Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C1(C)C=CC=CC=1.[CH:10]1([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.Br[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.C(OCC)C.O>[CH:10]1([O:16][C:26]2[C:27]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:23]=[CH:24][CH:25]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: OC1CCCCC1
Reactant: Brc1cccc2ccccc12
Agent: [Pd]
Agent: Cc1ccc(P(c2ccc(C)cc2)c2ccc3ccccc3c2-c2c(P(c3ccc(C)cc3)c3ccc(C)cc3)ccc3ccccc23)cc1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: c1ccc2c(OC3CCCCC3)cccc2c1
Temperature: 70 °C
Yield: 59.5 %

Procedure:
An oven dried Schlenk tube equipped with a teflon coated stir bar was charged with NaH (40 mg, 1.50 mmol), toluene (2 mL) and cyclohexanol (94 μL, 0.90 mmol). The mixture was heated to 70° C. for 10 min under an atmosphere of argon. To this was added 1-bromonaphthalene (104 μL, 0.75 mmol), Pd2 (dba)3 (10.3 mg, 0.0113 mmol), (R)-(+)-2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl (Tol-BINAP) (18.3 mg, 0.027 mmol), and 2 mL of toluene. The mixture was heated to 70° C. for 20 h at which time water (60 mL) and diethyl ether (60 mL) were added. The aqueous layer was separated and extracted with diethyl ether (60 mL). The organics were combined, washed with brine (60 mL) and dried over anhydrous MgSO4. The drying agent was removed by filtration and the mother liquor concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (50:1 hexanes:ethyl acetate) to afford 1-naphthyl cyclohexyl ether (101 mg, 60% yield) as a colorless oil.
Reaction SMILES: [O:1]([CH2:8][CH:9]([OH:30])[CH2:10][NH:11][CH:12]([CH3:29])[CH2:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[NH:22][C:21]2=[O:26])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)[CH:33]=[O:34]>>[O:1]([CH2:8][CH:9]1[O:30][C:33](=[O:34])[N:11]([CH:12]([CH3:29])[CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]([CH2:19][CH:20]3[S:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])=[CH:17][CH:16]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)NCC(O)COc1ccccc1
Reactant: CN(C)C=O
Product: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)N1CC(COc2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
211 mg of N,N'-carbonyldiimidazole were added to a solution of 500 mg of 5-{4-[2-(3-phenoxy-2-hydroxypropylamino)propoxy]benzyl}thiazolidine-2,4-dione (prepared as described in Example 3) in 5 ml of anhydrous dimethylformamide, whilst ice-cooling, and the mixture was then stirred at room temperature for 5 hours. At the end of this time, the dimethylformamide was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the resulting residue, which was then extracted with ethyl acetate. The extract was further washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extract by evaporation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a gradient elution method, with mixtures of ethyl acetate and hexane ranging from 1:1 to 2:1 by volume as the eluent, to give 410 mg of the title compound, melting at 54° C. to 56° C.
Reaction SMILES: [B-]C#N.[Na+].[C:5]([C:7]1[CH:11]=[CH:10][S:9][C:8]=1[CH:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[CH:6].ClCCCl>[I-].[Zn+2].[I-].C(OCC)C>[CH2:12]([C:8]1[S:9][CH:10]=[CH:11][C:7]=1[C:5]#[CH:6])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C#Cc1ccsc1C(O)c1ccccc1
Agent: [B-]C#N
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCCl
Product: C#Cc1ccsc1Cc1ccccc1
Reaction time: 8 h
Yield: 57 %

Procedure:
201 mg of sodium cyanotrihydroborate was added to a mixture of 85.7 mg of 3-ethynyl-2-(α-hydroxybenzyl)thiophene, 192 mg of zinc iodide and 1.5 ml of 1,2-dichloroethane at room temperature, followed by stirring at the same temperature overnight. 5 ml of diethyl ether was added to the reaction solution, followed by filtering through Celite. After the solvent was removed, the residue was subjected to silica gel column chromatography using 2% ethyl acetate/hexane, to give 45.2 mg of the target compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.C1CCN2C(=NCCC2)CC1.[F:32][C:33]1([F:40])[CH2:35][CH:34]1[CH:36]=[CH:37][C:38]#[N:39]>C(#N)C>[F:32][C:33]1([F:40])[CH2:35][CH:34]1[CH:36]([N:15]1[CH:14]=[C:13]([C:11]2[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[N:12]=2)[CH:17]=[N:16]1)[CH2:37][C:38]#[N:39]
Reactant: N#CC=CC1CC1(F)F
Reactant: Cn1cc(-c2cc3nccn3c(-c3cn[nH]c3)n2)cn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C(CC#N)C4CC4(F)F)c3)n2)cn1
Temperature: 50 °C
Reaction time: 24 h
Yield: 54.1 %

