Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].C([N-]C(C)C)(C)C.[Li+].Cl[Si](C)(C)C.Cl[C:23]([CH3:26])([CH3:25])[CH3:24]>C1COCC1.C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[C:23]([CH:4]1[C:3](=[O:7])[C:2]([CH3:8])([CH3:1])[CH2:6][CH2:5]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)Cl
Reactant: CC1(C)CCCC1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC1(C)CCC(C(C)(C)C)C1=O
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
A solution of 2,2-dimethylcyclopentanone (10.1 g, 90.0 mmol) in THF (200 ml) was added at −70° C. within 30 min to a stirred solution of lithium diisopropylamide (2 M in THF, 45.0 ml, 90.0 mmol). After 15 min of stirring at −70° C., chlorotrimethylsilane (19.6 g, 180 mmol) was added dropwise over a period of 10 min. The reaction mixture was allowed to warm to 0° C., stirred for 1 h at this temperature and 2 h at room temp. The formed suspension was filtered off by suction with the aid of a sintered funnel and washed with Et2O (100 ml), and the filtrate was concentrated under reduced pressure. Then, a solution of titanium tetrachloride (17.1 g, 90 mmol) in CH2Cl2 (30 ml) was added within 10 min at −60° C. to a solution of the obtained silyl enol ether (16.8 g, 88.9 mm0l) and 2-chloro-2-methylpropane (8.80 g, 95.0 mmol) in CH2Cl2 (200 ml). After stifling for further 30 min at −60° C., the reaction mixture was allowed to warm up to 0° C., quenched with H2O (500 ml) and extracted with Et2O (3×400 ml). The combined organic extracts were washed with 10% aq. NaHCO3 solution (2×150 ml) and brine (2×100 ml), dried (Na2SO4), and the solvent was evaporated on a rotary evaporator. The resulting residue was purified by silica gel FC (pentane/Et2O, 98:2, Rf=0.27) to provide 5-tert-butyl-2,2-dimethylcyclopentanone (13.8 g, 91%) as a colourless liquid. IR (neat): v=1722 (s, vC═O), 1463 [m, δas(CH3)], 1361 [m, δs(CH3)] cm−1. 1H NMR (CDCl3): δ=0.92/1.05 (2s, 6 H, 2-Me2), 0.99 (s, 9 H, 1′-Me3), 1.51-1.59 (m, 1 H, 5-H), 1.64-1.80 (m, 2 H, 3-Hax, 4-Hax), 1.92-2.15 (m, 2 H, 3-Heq, 4-Heq) ppm. 13C NMR (CDCl3): δ=22.3 (t, C-4), 23.0/24.8 (2q, 2-Me2), 27.8 (q, 1′-Me3), 32.3 (s, C-1′), 35.8 (t, C-3), 45.7 (s, C-2), 223.5 (s, C-1) ppm. MS (EI): m/z (%)=168 (24) [M]+, 153 (11) [M-CH3]+, 112 (100) [M-C4H8]+, 111 (52) [M-C4H9]+, 57 (45) [C4H9]+.
Reaction SMILES: [OH-].[Na+].C([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[C:12]([NH2:22])=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[CH3:21])[CH2:8][CH2:7]1)(=O)C.[C:23]1([NH2:34])[C:28]([F:29])=[C:27]([F:30])[C:26]([F:31])=[C:25]([NH2:32])[C:24]=1[F:33].[ClH:35].Cl>>[NH2:22][C:12]1[C:11]2[N:10]=[C:9]3[CH2:8][CH2:7][NH:6][CH2:20][CH2:19][C:18]3=[C:17]([CH3:21])[C:16]=2[CH:15]=[CH:14][CH:13]=1.[C:23]1([NH2:34])[C:28]([F:29])=[C:27]([F:30])[C:26]([F:31])=[C:25]([NH2:32])[C:24]=1[F:33].[ClH:35].[ClH:35]
Reactant: CC(=O)N1CCc2nc3c(N)cccc3c(C)c2CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Na+]
Product: Cc1c2c(nc3c(N)cccc13)CCNCC2

Procedure:
7-Amino-1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline and its dihydrochloride were prepared by hydrolysis with 2 N sodium hydroxide of 3-acetyl-7-amino-1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline, and subsequent conversion of the base into its dihydrochloride. Yield of the dihydrochloride: 83%; of theory; m.p. 285° C. (decomp.).
