Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C[AlH]CC(C)C)C.C(C[CH2:14][CH:15]1[CH:20]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:19][C:18](=[O:28])[NH:17][CH2:16]1)(O)=O.C[OH:30]>O1CCCC1.C1(C)C=CC=CC=1>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:20]2[CH2:19][C:18](=[O:28])[NH:17][CH2:16][CH:15]2[CH2:14][OH:30])=[CH:22][CH:23]=1
Reactant: CO
Reactant: O=C(O)CCC1CNC(=O)CC1c1ccc(F)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1CC(c2ccc(F)cc2)C(CO)CN1
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 67 %

Procedure:
DIBAL-H (15.1 ml, 0.0225 mol) was added at a rate of 50 ml/hour, by means of a syringe pump, to a solution of 3-carboxyethyl-4-(4-fluorophenyl)-piperidine-6-one (1.99 g, 0.0075 mol) in tetrahydrofuran (15 ml) at −70° C. under an argon atmosphere keeping the temperature below 0° C. The mixture was allowed to warm to 23° C. and stirred for 45 minutes, then a solution of methanol (0.9 ml) in toluene (7.5 ml) was added to destroy the excess DIBAL-H, followed by 30% potassium carbonate solution (8.5 ml), all below 30° C. The organic phase was separated, dried with anhydrous sodium sulphate, filtered, and evaporated to afford the title compound (1.54 g) as a slightly colored oil, which was crystallized by trituration with ether. Yield 67%.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[OH-].[K+]>CO>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH:19]=[C:20]([C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)[CH2:21][CH2:22]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: c1cnc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ncccc23)CC1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
1H-Pyrrolo[2,3-b]pyridine (3 g, 25 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (4.2 g, 21 mmol) and potassium hydroxide (3.56 g, 63 mmol) were added in MeOH (60 mL) and heated to reflux for 16 h. The reaction mixture was then cooled to room temperature and poured into ice water (300 mL). The mixture was extracted with 10% MeOH/CH2Cl2 (5×150 mL). The organic extracts was dried over Na2SO4 and concentrated to form a solid. The solid was washed with MeOH (150 mL), filtered and dried to give a light yellow solid 5.7 g (91%). TLC (silica, 50% EtOAc/hexanes): Rf=0.3. MS (electrospray): exact mass calculated for C17H21N3O2, 299.16; m/z found, 300.2 [M++H]. 1H NMR (CDCl3, 400 MHz) 10.97 (br s, 1H), 8.33 (dd, J=3.33 Hz, 1.37 Hz, 1H), 8.20 (dd, J=6.65 Hz, 1.37 Hz, 1H), 7.34 (br s, 1H), 7.25 (s, 1H), 7.13 (dd, J=4.89 Hz, 3.13 Hz, 1H), 4.14 (br s, 2H), 3.68 (t, J=5.28 Hz, 2H), 2.56 (br s, 2H), 1.49 (s, 9H).
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C:16]([CH3:21])([CH2:19][OH:20])[CH2:17]O)[C:9]=2[N:10]=[CH:11][N:12]=1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>CCCCCC.C1COCC1>[Cl:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C:16]3([CH3:21])[CH2:19][O:20][CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: CC(CO)(CO)n1ccc2c(Cl)ncnc21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(n2ccc3c(Cl)ncnc32)COC1
Temperature: -50 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
n-BuLi (6.6 mL of a 2.5 M solution in hexane, 16.5 mmol) was added to a solution of 2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropane-1,3-diol (Preparation 217, 3.63 g, 15.0 mmol), in THF (80 mL) at −78° C. The reaction mixture was allowed to warm to −50° C. in 2 hours and TsCl (3.15 mg, 16.5 mmol) in THF (20 mL) was added to the reaction. The reaction was allowed to warm to 0° C. in 3 hours and additional n-BuLi (6.6 mL of a 2.5 M solution in hexane solution, 16.5 mmol) was slowly added to the reaction mixture. The mixture was stirred for 1 hour at 0° C. and stirred at 60° C. for 16 hours. After cooling to room temperature, the reaction was quenched by 50 mL of saturated aqueous NH4Cl solution and 100 mL of water, and the mixture was extracted with EtOAc (3×100 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude residue was purified by column chromatogranhy on silica gel (gradient of EtOAc:heptane 20:80 to 70:30) to give a solid in 55% yield, 1.87 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=1)=[O:12].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:32]([CH3:36])([CH3:35])[CH:33]=O)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1.[BH3-]C#N.[Na+]>C(Cl)Cl>[CH3:31][O:30][C:28]1[CH:27]=[C:26]([C:32]([CH3:36])([CH3:35])[CH2:33][NH:1][C:2]2[CH:7]=[C:6]([OH:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=2[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[O:12])[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=1
Reactant: COc1cc(OC)cc(C(C)(C)C=O)c1
Reactant: COc1cc(C(=O)c2ccc(C(C)C)cc2)c(N)cc1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(OC)cc(C(C)(C)CNc2cc(O)c(OC)cc2C(=O)c2ccc(C(C)C)cc2)c1
Reaction time: 16 h

