Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]3[S:19][C:20]([CH3:30])=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C:13]=23)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:31][N:32]1C=CN=C1>[Fe-4](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+].[K+].[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([C:31]#[N:32])[N:15]=[C:14]3[S:19][C:20]([CH3:30])=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C:13]=23)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ccnc1
Reactant: COc1cccc(-c2c(C)sc3nc(Cl)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Agent: N#C[Fe-4](C#N)(C#N)(C#N)(C#N)C#N
Agent: [Cu]I
Agent: [K+]
Product: COc1cccc(-c2c(C)sc3nc(C#N)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 160 °C

Procedure:
To a stirred solution of 3-chloro-N-{6-chloro-2-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}benzenesulfonamide (Example 117) (70 mg, 0.146 mmol) in 1-methylimidazole (1 mL) at RT was added potassium ferrocyanide (12.34 mg, 0.029 mmol) and copper(I) iodide (2.78 mg, 0.015 mmol). The reaction mixture was heated to 160° C. under a nitrogen atmosphere. Extra potassium ferrocyanide (12.34 mg, 0.029 mmol) and copper(I) iodide (2.78 mg, 0.015 mmol) were added and the mixture heated to 180° C. overnight. The reaction mixture was then cooled to RT and purified by normal phase chromatography, eluting with a gradient of 0-40% ethyl acetate in DCM and then further purified by MDAP (acidic conditions), to give the title compound (5 mg). LCMS (A) m/z: 470 [M+1]+, Rt 1.53 min (acidic).
Reaction SMILES: N#N.[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([OH:21])[CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].F[C:29]1[CH:36]=[CH:35][C:32]([CH:33]=[O:34])=[CH:31][CH:30]=1>CN(C=O)C.O>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([O:21][C:29]2[CH:36]=[CH:35][C:32]([CH:33]=[O:34])=[CH:31][CH:30]=2)[CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Reactant: O=Cc1ccc(F)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCc2ccccc2)cc(Oc2ccc(C=O)cc2)c1
Temperature: 90 °C
Yield: 96.5 %

Procedure:
To a single necked round bottomed flask fitted with stop cock with N2(g) balloon, in DMF was added Methyl 3-(benzyloxy)-5-hydroxybenzoate (24 g) (Intermediate 12). Under stirring, potassium carbonate (38 g) followed by 4-fluorobenzaldehyde (13.84 g) were added at room temperature. The reaction was heated at 90° C. for 16 h with constant stirring. The reaction mixture was diluted with water and extracted with EtOAc. All organic layers were combined and washed with water, brine, dried over anhydrous sodium sulphate, filtered and concentrated under vacuum to get crude thick liquid product. The crude product was purified by flash column chromatography to yield title compound (32.5 g).
Reaction SMILES: [CH:1]([C:3]1[N:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)=[CH:5][C:4]=1[C:12]([O:14]C)=O)=O.[OH-].[NH3+:17][NH2:18]>>[C:12]1(=[O:14])[C:4]2[CH:5]=[C:6]3[N:11]([C:3]=2[CH:1]=[N:18][NH:17]1)[CH2:10][CH2:9][CH2:8][CH2:7]3
Reactant: N[NH3+]
Reactant: COC(=O)c1cc2n(c1C=O)CCCC2
Agent: [OH-]
Product: O=c1[nH]ncc2c1cc1n2CCCC1
Temperature: 100 °C
Yield: 75 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a reflux condenser was charged with methyl 3-formyl-5,6,7,8-tetrahydroindolizine-2-carboxylate (127d) (600 mg, 2.9 mmol) and hydrazinium hydroxide (20 mL). The reaction mixture was heated at 100° C. for 4 hours. After this time the reaction was cooled to room temperature and filtered to afford 127e as a yellow solid (413 mg, 75%). MS-ESI: (M+H)+ 190.1. 1H NMR (500 MHz, DMSO-d6) δ 12.17 (s, 1H), 8.24 (s, 1H), 6.33 (s, 1H), 4.16 (t, J=6.0 Hz, 2H), 2.88 (t, J=6.5 Hz, 2H), 2.00-1.96 (m, 2H), 1.84-1.79 (m, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(O[K])(C)(C)C.Cl[CH2:22][C:23]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:24].O>C1COCC1>[N:25]1([C:23](=[O:24])[CH2:22][O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: O=C(CCl)N1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OCC(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of tert-butyl 4-hydroxypiperidine-1-carboxylate (5.00 g) and tert-butoxy potassium (5.57 g) in THF (124 mL) was added 4-(chloroacetyl)morpholine (4.84 mL), and the mixture was stirred at room temperature overnight. Distilled water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the solution was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the obtained solid was washed with hexane-ethyl acetate to give the title compound (4.74 g).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=2)[NH:5]1.Cl[C:18]1[N+:23]([O-])=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=1.P(Cl)(Cl)Cl>C(=O)([O-])O.[Na+].CN(C)C=O>[OH:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[C:18]1[CH:19]=[CH:20][C:21]([CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:22][N:23]=1)=[CH:10][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=2
Reactant: COC(=O)c1ccc2c(c1)CC(=O)N2
Reactant: [O-][n+]1cc(CN2CCOCC2)ccc1Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClP(Cl)Cl
Product: COC(=O)c1ccc2[nH]c(O)c(-c3ccc(CN4CCOCC4)cn3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.9 %

