Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][CH2:10][C@@H:9]([NH:13][C:14]3[N:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=O)=[N:18][CH:19]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][NH2:32].CCN=C=NCCCN(C)C>CN(C=O)C.C1C=CC2N(O)N=NC=2C=1>[CH:1]1([N:7]2[CH2:12][CH2:11][CH2:10][C@@H:9]([NH:13][C:14]3[N:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([NH:32][O:31][CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][O:25]4)=[O:24])=[N:18][CH:19]=3)[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)/C=C/c1cnc(N[C@@H]2CCCN(C3CCCCC3)C2)cn1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(/C=C/c1cnc(N[C@@H]2CCCN(C3CCCCC3)C2)cn1)NOC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
A mixture of (2E)-3-(5-{[(3R)-1-cyclohexyl-3-piperidinyl]amino}-2-pyrazinyl)acrylic acid (209 mg), O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine (89 mg), HOBt (111 μg) and EDCI (158 mg) in DMF (4.5 mL) was stirred at 0° C. for 1 hr and the mixture was stirred at ambient temperature for 18 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between saturated sodium bicarbonate solution and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform-MeOH=95-5) to give (2E)-3-(5-{[(3R)-1-cyclohexyl-3-piperidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (198 mg) as an amorphous powder.
Reaction SMILES: [OH-].[Na+].[CH:3](=O)[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6].[BH4-].[Na+].[NH2:14][C@H:15]([C:22]([OH:24])=[O:23])[CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1>>[OH:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[CH2:3][NH:14][C@H:15]([C:22]([OH:24])=[O:23])[CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1
Reactant: O=Cc1ccccc1O
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@H](Cc1c[nH]cn1)NCc1ccccc1O
Reaction time: 1 h

Procedure:
To 20 ml of a 2N aqueous solution of sodium hydroxide in which 5 g of L-histidine had been dissolved, 3.5 ml of salicylaldehyde and 0.4 g of sodium borohydride were successively added. After stirring for 1 hour, additional 3.5 ml of salicylaldehyde and 0.4 g of sodium borohydride were successively added. After stirring at room temperature for 1 hour, the unsolubles were filtered out and the filtrate was extracted with diethyl ether. The pH was adjusted to 6 with hydrochloric acid to give 8 g of N-(2-hydroxybenzyl)-L-histidine.
Reaction SMILES: [H-].[Na+].[C:3]([O:12]C)(=[O:11])[CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=[O:8].[C:14]1([CH:24]=O)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.[OH-].[Na+]>CO>[C:14]1([CH:24]=[C:4]([CH2:5][CH2:6][C:7]([OH:9])=[O:8])[C:3]([OH:12])=[O:11])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: COC(=O)CCCC(=O)OC
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCC(=Cc1cccc2ccccc12)C(=O)O
Yield: 42.8 %

Procedure:
8.17 g (0.19 mole) of sodium hydride (as a 55% w/w dispersion in mineral oil) were added, whilst ice-cooling, to a solution of 25 g (0.16 mole) of dimethyl glutarate and 23.4 g (0.16 mole) of 1-naphthaldehyde dissolved in 200 ml of anhydrous methanol. The mixture was heated under reflux for 30 minutes, after which 190 ml (0.19 mole) of a 1N aqueous solution of sodium hydroxide were added to it, and the mixture was again heated under reflux for 1 hour. The solvent was removed by distillation under reduced pressure, and the resulting residue was mixed with water and washed with diethyl ether. The aqueous layer was acidified and then extracted with diethyl ether. The ethereal layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and then diisopropyl ether was added to the residue to precipitate crystals, which were collected by filtration to give 18.5 g of 2-(1 -naphthylmethylene)glutaric acid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[C:10](Cl)(=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1>ClCCl>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NCc1ccc(N)cc1
Solvent: ClCCl
Product: COc1ccc(C(=O)NCc2ccc(N)cc2)cc1
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 4-aminobenzylamine (7.14 g, 58.4 mmol) in dichloromethane (120 mL) were added at 0° C. under N2 triethylamine (16.4 mL, 118 mmol) and a solution of p-anisoyl chloride (10 g, 58.4 mmol) in dichloromethane (20 mL). The mixture was allowed to reach 25° C., stirred 16 h, and poured onto water/ice (ca. 200 mL). The resulting suspension was stirred for 15 minutes and the white solid was filtered off and dried. Weight: 15 g (100% yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9](=[O:17])[CH:10]([CH2:13]N(C)C)[CH2:11][CH3:12])[CH:6]=[CH:5][C:4]=1[O:18][CH2:19][C:20]([OH:22])=[O:21].C(=O)(O)[O-].[Na+]>O>[Cl:2][C:3]1[CH:8]=[C:7]([C:9](=[O:17])[C:10](=[CH2:13])[CH2:11][CH3:12])[CH:6]=[CH:5][C:4]=1[O:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: CCC(CN(C)C)C(=O)c1ccc(OCC(=O)O)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C=C(CC)C(=O)c1ccc(OCC(=O)O)c(Cl)c1