Procedure:
A mixture of 41.1 mg (144 μmol) (2-amino-4-hydroxy-5-methoxy-phenyl)-(4-isopropyl-phenyl)-methanone, 45 mg (216 μmol) 2-(3,5-dimethoxy-phenyl)-2-methyl-propionaldehyde, 180 mg molecular sieves (pore size 4 Å) and 0.50 ml CH2Cl2 is stirred for 90 min before 8.23 μl (144 μmol) and 22 mg NaCNBH3 are added. After 16 h the excess of reducing agent is destroyed by addition of 1 M hydrochloric acid and the mixture is basified with 1 M sodium hydroxide solution. The product is extracted with CH2Cl2 and purified by reversed phase preparative HPLC.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10](OC)=O)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Cl.S1C2C=C[N:20]=CC=2C=C1CN>>[S:1]1[C:5]2[CH:6]=[C:7]([CH2:10][NH2:20])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: NCc1cc2cnccc2s1
Reactant: COC(=O)c1ccc2ncsc2c1
Agent: Cl
Product: NCc1ccc2ncsc2c1

Procedure:
Intermediate T was prepared from methyl benzo[d]thiazole-6-carboxylate (T-2) following similar procedures for synthesizing intermediate D from D-2, as described above. MS (m/z): 165 (M+1)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.S(O[CH2:23][CH:24]1[CH2:29][CH2:28][CH:27]=[CH:26][O:25]1)(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][O:9][CH2:23][CH:24]2[CH2:29][CH2:28][CH:27]=[CH:26][O:25]2)=[CH:6][CH:5]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC=CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(COCC2CCC=CO2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
50 mg of 55% sodium hydride were added to a solution of 193 mg of 4-chlorobenzyl alcohol in 1 ml of dimethylformamide, and the mixture was stirred at room temperature for 30 minutes. A solution of 326 mg of 2-tosyloxymethyl-3,4-dihydro-2H-pyran in 2 ml of dimethylformamide was then added and the resulting mixture was allowed to react at 90° C. for 4 hours. The mixture was then treated and the product purified essentially as described in Example 34(a), to give 82 mg of 2-(4-chlorobenzyloxymethyl)-3,4-dihydro-2H-pyran, as a colourless oil.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([Cl:29])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:19]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[CH:28]=[C:27]([Cl:29])[S:26][C:16]=3[N:17]=2)[CH:21]=1
Reactant: Clc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCCc1ccc2c(c1)OCO2
Product: Clc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-methylenedioxyphenethylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.[Li]C(C)(C)C.C(OC([N:26]1[CH2:31][CH2:30][C:29]2([CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]2)[CH2:28][CH2:27]1)=O)(C)(C)C>C1COCC1>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:34]1[CH2:35][CH2:36][C:29]3([CH2:30][CH2:31][NH:26][CH2:27][CH2:28]3)[CH2:32][CH:33]=1)[CH:11]=[CH:10]2
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc2cc(C3=CCC4(CCNCC4)CC3)ccc2c1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Was prepared according to method A with the following variation: To a solution of 2-bromo-6-methoxynaphthalen in dry THF (30 mL) cooled to −40° C., tert-BuLi (1.5 M in pentane (5.55 mL)) was added drop-wise. The mixture was stirred for 1 h at −40° C. and then allowed to warm up to −10° C. 9-Oxo-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (495 mg, 1.85 mmol) in dry THF (10 mL) was added drop-wise and stirred for 3 h at 0° C. Beige solid. Mp. 146.9-149.5° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](OS(C(F)(F)F)(=O)=O)=[CH:6][C:5]=1[CH3:18])(=[O:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:24]1[O:25][CH:26]=[CH:27][CH:28]=1)CCC.[Cl-].[Li+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[C:7]1[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[C:5]([CH3:18])[CH:6]=1
Reactant: CC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1C
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)c1ccc(-c2ccco2)cc1C
Temperature: 25 °C
Yield: 91.9 %

