Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[C:15]1([S:21]([CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:30]=2[CH2:31][CH2:32][C:33](=[O:39])[NH:34]3)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCOCC1>[C:15]1([S:21]([CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:30]=2[CH:31]=[CH:32][C:33](=[O:39])[NH:34]3)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CCc2c(cccc2OCCCCS(=O)(=O)c2ccccc2)N1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: O=c1ccc2c(OCCCCS(=O)(=O)c3ccccc3)cccc2[nH]1
Reaction time: 2.5 h

Procedure:
1.87 gm of 2,3-dichloro-5,6-dicyano-benzoquinone were added to a solution of 1.8 gm of 5-(4-phenylsulfonyl-butoxy)-3,4-dihydro-carbostyril in 45 ml of dioxane, and the solution was boiled for 2.5 hours on an oil bath. The reaction mixture was then filtered while still hot, and the insoluble matter, which was formed during the reaction was washed with hot dioxane. The combined filtrates were diluted with 100 ml of chloroform and extracted several times with altogether 150 ml of 2N sodium hydroxide. After drying the chloroform extracts with sodium sulfate and filtering in the presence of activated charcoal, the filtrate was concentrated by evaporation, and ethyl acetate was added until white crystals were precipitated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][OH:15])=[C:12]([CH:16]([CH3:18])[CH3:17])[O:11][N:10]=1>ClCCl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH:14]=[O:15])=[C:12]([CH:16]([CH3:18])[CH3:17])[O:11][N:10]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CO
Solvent: ClCCl
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1C=O
Reaction time: 1.5 h
Yield: 93.9 %

Procedure:
To a solution of [3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methanol (2.40 g, 8.39 mmol) in dichloromethane (160 mL) was added pyridinium chlorochromate-silica gel (20.2 wt %, 44.7 g, 41.9 mmol). The mixture was stirred for approximately 1.5 hours and then run through a silica gel pad and concentrated to afford 3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolecarbaldehyde (2.24 g, 7.88 mmol, 94%). 1H-NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 7.64-7.55 (m, 3H), 3.83 (septet, J=7 Hz, 1H), 1.39 (d, J=7 Hz, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(O[N:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[N:36]1)(=O)=O.O>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([O:22][N:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[N:36]1)=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)On1nnc2ccccc21
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)On1nnc2ccccc21)OCc1ccccc1
Reaction time: 1 h
Yield: 62.3 %

Procedure:
N-Benzyloxycarbonyl-L-phenylalanine (1.5 g) and triethylamine (0.7 ml) are dissolved in ethyl acetate (15 ml). To the solution is added 1-methanesulfonyloxy-1,2,3-benzotriazole (1.1 g) under ice-cooling and the mixture is stirred for 1 hour. After allowing to stand overnight, to the reaction mixture are added ethyl acetate and water. The ethyl acetate layer is separated, washed with water and dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off and to the residue is added ether. The precipitated crystals are separated by filtration to give 1-(N-benzyloxycarbonyl-L-phenylalanyloxy)-1,2,3-benzotriazole (1.3 g), melting point: 120°-125° C.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:18]1[N:23]=[C:22]([NH:24][C@@H:25]2[C@@H:30]3[CH2:31][C@@H:27]([CH:28]=[CH:29]3)[C@@H:26]2[C:32]([NH2:34])=[O:33])[C:21]([Cl:35])=[CH:20][N:19]=1>>[Cl:35][C:21]1[C:22]([NH:24][C@@H:25]2[C@@H:30]3[CH2:31][C@@H:27]([CH:28]=[CH:29]3)[C@@H:26]2[C:32]([NH2:34])=[O:33])=[N:23][C:18]([NH:1][C:2]2[CH:16]=[CH:15][C:5]3[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:19][CH:20]=1
Reactant: CN1C(=O)CCC(C)(C)c2cc(N)ccc21
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: CN1C(=O)CCC(C)(C)c2cc(Nc3ncc(Cl)c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)n3)ccc21

