Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]/[CH:9]=[CH:10]\[CH2:11]O)=[CH:4][CH:3]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O-:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1.[CH2:24]([N:26]([CH2:34][CH3:35])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH3:25]>C(#N)C>[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([O-:23])(=[O:22])=[O:21])=[CH:18][CH:19]=1.[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][N+:26]([CH2:24][CH3:25])([CH2:34][CH3:35])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:4][CH:3]=1
Reactant: CCCCCCCN(CC)CC
Reactant: OC/C=C\Cc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CC#N
Product: CCCCCCC[N+](CC)(CC)C/C=C\Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Mix 5.40 g (0.016 mole) of (Z)-4-(4-chlorophenyl)but-2-en-1-ol 4-methylbenzenesulfonate and 10.96 g (0.064 mole) of N,N-diethylheptanamine in 200 ml of acetonitrile. Stir the mixture at room temperature for 2 hours. Evaporate and recrystallize from ethyl acetate to yield the title compound, m.p. 79°-80° C.
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1.C(N(CC)C(C)C)(C)C.[O:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[C:28]([C:35](Cl)=[O:36])=[N:27]1>ClCCl.C(OCC)(=O)C>[F:16][C:3]([F:2])([F:15])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]([NH:14][C:35]([C:28]2[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:26][N:27]=2)=[O:36])[CH3:13])=[CH:8][CH:7]=1
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Reactant: O=C(Cl)c1noc2ccccc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(NC(=O)c1noc2ccccc12)c1ccc(OCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
To a solution of (−)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (20 mg, 0.078 mmol, Amine-1, single enantiomer) and N,N-diisopropylethylamine (0.054 mL, 0.31 mmol) in dichloromethane (0.5 mL) is added dropwise a solution of benzo[d]isoxazole-3-carbonyl chloride (17 mg, 0.094 mmol) in dichloromethane (0.5 mL) at room temperature. The reaction mixture is stirred at room temperature for 1 hour. The mixture is diluted with ethyl acetate (3 mL) and washed with water (1.5 mL). The organic layer is dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified by column chromatography on NH-silica gel eluting with ethyl acetate and then preparative LC-MS to give 9.1 mg (32% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[N:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(N4CCCCC4)cc3c(=O)[nH]2)c1
Product: O=C(O)c1cnn(-c2nc(N3CCOCC3)c3cc(N4CCCCC4)c(Cl)cc3n2)c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-chloro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and morpholine in step E. MS (ESI): predicted mass calcd. for C21H23ClN6O3, 442.9
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Zn:21]>>[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Zn+2:21].[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: [Zn]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]
Product: [Zn+2]
Temperature: 150 °C

Procedure:
Stearic acid (75 grams) was added to 500 gram of zinc clay RA. The mixture was attrition milled for two hours and then heated at 150° C. for one more hour. The product again was attrition milled and then jet milled through a CJ-10 jet mill manufactured by Nisshin Engineering Co. Ltd. of Japan. The final product was sieved through a 200 mesh sieve to produce zinc stearate clay RB. There is some loss of material through dusting at the various milling processes. Its properties are listed below:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(Cl)Cl>[OH:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][N:4]([C:10](=[O:12])[CH3:11])[CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: OCCN1CCNCC1
Solvent: ClCCl
Product: CC(=O)N1CCN(CCO)CC1
Yield: 65 %

