Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH2:17][O:18][C:19](=[O:27])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:14]=[CH:13]1)[N:8]=[C:7]([C:28]([O:30]CC)=[O:29])[C:6](=[O:33])[NH:5]2.[OH-].[Li+].O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH2:17][O:18][C:19](=[O:27])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:14]=[CH:13]1)[N:8]=[C:7]([C:28]([OH:30])=[O:29])[C:6](=[O:33])[NH:5]2
Reactant: CCOC(=O)c1nc2cc(-n3cnc(COC(=O)Nc4ccccc4)c3)c(Cl)cc2[nH]c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(Nc1ccccc1)OCc1cn(-c2cc3nc(C(=O)O)c(=O)[nH]c3cc2Cl)cn1
Temperature: 50 °C
Reaction time: 1.25 h
Yield: 38.6 %

Procedure:
To a solution of the compound (76.0 mg, 162 μmol) of Example 42 in ethanol. (2 ml) were added 1 mol/L aqueous solution of lithium hydroxide (567 μl, 567 μmol) and water (1 ml), and the mixture was stirred for 75 minutes at 50° C. After cooling, water was added to the reaction mixture and the insolubles were filtered off. The filtrate was brought to pH4 with 3 mol/L hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and then air-dried, thereby obtaining 27.5 mg of title compound as light brown powder. Yield 39%.
Reaction SMILES: Cl.[CH:2]([N:5]([CH:42]([CH3:44])[CH3:43])[CH2:6][CH2:7][O:8][C:9]1[CH:41]=[CH:40][C:12]([C:13]([C:15]2[C:16]3[CH:34]=[CH:33][C:32]([O:35]S(C)(=O)=O)=[CH:31][C:17]=3[S:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26]S(C)(=O)=O)=[CH:22][CH:21]=2)=[O:14])=[CH:11][CH:10]=1)([CH3:4])[CH3:3]>C(O)C>[CH:42]([N:5]([CH:2]([CH3:4])[CH3:3])[CH2:6][CH2:7][O:8][C:9]1[CH:41]=[CH:40][C:12]([C:13]([C:15]2[C:16]3[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:17]=3[S:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[O:14])=[CH:11][CH:10]=1)([CH3:43])[CH3:44]
Reactant: CC(C)N(CCOc1ccc(C(=O)c2c(-c3ccc(OS(C)(=O)=O)cc3)sc3cc(OS(C)(=O)=O)ccc23)cc1)C(C)C
Agent: Cl
Solvent: CCO
Product: CC(C)N(CCOc1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1)C(C)C

Procedure:
A 5 g. portion of the product of Example 7 above was hydrolyzed as described above in Example 21, and the residue obtained after evaporation of the volatiles was dissolved in 300 ml. of water. Then solution was washed with 150 ml. of 15:1 diethyl ether:ethyl acetate, and was then made acid with methanesulfonic acid. The solution was then washed with 200 ml. of diethyl ether, and was degassed under vacuum and then made basic with sodium bicarbonate. The solids were collected, washed and vacuum dried to obtain 3.2 g. of crude product. The crude product was chromatographed over a 1 inch×24 inch silica gel column, eluting with a gradient composed of 2 liters of 2% methanol in chloroform phasing into 2 liters of 20% methanol in chloroform. The product-containing fractions were combined and evaporated to dryness to obtain 2.5 g. of purified product, which was characterized by its nmr spectrum (taken in dmso-d6 at 100 mHz): δ0.96 (12H, d, J=7 Hz, (CH(CH3)2)2 ; 2.72 (2H, t, J=6 Hz, NCH2); 2.96 (2H, m, J=7 Hz, (CH(CH3)2)2); 3.88 (2H, t, J=6 Hz, OCH2); 6.65 (2H, d, J=9 Hz, aromatic o to OH); 6.83 (1H, q, JH4-H5 =9 Hz, JH5-H7 =2 Hz, H5 of benzothiophene ring); 6.87 (2H, d, J=9 Hz, aromatic o to OCH2); 7.15 (2H, d, J=9 Hz, aromatic m to OH); 7.26 (1H, d, J=9 Hz, H4 of benzothiophene ring); 7.32 (1H, d, J=2 Hz, H7 of benzothiophene ring); 7.64 (2H, d, J=9 Hz, aromatic o to CO); 9.70 (2H, broad s, OH). High resolution mass spectrum: calculated for C29H31NO4S: 489.199, found 489.199; Ultraviolet spectrum λmax (ε) taken in ethanol 290 nm. (32,000); infrared absorption in KBr at 1605 cm31 1 attributable to the eneone system.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[C:16]([C:19]([NH:21][NH2:22])=[O:20])[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1)=[O:3].[C:23](=S)=[S:24].C(N(CC)CC)C.[OH-].[Na+]>C(O)C.O>[CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:20][C:23]([SH:24])=[N:22][N:21]=4)[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1)=[O:3]
Reactant: S=C=S
Reactant: CS(=O)c1ccc(-n2cnc3ccc(C(=O)NN)cc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CS(=O)c1ccc(-n2cnc3ccc(-c4nnc(S)o4)cc32)cc1
Yield: 67 %

