Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH:4]1[OH:32].BrC[C:35](OCC)=[O:36].[CH:40](N(C(C)C)CC)(C)C>C(#N)C>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([NH:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([N:7]2[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH:3]3[CH:4]([O:32][C:35](=[O:36])[CH2:1][N:2]3[CH3:40])[CH2:5][CH2:6]2)=[O:31])=[CH:20][CH:19]=1)=[O:30]
Reactant: CCOC(=O)CBr
Reactant: CCN(C(C)C)C(C)C
Reactant: CNC1c2ccccc2N(C(=O)c2ccc(NC(=O)c3ccccc3Cl)cc2)CCC1O
Solvent: CC#N
Product: CN1CC(=O)OC2CCN(C(=O)c3ccc(NC(=O)c4ccccc4Cl)cc3)c3ccccc3C21
Yield: 56.5 %

Procedure:
A mixture of 5-methylamino-4-hydroxy-1-[4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.13 g), ethyl α-bromoacetate (58 mg), diisopropylethylamine (49 mg) and acetonitrile (5 ml) is refluxed for 10 hours. Acetonitrile is distilled off under reduced pressure, and the resulting residue is dissolved in dichloromethane, washed with water, dried over magnesium sulfate, and distilled off under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=50:1), and recrystallized from chloroform/methanol to give 7-[4-(2-chlorobenzoylamino)benzoyl]-1-methyl-1,2,3,4a,5,6,7,11b-octahydro-3-oxo[1]benzazepino[4,5-b][1,4]oxazine (80 mg) as colorless prisms, m.p. 286°-290° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>CN(C)C1C=CN=CC=1.CC(C)=O>[C:19]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:22])[CH:20]=[CH2:21]
Reactant: C=CC(=O)Cl
Reactant: O=[N+]([O-])c1ccccc1CO
Agent: CN(C)c1ccncc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: C=CC(=O)OCc1ccccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
153.2 g (1.0 mole) of 2-nitrobenzyl alcohol, 95.7 g (0.94 mole) of triethylamine and 12.9 g (0.11 mole) of 4-(dimethylamino)pyridine were dissolved in 600 ml of acetone and to the resulting solution, there was dropwise added a solution of 95.0 g (1.05 mole) of acryloyl chloride in 150 mi of acetone at 0° C. over one hour with stirring. Then the stirring was continued for additional one hour. After filtering off the resulting salt, the filtrate was concentrated and purified by column chromatography (packed material: silica gel; eluent: hexane/ethyl acetate =10/1). Thus, 141 g of an oily liquid was recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:10][CH:11]=[CH:12][C:13]=1[C:14]#[N:15].[C:16](Cl)(=[O:18])[CH3:17].[Cl-].[Cl-].[Cl-].[Al+3].Cl>ClCCl.C(O)(C)C>[C:16]([C:11]1[NH:10][C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[C:13]([C:14]#[N:15])[CH:12]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: N#Cc1cc[nH]c1-c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(=O)c1cc(C#N)c(-c2ccc(Cl)cc2Cl)[nH]1
Reaction time: 3 h
Yield: 92.2 %

Procedure:
To a mixture of 2-(2,4-dichloro-phenyl)-1H-pyrrole-3-carbonitrile (6.00 g, 25.30 mmol, see EP 0312,723) in 120 mL of dichloromethane was added acetyl chloride (3.18 g; 40.49 mmol) at room temperature, under nitrogen. The resulting mixture was cooled to +2° C. and anhydrous aluminum trichloride (8.10 g, 60.73 mmol) was added in small portions during a period of 20 minutes, keeping the internal temperature below 5° C. Upon complete addition, the mixture was brought to room temperature and allowed to stir for 3 hours. Then, the mixture was slowly poured in a solution of ice-cooled 2M HCl (120 mL) and isopropanol (28 mL). The aqueous layer was separated and extracted twice with a mixture of dichloromethane (120 mL) and isopropanol (28 mL). The combined organic extracts were concentrated under reduced pressure to slurry, which was treated under stirring with isopropanol (30 mL) and diluted with water (60 mL) at room temperature. The solid was collected by suction and dried under vacuum at +50° C. to afford the 6.51 g of product as white, fluffy crystals. Yield=92%.
Reaction SMILES: [BH4-].[BH4-].[BH4-].[BH4-].[Na+].[Na+].[Na+].[Na+].[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[C:19]1[CH2:20][CH:21]2[N:27]([CH:28]=1)[C:26](=[O:29])[C:25]1[CH:30]=[C:31]([O:36][CH3:37])[C:32]([O:34][CH3:35])=[CH:33][C:24]=1[N:23](COCC[Si](C)(C)C)[CH2:22]2.C(O)C.C1COCC1>O>[CH3:37][O:36][C:31]1[C:32]([O:34][CH3:35])=[CH:33][C:24]2[N:23]=[CH:22][C@@H:21]3[CH2:20][C:19]([C:10]4[CH:11]=[CH:12][C:13]5[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=5)[CH:9]=4)=[CH:28][N:27]3[C:26](=[O:29])[C:25]=2[CH:30]=1
Reactant: COc1cc2c(cc1OC)N(COCC[Si](C)(C)C)CC1CC(c3ccc4ccccc4c3)=CN1C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COc1cc2c(cc1OC)C(=O)N1C=C(c3ccc4ccccc4c3)C[C@H]1C=N2
Temperature: 25 °C
Reaction time: 24 h
Yield: 21.7 %

