Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[O:26]([CH2:33][CH2:34]O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>C1COCC1>[O:9]=[C:6]1[C:5]2[CH:10]=[CH:11][C:2]([O:1][CH2:34][CH2:33][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:3]([CH2:12][N:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)[C:4]=2[O:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: OCCOc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(OCCOc3ccccc3)ccc3c2OCC3=O)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 53.5 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.287 mmol), 2-phenoxyethanol (0.0475 g, 0.344 mmol) and triphenylphosphine (0.113 g, 0.431 mmol) in THF (2 mL) was added with a solution of a 40% solution of diethyl azodicarboxylate in toluene (0.225 g, 0.517 mmol) in THF (0.5 mL), and the mixture was stirred at 70° C. for 3 hours in a sealed tube. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/ethyl acetate) to obtain tert-butyl 4-[(3-oxo-6-(2-phenoxyethoxy)-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0720 g, 53%).
Reaction SMILES: O[Li:2].O.C[O:5][C:6](=[O:45])[CH2:7][C:8]1[CH:44]=[CH:43][CH:42]=[CH:41][C:9]=1[CH2:10][CH2:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]3)=[CH:25][CH:24]=2)[N:13]=1>C1COCC1.O.CO>[C:37]([O:36][C:34]([N:31]1[CH2:32][CH2:33][CH:29]([C:26]2[CH:25]=[CH:24][C:23]([NH:22][C:14]3[N:13]=[C:12]([CH2:11][CH2:10][C:9]4[CH:41]=[CH:42][CH:43]=[CH:44][C:8]=4[CH2:7][C:6]([O-:45])=[O:5])[C:17]([C:18]([F:20])([F:19])[F:21])=[CH:16][N:15]=3)=[CH:28][CH:27]=2)[CH2:30]1)=[O:35])([CH3:40])([CH3:38])[CH3:39].[Li+:2]
Reactant: [Li]O
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)C3)cc2)ncc1C(F)(F)F
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)[O-])n3)cc2)C1
Product: [Li+]
Temperature: 25 °C
Reaction time: 70 h

Procedure:
LiOH.H2O (0.015 g, 0.65 mmol, 3 eq) was added to a solution of tert-butyl 3-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)pyrrolidine-1-carboxylate (I139) (0.13 g, 0.22 mmol) in THF (7 mL), water (1.5 mL) and methanol (1 mL) and the resulting mixture was allowed to stir at room temperature for 70 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4 and the solvent removed in vacuo to give the title compound (I140) (0.12 g, 99%) as a pale yellow oil; LCMS Method C: rt 6.56 min; m/z 571.1 [M-Li+2H]+, 515.1 [M-Li-tButyl+2H]+, 471.1 [M-Li-Boc+2H]+, 569.2 [M-Li-H]−.
Reaction SMILES: [N:1]([C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH:5]([OH:10])[C:6]([O:8][CH3:9])=[O:7])=[N+:2]=[N-:3].C(=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[N:29]=[C:28](S(C)(=O)=O)[N:27]=1.O>CN(C=O)C>[N:1]([C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH:5]([O:10][C:28]1[N:29]=[C:30]([O:32][CH3:33])[CH:31]=[C:26]([O:25][CH3:24])[N:27]=1)[C:6]([O:8][CH3:9])=[O:7])=[N+:2]=[N-:3]
Reactant: COC(=O)C(O)C(C)(N=[N+]=[N-])c1ccccc1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(N=[N+]=[N-])c1ccccc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 67.5 %

Procedure:
5.9 g (25 mmol) of methyl 3-azido-3-phenyl-2-hydroxybutyrate (Ex. 1) are dissolved in 80 ml of DMF, treated with 1.7 g (12.5 mmol) of potassium carbonate and 5.5 g (25 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine, and stirred for 6 hours at 50° C. and 12 hours at room temperature. The mixture is then poured onto 400 ml of water, and the precipitate formed is filtered off with suction, washed with water and dried. 6.3 g of a white powder are obtained.
Reaction SMILES: [C:1]1([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[K+].S(C1C=CC(C)=CC=1)([O:28][CH3:29])(=O)=O>CN(C=O)C.ClCCl>[CH3:29][O:28][C:8]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]=1[S:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: c1ccc(SC2CN(c3ccccc3)c3ncccc32)cc1
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(Sc2ccccc2)c2cccnc2n1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 25.1 %