Procedure:
[2-Chloro-4-(2-dimethylaminomethylbutyryl)phenyoxy]acetic acid hydrochloride (8.7 g., 0.025 mole), water (100 ml.), and saturated aqueous sodium bicarbonate (100 ml.) are combined and heated on a steam bath for 2.5 hours. The reaction mixture is acidified, extracted with ether and dried over magnesium sulfate. Distillation of the solvent at reduced pressure leaves 1.3 g. (20%) of [2-chloro-4-(2-methylenebutyryl)phenoxy]acetic acid which melts at 83.5°-85.5° C. after recrystallization from methyl cyclohexane (75 ml.).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CN(C=O)C>O>[Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:12])([CH3:14])[CH2:13][N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C[C@](C)(O)Cn2cc([N+](=O)[O-])nc2Cl)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
A mixture of (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (7.00 g, 32.2 mmol) and tert-butyl piperazine-1-carboxylate (6.29 g, 33.8 mmol) and DMF (70 ml) was stirred at 70° C. for 8 hours. The reaction mixture was allowed to return to room temperature, then diluted with water, and then the solution was extracted with ethyl acetate twice. The organic phases were combined, washed with water three times, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. To the residue, diethyl ether was added. The precipitates were filtered off, and dried at room temperature under reduced pressure to afford tert-butyl (S)-4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]piperazin-1-carboxylate (10.25 g, yield 79%) as a light yellow powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][C:10]([CH:12]=O)=[CH:9][CH:8]=2)[CH:2]=1.CN.Cl.[C:17]([BH3-])#[N:18].[Na+]>CO.O1CCOCC1>[CH3:17][NH:18][CH2:12][C:10]1[O:11][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(-c2cccnc2)o1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CNCc1ccc(-c2cccnc2)o1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.2 %

Procedure:
To a solution 23 (104 mg, 0.60 mmol) was added a solution of methylamine (2.0 M, 1.8 mL, 3.6 mmol) in anhydrous CH3OH, a solution of HCl (4.0 M, 0.3 mL, 1.2 mmol) in anhydrous 1,4-dioxane and sodium cyanoborohydride (38 mg, 0.6 mmol). The flask was purged with argon and stirred under an atmosphere of argon at room temperature for 48 h. The solution was adjusted to pH 2 with conc. HCl and the solvent was removed in vacuo. The residue was dissolved in water, washed with Et2O (3×10 mL), adjusted to pH 10 with NaOH(aq) (10 N), extracted with Et2O (3×20 mL), dried (Na2SO4), filtered and the solvent was removed in vacuo. The crude material was chromatographed on silica gel (CH3OH/CHCl3, 10/90, Rf=0.1) to afford the title compound 41 (94 mg, 84% yield) as a yellow oil: 1H NMR (CDCl3) δ 8.89 (m, 1H), 8.46 (m, 1H), 7.91 (m, 1H), 7.28 (m, 1H), 6.67 (d, J=3.2 Hz, 1H), 6.31 (d, J=3.2 Hz, 1H), 3.82 (s, 2H), 2.49 (s, 3H), 2.14 (br s, 1H); LRMS (ESI) m/z calcd for C11H13N2O [M+H]+ 189. found 189; m/z calcd for C10H8NO [M−NH(CH3)]+ 158. found 158; HRMS (ESI) m/z calcd for C11H13N2O [M+H]+ 189.1028. found 189.1041; HPLC>95% (tR=8.74 min, 60 (A):40 (B): 0.02 (C); tR=3.69 min, 60 (A):40 (B): 0.07 (C)).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.C([NH2:16])(=O)C.C([O-])([O-])=O.[K+].[K+]>>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH2:16])[CH:11]=[CH:10]2
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: CC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1ccc2cc(Cl)ccc2n1
Temperature: 200 °C
Reaction time: 1.5 h
Yield: 98.5 %