Procedure:
Solid sodium tetraborohydride (654 mg, 17.2 mmol) was added in three portions at two hourly intervals to a stirred solution of 10 (971 mg, 1.8 mmol) in a mixture of anhydrous ethanol (19 mL) and anhydrous THF (37 mL) and left to stir at room temperature for 24 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were evaporated in vacuo. The crude product was treated with ethanol (50 mL), water (30 mL) and silica gel (18.3 g) and left to stir at room temperature for 24 hours. The reaction mixture was filtered and the product extracted with ethyl acetate (3×50 ). The organic layers were combined and washed with brine (20 mL) and dried over anhydrous magnesium sulphate. Filtration and evaporation in vacuo afforded the crude product, which was purified using flash column chromatography with a 70-50% hexane in ethyl acetate as eluent. Pure fractions were combined and evaporated in vacuo to afford the pure product 11 as a yellow powder (151 mg, 0.39 mmol, 22% yield).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([N:22]2[CH2:36][C:25]3=[C:26]4[N:31]([N:32]=[C:24]3[CH2:23]2)[C:30]([CH3:33])=[C:29]([Cl:34])[C:28]([CH3:35])=[N:27]4)=[O:21])[CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[ClH:34].[NH:8]1[CH2:9][CH:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([N:22]2[CH2:36][C:25]3=[C:26]4[N:31]([N:32]=[C:24]3[CH2:23]2)[C:30]([CH3:33])=[C:29]([Cl:34])[C:28]([CH3:35])=[N:27]4)=[O:21])[CH2:11]1
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OCC1CN(C(=O)OC(C)(C)C)C1)C3
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OCC1CNC1)C3
Product: Cl
Yield: 2.5 %

Procedure:
A solution of 3-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-phenoxymethyl]-azetidine-1-carboxylic acid tert-butyl ester (920 mg; 1.8 mmol; 1 eq.) in TFA (5 mL) and DCM (5 mL) was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was taken up in water, the pH made basic with 5M NaOH and extracted with DCM (2×). The combined organic layer was dried over magnesium sulfate and concentrated in vacuo. Purification by mass directed preparative HPLC afforded the title compound (10 mg, 1%) a yellow gum. 1H NMR (CDCl3) δ 10.56 (s, 1H), 8.82 (s, 1H), 7.50-7.40 (m, 2H), 7.15-7.02 (m, 2H), 5.09 (s, 0.6H), 5.05 (s, 1.4H), 4.83 (s, 1.4H), 4.70 (s, 0.6H), 4.43-4.27 (m, 3H), 3.93-3.78 (m, 1H), 3.21-3.09 (m, 1H), 3.03 (s, 2H), 2.92 (s, 1H), 2.79 (s, 2H), 2.78 (s, 1H). HPLC (max plot) 99.3%, Rt 2.65 min. UPLC/MS: (MS+) 412.4 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[CH:12][N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31](O)=[O:32])=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[CH:12][N:13]=[C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:31](=[O:32])[CH2:30][O:29][C:28]5[CH:34]=[CH:35][C:25]([O:24][CH3:23])=[CH:26][CH:27]=5)[CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nc3c(N4CCNCC4)ncnc3s2)cc1
Reactant: COc1ccc(OCC(=O)O)cc1
Product: COc1ccc(OCC(=O)N2CCN(c3ncnc4sc(-c5ccc(F)cc5)nc34)CC2)cc1
Yield: 51 %

