hexanes were added, the mixture was stirred, and 18.67 g of 5-butyl-1-tert-butyl-1H-pyrazole-3-carboxamide was isolated by filtration as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[C:4]([NH:6][CH:7]([C:9]1[N:14]=[N:13][C:12]([NH:15][C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)=[N:11][CH:10]=1)[CH3:8])=O.P(Cl)(Cl)(Cl)=O>ClCCCl>[Br:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[C:4]1[N:14]2[C:9]([CH:10]=[N:11][C:12]([NH:15][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)=[N:13]2)=[C:7]([CH3:8])[N:6]=1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3Br)nn2)cc(OC)c1OC
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Nc2ncc3c(C)nc(-c4ccccc4Br)n3n2)cc(OC)c1OC
Yield: 1.6 %

Procedure:
In a similar manner as described for Example 1, 2-bromo-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (Intermediate 12) (0.45 g, 0.92 mmol) in 1,2-dichloroethane (20 mL) and phosphorus oxychloride (0.69 mL, 7.4 mmol) gave 7-(2-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (0.0069 g) as a yellow solid. 1H NMR (CDCl3): δ8.85 (s, 1H), 7.67 (d, J=7.9 Hz, 1H), 7.58 (dd, J=7.6, 1.4 Hz, 1H), 7.44 (dd, J=7.7, 7.3 Hz, 1H), 7.35 (ddd, J=7.9, 7.7, 1.4 Hz, 1H), 6.99 (s, 1H), 6.83 (s, 2H), 3.78 (s, 3H), 3.62 (s, 6H), 2.64 (s, 3H). MS m/z 470, 472 (M+1, M+3).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([N:14]=[C:15]=[S:16])[CH3:13].O>C(#N)C>[CH2:12]([NH:14][C:15](=[S:16])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH3:13]
Reactant: CCN=C=S
Reactant: COC(=O)c1ccc(N)cc1
Solvent: O
Solvent: CC#N
Product: CCNC(=S)Nc1ccc(C(=O)OC)cc1
Temperature: 80 °C

Procedure:
To a solution of methyl 4-aminobenzoate (2-2) (30.2 mg, 0.20 mmol) in anhydrous acetonitrile (0.4 mL) is added ethyl isothiocyanate (2-1) (17.52 μL, 0.20 mmol) and the reaction mixture is heated at 80° C. overnight. After cooling to room temperature, the mixture is poured into water (50 mL) and extracted with ethyl acetate (EtOAc) (3×50 mL). The combined organic layers are washed with brine and dried using MgSO4. The drying agents are removed by filtration and the solvent is removed under vacuum. The resulting residue is then purified by flash column chromatography (silica gel, EtOAc/hexane, 0%-40%) to provide methyl 4-(3-ethylthioureido)benzoate (2-3).