Procedure:
To a stirred solution of trifluoromethanesulfonic acid 4-acetyl-3-methylphenyl ester (1.76 g, 6.25 mmol) in dioxane (60 ml) was added 2-(tributylstannyl)furan (2.68 g, 7.5 mmol), lithium chloride (0.66 g, 15.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.722 g, 0.62 mmol) under nitrogen. The mixture was heated at reflux temperature for 2 hours, and cooled down to room temperature. The reaction mixture was diluted with water and the whole was extracted with diethylether. The organic layer was washed with saturated potassium fluoride aqueous solution, brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:10) to give title compound (1.15 g, 92%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]([OH:17])=O.C[N:19](C)C=O.C(Cl)(=O)C(Cl)=O>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]([NH2:19])=[O:17]
Reactant: CN(C)C=O
Reactant: Cc1oc(-c2ccccc2)nc1CCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCC(N)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
To a mixture of 3-(5-methyl-2-phenyl-4-oxazolyl)propionic acid (20.0 g), N,N-dimethylformamide (0.5 mL) and tetrahydrofuran; (300 mL) was dropwise added oxalyl chloride (13.18 g) under ice-cooling, and the mixture was stirred at room temperature for 1.5 hrs. The reaction mixture was concentrated, and the obtained residue was dissolved in tetrahydrofuran (100 mL). This solution was dropwise added to a mixture of 25% aqueous ammonia (200 mL) and tetrahydrofuran (100 mL) at room temperature. The reaction mixture was stirred at room temperature for 1.5 hrs and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give crystals (15.4 g, 77%) of 3-(5-methyl-2-phenyl-4-oxazolyl)propanamide. Recrystallization from chloroform-ethanol gave colorless prism crystals. melting point: 149-150° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([Cl:21])=[CH:16][CH:17]=2)[N:12]=1>>[Cl:21][C:15]1[N:14]=[C:13]2[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[O:9])=[N:12]2)=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccncc1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1ccncc1
Yield: 36.4 %

Procedure:
The procedure is similar to that described in Example 2, but starting with 4-pyridinecarboxylic acid (6.2 g), N,N'-carbonyldiimidazole (8.1 g) and 2-amino-7-chloro-1,8-naphthyridine (9 g). The product obtained, after precipitation in water (500 cc), washing with tetrahydrofuran (50 cc), then washing with water (200 cc) and drying (9.8 g; m.p. approximately 220° C.), is purified by crystallization in acetonitrile (850 cc). N-(7-Chloro-1,8-naphthyridin-2-yl)-4-pyridinecarboxamide (5.2 g), m.p. 228° C., is thereby obtained.
Reaction SMILES: [NH2:1][C:2]1[NH:7][CH2:6][C:5]2=[C:8]([CH3:14])[N:9]=[C:10]([CH2:11][CH2:12][CH3:13])[N:4]2[N:3]=1.[CH:15](O)=[O:16]>>[CH3:14][C:8]1[N:9]=[C:10]([CH2:11][CH2:12][CH3:13])[N:4]2[C:5]=1[CH2:6][NH:7][C:2]([NH:1][CH:15]=[O:16])=[N:3]2
Reactant: CCCc1nc(C)c2n1N=C(N)NC2
Reactant: O=CO
Product: CCCc1nc(C)c2n1N=C(NC=O)NC2

