Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[S:12])[NH:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:16]1COC[CH2:17]1>ICC>[CH2:16]([S:12][C:10]1[O:11][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:8]=2[N:9]=1)[CH3:17]
Reactant: C1CCOC1
Reactant: O=[N+]([O-])c1ccc2oc(=S)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCI
Product: CCSc1nc2cc([N+](=O)[O-])ccc2o1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
Dissolve 5-Nitro-3H-benzooxazole-2-thione (10.58 g, 53.9 mmol) in anhydrous THF (300 mL). Cool the mixture to 0° C. in an ice bath. Add NaH (4.90 g, 60% dispersion in mineral oil) slowly. Stir the resulting mixture at 0° C. for 10 min. Add iodoethane (20.0 mL, 0.250 mmol) to the stirring mixture. Allow the mixture to warm to room temperature and stir overnight. Adsorb the reaction mixture onto silica gel and subject to flash column chromatography in 2 batches (330 g, 120 g columns, eluting with 10-50% ethyl acetate/n-hexane both times) to yield the desired product (4.93 g, 41%). 1H NMR (400 MHz, DMSO-d6): δ 8.47 (d, J=2.4 Hz, 1H), 8.23 (dd, J=9.2, 2.6 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 3.37 (q, J=6.8 Hz, 2H), 1.45 (t, J=7.6 Hz, 3H).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[F:5][C:6]([F:18])([F:17])[C:7]1[N:11]2[N:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1>N1C=CC=CC=1.C1COCC1>[N:16]([C:13]1[CH:14]=[CH:15][C:10]2[N:11]([C:7]([C:6]([F:18])([F:17])[F:5])=[N:8][N:9]=2)[N:12]=1)=[C:1]=[S:2]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc2nnc(C(F)(F)F)n2n1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: FC(F)(F)c1nnc2ccc(N=C=S)nn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
Thiophosgene (1 mL, 12.7 mmol) was added to a solution of 3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-amine (860 mg, 4.23 mmol) in pyridine (10 mL) and THF (15 mL) and the resulting dark mixture was stirred at room temperature for 2 h. The dark mixture was partitioned between EtOAc and 1M HCl. The organic layer was washed with 1M HCl (2×), dried over sodium sulfate, and evaporated to dryness to afford 545 mg (60% pure) of 6-isothiocyanato-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine as a dark purple solid. LCMS [M+1]+ 278.5 (OMe adduct).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][CH:11]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=3)[N:20]=[CH:19][CH:18]=2)[CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])(=[O:9])=[O:8])=[CH:4][CH:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][CH:11]([C:17]2[N:21]([C:22]3[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=3)[N:20]=[CH:19][CH:18]=2)[CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: CCC(CC)C(NS(=O)(=O)c1ccc(Cl)s1)c1ccnn1-c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCC(CC)C(NS(=O)(=O)c1ccc(Cl)s1)c1ccnn1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
To a stirred solution of 5-chloro-N-{2-ethyl-1-[1-(4-methoxyphenyl)-1H-pyrazol-5-yl]butyl}thiophene-2-sulfonamide (0.30 g, 0.66 mmol) in CH2Cl2 (10 mL) at −780C was added a solution of boron tribromide (1.0 M, 0.99 mL, 0.99 mmol) dropwise. After 4 h at −78° C. and 18 h at room temperature, another 1.5 eq BBr3 (0.99 mL) was added at −78° C. The reaction mixture was gradually warmed to room temperature and stirred for 18 h. The reaction mixture was slowly poured into H2O and extracted with CH2Cl2 (3 x's), dried (MgSO4), filtered, and concentrated in vacuo. The resulting crude solid was purified by column chromatography (SiO2, EtOAc/hexane, 2:3), then precipitated with Et2O/hexane to yield a white solid in 34% yield.
Reaction SMILES: O[C@@H:2]1[C@H:7]2[N:8]([CH:12]([O:19][CH3:20])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9](=[O:11])[O:10][C@H:6]2[CH2:5][C@@H:4]2[CH2:21][O:22][CH:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:24][C@@H:3]12.COCCN(S(F)(F)[F:41])CCOC>C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:41][C@H:2]1[C@H:7]2[N:8]([CH:12]([O:19][CH3:20])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:9](=[O:11])[O:10][C@H:6]2[CH2:5][C@@H:4]2[CH2:21][O:22][CH:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:24][C@@H:3]12
Reactant: COC(c1ccccc1)N1C(=O)O[C@H]2C[C@@H]3COC(c4ccccc4)O[C@H]3[C@H](O)[C@H]21
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(c1ccccc1)N1C(=O)O[C@H]2C[C@@H]3COC(c4ccccc4)O[C@H]3[C@@H](F)[C@H]21
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.5 %