Procedure:
This compound was prepared from 2-(4-fluorophenyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidine using 4-methoxyphenoxyacetic acid in a yield of 51%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:39]([O:40][CH3:41])=[CH:38][CH:37]=[CH:36][C:4]=1[CH2:5][N:6]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:7](=[O:28])[CH2:8][CH2:9][C:10]1[CH:27]=[CH:26][C:13]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([O:20]C)=[O:19])=[CH:12][CH:11]=1.[Li+].[OH-].CCOC(C)=O>C1COCC1.O>[CH3:1][O:2][C:3]1[C:39]([O:40][CH3:41])=[CH:38][CH:37]=[CH:36][C:4]=1[CH2:5][N:6]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:7](=[O:28])[CH2:8][CH2:9][C:10]1[CH:27]=[CH:26][C:13]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1
Reactant: CCCCCCCN(Cc1cccc(OC)c1OC)C(=O)CCc1ccc(OCc2ccccc2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCN(Cc1cccc(OC)c1OC)C(=O)CCc1ccc(OCc2ccccc2C(=O)O)cc1
Yield: 79.4 %

Procedure:
Methyl 2-[(4-{3-[(2,3-dimethoxybenzyl)(heptyl)amino]-3-oxopropyl}phenoxy)methyl]-benzoate (39 mg, 0.069 mmol) was dissolved in THF/water (2/1, 2 ml) and LiOH (3.3 mg, 0.14 mmol) was added. The reaction was performed I a single node microwave oven (150° C., 7 min). Workup was done by adding EtOAc (10 ml) and washing the organic phase with two potions of HCl (2×5 ml, 1 M). The organic phase was dried (MgSO4) and the solvent was removed by evaporation to give 30 mg of 2-[(4-{3-[(2,3-dimethoxybenzyl)(heptyl)-amino]-3-oxopropyl}phenoxy)methyl]benzoic acid (yield 78.9).
Reaction SMILES: [C:1]([C:4]1([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH2:7][CH2:6][CH2:5]1)(=O)[CH3:2].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CO.[BH4-].[Na+]>O>[ClH:14].[CH2:16]([NH:23][CH:1]([C:4]1([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH2:7][CH2:6][CH2:5]1)[CH3:2])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(NCc1ccccc1)C1(c2ccc(Cl)c(Cl)c2)CCC1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Acetyl-1-(3,4-dichlorophenyl)cyclobutane (4.86 g) and benzylamine (2.2 ml) were stirred at a temperature of 140° to 150° C. under nitrogen for 1 hour 30 minutes. Methanol (50 ml) was added to the cooled reaction mixture and sodium borohydride (0.8 g) was added over a period of ten minutes. The mixture was stirred at ambient temperature for two hours and then the volume of the reaction mixture was reduced by a half and the mixture poured into water (300 ml). The aqueous mixture was extracted with ether and the ether extract dried and the ether removed by evaporation. The residue was distilled (b.p. 182°-186° at 0.5 mm Hg) and the distillate treated with hydrogen chloride in ether to give N-benzyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine hydrochloride (m.p. 227°-228° C.).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1.CO.CCO.[Cl:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]=[CH:35][CH:34]=1>[CH]Cl.O>[ClH:32].[NH2:24][C:19]1[N:18]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:25]=[CH:26][C:3]([NH:2][C:33]4[C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:36]=[CH:35][CH:34]=4)=[CH:4][CH:5]=3)=[CH:15][CH:14]=2)[CH:22]=[C:21]([CH3:23])[N:20]=1
Reactant: Clc1ccnc2ccccc12
Reactant: Cc1cc(Nc2ccc(NC(=O)c3ccc(N)cc3)cc2)nc(N)n1
Agent: Cl
Agent: [CH]Cl
Solvent: O
Solvent: CCO
Solvent: CO
Product: Cc1cc(Nc2ccc(NC(=O)c3ccc(Nc4ccnc5ccccc45)cc3)cc2)nc(N)n1

