Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.CC([SH:8])C.[Al].[CH3:10][O:11][C:12]1[N:17]=[C:16]([CH3:18])[N:15]=[C:14]([NH:19][C:20]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32](OC)=O)(=[O:25])=[O:24])=[O:21])[N:13]=1.Cl.[C:37]1([CH3:43])C=CC=C[CH:38]=1>>[CH3:10][O:11][C:12]1[N:17]=[C:16]([CH3:18])[N:15]=[C:14]([NH:19][C:20]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([CH:37]([CH3:43])[CH3:38])=[S:8])(=[O:24])=[O:25])=[O:21])[N:13]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Reactant: CC(C)S
Reactant: Cc1ccccc1
Agent: C[Al](C)C
Agent: Cl
Agent: [Al]
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=S)C(C)C)n1
Temperature: 80 °C

Procedure:
To 1.5 ml (2N) trimethylaluminum in 5 ml dry toluene under N2 was added dropwise 0.48 g (6.0 mmole) 2-propanethiol in 2 ml toluene. The resultant aluminum reagent was stirred at room temperature for 15 minutes, and 0.95 g (2.5 mmole) N-[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)aminocarbonyl]-2-methoxycarbonylbenzenesulfonamide was added in one portion. The suspension was heated to 80° C. for 3 hours, cooled to room temperature and 10% HCl (15 ml) was added. The mixture was stirred until a fine solid precipitated which was filtered off, washed with hexanes and air dried to yield 0.4 g of product melting at 155°-158° C. It showed infrared absorption peaks consistent for N-[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)aminocarbonyl]-2-isopropylthiocarbonylbenzenesulfonamide.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16][C:13]=3[CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:28].[Br:29]N1C(=O)CCC1=O.[N+]([O-])([O-])=O.[NH4+]>C(#N)C>[Br:29][C:14]1[C:13]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:19][CH2:20][C:12]=2[CH:11]=[C:10]2[C:15]=1[N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:7](=[O:28])[CH2:8][CH2:9]2
Reactant: COCCCN1C(=O)CCc2cc3c(cc21)CCN(C(=O)OC(C)(C)C)CC3
Reactant: O=C1CCC(=O)N1Br
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: CC#N
Product: COCCCN1C(=O)CCc2cc3c(c(Br)c21)CCN(C(=O)OC(C)(C)C)CC3
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 109.7 %

Procedure:
To a solution of 150 mg of t-butyl 1-(3-methoxypropyl)-2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate in 4.2 ml of acetonitrile were added 107 mg of N-bromosuccinimide and 3.7 mg of ammonium nitrate, followed by stirring at room temperature for 3.5 hours. The reaction mixture was concentrated to about ¼, and ethyl acetate, an aqueous sodium thiosulfate solution, and aqueous sodium bicarbonate was added thereto. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain 198 mg of t-butyl 11-bromo-1-(3-methoxypropyl)-2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]12[CH2:14][CH2:13][CH:12]1[CH2:11][N:10](C(OCC1C=CC=CC=1)=O)[CH2:9]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[Pd+2].[OH-].[C]>[C:1]([O:5][C:6]([C:8]12[CH2:14][CH2:13][CH:12]1[CH2:11][NH:10][CH2:9]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C12CCC1CN(C(=O)OCc1ccccc1)C2
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)C12CCC1CNC2
Yield: 136.5 %

Procedure:
To a solution of 368 mg (1.02 mmol) of 1-tert-butoxycarbonyl-3-benzyloxycarbonyl-3-azabicyclo[3.2.0]heptane in methanol (20 ml) was added 400 mg of 20% palladium hydroxide-carbon, followed by vigorous stirring in an atmosphere of hydrogen gas. After removing insoluble material by filtration through celite, the resulting filtrate was concentrated to give 274.6 mg of the title compound as a crude product.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[C:11]([O-:14])(=O)[CH3:12].[Na+].C(O[C:20](=[O:22])[CH3:21])(=O)C>>[C:2]([O:4][C@H:3]([C@H:5]([C@@H:7]([CH2:9][O:10][C:11](=[O:14])[CH3:12])[O:8][C:20](=[O:22])[CH3:21])[O:6][C:5](=[O:6])[CH3:7])[CH:2]=[O:1])(=[O:1])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[O-]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Agent: [Na+]
Product: CC(=O)OC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H](C=O)OC(C)=O
Temperature: 0 °C

