Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH2:23][CH:24]1[CH2:29][O:28][C:27]([CH3:31])([CH3:30])[O:26][CH2:25]1)(=O)=O.OCC(CO)CO>CN(C)C=O.O>[CH3:30][C:27]1([CH3:31])[O:28][CH2:29][CH:24]([CH2:23][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:7])=[CH:14][CH:15]=2)[CH2:25][O:26]1
Reactant: CC1(C)OCC(COS(C)(=O)=O)CO1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: OCC(CO)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCC(COc2ccc(C(=O)c3ccccc3)cc2)CO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Hydroxybenzophenone is treated with equimolar quantity of sodium hydride in dry dimethylformamide at 0° C. under an inert atmosphere. After stirring at ambient temperature for 2 hours, a bright yellow clear solution is obtained. To this solution is added equimolar quantity of (2,2-dimethyl-1,3-dioxan-5-yl)methyl methanesulfonate (its synthesis in two steps from commercially available 2-hydroxymethyl-1,3-propanediol is described in European Patent EP2103611). After stirring at ambient temperature for 16 hours, the reaction mixture is diluted with water and extracted with dichloromethane. The organic phase is evaporated to dryness and the crude product is purified by column chromatography. This provide the intermediate {4-[(2,2-dimethyl-1,3-dioxan-5-yl)methoxy]phenyl}(phenyl)methanone. This intermediate is then dissolved in acetone, excess of 1M hydrochloric acid is added and the reaction mixture is stirred for 2 hours at room temperature. The reaction mixture is evaporated to dryness under reduced pressure, and the residue is purified by column chromatography to provide the desired {4-[3-hydroxy-2-(hydroxymethyl)propoxy]phenyl}(phenyl)methanone.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10][O:11][CH2:12]Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:10][O:11][CH2:12][O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1]
Reactant: Oc1cccc(Cl)c1Cl
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCOc1cccc(Cl)c1Cl
Yield: 100.5 %

Procedure:
A mixed solution of 2,3-dichlorophenol (16.3 g, 0.10 mol), chloromethyl methyl ether (9.7 g, 0.12 mol), anhydrous potassium carbonate (27.6 g, 0.20 mol), and acetonitrile (150 ml) is stirred at a temperature between 50° C. and 60° C. for 40 minutes and evaporated under reduced pressure to remove acetonitrile. The residue is dissolved in methylene chloride, washed with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give 20.8 g (Yield 100%) of 2,3-dichlorophenyl methoxymethyl ether as a pale yellow oil. To a hexane solution (35 ml) of 8.12 g (0.07 mol) of N,N,N',N'-tetramethylethylenediamine is dropwise added 50 ml of 15% hexane solution of butyl lithium while being stirred at a temperature of -10° C. to 0° C. and the mixture is stirred for 15 minutes.
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:35][C:36]1[C:41]([O:42][CH3:43])=[CH:40][C:39]([O:44][CH3:45])=[CH:38][C:37]=1[O:46][CH3:47])[C:10](=[O:34])[CH2:11][CH2:12][C:13]1([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([O:32]C)=[O:31])=[CH:26][CH:25]=2)[C:18](=[O:19])[O:17]C(C)(C)[O:15][C:14]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[OH-].[Na+]>O>[CH2:1]([O:8][N:9]([CH2:35][C:36]1[C:37]([O:46][CH3:47])=[CH:38][C:39]([O:44][CH3:45])=[CH:40][C:41]=1[O:42][CH3:43])[C:10](=[O:34])[CH2:11][CH2:12][C:13]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=1)([C:14]([OH:22])=[O:15])[C:18]([OH:19])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(CC2(CCC(=O)N(Cc3c(OC)cc(OC)cc3OC)OCc3ccccc3)C(=O)OC(C)(C)OC2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(OC)c(CN(OCc2ccccc2)C(=O)CCC(Cc2ccc(C(=O)O)cc2)(C(=O)O)C(=O)O)c(OC)c1
Temperature: 100 °C
Yield: 91 %

