Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[CH:15]=[CH:14][C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:16].[Br:17]N1C(=O)CCC1=O>C([O-])(=O)C.[Na+]>[NH2:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[CH:15]=[C:14]([Br:17])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:16]
Reactant: NC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(=O)[O-]
Agent: [Na+]
Product: NC[C@H]1O[C@@H](n2cc(Br)c(=O)[nH]c2=O)C[C@@H]1O
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 65.3 %

Procedure:
To a solution of 5'-amino-2',5'-dideoxyuridine (0.113 g 0.5 mmole) in 100 ml of 0.05 M sodium acetate buffer, pH 6.0, is added 0.8 g (2.5 mmole) mercuric acetate. The solution is heated at 60° C for 5 hours and cooled on ice. Chelex 100 resin, 20 g, is added and the slurry stirred for 15 minutes at 0° C. The resin is removed by filtration and 0.177 g (1.0 mmole) of N-bromosuccinimide is added. The solution is stirred at room temperature for 30 minutes. The extent of bromination is followed spectrophotometrically at 300 nm, and the reaction terminated by the addition of aniline-ethanol when the absorbance increase plateaus. The reaction mixture is applied directly to a 2 × 15 cm column of Dowex 50 (H+) resin, the column washed with 200 ml of water, and eluted with 1 molar ammonium hydroxide. The solvent is removed at 40° C under reduced pressure, and the residue crystallized from ethanol-ether to provide 100 mg (69%) of the desired product.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]([NH:14][C:15](=[O:38])[CH2:16][C:17](=O)[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[C:28]([CH2:29][O:30]C4CCCCO4)=[CH:27][N:26]=[N:25]3)[CH:19]=2)=[CH:12][C:11]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])=[C:10]([O:46][CH2:47][C:48]([F:51])([F:50])[F:49])[CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:45][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[C:11]1[C:10]([O:46][CH2:47][C:48]([F:51])([F:50])[F:49])=[CH:9][C:8]2[N:7]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N:24]4[C:28]([CH2:29][OH:30])=[CH:27][N:26]=[N:25]4)[CH:19]=3)[CH2:16][C:15](=[O:38])[NH:14][C:13]=2[CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-n3nncc3CO)c2)=Nc2cc(OCC(F)(F)F)c(-c3ccccc3F)cc2N1

Procedure:
The title compound was prepared from (RS)-[2′-fluoro-5-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-2-(2,2,2-trifluoro-ethoxy)-biphenyl-4-yl]-carbamic acid tert.-butyl ester (Example M25) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (10 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:11][N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[CH2:17][OH:18]>>[NH2:1][C:2]1[CH:9]=[C:8]([O:18][CH2:17][C@@H:13]2[CH2:14][CH2:15][CH2:16][N:12]2[CH3:11])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: CN1CCC[C@H]1CO
Reactant: N#Cc1cnc(N)cc1F
Product: CN1CCC[C@H]1COc1cc(N)ncc1C#N

Procedure:
From intermediate 21 and (S)-(1-methylpyrrolidin-2-yl)methanol, reacted in an analogous manner to the preparation of intermediate 47. (UPLC-MS 3) tR 0.30 min; ESI-MS 233.2 [M+H]+.
Reaction SMILES: [P:1]([O-:10])([O:6][CH:7]([CH3:9])[CH3:8])[O:2][CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.[CH2:18]=[O:19]>>[OH:19][CH2:18][P:1](=[O:10])([O:6][CH:7]([CH3:9])[CH3:8])[O:2][CH:3]([CH3:5])[CH3:4]
Reactant: C=O
Reactant: CC(C)OP([O-])OC(C)C
Solvent: CCN(CC)CC
Product: CC(C)OP(=O)(CO)OC(C)C
Reaction time: 0.17 h
Yield: 89.6 %

Procedure:
A mixture of 33.2 g (0.20 mol) of diisopropyl phosphite, 2.8 mL (0.02 mol) of triethylamine, and 6.0 g (0.20 mol) of paraformaldehyde, was immersed in a 100° C. oil bath and then heated between 100°-120° C. for 45 minutes under nitrogen. An exotherm occurred within 10 minutes and all of the paraformaldehyde dissolved rapidly. The triethylamine was removed at reduced pressure, and the residue was bulb-to-bulb distilled in four portions to provide a total of 35.17 g (91%) of title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:18])=[C:15]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1COCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)c(-c3ccccc3)c2)=C(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)N3CCOCC3)c(-c3ccccc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 47.1 %