Procedure:
A solution of 2-(1-piperazinyl)-1-ethanol (6.5 g, 0.05 mol) in DCM (5 mL) was treated with acetic acid anhydride (5.1 g, 0.05 mol), added dropwise. During addition, the reaction temperature rose from 22 to 60° C. The reaction mixture was evaporated several times with toluene to yield 5.6 g (65%) of the sub-title compound.
Reaction SMILES: O.C(O[C:7]([CH2:9][O:10][C:11]1[C:16]([N+:17]([O-])=O)=[CH:15][C:14]([C:20]2[C:21](=[O:31])[N:22]([CH3:30])[C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][N:25]=2)=[C:13]([F:32])[CH:12]=1)=[O:8])CCC>C(OCC)(=O)C.C(O)(=O)C.[Fe]>[F:32][C:13]1[C:14]([C:20]2[C:21](=[O:31])[N:22]([CH3:30])[C:23]([C:26]([F:27])([F:29])[F:28])=[CH:24][N:25]=2)=[CH:15][C:16]2[NH:17][C:7](=[O:8])[CH2:9][O:10][C:11]=2[CH:12]=1
Reactant: CCCCOC(=O)COc1cc(F)c(-c2ncc(C(F)(F)F)n(C)c2=O)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(C(F)(F)F)cnc(-c2cc3c(cc2F)OCC(=O)N3)c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
Then, 2.8 g of iron powder was added to a mixture of 5 ml of acetic acid and 50 ml of water, and the mixture was heated to 50° C. To this was slowly added dropwise a solution of 2.8 g of 3-[4-(butoxycarbonylmethoxy)-2-fluoro-5-nitrophenyl]-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (the present compound obtained in step (3) above) in 25 ml of ethyl acetate and 25 ml of acetic acid. The mixture was stirred at an internal temperature of 60° to 70° C. for 1 hour. After completion of the reaction, the reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium hydrogencarbonate solution, water, and saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated, which afforded 1.22 g of 3-(7-fluoro-3-oxo-2H-1,4-benzoxazin-6-yl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 2-49; m.p., 182.5° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[N:22][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1.FC1C=C(C=[CH:78][CH:79]=1)CN1C=C(C2C3C(=NC=C(C4C=NC(N5CCN(C)CC5)=CC=4)C=3)NC=2)C=N1.[C:80](=O)([O-])[O-:81].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[N:22][C:23]([N:26]5[CH2:31][CH2:30][N:29]([CH2:78][CH2:79][O:81][CH3:80])[CH2:28][CH2:27]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Reactant: O=C([O-])[O-]
Reactant: CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCN1CCN(c2ccc(-c3cnc4c(c3)c(-c3cnn(Cc5cccc(F)c5)c3)cn4S(=O)(=O)c3ccc(C)cc3)cn2)CC1
Yield: 85.3 %

Procedure:
Using similar reaction conditions as described in step-i of example-126, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step 1 compound of example 137) (75 mg, 0.123 mmol) was alkylated using 2-1-bromo-2-methoxyethane (26 mg, 0.185 mmol) and potassium carbonate (43 mg, 0.308 mmol) in DMF (1 ml) to afford 70 mg (85.3% yield) of the titled compound. MS: m/z=666.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:15][CH2:16][CH3:17])[C:11]=1[S:12]([CH3:14])=[O:13])[CH:7]=[O:8])[CH3:2].[OH:18]O.O>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:15][CH2:16][CH3:17])[C:11]=1[S:12]([CH3:14])(=[O:18])=[O:13])[CH:7]=[O:8])[CH3:2]
Reactant: CCOc1cc(C=O)cc(OCC)c1S(C)=O
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: CCOc1cc(C=O)cc(OCC)c1S(C)(=O)=O
Temperature: 40 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
To a solution of (±)-3,5-diethoxy-4-methanesulfinyl-benzaldehyde (0.60 g, 2.34 mmol, 1.0 equiv) in conc. acetic acid (10 mL) was added a solution of 35% hydrogen peroxide in water (0.41 mL, 0.46 g, 4.68 mmol, 2.0 equiv) and the solution stirred for 2 h at 40° C. Periodically, every 2 hours another 2.0 equivalents of hydrogen peroxide were added to the reaction mixture to drive the reaction to completion. After 6 h the reaction mixture was extracted with ethyl acetate (3×50 mL) and the combined organic phases dried over MgSO4. The organic solvent was removed by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with heptane/ethyl acetate (1:1) providing 0.27 g (42%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.51 (t, J=7.0 Hz, 6H), 3.34 (s, 3H), 4.24 (q, J=7.0 Hz, 4H), 7.10 (s, 2H), 9.95 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 814.39, 46.59, 66.02, 106.62, 123.29, 140.08, 158.91, 190.95. MS (ISP): 273.0 [M+H]+.
Reaction SMILES: [I:1]Cl.[O:3]=[C:4]1[C:13]2[NH:14][CH:15]=[CH:16][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5]1.[CH2:17]([C:19]([O-:21])=[O:20])[CH3:18].C(O)(=O)C.[O-]S(C(F)(F)F)(=O)=O.[In+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>ClCCl.C(#N)C>[I:1][C:9]1[CH:8]=[CH:7][C:6]2[NH:5][C:4](=[O:3])[C:13]3[NH:14][CH:15]=[CH:16][C:12]=3[C:11]=2[CH:10]=1.[CH2:17]([C:19]([O-:21])=[O:20])[CH3:18]
Reactant: ClI
Reactant: O=c1[nH]c2ccccc2c2cc[nH]c12
Agent: CCC(=O)[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [In+3]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC#N
Product: O=c1[nH]c2ccc(I)cc2c2cc[nH]c12
Temperature: 45 °C
Reaction time: 20 h
Yield: 96 %

