Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][OH:12])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:20][C:21]([C:23]1[CH:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:41])[F:40])[C:31]2[C:26](=[CH:27][CH:28]=[N:29][C:30]=2[O:43][CH:44]([CH3:46])[CH3:45])[NH:25][C:24]=1[CH3:47])=O)C1C=CC=CC=1.C(O)(=O)/C=C/C(O)=O.ClCCl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:9][N:8]([CH2:10][CH2:11][O:12][C:21]([C:23]1[CH:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:41])[F:40])[C:31]2[C:26](=[CH:27][CH:28]=[N:29][C:30]=2[O:43][CH:44]([CH3:45])[CH3:46])[NH:25][C:24]=1[CH3:47])=[O:20])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCO)Cc1ccccc1
Reactant: CC1=C(C(=O)OCc2ccccc2)C(c2ccccc2C(F)(F)F)c2c(ccnc2OC(C)C)N1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC1=C(C(=O)OCCN(C)Cc2ccccc2)C(c2ccccc2C(F)(F)F)c2c(ccnc2OC(C)C)N1

Procedure:
To a solution of 21.05 g 2-(N-benzyl-N-methylamino)-ethanol in 42 mL toluene are added under nitrogen 0.74 g sodium hydride (80%). After stirring for 30 minites a solution of 8.42 g (0.0174 mole) (-)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylic acid benzyl ester is added dropwise. The reaction mixture is stirred under nitrogen and the exclusion of moisture for 4 hours by heating to boiling temperature under reflux. The reaction mixture is subsequently extracted with 2×50 mL 2N acetic acid. The reaction mixture is subsequently dried over sodium sulfate and evaporated to dryness. The residue is purified over silica gel with toluene:ethyl acetate (7:3) as elution agent. After distilling off the elution agent there is obtained an oily product. The oil is dissolved with 1.28 g fumaric acid in 180 mL ethyl acetate under heating to reflux temperature. After filtration the reaction mixture is evaporated to about 20 mL. The precipitated product is filtered off with suction, dispersed in 14 mL toluene and stirred with 3 mL 1M aqueous ammonium hydroxide solution. The toluene phase is washed with 2×5 mL of water. The organic phase is after drying over sodium sulfate evaporated to dryness. There is obtained an oily product, yield 0.8 g (8.5% of theory); [α]D =-40.8° (c=1/dichloromethane).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[O:13])[CH:6]=1.CCCCCC.C(OCC)(=O)C>CO.[C].[Pd]>[NH2:31][C:29]1[CH:28]=[CH:27][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3F)ccn2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.1 %

Procedure:
To a solution of a crude product of t-butyl 4-[4-(2-fluoro-4-nitrophenoxy)pyridin-2-ylcarbamoyl]piperidine-1-carboxylate (548 mg) in methanol (50 ml) was added 10% palladium carbon (100 mg), followed by stirring under a hydrogen atmosphere at room temperature for 2 hrs. The catalyst was filtered. The filtrate was concentrated under a reduced pressure to give a residue, which was then subjected to silica gel column chromatography (Fuji Silysia BW-300, eluent; hexane:ethyl acetate=1:1 to 1:2, then ethyl acetate) to provide a mixture of the starting material and the target compound. The mixture was dissolved in methanol (50 ml) again, and then 10% palladium carbon (100 mg) was added thereto, followed by stirring under a hydrogen atmosphere at room temperature for 2 hrs. The catalyst was filtered. The filtrate was concentrated under a reduced pressure to give a residue, which was then filtered by silica gel. The filtrate was concentrate under a reduced pressure to provide the titled compound (185 mg) as a yellow oil.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]([O:15][C:16](=[O:33])[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22](B2OCC(C)(C)CO2)=[CH:21][N:20]=1)([CH3:14])([CH3:13])[CH3:12].COC1C=CC2N=C(C3C=NC(N)=NC=3)SC=2C=1>>[C:11]([O:15][C:16](=[O:33])[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[S:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:21][N:20]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC1(C)COB(c2ccc(CNC(=O)OC(C)(C)C)nc2)OC1
Reactant: Clc1nc2ccccc2s1
Agent: COc1ccc2nc(-c3cnc(N)nc3)sc2c1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc3ccccc3s2)cn1
Reaction time: 1 h
Yield: 62.1 %