Procedure:
A solution of 1-[4-(methylsulfinyl)phenyl]-1H-benzimidazole-6-carbohydrazide (1.26 g, 4.00 mmol), carbon disulfide (0.601 mL, 10.0 mmol) and triethylamine (0.669 mL, 4.80 mmol) in ethanol (20 mL) was heated under reflux for 3 hr. After cooling, the reaction mixture was poured into water, and alkalified with 1 M aqueous sodium hydroxide solution. The obtained aqueous solution was filtered, and the filtrate was neutralized with 1M hydrochloric acid. The precipitate was collected by filtration, and washed with ethanol to give the title compound (0.955 g, yield 67%) as colorless crystals.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:8]2[CH:12]=[C:11]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=3)[N:10]=[C:9]2[CH3:22])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:30][NH:31][CH3:32].O>CN(C)C=O>[CH3:30][N:31]([CH3:32])[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:8]2[CH:12]=[C:11]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=3)[N:10]=[C:9]2[CH3:22])[CH:7]=1
Reactant: Cc1cc(C#Cc2cn(-c3cncc(F)c3)c(C)n2)ccn1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C#Cc2cn(-c3cncc(N(C)C)c3)c(C)n2)ccn1

Procedure:
3-Fluoro-5-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyridine (48) (100 mg, 0.34 mmol) was dissolved in 5 mL dimethyl formamide. Potassium carbonate (189 mg, 1.38 mmol) and dimethylamine hydrochloride (42 mg, 0.52 mmol) were added and the reaction mixture was refluxed overnight. The reaction mixture was poured into 60 mL water and extracted three times with ethyl acetate (50 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (dichloromethane/methanol 100:0→90:10 gradient) and the desired compound was obtained as an off-white solid (22 mg, 20%), MS: m/e=318.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([Cl:9])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:14](OC(=O)C)(=[O:16])[CH3:15].Cl>>[C:14]([C:7]1[C:2]([Cl:1])=[CH:3][C:4]([Cl:9])=[C:5]([F:8])[CH:6]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: Fc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1cc(F)c(Cl)cc1Cl
Temperature: 80 °C

