Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[S-:12][C:13]#[N:14].[NH4+]>CO.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([S:12][C:13]#[N:14])=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cc[nH]c2c1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COc1ccc2c(SC#N)c[nH]c2c1
Yield: 28.8 %

Procedure:
Using the procedure described in Tetrahedron Letters 40 (1999), 1195-1196, 6-methoxy-1H-indole (1.0 g, 6.8 mmole) and ammonium thiocyanate (0.621 g, 8.1 mmole) were dissolved in methanol (35 ml) and treated with ceric ammonium nitrate (8.56 g, 15.6 mmole)in methanol (175 ml) at room temperature. The reaction mixture was stirred for 15 m and then diluted with water (700 ml) and extracted with methylene chloride (4×125 ml). The combined organic extracts were dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by column chromatography (silica gel) using ethyl acetate:hexane (1:9) as the eluting solvent to afford 6-methoxy-3-thiocyanato-1H-indole (0.40 g 29% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.F[C:13](F)(F)[S:14](O)(=[O:16])=[O:15].CS(OS(C)(=O)=O)(=O)=O>>[CH3:13][S:14]([C:8]1[CH:9]=[CH:10][C:5]2[O:4][CH2:3][C:2]([CH3:11])([CH3:1])[C:6]=2[CH:7]=1)(=[O:16])=[O:15]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: CC1(C)COc2ccccc21
Agent: CS(=O)(=O)OS(C)(=O)=O
Product: CC1(C)COc2ccc(S(C)(=O)=O)cc21
Temperature: 135 °C
Yield: 119.7 %

Procedure:
A mixture of 3,3-dimethyl-2,3-dihydro-benzofuran (example 14c) (870 mg, 5.87 mmol), trifluoromethanesulfonic acid (0.1 mL, 1.17 mmol) and methanesulfonic anhydride (2.04 g, 11.74 mmol) was heated to 135° C. After reaching this temperature, the heater was removed and the mixture was cooled down to room temperature. The mixture was poured into a solution of ice-water. The aqueous layer was extracted twice with ethyl acetate and the organic combined extract was washed with water, an aqueous solution of sodium bicarbonate, brine, dried (MgSO4), filtered, and evaporated. The residue was chromatographed on silica gel (30% to 50% ethyl acetate in hexane) to afford 317 mg of 5-Methanesulfonyl-3,3-dimethyl-2,3-dihydro-benzofuran. 24% yield. 1H-NMR (300 MHz, CDCl3): 1.39 (s, 6H), 3.04 (s, 3H), 4.36 (s, 2H), 6.90 (d, J=8.2 Hz, 1H), 7.67 (d, J=2.1 Hz, 1H), 7.74 (dd, J1=8.5 Hz, J2=2.1 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[C:19](Cl)(=[O:24])[CH2:20][CH2:21][CH2:22][CH3:23]>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:19](=[O:24])[CH2:20][CH2:21][CH2:22][CH3:23])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: CCCCC(=O)Cl
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Product: CCCCC(=O)Nc1nc2c(OC)ccc(N3CCOCC3)c2s1

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and valeroyl chloride the title compound was obtained as a light yellow solid (48%), MS: m/e=350 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[CH:9]1[CH2:13][CH2:14][CH:5]2[CH2:6][N:7]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:8]1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[C:25]([Cl:40])=[CH:24][N:23]=1>>[Cl:40][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[N:27][C:22]([NH:1][C:2]2[CH:3]=[C:4]3[C:10](=[CH:11][CH:12]=2)[CH:9]2[CH2:13][CH2:14][CH:5]3[CH2:6][N:7]([C:15](=[O:20])[C:16]([F:19])([F:17])[F:18])[CH2:8]2)=[N:23][CH:24]=1
Reactant: Nc1ccc2c(c1)C1CCC2CN(C(=O)C(F)(F)F)C1
Reactant: CS(=O)(=O)Nc1ccccc1Nc1nc(Cl)ncc1Cl
Product: CS(=O)(=O)Nc1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(C(=O)C(F)(F)F)C2)ncc1Cl