Procedure:
First, 50 g of xylose, from Sigma Chemical Company, 12.5 g of sodium acetate (anhydrous) and 200 ml of acetic anhydride were heated to reflux for 1 hour and poured into 1 L of ice water. Xylose tetraacetate was isolated by filtration and recrystallized from 95% ethanol to yield 56.75 g (54%).
Reaction SMILES: [CH3:1][C:2]([CH:4]=[CH2:5])=[O:3].[CH:6]1[C:16]2[C:15](=[C:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=3[CH2:12][S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.C([O-])(=O)/C=C/C([O-])=O.C1C2C(=C3CCN(C)CC3)C3C=CC=CC=3CSC=2C=CC=1>C(O)C>[CH:6]1[C:16]2[C:15](=[C:17]3[CH2:22][CH2:21][N:20]([CH2:5][CH2:4][C:2](=[O:3])[CH3:1])[CH2:19][CH2:18]3)[C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=3[CH2:12][S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: C=CC(C)=O
Reactant: c1ccc2c(c1)CSc1ccccc1C2=C1CCNCC1
Agent: CN1CCC(=C2c3ccccc3CSc3ccccc32)CC1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CCO
Product: CC(=O)CCN1CCC(=C2c3ccccc3CSc3ccccc32)CC1

Procedure:
A solution of 2.8 g of methylvinylketone in 5 cc of ethanol is added dropwise within 2 minutes to a solution of 7.8 g of 4-(6,11-dihydrodibenzo[b,e]thiepin-11-ylidene)piperidine [M.P. of the fumarate 245°-247°, produced in a manner analogous to that described in Example 9(a), from 4-(6,11-dihydrodibenzo[b,e]thiepin-11-ylidene)-1-methylpiperidine] in 25 cc of ethanol. The reaction mixture is heated at reflux for 1 hour, is then completely concentrated at reduced pressure, and the oily residue, the title compound, is converted into the hydrogen fumarate form. M.P. 180°-182° (decomp.) from ethanol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:17])=[CH:4][C:5]2[CH:9]=[C:8]([CH:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[S:7][C:6]=2[C:15]=1[Cl:16].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(=O)CC.O>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][O:17][C:3]1[C:2]([Cl:1])=[C:15]([Cl:16])[C:6]2[S:7][C:8]([CH:10]3[CH2:11][CH2:12][CH2:13][CH2:14]3)=[CH:9][C:5]=2[CH:4]=1)[CH3:24]
Reactant: Oc1cc2cc(C3CCCC3)sc2c(Cl)c1Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cc2cc(C3CCCC3)sc2c(Cl)c1Cl
Yield: 76.1 %

Procedure:
A mixture of 9.0 g of 6,7-dichloro-2-cyclopentyl-5-hydroxybenzo[b]thiophene, 6.35 g of ethyl bromacetate, 4.0 g of potassium carbonate and 10 ml of dimethylformamide in 200 ml of 2-butanone is refluxed for 16 hours. The cooled mixture is diluted with water (200 ml), extracted with 3×300 ml-portions of dichloromethane, and the combined organic solution is dried over anhydrous magnesium sulfate. Removal of solvents leaves a colorless oil which crystallizes on cooling to give 8.9 g of ethyl[(6,7-dichloro-2-cyclopentylbenzo[b]thien-5-yl)oxy]acetate or prisms, mp 65°-67°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.C(N(CC)CC)C.Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=1>CN(C)C=O>[Cl:37][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][NH:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: Clc1cccc(CBr)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1NN=Cc2c(-c3ccccc3)[nH]c3cc(NCc4cccc(Cl)c4)cc1c23
Yield: 69.2 %