Procedure:
Alternatively, 1.5 mL (1.5 mmol) of a 1M solution of iodine monochloride in dichloromethane is added to a solution of 316 mg (1 mmol) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate cocrystallized with 1 equivalent of acetic acid and 652 mg (1 mmol) of indium triflate in anhydrous acetonitrile (20 mL). The solution is heated at 45° C. for 3 hours then stirred at room temperature for 20 hours. The solid is filtered, and triturated with acetonitrile and diisopropyl ether to give 368 mg (96%) of 8-iodo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: [C:1]1(S([O-])(=O)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[K+].[NH2-:16].[Na+].N>>[C:1]1([NH2:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)([O-])c1cccc2ccccc12
Reactant: [NH2-]
Agent: N
Agent: [K+]
Agent: [Na+]
Product: Nc1cccc2ccccc12
Yield: 86.8 %

Procedure:
In a 200-ml autoclave were placed 28.3 grams (0.115 mole) of anydrous potassium 1-naphthalene sulfonate, 9.7 grams (0.241 mole) of sodium amide and 105 ml of liquid ammonia in the same manner as in Example 1. The resultant mixture was heated at 110° C for 10 hours. The reaction pressure in the autoclave was 75 atm. during the reaction. After the ammonia was removed, 10 ml of water was added to the reaction mixture for hydrolysis. The product was extracted with ether and the ether was distilled off to produce crude 1-naphthyl amine. Recrystallization from ethanol gave 14.3 grams of 1-naphthyl amine having a melting point of 48° to 49° C. Yield ws 87.0%.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH:19]=[CH2:20])(=[O:18])=[O:17])=[CH:11][CH:10]=2)[O:3]1.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23].C(OCC)(=O)C.ClCCl>CO>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:21])([CH3:1])[O:3][B:4]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][S:16]([CH2:19][CH2:20][N:24]([CH2:25][CH3:26])[CH2:22][CH3:23])(=[O:18])=[O:17])=[CH:13][CH:14]=2)[O:5]1
Reactant: C=CS(=O)(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CCNCC
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCN(CC)CCS(=O)(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Yield: 56.3 %

Procedure:
To a solution of ethenesulfonic acid [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (0.500 g, 1.6 mmol) in methanol (5 mL) was added diethylamine (0.707 g, 4.0 mmol) in methanol (5 mL), and the reaction was stirred at room temperature and monitored by TLC (1:1 Ethyl acetate:hexanes). After 2 hr the reaction was concentrated in vacuum and the residue partitioned between ethyl acetate (50 mL) and water (50 mL). The ethyl acetate was then washed with 50% brine (1×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. Crude product was purified using a 10 g prepacked silica gel column, eluting with 1:1 ethyl acetate: dichloromethane to provide 2-diethylamino-ethanesulfonic acid [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide as a white solid (0.346 g, 0.90 mmol, 56%). 1H NMR (CDCl3, 300 MHz) δ 7.78 (d, J=6.65, 2H) 7.15 (d, J=6.66, 2H), 3.20 (m, 2H), 3.0 (m, 2H), 2.55 (q, J=7.15, 7.16 4H), 1.34 (s, 12H), 1.05 (t, J=7.19, 6H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH2:5][CH2:4][N:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[BH4-].[Na+].O.C(OCC)(=O)C>CO>[OH:8][CH:6]1[CH2:5][CH2:4][N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:2]([CH3:1])[CH2:7]1
Reactant: CC1CC(=O)CCN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC1CC(O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (0.94 g, 4.41 mmol) in methanol (5 mL) was added sodium borohydride (0.22 g, 5.73 mmol) and the reaction was stirred at room temperature for 1 h. Water was added slowly, followed by ethyl acetate. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to afford the desired product as a mixture of four stereoisomers, which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([F:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:27][CH2:28][C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:19]=[C:20]([Cl:26])[C:21]([F:25])=[C:22]([Cl:24])[CH:23]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([NH:27][CH2:28][C:29](=[O:30])[NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:5]
Reactant: NCC(=O)NCC(F)(F)F
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(F)c(Cl)c2)C(F)(F)F)cc1Br
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(CNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(F)c(Cl)c2)C(F)(F)F)cc1Br)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.1 %