Procedure:
4-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-phenylbenzoic acid (18 mg, 0.0459 mmol) and morpholine (6 mg, 0.0689 mmol) were dissolved in methylene chloride (3 ml), then WSC-HCl (22 mg, 0.1147 mmol) was added thereto and the mixture was stirred at room temperature for 6 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (hexane:ethyl acetate=1:1) to give the title compound (10 mg, 0.0216 mmol, 47%).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8](=[CH2:28])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:12])=[O:5])C.C[N+]1([O-])CC[O:33]CC1.[O-]S([O-])=O.[Na+].[Na+]>CC(O)(C)C.O.O=[Os](=O)(=O)=O>[OH:33][CH2:28][C:8]1([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:12])[O:5][C:4](=[O:3])[CH2:6][CH2:7]1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=C(CCC(=O)OCC)CCC(=O)OCCCCCCCCCCCCCC
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCCCCCCCCCCCCCOC(=O)CCC1(CO)CCC(=O)O1
Reaction time: 12 h
Yield: 62.8 %

Procedure:
A stirred solution of olefin 3.18 (0.115 g, 0.29 mmol) in t-BuOH (3 mL) and water (1 mL) at 0° C., containing N-methyl morpholine N-oxide (0.069 g, 0.59 mmol), was treated with 2.5% OsO4 solution (0.16 mL). The reaction mixture was brought to room temperature slowly and stirred for 12 h; Na2SO3 (200 mg) was added and, after stirring for a few more minutes, it was concentrated under suction. The residue was extracted with EtOAc (3×10 mL) and the combined extract was washed with water (1×10 mL) and dried (Na2SO4). The residue obtained after evaporation of the solvent was purified by flash column chromatography over silica gel using hexane:EtOAc (3:2) as eluant to give 3.2 (0.070 g ,63%) as white solid; m.p. 61° C. (EtOAc/hexane); IR (KBr) 3380 (OH) and 1728 (C=O) cm-1 ; 1H NMR (CDCl3) δ 0.85 (distorted t, 3H, CH3 (CH2)13), 1.10-1.40 (m, 22H, CH3 (CH2)11CH2CH2OCO), 1.60 (m, 2 H, CH3 (CH2)11CH2CH2OCO), 1.86-2.12 (m, 4 H, H-4, CH2CH2COOC14H29), 2.25-2.78 (multiplets, 4 H, H-3, CH2CH2COOC14H29), 2.90 (t, J=6.5 Hz, 1 H, OH), 3.50 (dd, J=12.1, 6.5 Hz, 1 H, CHHOH), 3.65 (dd, J=12.1, 6.5 Hz, 1 H, CHHOH), 4.05 (t, J=6.7 Hz, 2 H, CH3 (CH2)11CH2CH2OCO); 13C NMR (CDCl3) δ 14.09, 22.65, 25.85, 28.05, 28.33, 28.51, 29.15, 29.21, 29.32, 29.48, 29.55, 29.61, 30.97, 31.88, 65.16, 66.41, 87.54, 173.28, 177.03; FAB MS m/z (relative intensity) 385 (38, MH+), 171 (100, MH-C14H29OH). Anal. Calcd for C22H40O5 : C, 68.7; H, 10.49. Found: C, 68.63; H, 10.44.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[CH2:8][O:7]1.[C:15]1([C:21]2[C:29]3[C:28]([N:30]4[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]4)=[N:27][CH:26]=[N:25][C:24]=3[S:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]([OH:7])[CH2:8][NH:36][CH:33]1[CH2:34][CH2:35][N:30]([C:28]2[C:29]3[C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:22][S:23][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:31][CH2:32]1
Reactant: COc1ccc(OCC2CO2)c(F)c1
Reactant: NC1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1
Product: COc1ccc(OCC(O)CNC2CCN(c3ncnc4scc(-c5ccccc5)c34)CC2)c(F)c1
Yield: 40 %

Procedure:
Synthesis followed SP6 (3 h), using 300 μmol 2-((2-fluoro-4-methoxyphenoxy)methyl)oxirane and 1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give O-methylated intermediate 1-(2-fluoro-4-methoxyphenoxy)-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propan-2-ol upon purification by prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 4:6:1) with 40% yield. Product was obtained by O-demethylation according to SP12 (1 h) with 37% yield (LCMS: detected [M+1]=495.2).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH2:15]([NH2:18])[CH2:16][NH2:17]>>[NH2:17][CH2:16][CH2:15][NH:18][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:4][CH:3]=1
Reactant: NCCN
Reactant: CC(C)(C)OC(=O)c1ccc(Cl)nc1
Product: CC(C)(C)OC(=O)c1ccc(NCCN)nc1