Procedure:
2-Chlorobenzothiazole (31 μL, 0.25 mmol) and tert-butyl[5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)pyridin-2-yl]methylcarbamate (80 mg, 0.25 mmol) were reacted according to the procedure used for the preparation of 5-(6-methoxy-1,3-benzothiazol-2-yl)pyrimidin-2-amine. After 1 h at 80° C., the mixture was concentrated under reduced pressure and the residue was partitioned between DCM and H2O. The organic phase was concentrated. Flash chromatography (Heptane/EtOAc gradient) gave the product (53 mg) as a white solid. MS m/z (M+H) 342.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([C:28]([O:30]C)=[O:29])=[CH:8][CH:9]=[C:10]([C:11]3[CH2:15][C:14]([C:20]4[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=4)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=3)[C:5]=2[N:4]=[N:3]1.[OH-].[Li+]>O1CCCC1.O>[CH3:1][N:2]1[C:6]2[C:7]([C:28]([OH:30])=[O:29])=[CH:8][CH:9]=[C:10]([C:11]3[CH2:15][C:14]([C:20]4[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=4)([C:16]([F:19])([F:17])[F:18])[O:13][N:12]=3)[C:5]=2[N:4]=[N:3]1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2nnn(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1nnc2c(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)ccc(C(=O)O)c21

Procedure:
A solution of 3-methyl-4-methoxycarbonyl-7-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzotriazole (0.1 g), lithiumhydroxide (11 mg) in tetrahydrofuran (10 ml) and water (5 ml) was stirred for 30 minutes. Tetrahydrofuran was removed and extracted with ethyl acetate (3×5 ml). The combined organic layers were dried over sodium sulfate and concentrated to give 3-methyl-7-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzotriazole-4-carboxylic acid. 1H-NMR (400 MHz, DMSO): 7.80 (t, 1H), 7.73 (d, 1H), 7.69 (d, 1H), 7.62 (d, 1H), 4.74 (bd, 1H), 4.50 (s, 3H), 4.46 (bd, 1H). LC-MS: m/z=458.98 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].[CH3:8][C:9]([CH3:29])([O:11][C:12]([NH:14][C@@H:15]([C:19](ON1C(=O)CCC1=O)=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:5][CH2:4][C:3]([CH3:7])([CH3:6])[CH2:2][NH:1][C:19]([C@@H:15]([NH:14][C:12](=[O:13])[O:11][C:9]([CH3:8])([CH3:29])[CH3:10])[CH:16]([CH3:18])[CH3:17])=[O:20]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)(CN)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(C)(C)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A solution of commercial 3-amino-2,2-dimethyl-1-propanol (1.7 g, 16.5 mmol), N-[(1,1-dimethylethoxy)carbonyl]-D-Valine, 2,5-dioxo-1-pyrrolidinyl ester (Giuntini F. et al., J. Med. Chem. (2009), 52(13), 4026-4037, incorporated herein by reference) (4.7 g, 15.0 mmol) and 1M aqueous potassium carbonate (10 mL, 10.0 mmol) in acetonitrile (30 mL) was stirred at room temperature for 2 h. The mixture was concentrated to about one third of its volume, diluted with 1M hydrochloric acid and extracted three times with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered and the filtrate evaporated to a residue. The crude product was purified by silica gel chromatography using hexane/ethyl acetate (50:50) to isolate 4 g (88% yield) of tert-butyl N-[(1S)-1-[(3-hydroxy-2,2-dimethyl-propyl)carbamoyl]-2-methyl-propyl]carbamate.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:14]2[C:9](=[C:10]([NH:15][C:16](=[O:25])[C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[CH2:26][CH3:27])([OH:3])=[O:2].[C:28](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Cl:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([Cl:23])[C:17]=1[C:16]([NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[CH:7][C:6]([CH2:26][CH3:27])=[C:5]2[CH2:4][C:1]([O:3][CH3:28])=[O:2])=[O:25]
Reactant: O=C([O-])[O-]
Reactant: CCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CC(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CC(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
To a solution of 4-carboxymethyl-8-(2,6-dichlorobenzoylamino)-3-ethylquinoline (405 mg) in dimethylformamide were added potassium carbonate (305 mg) and methyl iodide (314 mg) and the mixture was stirred for 2 hours at ambient temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate: n-hexane, 1:3, v/v) and crystallized from ethanol-water to give 8-(2,6-dichlorobenzoylamino)-3-ethyl-4-(methoxycarbonylmethyl)quinoline (282 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:13])[CH:10]=[C:9]([CH3:11])[CH2:8][CH2:7][CH:6]([OH:12])[CH2:5]1.I[CH2:15][CH3:16]>C1(C)C=CC=CC=1>[CH2:15]([O:12][C:6]1[CH2:7][CH2:8][CH:9]([CH3:11])[CH2:10][C:4]([CH3:13])([CH3:3])[CH:5]=1)[CH3:16]
Reactant: CC1=CC(C)(C)CC(O)CC1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC1=CC(C)(C)CC(C)CC1
Temperature: 72 °C