Procedure:
To solution of amine E5 (267 mg, 0.720 mmol) in ˜1:1:1 MeOH:EtOH:H2O were sequentially added 4-chloroquinoline (1.06 g, 6.48 mmol) and 3 drops of cHCl, and the resulting mixture was refluxed for ˜24 h. After this time, solvent was removed under reduced pressure, and the resulting residue dried via two MeOH-azeotrope cycles. The residue was re-precipitated from MeOH/EtOAc, and then further purified by preparative HPLC, to afford Cpd. E as an amorphous yellow solid (16 mg, 4%). 1H NMR [(CD3)2SO]: 1.91 [s, 3H, ArCH3], 6.11 [s, 1H, ArH], 7.02 [d, J=6.77 Hz, 1H, ArH], 7.65 [d, J=8.55 Hz, 2H, ArH], 7.71 [br s, 2H, ArNH2], 7.84 [m, 4H, ArH], 8.04 [m, 2H, ArH], 8.15 [d, J=8.55 Hz, 2H, ArH], 8.63 [d, J=6.77 Hz, 1H, ArH], 8.70 [d, J=8.50 Hz, 1H, ArH], 10.38 [s, 2H, ArNHAr & ArH], 10.77 [br s, 1H, ArNHAr], 13.10 [v v br s, 2H, ArC(O)NHAr & quinoline-N+H]. LCMS (APCI+): 463 (100%). HPLC: 95.7%.
Reaction SMILES: C([O:8][C:9](=[O:25])[NH:10][C@@H:11]([CH3:24])[C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=O)C1C=CC=CC=1.CC(O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1.O>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([C@@H:12]2[O:25][C:9](=[O:8])[NH:10][C@H:11]2[CH3:24])=[CH:19][CH:18]=1)([CH3:21])([CH3:22])[CH3:23]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)c1ccc(C(C)(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: C[C@@H]1NC(=O)O[C@H]1c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 9 g (26.5 mmole) [(S)-2-(4-tert-butylphenyl)-1-methyl-2-oxoethyl]-carbamic acid benzyl ester o in 40 mL toluene and 10 mL 2-propanol was added dropwise a solution of 0.7 g (18.42 mmole) sodium borohydride in 2 mL water containing 1 drop 50% sodium hydroxide. The reaction mixture was stirred at room temperature for 15 hrs. The layers were separated and the organic phase was washed with 25 mL 10% sodium hydroxide. 2-Propanol was removed under reduced pressure and the remaining toluene solution was heated under reflux for 1 hr. The solvent was removed under reduced pressure. The residue was recrystallized from diethyl ether/hexane to provide (4S,5S)-5-(4-tert-butylphenyl)-4-methyl-oxazolidin-2-one p, 3 g; m.p. 199-200° C. Similarly, following the procedure described above, the following compounds were prepared:
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NCCS.[C:11]([O:15][C:16](=[O:28])[NH:17][C@@H:18]([C:25](F)=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:14])([CH3:13])[CH3:12]>O.C(Cl)Cl>[C:11]([O:15][C:16]([NH:17][C@H:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:25]([OH:2])=[O:26])=[O:28])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)F)c1ccccc1
Agent: Cl
Agent: NCCS
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a 50 mL round-bottom flask charged with a solution of sodium bicarbonate (78.0 mg, 0.93 mmol) in 4.5 mL water was added 2-aminoethanethiol hydrochloride (56.6 mg, 0.50 mmol). To this stirring solution was added dropwise over 60 seconds a solution of 25j (114.8 mg, 0.45 mmol) in 4.5 mL CH2Cl2. The reaction was vigorously stirred for 25 minutes at room temperature, then extracted twice with fresh CH2Cl2. The combined CH2Cl2 extracts were washed once with 5% aqueous HCl, once with 10% aqueous sodium bicarbonate, then once with water. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 132.3 mg (86% from 24j) of 26j as an off-white paste.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:10][C:11]1[C:16]([F:17])=[C:15]([CH:18]=O)[CH:14]=[CH:13][N:12]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[Cl:10][C:11]1[C:16]([F:17])=[C:15]([CH2:18][N:7]2[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]2)[CH:14]=[CH:13][N:12]=1
Reactant: CC(=O)N1CCNCC1
Reactant: O=Cc1ccnc(Cl)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(=O)N1CCN(Cc2ccnc(Cl)c2F)CC1