Reaction SMILES: O.O.[Sn](Cl)Cl.[Cl:6][C:7]1[C:15]2[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:18]=3[F:26])=[CH:13][CH:12]=[N:11][C:10]=2[NH:9][CH:8]=1.O.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][C:14]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=2[F:26])[NH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(Nc2ccnc3[nH]cc(Cl)c23)c(F)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Nc2ccnc3[nH]cc(Cl)c23)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
147 mg (650 μmol) of tin(II) chloride dihydrate are added to a solution of 40 mg (130 μmol) of 3-chloro-N-(2-fluoro-4-nitrophenyl)-1H-pyrrolo[2,3-b]pyridine-4-amine in 2.50 ml of DMF, and this solution is stirred at RT overnight. 5 ml of water are then added, and the pH is adjusted to 10 using saturated sodium bicarbonate solution. After filtration through Celite, the Celite is washed with 40 ml of ethyl acetate. The aqueous phase of the filtrate is extracted twice with 10 ml of ethyl acetate. The combined organic phases are washed in each case twice with 5 ml of water and 5 ml of saturated sodium chloride solution and dried with sodium sulfate. Concentration under reduced pressure affords the target compound which is reacted further without purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:18]=1)[C:10](=[O:17])[C:11]1[CH2:16][CH2:15][CH2:14][C:12]=1[N:13]=2)=[O:4].C[O-].[Na+].[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[CH:22](=[C:14]1[C:12]2[N:13]=[C:8]3[CH:7]=[CH:6][C:5]([C:3]([OH:2])=[O:4])=[CH:18][N:9]3[C:10](=[O:17])[C:11]=2[CH2:16][CH2:15]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc2nc3c(c(=O)n2c1)CCC3
Reactant: O=Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1ccc2nc3c(c(=O)n2c1)CCC3=Cc1ccccc1

Procedure:
1,2,3,10-tetrahydro-10-oxo-cyclopenta[d]pyrido[1,2-a]pyrimidine-7-carboxylic acid methyl ester, m.p. 153°-154° C. (5 g) in methanol (300 ml) containing 6.45 g of sodium methoxide was reacted with 10.9 g of benzaldehyde under stirring at reflux temperature for 96 hours. After cooling and concentration in vacuo to a small volume the precipitate was filtered and treated with acetic acid and then with water; the crude compound was recovered by filtration, washed with water until neutral and crystallized from CH2Cl2 /methanol and then from dioxane to give 3.25 g of 3-benzylidene-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d]pyrido[1,2-a]pyrimidine-7-carboxylic acid, m.p. 309°-310° C., NMR (CF3COOD) δ ppm: 3.44 (m) (4H, cyclopentane protons), 7.68 (m) (6H, =CH-- and phenyl protons), 8.44 (d) (1H, C-5 proton), 9.15 (d.d) (1H, C-6 proton), 10.23 (d) (1H, C-8 proton).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:25]([CH:26]4[CH2:28][CH2:27]4)=[CH:24][C:16]([C:17](OC(C)(C)C)=[O:18])=[CH:15][N:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.FC(F)(F)C(O)=O.C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:48][NH:49][S:50]([NH2:53])(=[O:52])=[O:51].N1(C2CCCCCCCCCC2)CCCN=CCCCCC1>ClCCl.C(OCC)(=O)C>[C:1]12([CH2:11][O:12][C:13]3[C:25]([CH:26]4[CH2:28][CH2:27]4)=[CH:24][C:16]([C:17]([NH:53][S:50](=[O:52])(=[O:51])[NH:49][CH3:48])=[O:18])=[CH:15][N:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CNS(N)(=O)=O
Reactant: CC(C)(C)OC(=O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)NC(=O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
