Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]([NH2:21])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH2:17][CH:18]2[CH2:20][CH2:19]2)[CH:7]=1.C(N(CC)CC)C.C([O:32][C:33](=O)[C:34]1[C:39]([N+:40]([O-:42])=[O:41])=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:43]Br)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:14])[F:15])=[C:8]([O:16][CH2:17][CH:18]2[CH2:19][CH2:20]2)[CH:7]=1)[N:21]1[CH2:43][C:35]2[C:34](=[C:39]([N+:40]([O-:42])=[O:41])[CH:38]=[CH:37][CH:36]=2)[C:33]1=[O:32]
Reactant: CCOC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Reactant: COC(=O)CC(N)c1ccc(OC(F)F)c(OCC2CC2)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CC(c1ccc(OC(F)F)c(OCC2CC2)c1)N1Cc2cccc([N+](=O)[O-])c2C1=O
Temperature: 90 °C
Yield: 77 %

Procedure:
To a solution of 3-amino-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionic acid methyl ester (490 mg, 1.5 mmol) and triethyl amine (0.43 ml, 3.1 mmol) in DMF (10 ml) was added 2-bromomethyl-6-nitro-benzoic acid ethyl ester (460 mg, 1.6 mmol). The mixture was heated at 90° C. under nitrogen atmosphere overnight. The solvent was removed in vacuo. The resulted oil was extracted with ethyl acetate (50 ml) and 1N HCl (50 ml). The organic layer was washed with water (30 ml), brine (30 ml) and dried over magnesium sulfate. The solvent was removed in vacuo and the resulted oil was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to give 3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester as a yellowish solid (550 mg, 75%). 1HNMR (CDCl3): δ0.31-0.37 (m, 2H), 0.59-0.67 (m, 2H), 1.22-1.28 (m, 1H), 3.09 (dd, J=7, 15 Hz, 1H), 3.28 (dd, J=9, 15 Hz, 1H), 3.65 (s, 3H), 3.79-3.91 (m, 2H), 4.18 (d, J=17 Hz, 1H), 4.46 (d, J=17 Hz, 1H), 5.83 (dd, J=7, 9 Hz, 1H), 6.61 (t, JH-F=75 Hz, 1H), 7.04-7.05 (m, 3H), 7.58-7.76 (m, 3H).
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH2:4].[Br:13]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:13][C:7]1[CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]([NH2:4])=[C:2]([F:1])[C:8]=1[F:9]
Reactant: Nc1c([N+](=O)[O-])ccc(F)c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c([N+](=O)[O-])cc(Br)c(F)c1F
Temperature: 90 °C
Yield: 73.6 %

Procedure:
To a solution of 3.00 g of 2,3-difluoro-6-nitroaniline in 30 ml of dimethylformamide, 6.14 g of N-bromosuccinimide was added, followed by an hour's stirring at 90° C. Water was added to the reaction liquid which then was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried on anhydrous magnesium sulfate and the solvent was distilled off. The residue was separated and purified on silica gel column chromatography (ethyl acetate/hexane=1/6) to provide 3.21 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[CH:4]=[C:5](OS(C(F)(F)F)(=O)=O)[N:6]=[CH:7]2.CC1(C)C(C)(C)OB([C:29]2[C:30]([NH2:35])=[N:31][CH:32]=[CH:33][CH:34]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[CH:4]=[C:5]([C:29]1[C:30]([NH2:35])=[N:31][CH:32]=[CH:33][CH:34]=1)[N:6]=[CH:7]2
Reactant: CC1(C)OB(c2cccnc2N)OC1(C)C
Reactant: O=S(=O)(Oc1cc2c(Cl)ccc(F)c2cn1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncccc1-c1cc2c(Cl)ccc(F)c2cn1
Temperature: 100 °C