Procedure:
To 5-{3-[benzyloxy(2,4,6-trimethoxybenzyl)amino]-3-oxopropyl}-2,2-dimethyl-5-[4-(methoxycarbonyl)phenyl]methyl-[1,3]dioxane-4,6-dione (5.38 g, 8.3 mmol) were added 50 mL of water, then 40 mL of 1,4-dioxane and finally a solution of NaOH (1.65 g, 41.4 mmol) in 20 mL of water. This mixture was heated at 100° C. for 2 h. The solution was then allowed to cool to rt. The solvent was removed under reduced pressure and the residue was partitioned between 100 mL of 10% KHSO4 and 100 mL of EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give 4.5 g of 2-{3-[benzyloxy(2,4,6-trimethoxybenzyl)amino]-3-oxopropyl}-2-(4-carboxyphenyl)methyl-malonic acid as an off white powder (95% yield).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([CH3:18])[C:9]=2[C:19](=[O:21])[CH3:20])=[CH:4][CH:3]=1.NC1C2C(=CC=CC=2)N=C(C)C=1C(=O)C.BrC1C=CC(CBr)=C([F:48])C=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([CH3:18])[C:9]=2[C:19](=[O:21])[CH3:20])=[C:22]([F:48])[CH:23]=1
Reactant: CC(=O)c1c(C)nc2ccccc2c1NCc1ccc(Br)cc1
Reactant: Fc1cc(Br)ccc1CBr
Agent: CC(=O)c1c(C)nc2ccccc2c1N
Product: CC(=O)c1c(C)nc2ccccc2c1NCc1ccc(Br)cc1F

Procedure:
1-(4-(4-Bromo-2-fluorobenzylamino)-2-methylquinolin-3-yl)ethanone was synthesized by the same process as described for 1-(4-(4-bromobenzylamino)-2-methylquinolin-3-yl)ethanone (Example 1, Intermediate 2c) starting from 1-(4-amino-2-methylquinolin-3-yl)ethanone and 4-bromo-2-fluorobenzyl bromide. MS(ES+): 387/389.
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4]>[Ni]>[CH2:2]([OH:1])[C@H:3]([C@@H:5]([C@@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O
Agent: [Ni]
Product: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO

Procedure:
L-Fucose (6-deoxy L-galactose) was reduced [a composition in total of 500 ml containing L-fucose at 1% and 20 ml of the Raney-nickel catalyst] to produce L-fucitol (6-deoxy L-galactitol). FIG. 59(a) shows HPLC analysis results of L-fucose before reduction and FIG. 59(b) shows HPLC analysis results of 6-deoxy D-galactitol after the reduction. The optical rotation of 6-deoxy L-galactitol was −1.7, and FIG. 60 shows 13C NMR spectrum of 6-deoxy D-galactitol.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C@@H:7]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:8]1.N1C(C)=CC=CC=1C>ClCCl>[CH3:1][S:2]([O:6][C@@H:7]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:19])[CH2:8]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](OS(C)(=O)=O)C1
Temperature: 25 °C

Procedure:
Methansulfonyl chloride (8.2 g; 72.0 mmol) is slowly added to an ice cold solution of commercially available tert-butyl [(1S,3R)-3-hydroxycyclopentyl]carbamate (12.1 g; 60.0 mmol) and 2,6-lutidine (9.6 g; 90.0 mmol) in dry dichloromethane (300 mL). The stirred reaction mixture is allowed to warm to ambient temperature over night. The reaction mixture is extracted with water, ice cold 1N HCl, half saturated brine, and dried over MgSO4. After filtration through a pad of neural alumina (act. 2-3) the solvent is removed under reduced pressure to yield the crude title compound as yellow oil that is processed without additional purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br>>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][Br:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCCCCCBr
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(O)ccc21
Product: CC(C)(C)OC(=O)N1CCCc2cc(OCCCCCCBr)ccc21
Yield: 40 %