Procedure:
To a N,N-dimethylformamide (10 mL) suspension of sodium hydride (97%, 0.784 g, 32.7 mmol) was added methyl 2-oxoindoline-5-carboxylate (2.34 g, 12.3 mmol). The formed mixture was stirred for 10 min at room temperature followed by the addition of 4-[(6-chloro-1-oxidopyridin-3-yl)methyl]morpholine (1.87 g, 8.2 mmol). The resulting reaction mixture was set under N2 atmosphere and stirred for 1 h at 135° C. The N,N-dimethylformamide solution was diluted with saturated aqueous sodium hydrogen carbonate (30 mL) and extracted with chloroform, and ethyl acetate (containing 5% methanol). The combined organic phases were concentrated in vacuo. The remaining N,N-dimethylformamide was removed by co-evaporation with toluene. The residue was dissolved in ethyl acetate/chloroform, (150 mL, 2:1), and phosphorus trichloride (4.5 g, 33 mmol) was added. The reaction mixture was stirred for 1 h at 60° C., and then cooled to room temperature. The mixture was poured into a saturated aqueous sodium hydrogen carbonate solution followed by extraction of the aqueous phase with chloroform (4×). The combined organic extracts were concentrated in vacuo, and the residue was purified on a silica gel column using chloroform/methanol, (10:1), as the eluent to afford 1.05 g (35% yield) of the title compound as a yellow-brown solid: 1H NMR (DMSO-d6, 400 MHz) δ 10.83 (br s, 1H), 8.11 (s, 1H), 8.04 (s, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.63 (t, J=8.0 Hz, 2H), 7.00 (d, J=8.0 Hz, 1H), 3.87 (s, 3H), 3.62 (br s, 4H), 3.41 (s, 2H), 2.42 (br s, 4H); MS (EI) m/z 368 (M++1).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][N:8]1[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]1.F[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23].[Cl-].[NH4+]>C1COCC1>[F:21][C:19]1[CH:18]=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[C:15]([NH:13][C:11]2[CH:10]=[N:9][N:8]([CH3:7])[CH:12]=2)[CH:20]=1
Reactant: Cn1cc(N)cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1cc(Nc2cc(F)ccc2[N+](=O)[O-])cn1
Reaction time: 0.25 h
Yield: 15.6 %

Procedure:
Potassium tert-butoxide (1.16 g, 10.3 mmol) was added to a solution of 1-methyl-1H-pyrazol-4-ylamine (0.50 g, 5.15 mmol) in THF (10 mL) at 0° C. under nitrogen and resultant mixture stirred for 15 min. 2,4-difluoro-1-nitrobenzene (0.98 g, 6.18 mmol) in THF (5 mL) was added and stirring continued for 1 h. The reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with EtOAc (×3). The combined EtOAc extracts were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by chromatography (SiO2, 0-2% methanol in DCM) to give the title compound as a red gummy solid (0.19 g, 16%). LCMS (Method B): RT 3.12 min [M+H]+ 236.9
Reaction SMILES: Cl[C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:7]=1.[NH:18]([CH2:22][CH2:23][OH:24])[CH2:19][CH2:20][OH:21]>O1CCOCC1>[OH:21][CH2:20][CH2:19][N:18]([C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:7]=1)[CH2:22][CH2:23][OH:24]
Reactant: NS(=O)(=O)c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: OCCNCCO
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cc(N(CCO)CCO)c([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 99.1 %