A solution of tert-butyl 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinate (0.50 g, 1.30 mmol) in dichloromethane (20 mL) was treated with trifluoroacetic acid (5.0 mL). The resulting mixture was stirred for 30 minutes and then concentrated in vacuo. The residue was treated with methanol (20 mL) and concentrated in vacuo. The residue was dissolved in anhydrous tetrahydrofuran (20 mL), treated with carbonyl diimidazole (0.42 g, 2.60 mmol), and refluxed under nitrogen for 30 min. The reaction mixture was cooled to ambient temperature and added (methylsulfamoyl)amine (0.43 g, 3.90 mmol) and 1,8-diazabicycloundec-7-ene (0.58 mL, 3.90 mmol). The reaction mixture was refluxed under nitrogen for 30 minutes. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (50 mL), washed with 1 M aqueous hydrochloric acid solution (2×30 mL) and brine (30 mL); dried over anhydrous sodium sulfate; filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) to provide the title compound (0.12 g, 22%): 1H NMR (300 MHz, DMSO-d6) δ 11.65 (br s, 1H), 8.46 (d, J=2.3 Hz, 1H), 7.73 (d, J=2.3 Hz, 1H), 7.58-7.51 (m, 1H), 3.92 (s, 2H), 2.52-2.48 (m, 3H), 2.07-1.98 (m, 1H), 1.97-1.90 (m, 3H), 1.72-1.55 (m, 12H), 0.98-0.90 (m, 2H), 0.77-0.70 (m, 2H); MS (ES+) m/z 420.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]3[CH:20]=[N:21][CH:22]=[C:18]3[C:17]([Cl:23])=[CH:16][C:15]=2[C:24]([O:26]C)=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]3[CH:20]=[N:21][CH:22]=[C:18]3[C:17]([Cl:23])=[CH:16][C:15]=2[C:24]([OH:26])=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(Cl)c2cncn2c1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2c(C(=O)O)cc(Cl)c3cncn23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
Methyl 5-[4-(tert-butoxycarbonyl)piperazin-1-yl]-8-chloroimidazo[1,5-a]pyridine-6-carboxylate (120 mg, 0.3123 mmol) was stirred in methanol (2 mL) and 3.0 M sodium hydroxide in water (0.4 mL, 1.0 mmol) was added. The mixture was stirred at room temperature overnight. Acidification with a few drops of 1 M HCl (checked with litmus paper pH 6), evaporation and trituration with water gave the desired compound (94 mg, 79%). LCMS calculated for C17H22ClN4O4 (M+H)+: m/z=381.1. found: 380.9.
Reaction SMILES: [O:1]=[C:2]([CH3:14])[C:3](=[N:9][O:10][CH2:11][CH2:12][CH3:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5].S(Cl)([Cl:18])(=O)=O>C(O)(=O)C>[Cl:18][CH2:14][C:2](=[O:1])[C:3](=[N:9][O:10][CH2:11][CH2:12][CH3:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCON=C(C(C)=O)C(=O)OCC
Solvent: CC(=O)O
Product: CCCON=C(C(=O)CCl)C(=O)OCC
Temperature: 0 °C
Yield: 85.4 %

Procedure:
Ethyl 3-oxo-2-propoxyiminobutyrate (syn isomer, 15.4 g.) and sulfuryl chloride (10.6 g.) were dissolved in acetic acid (15.4 ml.), warmed at 35° to 40° C. for 10 minutes with stirring and then stirred at ambient temperature for additional 6 hours. The reaction mixture was poured into ice-water (200 ml.) and the resultant mixture was extracted twice with chloroform. The extract was washed with an aqueous solution of sodium chloride, twice a saturated aqueous solution of sodium bicarbonate and once with water in turn, dried over magnesium sulfate, and then evaporated to dryness under reduced pressure to give ethyl 4-chloro-3-oxo-2-propoxyiminobutyrate (syn isomer, 15.4 g.), oil.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12].[CH2:16]([O:19][C:20]1([CH3:53])[CH2:25][CH2:24][N:23]([C:26]2[N:31]3[N:32]=[C:33]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37](Br)[CH:36]=4)[CH:34]=[C:30]3[N:29]=[C:28]([CH3:42])[C:27]=2[C@H:43]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[C:44]([O:46][CH3:47])=[O:45])[CH2:22][CH2:21]1)[CH:17]=[CH2:18]>C1COCC1.CCOC(C)=O.[Zn]>[CH2:16]([O:19][C:20]1([CH3:53])[CH2:25][CH2:24][N:23]([C:26]2[N:31]3[N:32]=[C:33]([C:35]4[CH:36]=[C:37]([C:2]5[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=5[O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])[CH:38]=[CH:39][CH:40]=4)[CH:34]=[C:30]3[N:29]=[C:28]([CH3:42])[C:27]=2[C@H:43]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[C:44]([O:46][CH3:47])=[O:45])[CH2:22][CH2:21]1)[CH:17]=[CH2:18]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(Br)c4)nn23)CC1
Reactant: C=CC[C@H](C)Oc1cc(C#N)ccc1Br
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(-c5ccc(C#N)cc5O[C@@H](C)CC=C)c4)nn23)CC1
Temperature: 60 °C
Yield: 59.5 %