Procedure:
The title compound was prepared in an analogous manner to the preparation of example 381 by combining 7-Amino-1,5,5-trimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide to yield an off-white solid, (64%). mp 233° C.; LCMS: m/z=481.06 (M+H+), 1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 7.97 (m, 2H), 7.79 (m, 2H), 7.51 (s, 1H), 7.24 (m, 2H), 6.33 (m, 2H), 4.15 (m, 1H), 3.16 (s, 3H), 2.89 (s, 1H), 2.78 (s, 1H), 2.54 (s, 1H), 2.12 (m, 3H), 1.94 (m, 2H), 1.41 (m, 1H), 1.25 (s, 6H).
Reaction SMILES: C([O:5][C:6](=[O:42])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]([F:38])([F:37])[F:36])[S:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:39][CH2:40][CH3:41])(C)(C)C.C(O)(C(F)(F)F)=O>>[F:37][C:35]([F:36])([F:38])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][N:17]([S:18]([C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)(=[O:19])=[O:20])[C:15]1[CH:14]=[CH:13][C:12]2[N:8]([CH2:7][C:6]([OH:42])=[O:5])[C:9]([CH2:39][CH2:40][CH3:41])=[N:10][C:11]=2[CH:16]=1
Reactant: CCCc1nc2cc(N(Cc3ccccc3C(F)(F)F)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(N(Cc3ccccc3C(F)(F)F)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)O

Procedure:
{5-[(2-Trifluoromethyl-benzyl)-(4-fluoro-benzenesulfonyl)-amino]-2-propyl-benzoimidazol-1-yl}-acetic acid tert-butyl ester was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ7.88 (d, 1H), 7.72 (m, 2H), 7.62 (m, 2H), 7.44 (m, 3H), 7.32 (d, 1H), 7.23 (d, 1H), 6.86 (dd, 1H), 5.03 (s, 2H), 4.95 (s, 2H), 2.67 (t, 2H), 1.72 (m, 2H), 0.96 (t, 3H). MS calculated for C26H23F4N3O4S—H: 548, observed: 548.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:23])=[C:5]2[C:19](=[CH:20][C:21]=1[CH3:22])[C:8]1[NH:9][C:10]3[CH:11]=[CH:12][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:14][C:15]=3[C:7]=1[CH2:6]2.C([SiH](CC)CC)C.O.[OH-].[Na+]>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[C:4]([CH3:23])=[C:5]2[C:19](=[CH:20][C:21]=1[CH3:22])[C@H:8]1[NH:9][C:10]3[CH:11]=[CH:12][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:14][C:15]=3[C@H:7]1[CH2:6]2
Reactant: COc1c(C)cc2c(c1C)Cc1c-2[nH]c2ccc(C(C)C)cc12
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C)cc2c(c1C)C[C@@H]1c3cc(C(C)C)ccc3N[C@H]21
Reaction time: 4 h