Procedure:
A mixture of trifluoromethanesulfonic acid 5-chloro-8-fluoroisoquinolin-3-yl ester (9.00 g, 27.4 mmol), 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (8.42 g, 38.3 mmol), Pd(PPh3)4 (0.63 g, 2 mol %), and Cs2CO3 (20.5 g, 62.9 mmol) in dioxane/H2O (4:1, 300 mL) were heated under nitrogen at 100° C. for 16 h. Solvents were evaporated in vacuo, water (100 mL) was added to the residue, and the mixture was extracted with EtOAc (3×75 mL). The EtOAc extract was dried over MgSO4, filtered, and concentrated in vacuo to give the crude product. It was purified by column chromatography on silica gel using EtOAc/Hexanes (1:3) to give the title compound. 1H NMR (CDCl3, 300 MHz): δ=6.87 (brs, 2H), 6.81 (dd, J=8.7, 4.8 Hz, 1H), 7.18 (dd, J=9.3, 9.0 Hz, 1H), 7.22 (dd, J=8.1, 4.2 Hz, 1H), 7.99 (dd, J=7.5, 2.1 Hz, 1H), 8.15 (dd, J=6.8, 1.8 Hz, 1H), 8.13 (t, J=1.2 Hz, 1H), 9.56 (d, J=1.2 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH3:9])[C:3]=1[C:10]1[CH2:14][CH2:13][O:12][N:11]=1.[Br:15]Br>S(=O)(=O)(O)O>[Br:15][C:7]1[C:2]([CH3:1])=[C:3]([C:10]2[CH2:14][CH2:13][O:12][N:11]=2)[C:4]([S:8][CH3:9])=[CH:5][CH:6]=1
Reactant: CSc1cccc(C)c1C1=NOCC1
Reactant: BrBr
Agent: O=S(=O)(O)O
Product: CSc1ccc(Br)c(C)c1C1=NOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 10 g (48 mmol) of 3-(2-methyl-6-methylthiophenyl)-4,5-dihydroisoxazole are added a little at a time to 120 ml of conc. sulfuric acid, and the mixture is stirred for about 30 minutes. 3.7 g (23 mmol) of bromine are then added dropwise, and the mixture is stirred at 0° C. for 2.5 hours. The mixture is then allowed to warm to room temperature over a period of about 45 minutes. A homogeneous solution is formed. For work-up, the reaction mixture is poured onto ice-water and extracted three times with methylene chloride. The organic phase is washed with sodium bicarbonate solution, dried with magnesium sulfate and concentrated. This gives 11.4 g of crude product which is used for the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:23][C:8]23[CH2:9][CH2:10][CH:11]4[CH:20]([CH:7]2[CH2:6][CH2:5][CH:4]3[CH:3]1[CH3:24])[CH2:19][CH:18]=[C:17]1[C:12]4([CH3:22])[CH2:13][CH2:14][CH:15]([OH:21])[CH2:16]1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>ClCCl>[CH3:1][N:2]1[CH2:23][C:8]23[CH2:9][CH2:10][CH:11]4[CH:20]([CH:7]2[CH2:6][CH2:5][CH:4]3[CH:3]1[CH3:24])[CH2:19][CH:18]=[C:17]1[C:12]4([CH3:22])[CH2:13][CH2:14][CH:15]([O:21][C:32](=[O:34])[CH3:33])[CH2:16]1
Reactant: CC1C2CCC3C4CC=C5CC(O)CCC5(C)C4CCC32CN1C
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 137.6 %

Procedure:
Compound 130A (15 mg, 0.045 mmol) was dissolved in 1 mL anhydrous dichloromethane. Triethylamine (32 μL, 0.228 mmol) was added followed by acetyl chloride (6.5 μL, 0.09 mmol). The mixture was stirred at room temperature overnight. The crude product was purified on silica gel column eluted with 0.3% ammonium hydroxide and 3% methanol in dichloromethane to give the desired product (23 mg, 68% yield).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]([CH2:17][O:18][CH3:19])([CH2:14][O:15][CH3:16])[C:11]([OH:13])=O)=[O:8])=[CH:4][CH:3]=1.C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C.[CH3:38][N:39]1[CH2:45][CH2:44][C:43]2[CH:46]=[C:47]([NH2:50])[CH:48]=[CH:49][C:42]=2[CH2:41][CH2:40]1>C1COCC1>[CH3:16][O:15][CH2:14][C:10]([NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:8])([CH2:17][O:18][CH3:19])[C:11](=[O:13])[NH:50][C:47]1[CH:48]=[CH:49][C:42]2[CH2:41][CH2:40][N:39]([CH3:38])[CH2:45][CH2:44][C:43]=2[CH:46]=1
Reactant: CN1CCc2ccc(N)cc2CC1
Reactant: COCC(COC)(NC(=O)c1ccc(Cl)s1)C(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: C1CCOC1
Product: COCC(COC)(NC(=O)c1ccc(Cl)s1)C(=O)Nc1ccc2c(c1)CCN(C)CC2
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
0.05 g (0.16 mmol) 2-[(5-chloro-thiophene-2-carbonyl)-amino]-3-methoxy-2-methoxymethyl-propionic acid are dissolved in 1.5 ml THF and at room temperature 0.04 g (0.16 mmol) 2-ethoxy-1-ethoxycarbonyl-1.2-dihydroquinoline (EEDQ) are added. After 30 min, 0.029 g (0.16 mmol) of 3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine is added and the mixture is stirred for 12 h at 40° C. Then it is concentrated by evaporation i.vac. And purified by chromatography through RP material (Microsorb C18 Varian; eluant: water/acetonitrile/trifluoroacetic acid=90:10:0.1=>0:100:0.1).
Reaction SMILES: [CH2:1]([NH:4][C:5]([N:7](N=O)[CH2:8][CH2:9][Cl:10])=[O:6])[CH2:2][Cl:3].CCCCCC>C1C=CC=CC=1>[Cl:3][CH2:2][CH2:1][NH:4][C:5]([NH:7][CH2:8][CH2:9][Cl:10])=[O:6]
Reactant: O=NN(CCCl)C(=O)NCCCl
Solvent: CCCCCC
Solvent: c1ccccc1
Product: O=C(NCCCl)NCCCl