Procedure:
In analogy to example 2.2, 6-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester and 1,6-dibromohexane were converted to yield 6-(6-Bromo-hexyloxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (40%) as light green oil, MS: 412 (MH+, 1Br);
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([O:24][CH3:25])=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[CH3:34][CH:35]([CH3:39])[C:36](=[S:38])[NH2:37]>C(Cl)Cl.CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:38][C:36]([CH:35]([CH3:39])[CH3:34])=[N:37][C:9]=2[C:11]2[C:12]([O:24][CH3:25])=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1OC
Reactant: CC(C)C(N)=S
Agent: O=C1CCC(=O)N1Br
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCOC(=O)Nc1cccc(-c2nc(C(C)C)sc2-c2ccnc(Cl)n2)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
To a solution of 2-propen-1-yl [3-[(2-chloro-4-pyrimidinyl)acetyl]-2-(methyloxy)phenyl]carbamate (15.4 g, 42 mmol) in DCM (150 mL), NBS (7.6 g, 42 mmol) was added and the solution was allowed to stir at rt for 30 min. The reaction mixture was then concentrated in vacuo and the resulting oil was diluted with DMSO (150 mL) and 2-methylpropanethioamide (6.6 g 63.8 mmol) was added at once. The reaction was complete after stirring 1 h at rt. The reaction mixture was diluted with EtOAc and organic layer was washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (DCM:petroleum ether 2:1) to afford the title compound of Step F (12.1 g, 63.8% yield) which was used directly in the next step.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]([NH2:18])=[O:17])[CH2:15][C@@:9]1([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@H:10]([O:19][CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:42][C:43](=O)[CH3:44].CN(C)C=O>C(OCC)C>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[O:17][CH:42]=[C:43]([CH3:44])[N:18]=3)[CH2:15][C@@:9]1([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@H:10]([O:19][CH2:20][C:21]1[CH:22]=[C:23]([C:31]([F:32])([F:33])[F:34])[CH:24]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:26]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CCl
Reactant: NC(=O)[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1coc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Temperature: 120 °C
Reaction time: 24 h
Yield: 12 %

Procedure:
A mixture of (1R*,2R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl) phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octan-6-carboxamide (Example 75; 250 mg, 0.44 mmol), chloroacetone (1 ml) and N,N-dimethylforamide (4 ml) was stirred at 120° C. for 24 hours. After cooling to room temperature the reaction mixture was diluted with diethyl ether (70 ml), washed with saturated aqueous NaHCO3, water and brine. The organic phase was dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compound (53 mg, 12%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([N:25]([CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([N:25]([CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: CS(=O)(=O)N(CCN1CCOCC1)c1ccc(C(=O)O)c(Cl)c1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CS(=O)(=O)N(CCN1CCOCC1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
1.2 g of 4-(2-chloroethyl)morpholine and 2.5 g of Cesium Carbonate were added to 334 mg of methyl 2-chloro-4-(methylsulfonamido)benzoate in 7 mL of DMF and stirred in the microwave at 150° C. for 30 minutes. The reaction mixture was extracted in Ethyl Acetate twice with water, dried over Magnesium Sulfate, filtered, concentrated to give crude methyl 2-chloro-4-(N-(2-morpholinoethyl)methylsulfonamido)benzoate. 476 mg of methyl 2-chloro-4-(N-(2-morpholinoethyl)methylsulfonamido)benzoate was hydrolyzed via Procedure M and purified by reverse phase HPLC to yield 460 mg of crude 2-chloro-4-(N-(2-morpholinoethyl)methylsulfonamido)benzoic acid. 100 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(N-(2-morpholinoethyl)methylsulfonamido)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2-morpholinoethyl)methylsulfonamido)benzamide. MS (Q1) 549 (M)+.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)#[N:2].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1.C(OCC)C.Cl>C(=O)=O.CO>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:7]([C:6]2[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[OH:8])=[CH:14][CH:13]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cl
Agent: O=C=O
Solvent: CO
Solvent: CCOCC
Product: N#Cc1ccc(C(O)c2ccc(Cl)cc2)cc1
Reaction time: 0.17 h
Yield: 96 %