Procedure:
To a mixture of 7-(1-methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (200 mg; 0.754 mmol) and DBU (56 μL; 0.37 mmol) in acetonitrile (10 mL) was added 3-(2,2-difluorocyclopropyl)acrylonitrile (0.75 mmol). The mixture was stirred in a sealed vial at 50° C. for 24 hours. Further 3-(2,2-difluorocyclopropyl)acrylonitrile (0.4 mmol) was added and the mixture was stirred for a further 24 hours at 50° C. The solvent was removed under reduced pressure and the material was purified on silica gel, eluting with methylene chloride/6% ammonium hydroxide in methanol (50:1 to 15:1) to give 3-(2,2-difluorocyclopropyl)-3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (160 mg) as a mixture of diastereoisomers. MS (apci) m/z=395.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][N:19]([CH3:27])[CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:24]1[CH2:25][CH2:26][CH:21]([CH2:20][N:19]([CH3:27])[CH3:18])[CH2:22][CH2:23]1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CN(C)CC1CCNCC1
Product: CN(C)CC1CCN(c2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Yield: 56.5 %

Procedure:
Following general procedure B, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (211 mg, 0.680 mmol) was reacted with N,N-dimethyl-1-(piperidin-4-yl)methanamine (97 mg, 0.680 mmol) to afford the desired product (160 mg, 46%) as a yellow glass: ESI MS m/z 417 [C21H26BrN3O+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]=[C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[O:8]2)=[CH:4][C:3]=1[N+:19]([O-])=O.[Cl-].[NH4+]>[Fe].O>[NH2:19][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:2]=1[Cl:1])[CH:6]=[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[O:8]1
Reactant: O=C1OC(=Cc2ccc(Cl)c([N+](=O)[O-])c2)c2ccccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Nc1cc(C=C2OC(=O)c3ccccc32)ccc1Cl
Temperature: 70 °C
Yield: 64.1 %

Procedure:
A stirred mixture of the above crude 3-(4-chloro-3-nitrobenzylidene)-3H-isobenzofuran-1-one (6.2 g), industrial methylated spirit (80 ml), water (60 ml) and ammonium chloride (2.14 g, 0.04 mol) was heated to 70° C., and iron powder (11.2 g, 0.2 gatom) was added in portions. When the addition was complete, the stirred mixture was heated under reflux for a further 2 hours, then it was filtered while hot through Celite. The collected inorganic solids were washed with hot industrial methylated spirit (3×150 ml), then the filtrate and washings were combined and the solvent was removed in vacuo. The residue was triturated with water (60 ml) and the resulting sticky solid was collected by filtration and triturated with industrial methylated spirit (80 ml). The resulting solid was collected by filtration, washed with industrial methylated spirit (2×1 ml) and dried in vacuo for 24 hours to give 3-(3-amino-4-chlorobenzylidene)-3H-isobenzofuran-1-one (3.58 g) as a yellow solid, m.pt. 148–153° C.; m/z (M+H)+. 272/274, 100% purity, which was used directly in the next stage.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[OH:8][C:9]1[C:10]([O:30][CH3:31])=[CH:11][C:12]2[C:21]3[CH:22]=[C:23]4[O:28][CH2:27][O:26][C:24]4=[CH:25][C:20]=3[CH2:19][CH:18]3[C:13]=2[C:14]=1[CH2:15][N:16]([CH3:29])[CH2:17]3.C1(C)C=CC=CC=1.[OH-].C1([N+](C)(C)C)C=CC=CC=1>CN(C)C=O>[CH3:31][O:30][C:10]1[C:9]([O:8][CH3:2])=[C:14]2[CH2:15][N:16]([CH3:29])[CH2:17][CH:18]3[CH2:19][C:20]4[CH:25]=[C:24]5[O:26][CH2:27][O:28][C:23]5=[CH:22][C:21]=4[C:12](=[C:13]23)[CH:11]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc2c3c(c1O)CN(C)CC3Cc1cc3c(cc1-2)OCO3
Agent: C[N+](C)(C)c1ccccc1
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2c3c(c1OC)CN(C)CC3Cc1cc3c(cc1-2)OCO3