Procedure:
A suspension of 1.11 mmole (0.205 g) of 1,3-bis(2-chloroethyl)urea in 8 ml methylene dichloride at -10° C. was saturated with dinitrogen trioxide in 20% excess of theoretical. The heterogeneous mixture gradually changed to a green homogeneous solution. The methylene dichloride was evaporated, and the residue was extracted with 3× 10 ml hexane. Evaporation of the hexane gave 0.1773 g of oil which was the crude BCNU (NSC 409962). The hexane insoluble portion, 0.0649 g, when treated with benzene, gave 0.020 g of 1,3-bis(2-chloroethyl)urea which was benzene insoluble. The benzene solubles were processed through a silica column (1× 10 cm) and 0.0245 g of crude BCNU was obtained. The combined fractions of crude product amounted to 0.2018 g (85.1%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N:5]1([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3([CH2:26][NH:27][CH2:28][CH3:29])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C>C1COCC1>[CH2:28]([N:27]([CH2:26][C:20]1([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][CH2:10][N:5]3[CH2:9][CH2:8][CH2:7][CH2:6]3)=[CH:19][CH:18]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[C:1](=[O:3])[CH3:2])[CH3:29]
Reactant: CC(=O)Cl
Reactant: CCNCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1)C(C)=O
Reaction time: 2 h
Yield: 42.5 %

Procedure:
Acetyl chloride (14 μL, 0.20 mmol) was added dropwise to a solution of N-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)ethanamine (70 mg, 0.20 mmol) and triethylamine (28 μL, 0.20 mmol) in THF (0.50 mL) at 0° C. and the reaction stirred for 2 hours. The reaction was quenched using NaHCO3 (10 mL), extracted with dichloromethane (3×10 mL) and the organic extracts dried over Na2SO4, filtered and concentrated in vacuo. The compound was purified by column chromatography on silica, eluting with DCM/MeOH/NH3 (95:5:0.5) to provide the title compound as a clear oil (33 mg, 42%). 1H NMR complicated by the presence of rotamers. 1H NMR (400 MHz, CDCl3) δ 7.20-7.12 (m, 2H), 6.92-6.86 (m, 2H), 4.06-4.00 (m, 2H), 3.88-3.76 (m, 2H), 2.56-2.48 (m, 2H), 3.42 (s, 2H), 2.66 (t, 2H), 2.58-2.52 (m, 4H), 2.48 (quartet, 2H), 2.08 (s, 3H), 2.06-1.92 (m, 6H), 1.84-1.76 (m, 4H), 0.98 (t, 0.6H) 0.86 (t, 2.4H). HRMS (ESI+) 389.2799 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[NH:6][CH:5]=1.[NH:14]1[CH:18]=[CH:17][CH:16]=[N:15]1.C(N(C(C)C)C(C)C)C>C(Cl)(Cl)Cl>[N:14]1([CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=3)[NH:6][CH:5]=2)[CH:18]=[CH:17][CH:16]=[N:15]1
Reactant: c1cn[nH]c1
Reactant: Fc1ccc2[nH]cc(CCBr)c2c1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc2[nH]cc(CCn3cccn3)c2c1