Procedure:
5,10-Dihydro-2-methoxy-1,3-dimethyl-8-isopropylindeno[1,2-b]indole (1.68 g, 5.5 mmol) was dissolved in trifluoroacetic acid (10 cm3) and stirred vigorously. Triethylsilane (1 cm3, 1.1 eq) was added, and stirring continued for 4 hours. The reaction was poured into water, stirred for 15 minutes, and neutralised with 2M NaOH. All organic material was extracted into ethyl acetate, washed with water and dried (Na2SO4 ). After removal of solvent, the solid material was recrystallised from 60°-80° petroleum ether as white needles. Yield: 1.18 g, 70% .M.p. 106° C. 1H NMR (CDCl3) δ: 7.05 (1H, s), 6.97 (1H, s), 6.88 (1H, dd, J=8.6 Hz), 6.55 (1H, d, J=8.1 Hz), 5.19 (1H, d, J=8.4 Hz), 4.18 (1H, ddd), 3.8 (1 H, br), 3.64 (3H, s), 3.36 (1H, dd, J=16.5, 8.3 Hz), 3.07 (1H, d(br) J=16.5 Hz), 2.81 (1H, septet, J=7.0 Hz), 2.25 (3H, s), 2.15 (3H, s), 1.20 (6H, d, J=7.0 Hz).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][C:5]1([CH3:18])[CH2:11][N:10]([CH3:12])[C:9](=[O:13])[C:8]2[CH:14]=[CH:15][CH:16]=[N:17][C:7]=2[O:6]1.[CH3:19][NH:20][CH3:21]>CO>[ClH:2].[CH3:19][N:20]([CH3:21])[CH2:3][CH2:4][C:5]1([CH3:18])[CH2:11][N:10]([CH3:12])[C:9](=[O:13])[C:8]2[CH:14]=[CH:15][CH:16]=[N:17][C:7]=2[O:6]1
Reactant: CNC
Reactant: CN1CC(C)(CCCl)Oc2ncccc2C1=O
Agent: Cl
Solvent: CO
Product: CN(C)CCC1(C)CN(C)C(=O)c2cccnc2O1
Reaction time: 192 h
Yield: 67 %

Procedure:
To 4.5 g (0.015 mole) of 2-(2-chloroethyl)-2,3-dihydro-2,4-dimethylpyrido[3,2-f]-1,4-oxazepin-5(4H)-one hydrochloride in 15 ml of methanol was added 40 ml of dimethylamine. The flask was sealed tightly and left standing at room temperature for 8 days. The methanol and dimethylamine were removed by rotary evaporation (70° C.; 30 mm). The residue was taken up in 150 ml of chloroform, washed with 2×50 ml dil aqueous sodium hydroxide, dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation (70° C.; 30 mm). The syrupy residue was treated with hydrogen chloride in isopropyl alcohol, which afforded 3.5 g (67%) of white crystals, m.p. 188°-90° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]1[O:11][CH2:10]1)[CH:2]=[CH2:3].[NH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]([CH3:33])[CH2:28][C:29](=[O:32])[NH:30][N:31]=2)=[CH:22][CH:21]=1>>[CH2:1]([O:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]([OH:11])[CH2:10][NH:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:27]([CH3:33])[CH2:28][C:29](=[O:32])[NH:30][N:31]=2)=[CH:24][CH:25]=1)[CH:2]=[CH2:3]
Reactant: CC1CC(=O)NN=C1c1ccc(OCCN)cc1
Reactant: C=CCOc1ccccc1OCC1CO1
Product: C=CCOc1ccccc1OCC(O)CNCCOc1ccc(C2=NNC(=O)CC2C)cc1

Procedure:
Prepared analogously to Example 1 from 1-(2-allyloxy-phenoxy)-2,3-epoxypropane and 6-[4-(2-aminoethoxy)phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.
Reaction SMILES: [C:1]([C:7]([O:9][CH3:10])=[O:8])#[C:2][C:3]([O:5][CH3:6])=[O:4].[Si]([CH:15]=[N+:16]=[N-:17])(C)(C)C.Cl>C1COCC1>[NH:16]1[CH:15]=[C:2]([C:3]([O:5][CH3:6])=[O:4])[C:1]([C:7]([O:9][CH3:10])=[O:8])=[N:17]1
Reactant: COC(=O)C#CC(=O)OC
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1c[nH]nc1C(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 111.9 %