Procedure:
A solution of 5-chloro-2,4-dinitrobenzenesulfonamide (VIII) [Herbert, R. B. and Hollman, R. G. Tetrahedron, 1965, 21, 663-675] (1.55 g, 5.5 mmol) and diethanolamine (1.16 g, 11 mmol) in dioxan (100 mL) was held at 60° C. for 1.5 h, then adsorbed directly onto silica gel. Excess solvent was evaporated under reduced pressure, and the residue was chromatographed on silica gel, eluting with EtOAc/MeOH (19:1), to give 5-[N,N-bis(2-hydroxyethyl)amino]-2,4-dinitrobenzenesulfonamide (IX) (1.91 g, 99%), mp (EtOAc/petroleum ether) 138°-139° C. 1H NMR ((CD3)2SO) δ 8.53 (s, 1 H, H-3), 7.97 (s, 1 H, H-6), 7.93 (br s, 2 H, SO2NH2), 4.88 (t, J=5.1 Hz, 2 H, OH), 3.65 (dt, J=5.2, 5.1 Hz, 4 H, CH2OH), 3.49 (t, J=5.1 Hz, 4 H, NCH2). 13C NMR δ 146.84 (C-5), 140.53 (C-1), 136.84, 134.39 (C-2,4), 125.70 (C-3), 54.27 (NCH2). Anal. (C10H14N4O8S) C,H,N.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([CH:14](O)[CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([CH:20]([CH3:22])[CH3:21])=[N:10]2)=[CH:5][CH:4]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[O:31])=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([CH:14]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:31])=[CH:28][CH:29]=3)[CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([CH:20]([CH3:22])[CH3:21])=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: COc1ccc(-n2cc(C(O)CC(C)C)c(C(C)C)n2)cc1
Product: COc1ccc(-n2cc(C(CC(C)C)Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)c(C(C)C)n2)cc1
Yield: 0.8 %

Procedure:
Using 1-[(1-(4-methoxyphenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl]-3-methylbutan-1-ol (0.57 g) synthesized in Example 54(1) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.48 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (8.0 mg, 1%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[CH2:26][CH2:25][CH2:24][NH:23][C:22]3=[O:27])[CH2:17][CH2:16]2)[CH2:10][NH:11][CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:28]1([C:38](Cl)=[O:39])[C:37]2[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=2[CH:31]=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[CH2:26][CH2:25][CH2:24][NH:23][C:22]3=[O:27])[CH2:17][CH2:16]2)[CH2:10][N:11]([CH3:12])[C:38]([C:28]2[C:37]3[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=3[CH:31]=[CH:30][CH:29]=2)=[O:39])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cl)c1cccc2c1CCCC2
Reactant: CNC[C@@H](CCN1CCC(N2CCCNC2=O)CC1)c1ccc(Cl)c(Cl)c1
Product: CN(C[C@@H](CCN1CCC(N2CCCNC2=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1cccc2c1CCCC2

Procedure:
Using standard acylation conditions N-[(S)-2-(3,4-dichlorophenyl)4-[4-[tetrahydro-2-oxo-1(2H)-pyrimidinyl]-1-piperidinyl]butyl]-N-methylamine (S. C. Miller,. WO 9505377) was reacted with 5,6,7,8-tetrahydro-1-naphthalenecarbonyl chloride (Example 1) and the product was converted to the citrate salt MS: m/z 571 (M+H). Analysis for C31H40O2Cl2N4.C6H8O7.3.0H2O: calculated: C,54.34; H, 6.66; N, 6.85; found: C, 54.26; H, 5.97; N, 6.47.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]#[N:10].[C:11]([C:15]1[C:24]2[O:23][CH2:22][CH2:21][NH:20][C:19]=2[CH:18]=[C:17]([C:25](=[O:27])[CH3:26])[CH:16]=1)([CH3:14])([CH3:13])[CH3:12].C(OCC)(=O)C>CN(C)C=O>[C:25]([C:17]1[CH:16]=[C:15]([C:11]([CH3:14])([CH3:12])[CH3:13])[C:24]2[O:23][CH2:22][CH2:21][N:20]([CH2:8][C:9]#[N:10])[C:19]=2[CH:18]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)c1cc2c(c(C(C)(C)C)c1)OCCN2
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1cc2c(c(C(C)(C)C)c1)OCCN2CC#N
Temperature: 90 °C
Reaction time: 6 h
Yield: 99.4 %