Procedure:
2-Amino-3,4-dihydro-5-methyl-7-propylimidazo[ 5,1-f]-as-triazine (Example 1a) (2.2 g.) in formic acid (50 ml., 99°) was heated under reflux for 24 hours and evaporated under reduced pressure. The residue was stirred with 2N sodium carbonate and the solid was collected and dried and had m.p. 188.5°-190.5°. Its hydrogen maleate salt had m.p. 159°-161° (crystallised from a mixture of methanol and ether).
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].Cl.Cl[CH2:20][C:21]1[C:22]([NH:33][CH2:34][CH3:35])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=2.ClCC1C(NCC)=NC2C(C=1)=CC(OC)=CC=2.[Li+].[OH-]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:20][C:21]2[C:22]([NH:33][CH2:34][CH3:35])=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=3)=[C:5]([OH:17])[N:4]=1)[CH3:2]
Reactant: CCNc1nc2ccc(OC)cc2cc1CCl
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCNc1nc2ccc(OC)cc2cc1Cc1c(O)nc(CC)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (250 mg, 1.07 mmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-N-ethyl-6-methoxyquinolin-2-amine hydrochloride SLA 28166 (308 mg, 1.07 mmol) followed by 2N aq. LiOH solution (1.07 ml, 2.14 mmol) and the mixture was stirred for 1.5 h at 150° C. under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL) and washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) followed by a new purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 92:8) provided 29 mg of 1-ethyl-4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxyisoquinolin-3-ol as a brown solid. This product was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.55 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 1-ethyl-4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 40 as a yellow solid (20 mg, 4% yield).
Reaction SMILES: [OH:1][C:2]1[C:23]([CH3:24])=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:17][C:16]([CH3:18])=[C:15]3[C:11]=2[CH2:12][C@H:13]2[C:19]([CH3:21])([CH3:20])[C@H:14]23)=[O:9])=[CH:4][C:3]=1[CH3:25].[Na+].[I-].[CH3:28][C:29]1([CH3:41])[O:34][CH2:33][CH:32]([CH2:35]OS(C)(=O)=O)[CH2:31][O:30]1>C(O)(C)C.[OH-].[Na+]>[CH3:28][C:29]1([CH3:41])[O:34][CH2:33][CH:32]([CH2:35][O:1][C:2]2[C:23]([CH3:24])=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]3[S:17][C:16]([CH3:18])=[C:15]4[C:11]=3[CH2:12][C@H:13]3[C:19]([CH3:21])([CH3:20])[C@H:14]34)=[O:9])=[CH:4][C:3]=2[CH3:25])[CH2:31][O:30]1
Reactant: CC1(C)OCC(COS(C)(=O)=O)CO1
Reactant: Cc1cc(CNC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1O
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1cc(CNC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCC1COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-3,5-dimethyl-benzylamide (28.8 mg, 0.08 mmol, Example 5 step b) in isopropanol (3.5 mL) and 2 N aq. NaOH (0.6 mL) is added a catalytic amount of NaI followed by methanesulfonic acid 2,2-dimethyl-[1,3]dioxan-5-ylmethyl ester (90 mg, 0.40 mmol, B. Xu, G. Kirschenheuter, A. F. Greslin, X. Cheng, J. Sennelo, M. Cattaneo, M. L. Zighetti, A. Chen, S.-A, Kim, H. S. Kim, N. Bischofberger, G. Cook, K. A. Jacobson, J. Med. Chem. 45 (2002) 5694-5709). The reaction mixture is shaken at rt for 8 h, diluted with 1 N aq. NaOH, and extracted twice with DCM. The organic extracts are dried over MgSO4, filtered and evaporated. The residue is purified by prep. HPLC to give (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-(2,2-dimethyl-[1,3]dioxan-5-ylmethoxy)-3,5-dimethyl-benzylamide (28 mg) as a colourless solid. LC-MS: tR=1.13 min, [M+1]+=484.34.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][N:13]2C(=O)C3=CC=CC=C3C2=O)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].O.NN>C(O)C>[CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][NH2:13])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: C=CCN1CCN(CCCN)CC1
Reaction time: 2.5 h
Yield: 90.3 %

Procedure:
To a solution of N-[3-(4-allyl-1-piperazinyl)propyl]phthalimide (35.6 g) in ethanol (400 ml) was added 100% hydrazine hydrate (14.3 g). The resulting mixture was refluxed with stirring for 2.5 hours. The reaction mixture was cooled and then filtered. The filter cake was washed with ethanol. The filtrate and washing were combined and evaporated under reduced pressure. The residual oil was subjected to column chromatigraphy (aluminum oxide), eluting with a mixture of chloroform and methanol (10:1). The fractions containing the object compound were collected and then evaporated under reduced pressure to give an oil of 3-(4-allyl-1-piperazinyl)propylamine (18.8 g).
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][C:5]2[NH:6][C:7]3[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=3[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][NH:14][C@@H:13]([CH2:17][CH2:18][O:19][CH3:20])[CH2:12]3)[C:4]=2[CH:3]=1.C=O.[C:29](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][C:2]1[CH:26]=[CH:25][C:5]2[NH:6][C:7]3[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=3[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH3:29])[C@@H:13]([CH2:17][CH2:18][O:19][CH3:20])[CH2:12]3)[C:4]=2[CH:3]=1
Reactant: COCC[C@H]1CN(C2=Nc3ccccc3Nc3ccc(C)cc32)CCN1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3ccc(C)cc32)CCN1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
Combine (S)-2-methyl-11-[3-(2-methoxy-ethyl)-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine (300.0 mg, 0.86 mmol), formaldehyde (76.4 μL, 0.94 mmol, 37% in water), and 1,2-dichloroethane (28.0 ml) and stir the mixture at ambient temperature for 5 minutes and add sodium triacetoxyborohydride (272.1 mg, 1.28 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion, extract the aqueous with dichloromethane and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (90:10) to give 260.4 mg (89%) of a yellow foam: mp=60° C., dec; mass spectrum (ion spray): m/z=365.2 (M+1).
Reaction SMILES: C([O:3][C:4](=O)[NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[F:16])C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O=P(Cl)(Cl)Cl>C(OC(=O)C)C>[F:16][C:9]1[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[C:13]2[C:8]=1[CH2:7][CH2:6][NH:5][C:4]2=[O:3]
Reactant: CCOC(=O)NCCc1cc(OC)ccc1F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(F)c2c1C(=O)NCC2
Temperature: 100 °C
Yield: 25.6 %