Procedure:
To a solution of (3aR,4R,4aR,8aR,9aS)-4-hydroxy-3-(methoxy(phenyl)methyl)-6-phenyloctahydro-2H-[1,3]dioxino[5′,4′:4,5]benzo[1,2-d]oxazol-2-one (1.77 g, 4.31 mmol) in dry DCM (25 mL) at room temperature was added bis(2-methoxyethyl)aminosulfur trifluoride (3.81 g, 17.2 mmol). The mixture was stirred at room temperature under N2 for 20 h. The mixture was slowly diluted with saturated aqueous NaHCO3 (80 mL), extracted with EtOAc (2×50 mL). The extracts were washed with brine and dried with MgSO4. The solvents were evaporated to give the crude product. This was purified by SiO2 column, eluted with 25-35% EtOAc in hexanes to give (3aS,4S,4aR,8aR,9aS)-4-fluoro-3-(methoxy(phenyl)methyl)-6-phenyloctahydro-2H-[1,3]dioxino[5′,4′:4,5]benzo[1,2-d]oxazol-2-one (900 mg, 51%). MS m/z 436.6 (M+23, 100%); 1H NMR (400 MHz, CDCl3) δ 7.34-7.50 (m, 10H), 6.15 (s, 1H), 5.49 (s, 1H), 4.91 (dd, J=51.4 Hz, 3.0 Hz, 1H), 4.40 (d, J=5.0 Hz, 1H), 4.29 (dd, J=11.2 Hz, 4.8 Hz, 1H), 3.66 (s, 3H), 3.25-3.55 (m, 3H), 2.59-2.71 (m, 1H), 2.20-2.25 (m, 1H), 1.23-1.32 (m, 1H).
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5].[O-:14][Mn](=O)(=O)=O.[K+].Cl>CC#N.O>[I:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[C:4]([OH:14])=[O:5]
Reactant: COc1cc(I)c(C=O)cc1OC
Reactant: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(I)c(C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
To a stirred solution of 2-iodo-4,5-dimethoxybenzaldehyde (1.0 g, 3.42 mmol) in CH3CN (25 mL) was added a solution of KMnO4 (0.76 g, 4.79 mmol) in water (15 mL) dropwise at 0° C. The resulting mixture was stirred at room temperature overnight. After the reaction was complete, the pH was adjusted to <7 with 1N HCl. The mixture was extracted with DCM and the organic layers combined, washed with brine, dried over sodium sulfate, and evaporated to give 2-Iodo-4,5-dimethoxybenzoic acid (0.89 g, 85%).
Reaction SMILES: O.C1O[CH:5]([C:6]2[CH:11]=[CH:10][C:9]([C@H:12]3[CH2:29][C@@:27]4([CH3:28])[C@@H:23]([CH2:24][CH2:25][C@:26]4([C:32]#[CH:33])[O:30]C)[C@H:22]4[C:13]3=[C:14]3[C@@:19](O)([CH2:20][CH2:21]4)[CH2:18][C:17](OC)([O:35]C)[CH2:16][CH2:15]3)=[CH:8][CH:7]=2)[O:4]C1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CC(C)=O>[C:32]([C@:26]1([OH:30])[CH2:25][CH2:24][C@H:23]2[C@H:22]3[C:13]([C@@H:12]([C:9]4[CH:10]=[CH:11][C:6]([CH:5]=[O:4])=[CH:7][CH:8]=4)[CH2:29][C@:27]12[CH3:28])=[C:14]1[C:19](=[CH:18][C:17](=[O:35])[CH2:16][CH2:15]1)[CH2:20][CH2:21]3)#[CH:33]
Reactant: C#C[C@]1(OC)CC[C@H]2[C@@H]3CC[C@@]4(O)CC(OC)(OC)CCC4=C3[C@@H](c3ccc(C4OCCO4)cc3)C[C@@]21C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(C=O)cc3)C[C@@]21C
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.8 %