Procedure:
Add 1,3-dihydro-N-phenyl-3-(phenylthio)-2H-pyrrolo(2,3-b)pyridine (4.0 g, 12.6 mmole) portionwise to potassium hydride (KH) (1.73 g of 35 weight-percent KH in oil, washed with hexane, 15.1 mmole) in dry DMF (50 mL) at 0° C. under a nitrogen atmosphere. Stir for 45 minutes at 0° C. Add methyl tosylate(3.04 g, 16.3 mmole), and warm the reaction mixture up to room temperature slowly. Stir for 16 hours at room temperature. Remove DMF by high vacuum distillation. Add saturated aqueous NH4Cl (150 mL) and extract with ethyl acetate. Wash the organic extracts with saturated aqueous NaCl, dry with MgSO4, filter and rotoevaporate to give an oil. Dissolve oil in dichloromethane and chromatograph on silica gel, eluting with ethyl acetate:hexane (1:6). Combine appropriate fractions and concentrate under reduced pressure to give an oil. Crystallize the oil with diethyl ether-hexane to give the title compound as a white solid (1.05 g, m.p.=86°-87.5° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)ccc1OCc1ccc(F)cc1
Temperature: 140 °C
Yield: 58.2 %

Procedure:
To a mixture of 5-bromo-2-hydroxy-benzaldehyde (5 g, 25 mmol), KI (2 g) and K2CO3 (7 g, 50 mmol) in DMF (100 mL) was added 1-chloromethyl-4-fluoro-benzene (3.96 g, 28 mmol). The mixture was heated at 140° C. for 2 h, then cooled to room temperature, partitioned between water and ethyl acetate. The organic layer was washed with water for 3 times, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give the title compound (4.5 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CI.[H-].[Na+].[CH3:23]COC(C)=O>C1COCC1.O>[C:1]([O:5][C:6](=[O:18])[N:7]([C:8]1([C:11]2[CH:12]=[CH:13][C:14]([I:17])=[CH:15][CH:16]=2)[CH2:9][CH2:10]1)[CH3:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(I)cc2)CC1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1(c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Part A. 1-(4-Iodophenyl)cyclopropyl-carbamic acid tert-butyl ester (2.14 g, 5.85 mmol) was stirred in THF (20 mL) at 0° C. under N2. MeI (3 mL) was added followed by portionwise addition of NaH (2.34 g, 5 eq). The reaction was stirred at rt overnight. Several drops of H2O and EtOAc (20 mL) were added to quench the reaction. The organic solvent was evaporated, and H2O was added. It was extracted with Et2O (2×), washed with brine, dried over MgSO4, and concentrated to dryness. The residue was purified by FCC (silica gel, CH2Cl2:hexanes=0:1 to 1:1 to 1:0) to give pure [1-(4-iodophenyl)cyclopropyl]-methyl-carbamic acid tert-butyl ester as a white solid (2.07 g, yield 95%). LC/MS (ESI+) 373.8 (M+H), tR=2.95 min (10–90% CH3CN in H2O in a 4-min run).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:8]1[CH:12]=[CH:11][CH:10]=[N:9]1>C(#N)C>[C:2]1([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1cn[nH]c1
Reactant: Brc1ccccc1
Solvent: CC#N
Product: c1ccc(-n2cccn2)cc1

Procedure:
Operating protocol A (82° C., 24 hours) was followed using 120.8 mg of Chxn-Thio-Al (0.4 mmoles), 211 μl of bromobenzene (2 mmoles), 204 mg of pyrazole (3 mmoles) and 1.2 ml of acetonitrile.
Reaction SMILES: CN(CC1C=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)C.[CH2:20]([CH:24]([C:40]([O:42][CH:43]1[CH2:48][C:47]([CH3:50])([CH3:49])[N:46]([O:51][CH3:52])[C:45]([CH3:54])([CH3:53])[CH2:44]1)=[O:41])[C:25]([O:27][CH:28]1[CH2:33][C:32]([CH3:35])([CH3:34])[N:31]([O:36][CH3:37])[C:30]([CH3:39])([CH3:38])[CH2:29]1)=[O:26])[CH2:21][CH2:22][CH3:23].[NH2-].[Li+].O1C[CH2:60][CH2:59][CH2:58]1>C(OCC)(=O)C.O>[C:16]([C:7]1[CH:6]=[C:59]([CH:58]=[C:9]([C:11]([CH3:13])([CH3:14])[CH3:12])[C:8]=1[OH:15])[CH2:60][C:24]([CH2:20][CH2:21][CH2:22][CH3:23])([C:40]([O:42][CH:43]1[CH2:44][C:45]([CH3:53])([CH3:54])[N:46]([O:51][CH3:52])[C:47]([CH3:50])([CH3:49])[CH2:48]1)=[O:41])[C:25]([O:27][CH:28]1[CH2:29][C:30]([CH3:39])([CH3:38])[N:31]([O:36][CH3:37])[C:32]([CH3:34])([CH3:35])[CH2:33]1)=[O:26])([CH3:17])([CH3:18])[CH3:19]
Reactant: C1CCOC1
Reactant: CN(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCCCC(C(=O)OC1CC(C)(C)N(OC)C(C)(C)C1)C(=O)OC1CC(C)(C)N(OC)C(C)(C)C1
Agent: [Li+]
Agent: [NH2-]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCC(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)(C(=O)OC1CC(C)(C)N(OC)C(C)(C)C1)C(=O)OC1CC(C)(C)N(OC)C(C)(C)C1
Yield: 55 %