Procedure:
Sodium hydride (60% in mineral oil) (5.4 gm) was added to 60 gm toluene in a reaction flask and stirred under nitrogen. 3,3,5-Trimethyl-4-cyclohepten-1-ol (15.4 gm) was added over 10 minutes at room temperature and stirred for 25 minutes. Iodoethane (23.4 gm) was next added over five minutes. The reaction was heated to 72° C. over 1.5 hours and then four hours at 112° C. The crude oil was washed once with 50 mL saturated sodium bicarbonate solution and distilled through a short Vigreux column. A heart cut fraction, 3,3,5-trimethyl-cyclohepten-1-yl ethyl ether, was obtained that weighed 14.9 gm and had a boiling point of 89° C. at 10 mm pressure. Its GC purity was 94%. The fraction was evaluated for its odor quality and characterized as having fresh diffusive citrus lime notes as well as fruity-peach/prune-rose floral.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:17]2[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[N:18]=2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C([Sn](CCCC)(CCCC)[C:82]1[CH:87]=[CH:86][CH:85]=[CH:84][N:83]=1)CCC>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:24]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:19]2[N:20]=[C:21]([CH3:23])[N:22]=[C:17]([C:4]3[CH:3]=[C:2]([C:82]4[CH:87]=[CH:86][CH:85]=[CH:84][N:83]=4)[CH:7]=[N:6][C:5]=3[NH:8][C:9]3[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)[N:18]=2)=[CH:27][CH:28]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(-c4ccccn4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 110 °C

