Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:26]=[CH:25][C:9]2[N:10]=[C:11]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:18]=4[N:19]=3)[N:12]([CH3:13])[C:8]=2[CH:7]=1)=[O:5])C.[OH-].[Na+]>CO.C1COCC1>[Cl:24][C:22]1[CH:21]=[CH:20][C:18]2[N:19]=[C:15]([NH:14][C:11]3[N:12]([CH3:13])[C:8]4[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:26]=[CH:25][C:9]=4[N:10]=3)[S:16][C:17]=2[CH:23]=1
Reactant: CCOC(=O)c1ccc2nc(Nc3nc4ccc(Cl)cc4s3)n(C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2ccc(C(=O)O)cc21
Yield: 89.8 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-3-methyl-3H-benzoimidazole-5-carboxylic acid (1 g) was prepared by following General Procedure E starting from 2-(6-chloro-benzothiazol-2-ylamino)-3-methyl-3H-benzoimidazole-5-carboxylic acid ethyl ester (1.2 g) and 2 N NaOH (5 mL) in methanol:THF (1:1, 20 mL).
Reaction SMILES: Cl[CH2:2][Si:3]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Na].[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.O>CN(C)C=O>[CH3:13][C:12]([CH3:15])([O:11][Si:3]([CH2:2][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)([CH3:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:14]
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)O[Si](C)(CCl)c1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)O[Si](C)(Cn1ccnc1)c1ccccc1
Reaction time: 3 h
Yield: 92.3 %

Procedure:
A mixture of 3.6 g (0.015 mol) of chloromethyl(1,1-dimethylethoxy)methyl(phenyl)silane and 1.3 g (0.015 mol) of imidazole sodium salt in 10 ml of dimethylformamide was stirred at 50° for 3 hours, allowed to stand at room temperature for 72 hours, poured into water, and extracted with ether. The ether extracts were washed three times with water and once with brine, dried over magnesium sulfate, and evaporated to leave 3.8 g of an oil. Impurities were removed by Kugelrohr distillation at 90° (airbath)/0.05 mm to leave 2.9 g (71%) of the title compound as a pale yellow oil: nD20 15291; ir (neat) 3105, 3070, 3045, 2970, 1590, 1500, 1425, 1360, 1250, 1235, 1185, 1110, 1055, 1020, 900, 805, 740, 700, 660 cm-1 ; nmr (CDCl3): 0.6 (3H, s), 1.3 (9H, s), 3.6 (2H, s), 6.8 (1H, s), 7.0 (1H, s) and 7.3-7.7 (6H, m).
Reaction SMILES: [CH2:1]([O:8][N:9]1[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(OCC)(=O)C>O1CCCC1>[CH2:1]([O:8][N:9]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccn(OCc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1ccn(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.1 %

Procedure:
To a solution of 1-benzyloxy-1H-pyrrole-3-carbaldehyde described in Preparation Example 63 (500 mg, 2.5 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (75 mg, 1.97 mmol), and the solution was stirred at room temperature for 10 minutes. Water and ethyl acetate were added to the reaction solution, which was then partitioned, silica gel was added to the organic layer, the solvent was evaporated in vacuo for adsorption, purification by silica gel column chromatography (hexane:ethyl acetate=2:1) was carried out, and the title compound (168 mg, 0.828 mmol, 33.1%) was obtained as a colorless oil.
Reaction SMILES: FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)C[N:7]([C:29]1[N:34]=[CH:33][C:32]([C:35]2[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=2)=[CH:31][N:30]=1)[C@@H]1CN(C2C(CO)=CN=C(N3CCCCC3)N=2)[C@H](CC)C1.CI.[H-].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH3:40][N:38]1[CH:39]=[C:35]([C:32]2[CH:31]=[N:30][C:29]([NH2:7])=[N:34][CH:33]=2)[CH:36]=[N:37]1
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1c1nc(N2CCCCC2)ncc1CO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(-c2cnc(N)nc2)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 142.7 %