Procedure:
To a solution of 4-cyanobenzaldehyde (3.93 g) in tetrahydrofaran was added dropwise 1.0M 4-chlorophenylmagnesium bromide-diethylether (30 mL) under nitrogen gas atmosphere and cooling in dry ice/methanol bath and the mixture was stirred at the same temperature for 10 minutes. To the reaction mixture was added 10% HCl solution and the aqueous layer was extracted with ethyl acetate (×2). The organic layer was washed with a saturated brine, dried over magnesium sulfate and concentrated in vacuo. To the resultant crude product was added diisopropyl ether and the resultant solid materials were collected by filtration to give (4-chlorophenyl)(4-cyanophenyl)methanol (6.98 g, yield: 96%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[C:19]([F:22])([F:21])[F:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]>N.[Ni]>[F:1][C:2]1[CH:9]=[C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[C:19]([F:20])([F:21])[F:22])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5]
Reactant: COc1ccc(Nc2ccc(C#N)c(F)c2)c(C(F)(F)F)c1
Agent: [Ni]
Agent: N
Product: COc1ccc(Nc2ccc(CN)c(F)c2)c(C(F)(F)F)c1
Yield: 99 %

Procedure:
2-fluoro-4-(4-methoxy-2-trifluoromethyl-phenylamino)-benzonitrile (2.85 g, 9.19 mmol) was hydrogenated in 40 mL saturated methanolic ammonia solution after the addition of 300 mg of Raney nickel at ambient temperature. After the catalyst had been filtered off and the mixture evaporated down the product was obtained in a yield of 99% of theory.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:4]=[C:3]1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[C:21](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O>CO.C(O)(=O)C>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:4]=[C:3]1[CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1
Reactant: Cn1c(C2CCNCC2)nc(-c2ccncc2)cc1=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCC(c2nc(-c3ccncc3)cc(=O)n2C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of 3-methyl-2-piperidin-4-yl-6-pyridin-4-yl-3H-pyrimidin-4-one (0.74 mmol) in methanol/acetic acid was added sodium triacetoxyborohydride (1.1 mmol) and 0.5 mL of 37% aqueous formaldehyde. The reaction was stirred at room temperature for 30 min. The solvent was removed under vacuum and the residue partitioned between dichloromethane and 1N NaOH. The product was purified on silica. M+1=284.
Reaction SMILES: [Na].[CH2:2]([N:9]1[CH2:15][CH2:14][CH2:13][NH:12]/[C:11](=[C:16]2/[C:17]([CH2:29][C:30]([O:32]C)=O)=[N:18][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:20]/2=[O:21])/[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>CO.O>[CH2:2]([N:9]1[CH2:15][CH2:14][CH2:13][N:12]2[C:30](=[O:32])[CH:29]=[C:17]3[NH:18][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])[C:20](=[O:21])[C:16]3=[C:11]2[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)CC1=NN(c2ccccc2Cl)C(=O)/C1=C1/CN(Cc2ccccc2)CCCN1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CO
Product: O=c1c2c3n(c(=O)cc2[nH]n1-c1ccccc1Cl)CCCN(Cc1ccccc1)C3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
An isopropanolic solution of MeONa, obtained by dissolving of sodium (0.055 g, 2.4 mmol, 2 eq.) in MeOH (3 ml) under nitrogen, was treated with methyl [(4Z)-4-(4-benzyl-1,4-diazepan-2-ylidene)-1-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]acetate (Compound of Formula (II) (530 mg, 1.2 mmol, 1 eq.). The reaction mixture was stirred at room temperature for 0.5 h, then cooled, diluted with water (8 mL) and neutralized to pH 6 by addition 1M HCl solution. The precipitate was filtered off and dried under vacuo. The crude was purified by flash chromatography to yield 129 mg of pure product 10-benzyl-2-(2-chlorophenyl)-2,3,8,9,10,11-hexahydro-1H-pyrazolo[4′,3′:3,4]pyrido [1,2-a][1,4]diazepine-1,5(7H)-dione. Yield 26%. 1HNMR (500 MHz, DMSO-d6): 1.62-1.68 (m, 2H); 2.83 (t, 2H, J=7.5 Hz); 3.62-3.66 (m, 2H); 4.40-4.76 (m, 2H); 5.73 (s, 1H); 7.21-7.32 (m, 5H); 7.44-7.50 (m, 2H); 7.55-7.60 (m, 1H); 7.61-7.67 (m, 1H); 10.75-10.68 (bs, 1H). MS (ESI+): 421.9.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[N:15]=[C:14]([CH2:16][C:17]3[N:18]=[CH:19][N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:21]=3)[O:13][N:12]=2)=[CH:3]1.[ClH:41]>>[ClH:41].[NH:20]1[CH:21]=[C:17]([CH2:16][C:14]2[O:13][N:12]=[C:11]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:2]([CH3:1])[CH:3]=3)[N:15]=2)[N:18]=[CH:19]1
Reactant: Cn1cc(-c2noc(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)n2)c2ccccc21
Agent: Cl
Product: Cn1cc(-c2noc(Cc3c[nH]cn3)n2)c2ccccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-(1-Methyl-1H-indol-3-yl)-5-[(1-triphenylmethyl-1H-imidazol-4-yl)methyl]-1,2,4-oxadiazole (1.25 g) was dissolved in methanolic hydrogen chloride solution (50 ml) and stirred at room temperature for 48 h. The title compound precipitated from solution as a white solid (0.92 g), m.p. 255°-257° C. Found: C, 56.95; H, 4.56; N, 21.99; Cl, 11.17; C15H13N5O.HCl requires C, 57.05; H, 4.47; N, 22.17; Cl, 11.22%; δH (360 MHz, DMSO-d6) 3.88 (3H, s, CH3), 4.61 (2H, s, CH2), 7.24 (1H, t, J=6.9 Hz, CH), 7.30 (1H, t, J=6.9 Hz, CH), 7.57 (1H, d, J=8.1 Hz, CH), 7.70 (1H, s, CH), 8.02 (1H, d, J,=7.4 Hz, CH), 8.10 (1H, s, CH), 9.10 (1H, s, CH); m/z 279 (M+, free base, 100%).
Reaction SMILES: [CH3:1][P:2](=[O:9])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5].C([Li])CCC.[CH3:15][Si:16]([CH3:26])([CH3:25])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br>C1COCC1>[CH3:15][Si:16]([CH3:25])([CH3:26])[C:17]1[CH:18]=[C:19]([CH2:20][CH2:1][P:2](=[O:9])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5])[CH:22]=[CH:23][CH:24]=1
Reactant: CCOP(C)(=O)OCC
Reactant: C[Si](C)(C)c1cccc(CBr)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOP(=O)(CCc1cccc([Si](C)(C)C)c1)OCC
Temperature: -10 °C
Reaction time: 0.75 h
Yield: 52.6 %