Procedure:
A mixture of 4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.100 g, 0.171 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (4.08 mg, 8.56 μmol), tris(dibenzylideneacetone)dipalladium(0) (7.84 mg, 8.56 μmol) and 2-(tributylstannyl)pyridine (0.082 g, 0.223 mmol) (Alfa Aesar) was purged with argon and toluene (0.9 mL) was added. The tube was sealed and the mixture was heated at 110° C. The reaction mixture was cooled to room temperature, treated with water, extracted with DCM (2×15 mL), dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography using an ISCO Combiflash Companion (12 g column, 20-50% EtOAc in hexanes over 30 min; product eluted with about 30-35% EtOAc). 1H NMR (400 MHz, CDCl3) δ 11.82 (s, 1H); 9.41 (d, J=2.5 Hz, 1H); 8.93 (d, J=2.3 Hz, 1H); 8.66 (d, J=4.9 Hz, 1H); 8.30 (d, J=2.7 Hz, 1H); 7.93 (dd, J=8.9, 2.6 Hz, 1H); 7.67-7.75 (m, 1H); 7.59-7.65 (m, 1H); 7.15-7.24 (m, 5H); 6.85 (dd, J=20.0, 8.6 Hz, 4H); 6.72 (d, J=8.8 Hz, 1H); 4.87 (d, J=17.2 Hz, 4H); 3.94 (s, 3H); 3.81 (s, 3H); 3.76 (s, 3H); 2.59 (s, 3H). m/z (ESI, +ve ion) 627.0 (M+H)+.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:27][C:28](=[O:39])[NH:29][C@@H:30]1[CH2:35][CH2:34][C@@H:33]([CH2:36][CH2:37][OH:38])[O:32][CH2:31]1)([CH3:26])([CH3:25])[CH3:24].S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(OCC)(=O)C.CCCCCC>[C:23]([O:27][C:28](=[O:39])[NH:29][C@@H:30]1[CH2:35][CH2:34][C@@H:33]([CH2:36][CH:37]=[O:38])[O:32][CH2:31]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](CCO)OC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](CC=O)OC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
Dess-Martin periodinane (162 mg, 0.38 mmol, 2.0 eq) is added dropwise at 0° C. to a stirred solution of (3R,6S)-[6-(2-hydroxy-ethyl)-tetrahydro-pyran-3-yl]-carbamic acid tert-butyl ester (47 mg, 0.19 mmol, 1.0 eq) in dichloromethane (3 mL). The reaction mixture is stirred 0° C. for 30 minutes then at room temperature for 1 hour. Then a saturated sodium thiosulfate aqueous solution (2 mL) is added, followed by a saturated sodium hydrogen carbonate aqueous solution (2 mL). The resulting mixture is stirred for 30 minutes and extracted with dichloromethane (3×10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: n-hexane:ethyl acetate, 10:1 to 1:1, v/v) to afford (3R,6S)-[6-(2-oxo-ethyl)-tetrahydro-pyran-3-yl]-carbamic acid tert-butyl ester as a white solid (20 mg, 43% yield).
Reaction SMILES: [CH3:1][N:2]1[C:19](=O)[C:18](=O)[N:5]2[C:6]3[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=3[CH2:8][N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[CH:4]2[CH2:3]1.B#B.C(O)(=O)C.O>O1CCCC1>[CH3:1][N:2]1[CH2:19][CH2:18][N:5]2[C:6]3[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=3[CH2:8][N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[CH:4]2[CH2:3]1
Reactant: CN1CC2c3cccn3Cc3ccccc3N2C(=O)C1=O
Agent: B#B
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN2c3ccccc3Cn3cccc3C2C1

Procedure:
348 g of 2-methyl-3,4-dioxo-1,2,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine are added portionwise over 1 hour to 4,500 ml of tetrahydrofuran and 7,410 ml of 1-molar diborane in tetrahydrofuran while cooling with ice to 18° and stirring under nitrogen. The mixture is refluxed for 24 hours, again cooled to 5° and combined with 1,200 ml of glacial acetic acid followed by 900 ml of water. The solution is refluxed for 24 hours, evaporated and the residue taken up in 10,500 ml of methanol. The solution is again refluxed for 2 hours, evaporated, the residue dissolved in 3,000 ml of water and the pH of the solution adjusted to 14 with 1,200 ml of1% aqueous sodium hydroxide. The mixture is extracted with diethyl ether, the extract dried, filtered and evaporated to yield the 2-methyl-1,2,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4 ]benzodiazepine melting at 98°-100°.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:7]1([CH:14]=[CH:13][CH:12]=[C:10]([OH:11])[CH:9]=1)[OH:8].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:2]([O:8][C:7]1[CH:9]=[C:10]([OH:11])[CH:12]=[CH:13][CH:14]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCBr
Reactant: Oc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOc1cccc(O)c1