Procedure:
10.65 g. (±)-5,6,6a,7-tetrahydro-3-hydroxy-2-methoxy-9,10-methylenedioxy-5-methyl-4H-dibenz(de,g)isoquinoline trifluoroacetate (see Example 1) are dissolved in 500 ml. of a mixture of toluene and dimethyl formamide (9:1) in a manner analogous to that described in Example 7 and methylated with phenyltrimethyl ammonium hydroxide. When the methylation is finished (monitoring with TLC), the reaction mixture is evaporated in a vacuum. After partitioning the residue between water and methylene chloride, working up the organic phase and crystallising from methanol/chloroform, there is obtained (±)-5,6,6a,7-tetrahydro-2,3-dimethoxy-9,10-methylenedioxy-5-methyl-4H-dibenz(de,g)isoquinoline in the form of cream-coloured crystals; m.p. 169°-172° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15](O)[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.S(Cl)([Cl:24])=O.CCCCCC>CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=3[NH:13][C:14](=[O:17])[C:15]=2[Cl:24])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ccc(C2=C(Cl)C(=O)Nc3ccccc3S2)cc1
Yield: 64.8 %

Procedure:
Under a nitrogen blanket, a 2.0 g sample of dl-cis-2-(4-methoxyphenyl)-2,3-dihydro-3-hydroxy-1,5-benzothiazepin-4(5H)-one (6.8 mmol) was refluxed neat with 20 mL of thionyl chloride (27.6 mmol) for approximately 2 hours. Then, 50 mL of hexane and about 20 mL of ether were added, and solid product was filtered off. The solid was dried under vacuum to obtain 1.4 g of 2-(4-methoxyphenyl)-3-chloro-1,5-benzothiazepin-4(5H)-one (66 percent yield of theory).
Reaction SMILES: C(O[C:6](=[O:24])[N:7]([CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)(C)(C)C.[CH2:25]([O:27][C:28](=[O:40])[CH:29](C(OCC)=O)[C:30](OCC)=[O:31])[CH3:26]>>[CH2:25]([O:27][C:28]([C:29]1[C:6](=[O:24])[N:7]([CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[C:30]=1[OH:31])=[O:40])[CH3:26]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2ccccc2c1)n1cccc1
Product: CCOC(=O)c1c(O)c2cccn2n(Cc2ccc3ccccc3c2)c1=O

Procedure:
Prepared according to the thermal cyclization condition used in Example 1 step c) from naphthalen-2-ylmethyl-pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.) and 2-ethoxycarbonyl-malonic acid diethyl ester (3.0 eq.). ESI (m/z): 363 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([C:9]1[NH:10][C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]([C:14]([OH:17])([CH3:16])[CH3:15])[N:13]=1)[CH3:8].[C:23]([N:42]1[C:46]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[C:53]2[CH:60]=[CH:59][C:56]([CH2:57]Br)=[CH:55][CH:54]=2)=[N:45][N:44]=[N:43]1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C(=O)C>[CH2:7]([C:9]1[N:10]([CH2:57][C:56]2[CH:55]=[CH:54][C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=3[C:46]3[N:42]([C:23]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:43]=[N:44][N:45]=3)=[CH:60][CH:59]=2)[C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]([C:14]([OH:17])([CH3:16])[CH3:15])[N:13]=1)[CH3:8]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)c1[nH]c(CC)nc1C(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(C(C)(C)O)nc(CC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.7 %