Procedure:
A mixture of 11.9 g (45.2 mmol) of N,N-dimethyl-3,5-di-t-butyl-4-hydroxybenzylamine, 18.8 g (37.7 mmol) of di-(1-methoxy-2,2,6,6-tetramethylpiperidin-4-yl) n-butylmalonate, 173 mg of lithium amide, and 100 ml of tetrahydrofuran is refluxed for 90 minutes. The reaction mixture is diluted with ethyl acetate (350 ml). The organic solution is washed with 1N HCl (2×100 ml), water (2×250 ml), and saturated NaHCO3 solution (250 ml), then dried over magnesium sulfate and evaporated to obtain a brown oil. Crystallization from 9:1 methanol:water affords 14.9 g (55% yield) of a white solid (mp 111°-13° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=2)[C@H:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1COCC1.[Li+].[OH-].Cl>O.CO>[CH3:1][C:2]1([CH3:24])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[C@H:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(N2C(=O)OC(C)(C)[C@@H]2c2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)OC(=O)N(c2ccc(C(=O)O)cc2)[C@H]1c1ccccc1
Temperature: 50 °C
Yield: 48.4 %

Procedure:
To a flask charged with (S)-methyl 4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)benzoate (2.70 g, 8.30 mmol) were added THF (48.5 mL), MeOH (48.5 mL) and water (48.5 mL) respectively. To the resulting turbid solution was added LiOH (0.994 g, 41.5 mmol), and the resulting mixture was heated at 50° C. overnight. The resulting mixture was cooled in an ice water bath and brought to pH˜2 by the addition of 2N HCl (˜15 mL) leading to a light yellow solution to which water was added (˜100 mL). This lead to the formation of a white precipitate which was collected by vacuum filtration and washed with excess water. After drying under high vacuum overnight, (S)-4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)benzoic acid (1.25 g, 4.02 mmol, 48.4% yield) was obtained as a white solid. NMR indicated that the product formed as a THF adduct with a 3:2 product to THF ratio. 1H NMR (400 MHz, DMSO-d6) δ=12.76 (br. s., 1H), 7.87-7.81 (m, 2H), 7.63-7.57 (m, 2H), 7.41-7.34 (m, 2H), 7.34-7.30 (m, 1H), 7.30-7.19 (m, 2H), 5.51 (s, 1H), 1.63 (s, 3H), 0.91 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[N:6][CH:7]=1.C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[CH3:17][N:18]([CH3:20])[CH:19]=[C:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)Cc1cncc(Br)c1
Reactant: CCOC(OCC)N(C)C
Product: CCOC(=O)C(=CN(C)C)c1cncc(Br)c1

Procedure:
5.1 g (20.9 mmol) of the compound from Example 10A are stirred in 7.2 ml (6.2 g, 41.8 mmol) of dimethylformamide diethyl acetal at a bath temperature of 100° C. for 16 h. After cooling, the mixture is concentrated under reduced pressure, the residue is stirred in diisopropyl ether, and the solid is filtered off and finally washed with diisopropyl ether. The crude product is dried under reduced pressure for 16 h.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].O=S(Cl)Cl.[CH3:18]O>>[CH3:18][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=[C:2]([I:1])[CH:3]=1
Reactant: O=C(O)c1cc(I)cc([N+](=O)[O-])c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(I)cc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 99 %

Procedure:
To a solution of 3-iodo-5-nitrobenzoic acid (20.00 g, 0.068 mol) in methanol (50 mL) was added SOCl2 (5.45 mL, 0.075 mol) at 0° C. The reaction mixture was allowed to warm to room temperature and was then heated to reflux for 2 hours. The reaction was cooled and solvent was removed in vacuo to afford 3-Iodo-5-nitro-benzoic acid methyl ester as light yellow solid (20.67 g, 99%). MS (M+H)=309.
Reaction SMILES: [B].O1[CH2:7][CH2:6][CH2:5]OO1.[C:8]1([CH3:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:5]=[CH:6][C:7]1[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=1.[CH2:14]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:5]
Reactant: Cc1ccccc1
Reactant: C1COOOC1
Agent: [B]
Product: C=Cc1ccccc1
Product: CCc1ccccc1