Procedure:
Water (2 ml) is added to 1.2 g of 4-(3,3-dimethoxy-17α-ethinyl-5α-hydroxy-17β-methoxy-estr-9-en-11β-yl)benzaldehyde ethylene acetal in 20 ml of acetone. After the addition of 300 mg of 4-toluenesulfonic acid, the mixture is stirred for 2 hours at room temperature. The reaction solution is stirred into 300 ml of ice water, a flaky precipitate being obtained. After neutralization with sodium bicarbonate solution and stirring for 30 minutes, the precipitate is filtered off with suction, washed with water and dried under vacuum, 786 mg being obtained as a yellow foam. The crude product is purified by preparative layer chromatography on silica gel PF254+366nm (MERCK AG) with a mixture of 4:1 of toluene:acetone as mobile phase, 430 mg of 4-(17α-ethinyl-17β-hydroxy-3-oxoestra-4,9-diene-11β-yl)benzaldehyde being obtained. The product is recrystallized from boiling t-butyl methyl ether with addition of n-hexane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:10][S:11]([C:14]1[CH:27]=[CH:26][C:17]([CH2:18][CH:19]([C:23](=O)[CH3:24])[C:20](=O)[CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12]>CS(O)(=O)=O.C1(C)C=CC=CC=1>[Cl:8][C:7]1[C:2]2[N:1]=[C:23]([CH3:24])[C:19]([CH2:18][C:17]3[CH:16]=[CH:15][C:14]([S:11]([CH3:10])(=[O:13])=[O:12])=[CH:27][CH:26]=3)=[C:20]([CH3:21])[C:3]=2[C:4]([OH:9])=[CH:5][CH:6]=1
Reactant: Nc1cc(O)ccc1Cl
Reactant: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(C)=O
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: Cc1nc2c(Cl)ccc(O)c2c(C)c1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C

Procedure:
A mixture of 3-amino-4-chlorophenol (1.0 g), 3-(4-methanesulfonylbenzyl)pentane-2,4-dione (0.53 g), methanesulfonic acid (3 drops) and toluene (20 mL) was heated at reflux for 3 hours. The mixture was cooled to room temperature and the solvent removed under reduced pressure. The residue was diluted with ethyl acetate and then washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (1:0 to 99:1 by volume) gave title compound as a pale yellow solid, 0.32 g.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](O)=[C:9]([C:18]#[N:19])[C:8]2=[O:20])=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:25]>O>[Cl:25][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]([CH2:6][C:5]2[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=2)[C:8](=[O:20])[C:9]=1[C:18]#[N:19]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1c(O)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Solvent: O
Product: N#Cc1c(Cl)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Temperature: 100 °C

Procedure:
To 1-(4-Fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-quinoline-3-carbonitrile (1 eq, 0.250 g, 0.85 mmole) was added POCl3 neat. The resulting solution was heated to 100° C. for 8 hours, Reaction mixture was added dropwise to water (20 mL) which had been heated to 80° C. then cooled to RT and extracted with ethyl acetate (25 mL×3). Combined organic phase was washed consecutively with water, brine before drying over sodium sulfate. Organic phase was evaporated and the residue was purified by flash chromatography to afford 4-Chloro-1-(4-fluoro-benzyl)-2-oxo-1,2-dihydro-quinoline-3-carbonitrile as a yellow solid (0.156 g, 59%. LCMS calc M+H 313, obs M+H 313).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:15]([NH2:17])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.[H][H]>CO.[C].[Pd]>[NH2:1][C@H:2]([C:15]([NH2:17])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:12])[CH3:13])[CH:5]=1
Reactant: [H][H]
Reactant: CC(C)(C)c1cc(C[C@H](NC(=O)OCc2ccccc2)C(N)=O)ccc1O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1cc(C[C@H](N)C(N)=O)ccc1O