Procedure:
Potassium carbonate (3.6 g, 26 mmol) and bromoacetonitrile (15.4 g, 128.6 mmol) were added to a solution of 1-[8-(tert-butyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-1-ethanone (6.0 g, 25.5 mmol) in dimethylformamide (100 ml) and the mixture was stirred at 90° C. for 6 hours. Ethyl acetate was added, the reaction mixture was washed with water and brine in that order and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and then the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (6.9 g) as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.C([Li])CCC.C(O[B:22]1[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]1)(C)C.C(O)(=O)C>C1COCC1.CCCCCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([B:22]3[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]3)=[CH:11][CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-n2cccn2)cc1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CC1(C)OB(c2ccnn2-c2ccc(F)cc2)OC1(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a stirred solution of commercially available 1-(4-fluorophenyl)-1H-pyrazole [CAS No 81329-32-0] (2.27 g, 14.0 mmol) in THF (100 ml) was added drop wise at −78° C. under argon atmosphere n-butyl lithium (1.6N in hexane, 10.5 ml, 16.8 mmol. The reaction mixture was allowed to stir for 1 h at −78° C. Afterwards commercially available 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.84 g, 3.12 ml, 15.0 mmol) was added drop wise at −78° C., and the mixture was stirred for 1.5 h at −78° C. The mixture was allowed to reach room temperature within 1 h, and acetic acid (0.925 g, 881 μl, 15.4 mmol) was added. The mixture was filtered using a Celite pad, which was washed with ethyl acetate, and the filtrate was evaporated to dryness. The crude product (4.36 g, light brown solid) was purified by flash chromatography on silica gel (heptane/ethyl acetate, 10-50%) to yield the title compound as an off-white solid (2.04 g, 51%), MS (ISP) m/z=289.5 [(M+H)+], mp 133° C.
Reaction SMILES: [C:1](=O)([O-:3])[O-:2].[Ba+2].[CH3:6][CH2:7][CH2:8][CH2:9][CH:10]1[C:45](=[O:46])[O:44][CH:43]([CH:47]([CH:49]([OH:57])[CH2:50][CH2:51][CH2:52][NH:53][C:54]([NH2:56])=[NH:55])[CH3:48])[CH:42]([CH3:58])[CH:41]=[C:40]([CH3:59])[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]([OH:60])[CH2:34][CH:33]([OH:61])[CH2:32][CH:31]([OH:62])[CH2:30][CH:29]([OH:63])[CH2:28][CH:27]([OH:64])[CH:26]([O:65][C@H:66]2[O:70][C@H:69]([CH2:71][OH:72])[C@@H:68]([OH:73])[C@@H:67]2[OH:74])[CH:25]=[C:24]([CH3:75])[CH:23]([OH:76])[CH2:22][CH2:21][CH2:20][CH:19]([OH:77])[CH2:18][CH2:17][CH2:16][CH:15]([OH:78])[CH2:14][CH2:13][CH:12]([CH3:79])[CH:11]1[OH:80].S([O-])([O-])(=O)=O.CO>C(O)=O>[CH3:6][CH2:7][CH2:8][CH2:9][CH:10]1[C:45](=[O:46])[O:44][CH:43]([CH:47]([CH:49]([OH:57])[CH2:50][CH2:51][CH2:52][NH:53][C:54]([NH2:56])=[NH:55])[CH3:48])[CH:42]([CH3:58])[CH:41]=[C:40]([CH3:59])[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]([OH:60])[CH2:34][CH:33]([OH:61])[CH2:32][CH:31]([OH:62])[CH2:30][CH:29]([OH:63])[CH2:28][CH:27]([OH:64])[CH:26]([O:65][C@H:66]2[O:70][C@H:69]([CH2:71][OH:72])[C@@H:68]([OH:73])[C@@H:67]2[OH:74])[CH:25]=[C:24]([CH3:75])[CH:23]([OH:76])[CH2:22][CH2:21][CH2:20][CH:19]([OH:77])[CH2:18][CH2:17][CH2:16][CH:15]([OH:78])[CH2:14][CH2:13][CH:12]([CH3:79])[CH:11]1[OH:80].[CH:1]([O-:3])=[O:2]
Reactant: O=C([O-])[O-]
Agent: CCCCC1C(=O)OC(C(C)C(O)CCCNC(=N)N)C(C)/C=C(\C)CCCCC(O)CC(O)CC(O)CC(O)CC(O)C(O[C@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)/C=C(\C)C(O)CCCC(O)CCCC(O)CCC(C)C1O
Agent: CCCCC1C(=O)OC(C(C)C(O)CCCNC(=N)N)C(C)C=C(C)CCCCC(O)CC(O)CC(O)CC(O)CC(O)C(O[C@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)C=C(C)C(O)CCCC(O)CCCC(O)CCC(C)C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Solvent: O=CO
Product: O=C[O-]
Reaction time: 0.17 h