Procedure:
N-(2-{5-Chloro-2-[10-(2,2,2-trifluoro-acetyl)-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino]-pyrimidin-4-ylamino}-phenyl)-methanesulfonamide was prepared from 1-(4-amino-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-10-yl)-2,2,2-trifluoro-ethanone and N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-phenyl]-methanesulfonamide in an analogous manner to Example 290. Product isolated as a pale yellow foam (263 mg, 64%). LCMS (m/e) 581 (M+1); 1H-NMR (CDCl3, 400 MHz) major rotomer δ 7.96 (s, 1H), 7.70-62 (m, 1H), 7.55-7.45 (m, 2H), 7.40-7.31 (m, 2H), 7.25-7.05 (m, 3H), 7.00-6.90 (m, 1H), 4.30-4.10 (m, 1H), 3.90-3.79 (m, 1H), 3.50-3.39 (m, 1H), 3.37-3.27 (m, 1H), 3.20-3.10 (m, 1H), 2.96 (s, 1H), 2.96-2.90 (m, 1H), 2.10-1.95 (m, 2H), 1.80-1.70 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.CCN(C(C)C)C(C)C.[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25]([N:28]2[CH2:43][CH2:42][C:31]3[N:32]=[CH:33][N:34]=[C:35]([O:36][C@H:37]4[CH2:41][CH2:40][NH:39][CH2:38]4)[C:30]=3[CH2:29]2)=[CH:24][C:23]=1[CH3:44]>CN(C=O)C>[CH3:1][C:2]1[O:3][C:4]([C:8]([N:39]2[CH2:40][CH2:41][C@H:37]([O:36][C:35]3[C:30]4[CH2:29][N:28]([C:25]5[CH:26]=[N:27][C:22]([O:21][CH3:20])=[C:23]([CH3:44])[CH:24]=5)[CH2:43][CH2:42][C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:38]2)=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(C(=O)O)o1
Reactant: COc1ncc(N2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ncc(N2CCc3ncnc(O[C@H]4CCN(C(=O)c5oc(C)nc5C)C4)c3C2)cc1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.2 %

Procedure:
A mixture of 2,4-dimethyl-oxazole-5-carboxylic acid (36.4 mg, 0.258 mmol), HTBU (98 mg, 0.258 mmol), DIPEA (86p1, 0.49 mmol) in DMF (5 mL) was stirred at rt for 20 min. then a solution of 6-(6-methoxy-5-methyl-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (prepared in example 1, method 1b, step 2) (80 mg, 0.23 mmol) and DIPEA (86 μl, 0.49 mmol) in DMF (0.4 mL) was added. The reaction mixture was stirred 30 min at rt. The reaction mixture was directly purified by preparative reverse phase Gilson HPLC and subsequent neutralization of the combined fractions over PL-HCO3 MP gave (2,4-dimethyl-oxazol-5-yl)-{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone (91 mg, 84% yield) as a white lyophilized powder. 1H-NMR (400 MHz, methanol-d4, 298K) δ ppm 2.17 (s, 3H) 2.27-2.52 (m, 8H) 2.95-3.03 (m, 2H) 3.44-3.55 (m, 2H) 3.70-4.26 (m, 9H) 5.76-5.92 (m, 1H) 7.40 (br. s., 1H) 7.64 (br. s., 1H) 8.55-8.62 (m, 1H), LCMS: [M+H]+=465.2, Rt(1)=1.51 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.B([O-])([O-])O.[Na+].[Na+]>CO>[N:10]1([CH2:5][C:4]2[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][CH:7]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=Cc1cccc(O)c1
Reactant: C1CCNCC1
Agent: [Na+]
Agent: [O-]B([O-])O
Solvent: CO
Product: Oc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Yield: 85 %

Procedure:
3-Hydroxybenzaldehyde (III) (0.246 mol, 30 g) was dissolved into 150 ml of methanol. Piperidine (IV) (0.6 mol, 52 g) was added to the solution and the mixture was stirred at room temperature to dissolution. To the solution was added under ice cooling sodium hydrogen borate (0.247 mol, 9.4 g) while stirring over 1 hour, followed by continued stirring for 1 hour at room temperature. The reaction mixture was concentrated under vacuum. The residue was dissolved in 200 ml of 3N hydrochloric acid and washed twice with 50 ml of ethyl acetate. The water layer was alkalinized (pH 10) with about 50 ml of concentrated aqueous ammonia to deposit crystals. The crystals were collected by filtration, washed with water, dried under vacuum, and recrystallized from a mixed solvent of acetone and n-hexane, to obtain 40 g of 3-piperidinomethylphenol (V) (yield: 84.7%). m.p. 135°-138° C.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[I-:10].[Na+]>CC(C)=O>[I:10][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)CI
Yield: 77.8 %