Procedure:
1-Acetylpiperazine (0.164 g, 1.28 mmol) was dissolved in 5 mL DCE and the resulting solution was added to 2-chloro-3-fluoro-pyridine-4-carbaldehyde (14-2, 0.170 g, 1.07 mmol). NaBH(OAc)3 (0.248 g, 1.17 mmol) was added followed by the addition of 0.100 mL of HOAc. After 45 min the reaction was quenched with sat NaHCOC3 (aq). The mixture was extracted 3× with DCM, and the organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (10 g column, DCM (for 4 min) gradient to 95:5 DCM/MeOH (over 8 min)), desired comes off shortly after 95:5 is attained (13 min) affording good separation from close peak preceeding desired. Afforded pure titled compound. 1H NMR (CDCl3) δ 8.18 (d, 1H, J=4.9 Hz), 7.38 (t, 1H, J=4.6 Hz), 3.66 (m, 4H), 3.50-3.48 (m, 2H), 2.50-2.46 (m, 4H), 2.09 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([C:17]([O:19]C)=[O:18])[C:13](=[O:16])[NH:14][N:15]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[N:14]([CH2:26][C:25]4[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=4)[N:15]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: Fc1ccc(CCl)cc1
Reactant: COC(=O)c1cc(-c2ccc3occc3c2)n[nH]c1=O
Product: O=C(O)c1cc(-c2ccc3occc3c2)nn(Cc2ccc(F)cc2)c1=O
Yield: 73.4 %

Procedure:
The general procedure of Example 1 (3) was carried out by use of 6-(1-benzofuran-5-yl)-4-methoxycarbonyl-2H-pyridazin-3-one and 4-fluorobenzyl chloride, to thereby yield the title compound as a yellow powder (yield: 73.4%).
Reaction SMILES: [Na].[CH3:2][O:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])[C:9]=1[CH3:26].CCN(CC)CC.[C:34]1([CH3:62])[CH:39]=[CH:38][C:37]([S:40]([CH2:43][CH2:44][O:45][C:46](=[O:61])[CH2:47][O:48][C:49]2[CH:54]=[C:53]([CH3:55])[C:52]([S:56](Cl)(=[O:58])=[O:57])=[C:51]([CH3:60])[CH:50]=2)(=[O:42])=[O:41])=[CH:36][CH:35]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:34]1([CH3:62])[CH:39]=[CH:38][C:37]([S:40]([CH2:43][CH2:44][O:45][C:46](=[O:61])[CH2:47][O:48][C:49]2[CH:50]=[C:51]([CH3:60])[C:52]([S:56]([N:21]3[C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]=[C:17]3[S:15]([CH2:14][C:10]3[C:9]([CH3:26])=[C:8]([O:7][CH2:6][CH2:5][CH2:4][O:3][CH3:2])[CH:13]=[CH:12][N:11]=3)=[O:16])(=[O:57])=[O:58])=[C:53]([CH3:55])[CH:54]=2)(=[O:41])=[O:42])=[CH:36][CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)CCOC(=O)COc2cc(C)c(S(=O)(=O)Cl)c(C)c2)cc1
Reactant: COCCCOc1ccnc(CS(=O)c2nc3ccccc3[nH]2)c1C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3n2S(=O)(=O)c2c(C)cc(OCC(=O)OCCS(=O)(=O)c3ccc(C)cc3)cc2C)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.8 %

Procedure:
To a heterogeneous solution of 2-[4-(3-methoxy-propoxy)-3-methyl-pyridin-2-yl-methanesulfinyl]-1H-benzimidazole sodium salt (RABEPRAZOLE sodium salt, 1.0 g, 2.62 mmol) and 5 mL of Et3N in 20 mL of CH2Cl2 was added the chlorosulfonyl ester (Intermediate 13, 1.57 g, 3.41 mmol, 1.3 eq). About 1 g of solid NaHCO3 was added after the chlorosulfonyl ester has dissolved completely in the reaction mixture. The mixture was stirred at room temperature for 3 h. Thereafter the solvent was removed by evaporation and the residual oil was purified by column chromatography (silica gel, CH2Cl2 to 1% MeOH in CH2Cl2) to give 1.7 g (77%) of 3,5-dimethyl-4-{2-[4-(3-methoxy-propoxy)-3-methyl-pyridin-2-yl-methanesulfinyl]-benzimidazole-1-sulfonyl}phenoxyacetic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 58) as a white foam.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11]C2)[S:6][N:5]=1.[CH2:16]([C:23]1[CH:28]=[C:27]([CH3:29])[N:26]=[C:25](Cl)[N:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.O>[CH2:16]([C:23]1[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]([NH:15][C@@H:12]2[CH2:13][CH2:14][N:9]([C:7]3[S:6][N:5]=[C:4]([CH3:3])[N:8]=3)[CH2:11]2)[N:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Reactant: Cc1nsc(N2CCC(N)CC2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Cc2ccccc2)nc(N[C@@H]2CCN(c3nc(C)ns3)C2)n1