Procedure:
A mixture of 2,6-dichloroquinoline (500 mg, 2.5 mmol), acetamide (3 g, 50.8 mmol) and K2CO3 (1.75 g, 12.7 mmol) in a round bottom flask was stirred at 200° C. for 1.5 hours until TLC indicated that 2,6-dichloroquinoline was consumed. The resulting mixture was cooled to room temperature, and was partitioned between dichloromethane and H2O, the organic layer was dried over anhydrous Na2SO4, concentrated, and the residue was purified by a standard method to give 440 mg of the title compound. LCMS (m/z): 179.7 (M+1)+
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.CC(C)([O-])C.[Na+]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:3][CH:4]=1
Reactant: COc1ccc(Cl)cc1
Reactant: C1COCCN1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: COc1ccc(N2CCOCC2)cc1
Yield: 94.7 %

Procedure:
According to the general procedure B, 4-chloroanisole (82 mg, 0.55 mmol) reacted with morpholine (46 mg, 0.53 mmol) using 1 mol % of catalyst and sodium tert-butoxide (63 mg, 0.60 mmol) at 70° C. for 27 h to give the title compound (97 mg, 95%) as a solid: 1H-NMR (400 MHz, CDCl3): δ 6.92-6.85 (m, 4H), 3.87 (t, 4H, J=4.8 Hz), 3.78 (s, 3H), 3.07 (t, 4H, J=4.8 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 153.92, 145.60, 117.77, 114.47, 67.00, 55.52, 50.78. GC/MS(EI); m/z 193 (M+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][C:18](=[CH:25][C:26]2([CH3:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:19]3=[O:24])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>[Ni].C(O)C>[C:11]([C:9]1[CH:8]=[C:7]([C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][CH:18]([CH2:25][C:26]2([CH3:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:19]3=[O:24])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: CC1(C=C2Cc3c(cccc3-c3cc(C(C)(C)C)cc(C(C)(C)C)c3)C2=O)CCCCC1
Agent: [Ni]
Solvent: CCO
Product: CC1(CC2Cc3c(cccc3-c3cc(C(C)(C)C)cc(C(C)(C)C)c3)C2=O)CCCCC1
Yield: 79.6 %

Procedure:
A mixture of Raney nickel (slurry in water, 12.5 g), compound 12 (12.5 g, 29.16 mmol, 1 equiv) and ethanol (1000 mL) was hydrogenated @ 50 psi at room temperature for 4 hours. The mixture was filtered through Celite and the filter cake was washed with ethanol (500 mL). The filtrate was concentrated under reduced pressure to give crude compound 13 (10.0 g, 80% yield) as a pale-yellow oil. This material was used subsequently.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[C:12]([NH:14][C:15]([CH:17]3[CH2:19][CH2:18]3)=[O:16])[N:13]=2)[CH:10]=1.CO>O1CCCC1>[NH2:24][C:22]1[CH:21]=[CH:20][C:3]([O:4][C:5]2[CH:6]=[CH:7][C:8]3[N:9]([CH:11]=[C:12]([NH:14][C:15]([CH:17]4[CH2:19][CH2:18]4)=[O:16])[N:13]=3)[CH:10]=2)=[C:2]([F:1])[CH:23]=1
Reactant: O=C(Nc1cn2cc(Oc3ccc([N+](=O)[O-])cc3F)ccc2n1)C1CC1
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Temperature: 40 °C
Yield: 91.6 %