Procedure:
[2-(2-Fluoro-5-methoxy-phenyl)-ethyl]carbamic acid ethyl ester (I-44c: 1.6 g, 0.006 mol) was reacted with P2O5 (1.87 g, 0.013 mol) and POCl3 (16 mL) and the resulting mixture was refluxed for 4 hrs at 100° C. The reaction was monitored by TLC (100% ethylacetate). The reaction mass was cooled to room temperature and concentrated under reduced pressure. The concentrate was quenched with ice-water and basified with 2N Na2CO3 solution to pH 8. The resulting solution was partitioned between ethyl acetate and water. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated. Purification by column chromatography on silica gel (2% methanol in DCM) afforded 0.3 g of the product (23.25% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH3:28])[CH2:14][C:15]2[O:16][C:17]([C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[O:21])=[N:18][N:19]=2)(=[O:12])=[O:11])=[C:5]([CH3:29])[CH:4]=1.[Cl:30][C:31]1[N:36]=[CH:35][C:34]([CH:37]=O)=[CH:33][CH:32]=1.ClCCCl>>[Cl:30][C:31]1[N:36]=[CH:35][C:34]([CH2:37][N:25]2[CH2:24][CH2:23][N:22]([C:20]([C:17]3[O:16][C:15]([CH2:14][N:13]([CH3:28])[S:10]([C:6]4[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH3:29])(=[O:11])=[O:12])=[N:19][N:18]=3)=[O:21])[CH2:27][CH2:26]2)=[CH:33][CH:32]=1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N3CCNCC3)o2)c(C)c1
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N3CCN(Cc4ccc(Cl)nc4)CC3)o2)c(C)c1

Procedure:
The title compound was prepared according to general procedure CD using 4-methoxy-N,2,6-trimethyl-N-{[5-(piperazin-1-ylcarbonyl)-1,3,4-oxadiazol-2-yl]methyl}benzenesulfonamide (210 mg, 0.50 mmol), 6-chloropyridine-3-carbaldehyde (84 mg, 0.60 mmol), STAB (210 mg, 0.99 mmol) DCE (4.0 mL) and a few 4 Å molecular sieves. The crude product recrystallised from IPA/MeOH/DCM.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:12])=[CH:5][C:6]=1/[CH:7]=[CH:8]/[C:9](O)=[O:10].S(Cl)([Cl:15])=O>C1C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([CH3:12])=[CH:5][C:6]=1/[CH:7]=[CH:8]/[C:9]([Cl:15])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(/C=C/C(=O)O)c(C)s1
Solvent: c1ccccc1
Product: Cc1cc(/C=C/C(=O)Cl)c(C)s1

Procedure:
To a solution of (E)-3-(2,5-dimethylthiophene-3-yl)acrylic acid (328 mg, 1.8 mmol) in benzene (10 ml) was added thionyl chloride (0.5 ml) and the mixture was heated to reflux for 60 min. Volatiles were removed by evaporation to give crude (E)-3-(2,5-dimethylthiophene-3-yl)acryloyl chloride. Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine (250 mg, 1.4 mmol) and (E)-3-(2,5-dimethylthiophene-3-yl)acryloyl chloride obtained as above according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/ethanol yielded the titled compound. MW: 367.91; mp:>230° C.; 1H-NMR (CDCl3) δ: 8.98-8.83 (2H, m), 8.25-8.16 (1H, m), 8.10-8.02 (1H, m), 7.76-7.68 (2H, m), 7.60-7.42 (3H, m), 6.78-6.73 (1H, m), 6.61 (1H, d, J=16.1 Hz), 2.75 (3H, s), 2.38 (3H, s).