Procedure:
To a stirred solution of (E)-2-bromo-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoic acid (300 mg, 0.638 mmol) in CH2Cl2 (5.0 mL) was added 2-amino-N-(2,2,2-trifluoroethyl)acetamide (172. mg, 0.638 mmol) followed by benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (364.5 mg, 0.701 mmol) and DIPEA (0.32 mL, 1.914 mmol), and the resultant reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined CH2Cl2 layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 40% ethyl acetate/petroleum ether) afforded the title compound as an off-white solid (121 mg, 31%): 1H NMR (400 MHz, CDCl3) δ 8.69 (t, J=6.0 Hz, 1H), 8.58 (t, J=6.0 Hz, 1H), 7.92 (s, 1H), 7.87 (d, J=6.4 Hz, 2H), 7.62 (d, J=8.4 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.0 (m, 1H), 6.76 (d, J=15.6 Hz, 1H), 4.83 (t, J=8.0 Hz, 1H), 3.98 (m, 4H); ESIMS m/z 610.97 ([M+H]+); IR (thin film) 3303, 1658, 1166, 817 cm−1.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[CH3:15][C:16]([O:19][C:20]([CH2:22][C@H:23]([NH:36][C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[C:24](OC1C=CC([N+]([O-])=O)=CC=1)=[O:25])=[O:21])([CH3:18])[CH3:17].C(N(CC)CC)C.C(OCC)(=O)C>CN(C)C=O>[NH:36]([C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[C@H:23]([C:24]([NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:25])[CH2:22][C:20](=[O:21])[O:19][C:16]([CH3:15])([CH3:18])[CH3:17]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1

Procedure:
3.0 g of phenylalanine methyl ester hydrochloride together with 6.17 g of Z-Asp(OtBu)-ONP are dissolved in 25 ml of absolute N,N-dimethylformamide to give a clear solution and are mixed with 1.93 ml of triethylamine whilst stirring. The deep yellow solution is stirred overnight at room temperature, is then taken up in a large amount of ethyl acetate, and is washed 3 times with dilute aqueous citric acid solution, 5 times with dilute aqueous soda solution and finally with saturated aqueous sodium chloride solution until the wash liquid remains neutral. After drying over sodium sulphate the solution is evaporated and the resulting oil, which is soluble in ether and in chloroform, is purified by column chromatography on silica gel (the substance is eluted with toluene and toluene/ether, 4 : 1); a colourless oily product is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][O:17]C2CCCCO2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1.CC(O)=O.O>[C:1]([O:5][C:6](=[O:33])[N:7]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][OH:17])[CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccccc1CN(Cc1cccc(CCOC2CCCCO2)c1)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccccc1CN(Cc1cccc(CCO)c1)C(=O)OC(C)(C)C

Procedure:
(2-Methoxy-benzyl)-{3-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-benzyl}-carbamic acid tert-butyl ester (51 g) was dissolved in a mixture of THF (250 mL), AcOH (225 mL) and water (150 mL) and the resulting mixture refluxed for a total of 10 hours. The majority of the tetrahydrofuran and acetic acid was evaporated and the pH of was adjusted to 8 using saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (3×250 mL) and the combined organics were washed with water (250 mL), brine (250 mL), dried over sodium sulfate, filtered and evaporated. The crude material was purified in two portions by column chromatography eluting with dichloromethane:ethyl acetate (95:5 to 80:20 gradient) to give a yellow oil (total of 17.2 g).
Reaction SMILES: CC1(C)C2C(=CC(N[C:12]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=4)[N:15]=[CH:14][N:13]=3)=CC=2)N(C(=O)C)C1.CC1(C)C2C(=CC([N+]([O-])=O)=CC=2)NC1C(=O)C.O.O.[Sn](Cl)[Cl:52].Cl>C(OCC)C>[Cl:52][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[N:15]=[CH:14][N:13]=1
Reactant: CC(=O)N1CC(C)(C)c2ccc(Nc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cc21
Reactant: Cl[Sn]Cl
Agent: CC(=O)C1Nc2cc([N+](=O)[O-])ccc2C1(C)C
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1-{3,3-Dimethyl-6-[6-(4-trifluoromethylphenyl)pyrimidin-4-ylamino]-2,3-dihydroindol-1-yl}ethanone. To a solution of 1-(3,3-dimethyl-6-nitro-2,3-dihydroindol-yl)ethanone (110 mg, 0.47 mmol) in ethyl ether (3 mL), magnetically stirred in a round-bottomed flask at 0° C., was added tin (II) chloride dihydrate (0.67 g, 2.96 mmol, Aldrich) and concd HCl (0.3 mL). The reaction mixture was stirred at 0° C. for 10 min, allowed to warm to 25° C. then stirred at that temperature overnight. The reaction mixture was washed with 10 N NaOH (10 mL), extracted with EtOAc and concentrated in vacuo. Analogous to the procedure used to prepare Example 5(b), the crude product and 4-chloro-6-(4-trifluoromethylphenyl)pyrimidine, Example 5(a), (0.19 g, 0.75 mmol) provided, after purification by silica gel chromatography (3:2 hexanes/EtOAc), the title product. MS (ESI, pos. ion) m/z: 427 (M+1). MP: 227-230° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[N+]=[N-])[C:4]=2[CH:3]=1.[NH3:17].[S:18](=[O:20])=[O:19].CCCCCC>O1CCCC1>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]([S:18]([NH2:17])(=[O:20])=[O:19])[C:4]=2[CH:3]=1
Reactant: [N-]=[N+]=C1c2ccccc2-c2ccc(Cl)cc21
Reactant: N
Reactant: O=S=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: NS(=O)(=O)C1c2ccccc2-c2ccc(Cl)cc21

