Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([CH2:22][CH2:23][C:24]([NH:26][CH2:27][C:28]([OH:30])=O)=[O:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C>[CH:7]([N:8]([CH3:9])[C:28]([CH2:27][NH:26][C:24](=[O:25])[CH2:23][CH2:22][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:30])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CNC(c1ccccc1)c1ccccc1
Reactant: O=C(O)CNC(=O)CCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(C(=O)CNC(=O)CCc1ccccc1)C(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 46 %

Procedure:
A solution of 2.0 mmol N-(diphenylmethyl)methylamine, 2.0 mmol (3-phenyl-propionylamino)-acetic acid (CA [56613-60-6]) and 6.0 mmol DIPEA in 10 ml of acetonitrile was treated with 2.2 mmol of TBTU. After 2 hours at room temperature, the reaction mixture was concentrated, diluted with water and extracted 3 times with ethyl acetate. The organic phase was dried and the residue purified by chromatography (SiO2; dichloromethane/methanol) to give the title compound as a slightly yellowish solid.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH:17]3OC(=O)N[CH2:18]3)[CH:14]=2)[NH:9][CH:8]=1)[CH3:4].Cl.NC1C=CC(CC2[O:34][C:33](=[O:35])[NH:32]C2)=CC=1.CN1CCC(C2C3C(=CC=C(CC4COC(=O)N4)C=3)NC=2)CC1.Cl.C(N)C>>[CH3:4][N:3]([CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][C@H:17]3[CH2:18][O:35][C:33](=[O:34])[NH:32]3)[CH:14]=2)[NH:9][CH:8]=1)[CH3:2]
Reactant: Nc1ccc(CC2CNC(=O)O2)cc1
Reactant: CN(C)CCc1c[nH]c2ccc(CC3CNC(=O)O3)cc12
Agent: CCN
Agent: CN1CCC(c2c[nH]c3ccc(CC4COC(=O)N4)cc23)CC1
Agent: Cl
Product: CN(C)CCc1c[nH]c2ccc(C[C@H]3COC(=O)N3)cc12

Procedure:
By steps identical to steps (d) to (f) of Synthetic Example 1 and Synthetic Example 2 or steps (d) and (e) of Synthetic Example 1 and Synthetic Example 3 and steps (e) to (h) of Synthetic Example 4, the product from step (a) was converted to (S)-N,N-dimethyl-2-[5-(2-oxo-l,3-oxazolidin-4-ylmethyl)-1H. indol-3-yl]ethylamine.
Reaction SMILES: C(N(CC)[CH2:4][CH2:5][C:6](=[O:19])[CH2:7][CH:8]([CH3:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)C.CC(CC1C=CC=C(OC)C=1)CC(=O)C=C.[CH2:38]([CH:40]1[C:44](=[O:45])[CH2:43][CH2:42][C:41]1=[O:46])[CH3:39]>[OH-].[K+]>[CH2:38]([C:40]1([CH2:4][CH2:5][C:6](=[O:19])[CH2:7][CH:8]([CH3:18])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:44](=[O:45])[CH2:43][CH2:42][C:41]1=[O:46])[CH3:39]
Reactant: CCN(CC)CCC(=O)CC(C)Cc1cccc(OC)c1
Reactant: CCC1C(=O)CCC1=O
Agent: C=CC(=O)CC(C)Cc1cccc(OC)c1
Agent: [K+]
Agent: [OH-]
Product: CCC1(CCC(=O)CC(C)Cc2cccc(OC)c2)C(=O)CCC1=O

Procedure:
Add a mixture of 1-diethylamino-6-(m-methoxyphenyl)-5-methylhexan-3-one and 5-methyl-6-(m-methoxyphenyl)hex-1-en-3-one (6 g, prepared by slow distillation of the former substance) to 2-ethylcyclopentane-1,3-dione (3.5 g) in 0.12% methanolic potassium hydroxide (10 cc) and heat the mixture under reflux for 6 hours. Remove most of the solvent under reduced pressure and add ether (25 cc) and benzene (25 cc) to the residue. Wash the solution with 5% aqueous sodium hydroxide, water, dilute hydrochloric acid, and brine, and dry. Evaporate the solvent to obtain a viscous brown gum, which is the triketone 2-ethyl-2-(6-m-methoxyphenyl-5-methyl-3-oxohexyl)cyclopentane-1,3-dione.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Br:18][C:19]1[C:27]2[N:26]=[C:25](Cl)[NH:24][C:23]=2[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=1>>[Br:18][C:19]1[C:27]2[N:26]=[C:25]([N:15]3[CH2:16][CH2:17][N:12]([C:3]4[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:5][N:4]=4)[CH2:13][CH2:14]3)[NH:24][C:23]=2[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=1
Reactant: FC(F)(F)c1cnc(N2CCNCC2)c(Cl)c1
Reactant: FC(F)(F)c1cc(Br)c2nc(Cl)[nH]c2c1
Product: FC(F)(F)c1cnc(N2CCN(c3nc4c(Br)cc(C(F)(F)F)cc4[nH]3)CC2)c(Cl)c1