Procedure:
To a suspension of N-[6-(2-fluoro-4-nitrophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (10 g, 28.1 mmol) in tetrahydrofuran (80 mL)/methanol (80 mL) were added iron chloride•hexahydrate (0.5 g), hydrazine•monohydrate (8.2 mL, 168 mmol) and activated carbon (1.0 g), and the mixture was heated under reflux for 16 hr. After cooling to 40° C., the mixture was filtered through celite and washed with methanol. The solvent of the filtrate was evaporated under reduced pressure, and the precipitate was washed with water/methanol (=10/1) and collected by filtration to give the title compound (8.4 g, 92%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:24])([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]([O:19]C(C)(C)C)=[O:18])[CH:13]=2)[N:8]=1)[C:3]([F:6])([F:5])[F:4].FC(F)(F)C(O)=O>ClCCl>[F:24][C:2]([F:1])([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]([OH:19])=[O:18])[CH:13]=2)[N:8]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: CC(C)(C)OC(=O)c1ccc2nc(C(F)(F)C(F)(F)F)ccc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc2nc(C(F)(F)C(F)(F)F)ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.2 %

Procedure:
To a solution of tert-butyl 2-pentafluoroethylquinoline-6-carboxylate (165 mg, 0.475 mmol) in dichloromethane (5 mL), cooled to 0° C., was added trifluoroacetic acid (2 mL, 26 mmol) and the reaction mixture allowed to warm to room temperature and stirred for 16 h. The reaction mixture was concentrated under reduced pressure to give the crude product, 2-pentafluoroethylquinoline-6-carboxylic acid (140 mg, 100%). 1H NMR (400 MHz, CDCl3+2drops CD3OD) δ 7.79 (1H, d), 8.26 (1H, d), 8.39 (1H, dd), 8.47 (1H, d), 8.67 (1H, d). LCMS: Retention time: 1.49 min. MS (ESI) m/z 292 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][O:6][S:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: CN(C)CCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCN(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.5 %

Procedure:
To a mixture of 0.206 g (2 mmole) of 3-dimethylamino-propan-1-ol, and 2 mL of pyridine (2 ml) was added 0.001 g of 4-dimethylaminopyridine and 0.381 g (2 mmole) of p-toluenesulphonyl chloride. The mixture was stirred at ambient temperature overnight and then concentrated under reduced pressure. The residue was taken up in 10 mL of dichloromethane and washed once with 5 mL of saturated sodium bicarbonate, twice with 5 mL of water, and then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.085 g of toluene-4-sulfonic acid 3-dimethylamino-propyl ester as a colorless oil.
Reaction SMILES: CN(C)C1C=CC=CC=1.[Br:10][CH2:11][C:12](Br)=[O:13].[CH2:15]([O:22][C:23]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[C:26]([NH2:27])=[C:25]([C:34]([F:37])([F:36])[F:35])[CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([C:34]([F:36])([F:37])[F:35])[C:26]([NH:27][C:12](=[O:13])[CH2:11][Br:10])=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1c(C(F)(F)F)cc(OCc2ccccc2)cc1C(F)(F)F
Reactant: O=C(Br)CBr
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(CBr)Nc1c(C(F)(F)F)cc(OCc2ccccc2)cc1C(F)(F)F
Reaction time: 1 h
Yield: 64.7 %