Procedure:
The tert-butyl 6-chloropyridine-3-carboxylate was heated with ethylenediamine (20 ml) at 80° C. overnight. The solvent was removed in vacuo. The residue was partitioned between dichloromethane and 2.5 M aqueous sodium hydroxide solution. The aqueous layer was extracted a further three times with dichloromethane. The combined organic layers were washed with water, dried and concentrated in vacuo to give tert-butyl 6-[(2-aminoethyl)amino]pyridine-3-carboxylate.
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][CH:22]([CH2:25][CH:26]=O)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].[N:28]1[N:29]=[C:30]([NH2:33])[NH:31][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][CH:22]([CH2:25][CH2:26][NH:33][C:30]3[NH:31][CH:32]=[N:28][N:29]=3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4]
Reactant: Nc1nnc[nH]1
Reactant: CN(c1cccc2cc(C3=NCC(CC=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(c1cccc2cc(C3=NCC(CCNc4nnc[nH]4)S3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 0.17 h
Yield: 51.6 %

Procedure:
To a solution of N-methyl-N-{2-[5-(2-oxoethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}thiophene-2-sulfonamide (200 mg) and 4H-1,2,4-triazol-3-amine (80 mg) in acetic acid (3 mL) was added sodium triacetoxyborohydride (200 mg) at room temperature, and the mixture was stirred for 10 min. The reaction mixture was neutralized with saturated aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (120 mg, yield 50%) as white crystals from a fraction eluted with ethyl acetate. melting point 195° C.
Reaction SMILES: [C:1]([C:4]1[NH:8][C:7]2[C:9]([Cl:13])=[C:10]([Cl:12])[S:11][C:6]=2[CH:5]=1)([OH:3])=O.[C:14]([O:18][C:19](=[O:32])[NH:20][CH2:21][C@H:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][C@H:23]1[NH2:31])([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:14]([O:18][C:19](=[O:32])[NH:20][CH2:21][C@H:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][C@H:23]1[NH:31][C:1]([C:4]1[NH:8][C:7]2[C:9]([Cl:13])=[C:10]([Cl:12])[S:11][C:6]=2[CH:5]=1)=[O:3])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)NC[C@H]1c2ccccc2C[C@H]1N
Reactant: O=C(O)c1cc2sc(Cl)c(Cl)c2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC[C@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.7 %

Procedure:
5-Carboxy-2,3-dichloro-4H-thieno[3,2-b]pyrrole (Method 4, 472 mg, 2.0 mmol), tert-butyl[(1R,2R)-2-amino-2,3-dihydro-1H-inden-1-yl]methylcarbamate (Method 13; 524 mg, 2.0 mmol), DIPEA (348 μL, 2.0 mmol), HOBT (270 mg, 2.0 mmol) and EDCI (480 mg, 2.5 mmol) were dissolved in DCM (10 mL) and stirred at ambient temperature for 20 hours. The volatiles were removed by evaporation under reduced pressure, the residue dissolved in EtOAc (50 mL), washed with water (3×25 mL), brine (25 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure to give the title compound (900 mg, 93%) as a pale brown foam.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH:23][C:24](=[O:39])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([N:34]2[CH:38]=[CH:37][N:36]=[CH:35]2)[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]#[C:14][C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:26]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([N:34]5[CH:38]=[CH:37][N:36]=[CH:35]5)[CH:29]=4)[CH2:25][C:24](=[O:39])[NH:23][C:9]=3[CH:10]=2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1NC(=O)CC(=O)c1ccnc(-n2ccnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2ccnc(-n3ccnc3)c2)=Nc2ccc(C#Cc3ccc(F)cc3)cc2N1

Procedure:
Prepared from {4-(4-fluoro-phenylethynyl)-2-[3-(2-imidazol-1-yl-pyridin-4-yl)-3-oxo-propionylamino]-phenyl}-carbamic acid tert.-butyl ester (Example K43) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light brown solid (189 mg).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:11][C:12]1[N:13]=[CH:14][N:15]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=2)[CH:16]=1
Reactant: Cc1c[nH]cn1
Reactant: O=[N+]([O-])c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cn(-c2cccc([N+](=O)[O-])c2)cn1
Temperature: 110 °C
Reaction time: 48 h
Yield: 15.4 %