Procedure:
A mixture of 24.8 ml of 1-Bromopentane, 66.0 g of resorcinol, and 41.5 g of potassium carbonate is stirred in 400 ml of anhydrous dimethylformamide at 60° C. for 17 hours. This mixture is filtered through Celite and concentrated under vacuum. The residue is taken up in water and extracted 3 times with ether. The combined extracts are washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue is flash chromatographed on normal phase silica gel eluting with a 4:1 ratio of hexane:ether to yield 3-pentyloxyphenol as a clear oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@:11]2([OH:18])[C:13](=O)[NH:14][C:15](=O)[C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:12][C@:11]2([OH:18])[C@@H:10]([CH2:15][NH:14][CH2:13]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)[C@@]2(O)CN(Cc3ccccc3)C[C@@H]12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O[C@]12CNC[C@H]1CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a stirred solution of (cis)-5-benzyl-3a-hydroxytetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (450 mg, 1.83 mmol) in THF (9 mL) under nitrogen, was added LAH (9.42 mL, 1.0 M in diethyl ether) to form a white suspension. The resulting mixture was stirred at ambient temperature for 21 hrs. The reaction mixture was cooled to 0° C. and quenched by the addition of water (0.3 mL), 15% NaOH (0.3 mL) and water (0.9 mL), as described by Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis Vol. 1, Wiley, New York 1967, pp 581-595. The mixture was filtered and the precipitate washed with EtOAc (60 mL). The filtrates were combined and concentrated with toluene to give the crude title compound as a clear oil that was carried forward to the next step without further purification. m/z (APCI+) for C13H18N2O 219.2 (M+H)+.
Reaction SMILES: C([O:5][C:6](=O)[N:7]([CH2:9][CH2:10][O:11][CH2:12][CH3:13])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O.[Cl:22][CH2:23]Cl>>[Cl:22][CH2:23][C:6]([N:7]([CH2:9][CH2:10][O:11][CH2:12][CH3:13])[CH3:8])=[O:5]
Reactant: CCOCCN(C)C(=O)OC(C)(C)C
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOCCN(C)C(=O)CCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl(2-ethoxyethyl)methylcarbamate (1.2 g) in dichloromethane (6 ml) was added trifluoroacetic acid (6 ml) on an ice bath. The solution was stirred for 30 minutes while warming to room temperature, then the solvent was evaporated in vacuo. Synthesized from the resulting (2-ethoxyethyl)methylamine trifluoroacetate (crude product) (2.3 g) according to an analogous synthetic method to Preparation Example 119, the title compound (799 mg) was obtained.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([C:7]#[N:8])=[CH:3][CH:2]=1.C[Si]([N-:14][Si](C)(C)C)(C)C.[Li+].[ClH:20]>C(OCC)C>[ClH:20].[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([C:7]([NH2:14])=[NH:8])=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cc1ccc(C#N)cc1
Agent: Cl
Agent: [Li+]
Solvent: CCOCC
Product: Cc1ccc(C(=N)N)cc1
Reaction time: 2 h

Procedure:
To a solution of 12.4 g p-tolunitrile in 500 mL of diethyl ether was added 23 g of solid lithium bis(trimethylsilyl)amide at ambient temperature. The mixture was stirred for 2 hours then hydrolysed with 10% HCl at 0° C. The mixture was stirred for an additional 30 minutes and then concentrated to dryness to yield 6 g of 4-methylbenzamidine hydrochloride which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[C:37][CH2:38][CH2:39][CH2:40]I)=[CH:32][CH:31]=1>CN(C=O)C>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH:37]([C:12]2([S:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:10])=[O:11])[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])[CH2:38][CH2:39][CH3:40])=[CH:32][CH:31]=1
Reactant: Clc1ccc(C#CCCCI)cc1
Reactant: COc1ccc(S(=O)(=O)C2SC(=O)NC2=O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(Cc1ccc(Cl)cc1)C1(S(=O)(=O)c2ccc(OC)cc2)SC(=O)NC1=O
Reaction time: 0.25 h