Procedure:
The results indicate the boron-containing catalyst was successfully used for reacting trioxane and toluene to form styrene and ethylbenzene. The trioxane utilized was s-trioxane, m.p. 58°-60° C., mol. wt. 90.08.
Reaction SMILES: C(O[C:4]([N:6]1[CH2:11][CH2:10][C:9]2[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:13]=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[C:8]=2[CH2:7]1)=O)C.C(OC(N1CCC(=O)CC1)=O)C.C(N)C1C=CC=CC=1.ClC1C=CC(C=C[N+]([O-])=O)=CC=1>C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:22]([N:12]1[C:9]2[CH2:10][CH2:11][N:6]([CH3:4])[CH2:7][C:8]=2[C:14]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[CH:13]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)N1CCc2c(c(-c3ccc(Cl)cc3)cn2Cc2ccccc2)C1
Agent: CCOC(=O)N1CCC(=O)CC1
Agent: O=[N+]([O-])C=Cc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: NCc1ccccc1
Solvent: c1ccccc1
Product: CN1CCc2c(c(-c3ccc(Cl)cc3)cn2Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1-Benzyl-3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid ethyl ester. To a stirred solution of 3.0 g of 4-oxo-piperidine-1-carboxylic acid ethyl ester in benzene (35 mL) was added 1.91 mL of benzylamine. The mixture was heated at reflux for 24 h using a Dean-Stark apparatus. The solvent was removed to give a pale yellow oil. A portion of the crude product (0.50 g) was dissolved in toluene (4 mL) and 0.35 g of 1-chloro-4-(2-nitro-vinyl)-benzene was added, followed by 0.7 g of 4 Å molecular sieves. The resulting mixture was stirred for 12 h at RT. The mixture was then filtered through diatomaceous earth and the filtrate was washed with satd. aq. NH4Cl (3×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography on SiO2 (8% EtOAc/hexanes) afforded 0.25 g the title compound. TLC (SiO2, 25% EtOAc/hexanes): Rf=0.34. MS (ESI): exact mass calculated for C23H23ClN2O2, 394.14. found, m/z 395.2 [M+H]+, 397.2 [M+H]+, 417.1 [M+Na]+.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.[NH2:21][C:22]1[CH:33]=[CH:32][C:25]2[N:26]([CH3:31])[C:27](=[O:30])[CH2:28][O:29][C:24]=2[CH:23]=1>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:21][C:22]3[CH:33]=[CH:32][C:25]4[N:26]([CH3:31])[C:27](=[O:30])[CH2:28][O:29][C:24]=4[CH:23]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: CN1C(=O)COc2cc(N)ccc21
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc4c(c3)OCC(=O)N4C)nn12

Procedure:
The titled compound was prepared in analogous fashion as Example 113 using 2-methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine and 7-amino-4-methyl-4H-benzo[1,4]oxazin-3-one to give 7-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-4-methyl-4H-benzo[1,4]oxazin-3-one as a pale yellow foam. LCMS (E/I+) 402 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 7.75 (dd, 1H, J=1.5, 7.5 Hz), 7.64 (s, 1H), 7.41 (td, 1H, J=2, 8.2 Hz), 7.05 (m, 2H), 6.94 (d, 1H, J=4.6 Hz), 6.86 (m, 4H), 4.55 (s, 2H), 2.79 (s, 3H), 2.89 (s, 3H).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].[I-].[Na+].Cl[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:14]([CH2:41][CH2:42][CH3:43])[N:15]=[C:16]2[C:25]=1[C:24]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:18]=[C:17]2[N:26]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>CN(C=O)C>[C:1]([O:4][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:14]([CH2:41][CH2:42][CH3:43])[N:15]=[C:16]2[C:25]=1[C:24]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:18]=[C:17]2[N:26]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3ccccc3c2c1CCCCCl
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3ccccc3c2c1CCCCOC(C)=O
Temperature: 90 °C
Yield: 77.1 %