Procedure:
The reaction of 1-(3-chloro-5-trifluoromethylpyridin-2-yl)piperazine (212 mg, 0.8 mmol, ABCR) and 4-bromo-2-chloro-6-trifluoromethyl-1H-benzoimidazole (210 mg, 0.7 mmol, Example 6b) under the conditions of Example 3c afforded the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 530 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:13]3[C:14]([CH3:28])=[C:15]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:33](Cl)(=[O:35])[CH3:34].O>ClCCl>[C:33]([C:8]1[CH:7]=[CH:6][C:5]([CH:9]2[C:13]3[C:14]([CH3:28])=[C:15]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26])[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][CH2:10]2)=[CH:4][C:3]=1[O:2][CH3:1])(=[O:35])[CH3:34]
Reactant: COc1cccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1cc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
To a solution of N-(3-(3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (1.0 g, 2.62 mmol) obtained in Example 72 in dichloromethane (20 mL) was added at −50° C. under an argon atmosphere aluminum chloride (769 mg, 5.77 mmol) and the resulting mixture was stirred for 10 minutes. To the reaction solution was added dropwise at the same temperature acetyl chloride (0.62 mL, 8.65 mmol and the resulting mixture was warmed to room temperature. The reaction solution was added to water and the product was extracted with ethyl acetate. The combined organic layers were washed with an aqueous saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 993 mg (yield: 89%) of the title compound. Melting point: 131-133° C. (ethyl acetate-hexane).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26])#[N:21]>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([C:20]#[N:21])[CH:23]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: N#Cc1cccc(C(=O)NCCCCn2cnc3c(N)nc4ccccc4c32)c1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 3-cyanobenzoyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-cyanobenzamide as a white crystalline solid, m.p. 200.0-201.0° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ 8.68 (t, J=5.7 Hz, 1H), 8.22 (s, 1H), 8.17 (t, J=1.8 Hz, 1H), 8.10-7.97 (m, 3H), 7.69-7.60 (m, 2H), 7.42 (dt, J=7.5, 1.2 Hz, 1H), 7.20 (dt, J=7.5, 1.5 Hz, 1H), 6.62 (s, 2H), 4.63 (t, J=6.9 Hz, 2H), 3.32 (m, 2H), 1.91 (quintet, J=7.5 Hz, 2H), 1.59 (quintet, J=7.5 Hz, 2H); IR (KBr) 3455, 3295, 3072, 2941, 2231, 1638, 1581, 1527, 1479, 1396, 1312, 1251, 1205 cm−1; MS (EI) m/e 384.1699 (384.1699 calcd for C22H20N6O).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH:18]([C:20](=[O:22])[CH3:21])[CH3:19])[C:4]2[C:9]([C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.N12CCN(CC1)CC2.O>ClCCl>[CH3:1][C:2]1[N:3]([CH:18]([CH:20]([O:22][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=2)(=[O:32])=[O:31])[CH3:21])[CH3:19])[C:4]2[C:9]([C:10]=1[C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CC(=O)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2ccccc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC(C)C(C)n2c(C)c(C(=O)OC(C)(C)C)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
To a mixture of tert-butyl 2-methyl-1-(3-oxobutan-2-yl)-1H-indole-3-carboxylate (1.1 g, 3.6 mmol) in dichloromethane (4 mL) were added 4-methylbenzene-1-sulfonyl chloride (1.3 g, 7.2 mmol), and 1,4-diazabicyclo[2.2.2]octane (1.2 g, 10.8 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 3 hours. The reaction mixture was added to water (30 mL). The aqueous layers was extracted with dichloromethane (10 mL×3). The combined organic layers was dried over sodium sulfate and concentrate to afford tert-butyl 2-methyl-1-(3-(tosyloxy)butan-2-yl)-1H-indole-3-carboxylate (1.6 g, yield: 96%) as a yellow oil. LRMS (M+H+) m/z: calcd 457.19. found 458.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]#[N:14])[CH:7]=[CH:6]2.[I:15]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>C(#N)C.C(O)(C(F)(F)F)=O>[I:15][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([C:13]#[N:14])=[CH:9]2
Reactant: COc1ccc2cc(C#N)ccc2c1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2cc(C#N)ccc2c1I
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 6-methoxynaphthalene-2-carbonitrile (1.0 g, 5.5 mmol), N-iodosuccinimide (1.4 g, 6.0 mmol) in ACN (10 ml) and TFA (125 μl) is stirred at RT for 4 h. A saturated aqueous solution of sodium hydrogencarbonate is added and the mixture extracted with DCM. The combined organic layers are extracted with an aqueous solution of sodium thiosulfate, dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 1.68 g (99%). HPLC-MS: tR=1.32 min (METHOD—1).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19].C(OCC)(=O)C>CC(C)=O>[CH2:19]([O:10][C:8]1[CH:9]=[C:4]([C:2](=[O:3])[CH3:1])[CH:5]=[CH:6][CH:7]=1)[CH:18]=[CH2:17]
Reactant: CC(=O)c1cccc(O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: C=CCOc1cccc(C(C)=O)c1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
3-Hydroxyacetophenone (1.36 g, 10.0 mmol) was dissolved in acetone (50 mL), then added with potassium carbonate (2.76 g, 20.0 mmol) and allylbromide (1.27 mL, 15.0 mmol) at room temperature, and heated to reflux for 2 hours. The reaction solution was cooled to room temperature, added with ethyl acetate, and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (n-hexane/ethyl acetate=10/1), and 1-(3-(allyloxy)phenyl)ethanone (1.76 g, 100%) was obtained as a pale yellow oil.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:36])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][CH:28]=1)([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].CO.[H][H]>[Pd].C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([CH3:36])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([NH2:33])=[CH:31][CH:32]=1)([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CCCCCCCCC1(COc2ccc([N+](=O)[O-])cc2)CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1
Agent: [Pd]
Solvent: c1ccccc1
Solvent: CO
Product: CCCCCCCCC1(COc2ccc(N)cc2)CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1