Procedure:
A mixture of 229.6 g of 1,3-dichloro-4-fluorobenzene and 205.34 g of aluminum chloride was heated at 80° C. A 56 g portion of acetic anhydride was added dropwise over 2 hours, then the reaction ws heated at 100° C. for 8 hours, poured onto a mixture of concentrated hydrochloric acid and ice and extracted several times with ether. The ether extracts were combined, washed with water, dried and the solvents evaporated. The solid was purified by vacuum distillation, giving 156.63 g of 6-acetyl-1,3-dichloro-4-fluorobenzene.
Reaction SMILES: [F:1]C1C=CC(COC2CN(C(C3C=CC=CC=3)C3C=CC=CC=3)C2)=CC=1.Cl[C:28]1[CH:45]=[CH:44][C:31]([CH2:32][O:33][CH:34]2[CH2:37][N:36]([C:38]([NH:40][CH2:41][CH:42]=[CH2:43])=[O:39])[CH2:35]2)=[CH:30][CH:29]=1>>[F:1][C:28]1[CH:45]=[CH:44][C:31]([CH2:32][O:33][CH:34]2[CH2:37][N:36]([C:38]([NH:40][CH2:41][CH:42]=[CH2:43])=[O:39])[CH2:35]2)=[CH:30][CH:29]=1
Reactant: C=CCNC(=O)N1CC(OCc2ccc(Cl)cc2)C1
Reactant: Fc1ccc(COC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Product: C=CCNC(=O)N1CC(OCc2ccc(F)cc2)C1

Procedure:
This material was prepared from compound (9) using the procedure described for compound (2), m.p. 97-99° C. Found: C, 63.57; H, 6.59; N, 10.66. C14H17ClN2O2 requires C, 63.62; H, 6.48; N, 10.59.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:16]([C:26]([OH:28])=[O:27])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:29].[CH2:30](O)[CH3:31].S(=O)(=O)(O)O.C(OCC)(=O)C>O>[NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:16]([C:26]([O:28][CH2:30][CH3:31])=[O:27])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:29]
Reactant: NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)O)C1c1ccc(Cl)cc1Cl
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1c2ccccc2C(=O)N(C2CCCCC2N)C1c1ccc(Cl)cc1Cl

Procedure:
To 4.33 g of (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid were added 50 ml of ethanol and 2 ml of concentrated sulfuric acid, followed by heating under reflux overnight. Ethyl acetate and water were added thereto to carry out a liquid separation operation, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 2.3 g of ethyl (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate as a yellow foam.
Reaction SMILES: ClC1(C2C=CC=CC=2OC)C2C(=CC=C(Cl)C=2)NC1=O.FC(F)(F)C(O)=O.F[C@@H]1CN[C@H](C(OC)=O)C1.[Cl:38][C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[N:44](S(C1C=CC(OC)=CC=1OC(F)(F)F)(=O)=O)[C:43](=[O:64])[C:42]2([N:73]1[CH2:81][C@@H:80]([F:82])[CH2:79][C@H:74]1[C:75]([O:77][CH3:78])=[O:76])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=1[O:71][CH3:72]>>[Cl:38][C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[NH:44][C:43](=[O:64])[C:42]2([N:73]1[CH2:81][C@@H:80]([F:82])[CH2:79][C@H:74]1[C:75]([O:77][CH3:78])=[O:76])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=1[O:71][CH3:72]
Reactant: COC(=O)[C@@H]1C[C@H](F)CN1C1(c2ccccc2OC)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC(F)(F)F)c2ccc(Cl)cc21
Agent: COC(=O)[C@@H]1C[C@H](F)CN1
Agent: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1C[C@H](F)CN1C1(c2ccccc2OC)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.70 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and 1.03 g of the compound obtained in Step 16-1 as starting materials, 1.98 g of a diastereoisomer mixture of the title compound (pea green amorphous) was obtained by a similar method to Step 4-2.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.Cl[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCc1ccccn1
Reactant: COc1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: COc1ccc(N(Cc2cnn(Cc3ccccn3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 26.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.94 g) and 2-(chloromethyl)pyridine hydrochloride (0.33 g) as starting materials, 5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-{[1-(2-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.28 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, 5-hydroxy-N-(6-methoxypyridin-3-yl)-N-{[1-(2-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide dihydrochloride (0.085 g) was obtained.
Reaction SMILES: C1(N2CCN(C3N=C(N)C=CN=3)CC2)CCCC1.ClC(OC1C=CC=CC=1)=O.N1C=CC=CC=1.C1([O:41][C:42](=O)[NH:43][C:44]2[CH:49]=[CH:48][N:47]=[C:46]([N:50]3[CH2:55][CH2:54][N:53]([CH:56]4[CH2:60][CH2:59][CH2:58][CH2:57]4)[CH2:52][CH2:51]3)[N:45]=2)C=CC=CC=1.Cl.[F:63][C:64]1([F:70])[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1>C(Cl)Cl.CCN(CC)CC>[CH:56]1([N:53]2[CH2:52][CH2:51][N:50]([C:46]3[N:45]=[C:44]([NH:43][C:42]([N:67]4[CH2:68][CH2:69][C:64]([F:70])([F:63])[CH2:65][CH2:66]4)=[O:41])[CH:49]=[CH:48][N:47]=3)[CH2:55][CH2:54]2)[CH2:60][CH2:59][CH2:58][CH2:57]1
Reactant: FC1(F)CCNCC1
Reactant: O=C(Nc1ccnc(N2CCN(C3CCCC3)CC2)n1)Oc1ccccc1
Agent: Cl
Agent: Nc1ccnc(N2CCN(C3CCCC3)CC2)n1
Agent: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccnc(N2CCN(C3CCCC3)CC2)n1)N1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5 %