Procedure:
Potassium acetate (0.83 g, 8.432 mmol) and sodium iodide (16 g, 1.05 mmol) was added to a solution of di(tert-butyl) 1-(4-chlorobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate (2.18 g, 4.22 mmol) in DMF (15 mL). The reaction mixture was heated at 90° C. under a nitrogen atmosphere for 4.5 hours. The reaction was allowed to cool to ambient temperature and the volatiles were removed under reduced pressure. The resulting oil was partitioned between ethyl acetate and water. The organic layer was isolated and washed with water (2×25 mL) and brine (3×20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield an oil that was dried under vacuum to provide 1.76 g of 4-{4-[bis(tert-butoxycarbonyl)amino]-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl}butyl acetate.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[F:19][C:20]1([F:26])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:24][CH2:25][C:20]([F:26])([F:19])[CH2:21][CH2:22]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: FC1(F)CCNCC1
Solvent: CO
Product: Fc1ccc(C2CCc3c2nc(Cl)nc3N2CCC(F)(F)CC2)cc1
Temperature: 25 °C
Yield: 69.2 %

Procedure:
To a solution of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (90 mg, 0.318 mmol) in MeOH (3179 μL), 4,4-difluoropiperidine (115 mg, 0.95 mmol) was added. The reaction was allowed to stir at rt. When the reaction was complete, removed solvent and applied residue to Silica gel. Eluted with EtOAc/Hex to afford the desired 2-chloro-4-(4,4-difluoropiperidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (80.8 mg, 0.220 mmol, 69.1% yield). LC-MS (M+H)+=368.0.
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26]2[N:31]=[CH:30][C:29](Br)=[CH:28][N:27]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[CH3:34][O:35][CH:36]1[CH2:40][CH2:39][NH:38][CH2:37]1.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>ClCCl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[CH2:19]([N:18]([C:26]1[N:31]=[CH:30][C:29]([N:38]2[CH2:39][CH2:40][CH:36]([O:35][CH3:34])[CH2:37]2)=[CH:28][N:27]=1)[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:5])=[O:33])[S:12][CH:13]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(Br)cn1
Reactant: COC1CCNC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(N2CCC(OC)C2)cn1

Procedure:
The compound obtained using 2-[(4-{2-[(5-bromopyrimidin-2-yl)(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 442-1 and 3-methoxypyrrolidine as starting materials and by an operation similar to that of Example 442-2 was treated with dichloromethane and trifluoroacetic acid. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=10:1) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]([OH:26])=O)[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C([N:48]3[CH2:53][CH2:52][NH:51][C:50](=[O:54])[CH2:49]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]([N:48]3[CH2:53][CH2:52][NH:51][C:50](=[O:54])[CH2:49]3)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:11])([F:10])[F:12])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccnc3)n2)CCN1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3cc(Br)cc(OC(F)(F)F)c3)n(-c3cccnc3)n2)CCN1

Procedure:
75 mg (0.16 mmol) of the compound of Example 39A is reacted analogously to the synthesis of the compound of Example 4 with 17 mg (0.17 mmol) of 2-oxopiperazine. 21 mg (25% of theory) of the title compound is obtained as a fine precipitate as well as 37 mg (46% of theory) of the title compound after the filtrate is purified by means of preparative HPLC (mobile solvent: acetonitrile/water gradient).
Reaction SMILES: [CH3:1][CH:2]([NH:9][CH2:10][CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O=[Sb:13]O[Sb]=O.CCCCCC.[C:23](=[S:25])=[S:24]>O>[CH3:1][CH:2]([N:9]([CH2:10][CH3:11])[C:23](=[S:24])[S-:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Sb+3:13].[CH3:1][CH:2]([N:9]([CH2:10][CH3:11])[C:23](=[S:24])[S-:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:1][CH:2]([N:9]([CH2:10][CH3:11])[C:23](=[S:24])[S-:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: S=C=S
Reactant: CCCCCCC(C)NCC
Reactant: O=[Sb]O[Sb]=O
Solvent: CCCCCC
Solvent: O
Product: CCCCCCC(C)N(CC)C(=S)[S-]
Product: [Sb+3]
Temperature: 68 °C

Procedure:
In a 3-liter, three-neck, round-bottom flask equipped with a stirrer, thermometer, dropping funnel and condenser was placed 157 g. (grams) (1.0 mole) of N-(2-octyl)-N-ethylamine, 49 g. (0.168 mole) of antimony trioxide and 1000 ml. (milliliters) of hexane. The stirred mixture was heated to reflux (68°C.) and 80 g. (1.05 moles) of carbon disulfide was added over a period of 1 hour. The mixture was stirred at reflux for an additional 3 hours, and then the water generated during the reaction was azeotroped off (9 ml.). The mixture was filtered hot in order to remove any unreacted antimony oxide. The hexane solution was cooled to room temperature and the hexane was then removed at reduced pressure. A viscous oil was isolated having an Index of refraction ND22 =1.627.