Procedure:
To a solution of diethyl methylphosphonate (2.28 g, 15 mmol) in THF (20 ml) was added n-butyllithium (17 mmol, 1.6 M solution in hexane) at −78° C. After 45 min, the white suspension was added to a solution of the bromide 37 (3.65 g, 15 mmol) in THF (20 ml) and the mixture was stirred for 1.5 h. The temperature was then increased to −10° C. and after 1 h the deeply red colored solution was quenched by addition of saturated NH4Cl (aq). Volatiles were removed under reduced pressure and the residue was purified by flash chromatography (silica, EtOAc) to give 2.48 g (53%) of 38 as a colorless liquid. IR (film): 3473, 2955, 1248, 1058 and 1031; 1H NMR (200 MHz, CDCl3): δ0.30 (9H, s), 1.31 (6H, t, J=7 Hz), 2.10 (2H, m), 2.92 (2H, m), 4.11 (4H, m) and 7.29 (4H, m); 13C NMR (50 MHz, CDCl3): δ−1.2, 16.4, 26.3, 28.6, 29.0, 61.5, 127.9, 128.4, 131.2, 132.9, 139.9, 140.2 and 140.7; HR-MS (EI): e/m 314.1453 (M+C15H27O3PSi requires 314.1467).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Br:9].[N-:10]=[N+:11]=[N-:12].[Na+].O>CN(C)C=O>[N:10]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Br:9])=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=[N-]
Reactant: BrCc1ccccc1Br
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccccc1Br
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.9 %