Procedure:
To a solution of 5-(4-methoxyphenylsulfonyl)-thiazolidine-2,4-dione [U.S. Pat. No. 5,605,918; February 1997; Wrobel, et al.]((2.74 g, 9.5 mMol) in DMF (50 ml) was added sodium hexamethyldisilazide (1.0 M solution in THF—19.0 ml, 19.0 mmol) at room temperature, under nitrogen, and this was stirred for 15 minutes. To this was added 1-(4-chlorophenyl)-5-iodo-1-pentyne (2.70 g, 9.5 mmol) over 5 minutes, and this solution was stirred overnight at room temperature. The reaction mixture was quenched in water, and the solid that was obtained was recrystallized from methanol to give 1.59 g of the title compound as colorless crystals, m.p. 172-174°; NMR (CDCl3) δ 1.59 (m, 1H); 2.0 (m, 1H); 2.36 (dq (doublet of quartets?), 1H); 2.5 (t, 2H); 2.67 (dq, 1H); 3.88 (s, 3H); 7.0 (d, 2H); 7.26 (s, 4H) 7.86 (d, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:16])[CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[F:26])[CH:21]=O>C1C=CC=CC=1.C([O-])(=O)C.[NH2+]1CCCCC1>[F:17][C:18]1[CH:19]=[C:20]([CH:21]=[C:5]([C:4](=[O:16])[CH2:3][O:2][CH3:1])[C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: COCC(=O)CC(=O)OCc1ccccc1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: COCC(=O)C(=Cc1ccc(F)c(F)c1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.2 %

Procedure:
To a solution of benzyl 4-methoxyacetoacetate (84 g, 0.37 mol), 3,4-difluorobenzaldehyde (52.5 g, 0.0.37 mmol), and piperidinium acetate (1.58 g, 2.63 mmol) in benzene (1L) were added molecular sieves (400 g) and the mixture was stirred at room temperature for 48 h. The molecular sieves were removed by filtration and the solvent was evaporated from the filtrate under reduced pressure. The residue was purified by column chromatography on silica gel using chloroform/ethyl acetate (100:3) to get the product as a white powder (118 g, 91%). The NMR showed this product to be a mixture of cis and trans isomers.
Reaction SMILES: [NH3:1].[ClH:2].[C:3]1([C:9]2([CH2:15][O:16][CH:17]([C:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=3)[C:18]([O:20]C)=O)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[ClH:2].[C:3]1([C:9]2([CH2:15][O:16][CH:17]([C:22]3[CH:23]=[C:24]([C:32]([F:33])([F:34])[F:35])[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=3)[C:18]([NH2:1])=[O:20])[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: N
Reactant: COC(=O)C(OCC1(c2ccccc2)CCNCC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CO
Product: NC(=O)C(OCC1(c2ccccc2)CCNCC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 48 h

Procedure:
Ammonia gas was passed through a solution of the product of Example 9 (0.644 g) in dry methanol (50 ml) at -15° C. until saturated. The reaction flask was sealed with a rubber septum and allowed to stand at room temperature for 48 hours, then solvents were evaporated at reduced pressure. The residue was dissolved in acetonitrile (1 ml) and 2N aqueous hydrochloric acid (2 ml), and the solution freeze dried. The residue was boiled with ethyl acetate, allowed to cool, and the title compound collected by filtration as a colourless solid, mp 146°-148° C. Analysis Calcd. for C22H22F6N2 O2.HCl.H2O: C, 51.32; H, 4.89; N, 5.44; Found: C, 51.28; H, 4.73; N, 5.84%. MS (Cl+) 461 (M+H)+.