Procedure:
To a solution of (S)-4-bromo-3-(pent-4-en-2-yloxy)benzonitrile (0.136 g, 0.51 mmol, 1.5 equiv) in THF (3.4 mL) was added Reike zinc (0.67 mL of a 10 g/100 mL slurry in THF, 1.03 mmol, 3 equiv). The reaction was then heated at 60° C. for 2 h. Upon cooling to ambient temperature, the zincate solution was filtered and added to a solution of (S)-methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.20 g, 0.34 mmol, 1 equiv) in THF (1.7 mL). The reaction was then heated at 60° C. for 18 h. Upon cooling to ambient temperature, the reaction was diluted with EtOAc and washed with a saturated aqueous solution of NaHCO3. The EtOAc layer was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc in hexane) to provide the product as a colorless oil (0.14 g, 59%). 1H NMR (400 MHz, CDCl3) [note: 4H of piperidine not observed] δ 8.12 (s, 1H), 8.07 (d, J=6.8 Hz, 1H), 7.56-7.48 (m, 3H), 7.36 (dd, J=7.8, 1.3 Hz, 1H), 7.24 (s, 1H), 6.85 (br. s., 1H), 6.06-5.92 (m, J=11.2, 11.2, 5.0 Hz, 2H), 5.72 (s, 1H), 5.40 (dd, J=17.1, 1.5 Hz, 1H), 5.13-5.05 (m, J=3.5 Hz, 2H), 5.03 (s, 1H), 4.52-4.43 (m, J=5.8 Hz, 1H), 4.01 (d, J=4.5 Hz, 2H), 3.75 (s, 3H), 2.63 (s, 3H), 2.48-2.39 (m, 1H), 2.38-2.28 (m, J=7.5 Hz, 1H), 2.05-1.94 (m, 2H), 1.78-1.68 (m, 1H), 1.59 (br. s., 1H), 1.36 (br. s., 3H), 1.30 (d, J=6.0 Hz, 3H), 1.26 (s, 9H). LCMS (M+1)=692.35.
Reaction SMILES: O[C:2]1[CH:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4](=[O:7])[O:5][CH:6]=1.O.[NH2:15][NH2:16]>C(O)C>[OH:5][CH2:6][C:2]1[N:16]=[N:15][C:4](=[O:7])[C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1OC=C(O)C1c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=C1N=NC(CO)=C1c1ccccc1

Procedure:
4-Hydroxy-3-phenyl-2-furanone (3 g, 0.017 mol) was dissolved in ethanol (17 ml) with hydrazine hydrate (0.83 ml, 0.017 mol) and heated at reflux for 10 days (over this time the solvent evaporated). The residue was redissolved in ethanol (17 ml) and heated at reflux then allowed to cool and the solid that crystallised out was collected by filtration (2.2 g, mp=173° C.). Data for the title compound: 1H NMR (360 MHz, d6-DMSO) δ 4.45 (1H, s), 5.31 (1H, s), 7.14 (1H, t, J=7.3 Hz), 7.34 (2H, t, J=7.3 Hz), 7.55 (2H, d, J=7.3 Hz); MS (ES+) m/e 191 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:7](=[O:10])[N:8]([CH3:9])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].Cl[CH2:28][CH2:29][CH2:30][CH:31]([C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1)[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1>O.CC(C)CC(=O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH:11]3[CH2:12][CH2:13][N:14]([CH2:28][CH2:29][CH2:30][CH:31]([C:32]4[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=4)[C:39]4[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=4)[CH2:15][CH2:16]3)[C:7](=[O:10])[N:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Reactant: Cn1c(=O)n(C2CCNCC2)c2ccc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: Cn1c(=O)n(C2CCN(CCCC(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c2ccc(Cl)cc21
Reaction time: 8 h

Procedure:
A mixture of 5,3 parts of 5-chloro-1,3-dihydro-3-methyl-1-(4-piperidinyl)-2H-benzimidazol-2-one, 6.4 parts of sodium carbonate, 0.2 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 30 minutes with water-separator. After cooling, there are added 7 parts of 1-chloro-4,4-bis(4-fluorophenyl)-butane and stirring at reflux temperature is continued overnight. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The oily residue is triturated in 2,2'-oxybispropane. The product is filtered off, dried and crystallized from 2-propanol, yielding 5-chloro-1-{1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl}-1,3-dihydro-3 -methyl-2H-benzimidazol-2-one; mp. 155.8° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4](O)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:12])([F:13])[F:14])[C:3]=1[CH2:4][OH:5]