Procedure:
Under an argon atmosphere, N,N-dimethylaniline (2.78 mL, 21.9 mmol) and bromoacetyl bromide (1.91 mL, 21.9 mmol) were added dropwise to a solution of 4-benzyloxy-2,6-bis(trifluoromethyl)aniline (4.90 g, 14.6 mmol) in anhydrous toluene (150 mL) under ice cooling. Immediately after the dropwise addition, the mixture was heated under reflux and then stirred for 1 hour. After cooling, the reaction mixture was filtered through Celite and the insoluble matter was washed with toluene. The residue obtained by distilling the filtrate under reduced pressure was purified by chromatography on a silica gel column (developing solvent; hexane:acetone=10:1→6:1→5:1). The crude product thus obtained was recrystallized from hexane-acetone, whereby 4.31 g (yield: 64.7%) of N-[4-benzyloxy-2,6-bis(trifluoromethyl)phenyl]-2-bromoacetamide was obtained as colorless needle-like crystals.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].[CH3:7][S:8]([C:10](SC)=[CH:11][N+:12]([O-:14])=[O:13])=O>CO>[CH3:7][S:8][C:10]([NH:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:11][N+:12]([O-:14])=[O:13]
Reactant: NCC(F)(F)F
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Solvent: CO
Product: CSC(=C[N+](=O)[O-])NCC(F)(F)F

Procedure:
A solution of 2,2,2-trifluoroethylamine (4.0 g) in methanol (45 ml) was added dropwise to a suspension of 1-methylsulphinyl-1-methylthio-2-nitroethylene (3.6 g) in methanol (150 ml) at 20° for 24 hours. Evaporation of the reaction mixture and recrystallisation from ether gave the title compound as a pale orange crystalline solid m.p. 101°-102°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27](C(OC(C)(C)C)=O)[C:28](=[O:34])[C@@H:29]4[CH2:33][CH2:32][CH2:31][NH:30]4)=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:42]([CH3:44])[CH3:43])[NH:11]1>Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:34])[C@@H:29]4[CH2:33][CH2:32][CH2:31][NH:30]4)=[CH:25][CH:26]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:42]([CH3:44])[CH3:43])[NH:11]1
Reactant: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(N(C(=O)OC(C)(C)C)C(=O)[C@@H]4CCCN4)cc3)nc(=O)c1-2
Agent: Cl
Product: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(NC(=O)[C@@H]4CCCN4)cc3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.8 %

Procedure:
Fifty mg (0.076 mmol) of (S)-1-(2,4,6-trichloro phenyl)-3-isopropyl-6-(4-(N-t-butoxycarbonylprolinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one was dissolved in 2 mL of 4 M HCl, and the solution was stirred 1 h at RT. The solution was concentrated under reduced pressure to afford 45 mg (100%) of (S)-1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(prolinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as a white, amorphous solid. 1H NMR (300 MHz, DMSO) δ 12.42(s, 1H); 10.67(s, 1H); 7.97(s, 2H); 7.49(d, 2H, J=8.5 Hz); 7.23(d, 2H, J=8.4 Hz); 4.27-4.31(m, 1H); 3.82(s, 2H); 3.18-3.34(m, 5H); 2.28-2.40(m, 1H); 1.84-1.95(m, 3H); 1.28(d, 6H, J=6.9 Hz).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:35])[NH:10][C@H:11]([C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30](Br)=[C:29]([CH3:34])[CH:28]=2)[N:26]=1)=[O:16])[CH:12]([CH3:14])[CH3:13].[CH3:36][C:37]1[CH:38]=[C:39]([NH2:52])[CH:40]=[CH:41][C:42]=1B1OC(C)(C)C(C)(C)O1.C1(C)C=CC=CC=1.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>[CH3:7][O:8][C:9](=[O:35])[NH:10][C@H:11]([C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:42]3[CH:41]=[CH:40][C:39]([NH2:52])=[CH:38][C:37]=3[CH3:36])=[C:29]([CH3:34])[CH:28]=2)[N:26]=1)=[O:16])[CH:12]([CH3:14])[CH3:13]
Reactant: Cc1cc(N)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(Br)c(C)c2)c[nH]1)C(C)C
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(N)cc3C)c(C)c2)c[nH]1)C(C)C
Temperature: 100 °C