Procedure:
To a solution of [4-((2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidin-1-yl)-2-piperidin-1-yl-pyrimidin-5-yl]-methanol (40 mg, 0.06 mmol) and methyl iodide (0.004 mL, 0.7 mmol) in 1 mL of DMF is added sodium hydride (2.8 mg, 0.07 mmol) and stirred at room temperature for 1 day. Saturated NH4Cl aqueous solution is added at room temperature and then extracted twice with 50 mL of EtOAc. The combined organic layer is washed with brine, dried over Na2SO4 and concentrated. Column chromatography (eluent: hexane/EtOAc) give (3,5-bis-trifluoromethyl-benzyl)-[3S,5R)-5-ethyl-1-(5-methoxymethyl-2-piperidin-1-yl-pyrimidin-4-yl)-pyrrolidin-3-yl]-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine (15 mg, 37% yields) as white solid.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:18]1([NH:21][C:22]([C:24]2[S:37][C:27]3=[N:28][C:29](S(C)=O)=[C:30]([Cl:33])[C:31]([CH3:32])=[C:26]3[C:25]=2[NH2:38])=[O:23])[CH2:20][CH2:19]1>C1COCC1>[CH:18]1([NH:21][C:22]([C:24]2[S:37][C:27]3=[N:28][C:29]([O:7][CH2:1][CH2:2][O:3][CH2:4][CH2:5][OH:6])=[C:30]([Cl:33])[C:31]([CH3:32])=[C:26]3[C:25]=2[NH2:38])=[O:23])[CH2:20][CH2:19]1
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Reactant: OCCOCCO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Cl)c(OCCOCCO)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 38.9 %

Procedure:
To a solution of diethylene glycol (1.118 g, 10.54 mmol) in THF (3 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl)amide (1.0 M in hexanes) (3.50 ml, 3.50 mmol). The reaction mixture is stirred for 15 minutes and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (0.345 g, 1.00 mmol). The reaction mixture is heated at 75° C. for 1 hour, cooled to room temperature, and then quenched by the addition of water (15 ml). Ice is added to the reaction mixture and, while stirring, a yellow precipitate is formed. This solid is collected by filtration and placed in the vacuum oven to dry (60° C. for 16 hours). This affords the title compound as a yellow solid (0.150 g, 39%). Mass (m/z): 386.2 (M++1), 384.1 (M+−1).
Reaction SMILES: C(N1C([N+]([O-])=O)=CN=C1)C.C(N1C([N+]([O-])=O)=CN=C1)CC.C(N1C([N+]([O-])=O)=CN=C1)CCC.[CH2:34]([N:36]1[C:40]([N+:41]([O-:43])=[O:42])=[CH:39][N:38]=[C:37]1[CH2:44][OH:45])C.C(N1C([N+]([O-])=O)=CN=C1CO)CC.C(N1C([N+]([O-])=O)=CN=C1CO)CCC.OCC1NC([N+]([O-])=O)=CN=1>>[CH3:34][N:36]1[C:40]([N+:41]([O-:43])=[O:42])=[CH:39][N:38]=[C:37]1[CH2:44][OH:45]
Reactant: CCn1c([N+](=O)[O-])cnc1CO
Agent: CCCCn1c([N+](=O)[O-])cnc1CO
Agent: CCCCn1cncc1[N+](=O)[O-]
Agent: CCCn1c([N+](=O)[O-])cnc1CO
Product: Cn1c([N+](=O)[O-])cnc1CO

Procedure:
When 1-ethyl-5-nitroimidazole, 1-propyl-5-nitroimidazole, 1-n-butyl-5-nitroimidazole, and 4(5)-nitroimidazole are used in the above reaction, respectively, the following compounds are prepared: 1-ethyl-2-hydroxymethyl-5-nitroimidazole; 1-propyl-2-hydroxymethyl-5-nitroimidazole; 1-n-butyl-2-hydroxymethyl-5-nitroimidazole; and 2-hydroxymethyl-5-nitroimidazole.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:52])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]2[C:43]([CH2:44][O:45][CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][O:47]3)=[CH:42][N:41]=[N:40]2)[CH:34]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:17])[CH3:18])[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32](=[O:52])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]2[C:43]([CH2:44][O:45][CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][O:47]3)=[CH:42][N:41]=[N:40]2)[CH:34]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Product: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(isopropyl-methyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J37) (340 mg, 0.98 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (393 mg, 0.98 mmol) according to the general procedure M. Obtained as a light yellow foam (510 mg, 77%).
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH:16]=O)=[CH:15][C:10]=3[N:9]=[C:8]2[NH:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][C:33]=4[O:34][CH3:35])[CH:26]=3)[N:21]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH2:16][N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[CH:15][C:10]=3[N:9]=[C:8]2[NH:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][C:33]=4[O:34][CH3:35])[CH:26]=3)[N:21]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:42])([CH3:41])[CH3:43])[N:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: COc1ccncc1-c1ccc2c(c1)c(Nc1nc3cc(C=O)ccc3n1C1CCCCC1)nn2COCC[Si](C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccncc1-c1ccc2c(c1)c(Nc1nc3cc(CN4CCOCC4)ccc3n1C1CCCCC1)nn2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.8 %