Procedure:
A mixture of t-butyl chloroacetate (20 g) and sodium iodide (25 g) is stirred in acetone (200 ml) for twenty hours. The acetone is removed by distillation under reduced pressure. The residue is partitioned between diethyl ether (100 ml) and water (50 ml). The ether layer is washed with water, 5% sodium thiosulfate solution, and water. The organic layer is dried over sodium sulfate, and evaporated under reduced pressure. There is obtained 25 grams of t-butyl iodoacetate. NMR: 63.5, 1.38.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[Cl-].[Li+].C(N(CC)CC)C.CS([Cl:42])(=O)=O>CN(C)C1C=CN=CC=1.ClCCl>[Cl:42][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CO)cc2)CC3)cc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
To a mixture of N-[4-(hydroxymethyl)phenyl]-7-(4methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (2.20 g), lithium chloride (505 mg), triethylamine (1.67 ml), DMAP [4-dimethylaminopyridine] (catalytic amount) and dichloromethane (200 ml) was added methanesulfonyl chloride (645 μl), and the mixture was stirred at room temperature for 42 hours and concentrated under reduced pressure. To the residue was added 0.5N hydrochloric acid (200 ml), and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give N-[4-(chloromethyl)-phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (973 mg) as colorless crystals.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:14][CH2:15][CH2:16]OS(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+].O>CC(C)=O>[Cl:14][CH2:15][CH2:16][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: ClCCn1c2ccccc2c2ccccc21
Temperature: 25 °C
Yield: 43.2 %

Procedure:
17.9 g (107 mmol) of carbazole and 500 ml of acetone as solvent were placed in a 1000 ml four-necked flask with a mechanical stirrer and bulb-shaped cooler. To this was added an aqueous solution prepared from 22.0 g (93.7 mmol)of 2-chloroethyl-p-toluene sulfonate, 12.5 g of sodium hydroxide and 9.2 ml of water. The resultant product was heated to 60° C. in a silicone oil bath, and subjected to the reaction for 20 hours. After the reaction was completed, the product was cooled to the ambient temperature. The precipitated solid was subjected to suction filtration with a glass filter. The resultant liquid was concentrated in an evaporator and dried under vacuum to obtain a brown solid, which was recrystallized in the presence of ligroin to obtain 9.3 g of a white crystal.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([C:23]1[C:24]([O:29][CH2:30][CH3:31])=[N:25][CH:26]=[CH:27][CH:28]=1)[OH:22]>N1C=CC=CC=1.ClCCl>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3])[C:16](=[O:21])[C:15]2([C:23]1[C:24]([O:29][CH2:30][CH3:31])=[N:25][CH:26]=[CH:27][CH:28]=1)[O:22][C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3]
Reactant: CCOc1ncccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1ncccc1C1(OC(=O)Oc2ccccc2)C(=O)N(C(=O)Oc2ccccc2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.3 %

Procedure:
2.6 ml (21 mmol) of phenyl chloroformate were slowly added dropwise to a solution, cooled to 0° C., of 3.00 g (9.8 mmol) of 5-chloro-3-(2-ethoxypyridin-3-yl)-3-hydroxy-1,3-dihydroindol-2-one from example a.1 in 10 ml of pyridine, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and extracted with water. The organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was stirred with diethyl ether. 2.58 g of the title compound were obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([CH:24]([OH:27])[CH2:25][CH3:26])=[C:5]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1COCC1.C(OC(C)C)(C)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:6]([C:24](=[O:27])[CH2:25][CH3:26])=[C:5]2[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCC(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
In the same manner as in Example 311, the title compound was synthesized using 6-bromo-3-(1-hydroxypropyl)-2-(4-methanesulfonylbenzyl)-4-phenyl-2H-isoquinolin-1-one. Crystals (THF-diisopropyl ether).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[F:12][C:13]([F:21])([F:20])[C:14]([C:16]([F:19])([F:18])[F:17])=[O:15]>ClCCCl>[F:12][C:13]([F:21])([F:20])[C:14]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])([OH:15])[C:16]([F:19])([F:18])[F:17]
Reactant: Oc1ccccc1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Oc1ccccc1C(O)(C(F)(F)F)C(F)(F)F
Temperature: -35 °C
Reaction time: 36 h
Yield: 82.4 %