Procedure:
A solution of 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-ylamine dihydrochloride (54.2 mg, 0.2 mmol), 4-benzyl-2-chloro-6-methyl-pyrimidine (48.1 mg, 0.22 mmol)) and N,N-diisopropylethyl amine (120 L, 0.7 mmol) in dioxane (0.6 mL) was heated at 200° C. in a microwave oven for 1 hour. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with EtOAc as eluent. The title compound was obtained as a yellow viscous oil (22 mg, 29%).
Reaction SMILES: CO[C:3]1[CH:8]=CC(C2C=CC(=O)NN=2)=C[C:4]=1OCCC.C(OC1C=C(C2C=CC(=O)NN=2)C=CC=1OC)C=C.[CH2:39]([O:41][C:42]1[CH:43]=[C:44]([C:50]2[CH:51]=[CH:52][C:53](=[O:56])[NH:54][N:55]=2)[CH:45]=[CH:46][C:47]=1[O:48][CH3:49])[CH3:40].C(OC1C=CC(C2C=CC(=O)NN=2)=CC=1OC)(C)C>>[CH3:49][O:48][C:47]1[CH:46]=[CH:45][C:44]([C:50]2[CH:51]=[CH:52][C:53](=[O:56])[NH:54][N:55]=2)=[CH:43][C:42]=1[O:41][CH2:39][CH2:40][CH:3]([CH3:8])[CH3:4]
Reactant: CCCOc1cc(-c2ccc(=O)[nH]n2)ccc1OC
Reactant: CCOc1cc(-c2ccc(=O)[nH]n2)ccc1OC
Agent: C=CCOc1cc(-c2ccc(=O)[nH]n2)ccc1OC
Agent: COc1cc(-c2ccc(=O)[nH]n2)ccc1OC(C)C
Product: COc1ccc(-c2ccc(=O)[nH]n2)cc1OCCC(C)C

Procedure:
The following are obtained analogously: 6-(4-methoxy-3-n-propoxyphenyl)-3[2H]pyridazinone, m.p. 196°, 17.5% of theory, 6-(3-allyloxy-4-methoxyphenyl)-3[2H]pyridazinone, m.p. 175°, 16.3% of theory, 6-(3-ethoxy-4-methoxyphenyl)-3[2H]pyridazinone, m.p. 171°, 15.1% of theory and 6-(4-isopropoxy-3-methoxyphenyl)-3[2H]pyridazinone, m.p. 200°, 26.4% of theory.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][C:10]([O:11][CH3:12])=[C:7]([O:8][CH3:9])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21]([O:28][CH2:29][C@@H:30]([CH3:33])[CH2:31]Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[CH2:21]([O:28][CH2:29][C@@H:30]([CH3:33])[CH2:31][N:2]([CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][C:10]([O:11][CH3:12])=[C:7]([O:8][CH3:9])[CH:6]=1)[CH3:1])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[C@@H](CBr)COCc1ccccc1
Reactant: CNCCc1ccc(OC)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CCN(C)C[C@H](C)COCc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 10.93 g (0.056 mol) of N-methylhomoveratrylamine in 50 ml of abs. dimethylformamide was treated at 5° with 15.7 g of potassium carbonate and 13.6 g (0.056 mol) of (R)-(-)-3-benzyloxy-2-methylpropyl bromide [Helv. Chim. Acta 60, 940, (1977)]. The mixture was stirred at room temperature for 18 hours and then evaporated under reduced pressure. The residue was taken up in a mixture of water and ethyl acetate. The organic extracts were dried over magnesium sulphate and evaporated under reduced pressure. The residue was distilled at 218°/260 Pa. The N-[(S)-3-(benzyloxy)-2-methylpropyl]-3,4-dimethoxy-N-methylphenethylamine, which was obtained as a colourless oil, was used directly in the next step. [α]D ;20 =+7.3° (c=1, ethanol).