Procedure:
To a solution of 9.89 g (26.7 mmol) of Z-Tyr(3-tBu)-NH2 in 350 ml of methanol, 3.5 g of 10% palladium carbon was added and the mixture was stirred in a hydrogen atmosphere at room temperature for 10 hours. After filtering, the filtrate was concentrated under reduced pressure and the resulting residue was subjected to silica gel column chromatography (eluting solvent; methylene chloride:methanol=20:1) to yield Tyr(3-tBu)-NH2 in the amount of 5.11 g (81%). NMR(method g,CDCl3): δ 1.40(9H,s), 2.64(1H,dd,J=9.6,13.9 Hz), 3.18(1H,dd,J=4.0,13.9 Hz), 3.49(1H,s), 3.58(1H,dd,J=4.0,9.6 Hz), 5.45(1H,brs), 6.65(1H,d,J=7.9 Hz), 6.92(1H,dd,J=2.0,12.0 Hz), 7.10(1H,d,J=2.0 Hz), 6.94(1H,d,6.6 Hz), 7.2-7.4(8H,m), 7.7-7.9(2H,m), 8.46(1H,d,7.6 Hz), 9.06(1H,d).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17]2[N:22]=[C:21]([NH:23][CH2:24][CH:25]3[CH2:30][CH2:29][CH:28]([N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[CH2:27][CH2:26]3)[C:20]([N+:36]([O-:38])=[O:37])=[CH:19][N:18]=2)[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[CH2:15][NH:16][C:17]1[N:22]=[C:21]([NH:23][CH2:24][C@H:25]2[CH2:26][CH2:27][C@H:28]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:29][CH2:30]2)[C:20]([N+:36]([O-:38])=[O:37])=[CH:19][N:18]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CNc2ncc([N+](=O)[O-])c(NCC3CCC(N4CCCC4)CC3)n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1cccc(CNc2ncc([N+](=O)[O-])c(NC[C@H]3CC[C@H](N4CCCC4)CC3)n2)c1

Procedure:
To a solution of [3-({5-nitro-4-[(4-pyrrolidin-1-yl-cyclohexylmethyl)-amino]-pyrimidin-2-ylamino}-methyl)-benzyl]-carbamic acid tert-butyl ester (132 mg, 0.25 mmol) in DCM (1 mL) was added TFA (2 mL). After 20 min the reaction mixture was concentrated in vacuo and the resulting oil taken up in EtOAc and the solution washed with sat. NaHCO3. The aqueous layer was then extracted with 90:10 CHCl3/i-PrOH. The combined organic layers were concentrated in vacuo and the residue purified by column chromatography (silica gel, 96:4 to 93:7 DCM/10% NH4OH in MeOH) to afford the title compound (25 mg), m/z 440 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=[O:10].C(=O)([O-])[O-].[K+].[K+].[Cl:17]Cl>ClC1C=CC=CC=1Cl.O>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]([Cl:17])=[O:10]
Reactant: Cc1nn(C)c(Cl)c1C=O
Reactant: ClCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Clc1ccccc1Cl
Product: Cc1nn(C)c(Cl)c1C(=O)Cl
Yield: 77 %