Procedure:
To a solution of dimethyl acetylenedicarboxylate (1.73 mL, 14.07 mmol) in THF (65 mL) at 0° C. was added dropwise TMS-diazomethane (7.74 mL, 15.48 mmol, 2M/hexanes) and the mixture was allowed to warm to ambient temperature in 2 h. After 18 h, 1M hydrochloric acid (10 mL) was added until bubbling stopped and stirring at ambient temperature continued for 30 min. The mixture was diluted with EtOAc and washed with saturated sodium bicarbonate/water. The organic layer was dried over sodium sulfate and concentrated to provide the title compound as a yellowish solid (2.9 g, 99%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.95 (s, 1H), 8.2 (s, 1H), 3.8 (s, 3H), 3.7 (s, 3H); ES-LCMS: 184.9 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31](O)=[O:32])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[NH2:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31]([NH:34][CH:35]4[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH2:40]4)=[O:32])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c7) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10](Cl)=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH2:13]([O:20][N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:29]=2)[N:24]=[C:23]([NH:35][NH2:36])[C:22]1=[O:37])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>O1CCCC1>[CH2:13]([O:20][N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]([F:32])([F:33])[F:34])[CH:29]=2)[N:24]=[C:23]([NH:35][NH:36][C:10](=[O:11])[CH2:9][P:4]([O:6][CH2:7][CH3:8])([O:3][CH2:1][CH3:2])=[O:5])[C:22]1=[O:37])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOP(=O)(CC(=O)Cl)OCC
Reactant: NNc1nc2ccc(C(F)(F)F)cc2n(OCc2ccccc2)c1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(=O)(CC(=O)NNc1nc2ccc(C(F)(F)F)cc2n(OCc2ccccc2)c1=O)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
A solution of (diethoxyphosphoryl)acetyl chloride (5.8 g, 27 mmol) in 40 ml of dry tetrahydrofuran was added to a solution of 1-benzyloxy-3-hydrazino-7-trifluoromethylquinoxalin-2(1H)-one (8.75 g, 25 mmol) and dry triethylamine (3.6 ml, 27 mmol) in 200 ml of dry tetrahydrofuran. The mixture was stirred at room temperature for 3 h and filtered. The filtrate was evaporated to dryness, and the residue was crystallized by trituration with water (200 ml) to give 12.85 g (97%) of the title compound. M.p. 163°-166° C.
Reaction SMILES: [O-2].[Zn+2:2].[Zn].[Br-].[K+].[P:6](=[O:10])([OH:9])([OH:8])[OH:7]>O>[P:6]([O-:10])([O-:9])([O-:8])=[O:7].[Zn+2:2].[P:6]([O-:10])([O-:9])([O-:8])=[O:7].[Zn+2:2].[Zn+2:2]
Reactant: O=P(O)(O)O
Agent: [Br-]
Agent: [K+]
Agent: [O-2]
Solvent: O
Product: O=P([O-])([O-])[O-]
Yield: 121.4 %

