Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl.[NH2:19][OH:20].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[Cl:1][C:2]1[C:11]([CH:12]=[N:19][OH:20])=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=O)c1Cl
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C=NO)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.4 %

Procedure:
15.00 g (54 mmol) of methyl 2-chloro-3-formyl-4-methylsulfonylbenzoate and 4.20 g (60 mmol) of hydroxylamine hydrochloride were taken up in 300 ml of methanol, and a solution of 3.18 g (30 mmol) of sodium carbonate in 80 ml of water was added dropwise. After the mixture had been stirred at room temperature for 12 hours, the methanol was distilled off and the residue was diluted with water and extracted with diethyl ether. The organic phase was dried and the solvent was removed. 14.40 g (91% of theory) of methyl 2-chloro-3-hydroxyiminomethyl-4-methylsulfonylbenzoate were obtained.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:28][CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>>[C:34]([Si:31]([CH3:33])([CH3:32])[O:30][CH2:29][CH2:28][N:22]1[CH2:21][CH2:20][N:16]2[C:17]3[CH:18]=[CH:19][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:12][C:13]=3[CH:14]=[C:15]2[C:23]1=[O:24])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(CCO[Si](C)(C)C(C)(C)C)C2=O)CC1
Yield: 52 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and (2-bromoethoxy)-tert-butyldimethylsilane, to give the desired product as a white solid (52%).
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([CH2:19][O:20][CH3:21])[C:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:6]2[CH:5]=[CH:4][CH:3]=1.O.[CH3:23][O:24][C:25]1[CH:30]=[C:29]([CH2:31][O:32][CH3:33])[CH:28]=[C:27]([O:34][CH3:35])[C:26]=1OB(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:35][O:34][C:27]1[CH:28]=[C:29]([CH2:31][O:32][CH3:33])[CH:30]=[C:25]([O:24][CH3:23])[C:26]=1[C:2]1[N:7]2[N:8]=[C:9]([CH2:19][O:20][CH3:21])[C:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: COCc1nn2c(Br)cccc2c1NC(=O)OC(C)(C)C
Reactant: COCc1cc(OC)c(OB(O)O)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: COCc1cc(OC)c(-c2cccc3c(NC(=O)OC(C)(C)C)c(COC)nn23)c(OC)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
To a solution of tert-butyl N-[7-bromo-2-(methoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate (300 mg) dissolved in 1,2-dimethoxyethane (10 mL) and water (5 mL) was added 2,6-dimethoxy-4-methoxymethylphenylboric acid (323 mg), tetrakis(triphenylphosphine)palladium(0) (146 mg) and barium hydroxide octahydrate (398 mg), and the reaction mixture was heated and stirred for 2 hours at 80° C. under a nitrogen stream. Water was added to the obtained reaction mixture, the reaction mixture was extracted with ethyl acetate, and the organic extract was washed with brine. The obtained organic extract was dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and the title compound (245 mg) was obtained as a light yellow amorphous solid from the n-hexane:ethyl acetate (1:1) fraction.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1B(O)O.O=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:11]2[C:10]([F:9])=[CH:15][CH:14]=[CH:13][C:12]=2[F:16])=[CH:4][CH:3]=1
Reactant: OB(O)c1c(F)cccc1F
Reactant: Oc1ccc(Br)cc1
Agent: O=O
Solvent: ClCCl
Product: Fc1cccc(F)c1Oc1ccc(Br)cc1

Procedure:
Into a 100 mL round bottom flask was added 4-bromophenol (2.19 g, 12.7 mmol), 2,6-difluorophenylboronic acid (1.00 g, 6.33 mmol), cupric acetate (1.4 g, 7.70 mmol) and DCM (50 mL). TEA (4.0 mL, 29.0 mmol) was then added followed by 4 A° molecular sieves and the reaction mixture was stirred at rt for 48 h with an air balloon to supply oxygen. Purification by flash column chromatography using 5% EtOAc in hexanes afforded the title compound as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21](O)=[O:22])[NH:3]1.[C:24]1([C@@H:30]([NH2:38])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([C@@H:30]([NH:38][C:21]([C@H:11]2[CH2:10][CH2:9][C@H:8]3[C@H:7]4[C@H:16]([CH2:15][CH2:14][C@:12]23[CH3:13])[C@:17]2([CH3:20])[C:4]([NH:3][C:2](=[O:1])[CH2:19][CH2:18]2)=[CH:5][CH2:6]4)=[O:22])[CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reactant: N[C@@H](Cc1ccccc1)c1ccccc1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)N[C@@H](Cc1ccccc1)c1ccccc1
Yield: 92 %