Procedure:
0.088 g (0.446 millimole) of barium carbonate are heated to boiling in 5 ml of formic acid until a clear solution is obtained. The colorless solution is evaporated to dryness in vacuo. The residue is dissolved in 10 ml of methanol and the solution thus obtained is added to a suspension of 1.0 g (0.887 millimole) or primycin sulfate and 70 ml of methanol. The reaction mixture is heated to boiling for 10 minutes under constant stirring. The precipitated barium sulfate is filtered hot through a Celite filtration auxiliary agent. The filtrate is evaporated in vacuo and the solid residue is treated with ether. The white powdery product is washed with 20 ml of a 2:1 mixture of acetone and water and thereafter with anhydrous ether. Thus 0.96 g of primycin formate is obtained, yield 94.8%. Mp.: 162°-164° C., /α/D25 =+31.9°. (in a 2:2:1 mixture of n-butanol, ethanol and water, c=0.1%)
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.C(N(CC)CC)C.Cl.Cl.[NH2:38][O:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43]>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:38][O:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCON
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
A solution of the carboxylic acid (6b, 553 mg, 2.00 mmol) of Example 9 or 16 in dehydrated methylene chloride (10 mL) was cooled to 0° C. under an argon atmosphere, followed by adding dropwise isobutyl chloroformate (289 μL, 2.20 mmol). Then, triethylamine (293 μL) was added, followed by stirring for 30 minutes. Thereby, a mixed acid anhydride was prepared in the reaction system. To this reaction mixture were gradually added 2-(aminooxy)-N,N-dimethylethanamine dihydrochloride (591 mg) described in Reference Example 18 and triethylamine (930 μL) while washing with dehydrated methylene chloride (7.0 mL), followed by stirring at the same temperature for 1 hour. This reaction mixture was filtered though Kiriyama filter paper. Subsequently, the residue was washed with methanol and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in methylene chloride and water, and the organic layer extracted with methylene chloride was dried over magnesium sulfate, followed by distilling off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (amino silica, chloroform/methanol=10/1) to afford 291.1 mg of the title compound as a colorless oil (yield 40%).
Reaction SMILES: C([NH:4][C:5]1[C:6]([OH:13])=[N:7][C:8]([NH2:12])=[N:9][C:10]=1[OH:11])(=O)C.[ClH:14]>>[ClH:14].[NH2:12][C:8]1[N:9]=[C:10]([OH:11])[C:5]([NH2:4])=[C:6]([OH:13])[N:7]=1
Reactant: CC(=O)Nc1c(O)nc(N)nc1O
Agent: Cl
Product: Nc1nc(O)c(N)c(O)n1
Reaction time: 1 h
Yield: 46 %

Procedure:
5-Acetamido-2-amino-4,6-dihydroxypyrimidine (700 g crude) (ex. guanidinium carbonate, diethyl acetamido malonate and ethanol refluxed 48 hours), concentrated hydrochloric acid (2 liters water), (200 ml), were heated to 70° and kept at 70°-75° for 1 hour, then cooled in an ice bath. The product was filtered, washed with HCl (80 ml conc HCl in water 170 ml), then acetone (1 liter), and air dried at 40° to give the title compound (344.5 g). Found: C 24.53, H 4.33, N 28.9 Cl 17.9; C4H6N4O2 ·HCl·H2O requires C 24.4, H 4.6, N 28.5, Cl 18.0%. NMR C13 84.59, 115.24, 157.22 ppm DMSO MS/FAB M+H 143. Vacuum oven drying at 0.5 mm and 85° C. with argon protection gave 320 g (46% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25]>N1C=CC=CC=1>[F:19][C:20]([F:30])([F:31])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1)=[O:25]
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: COc1ccc2nc(-c3ccc(NC(=O)c4cccc(C(F)(F)F)c4)cc3)sc2c1
Yield: 86.3 %