Reactant: Nc1cccc(C(F)(F)F)c1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1cccc(C(F)(F)F)c1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
2-amino-6-(trifluoromethyl)benzoic acid (20 g, 97 mmol) was dissolved in tetrahydrofuran (120 mL) in a 3-neck RB flask equipped with an addition funnel and a condenser. The solution was cooled in an ice-water bath. LiAlH4 (83 mL, 166 mmol) (2M solution in THF) was then added dropwise. After all of the LiAlH4 solution was added, the reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. The reaction was then quenched by adding 10 mL of Water, then 10 mL of 15% NaOH and then 25 mL of Water. The salts were filtered off and the solvents were evaporated under vacuum. The product was used as is (18 g, 97% yield.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[C:9]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[NH:10][NH2:11]>CCCCCC>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=[N:11][NH:10][C:9]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:4][CH2:3]1
Reactant: CC1CCC(=O)CC1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCCCCC
Product: CC1CCC(=NNC(=O)OC(C)(C)C)CC1
Yield: 89.1 %

Procedure:
To a 230 ml hexane solution of 23.6 ml (192 mmol) of 4-methylcyclohexanone, 25.5 g (192 mg) of t-butyl carbazate was added, followed by heating the mixture under reflux for 20 minutes. Then, the reaction mixture was brought to room temperature, and precipitated solids were collected by filtration to obtain 38.7 g (89%) of the captioned compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([CH3:10])=[N:5][S:6][C:7]=1[C:8]#[N:9].NC(N)=S.C[S:16]([C:19]1[CH2:23][C:22]([CH3:25])([CH3:24])[O:21][N:20]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:24][C:22]1([CH3:25])[O:21][N:20]=[C:19]([S:16][CH2:2][C:3]2[C:4]([CH3:10])=[N:5][S:6][C:7]=2[C:8]#[N:9])[CH2:23]1
Reactant: CC1(C)CC(S(C)(=O)=O)=NO1
Reactant: Cc1nsc(C#N)c1CBr
Agent: NC(N)=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1nsc(C#N)c1CSC1=NOC(C)(C)C1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
4-Bromomethyl-5-cyano-3-methyl-isothiazole (50% purity) (0.65 g, 1.5 mmol) was dissolved in ethanol (30 ml) and thiourea (242 mg, 3.2 mmol) was added. The mixture was stirred at room temperature until the solids were dissolved. 3-Methane-sulfonyl-5,5-dimethyl-4,5-dihydroisoxazole (540 mg, 3.2 mmol) and potassium carbonate (440 mg, 3.2 mmol) were added and the mixture was heated under reflux for 1 hour. The solids were removed by filtration and the filtrate was concentrated. The crude product was purified by chromatography on silica gel (eluent: ethyl acetate/hexane) to give the product (0.25 g, 62% yield). 1H-NMR (400 MHz, CDCl3): 1.44 (6H, s, Me), 2.6 (3H, s, Me), 2.8 (2H, s, CH2), 4.4 (2H, s, CH2).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)=O)=[C:4]([O:28][CH3:29])[CH:3]=1>ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([O:28][CH3:29])[C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:13]=[C:14]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=3)[C:26]=2[CH:27]=1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccccc2Oc2ccc(F)cc2OC)cc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(C2=Nc3ccccc3Oc3c(OC)cc(F)cc32)cc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 6.5 %

Procedure:
A stirring mixture of title compound 92 (2 g, 5.06 mmol) in polyphosphoric acid (4.76 ml, 41.7 mmol) was heated at 130° C. for 3 h. The reaction mixture was cooled, diluted with dichloromethane and water and stirred overnight. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, filtered and solvent evaporated. The crude residue was purified via ISCO (0-25% Hex/EtOAc; 40 g silica gel column) to afford title compound 93 (125 mg, 6.5%) as a light yellow solid. LRMS (ESI): (calc) 377.11. (found) 378.4 (MH)+.