Procedure:
The title compound was prepared in a yield of 92% in a similar manner to that described in Example 1 by reacting 3-oxo-4-azaandrost-5-ene-17β-carboxylic acid and (S)-1,2-diphenylethylamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:33](=[O:36])[CH:34]=[CH2:35])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.5 %

Procedure:
4-(4-Amino-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (7.1 g, 21 mmol) was dissolved in DCM (70 ml). To this was added diisopropylethylamine (7.3 ml, 42 mmol) in one portion followed by the drop wise addition of acryloyl chloride (1.54 ml, 19 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. The THF was removed under vacuum and the resulting crude material was purified by column chromatography (elution: 60% heptane, 40% ethyl acetate) to give the title compound (5.3 g, 20% yield) as a pale yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:16]([CH3:15])(=[O:18])=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (9.2 g) in dichloromethane (170 ml), stirring at 0° C. was added methane sulphonyl chloride (5.33 ml) and triethylamine (0.24 ml). The reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was partitioned between chloroform and water. The combined organics were washed with brine and dried (MgSO4). The solvent was removed in vacuo to yield 14 g of 4-methanesulfonyl-piperidine-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH:1]1([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][C:26]([N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)=[O:27])=[C:21]([C:34](=[O:38])[N:35]([CH3:37])[CH3:36])[CH:20]=4)[CH:17]=3)[N:12](COC(=O)C(C)(C)C)[CH:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][O:2]1.[OH-].[Na+]>O1CCCC1.CO>[CH:1]1([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][C:26]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)=[O:27])=[C:21]([C:34](=[O:38])[N:35]([CH3:36])[CH3:37])[CH:20]=4)[CH:17]=3)[NH:12][CH:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][O:2]1
Reactant: CN(C)C(=O)c1cc(-c2cnc3c(c2)c(C2OCc4ccccc42)cn3COC(=O)C(C)(C)C)ccc1NC(=O)N1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C(=O)c1cc(-c2cnc3[nH]cc(C4OCc5ccccc54)c3c2)ccc1NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,2-dimethyl-propionic acid 3-(1,3-dihydro-isobenzofuran-1-yl)-5-{3-dimethylcarbamoyl-4-[(morpholine-4-carbonyl)-amino]-phenyl}-pyrrolo[2,3-b]pyridin-1-ylmethyl ester was dissolved in tetrahydrofuran. 1 M sodium hydroxide in methanol was added to the mixture, and the reaction was stirred for 2 hours at room temperature. The reaction was quenched with sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried, filtered, and concentrated. The crude material was purified then by mass-triggered reverse-phase HPLC to afford morpholine-4-carboxylic acid {4-[3-(1,3-dihydro-isobenzofuran-1-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-dimethylcarbamoyl-phenyl}-amide. 1H NMR (250 MHz, DMSO-d6) δ 11.74 (s, 1H), 8.75 (s, 1H), 8.47 (s, 1H), 7.69 (d, J=8.7 Hz, 1H), 7.55-7.49 (m, 3H), 7.44-7.22 (m, 4H), 7.10 (d, J=7.6 Hz, 1H), 6.48 (s, 1H), 5.13 (m, 2H), 3.62-3.58 (m, 4H), 3.42-3.35 (m, 4H in water peak), 2.98 (s, 3H), 2.94 (s, 3H); MS: m/z 512.3 (M+H+).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:5]([CH2:6][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[NH2:8])=[CH:4]1.C(N(CC)CC)C.[F:26][C:27]1[CH:37]=[CH:36][C:30]([CH:31]=[CH:32][C:33](O)=[O:34])=[CH:29][CH:28]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:26][C:27]1[CH:28]=[CH:29][C:30]([CH:31]=[CH:32][C:33]([NH:8][C@H:7]([C:9]([O:11][CH3:12])=[O:10])[CH2:6][C:5]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:3]([CH3:2])[CH:4]=2)=[O:34])=[CH:36][CH:37]=1
Reactant: COC(=O)[C@@H](N)Cc1cn(C)c2ccccc12
Reactant: O=C(O)C=Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cn(C)c2ccccc12)NC(=O)C=Cc1ccc(F)cc1
Yield: 95.4 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 20 (2.0 g), triethylamine (1.1 mL), 4-fluorocinnamic acid (1.4 g), WSC.HCl (1.6 g), and methylene chloride (80 mL), to give the captioned compound (2.7 g, 94%) as an oily product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1S([O-])(=O)=O.[Na+].[NH2-:15].[Na+].N>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[NH2:15]
Reactant: Cc1cc(C)c(C)c(S(=O)(=O)[O-])c1
Reactant: [NH2-]
Agent: N
Agent: [Na+]
Product: Cc1cc(C)c(C)c(N)c1
Yield: 78.4 %