Procedure:
A mixture of 103 mg (0.42 mmol) 2-(4-cyclopentyl-piperazin-1-yl)-pyrimidin-4-ylamine (intermediate 1), 67 mg (0.428 mmol) phenyl chloroformate (commercially available) and 0.1 g (0.12 mmol) pyridine in 4 mL DCM was shaken for 30 min at room temperature. A fraction of this mixture containing 0.07 mmol of the intermediately built [2-(4-cyclopentyl-piperazin-1-yl)-pyrimidin-4-yl]-carbamic acid phenyl ester was treated with 64.8 mg (0.41 mmol) 4,4-difluoro-piperidine, hydrochloride and 0.05 mL NEt3. The mixture was shaken at room temperature and concentrated. Methanol, DMF and water were added and the mixture was subjected to preparative HPLC purification on reversed phase eluting with a gradient of acetonitrile/water (0.05% triethylamine). The combined product fractions were evaporated to dryness to yield 1.1 mg (5%) of the title compound. MS (m/e): 395.3 (MH+).
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9].CN(C)C=O.[BH4-].[Na+]>C1C=CC=CC=1.O1CCOCC1.C([O-])(O)=O.[Na+]>[F:5][C:6]1[C:7]([CH2:8][OH:9])=[CH:11][CH:12]=[CH:13][N:14]=1
Reactant: O=C(O)c1cccnc1F
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: OCc1cccnc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Thionyl chloride (0.43 mL, 5.87 mmol) was added to a slurry of 2-fluoronicotinic acid (9, 0.69 g, 4.89 mmol) and N,N-dimethylformamide (0.1 mL, catalytic amount) in benzene (60 mL) at room temperature under nitrogen, after which the mixture was heated at reflux for 3 h. The solvent was removed under reduced pressure to provide an amber oil that was dissolved in 1,4-dioxane (40 mL) under nitrogen. The solution was treated with sodium borohydride (0.38 g, 10.0 mmol) and the mixture was stirred at room temperature for 24 h. The suspension was diluted with saturated NaHCO3 solution (200 mL) and extracted with diethyl ether (3×200 mL). The combined organic extracts were dried over Na2SO4, filtered and the solvents were removed under reduced pressure to provide the title compound: 1H NMR (300 MHz) 8.13 (d, J=3.7 Hz, 1H), 7.93-7.88 (m, 1H), 7.24-7.19 (m, 1H), 4.78 (s, 2H), 2.14 (bs, 1H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].[CH3:13]I.[Cl-].[NH4+]>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:13]
Reactant: CI
Reactant: Fc1cccc2[nH]ccc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cn1ccc2c(F)cccc21
Temperature: 0 °C
Yield: 99.7 %