Procedure:
A solution of 3-(2-bromo-ethyl)-5-fluoro-1H-indole (7.26 g, 30 mmol), pyrazole (2.04 g, 30 mmol) and ethyl-diisopropylamine (5.1 ml, 30 mmol) in abs. chloroform (80 ml) was stirred at 90° C. for 12 h. The reaction solution was then washed twice with water, dried over Na2SO4 and concentrated i. vac. and the residue which remained was purified by flash chromatography with CHCl3/MeOH (20:1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=2[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:6]=[CH:7][CH:8]=1.[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>O1CCOCC1>[N:26]1([CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=3[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:6]=[CH:7][CH:8]=2)[CH:30]=[CH:29][N:28]=[CH:27]1
Reactant: c1c[nH]cn1
Reactant: CC(C)Cc1cc(-c2cccc(CBr)c2)c(S(=O)(=O)NC(C)(C)C)s1
Solvent: C1COCCO1
Product: CC(C)Cc1cc(-c2cccc(Cn3ccnc3)c2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 80 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of 3-(3-bromomethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (58 mg, 0.13 mmol; see step (e)) in dioxane (2.0 mL) was added imidazole (22 mg, 0.33 mmol) and the reaction mixture was stirred for 1 h at 80° C. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography using MeOH:CH2Cl2 (5:95) as eluent to give the sub-title compound in 68% yield as a colourless syrup (38.4 mg, 0.088 mmol).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]([F:27])([F:26])[C:11]1[N:16]=[C:15]([N:17]2[CH2:21][C@@H:20]3[C:22](=[O:25])[CH2:23][CH2:24][C@@H:19]3[CH2:18]2)[CH:14]=[CH:13][CH:12]=1>O1CCCC1>[C:1]1([C@:22]2([OH:25])[C@@H:20]3[C@@H:19]([CH2:18][N:17]([C:15]4[CH:14]=[CH:13][CH:12]=[C:11]([C:10]([F:26])([F:9])[F:27])[N:16]=4)[CH2:21]3)[CH2:24][CH2:23]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@H]12
Solvent: C1CCOC1
Product: O[C@]1(c2ccccc2)CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Temperature: -10 °C

Procedure:
Phenylmagnesium bromide in tetrahydrofuran (0.266 mL, 0.266 mmol) was added to (3aR,6aS)-2-[6-(trifluoromethyl)pyridin-2-yl]hexahydrocyclopenta[c]pyrrol-4(1H)-one (60 mg, 0.222 mmol) from Example 32 in tetrahydrofuran (1 mL) at −40° C., and the reaction mixture was allowed to warm to −10° C. in 20 minutes. The reaction was quenched with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The combined organic washes were purified by silica gel chromatography using 0-40% ethyl acetate/hexane as eluent to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.78 (dt, J=8.2, 1.6, 2H), 7.45 (t, J=7.7, 3H), 7.37-7.27 (m, 1H), 6.90 (d, J=7.2, 1H), 6.70 (d, J=0.5, 1H), 6.46 (d, J=8.6, 1H), 4.02-3.94 (m, 1H), 3.92-3.82 (m, 1H), 3.62-3.42 (m, 2H), 3.07 (td, J=9.3, 2.8, 1H), 3.02-2.92 (m, 1H), 2.38-2.22 (m, 2H), 2.17-1.98 (m, 2H); MS (ESI+) m/z 349 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[OH-].[Na+].O.[Br:11][CH:12]([CH3:16])[C:13](Br)=[O:14]>C(Cl)(Cl)Cl>[Br:11][CH:12]([CH3:16])[C:13]([NH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4])=[O:14]
Reactant: CC(Br)C(=O)Br
Reactant: CC(C)(N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(Br)C(=O)NC(C)(C)C(=O)O
Temperature: -12 °C
Reaction time: 17 h
Yield: 70.4 %

Procedure:
To a stirring mixture of 2-aminoisobutyric acid (52.08 g; 0.51 mol), sodium hydroxide (20.20 g; 0.51 mol), 200 mL water and 50 mL chloroform cooled to −12° C., was added a solution of 2-bromopropionyl bromide (100 g; 0.463 mol) in 150 mL chloroform. The temperature was maintained between −15 to −12° C. during the addition. The reaction mixture was then allowed to warm to room temperature and stirred for 17 hours. The precipitated solid was filtered, mixed with 700 mL hot toluene, then cooled to room temperature. The solid was filtered and dried under vacuum to afford 77.6 g (70%) of product.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16])[NH:6]2.Cl[CH2:20][C:21]1[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[O:23][N:22]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][C:15]([F:16])([F:17])[F:18])[N:6]2[CH2:20][C:21]1[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=2)[O:23][N:22]=1
Reactant: N#Cc1ccc2[nH]c(CCC(F)(F)F)cc2c1Cl
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Product: N#Cc1ccc2c(cc(CCC(F)(F)F)n2Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1Cl