Procedure:
To the title compound of Example 7 (hydrochloride) (40 mg, 0.13 mmol), and triethylamine (0.053 mL, 0.38 mmol) in N,N-dimethylformamide (0.9 mL) was added 1-bromomethyl-3-chloro-benzene (0.17 mL, 0.13 mmol) dropwise with stirring. After stirring overnight, the mixture was chromatographed on silica eluting with 2:1 hexane:ethyl acetate to afford, after isolation, the title compound (36 mg, 0.090 mmol) as a yellow powder in 71% yield.
Reaction SMILES: CC([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:7]2)=O.[S].N1[CH2:29][CH2:28][O:27]CC1.Cl.[OH-:31].[K+]>O.C(O)C>[C:17]1([S:14]([NH:13][CH:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:29][C:28]([OH:31])=[O:27])[CH:5]=3)[CH2:9]2)(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [OH-]
Reactant: C1COCCN1
Reactant: CC(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2
Agent: Cl
Agent: [K+]
Agent: [S]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2

Procedure:
8.3 g (26 mmol) of (2-benzenesulphonamido-indan-5-yl) methyl ketone, 2.1 g (65 mmol) of sulphur and 5.7 g (65 mmol) of morpholine are heated at 135° C. for 2 hours. Ice and hydrochloric acid are added and (2-benzenesulphonamido-indan-5-yl)-acetic acid thiomorpholide is extracted with ethyl acetate. It is purified by chromatography over silica gel using 8:2 ethylene chloride/ethyl acetate, which gives 10.6 g (97% of theory) in the form of a resin. The product is then heated under reflux for 2.5 hours with 10 g of potassium hydroxide in 100 ml of water and 40 ml of ethanol. The mixture is concentrated in vacuo, the alkaline phase is washed with methylene chloride, and the reaction product is precipitated by means of hydrochloric acid. It is recrystallised from isopropanol and from ethyl acetate/diisopropyl ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[C:10]([F:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C([O-])([O-])=O.[K+].[K+]>CO>[F:16][C:10]([F:17])([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCOC(=O)C(F)(F)Oc1cccc(F)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 3-fluorophenol (2.24 g, 20.0 mmol), ethyl 2-bromo-2,2-difluoroacetate (8.12 g, 40.0 mmol) and K2CO3 (6.91 g, 50.0 mmol) in MeOH (20 mL) was stirred at 70° C. overnight. It was then cooled to rt and filtered and the filtrate was concentrated in vacuo to give the title compound, which was used for next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[NH:17]1[C:25]2[C:20](=[CH:21][C:22]3[CH2:28][CH2:27][CH2:26][C:23]=3[CH:24]=2)[C:19](=[O:29])[C:18]1=[O:30].Cl>C(OCC)C.C(OCC)(=O)C.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]1([OH:29])[C:20]2[C:25](=[CH:24][C:23]3[CH2:26][CH2:27][CH2:28][C:22]=3[CH:21]=2)[NH:17][C:18]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1OCc1ccccc1
Reactant: O=C1Nc2cc3c(cc2C1=O)CCC3
Agent: Cl
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1Nc2cc3c(cc2C1(O)c1ccccc1OCc1ccccc1)CCC3
Temperature: 25 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
Several drops of a 6 mL diethyl ether solution of 5.3 g of 2-benzyloxybromobenzene were added to a suspension of 583 mg of magnesium in 2 mL of diethyl ether under a nitrogen atmosphere to initiate the reaction, after which the rest was gradually added dropwise at a rate at which heating reflux was maintained. Upon completion of the dropping, the reaction mixture was heated and refluxed for 2 hours in an oil bath, and then cooled to room temperature. A reagent prepared as above was gradually added dropwise under ice cooling and a nitrogen atmosphere to an 11 mL tetrahydrofuran solution of 1.5 g of 1,5,6,7-tetrahydrocyclopenta[f]indol-2,3-dione. Upon completion of the dropping, the temperature was raised to room temperature, and then the reaction mixture was stirred for 16 hours at that temperature. A 1 mol/L hydrochloric acid aqueous solution was poured into the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate, and the drying agent was then filtered off and the solvent was distilled off under reduced pressure. The residue was refined by column chromatography (silica gel 60, mobile phase: ethyl acetate/hexane=1/2; v/v) to obtain 1.10 g of the titled compound (colorless powder).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22]C(OC(C)(C)C)=O)=[CH:18][CH:17]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:30]>>[BrH:30].[CH2:1]([CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCN2CCCC(Cc3ccccc3)C2)cc1
Agent: Br
Product: Nc1ccc(CCN2CCCC(Cc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 55 %