Procedure:
In a 200-ml autoclave were placed 11.2 grams (0.05 mole) of anydrous sodium 2,3,5-trimethylbenzene sulfonate, 5.2 grams (0.13 mole) of sodium amide and 60 ml liquid ammonia in the same manner as in Example 1. The resultant mixture was heated at 160° C for 9 hours. The reaction pressure in the autoclave was 140 atm. during the reaction. After the ammonia was removed, 10 ml of water was added to the reaction mixture for hydrolysis. The product was extracted with ether and the ether was distilled off to produce crude 2,3,5-trimethyl aniline. The recrystallization thereof from petroleum ether gave 5.3 grams of 2,3,5-trimethyl aniline having a melting point of 36° C. Yield was 78.8%.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:16])[C:10]2=[N+]=[N-])[C:7]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(=[O:3])[CH3:2].[CH2:24](B(CC)CC)[CH3:25].O>C1COCC1>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:16])[CH:10]2[CH2:24][CH3:25])[C:7]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(=[O:3])[CH3:2]
Reactant: CCB(CC)CC
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(=[N+]=[N-])C2SC1
Solvent: C1CCOC1
Solvent: O
Product: CCC1C(=O)N2C(C(=O)OC(C)(C)C)=C(COC(C)=O)CSC12
Temperature: -78 °C

Procedure:
A 2 liter, 3-necked round bottom flask fitted with 2 dropping funnels was charged with 200 ml THF and cooled to -78° C. under N2. One dropping funnel was charged with a solution of 6.33 g (15.3 mM] t-butyl 3-acetyloxymethyl-7-diazo-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate in 300 ml THF. The other funnel was charged with 32 ml 1M-triethylborane in THF, 1.2 ml H2O, and 300 ml THF. The funnels were adjusted so their contents were added to the flask at 2.5 ml/min and the temperature of the reaction mixture maintained at -78°. After the addition, the cooling bath was removed and the reaction mixture allowed to warm. When the temperature reached -45° C., 6.67 ml 30% H2O2 was added. At -15°, the reaction mixture was washed with 300 ml brine, the organic layer diluted with 300 ml CH2Cl2, washed with 300 ml brine, dried over MgSO4, filtered and stripped to give 7.46 g of yellow oil which was chromatographed on a flash column with CHCl3 /EtOAc (25:1) to yield 1.289 g (19%) t-butyl-3-acetyl-oxymethyl-7α-ethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate a 4:1 mixture of the α and β isomers. NMR(CDCl3): δ1.08, t (J=8 Hz), 3H; 1.50, s, 9H; 1.8, br, qt, 2H; 2.05, s, 3H; 3.1, brm, 1H; 3.4, d, 2H; 4.35, d (J=2Hz), 1H; 4.82, AB qt (J=12, 6Hz) 2H.
Reaction SMILES: CN(C)[CH:3]=[O:4].[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[C:24]([OH:25])=[C:23]([O:26][CH3:27])[C:22]([O:28][CH3:29])=[CH:21][C:20]=1C.N1C=CC=CC=1>O=O>[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[C:24](=[O:25])[C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[C:3](=[O:4])[C:20]=1[CH3:21]
Reactant: COc1cc(C)c(CCCCCCCCCCCCO)c(O)c1OC
Reactant: CN(C)C=O
Agent: O=O
Solvent: c1ccncc1
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCCCO)=C(C)C1=O