Procedure:
Prepared as described in the Amide Coupling section using 2-(4-aminophenyl)-6-methoxybenzothiazole (0.06 g, 0.23 mmol) and 3-trifluoromethylbenzoyl chloride (0.054 g, 0.26 mmol) in dry pyridine (7.5 ml) to give the title compound (0.085 g, 85%) as a colourless solid after work-up.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]#[N:12])[C:5]=1[Cl:13])#[N:2].Cl.N[C:16]1[C:21]([F:22])=[C:20]([F:23])[CH:19]=[CH:18][C:17]=1[SH:24]>>[F:22][C:21]1[C:16]2[N:2]=[C:1]([CH2:3][C:4]3[C:5]([Cl:13])=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=3)[S:24][C:17]=2[CH:18]=[CH:19][C:20]=1[F:23]
Reactant: Nc1c(S)ccc(F)c1F
Reactant: N#CCc1cccc(CC#N)c1Cl
Agent: Cl
Product: N#CCc1cccc(Cc2nc3c(F)c(F)ccc3s2)c1Cl
Yield: 20 %

Procedure:
The procedure of Example 22-i) was repeated using 1,3-biscyanomethyl-2-chlorobenzene (870 mg, 4.4 mmol) and 2-amino-3,4-difluorothiophenol hydrochloride (956 mg, 4.8 mmol) and the resultant product was recrystallized from ethyl acetate-hexane to give 3-[(4,5-difluorobenzothiazol-2-yl)methyl]-2-chlorophenylacetonitrile (295 mg, 20%) as a colorless powder.
Reaction SMILES: C([O:8][C:9](=[O:17])[CH2:10][N:11]1[C:15]([CH3:16])=[N:14][CH:13]=[N:12]1)C1C=CC=CC=1>CCO>[CH3:16][C:15]1[N:11]([CH2:10][C:9]([OH:17])=[O:8])[N:12]=[CH:13][N:14]=1
Reactant: Cc1ncnn1CC(=O)OCc1ccccc1
Solvent: CCO
Product: Cc1ncnn1CC(=O)O

Procedure:
The final compound (5-methyl-[1,2,4]triazol-1-yl)-acetic acid was prepared using a method analogous to that of Example 14 step 14.2, (5-methyl-[1,2,4]triazol-1-yl)-acetic acid benzyl ester replacing intermediate 14.1 and using EtOH instead of MeOH/AcOH. LC-MS (B): tR=0.19 min; [M+H]+: 142.24.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@H:10]([N:13]([CH3:15])[CH3:14])[CH2:9]2)=[CH:4][CH:3]=1.[CH2:16]([N:19]1[C:27](=[O:28])[C:26]2[C:21](=[N:22][C:23](SC)=[N:24][CH:25]=2)[N:20]1[C:31]1[N:36]=[C:35]([N:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]2=[O:43])[CH:34]=[CH:33][CH:32]=1)[CH:17]=[CH2:18]>>[CH2:16]([N:19]1[C:27](=[O:28])[C:26]2[C:21](=[N:22][C:23]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([N:8]4[CH2:12][CH2:11][C@H:10]([N:13]([CH3:15])[CH3:14])[CH2:9]4)=[CH:4][CH:3]=3)=[N:24][CH:25]=2)[N:20]1[C:31]1[N:36]=[C:35]([N:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]2=[O:43])[CH:34]=[CH:33][CH:32]=1)[CH:17]=[CH2:18]
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1cccc(-n2ccccc2=O)n1
Reactant: CN(C)[C@H]1CCN(c2ccc(N)cc2)C1
Product: C=CCn1c(=O)c2cnc(Nc3ccc(N4CC[C@H](N(C)C)C4)cc3)nc2n1-c1cccc(-n2ccccc2=O)n1

Procedure:
The entitled compound was obtained as a yellow solid (36.7 mg) in the same manner as in Production Example 12-2, for which, however, (3S)-1-(4-aminophenyl)-N,N-dimethylpyrrolidin-3-amine was used in place of [5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used in Production Example 12-2, and 6′-[2-allyl-6-(methylthio)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-2H-1,2′-bipyridin-2-one was used in place of 2-allyl-6-(methylthio)-1-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidin-3-one.