Procedure:
3-benzyl-1-[2-(4-tert-butoxycarbonylaminophenyl) ethyl]piperidine (0.67 g, 1.69 mmol) was dissolved in HBr (saturated solution in methanol, 10 mL) and the resulting solution stirred at 25° C. for 20 h. Then, after concentration in vacuum, the resultant mixture was treated with NaHCO3(water saturated solution, 50 mL) and extracted twice with EtOAc (2×50 mL). The collected organic phase was washed with brine (50 mL), dried and concentrated in vacuum. The crude compound was purified by filtration on silica gel using CH2Cl2/MeOH as eluant to afford the free amine as a pale yellow oil (0.272 g, 55%). 1H NMR (CDCl3): 0.85-1.05 (m, 1H), 1.5-1.9 (m, 4H), 1.9-2.1 (m, 2H), 2.4-2.6 (m, 4H), 2.65-2.8 (m, 2H), 2.85-3.05 (m, 2H), 3.53 (bs, 2H), 6.61 (d, J=8.1Hz, 2H), 6.97 (d, J=8.1 Hz, 2H), 7.145 (d, J=7.8Hz, 2H), 7.18 (d, J=7.2, 1H), 7.275 (t, J-7.2Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]2[CH2:17][CH2:18][N+:19]([O-])=O.[C:22](OC(=O)C)(=[O:24])[CH3:23].[H][H]>[Ni].O1CCCC1>[C:22]([NH:19][CH2:18][CH2:17][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][C:7]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:24])[CH3:23]
Reactant: CCOC(=O)c1[nH]c2ccc(OC)cc2c1CC[N+](=O)[O-]
Reactant: [H][H]
Reactant: CC(=O)OC(C)=O
Agent: [Ni]
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c2ccc(OC)cc2c1CCNC(C)=O

Procedure:
A mixed solution of ethyl 5-methoxy-3-(2-nitroethyl)-1H-indole-2-carboxylate (500 mg), tetrahydrofuran (40.0 mL), and acetic anhydride (2.00 mL) was pumped through Raney nickel cartridge, using H-cube (registered trademark) (ThalesNano Inc.) apparatus (catalyst cartridge: CatCart (registered trademark) (ThalesNano Inc.) hydrogen pressure: 60 bar, reaction temperature: 60° C., flow rate: 1 mL/s, solution concentration: 0.05 M). The obtained mixture was concentrated under reduced pressure and the obtained residue was washed with a mixed solvent of hexane:ethyl acetate=2:1 to obtain ethyl 3-(2-acetamidoethyl)-5-methoxy-1H-indole-2-carboxylate (450 mg) as a white solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:55][N:56]1[CH2:61][CH2:60][CH:59]([NH2:62])[CH2:58][CH2:57]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:62][CH:59]5[CH2:60][CH2:61][N:56]([CH3:55])[CH2:57][CH2:58]5)=[O:28])=[CH:24][CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(N)CC1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)cc2)CC1