Procedure:
To a dimethylformamide solution (30 ml) of 6-(12-hydroxydodecyl)-2,3-dimethoxy-5-methylphenol (1.7 g) are added pyridine (50 mg) and bis(4-hydroxysalicylidene)ethylenediiminocobalt(II) (36 mg), and the mixture is stirred in oxygen streams at atmospheric temperature and pressure for 72 hours. The reaction product is isolated as in Example 7 and recrystallized from ether. The above procedure yields 6-(12-hydroxydodecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (1.37 g), m.p. 63° C.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][C:16]([F:28])([F:27])[O:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[F:15][C:16]([F:27])([F:28])[O:17][C:18]1[CH:23]=[C:22]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Nc1nnc(-c2cccc(OC(F)(F)F)c2)c(-c2ccccc2)n1
Yield: 25.7 %

Procedure:
6-(3-trifluoromethoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine (170 mg, 25%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.50 g, 1.99 mmol) and 3-(trifluoromethoxy)phenyl boronic acid (0.44 g, 2.13 mmol) according to the general procedure of Example 1.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29]([OH:31])=O.Cl.[CH3:33][NH:34][OH:35].O>C(Cl)Cl>[OH:35][N:34]([CH3:33])[C:29](=[O:31])[CH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:15]1[C:14]([Cl:13])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:20]
Reactant: CNO
Reactant: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: CN(O)C(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1'-Carbonyl-diimidazole (5.5 g; 34 mmol) is slowly added to a warm solution of 2-[(2,6-dichlorophenyl)-amino]-benzeneacetic acid (6.5 g; 22 mmol) in CH2Cl2 (600 mL) and stirred at room temperature for 2.0 hours when a clear solution is formed. N-Methylhydroxylamine hydrochloride (5.5 g; 66 mmol) is slowly added to the solution and the mixture stirred at room temperature for 48 hours. It is decomposed with water, extracted with CH2Cl2 and dried over Na2SO4. The solvent is evaporated off and the residue flash chromatographed over silica gel (250 g) using 10% EtOH-CH2Cl2 as eluant to give the pure product as white solid which is recrystallized from toluene-CH2Cl2. Yield 2.95 g (41.2%); mp 135°-138° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH2:23])[CH:19]=3)[N:14]=1)[CH2:9][CH2:8]2.[CH:25]([N:28]=[C:29]=[O:30])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:29]([NH:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([NH:12][CH:10]1[C:11]3[C:7](=[CH:6][C:5]([CH3:24])=[CH:4][C:3]=3[O:2][CH3:1])[CH2:8][CH2:9]1)[CH:22]=[CH:21]2)=[O:30])([CH3:27])[CH3:26]
Reactant: CC(C)N=C=O
Reactant: COc1cc(C)cc2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Product: COc1cc(C)cc2c1C(Nc1ccc3cc(NC(=O)NC(C)C)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method described in example 3 from rac-N2-(7-methoxy-5-methyl-indan-1-yl)-quinoline-2,6-diamine and isopropyl isocyanate; MS: m/e=405.6 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:10](=[O:12])[CH2:9][CH2:8][NH:7][C:6](=[O:13])[C:5]=2[C:4]([CH3:14])=[CH:3]1.CC(C)([O-])C.[K+].Br[CH2:22][CH2:23][CH2:24][Cl:25]>C1COCC1>[Cl:25][CH2:24][CH2:23][CH2:22][N:7]1[CH2:8][CH2:9][C:10](=[O:12])[C:11]2[N:2]([CH3:1])[CH:3]=[C:4]([CH3:14])[C:5]=2[C:6]1=[O:13]
Reactant: ClCCCBr
Reactant: Cc1cn(C)c2c1C(=O)NCCC2=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cn(C)c2c1C(=O)N(CCCCl)CCC2=O
Yield: 50.3 %

Procedure:
Using Compound 12 (0.96 g, 5 mmole), potassium t-butoxide (1.12 g, 10 mmole), 1-bromo-3-chloropropane (3.46 g, 22 mmole) and THF (50 ml), the title compound (676 mg) was obtained in a similar manner as in Preparation Example 6 (yield: 50%).
Reaction SMILES: C(O)C.CNC.C([Li])CCC.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C(Br)(Br)(Br)[Br:21]>O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([Br:21])[CH:15]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccncc1
Agent: CNC
Agent: [Li]CCCC
Solvent: CCO
Solvent: O
Product: COc1ccnc(Br)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 20.6 %