Procedure:
94.11 g (1000 mmol) of phenol and 166.02 g (100 mmol) of AlCl3 were initially charged in 1200 ml of 1,2-dichloroethane and cooled to −35° C. At this temperature, the precalculated amount of 166.02 g (1000 mmol) of hexafluoroacetone was metered in from a bomb. Subsequently, the reaction mixture was allowed to come to room temperature (20° C., RT) and stirred at RT for a further 36 h. The reaction flask was subsequently flushed with N2 and the offgas passed into a wash bottle containing water. For workup of the remaining reaction solution, 500 ml of water were added cautiously and the mixture was stirred well. Subsequently, the organic phase was removed, the aqueous phase was extracted with CH2Cl2 and dried over magnesium sulphate, and the solvent was removed on a rotary evaporator. As this was done, the residue crystallized out. For purification, the resulting crystals were slurried in n-hexane and filtered off, and 230 g (842 mmol, yield: 82.4% of theory) of a white, crystalline solid were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[C:21](O)=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH2:53][C:54]1[C:62]([NH2:63])=[CH:61][CH:60]=[CH:59][C:55]=1[C:56]([NH2:58])=[O:57]>CN(C=O)C>[NH2:53][C:54]1[C:55]([C:56](=[O:57])[NH2:58])=[CH:59][CH:60]=[CH:61][C:62]=1[NH:63][C:21]([CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:20][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[O:22]
Reactant: O=C(O)C1c2ccccc2CCN1C(=O)OCc1ccccc1
Reactant: NC(=O)c1cccc(N)c1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1cccc(NC(=O)C2c3ccccc3CCN2C(=O)OCc2ccccc2)c1N
Temperature: 55 °C
Reaction time: 0.17 h

Procedure:
Step-1: To a solution of 2-((benzyloxy)carbonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (560 mg, 1.8 mmol) in anhydrous DMF (7 ml) was added EDC.HCl (1.035 g, 5.4 mmol), HOAt (367 mg, 2.7 mmol) and triethylamine (0.375 ml, 2.7 mmol) at RT and the mixture was stirred for 10 min. To this reaction mixture, 2,3-diaminobenzamide (302 mg, 2 mmol) was added and heated to 55° C. over night. The reaction mixture was poured into ice cold water and stirred for 30 min. The precipitate formed was filtered and dried under vacuum to yield benzyl 1-((2-amino-3-carbamoylphenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate. MS (ES+): m/z 445.22 [M+H]+
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:32][CH2:31][N:30]([C:33](OC(C)(C)C)=O)[CH2:29][CH2:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.[F:40][C:41]([F:46])([F:45])[C:42](O)=O>ClCCl>[CH3:1][C@@:2]1([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:22]=[CH:23][C:24]([N:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:15]5[CH:20]=[CH:19][C:42]([C:41]([F:46])([F:45])[F:40])=[CH:17][CH:16]=5)[CH2:29][CH2:28]4)=[CH:25][CH:26]=3)=[CH:19][CH:20]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ccc(OC[C@@]4(C)Cn5cc([N+](=O)[O-])nc5O4)cc3)cc2)CC1
Solvent: ClCCl
Product: C[C@]1(COc2ccc(-c3ccc(N4CCN(Cc5ccc(C(F)(F)F)cc5)CC4)cc3)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
790 mg of (R)-2-methyl-2-(4′-(4-tert-butoxycarbonylpiperazin-1-yl)biphenyl-4-yloxymethyl)-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole was dissolved in 10 ml of trifluoroacetic acid and 5 ml of dichloromethane, followed by stirring at room temperature overnight. Thereafter, the reaction solution was concentrated under a reduced pressure, and then, 6 ml of dichloromethane and 6 ml of triethylamine were added thereto. The mixture was stirred at room temperature for 5 minutes, and it was then concentrated under a reduced pressure. The residue was dissolved in 15 ml of DMF, and then, 0.4 ml of 4-trifluoromethylbenzaldehyde and 625 mg of triacetoxy sodium borohydride were added thereto while cooled by ice, followed by stirring at room temperature overnight. Thereafter, water was added to the reaction solution, the mixture was stirred, and the insoluble precipitate was removed by filtration. The filtrate was washed with water and then dissolved in dichloromethane. The obtained solution was washed with a saturated aqueous solution of sodium chloride, and then dried over sodium sulfate. The sodium sulfate was filtered, and the filtrate was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1). The resultant product was then recrystallized from a mixed solvent consisting of dichloromethane and ethyl acetate to obtain 585 mg (yield: 60.5%) of light yellow powders, (R)-2-methyl-6-nitro-2-(4′-(4-(4-trifluoromethylbenzyl)piperazin-1-yl)biphenyl-4-yloxymethyl)-2,3-dihydroimidazo[2,1-b]oxazole.
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1.[C:32](Cl)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>>[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][N:29]([C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:28][CH2:27]4)[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:13])=[O:14])=[CH:5][CH:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C3CCNCC3)c2)c2ccc(F)cc21
Agent: Cl
Product: CC(C)(C)C(=O)N1CCC(n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Yield: 104.6 %