Procedure:
In a 20 mL vial was added 1-cyclohexyl-2-(5-(4-methoxypyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-ylamino)-1H-benzo[d]imidazole-5-carbaldehyde (28 mg, 0.047 mmol.), morpholine (10 mg, 0.11 mmol) and methylene chloride (2 mL). A catalytic amount of acetic acid was added and the reaction mixture stirred at room temperature for 10 min. Sodium triacetoxyborohydride (30 mg, 0.14 mmol) was then added and the reaction mixture stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride and washed with water, saturated sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and concentrated to give the title compound (15 mg) which was used directly in the next step.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]([N:9]1[C:13]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=2[C:11]([O:19]C(C)=O)=[CH:10]1)=[O:8]>O>[Cl:18][C:15]1[CH:14]=[C:13]2[C:12]([C:11]([OH:19])=[CH:10][N:9]2[C:7](=[O:8])[CH3:6])=[CH:17][CH:16]=1
Reactant: CC(=O)Oc1cn(C(C)=O)c2cc(Cl)ccc12
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)n1cc(O)c2ccc(Cl)cc21
Temperature: 0 °C

Procedure:
A solution of 572 ml of concentrated sulfuric acid is added to 63 ml of water with stirring and cooling. When the acid solution is at room temperature, 134 g (0.53M) of 6-chloroindoxyl-1,3-diacetate is added, portionwise, with stirring over a period of one hour keeping the temperature of the solution between 20° C. and 25° C. After stirring for 30 additional minutes after the addition is complete, the solution is poured onto 2 kilograms of ice. The ice is allowed to melt and the insoluble product is recovered by filtration and washed with cold water. This product is then protected from light and air and dried in a vacuum oven at room temperature. The yield of light yellow solid is about 110 g. This product is very unstable and may not be stored for long periods without decomposition. It is used immediately in the next step.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2([C:13]#[N:14])[CH2:11][C:10](=[O:12])[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>C(Cl)Cl.CO>[F:1][C:2]1[C:3]([C:8]2([C:13]#[N:14])[CH2:11][CH:10]([OH:12])[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1(c2ncccc2F)CC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: N#CC1(c2ncccc2F)CC(O)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a solution of 1-(3-fluoropyridin-2-yl)-3-oxocyclobutanecarbonitrile (231 g, 1.22 mol) in a mixture of DCM (2 L) and MeOH (200 mL) was added NaBH4 portionwise at −78° C. The reaction mixture was stirred at −78° C. for 1 h and quenched with a mixture of methanol and water (1/1). The organic layer was washed with water (500 mL×3), dried over Na2SO4, and concentrated. The residue was purified on silica gel (50% EtOAc/hexanes) to provide the title compound as an amber oil (185.8 g, 77.5%). LRMS (M+H+) m/z 193.2.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=1.Cl[CH2:14][CH:15]=O>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[CH:14]=[CH:15][N:12]=[C:8]2[CH:7]=1
Reactant: COCCOc1ccnc(N)c1
Reactant: O=CCCl
Solvent: C1CCOC1
Product: COCCOc1ccn2ccnc2c1
Temperature: 75 °C
Yield: 102.7 %