Procedure:
A solution of N,N-dimethylamine ethanol (78.086 g, 0.876 mole) in anhydrous hexanes(1241 mL.) was cooled to 0° C. and butyllithium (2M soln. 876 mL., 1.757 mole) was added by use of an addition funnel. After 30 minutes at 0° C., 4-methoxypyridine(47.87 g, 0.438 mole) was added. Stirring continued at 0° C. for one hour before the reaction mixture was cooled to −78° C. and a solution of CBr4 (363 g, 1.093 mole) was added. The reaction temperature was maintained at 0° C. for 2.5 hours. The water was then added to quench the reaction. The aqueous layer was then separated and extracted with methylene chloride. The organic extractions were washed with brine, dried over magnesium sulfate and evaporated to give crude product. The crude product was purified by column chromatography using 80/20 ethyl acetate/hexanes as the eluants. The purified product was collected and concentrated to give 4-methoxy-2-bromopyridine (17 g. 22% yield).
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9](=[O:19])[C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=1[CH3:18])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl.[N:21]([O-])=[O:22].[Na+]>C(O)C>[O:1]=[C:2]([C:8](=[N:21][OH:22])[C:9](=[O:19])[C:10]1[C:11]([CH3:18])=[CH:12][C:13]([CH3:17])=[CH:14][C:15]=1[CH3:16])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: O=N[O-]
Reactant: CCOC(=O)C(=O)CC(=O)c1c(C)cc(C)cc1C
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)C(=NO)C(=O)c1c(C)cc(C)cc1C

Procedure:
N2O3 gas was slowly passed into a stirred solution of the product of step A (16.2 g) in 300 mL of ethanol until the disappearance of starting material was confirmed by TLC. N2O3 gas was generated by the dropwise addition of 12 N aqueous HCl solution into an aqueous slurry of NaNO2. The solvent was removed from the mixture and 200 mL of water was added to the residue. The product was then extracted into ether. The ether extract was dried over Na2SO4 and evaporated to give 16.1 g of a semi-solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]O)=[C:7]([F:13])[CH:6]=1)[CH:2]=[CH2:3].S(Cl)([Cl:16])=O>ClCCl.CN(C=O)C>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][Cl:16])=[C:7]([F:13])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(CO)c(F)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCOc1ccc(CCl)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
A solution of 4.20 g (23.1 mmol) (4-allyloxy-2-fluoro-phenyl)-methanol in 80 ml dichloro-methane and 0.5 ml DMF was cooled to 0° C. 2.17 ml (3.57 g, 30.0 mmol) thionyl chloride were added slowly and then stirred for 1 h at room temperature. Dichloromethane was distilled off. The residue was taken up in 100 ml ethyl acetate and washed with concentrated sodium carbonate solution. The organic phase was dried and evaporated to give 4.47 g (97%) 1-allyloxy-3-fluoro-4-chloromethyl-benzene as colored oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH:13]=O)=[CH:11][N:10]=[C:9]1[S:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:22][C:23]#[N:24]>>[CH2:1]([N:8]1[C:12](/[CH:13]=[C:22](/[C:21]2[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:19]([O:18][CH3:17])[CH:20]=2)\[C:23]#[N:24])=[CH:11][N:10]=[C:9]1[S:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CC#N)cc1OC
Reactant: CSc1ncc(C=O)n1Cc1ccccc1
Product: COc1ccc(/C(C#N)=C/c2cnc(SC)n2Cc2ccccc2)cc1OC
Yield: 92.4 %

Procedure:
1-Benzyl-2-(methylsulfanyl)-1H-imidazole-5-carbaldehyde (465 mg) was condensed with 3,4-dimethoxybenzyl cyanide (354 mg) through Method A (production step 2), to thereby yield the target product (yield: 723 mg, 92%).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:22])=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([C@@H:14]1[CH2:16][C@@H:15]1[F:17])[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21].C(OC([NH:30][C@@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)=O)(C)(C)C>>[NH2:30][C@@H:31]1[CH2:35][CH2:34][N:33]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:21])[C:6]([C:18]([OH:20])=[O:19])=[CH:7][N:8]3[C@@H:14]3[CH2:16][C@@H:15]3[F:17])=[C:3]([CH3:22])[C:2]=2[F:1])[CH2:32]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Product: Cc1c(F)c(N2CC[C@@H](N)C2)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Yield: 66.1 %

Procedure:
A hundred milligrams of 6,7,8-trifluoro-1-[(1R,2S)-2-fluorocyclopropyl]-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 120 mg of (R)-3-t-butoxycarbonylaminopyrrolidine were reacted in the same manner as in Example 7, and the reaction mixture was worked up similarly to yield 80 mg of the titled compound as a grayish white to yellowish white substance.