Procedure:
Initial charging of 11 g of a 10% solution of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde in 1,2-dichlorobenzene at 10° C., is followed by addition of a solution of 4.6 g of potassium carbonate in 20 ml of water. At 10° C., while illuminating with a mercury lamp, 8 g of chlorine gas are introduced within 1 hour. After the gas introduction has ended, the reaction solution is admixed with water, and the organic phase is removed and washed with water. After removal of the solvent, 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride is obtained in a yield of 77%.
Reaction SMILES: C(=O)(OC(Cl)(Cl)Cl)[O:2][C:3](Cl)(Cl)[Cl:4].[CH2:13]([O:15][CH2:16][CH2:17][OH:18])[CH3:14].N1C=CC=CC=1>O1CCCC1>[C:3]([Cl:4])(=[O:2])[O:18][CH2:17][CH2:16][O:15][CH2:13][CH3:14]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOCCO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOCCOC(=O)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a solution of bis(trichloromethyl) carbonate (2.97 g) in tetrahydrofuran (20 mL) was added dropwise a solution of 2-ethoxyethanol (1.80 g) in tetrahydrofuran (10 mL) under ice-cooling. Then, a solution of pyridine (2.43 mL) in tetrahydrofuran (10 mL) was added dropwise thereto, and stirred at room temperature for 2 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added water (50 mL), and extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with 0.2 N hydrochloric acid (20 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to give 2-ethoxyethyl chlorocarbonate (1.29 g). To a solution of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.23 g) obtained in Reference Synthetic Example 1 in tetrahydrofuran (15 mL) was added pyridine (0.68 mL), then a solution of 2-ethoxyethyl chlorocarbonate obtained above in tetrahydrofuran (5 mL) was added dropwise thereto, and stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, and water (50 mL) was added thereto, and then, extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with 5% aqueous solution of citric acid (50 mL) and saturated saline (50 mL), and dried over anhydrous magnesium sulfate, followed by concentrating under reduced pressure. The residue was purified with silica gel column chromatography (eluted with ethyl acetate:hexane=1:5, then 2:3). The purified material was dissolved in diethyl ether (3 mL), and added 4N hydrogen chloride-ethyl acetate solution (3 mL). After stirring at room temperature overnight, the depositting solid was collected by filtration, and dried under reduced pressure to give title compound as white solid (0.94 g).
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:9][CH2:8][CH2:7][NH:6]1)([O-:3])=[O:2].[Cl:10]/[CH:11]=[CH:12]\[CH2:13]Cl>>[Cl:10]/[CH:11]=[CH:12]\[CH2:13][N:6]1[CH2:7][CH2:8][NH:9][C:5]1=[CH:4][N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])C=C1NCCN1
Reactant: Cl/C=C\CCl
Product: O=[N+]([O-])C=C1NCCN1C/C=C\Cl

Procedure:
Method B, reacting 2-(nitromethylene)imidazolidine with cis-1,3-dichloropropene. Melting point: 117°-118°.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1
Reactant: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Product: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyridin-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 470 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[CH:19]([OH:22])([CH3:21])[CH3:20].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:22][CH:19]([CH3:21])[CH3:20])[N:3]=1
Reactant: CC(C)O
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)Oc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, isopropyl alcohol and DBU in DME. EI-MS m/e (%): 244 (M+, 40), 202 ([M—C3H6]+, 100).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH:12]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:13]([N:15]2[CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH2:16]2)=[O:14])[CH:5]=1.[OH-].[Na+]>CO.O1CCOCC1>[C:26]([O:25][C:23]([NH:22][CH:12]([C:13]([N:15]1[CH2:16][CH2:17][CH:18]([CH3:21])[CH2:19][CH2:20]1)=[O:14])[CH2:11][CH2:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:30])=[O:2])=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)c1cccc(CCC(NC(=O)OC(C)(C)C)C(=O)N2CCC(C)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CC1CCN(C(=O)C(CCc2cccc(C(=O)O)c2)NC(=O)OC(C)(C)C)CC1
Yield: 95.5 %

Procedure:
A solution of 90 mg (0.22 mmol) of 3-[3-tert-butoxycarbonylamino-4-(4-methyl-piperidin-1-yl)-4-oxo-butyl]-benzoic acid methyl ester (prepared in the synthesis of Example 77) in 1 mL of 1:1 MeOH/1,4-dioxane and 0.5 mL of 1 N NaOH is stirred for 3 h. The organic phase is separated and suspended in 2 mL of water. The pH is adjusted to 2 with HCl, and the resulting precipitate is filtered to provide 85 mg (98%) of 3-[3-tert-butoxycarbonylamino-4-(4-methyl-piperidin-1-yl)-4-oxo-butyl]-benzoic acid.
Reaction SMILES: [Se](=O)=[O:2].[C:4]([C:7]1[CH:8]=[CH:9][C:10]([F:22])=[C:11]([C:13]2[C:14]([C:20]#[N:21])=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[CH:12]=1)(=[O:6])[CH3:5]>O1CCOCC1.O.O1CCOCC1>[F:19][C:16]1[CH:15]=[C:14]([C:20]#[N:21])[C:13]([C:11]2[CH:12]=[C:7]([C:4](=[O:6])[CH:5]=[O:2])[CH:8]=[CH:9][C:10]=2[F:22])=[CH:18][CH:17]=1
Reactant: O=[Se]=O
Reactant: CC(=O)c1ccc(F)c(-c2ccc(F)cc2C#N)c1
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cc(F)ccc1-c1cc(C(=O)C=O)ccc1F
Temperature: 25 °C