Procedure:
Following the general method as outlined in Example 89, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indole hydrochloride (Intermediate 17; 200 mg; 0.47 mmol) and pivaloyl chloride (0.12 mL; 0.98 mmol), 250 mg (>100%) of the title compound was obtained as a yellow solid, which was used directly without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].N1C(C)=CC(C)=CC=1C>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[CH2:4][CH2:3]1
Reactant: CC1(C)CCNc2ccccc21
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClC(Cl)Cl
Product: CC1(C)CCN(c2ccccc2[N+](=O)[O-])c2ccccc21
Temperature: 250 °C
Reaction time: 1 h

Procedure:
1b (0.762 g, 4.73 mmol), ortho-fluoronitrobenzene (0.88 g, 5.67 mmol, 1.19 eq), and 2,4,6-collidine (0.66 mL, 1.05 eq) were pre-stirred 40s in a conical microwave container. It was then heated with stirring at a Personal Chemistry Microwave reactor with normal absorption at 250° C. for 1 h. The crude mixture was dissolved in CHCl3, and was purified by flash chromatography (hexanes/EtOAc) to give 0.66 g of crude 1c. LC-MS ESI 283 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[CH:4]=[C:3]([C:11](OC)=[O:12])[CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C>O1CCCC1>[OH:12][CH2:11][C:3]1[CH:2]=[N:1][CH:6]=[C:5]([CH:4]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cncc(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1cncc(CO)c1
Temperature: 0 °C
Yield: 26 %

Procedure:
1.67 g of dimethyl pyridine-3,5-dicarboxylate was dissolved in 30 ml of anhydrous tetrahydrofuran, and with stirring under ice cooling, 162 mg of lithium aluminium hydride was added. The mixture was stirred at this temperature for 30 minutes. The reaction mixture was poured into ice water, and ethyl ether was added to extract it. The extract was worked up in a customary manner to give crude methyl 5-hydroxymethylnicotinate. The crude product was dissolved in 20 ml of methylene chloride, and 2.2 g of pyridinium chlorochromate was added. The mixture was stirred overnight at room temperature. The reaction mixture was poured into ice water. The organic layer was separated, worked up in a customary manner, and purified by silica gel column chromatography Wakogel C-200, 80 g; eluting solvent: chloroform/methanol=20/1) to give 0.37 g (yield 26%) of
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].[C:10]([C:12]1[C:13]([S:23](Cl)(=[O:25])=[O:24])=[N:14][N:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[N:17][C:16]=12)#[N:11]>N1C=CC=CC=1.CC(O)C>[C:10]([C:12]1[C:13]([S:23]([NH:4][C:3]2[C:2]([Cl:1])=[CH:8][CH:7]=[CH:6][C:5]=2[Cl:9])(=[O:24])=[O:25])=[N:14][N:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[N:17][C:16]=12)#[N:11]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: Cc1cc(C)n2nc(S(=O)(=O)Cl)c(C#N)c2n1
Solvent: c1ccncc1
Solvent: CC(C)O
Product: Cc1cc(C)n2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)c(C#N)c2n1
Temperature: 70 °C
Reaction time: 24 h
Yield: 55.4 %

Procedure:
A solution of 0.67 g (4.1 mmole) of 2,6-dichloroaniline was stirred at room temperature as a solution of 1.1 g (4.1 mmole) of 3-cyano-5,7-dimethylpyrazolo-[1,5-a]pyrimidine-2-sulfonyl chloride in 3 ml pyridine was added. The mixture was heated at 70° C. for 15 hours, then at 130° C. for 24 hours, and cooled to room temperature. The mixture was diluted with 2-propanol and stirred at room temperature for 1 hour. The tan solid was collected by filtration, washed well with 2-propanol and dried to give 0.9 g tan powder. This was completely dissolved in 2N NaOH and extracted with CH2Cl2. The aqueous layer was separated and acidified with glacial HOAc, which gave a precipitate. This was collected by filtration, washed well with water and dried to give 0.2 g (12.3 -percent) of the product as an off-white solid, m.p. 280°-285° C. (decomposition and degassing). 1H NMR (DMSO-d-6): 11.1 (br., 1H, NH), 7.5-7.4 (m, 3H, benzene), 7.5 (s, 1H, pyrazolopyrimidinyl H-6), 2.67 (s, 3H, CH3), 2.63 (s, 3H, CH3) 13C NMR (DMSO-d-6): 165, 156, 150, 148, 136, 130, 129, 114, 111, 80, 24, 16. IR (KBr): 3220, 2240, 1620, 1540, 1440, 1355, 1170 cm-1.