Procedure:
Using Paar's hydrogenation apparatus, a mixture of 4 g of 6-acetoxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)-2-octylchroman (prepared as described in Preparation 16), 0.8 g of 10% w/w palladium-on-carbon, 30 ml of methanol and 10 ml of benzene was stirred for 5 hours under 3-5 atmospheres (about 3-5 bars) pressure or hydrogen. The catalyst was filtered off, and the filtrate was condensed by evaporation under reduced pressure. The crystals thus obtained were washed with hexane to give the title compound, melting at 112°-114° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][C:13]1[C:14](=[O:28])[N:15]([CH:25]([CH3:27])[CH3:26])[N:16]=[CH:17][C:18]=1[NH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23].N1C=CC=CC=1.Cl>ClCCl>[Cl:12][C:13]1[C:14](=[O:28])[N:15]([CH:25]([CH3:26])[CH3:27])[N:16]=[CH:17][C:18]=1[NH:19][CH2:20][CH:21]([OH:24])[CH2:22][O:23][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: CC(C)n1ncc(NCC(O)CO)c(Cl)c1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(O)CNc2cnn(C(C)C)c(=O)c2Cl)cc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
1.60 g of p-toluenesulfonyl chloride was added to a mixture comprising 2.09 g of 4-chloro-5-(2,3-dihydroxypropylamino)-2-i-propyl-3(2H)pyridazinone prepared in Reference Example 6, 12 ml of pyridine and 20 ml of dichloromethane, under cooling with ice. The mixture was stirred for 6 hours, and then left to stand for 2 days in an ice chamber. The reaction mixture was acidified to a pH of about 2 by adding cooled dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed sequentially with water, a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over sodium sulfate. Then, the solvent was distilled off to obtain a colorless oily substance. The oily substance was purified by silica gel column chromatography, and 2.45 g of the above identified compound was obtained as a colorless viscous oily substance from the eluate with choroform-methanol (25:1, v/v).
Reaction SMILES: [O:1]1[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH2:4][N:5]([S:7]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[CH3:17])(=[O:9])=[O:8])[CH3:6])[CH2:2]1.[C:24]([O-:27])(=[O:26])[CH3:25].[Na+]>C(O)(=O)C>[C:24]([O:27][CH2:2][C:3]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([OH:1])[CH2:4][N:5]([S:7]([C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[CH3:17])(=[O:8])=[O:9])[CH3:6])(=[O:26])[CH3:25]
Reactant: Cc1ccc(C)c(S(=O)(=O)N(C)CC2(c3ccccc3)CO2)c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCC(O)(CN(C)S(=O)(=O)c1cc(C)ccc1C)c1ccccc1
Reaction time: 48 h
Yield: 57.5 %