Procedure:
Selenium dioxide (0.556 g, 5.00 mmol) dissolved in 1,4dioxane:water (4:1, 5 ml) was added in one portion to 5′-acetyl-4,2′-difluorobiphenyl-2-carbonitrile (0.92 g, 3.58 mmol) in 1,4-dioxane (10 ml) and the mixture heated at reflux for 18 h. The reaction was allowed to cool to room temperature, filtered and the filtrate evaporated to give an orange-coloured glassy solid which was used without further purification (0.97 g).
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][CH2:27][CH2:28]O)[CH:22]=[CH:23][C:24]=1[Cl:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][CH2:27][CH2:28][O:17][C:14]2[CH:13]=[CH:12][C:11]([CH:4]([O:3][CH2:1][CH3:2])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:16][CH:15]=2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: CCOC(=O)CC(OCC)c1ccc(O)cc1
Reactant: OCCCc1ccc(Cl)c(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(OCC)c1ccc(OCCCc2ccc(Cl)c(Cl)c2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
Ethyl 3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.420 mmol) produced in Example 1 (1C) and 3-(3,4-dichlorophenyl)propanol (129 mg, 0.630 mmol) synthesized in (11A) were dissolved in tetrahydrofuran (10 mL), and triphenylphosphine (178 mg, 0.680 mmol) and a 40% diethyl azodicarboxylate toluene solution (309 μL, 0.680 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 50° C. for 4 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a colorless oily substance (130 mg, yield: 73%).
Reaction SMILES: [N:1]1[CH:6]=CC=C(CNC(C2C=CC3NC(C4C(C(=O)NC(C)C)=CNN=4)=NC=3C=2)=O)[CH:2]=1.[CH3:31][C:32]1[C:52]([CH3:53])=[CH:51][C:35]2[NH:36][C:37]([C:39]3[C:47]4[C:42](=[CH:43][CH:44]=[C:45]([C:48]([OH:50])=O)[CH:46]=4)[NH:41][N:40]=3)=[N:38][C:34]=2[CH:33]=1.[ClH:54].CNC>>[ClH:54].[ClH:54].[CH3:2][N:1]([CH3:6])[C:48]([C:45]1[CH:46]=[C:47]2[C:42](=[CH:43][CH:44]=1)[NH:41][N:40]=[C:39]2[C:37]1[NH:38][C:34]2[CH:33]=[C:32]([CH3:31])[C:52]([CH3:53])=[CH:51][C:35]=2[N:36]=1)=[O:50]
Reactant: CC(C)NC(=O)c1c[nH]nc1-c1nc2cc(C(=O)NCc3cccnc3)ccc2[nH]1
Reactant: Cc1cc2nc(-c3n[nH]c4ccc(C(=O)O)cc34)[nH]c2cc1C
Agent: CNC
Agent: Cl
Product: Cc1cc2nc(-c3n[nH]c4ccc(C(=O)N(C)C)cc34)[nH]c2cc1C

Procedure:
By proceeding in a manner similar to Example 246(j) above, but (i) using 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carboxylic acid [97 mg, Example 263] and dimethylamine hydrochloride (23 mg), (ii) carrying out the reaction at ambient temperature overnight, and (iii) subjecting the reaction product to flash column chromatography [eluting with ethyl acetate to ethyl acetate/methanol (97:3, v/v)] followed by treatment with 4M hydrogen chloride in 1,4-dioxane and trituration with dichloromethane and diethyl ether there was prepared 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carboxylic acid dimethylamide dihydrochloride (8 mg) as a white solid. LC-MS (METHOD M): RT=9.37 minutes, 320 (M+H)+.