Procedure:
A mixture of (20) (5.3 g, 23.4 mmoL) in tetrahydrofuran was alternately treated with ammonia and sulfur dioxide gas a number of times until TLC (30% EtOAC/hexane) indicated that the starting material had been consumed. The reaction was then concentrated and the residue was diluted with water (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic phases were washed with brine (3×100 mL), dried (MgSO4), and concentrated. The crude solid was recrystallized from ethyl acetate/hexane to provide 3.1 (47%) of product (21): mp 190°-194° C.
Reaction SMILES: Cl[C:2]1[C:3]([F:18])=[C:4]([N:8]2[C:12]([O:13][CH3:14])=[C:11]([C:15]([OH:17])=[O:16])[N:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.FC1[C:26]([O:27]C)=CC=CC=1N.N([O-])=O.[Na+].[N-]=[N+]=[N-].[Na+]>C(O)(C(F)(F)F)=O.O>[F:18][C:3]1[C:2]([O:27][CH3:26])=[CH:7][CH:6]=[CH:5][C:4]=1[N:8]1[C:12]([O:13][CH3:14])=[C:11]([C:15]([OH:17])=[O:16])[N:10]=[N:9]1
Reactant: COc1cccc(N)c1F
Reactant: COc1c(C(=O)O)nnn1-c1cccc(Cl)c1F
Agent: O=N[O-]
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cccc(-n2nnc(C(=O)O)c2OC)c1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-(3-Chloro-2-fluorophenyl)-5-methoxy-1H-1,2,3-triazole-4-carboxylic acid: To a solution of 2-fluoro-3-methoxyaniline (1 g, 7.09 mmol) in TFA (10 mL) and water (5 mL) at 0° C. was added an aq. solution of NaNO2 (0.733 g, 10.63 mmol) dropwise. The resulting mixture was stirred at 0° C. for 0.5 h and NaN3 (0.921 g, 14.17 mmol) was added portionwise. The reaction mixture was gradually warmed to rt and stirred for 4 h. The reaction was quenched with water (150 mL) and extracted with EtOAc (2×100 mL). The organic layer was washed with sodium phosphate solution (10%) and brine (50 mL), dried, and concentrated. The resulting brown oil was re-dissolved in DMSO (20 mL) and added t-butylpropiolate (1 mL) followed by K2CO3 (1 g), Cu(OAc)2 (0.2 g), and sodium ascorbate (100 mg). The resulting mixture was stirred at rt overnight. The reaction was quenched with water (200 mL) and extracted with EtOAc (2×100 mL). The organic layer was dried and concentrated. The residue was purified by silica gel chromatography to yield the desired product as brown oil. 1H NMR (400 MHz, CDCl3) δ 13.19 (br. s., 1H), 7.36-7.20 (m, 2H), 7.17-6.95 (m, 1H), 6.76 (td, J=8.1, 1.3 Hz, 1H), 3.91 (s, 3H), 1.74-1.49 (m, 10H). MS(ESI) m/z: 238.0 (M+H)+.