Procedure:
0.52 g of potassium t-butoxide was added to a solution of 1.00 g of ethyl 2-ethyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate (prepared as described in Preparation 37) in 26 ml of N,N-dimethylacetamide, and the resulting mixture was stirred at room temperature for 10 minutes. A solution of 2.71 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide in 35 ml of N,N-dimethylacetamide was then added dropwise to the resulting solution, after which the reaction mixture was stirred at 50° C. for 4 hours. At the end of this time, the reaction mixture was worked up in a similar manner to that described in Example 18(a), to give 2.01 g of the title compound as crystals, melting at 150°-152° C.
Reaction SMILES: C([Li])(CC)C.CCCCCC.C1CCCCC1.[Cl:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]2[N:25]([Si](C(C)C)(C(C)C)C(C)C)[CH:26]=[CH:27][C:20]=12.CN(C)[CH:40]=[O:41].O1CCOCC1.Cl>O1CCCC1.O>[Cl:18][C:19]1[C:24]([CH:40]=[O:41])=[CH:23][N:22]=[C:21]2[NH:25][CH:26]=[CH:27][C:20]=12
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1COCCO1
Solvent: O
Solvent: CCCCCC
Product: O=Cc1cnc2[nH]ccc2c1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
s-Butyllithium-hexane/cyclohexane solution (1.06 M, 27 mL, 29 mmol) was added to 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (5.74 g, 18.6 mmol) in tetrahydrofuran (50 mL) cooled to −78° C., and the reaction mixture was stirred for 1 hour. The reaction mixture was stirred with N,N-dimethylformamide (7.0 mL, 90 mmol) for another 1 hour and then with 4 M hydrogen chloride-1,4-dioxane solution (20 mL) for 30 minutes, and after addition of water, extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (15 mL) and stirred with trifluoroacetic acid (15 mL) for one day. The reaction mixture was concentrated under reduced pressure, diluted with water and neutralized with saturated aqueous sodium hydrogen carbonate, and the residue was collected by filtration and dried under reduced pressure. The crude product was mixed with ethyl acetate (20 mL) and hexane (20 mL), and the solid was collected by filtration, washed with hexane and dried under reduced pressure to give the title compound as a pale yellow solid (2.72 g, yield 81%).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].Cl[CH2:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[N:13]=[CH:14][N:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[C:25]([F:26])[C:20]=4[C:19](=[O:27])[N:18]([CH3:28])[CH2:17][C:16]=23)[N:8]=1>CN(C)C=O>[CH2:1]([NH:4][CH2:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[N:13]=[CH:14][N:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[C:25]([F:26])[C:20]=4[C:19](=[O:27])[N:18]([CH3:28])[CH2:17][C:16]=23)[N:8]=1)[CH2:2][CH3:3]
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2cccc(F)c2C1=O
Reactant: CCCN
Solvent: CN(C)C=O
Product: CCCNCc1nc(-c2ncn3c2CN(C)C(=O)c2c(F)cccc2-3)no1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.7 %

Procedure:
1 ml (12.2 mmol) of propylamine was added to a suspension of 1.7 g (4.9 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-5-methyl-5,6-dihydro-4H-imidazo-[1,5-a][1,4]benzodiazepin-6-one in 40 ml of N,N-dimethylformamide and the mixture was stirred at room temperature for 12 hours. The solution was evaporated and the residue was partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous solution was extracted with methylene chloride and the organic phases were dried with magnesium sulfate, filtered and evaporated. The residue was chromatographed (silica gel, ethyl acetate/methanol 9:1). There were obtained 1.21 g (67%) of 3-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, Rf=0.22 (silica gel, ethyl acetate/methanol 4:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](OC)=[O:11])=[CH:5][CH:4]=1.CC(C[AlH]CC(C)C)C.CCOCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]=[O:11])=[CH:5][CH:4]=1
Reactant: COC(=O)Cc1ccc(OC)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccc(CC=O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To a stirred solution of methyl 4-methoxyphenylacetate (45.0 g) in toluene (250 ml) cooled to -78° C., add a 1.5M solution of DIBALH in toluene (167 ml) over 5 h, maintaining the reaction temperature at -78° C. Stir for an additional 0.5 h, then pour into 1:1 ice/1M HCl (1500 ml) and Et2O (500 ml). Stir the slurry for 1 h, separate the layers and extract the aq. layer with Et2O (2×500 ml). Wash the combined organic layers with sat'd NaHCO3 (500 ml) and sat'd NaCl, dry (MgSO4), filter and evaporate to give an oil. Perform bulb-to-bulb distillation (100°-130° C., 1 mmHg) to obtain the title compound (33.9 g, 90%) as a colorless liquid. 1H Nmr (CDCl3) δ9.71 (1H, t, J=2.4 Hz), 7.12 (2H, m), 6.89 (2H, m), 3.79 (3H, s) 3.61 (2H, m).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH:5]([N:24]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:2].C(O)C.[ClH:42]>C1COCC1>[ClH:42].[NH2:24][CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:4]([O:3][CH2:1][CH3:2])=[O:38]
Reactant: CCCCCCCCCCCCCCCCCCC(N=C(c1ccccc1)c1ccccc1)C(=O)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCC(N)C(=O)OCC
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a stirred solution of ethyl-N-(diphenylmethylene)-2-aminoeicosanoate prepared as in Example 28A (104 g, 0.200 mol) in a 1:1 mixture (300 ml) of absolute ethanol and THF was added 0.5 N hydrochloric acid (1.0 l) at room temperature over 10 min. The resulting solution was stirred for 30 min. Ethanol and THF were removed in vacuo and the aqueous slurry was extracted with CH2Cl2 (4×1 l). The extracts were combined and dried (MgSO4). The solvent was removed in vacuo and the crude product was recrystallized from hexane to give 74.3 g (95% yield) of colorless needles: mp 91-4° C.; 1H NMR (CDCl3) δ 0.88 (t, J=6.6 Hz, 3 H), 1.26 (m, 33 H), 1.43 (m, 1 H), 1.56 (m, 1 H), 2.03 (quart, J=7.4 Hz, 2 H), 4.03 (m, 1 H), 4.27 (m, 2 H), 8.84 (br s, 3 H).
Reaction SMILES: [Br:1][C:2]1[C:3]([N+:10]([O-])=O)=[CH:4][C:5]([CH3:9])=[N+:6]([O-])[CH:7]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>Cl>[Br:1][C:2]1[C:3]([NH2:10])=[CH:4][C:5]([CH3:9])=[N:6][CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])c(Br)c[n+]1[O-]
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Solvent: O
Product: Cc1cc(N)c(Br)cn1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
To a solution of 5-bromo-2-methyl-4-nitropyridine 1-oxide (2.54 g, 10.9 mmol, 1 eq) in 10 mL concentrated hydrochloric acid was added tin chloride dihydrate (9.96 g, 43.8 mmol, 4.01 eq). The reaction mixture was stirred at 90° C. for 24 hours, and then additional tin chloride dihydrate (3.15 g, 13.8 mmol, 1.27 eq) and 5 mL concentrated hydrochloric acid was added. The reaction mixture was kept at 90° C. for an additional 24 hours, and then cooled to room temperature and adjusted to neutral pH with 2 M aqueous sodium carbonate. The solution was extract three times with dichloromethane, and the combined organic extracts dried over magnesium sulfate and concentrated to give 5-bromo-2-methylpyridin-4-amine LCMS (ESI) m+H=187.2; 1H NMR (400 MHz, DMSO-d6) δ: 8.07 (s, 1H), 6.51 (s, 1H), 6.13 (s, 2H), 2.22 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[BH4-].C([Na])#N.N[C:26]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:27]=1[CH:28]([OH:44])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:30]=1>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][C:26]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:27]=1[CH:28]([OH:44])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2N)c1
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Agent: N#C[Na]
Agent: [BH4-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2Cc2cccc(OCc3ccccc3)c2)c1
Temperature: 25 °C