Procedure:
A mixture of 5.30 g of 1,2-epoxy-2-phenyl-3-[N-(2,5-dimethylphenylsulfonyl)-N-methylamino]propane which had been prepared in accordance with Reference Examples 4 to 8, 3.30 g of anhydrous sodium acetate and 50 ml of acetic acid was stirred at 100° to 110° C. for 2 days. After evaporation, the residue was dissolved in 150 ml of benzene, washed subsequently with water, a saturated aqueous sodium bicarbonate and saturated brine, and then dried over anhydrous magnesium sulfate. After evaporation, the residue was purified by silica gel column chromatography (developing solvent: n-hexane-ethyl acetate (5:1)) to obtain 3.60 g of the titled compound.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[OH-].[Na+].[Br:12]Br>O>[Br:12][C:7]1[C:3]([C:2]([F:9])([F:8])[F:1])=[N:4][NH:5][CH:6]=1
Reactant: BrBr
Reactant: FC(F)(F)c1cc[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: FC(F)(F)c1n[nH]cc1Br
Temperature: 0 °C
Reaction time: 7 h
Yield: 78.5 %

Procedure:
3.50 g of 3-(trifluoromethyl)-1H-pyrazole was suspended in 45 ml of water, and 3.2 g of 50% aqueous solution of sodium hydroxide was added to it. The mixture was cooled to 0° C., and then 3.20 g of bromine was added to the mixture, followed by stirring at room temperature for 7 hours. The reaction mixture was extracted by ethyl acetate. The organic layer was washed with water dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Hexane was added to the residue, as a result, a crystal was formed. The crystal was collected to obtain 3.38 g of 4-bromo-3-(trifluoromethyl)-1H-pyrazole.
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:14]([O-])=[CH:15][C:16](=O)[C:17]([O:19]CC)=[O:18])[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[CH3:47][C:48]1[N:53]=[CH:52][C:51]([NH:54][NH2:55])=[CH:50][CH:49]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:14]2[N:54]([C:51]3[CH:52]=[N:53][C:48]([CH3:47])=[CH:49][CH:50]=3)[N:55]=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:11])([F:12])[F:13])[CH:8]=1
Reactant: Cc1ccc(NN)cn1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Br)cc(OC(F)(F)F)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: Cc1ccc(-n2nc(C(=O)O)cc2-c2cc(Br)cc(OC(F)(F)F)c2)cn1

Procedure:
656 g (1.35 mmol) of the compound of Example 5A is reacted analogously to the synthesis of the compound of Example 20A with 359 mg (2.02 mmol) of 6-methylpyridin-3-yl-hydrazine hydrochloride. After hydrolysis, 53 mg (9% of theory) of the title compound is obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[N:28]1[C:32]([CH2:33]O)=[C:31]([C:35]([F:38])([F:37])[F:36])[N:30]=[N:29]1.C(Br)(Br)(Br)[Br:40]>ClCCl>[Br:40][CH2:33][C:32]1[N:28]([C:22]2[C:21]([Cl:20])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:27])[N:29]=[N:30][C:31]=1[C:35]([F:38])([F:37])[F:36]
Reactant: OCc1c(C(F)(F)F)nnn1-c1c(Cl)cccc1Cl
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1nnn(-c2c(Cl)cccc2Cl)c1CBr
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 99.8 %

Procedure:
Triphenylphosphine (16.4 g, 62.5 mmol) is added to a suspension of [3-(2,6-dichlorophenyl)-5-trifluoromethyl-3H-[1,2,3]triazol-4-yl]-methanol (13 g, 41.69 mmol) in dichlormethane (80 mL). The mixture is cooled to 0° C. and carbon tetrabromide (20.7 g, 62.5 mmol) is added. The reaction is stirred at room temperature for 1.5 hours. The solvent is evaporated under reduced pressure and the residue is purified by flash chromatography eluting with hexanes/EtOAc (95:5 to 8:2) to obtain the title compound (15.6 g, 96% yield). ES/MS m/e 374 (M+1).
Reaction SMILES: [Br-:1].C([N+](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:28][CH2:27][C:26](=[O:29])[N:25]([CH3:30])[C:24]=2[CH:31]=1>C(Cl)Cl.CO>[NH2:19][C:20]1[C:21]([Br:1])=[CH:22][C:23]2[O:28][CH2:27][C:26](=[O:29])[N:25]([CH3:30])[C:24]=2[CH:31]=1
Reactant: CN1C(=O)COc2ccc(N)cc21
Reactant: [Br-]
Agent: CC(C)(C)[N+](C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: ClCCl
Solvent: CO
Product: CN1C(=O)COc2cc(Br)c(N)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 36 %