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-(3,3,3-trifluoropropyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole: 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1 H), 8.23 (d, J=7.8 Hz, 1 H), 7.86 (d, J=7.9 Hz, 1H), 7.67 (dd, J=7.8 Hz, 1 H), 7.45 (s, 2 H), 6.56 (s, 1 H), 5.45 (s, 2 H), 3.27 (t, 2 H), 2.89-2.61 (m, 2 H); MS (ES) m/z 499 (M+1).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].Br[CH2:14][C:15]#[CH:16]>C1(C)C=CC=CC=1>[CH3:16][C:15]1[N:3]=[N:2][N:1]([C:4]2[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=2)[CH:14]=1
Reactant: [N-]=[N+]=Nc1ccc([N+](=O)[O-])cc1
Reactant: C#CCBr
Solvent: Cc1ccccc1
Product: Cc1cn(-c2ccc(N)cc2)nn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
A solution of 1-azido-4-nitrobenzene (0.500 g, 3.05 mmol) and 3-bromoprop-1-yne (1.45 g, 12.2 mmol) in toluene (3 mL) was heated to 60° C. for 24 hours in a sealed tube. Additional 3-bromoprop-1-yne (1.45 g, 12.2 mmol) was added and the solution stirred at 60° C. overnight. The reaction mixture was concentrated to an orange solid. The crude residue was dissolved in ethanol (100 mL). 10 wt % Palladium on carbon (150 mg) was added and the mixture was pressurized to 50 psi hydrogen and stirred for 18 hours. The reaction mixture was filtered through celite and the filtrate was concentrated. The residue was slurried in ethyl acetate. The mixture was filtered, and the solid dried under vacuum to give 4-(4-methyl-1H-1,2,3-triazol-1-yl)aniline (300 mg). 1HNMR (400 MHz, CD3OD, δ): 8.37 (s, 1H), 8.03 (m, 2H), 7.58 (m, 2H), 2.44 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.[OH:5][C:6]1[CH:7]=[C:8]([CH:18]=[O:19])[CH:9]=[C:10]2[C:15]=1[O:14][C:13]([CH3:17])([CH3:16])[CH:12]=[CH:11]2.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][O:2][CH2:3][O:5][C:6]1[CH:7]=[C:8]([CH:18]=[O:19])[CH:9]=[C:10]2[C:15]=1[O:14][C:13]([CH3:16])([CH3:17])[CH:12]=[CH:11]2
Reactant: COCCl
Reactant: CC1(C)C=Cc2cc(C=O)cc(O)c2O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1cc(C=O)cc2c1OC(C)(C)C=C2

Procedure:
Chloromethyl methyl ether (4 mL, 5 mmol) was added to a solution of 9 (103 mg, 0.5 mmol) and N,N-diisopropylethylamine (0.2 mL, 1 mmol) in 4 mL of methylene chloride. The reaction mixture was refluxed overnight and concentrated in vacuo. 10 (48 mg, 38%) was purified with ethyl acetate/hexane (1/50). 1H NMR (CDCl3): δ 1.52 (s, 6H), 3.54 (s, 3H), 5.25 (s, 2H), 5.71 (d, J=9.67 Hz, 1H), 6.38 (d, J=9.96 Hz, 1H), 7.26 (d, J=1.76 Hz, 1H), 7.52 (d, J=1.76 Hz, 1H), 9.80 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[Cl:15][C:16]1[C:21]2[N:22]=[C:23]([SH:25])[S:24][C:20]=2[CH:19]=[CH:18][CH:17]=1>>[Cl:15][C:16]1[C:21]2[N:22]=[C:23]([S:25][CH2:2][C:3]([N:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:8][CH2:7][CH2:6]3)=[O:4])[S:24][C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(CCl)N1CCCc2ccccc21
Reactant: Sc1nc2c(Cl)cccc2s1
Product: O=C(CSc1nc2c(Cl)cccc2s1)N1CCCc2ccccc21
Yield: 72 %