Procedure:
To a mixture of 112.9 g of m-fluoronitrobenzene and 65.69 g of 4-methylimidazole in 1 liter of dimethylsulfoxide is added 58.51 g of potassium carbonate followed by heating under dry conditions at 110° C. for 39 hours. The reaction mixture is poured into 3.3 liters of water and stored in a refrigerator for 2 days. The mixture is filtered and the cake washed with copious volumes of water followed by suction drying to give 25 g of brown solid. The solid is crystallized from ethyl acetate to give 15.0 g of the desired product as a beige solid, m.p. 119°-120° C. From the combined recrystallization filtrates is obtained 800 mg of 5-methyl-1-(3-nitrophenyl)-1H-imidazole as a beige solid, m.p. 130°-132° C.
Reaction SMILES: CS[C:3](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[S:4][CH3:5].[NH2:11][C:12]1[CH:16]=[CH:15][NH:14][N:13]=1>C(O)C>[NH2:8][C:7]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:3]([S:4][CH3:5])[C:6]=1[C:9]#[N:10]
Reactant: Nc1cc[nH]n1
Reactant: CSC(SC)=C(C#N)C#N
Solvent: CCO
Product: CSc1nc2ccnn2c(N)c1C#N
Temperature: 25 °C
Yield: 88.3 %

Procedure:
10.3 g of bismethylthio methylenepropane dinitrile, 5.0 g of 3-aminopyrazole and 250 ml of ethanol were stirred under reflux with heating for about 6 hours and then cooled to room temperature, and the precipitated crystals were collected by filtration. The collected crystals were washed with ethanol and then dried to obtain 10.9 g of 7-amino-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile (compound No. 1) having a melting point of at least 240° C.
Reaction SMILES: COC([C@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12](OC)=[O:13])[CH2:7][C@H:6]1[C:16](=[O:22])[N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=O.CC(C)([O-])C.[K+].O>C1(C)C=CC=CC=1>[CH2:18]([N:17]([CH2:20][CH3:21])[C:16]([CH:6]1[CH:5]2[CH2:10][CH2:9][N:8]([CH2:11][C:12]2=[O:13])[CH2:7]1)=[O:22])[CH3:19]
Reactant: CCN(CC)C(=O)[C@@H]1CN(CC(=O)OC)CC[C@@H]1C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC)C(=O)C1CN2CCC1C(=O)C2
Temperature: 25 °C
Yield: 30.7 %

Procedure:
A solution of 12 (159 g, 0.503 mole) in toluene (700 ml) was added dropwise over a period 2.5 hours to a solution of potassium t-butoxide (169 g, 1.51 mole) in toluene (1.9L) at 110° C. under a nitrogen condition. The mixture was heated at reflux for 1 hour and cooled down to room temperature. Water (400 ml) was added then the layers were heated at reflux for 2 hours. After the organic layer was separated, the aqueous layer was neutralized and extracted with EtOAc for 15 hours with continuous extraction apparatus. The combined extracts were dried over MgSO4 and concentrated down. Recrystallization from EtOH gave 13 (34.6 g, 31%) as a colorless crystal. The stereochemistry was determined by X-Ray analysis, 13C and NMR.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2OS(C(F)(F)F)(=O)=O)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:22][C:23]1[CH:28]=[C:27]([C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:26]=[CH:25][N:24]=1
Reactant: CC1(C)OB(c2ccnc(Cl)c2)OC1(C)C
Reactant: O=S(=O)(OC1=C(c2ccc(F)cc2)CCCC1)C(F)(F)F
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(C2=C(c3ccnc(Cl)c3)CCCC2)cc1
Temperature: 100 °C
Yield: 58.3 %