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.66 (m, 6H) 1.72 (m, 4H) 1.92-1.99 (m, 5H) 2.15 (s, 3H) 2.76 (d, J=11.4 Hz, 2H) 3.71 (m, 1H) 4.04 (t, J=14.2 Hz, 2H) 4.78 (t, J=7.8 Hz, 1H) 7.77 (s, 4H) 8.03 (d, J=7.6 Hz, 1H) 8.27 (s, 1H) 9.67 (s, 1H). Melting point: 234-2350C. [M+H] calc'd for C26H33F2N7O2, 514. found 514.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([C:16](=O)/[CH:17]=[CH:18]/[N:19](C)C)=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.Cl.[F:25][C:26]([F:32])([F:31])[CH2:27][CH2:28][NH:29]N>CCO>[Si:1]([O:8][CH2:9][C:10]1[C:11]([C:16]2[N:29]([CH2:28][CH2:27][C:26]([F:32])([F:31])[F:25])[N:19]=[CH:18][CH:17]=2)=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: NNCCC(F)(F)F
Reactant: CN(C)/C=C/C(=O)c1ncccc1CO[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCc1cccnc1-c1ccnn1CCC(F)(F)F
Temperature: 80 °C
Yield: 76 %

Procedure:
To (E)-1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-3-(dimethylamino)prop-2-en-1-one (crude above, 1.73 g, 5.41 mmol, 1 eq.) in EtOH (10 mL) was added (3,3,3-trifluoropropyl)hydrazine dihydrochloride (1.30 g, crude above, 6.49 mmol, 1.2 eq.) at RT. The mixture was heated at 80° C. for 1 h, concentrated, and diluted with EtOAc (50 mL) and NaHCO3(sat) solution (10 mL). The layers were separated and aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3-((tert-butyldimethylsilyloxy)methyl)-2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridine (1.58 g; 76% for 2 steps). 1H NMR (400 MHz, CDCl3) δ 8.53 (dd, J=4.7, 1.6 Hz, 1H), 7.96-7.88 (m, 1H), 7.51 (d, J=1.9 Hz, 1H), 7.29 (dd, J=7.9, 4.7 Hz, 1H), 6.34 (d, J=1.9 Hz, 1H), 4.62 (s, 2H), 4.45-4.33 (m, 2H), 2.82-2.61 (m, 2H), 0.85 (s, 8H), −0.00 (s, 5H). MS (ESI) m/z 386.2 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[NH:15][NH2:16])=[CH:9][CH:8]=2)[N:5]=[CH:4][N:3]1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])=[CH:20][CH:19]=1.[CH3:32]N(C)C=O.C(O)(=O)C.C(O)(=O)C.C(N)=N>O>[O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:32]=[N:16][NH:15][C:14]3=[O:17])=[CH:9][CH:8]=2)[N:5]=[CH:4][N:3]1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([F:30])([F:31])[CH:27]([F:28])[F:29])=[CH:20][CH:19]=1
Reactant: CN(C)C=O
Reactant: NNC(=O)Nc1ccc(-n2ncn(-c3ccc(OCC(F)(F)C(F)F)cc3)c2=O)cc1
Agent: N=CN
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]ncn1-c1ccc(-n2ncn(-c3ccc(OCC(F)(F)C(F)F)cc3)c2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
4-[4-[5-Oxo-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1H,4H-1,2,4-triazol-1-yl]phenyl]semicarbazide (4.75 g) was added to N,N-dimethylformamide (60 ml). To the mixture were added acetic acid (4 g) and formamidine acetate (6 g), and the resulting mixture was stirred at room temperature for 3 hours and then at 80° C. for 1.5 hours. After cooling, the reaction solution was diluted with water (30 ml). The precipitated crystals were collected by filtration and washed with water (100 ml). The crystals were dried and dissolved in a mixture of tetrahydrofuran (300 ml) and ethyl acetate (600 ml) with warming. The solution thus obtained was dried over anhydrous magnesium sulfate, filtrated and concentrated under reduced pressure. Ethyl acetate (50 ml) was added to the residue and the precipitated crystals were collected by filtration and recrystallized from tetrahydrofuran to give 4-[4-[5-oxo-4-[4-(2,2,3,3-tetrafluoropropoxy)-phenyl]-1H,4H-1,2,4-triazol-1-yl]phenyl]-3(2H,4H)-1,2,4-triazolone (2.4 g, 49%) as a white crystalline powder.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:3]=1.[C:17](OC(=O)C)(=[O:19])C.O>C(O)=O>[CH:17]([NH:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=2)[N:3]=1)=[O:19]
Reactant: NC1=NN(c2cccc(C(F)(F)F)c2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: O=CO
Product: O=CNC1=NN(c2cccc(C(F)(F)F)c2)CC1