Procedure:
A mixture of 4-(2-methoxyethoxy)pyridin-2-amine (20.0 g, 119 mmol), 2-chloroacetaldehyde (32.2 ml, 250 mmol) and tetrahydrofuran (100 mL) were heated in a sealed tube to 75° C. over 3 days. The reaction mixture was concentrated under reduced pressure and dissolved in ethyl acetate. The resulting solution was washed twice sodium bicarbonate. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to yield title compound (23.5 g, quantitative yield) MS APCI (+) m/z 193 (M+1) detected.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[F:19][C@@H:20]1[CH2:24][NH:23][C@H:22]([C:25]([NH2:27])=[O:26])[CH2:21]1>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([N:23]3[CH2:24][C@@H:20]([F:19])[CH2:21][C@H:22]3[C:25]([NH2:27])=[O:26])=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: NC(=O)[C@@H]1C[C@H](F)CN1
Agent: Cl
Product: NC(=O)[C@@H]1C[C@H](F)CN1C(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 47 b, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3 c, 50 mg, 214 μmol) and (2S,4S)-4-fluoro-2-pyrrolidinecarboxamide hydrochloride (1:1) (CAN 426844-23-7; 40 mg, 236 μmol) as starting materials and isolated (68 mg, 91%) as off-white solid; LC-MS (UV peak area, ESI) 100%, 348.1721 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[C:16]3=[N:17][C:18]([C:22]4[CH:27]=[CH:26][N:25]=[CH:24][N:23]=4)=[CH:19][C:20](=[O:21])[N:15]3[CH2:14][CH2:13][CH2:12]2)=[O:10])=[C:4]([O:28][CH3:29])[CH:3]=1.[H-].[Na+].[CH3:32]I>CN(C)C=O.O.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([CH3:32])[C:16]3=[N:17][C:18]([C:22]4[CH:27]=[CH:26][N:25]=[CH:24][N:23]=4)=[CH:19][C:20](=[O:21])[N:15]3[CH2:14][CH2:13][CH2:12]2)=[O:10])=[C:4]([O:28][CH3:29])[CH:3]=1
Reactant: COc1cc(Cl)ccc1NC(=O)C1CCCn2c1nc(-c1ccncn1)cc2=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Cl)ccc1NC(=O)C1(C)CCCn2c1nc(-c1ccncn1)cc2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
To a suspension of 0.100 g (0.24 mmol) of 4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylic acid N-(4-chloro-2-methoxy-phenyl)-amide (example 1) in 1.00 mL of dimethylformamide was added 0.010 g (0.24 mmol) of sodium hydride at 0° C. and the resulting mixture was stirred at room temperature for 2 hours. 0.020 mL (0.24 mmol) of methyl iodide was added and the mixture was stirred at room temperature for 1 hour. The mixture was dissolved in water and dichloromethane. The organic phases were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography (cyclohexane/ethyl acetate in proportions of 80/20 to 70/30) to afford 0.053 g (51%) of a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl.O.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:19]([CH3:18])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CNc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)Cc1cccc(Br)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.9 %