Procedure:
Trifluoro-methanesulfonic acid 2-(4-fluoro-phenyl)-cyclohex-1-enyl ester (200 mg, 0.62 mmol), 2-Chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (162 mg, 0.68 mmol), Bis(triphenylphosphine)Palladium (II) dichloride (43 mg, 0.062 mmol), Sodium Carbonate solution (2.0 M, 1.54 mL, 3.1 mmol) and DMF (3 mL) are mixed in a 5 mL microwave tube with a stir bar and the mixture is heated to 100° C. in microwave reactor for 30 min. The mixture is poured to water (10 mL) and extracted with EtOAc (10 mL×3). The organic extracts are washed with water (20 mL×1), brine (20 mL×1) and dried over anhydrous sodium sulfate. After concentration, the crude is purified by silica flash column chromatography using EtOAc in Heptane (gradient from 0% to 20%) to give 104 mg of the desired product.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:29]=[CH:28][C:8]([CH2:9][N:10]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:11]2)=[CH:7][CH:6]=1.[S:30]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[NH:33][C:32](=[O:40])[CH2:31]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:40]=[C:32]1[N:33]([CH2:2][CH2:3][O:4][C:5]2[CH:29]=[CH:28][C:8]([CH2:9][N:10]3[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:12]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:11]3)=[CH:7][CH:6]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[S:30][CH2:31]1
Reactant: O=C1CSc2ccccc2N1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCCBr)cc2)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCc1cn(Cc2ccc(OCCN3C(=O)CSc4ccccc43)cc2)nc1-c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
A mixture of ethyl 3-[1-[4-(2-bromoethoxy)benzyl]-3-phenyl-1H-pyrazol-4-yl]propionate (883 mg), 2H-1,4-benzothiazin-3(4H)-one (320 mg), potassium carbonate (530 mg) and N,N-dimethylformamide (10 ml) was stirred at 80° C. for 8 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). After a mixture of the resulting colorless oily substance, 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 3 hours, 1N hydrochloric acid (5 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated to obtain 3-[1-[4-[2-(3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl)ethoxy]benzyl]-3-phenyl-1H-pyrazol-4-yl]propionic acid (680 mg, yield: 69%) as a colorless amorphous substance.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([CH:7]2[NH:12][CH2:11][CH2:10][NH:9][CH2:8]2)=[N:3]1.[CH2:13]([N:15]1[C:24]2[C:19](=[CH:20][C:21]([F:26])=[C:22](F)[CH:23]=2)[C:18](=[O:27])[C:17]([C:28]([OH:30])=[O:29])=[CH:16]1)[CH3:14]>N1C=CC=CC=1>[CH2:13]([N:15]1[C:24]2[C:19](=[CH:20][C:21]([F:26])=[C:22]([N:9]3[CH2:10][CH2:11][NH:12][CH:7]([C:4]4[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=4)[CH2:8]3)[CH:23]=2)[C:18](=[O:27])[C:17]([C:28]([OH:30])=[O:29])=[CH:16]1)[CH3:14]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: Cn1ccc(C2CNCCN2)n1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4ccn(C)n4)C3)cc21

Procedure:
A 1.0 g portion of 3-(1-methyl-1H-pyrazol-3-yl)piperazine and 508 mg of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid were dissolved in 5 ml of pyridine and heated at 85°-95° C. for 18 hours, in a pressure bottle which had been evacuated and filled with argon. Methanol was added and the solid collected, giving 610 mg of 1-ethyl-6-fluoro-1,4-dihydro-7-[3-(1-methyl-1H-pyrazol-3-yl)-1-piperazinyl]-4-oxo-3-quinolinecarboxylic acid.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1.[CH3:21][N:22]1[C:26]([CH:27]=[O:28])=[CH:25][CH:24]=[N:23]1>>[Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:27]([OH:28])[C:26]4[N:22]([CH3:21])[N:23]=[CH:24][CH:25]=4)=[C:13]([C:15]([O:17][CH3:18])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: Cn1nccc1C=O
Product: COC(=O)c1nc2n(c1C(O)c1ccnn1C)CCOc1cc(F)c(Br)cc1-2
Yield: 33 %

Procedure:
Methyl 10-bromo-9-fluoro-3-(hydroxy(1-methyl-1H-pyrazol-5-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate was prepared similarly according to the procedure in Example 9. Methyl 10-bromo-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxylate was reacted with 1-methylpyrazole-5-carbaldehyde to afford 219 mg (33% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:20])[CH2:10][CH2:11][NH:12][C:13](SC)=[CH:14][N+:15]([O-:17])=[O:16])=[CH:4][N:3]=1.[CH3:21][O:22][NH2:23]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:20])[CH2:10][CH2:11][NH:12][C:13]([NH:23][O:22][CH3:21])=[CH:14][N+:15]([O-:17])=[O:16])=[CH:4][N:3]=1
Reactant: CSC(=C[N+](=O)[O-])NCCN(C)Cc1ccc(Cl)nc1
Reactant: CON
Solvent: CCO
Product: CONC(=C[N+](=O)[O-])NCCN(C)Cc1ccc(Cl)nc1
Yield: 63.4 %

Procedure:
To a solution of 0.95 g of the compound synthesized in Example 1 above in 30 ml of ethanol was added O-methylhydroxylamine (0.16 g), and the mixture was heated under reflux for 1 hour. The ethanol was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the desired N-(2-chloro-5-pyridylmethyl)-N-methyl-N'-(1-methoxyamino-2-nitrovinyl)ethylenediamine (0.6 g) having an nD20 of 1.5466.