Procedure:
In DMF (40 ml) was dissolved 4-fluoroindole (2.00 g, 14.8 mmol). To the resulting solution was added sodium hydride (60% in oil, 0.71 g, 17.8 mmol) in portions under stirring at 0° C. After the reaction mixture was stirred for 40 minutes at the same temperature, methyl iodide (1.11 ml, 17.8 mmol) was added at 0° C. The reaction mixture was stirred further at the same temperature for 4 hours. A saturated aqueous solution of ammonium chloride was added to terminate the reaction. The reaction mixture was extracted with ether, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane-ethyl acetate (5:1, v/v) eluate fractions, 4-fluoro-1-methylindole (2.20 g, 100%) was obtained as a yellow oil.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]1([N+:12]2[C:17](Cl)=[CH:16][C:15]([NH2:19])=[CH:14][N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+].[H][H]>[Ni].O>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]1([N+:12]2[CH:17]=[CH:16][C:15]([NH2:19])=[CH:14][N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: Nc1cn[n+](-c2ccccc2)c(Cl)c1
Agent: [Ni]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1cc[n+](-c2ccccc2)nc1

Procedure:
20.3 parts of 1-phenyl-4-amino-6-chloropyridazinium perchlorate, 200 parts of water, 10 parts of sodium bicarbonate and about 5 parts of Raney nickel are stirred for about three hours in an autoclave at 20° to 25°C and a hydrogen pressure of 200 atmospheres gauge. The reaction solution is filtered from catalyst and evaporated. The cyrstalline residue is washed with a little water. 15.6 parts (86.7% of theory) of 1-phenyl-4-aminopyridazinium perchlorate is obtained; C10H10O4N3Cl, melting point 184° to 186°C after having been recrystallized from methanol.
Reaction SMILES: [OH:1][CH2:2][CH2:3][P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6].Cl[CH2:11][CH2:12][S:13](Cl)(=[O:15])=[O:14]>N1C=CC=CC=1>[CH:12]([S:13]([O:1][CH2:2][CH2:3][P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6])(=[O:15])=[O:14])=[CH2:11]
Reactant: COP(=O)(CCO)OC
Reactant: O=S(=O)(Cl)CCCl
Solvent: c1ccncc1
Product: C=CS(=O)(=O)OCCP(=O)(OC)OC

Procedure:
Dimethyl 2-vinylsulfonyloxyethylphosphonate was prepared in the same way as in Example 1 from 3.8 g of dimethyl 2-hydroxyethylphosphonate, 1.9 g of pyridine and 4.0 g of 2-chloroethylsulfonyl chloride. The yield was 20 mol%. The NMR spectrum (CDCl3) of this product was as follows:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:11]1(=[O:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][NH:12]1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1>C1COCC1.CN(C=O)C>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:12]2[CH:13]=[CH:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]2=[O:21])=[CH:25][CH:26]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=c1[nH]ccc2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=c1c2ccccc2ccn1Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
According to Scheme 11: To a solution of NaHMDS (2 eq, 3.00 mmol, 0.50 g) in THF (3 mL) at 0° C. was added isoquinolin-1(2H)-one (1 eq, 1.00 mmol, 0.20 g) dissolved in THF (3 mL) and DMF (5 mL). The reaction mixture was stirred for 10 min at 0° C. then cooled at −70° C. The 1-(bromomethyl)-4-fluorobenzene (4 eq, 4.00 mmol, 0.80 g) was added in one portion to the reaction mixture. The reaction mixture was allowed to warm to room temperature, for one hour. Upon completion the reaction mixture was concentrated under vacuum and the crude residue partitioned between water and AcOEt, the aqueous layer was extracted with AcOEt. The combined organic layers were successively washed with water (2.30 mL), HCl (1M, 2.30 mL), brine (2.20 mL), dried over Na2SO4, filtered and evaporated to afford a yellow oil. The crude compound was purified on silica gel using cyclohexane/AcOEt 80/20 as eluent to afford 2-(4-fluorobenzyl)isoquinolin-1(2H)-one as a white solid (0.70 mmol, 0.26 g, 74%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[Br:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[Br:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[O:20][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1ccc(COc2cccc(Br)c2)cc1
Temperature: 40 °C
Reaction time: 12 h
Yield: 70.8 %