Procedure:
Potassium carbonate (224 mg, 1.619 mmol) was added to a mixture of ((S)-1-{(S)-2-[4-(4-bromo-3-methyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (150 mg, 0.324 mmol) and 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (90.6 mg, 0.389 mmol) in toluene (0.6 mL, 6 mmol) and water (0.3 mL, 20 mmol). The reaction mixture was degassed and flushed with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (44.9 mg, 0.039 mmol) was added under nitrogen and then the reaction mixture was capped and heated at 100° C. overnight, cooled to RT and partitioned between ethyl acetate (10 mL) and water (2 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to give a brownish oil, which was purified by silica gel chromatography (12 g silica gel, 0-100% EtOAc/hexanes). Desired fractions were combined and concentrated to give the title compound as a light yellowish foam (135 mg, 85% yield). (m/z): [M+H]+ calcd for C28H35N5O3 490.27 found 490.6.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:21]=[C:20]([F:22])[C:7]([CH2:8][N:9]2[C:13]3[CH2:14][CH2:15][CH2:16][C:12]=3[C:11]([C:17](=[NH:19])[NH2:18])=[N:10]2)=[C:6]([F:23])[CH:5]=1)[CH3:2].N1CCCCC1.C[N:31](C)[CH:32](N(C)C)[CH:33]([O:36][CH3:37])[C:34]#N>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([F:23])[C:7]([CH2:8][N:9]2[C:13]3[CH2:14][CH2:15][CH2:16][C:12]=3[C:11]([C:17]3[N:18]=[C:32]([NH2:31])[C:33]([O:36][CH3:37])=[CH:34][N:19]=3)=[N:10]2)=[C:20]([F:22])[CH:21]=1)[CH3:2]
Reactant: CCOc1cc(F)c(Cn2nc(C(=N)N)c3c2CCC3)c(F)c1
Reactant: COC(C#N)C(N(C)C)N(C)C
Solvent: C1CCNCC1
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(OC)c(N)n3)c3c2CCC3)c(F)c1
Temperature: 100 °C

Procedure:
4.21 g of 1-(4-ethoxy-2,6-difluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]-pyrazole-3-carboximidamide 1-2-1 (13.2 mmol, 1.00 eq.) were suspended in 47 mL of dry 3-methyl-1 butanole, 0.26 mL of piperidine (2.63 mmol, 0.20 eq.) and 3.09 g of 3,3-bis(dimethylamino)-2-methoxypropanenitrile 1-3-1 (18.0 mmol, 1.37 eq.) were added under nitrogen atmosphere and stirred over night at 100° C. bath temperature. The reaction mixture was cold with an ice bath the precipitate was filtered of, washed with 3-methyl-1 butanol and dried at 50° C. to give 1.77 g (4.41 mmol, 33.5%) of analytically pure target compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl.[F:12][C:13]1([F:17])[CH2:16][NH:15][CH2:14]1.C(N(C(C)C)CC)(C)C>C1COCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:16][C:13]([F:17])([F:12])[CH2:14]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: FC1(F)CNC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(N2CC(F)(F)C2)nc1
Temperature: 120 °C

Procedure:
The 2-chloro-5-nitro-pyridine (317 mg, 2 mmol) and 3,3-difluoroazetidine hydrochloride (259 mg, 2 mmol) was mixed in 8 mL of THF. Diisopropylethylamine (1.4 mL) was added and the mixture was heated in a microwave at 120° C. for 20 minutes. After cooling to room temperature, the solid was filtered and the filtrate was distributed between ethyl acetate and water. The organic layers were evaporated and the solid material was triturated with methanol. The resulting solid was filtered to give 5-nitro-2-(3,3-difluoroazetidin-1-yl)pyridine. LCMS calcd for C8H7F2N3O2 m/e 215.16, obsd 216.1 (ES, M+H). Hydrogenation of the nitro compound, as above, provided 3-amino-6-(3,3-difluoroazetidin-1-yl)pyridine.