Procedure:
Zinc-containing wastes resulting from the production of 2,2-hydroxy-5-methylphenylbenzotriazole in the amount of 725 g containing 625 g of zinc oxide and 65 g of metallic zinc are ground in a ball mill by the wet grinding method in the presence of 700 g of water, whereafter an additional 1,500 g of water and 86 g of potassium bromide are added to the ground mixture. Under continuous stirring the suspension is heated to a temperature of 80° C. and 687 g of phosphoric acid are added as calculated for 100% H3PO4. After 30 minutes the suspension is filtered, the residue is washed and dried to give 1.2 kg of zinc phosphate (the yield is 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:23])[C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[Br:32][CH:33]([CH2:37][CH2:38]Cl)[C:34](Br)=[O:35].[OH-].[Na+]>C(#N)C.O>[Br:32][CH:33]1[CH2:37][CH2:38][N:1]([C:2]2[CH:7]=[CH:6][C:5]([N:8]([CH3:23])[C:9](=[O:22])[C:10]3[CH:15]=[CH:14][C:13]([CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)=[CH:12][CH:11]=3)=[CH:4][CH:3]=2)[C:34]1=[O:35]
Reactant: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N)cc1
Reactant: O=C(Br)C(Br)CCCl
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N2CCC(Br)C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(4-Aminophenyl)-4-cyclohexyl-N-methylbenzamide (3.0 g) in acetonitrile (30 ml) was mixed with trisodium phosphate (0.95 g) and, at 0° C., 2-bromo-4-chlorobutyryl bromide (2.9 g) was added. After one hour, a solution of sodium hydroxide (0.85 g) in water (10 ml) was added and the mixture was stirred vigorously at room temperature for 6 hours. The same amount of sodium hydroxide solution was then added, and stirring was continued for 48 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (mobile phase ethyl acetate/heptane 1:2). This resulted in the product with the molecular weight of 455.40 (C24H27BrN2O2); MS (ESI): 456 (M+H+).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)=[C:2]=[O:3].[NH2:17][C@H:18]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[CH3:36][CH:35]([CH3:37])[C:34]([NH:33][C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([CH:24]2[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][C@H:18]([NH:17][C:2]([NH:1][C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)=[CH:6][CH:5]=3)=[O:3])[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:26][CH2:25]2)[CH:28]=1)=[O:38]
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)Nc3ccc(Oc4ccccc4)cc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure P and Scheme AB using 1-isocyanato-4-phenoxybenzene and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 591.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:14]([CH3:15])[CH2:13][N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:11]=2)=[CH:5][CH:4]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[C:14]([CH3:15])=[CH:13][N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:11]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(NC2=NN(c3ccccc3)CC2C)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc(Nc2nn(-c3ccccc3)cc2C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 200 ml round bottom flask, under nitrogen, was charged with N-(4-methoxyphenyl)-4-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-3-amine (0.85 g, 3.02 mmol) and DCM (60.42 ml, 0.05 M). To this solution was added slowly manganese dioxide (0.58 g, 6.65 mmol). Reaction stirred at RT under a nitrogen atmosphere for 16 h. The reaction mixture was diluted with DCM and filtered over Celite®. The filtrate was concentrated to afford brown oil, which was purified by ISCO silica gel chromatography (20-40% EtOAc/hexanes) to afford N-(4-methoxyphenyl)-4-methyl-1-phenyl-1H-pyrazol-3-amine. MS m/z=280.2 [M+H]+. Calc'd for C17H17N3O: 279.34.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br[C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C=C(Br)C(F)(F)F
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Temperature: 70 °C
Yield: 79.9 %

Procedure:
A mixture of 3,5-dichlorophenylboronic acid (3.8 g, 20.0 mmol), 2-bromo-3,3,3-trifluoro-prop-1-ene (4.9 g, 28 mmol), Cs2CO3 (20 mL, 2 M, 40 mmol) and Pd(PPh3)2Cl2 (421 mg) in THF (30 mL) was heated at 70° C. in a sealed tube for 4 h. The mixture was cooled to rt and partitioned between ether and H2O. The aqueous layer was extracted with EA and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography over silica gel eluted with hexanes to give 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (3.85 g; yield 80%). 1H NMR (500 MHz, CDCl3): δ 7.41 (s, 1H), 7.35 (s, 2H), 6.06 (s, 1 H), 5.83 (s, 1 H) ppm.
Reaction SMILES: C([C:3]1[C:4](CC)=[C:5]([CH:12]([C:16](C(O)=O)=O)[C:13]([O-:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH3:11])C.C(=O)([O-])[O-].[K+].[K+].[CH3:29][CH2:30]OCC>C=O>[CH2:29]([O:15][C:13](=[O:14])[C:12]([C:5]1[CH:4]=[CH:3][C:8]([O:9][CH2:10][CH3:11])=[CH:7][CH:6]=1)=[CH2:16])[CH3:30]
Reactant: CCOc1ccc(C(C(=O)[O-])C(=O)C(=O)O)c(CC)c1CC
Reactant: CCOCC
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=C(C(=O)OCC)c1ccc(OCC)cc1