Procedure:
In methanol (15 ml) were dissolved 2-amino-5-chloro-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol produced in Example 1-(2) (0.6 g) and 3-benzyloxybenzaldehyde (0.38 g). To the solution was added acetic acid (0.12 g). To the mixture was added dropwise, while stirring at room temperature, cyano sodium borohydride (0.13 g). The reaction mixture was stirred for one hour at 60° C., to which was then added water (50 ml), followed by extraction with ethyl acetate (80 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography to give 2-(3-benzyloxybenzyl)-5-chloro-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (0.9 g) as a colorless oily product.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([C:13]#[C:14][CH3:15])=[C:10]([NH2:12])[CH:11]=1)([O-:5])=[O:4].ClC(OCC)=O.[O-]CC.[Na+].C(O)C>CN(C=O)C.C(OCC)(=O)C>[CH3:15][C:14]1[NH:12][C:10]2[C:9]([CH:13]=1)=[CH:8][CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:11]=2
Reactant: CC#Cc1ccc([N+](=O)[O-])cc1N
Agent: CCOC(=O)Cl
Agent: CC[O-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc2ccc([N+](=O)[O-])cc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cool a mixture of sodium hydride (60% dispersion in oil, 0.33 g, 8.19 mmol) in anhydrous DMF to 0° C. under inert atmosphere. Add 5-nitro-2-prop-1-ynyl-phenylamine 17 (1.31 g, 7.44 mmol) in 10 mL DMF and stir 5 minutes. Add ethyl chloroformate (0.78 mL, 8.19 mmol), warm to ambient temperature, and stir 2 hours. Quench the reaction with saturated aqueous sodium bicarbonate, add ethyl acetate, and wash with saturated aqueous sodium bicarbonate followed by saturated aqueous brine. Dry the organic layer over sodium sulfate, filter, and concentrate in vacuo. Add to the residue a solution of sodium ethoxide in ethanol (0.6 M, 50 mL, 0.30 mmol) and reflux 14 hours. Cool to ambient temperature and concentrate in vacuo. Redissolve the residue in diethyl ether and wash with saturated aqueous sodium bicarbonate followed by saturated aqueous brine. Dry the organic layer over sodium sulfate, filter, concentrate in vacuo, and chromatograph the residue over silica gel, eluting with hexanes/ethyl acetate (9:1) to afford the title compound, 0.79 g (60%). LRMS (API ES−)=175.0 (M−H).