Procedure:
The title compound was synthesized according to General Procedure A using compound 4 as the electrophile and 4-chlorobenzo[d]thiazole-2-thiol as the nucleophile to yield 22 as a white solid (72%): MS m/z: 375 (M+H)+. Anal. Calcd. For, C18H15ClN2OS2: C, 57.67; H, 4.03; N, 7.47; S, 17.11; Cl, 9.46. Found: C, 57.79; H, 4.08; N, 7.48; S, 17.33; Cl, 9.41.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](C=O)[C:3]=1[O:10][CH3:11].[Na].FC(F)(F)C(OO)=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.C(OCC)C>[Br:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([OH:16])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)C(F)(F)F
Reactant: COc1c(Br)cccc1C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: CCOCC
Product: COc1c(O)cccc1Br
Reaction time: 8 h

Procedure:
A solution of 0.037 g 2-bromo-6-formyl-anisole in 1 ml methylene chloride is treated with 0.54 sodium dibasic phosphate and 1.3 ml trifluoroperacetic acid, stirred overnight, treated with 10% aqueous sodium carbonate (5 ml) and 5 ml diethyl ether, stirred for 1.5 hours, and partitioned between water and ether. The ether portion is extracted with 1 N aqueous sodium hydroxide, the hydroxide extracts acidified and then extracted with ether. Concentration of the ether extracts affords 3-bromo-2-methoxyphenol.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].Cl.N1C=CC=CC=1.[Br:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][C:25]=1[OH:31]>C(OCCO)C>[Br:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])=[CH:26][C:25]=1[OH:31]
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Reactant: Nc1ccc(Br)c(O)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cccc2c(Nc3ccc(Br)c(O)c3)c(C#N)cnc12
Temperature: 100 °C

Procedure:
Using an analogous procedure to that described in Example 274. A reaction mixture of 250.0 mg (1.1 mmol) of 4-chloro-8-methoxy -3-quinolinecarbonitrile, 131.7 mg (1.1 mmol) of pyridine hydrochloride and 286.7 mg (1.3 mmol) of 4-bromo-3-hydroxy-aniline in 10 mL of 2-ethoxyethanol was heated at 100° C. for 1.5 hr. The work up gave 374.1 mg (88.6%) of the product as a pink solid, m.p. 146° C. (dec.), mass spectrum (electrospray, m/e): M+H 369.9.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([CH:16]=[CH2:17])[CH:5]=1.[CH:18]([O:22][C:23]1[C:28]([CH:29]=[CH:30][C:31](O)=[O:32])=[CH:27][CH:26]=[C:25]([C:34]([F:37])([F:36])[F:35])[N:24]=1)([CH2:20][CH3:21])[CH3:19]>>[CH:18]([O:22][C:23]1[C:28]([CH:29]=[CH:30][C:31]([NH:2][CH2:3][C:4]2[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=2)=[O:32])=[CH:27][CH:26]=[C:25]([C:34]([F:37])([F:35])[F:36])[N:24]=1)([CH2:20][CH3:21])[CH3:19]
Reactant: C=Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Reactant: CCC(C)Oc1nc(C(F)(F)F)ccc1C=CC(=O)O
Agent: Cl
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2OC(C)CC)cc(F)c1NS(C)(=O)=O
Yield: 25.6 %

Procedure:
N-(4-Aminomethyl-2-ethenyl-6-fluoro-phenyl)-methanesulfonamide HCl salt (35 mg, 0.13 mmol) was reacted with 3-(2-sec-butoxy-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (22 mg) to give the title compound (10 mg) after purification by column chromatography (Hex/EtOAc=1/1).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:16][CH2:17][CH3:18])[N:4]=[C:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:7][C:6]2=O.P(Cl)(Cl)([Cl:21])=O>C(OCC)C>[Cl:21][C:6]1[C:5]2=[N:4][N:3]([CH2:16][CH2:17][CH3:18])[C:2]([NH2:1])=[C:14]2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: CCCn1nc2c(=O)[nH]c3ccccc3c2c1N
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCCn1nc2c(Cl)nc3ccccc3c2c1N
Temperature: 25 °C

Procedure:
A solution of 1-amino-2-propyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one (86 mg, 0.36 mmol) in phosphorus oxychloride (3 mL) was heated at 100° C. for 45 minutes and then allowed to cool to ambient temperature. The reaction mixture was diluted with diethyl ether (10 mL). A solid was isolated by filtration, rinsed with diethyl ether, and dried to provide 4-chloro-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-amine.