Procedure:
3-Amino-1-(3-trifluoromethylphenyl)-2-pyrazoline (1.907 g) was dissolved in formic acid (20 ml). The solution was stirred at 60° and acetic anhydride (2.4 ml) was added dropwise. The mixture was heated for 1 hour at 60° and then poured into water and stirred to decompose the residual excess anhydride. 3-Formamido-1-(3-trifluoromethylphenyl)-2-pyrazoline resulted as a crystalline solid m.p. 128°-129°. This compound was then used to prepare the compound of Example 1, as hereinbefore described.
Reaction SMILES: [C:1](O)(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:24][C:25]([CH3:38])([CH2:36][CH3:37])[C:26](=[O:35])[C:27]([CH:29]1[CH2:34][CH2:33][CH2:32][NH:31][NH:30]1)=[O:28]>C(Cl)Cl>[C:1]([N:30]1[CH:29]([C:27](=[O:28])[C:26](=[O:35])[C:25]([CH3:38])([CH3:24])[CH2:36][CH3:37])[CH2:34][CH2:33][CH2:32][NH:31]1)(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6]
Reactant: C#CCCCC(=O)O
Reactant: CCC(C)(C)C(=O)C(=O)C1CCCNN1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCCCC(=O)N1NCCCC1C(=O)C(=O)C(C)(C)CC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62.8 %

Procedure:
To a solution of 5-hexynoic acid (0.467 g, 4 mmol) in 10 ml CH2Cl2 was added triethylamine (0.56 ml, 4 mmol), followed by isobutyl chloroformate (0.53 ml, 4 mmol) at 0° C. After stirring for 5 minutes, a solution of 3,3-dimethyl-1-perhydropyridazinyl pentane-1,2-dione (0.424 g, 2 mmol) in 1 ml CH2Cl2 was added. The reaction was gradually warmed up to room temperature. The crude material was subject to silica gel purification to yield final product as clear oil (0.385 g, 63%). 1H NMR (CDCl3, 400 MHz) δ 0.91 (t, 3H, J=7.0); 1.26 (s, 6H); 1.76(m, 8H); 2.28 (m, 2H); 2.50 (m, 2H); 2.88 (m, 2H); 3.60 (m, 1H); 4.50 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Si:26]([O:33][CH2:34][CH2:35]I)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].C(OCC)(=O)C.ClCCl>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:35][CH2:34][O:33][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCI
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCO[Si](C)(C)C(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Alternately, combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (1.72 g, 5.43 mmol) and sodium hydride (0.36 g, 60% in oil, 8.15 mmol) in dimethylformamide (40 mL). After 4 hours, add 2-(t-butyldimethylsilyloxy)ethyl iodide (1.56 g, 5.43 mmol). After 72 hours, heat to 80° C. After 3 hours, cool to ambient temperature and add ice to quench. Partition the reaction mixture between ethyl acetate (250 mL) and a saturated aqueous solution of sodium bicarbonate (200 mL). Separate the layers and extract the organic layer with water. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 40% ethyl acetate/dichloromethane to give 1-(t-butoxycarbonyl)-4-(1-(2-(t-butyldimethylsilyloxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.