Procedure:
Tetra-tert-butyl ammonium bromide (6.77 g, 14.04 mmol) was added to a solution of 6-amino-4-methyl-4H-benzo[1,4]oxazin-3-one (2.5 g, 14.04 mmol) in methylene chloride (100 ml) and MeOH (50 ml). The mixture was stirred at room temperature for 20 minutes, then quenched with aqueous sodium bisulfite solution. The mixture was extracted with methylene chloride, and the combined organic extracts were dried over MgSO4, filtered, concentrated under reduced pressure and purified via column chromatography to give 1.30 g of 6-amino-7-bromo-4-methyl-4H-benzo[1,4]oxazin-3-one as a light yellow solid, 40%.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.[NH2:11][CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][NH:11][C:8]([C:4]2[S:3][C:2]([Br:1])=[N:6][C:5]=2[CH3:7])=[O:10])[CH:14]=1
Reactant: Cc1nc(Br)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(Br)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.1 %

Procedure:
To a solution of 2-bromo-4-methyl-thiazole-5-carboxylic acid (10.0 g, 45.0 mmol) in methylene chloride (200 mL) was added 3-(aminomethyl) pyridine (5.05 mL, 49.5 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 21.9 g, 49.5 mmol) and N,N-diisopropylethylamine (15.7 mL, 90.1 mmol). The mixture was stirred under nitrogen at room temperature for 16 hr, then diluted with methylene chloride (300 mL), washed with water (300 mL) and brine (2×200 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by flash chromatography over silica gel (methylene chloride:methanol, 95:5) to provide 2-bromo-4-methyl-thiazole-5-carboxylic acid (pyridine-3-ylmethyl)-amide as a yellow solid (13.5 g, 96% yield). MS (M+H)+=313; Rt=1.01 min.
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:27]=[C:26]([CH3:28])[S:25][C:16]=2[N:17]=[C:18]([C:20]2[O:24][N:23]=[CH:22][CH:21]=2)[N:19]=1>>[O:24]1[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:27]=[C:26]([CH3:28])[S:25][C:16]=3[N:17]=2)=[CH:21][CH:22]=[N:23]1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: Cc1cc2c(Cl)nc(-c3ccno3)nc2s1
Product: Cc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(isoxazol-5-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-methylenedioxyphenethylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].N1C=CC=CC=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](=[O:26])[CH3:25])=[CH:19][C:18]=1[S:27](Cl)(=[O:29])=[O:28]>O1CCOCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](=[O:26])[CH3:25])=[CH:19][C:18]=1[S:27]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1)(=[O:28])=[O:29]
Reactant: N#Cc1cccc(N)c1
Reactant: CC(=O)Cc1ccc(Cl)c(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC(=O)Cc1ccc(Cl)c(S(=O)(=O)Nc2cccc(C#N)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Aminobenzonitrile (442 mg, 3.7 mmol, 1 eq) is dissolved in dry pyridine (606 ul, 7.5 mmol, 2 eq), under an inert atmosphere of argon. 2-Chloro-5-(2-oxo-propyl)-benzenesulfonyl chloride (Intermediate A)(1.0 g, 3.7 mmol) in 1,4-dioxane (2 ml) is added and the reaction mixture is stirred at room temperature overnight. The solvents are removed in vacuo and the residue is dissolved in DCM and 0.5M HCl. The phases are separated and the organic portion is washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][CH:15]=[C:16]([C:18]([OH:20])=[O:19])[CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].O=P(Cl)(Cl)[Cl:23].O>C(O)(=O)C>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:23])=[C:6]2[CH:5]=[N:4]1)=[CH:14][CH:15]=[C:16]([C:18]([OH:20])=[O:19])[CH:17]=3)[CH3:2]
Reactant: CCn1nccc1Nc1cc(C(=O)O)ccc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: CCn1ncc2c(Cl)c3ccc(C(=O)O)cc3nc21

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl)-4-carboxyanthranilic acid (2.5 g) and POCl3 (20 ml) was refluxed overnight. The reaction mixture was poured into water, acidified with acetic acid and the solids which formed were collected by filtration. The solid was taken up in 10% NaOH, washed with ether and then the aqueous layer was acidified with concentrated HCl. The mixture was extracted with ether, the ether layer was dried over MgSO4 filtered and evaporated to afford 1 g of 1-ethyl-4-chloro-7-carboxy-1H-pyrazolo[3,4-b]quinoline, as a yellow powder.