Procedure:
The keto-ester III (143.8 g) was stirred in dilute formaldehyde solution (62 ml 37% formaldehyde+water 220 ml) and to the suspension potassium carbonate solution (54.5 g, in water 280 ml) was added dropwise. At the end of the addition, ether was added to the stirred suspension to dissolve the gummy precipitate which formed and after an additional 15 minutes, gas evolution commenced. When this gas evolution ceased (after about 2 hours) the reaction mixture was extracted with additional ether and the combined ether extracts were washed with water and evaporated after drying with Na2SO4. The yield of the ethyl-2-(p-ethoxyphenyl)acrylate (II) (isolated as a yellow oil) was 97.8 g (79.8%).
Reaction SMILES: C[C@H]1CN(C)[C@H](C)CN1C1C=CC(N)=CC=1.[CH3:17][N:18]1[C@H:23]([CH3:24])[CH2:22][N:21]([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=2)[CH2:20][C@@H:19]1[CH3:34]>[Pd]>[CH3:34][C@H:19]1[N:18]([CH3:17])[C@@H:23]([CH3:24])[CH2:22][N:21]([C:25]2[CH:26]=[CH:27][C:28]([NH2:31])=[CH:29][CH:30]=2)[CH2:20]1
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2)C[C@H](C)N1C
Agent: [Pd]
Agent: C[C@@H]1CN(c2ccc(N)cc2)[C@@H](C)CN1C
Product: C[C@@H]1CN(c2ccc(N)cc2)C[C@H](C)N1C
Yield: 104.9 %

Procedure:
Using the method described above for the synthesis of racemic-4-(trans-2,4,5-Trimethyl-piperazin-1-yl)-phenylamine, treatment of cis-1,2,6-trimethyl-4-(4-nitrophenyl)piperazine (1.28 g, 5.13 mmol) with H2 and 10% Pd/C (130 mg) provided crude 4-(cis-3,4,5-Trimethyl-piperazin-1-yl)-phenylamine (1.18 g, 101% recovery, >85% purity as determined by LC/MS analysis @ UV 254 nm detection). The crude product was used in the next step without further purification. LCMS-ESI (m/z): calcd for C13H21N3, 219; [M+H]+ found, 220.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH3:15])[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30]([NH:33][CH3:34])(=[O:32])=[O:31])[C:20]([Cl:35])=[CH:19][N:18]=1.Cl>C(O)(C)C.O1CCOCC1.C(Cl)Cl>[Cl:35][C:20]1[C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30]([NH:33][CH3:34])(=[O:32])=[O:31])=[N:22][C:17]([NH:1][C:2]2[C:7]3[N:8]([CH3:15])[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:6]=3[CH:5]=[CH:4][CH:3]=2)=[N:18][CH:19]=1
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1CCN(C)c2c(N)cccc2C1=O
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2cccc3c2N(C)CCN(C)C3=O)ncc1Cl
Temperature: 120 °C
Yield: 54 %

Procedure:
9-Amino-1,4-dimethyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (#) (50 mg, 0.24 mmol) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide (#) (89 mg, 0.27 mmol) were combined in isopropanol (1 mL). 4 N HCl in dioxane (67 μL) was added, and the resulting mixture was heated to 120° C. in the microwave for 40 min. The resulting solution was diluted with CH2Cl2 (50 ml) washed with saturated aqueous NaHCO3 (2×50 ml), dried over MgSO4, filtered, and concentrated. The resulting residue was purified with silica gel chromatography (0-100% EtOAc in hexanes) to obtain 2-[5-Chloro-2-(1,4-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide as a white foam (65 mg, 53%). LCMS: m/z=503.20 (M+H+), 1H NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 8.68 (s, 1H), 8.40 (t, J=7.1 Hz, 2H), 7.97 (m, 2H), 7.62 (t, 7.6 Hz, 1H), 7.27 (m, 2H), 7.14 (t, J=7.6 Hz, 1H), 5.88 (m, 1H), 3.38 (m, 4H), 3.21 (s, 3H), 2.82 (s, 3H), 2.67 (d, J=5.3 Hz, 3H).