Procedure:
6 g (28 mmol) of (3-bromophenyl)acetic acid in 50 ml of dichloromethane are introduced into a three-necked flask under a stream of nitrogen. At 0° C., 2.7 ml (28 mmol) of oxalyl chloride are added dropwise and the mixture is then stirred at room temperature for 18 hours. The reaction medium is evaporated to dryness and the residue is placed in 10 ml of tetrahydrofuran and added dropwise to a mixture of 3.2 g (28 mmol) of N-methylaniline, 50 ml of tetrahydrofuran and 4.6 ml (33 mmol) of triethylamine. The reaction medium is stirred at room temperature overnight, immersed in water and extracted with ethyl acetate. After separation of the phases once settling has taken place, the organic phase is dried over magnesium sulfate, filtered and evaporated. 5.7 g (67%) of the desired product, with a melting point of 60° C., are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[CH2:34]([O:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[N:48]1[CH2:54][CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[CH3:35].C(N(CC)C(C)C)(C)C.CO.ClCCl>C(#N)C.C(OCC)(=O)C.ClCCl>[CH3:32][O:31][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:51]2[CH2:52][CH2:53][CH2:54][N:48]([C:40]3[N:39]([CH2:38][CH2:37][O:36][CH2:34][CH3:35])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:49][CH2:50]2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Agent: I
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) (5.5 g, 11.9 mmol), 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (7.0 g, 12.9 mmol), and N,N-diisopropylethylamine (9.0 mL, 51.4 mmol) in acetonitrile (100 mL). Heat to reflux. After 18 hours, cool to ambient temperature and dilute the reaction mixture with ethyl acetate (400 mL). Extract with a saturated aqueous sodium bicarbonate solution and then with brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 25% methanol/dichloromethane containing aqueous concentrated ammonia (20 mL/3 L). Combine the product containing fractions to give a residue. Dissolve the residue in dichloromethane and filter. Evaporate the filtrate in vacuo to give the title compound: mp; 43-48° C.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:36])[N:33]([CH3:35])[CH3:34])=[CH:27][CH:26]=2)=[N:4]1)[CH3:2].[CH3:37][NH:38][CH3:39].C1COCC1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:37][N:38]([CH2:23][C:19]1[CH:18]=[C:17]([C:15]2[NH:14][C:10]3=[N:11][CH:12]=[CH:13][C:8]([C:6]4[C:5]([C:25]5[CH:26]=[CH:27][C:28]([NH:31][C:32](=[O:36])[N:33]([CH3:35])[CH3:34])=[CH:29][CH:30]=5)=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=4)=[C:9]3[CH:16]=2)[CH:22]=[CH:21][CH:20]=1)[CH3:39]
Reactant: CNC
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4cccc(C=O)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To N′-(4-{1-ethyl-4-[2-(3-formylphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyrazol-3-yl}phenyl)-N,N-dimethylurea (11.45 g, 23.9 mMol) was added a solution of 2 M dimethylamine in THF (24 mL, 48 mMol). The slurry was rinsed down with THF (150 mL) and treated with NaBH(OAc)3 (8.6 g, 40.6 mMol). (Gentle gas evolution was seen and the reaction got slightly warm to the touch.) The reaction was stirred at RT for 1 h (started out as a thick suspension that slowly became a homogeneous fine suspension) and concentrated to dryness under vacuum. The residue that remained was basified with aq. 1 N Na2CO3, (200 mL) and aq. 1 N NaOH (25 mL), extracted with CHCl3 (300 mL) washed with brine, dried (Na2SO4), filtered, and evaporated to dryness under vacuum. Trituration with (1:1) Et2O/pet. ether, filtration, and drying under vacuum gave the title compound (11.20 g, 92%) as a yellow solid (>95% pure by HPLC): MS (ES) m/e 508.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) 12.14 (d, J=1.8 Hz, 1 H), 8.31 (s, 1 H), 8.27 (s, 1 H), 8.07 (d, J=4.8 Hz, 1 H), 7.78 (d, J=8.1 Hz, 1 H), 7.77 (s, 1 H), 7.43 (d, J=8.6 Hz, 2 H), 7.39 (d, J=8.1 Hz, 1 H), 7.27 (d, J=8.6 Hz, 2 H), 7.27 (dd, 1 H), 6.79 (d, J=5.1 Hz, 1 H), 6.76 (d, J=2.0 Hz, 1 H), 4.27 (q, J=7.3 Hz, 2 H), 3.43 (s, 2 H), 2.18 (s, 6 H), 1.51 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:10]=2)[C:5]([NH:17]C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.[ClH:25]>C(OCC)(=O)C>[ClH:25].[NH2:17][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:7]=2)[C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)c2ccc(OS(C)(=O)=O)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Oc1ccc2c(Br)ccc(N)c2c1
Reaction time: 30 h

Procedure:
A solution of the product from Step C (4.60 g, 11.0 mmol) in ethyl acetate (200 mL) was saturated with HCl gas. The solution was stirred for 30 hours and then concentrated in vacuo to yield the titled compound as a brown solid.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:8]([OH:7])[C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCC#CCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCCCCC#CCO

Procedure:
A process for preparing the sex pheromone of Lymantria dispar L. effectively which comprises the steps of reacting 1-bromodecane and propargyl alcohol tetrahydropyranylether in the presence of sodium hydroxide to give 1-tetrahydropyranyloxy-2-tridecyne, treating the tetrahydropyranyloxy-2-tridecyne with p-toluenesulfonic acid to give 2-tridecyn-1-ol, catalystic-hydrogenating the 2-tridecyn-1-ol in the presence of Lindlar catalyst to give (Z)-2-tridecen-1-ol, oxidizing the (Z)-2-tridecen-1-ol with peroxide to give (±)-cis-2,3-epoxy-1-tridecanol, reacting the (±)-cis-2,3-epoxy-1-tridecanol with acid anhydride in the presence of hydrolase in an organic solvent for a stereoselective acylation and recovering unreacted optically active (2R, 3S)-cis-2,3-epoxy-1-tridecanol after the acylation, reacting the optically active (2R, 3S)-cis-2,3-epoxy-1-tridecanol with toluenesulfonylchloride to give (2R, 3S)-cis-1-p-toluenesulfoxy-2,3-epoxytridecane, and reacting the (2R, 3S)-cis-1-p-toluenesulfoxy-2,3-epoxytridecane with di(4-methylpentyl) lithium copper reagent to yield (7R, 8S)-cis-2-methyl-7,8-epoxyoctadecane which is the sex pheromone of Lymantria dispar L.