Reaction SMILES: [CH:1]1([CH:7](O)[C:8]2[CH:9]=[C:10]([C:15]3(O)[CH2:20][CH2:19][S:18][CH2:17][CH2:16]3)[S:11][C:12]=2[CH2:13][CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:25])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:25][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:8]1[CH:9]=[C:10]([C:15]2[CH2:20][CH2:19][S:18][CH2:17][CH:16]=2)[S:11][C:12]=1[CH2:13][CH3:14]
Reactant: O=S(Cl)Cl
Reactant: CCc1sc(C2(O)CCSCC2)cc1C(O)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCc1sc(C2=CCSCC2)cc1C(Cl)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 4-{4-[cyclohexyl(hydroxy)methyl]-5-ethylthiophen-2-yl}tetrahydro-2H-thiopyran-4-ol (532 mg) synthesized in Example 85 (3) in toluene (10 mL) was added thionyl chloride (137 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (491 mg, 92%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH:10]([F:13])[CH2:11]I)[CH:3]=1.C1CCN2C(=NCCC2)CC1.CCOC(C)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][C:10]([F:13])=[CH2:11])[CH:3]=1
Reactant: FC(CI)CCc1cccc(Br)c1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: C=C(F)CCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
A solution of 0.405 gm (1.1 mmol) of 1-bromo-3-(3-fluoro-4-iodobutyl)-benzene in CH2Cl2 was treated with 0.82 mL (5.5 mmol) of DBU at room temperature, stirred at room temperature for 24 h and poured into EtOAc. The resultant organic phase was washed sequentially with water and brine, dried over Na2SO4 and concentrated under reduced pressure. Chromatography of the concentrate on silica gel with a gradient of hexanes to 7.0% EtOAc-hexanes gave 1-bromo-3-(3-fluorobut-3-enyl)benzene as an oil, 0.20 gm (80% yield); 1H NMR (400 MHz, CDCl3) δ: 2.45 (m, 2H), 2.78 (t, 2H, J=7.8 Hz), 3.29 (dd, 1H, J=2.8, 50.1 Hz), 4.50 (dd, 1H, J=2.8, 7.3 Hz), 7.12 (m, 2H), 7.32 (m, 2H).
Reaction SMILES: [C:1]([Cl:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([N:12]1[C:18](=[O:19])[C:17]([CH3:21])([CH3:20])[C:16](=[O:22])[N:15]([CH3:23])[C:14]2[CH:24]=[C:25]([CH2:28][NH:29][CH2:30][CH2:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[CH:26]=[CH:27][C:13]1=2)[CH3:11].C(=O)([O-])O.[Na+].C(O)C.Cl>C(O)(C)C.C(N(CC)CC)C.C(#N)C>[ClH:9].[CH2:10]([N:12]1[C:18](=[O:19])[C:17]([CH3:21])([CH3:20])[C:16](=[O:22])[N:15]([CH3:23])[C:14]2[CH:24]=[C:25]([CH2:28][N:29]([CH2:30][CH2:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:26]=[CH:27][C:13]1=2)[CH3:11]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNCCc3cccnc3)ccc21
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: CC#N
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCc3cccnc3)C(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzoyl chloride(0.13 ml) was added to an acetonitrile solution (6 ml) of 1-ethyl-3,3,5-trimethyl-7-[(2-pyridin-3-ylethylamino)methyl]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(0.38 g) and triethylamine(0.17 ml) under ice cooling. The mixture was stirred at room temperature overnight. An aqueous sodium hydrogencarbonate solution was added to the reaction mixture, followed by extraction by ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol=91:9). The purified product was condensed under reduced pressure. A 1N-hydrogen chloride ethanol solution(0.87 ml) was added to an isopropyl alcohol solution (10 ml) of the residue, and the liquid was condensed under reduced pressure. The residue was recrystallized from the ethanol-ether mixture to give the title compound(0.26 g) as a pale brown white powder.