Procedure:
To a solution of methyl 4-(bromomethyl)benzoate (1 g, 4.4 mmol) in acetone (60 mL) were added 3-bromophenol (1 g, 5.8 mol) and potassium carbonate (1.24 g, 9 mmol). After stirring at 40° C. for 12 hours, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was separated, washed with water (30 mL) and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10:1) to give methyl 4-((3-bromophenoxy)methyl)benzoate (1 g, 71.4%) as a white solid. LRMS (M+H+) m/z: calcd 320.00. found 320. 1H NMR (300 MHz, d6-DMSO): δ 7.98 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.1 Hz, 2H), 7.28-7.22 (m, 2H), 7.15-7.12 (m, 1H), 7.05-7.01 (m, 1H), 5.23 (s, 2H), 3.84 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][C@@:8]1([C:14]([OH:16])=[O:15])[C@H:12]([CH3:13])[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH2:18]([N:10]1[CH2:11][C@@H:12]([CH3:13])[C@@:8]([CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:17])([C:14]([OH:16])=[O:15])[CH2:9]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[C@@H]1CNC[C@]1(CC(=O)OC(C)(C)C)C(=O)O
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H]1CN(Cc2ccccc2)C[C@]1(CC(=O)OC(C)(C)C)C(=O)O
Temperature: 40 °C

Procedure:
A mixture of (3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidine-3-carboxylic acid obtained in Example 1i (1.8 g, 7.4 mmol), benzaldehyde (1.51 ml, 14.8 mmol), acetic acid (0.635 ml, 11.1 mmol), sodium triacetoxyborohydride (3.14 g, 14.8 mmol) and methanol (35 ml) was heated at 40° C. for 38 hours and 30 minutes. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (ODS silica gel, elution solvent: water/methanol) to give the title compound as Lot A (584 mg) and Lot B (708 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]=[N:6][NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:2].ClN1C(=O)CCC1=O.[CH2:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)(O)[O-].[K+]>C(OC(=O)C)C.O>[CH2:8]([N:7]1[CH:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:13])=[N:6]1)[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C=Cc1ccccc1
Reactant: CCCCCNN=CC(=O)OCC
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCN1N=C(C(=O)OCC)CC1c1ccccc1
Temperature: 60 °C
Yield: 22 %

Procedure:
To a magnetically stirred solution of (pentylhydrazono)acetic acid ethyl ester (Intermediate II-1) (35.16 g, 179 mmol) in ethylacetate (450 ml) was added N-chlorosuccinimide (NCS) (26.34 g, 197 mmol) and the resulting mixture was heated at 60° C. for 1 hour in a nitrogen atmosphere. To the reaction mixture was added styrene (41.1 ml, 359 mmol) and potassium bicarbonate (89.8 g, 897 mmol) and water (8 ml). The resulting mixture was heated at 70° C. for 16 hours. The resulting mixture was allowed to attain room temperature, concentrated in vacuo and the resulting residue was chromatographically separated using Sepacore equipment (eluant: dichloromethane/methanol=98/2 v/v) to give ethyl 1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylate (Intermediate (V-1) (12.1 g, 22% yield) as an oil. 1H-NMR (400 MHz, CDCl3) δ 0.83 (t, J=7, 3H), 1.13-1.28 (m, 4H), 1.35 (t, J=7, 3H), 1.53-1.67 (m, 2H), 2.89 (dd, J=16 and 13, 1H), 3.01-3.09 (m, 1H), 3.14-3.22 (m, 1H), 3.41 (dd, J=16 and 12, 1H), 4.31 (double (diastereotopic) quartet, J˜7, 2H), 4.63 (dd, J=13 and 12, 1H), 7.27-7.39 (m, 5H).