Procedure:
After a mixture of 30 g (120 mmol) of 1-bromomethyl-2-bromobenzene and 15.6 g (240 mmol) of sodium azide in 300 ml of dimethylformamide was stirred at 25° C. for 20 hours it was poured into 500 ml of water and extracted with ethyl acetate. The extracts were washed with water and brine, dried (Na2SO4) and concentrated to give 24.9 g (98%) of the product as an oil.
Reaction SMILES: C(OC1C=CC([C:10]2[S:14][C:13]3[CH:15]=[C:16](OCC)[CH:17]=[CH:18][C:12]=3[CH:11]=2)=CC=1)C.COC1C=C(C=C(OC)C=1OC)C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].O>C(Cl)Cl.CCOC(C)=O>[S:14]1[CH:10]=[CH:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]1=2
Reactant: CCOc1ccc(-c2cc3ccc(OCC)cc3s2)cc1
Agent: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: c1ccc2sccc2c1
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
To a well-stirred solution of 2-(4'-ethoxyphenyl)-6-ethoxybenzo[b]thiophene (0.095 g, 0.32 mmol) and 3,4,5-trimethoxybenzoyl chloride (0.159 g, 0.69 mmol) in CH2Cl2 (15 mL) was added AlCl3 (0.139 g, 1.04 mmol) portion-wise over a 5 minute period. After 30 min., water was added, and the product was isolated initially by extraction with CH2Cl2 and subsequently by extraction with EtOAc. The organic layers were separately washed with brine and then combined and dried over MgSO4. Purification by flash chromatography (silica gel, 80:20 hexane/EtOAc) afforded benzo[b]thiophene (0.110 g, 0.2 mmol, 69%) as an off-white solid. 1H-NMR (CDCl3, 360 Mhz) δ 7.65 (d, J=8.9 Hz, 1H, ArH), 7.32 (d, J=2.3 Hz, 1H, ArH), 7.29 (d, J=8.8 Hz, 2H, ArH), 7.06 (s, 2H, ArH), 7.00 (dd, J=8.9, 2.4 Hz, 1H, ArH), 6.73 (d, J=8.7 Hz, 2H, ArH), 4.12 (q, J=7.0 Hz, 2H, --CH2), 3.97 (q, J=6.9 Hz, 2H, --CH2), 3.83 (s, 3H, --OCH3), 3.73 (S, 6H, --OCH3), 1.47 (t, J=6.9 Hz, 3H, --CH3), 1.37 (t, J=7.0 Hz, 3H, --CH3).
Reaction SMILES: [CH:1](=[O:5])/C=C/C.[CH2:6]([N:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:11](=[O:22])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)[CH2:7][CH:8]=[CH2:9]>C(Cl)Cl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C(OC(C)C)=CC=CC=3)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[O:18][CH3:19])[C:11]([N:10]([CH2:6][CH2:7]/[CH:8]=[CH:9]/[CH:1]=[O:5])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:22]
Reactant: C/C=C/C=O
Reactant: C=CCCN(C(=O)c1ccc(OC)c(OC)c1)c1ccccc1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: ClCCl
Product: COc1ccc(C(=O)N(CC/C=C/C=O)c2ccccc2)cc1OC
Temperature: 40 °C
Yield: 97 %

Procedure:
Crotonaldehyde (0.5 mL, 3 equiv) was added to a solution of compound 34 (608 mg, 1.95 mmol) in degassed CH2Cl2 (17 mL). Hoveyda-Grubbs' 2nd (31 mg, 2.5% mol) was added and the reaction mixture was heated to 40° C. under Ar atmosphere overnight. The reaction mixture was filtered over Celite and the filtrate was concentrated to dryness. The residue was purified by column chromatography on SiO2 (Petroleum ether/EtOAc=2:3) to afford the title compound 35 as white solid (Yield 644 mg, 97%).