Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]([NH:18][CH:19]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]4)=[O:17])[S:15][C:8]=23)=[C:4]([F:33])[CH:3]=1.[C:34]1([CH2:40][C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1.C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:33][C:4]1[CH:3]=[C:2]([NH:1][C:44]([NH:43][C:41](=[O:42])[CH2:40][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[S:45])[CH:32]=[CH:31][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]([NH:18][CH:19]3[CH2:23][CH2:22][NH:21][CH2:20]3)=[O:17])[S:15][C:8]=12
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc3nccc(Oc4ccc(N)cc4F)c3s2)C1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(C(=O)NC4CCNC4)sc23)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.3 %

Procedure:
A solution of 290 (40 mg, 0.084 mmol) and 2-phenylacetyl isothiocyanate (22 mg, 0.126 mmol) in THF (2 mL) was stirred for 30 min. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (eluent EtOAc), to afford a solid material, which was dissolved in a mixture of TFA/DCM (0.5 mL/0.5 mL) and stirred at room temperature for 2 h. Solvents were removed under reduced pressure and the residue was purified by preparative HPLC (Aqusil C18, gradient eluent, 60-95% MeOH in water, 45 min) to afford the title compound 291 (8 mg, 80% yield) as an off-white solid. 1H NMR (d-DMSO) δ (ppm): 9.27(d, 1H), 8.57(d, 1H), 8.37(s, 1H), 8.30(s, 1H), 8.01(d, 1H), 7.53(m, 2H), 7.33-7.31(m, 4H), 7.29-7.25(m, 1H), 6.74(d, 1H), 4.46(m, 1H), 3.82(s, 2H), 3.11-3.03(m, 2H), 2.18-2.09(m, 2H), 1.93-1.89(m, 2H). MS (m/z): 550.2(M+H) (found).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:20])[C:13]=2[N+:17]([O-])=O)[C:8]1=[O:21])(=[O:3])[CH3:2].C(O)C.[Cl-].[NH4+].O>[Fe].C(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:20])[C:13]=2[NH2:17])[C:8]1=[O:21])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCn1ccc2c([N+](=O)[O-])c(Cl)ccc2c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CC(=O)OCCn1ccc2c(N)c(Cl)ccc2c1=O
Reaction time: 0.75 h

Procedure:
A round bottom flask was charged with 2-(6-chloro-5-nitro-1-oxoisoquinolin-2(1H)-yl)ethyl acetate (450.00 mg, 0.0014484 mol), ethanol (20 mL, 0.3 mol) and ammonium chloride (774.8 mg, 0.01448 mol) in water (10 mL, 0.6 mol) was added at 85° C. followed by iron (324 mg, 0.00579 mol) in two portions. The reaction was stirred at that temperature for 45 minutes and then poured into methylene chloride (200 mL) and extracted. The solvent was removed to give the pure product as a light yellow solid. MS m/z=281.3 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]3[CH2:23][O:22]3)[N:9]=2)=[CH:4][CH:3]=1.[O:24]1[C:28]2([CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[O:27][CH2:26][CH2:25]1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]([OH:22])[CH2:23][N:31]3[CH2:32][CH2:33][C:28]4([O:27][CH2:26][CH2:25][O:24]4)[CH2:29][CH2:30]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: CC(=O)N1CCc2c(c(-c3ccc(Cl)cc3)nn2CC2CO2)C1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCc2c(c(-c3ccc(Cl)cc3)nn2CC(O)CN2CCC3(CC2)OCCO3)C1
Reaction time: 8 h
Yield: 80.8 %

Procedure:
To a stirred solution of 3.20 g (9.64 mmol) of 1-[3-(4-chloro-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone and 2.07 g (14.5 mmol) of 1,4-dioxa-8-azaspiro[4.5]decane in CH2Cl2 (65 mL) was added 1.79 g (2.89 mmol) of Yb(OTf)3.H2O. The reaction was stirred overnight and was then directly purified by flash chromatography (silica, 0-5% MeOH/CH2Cl2) to afford 3.70 g (81%) of the title compound. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.35. MS (electrospray), m/z calculated for C24H31ClN4O4 [M++H], 475.20, observed 475.1.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:24](=[O:25])[N:5]2[C:6]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])=[C:7]([Cl:10])[CH2:8][S:9][C@H:4]12.C[Si](CC(N)=O)(C)C.[O:34]1[C:39]([C:40](=[N:44][O:45][CH2:46][CH2:47][CH3:48])[C:41](O)=[O:42])=[CH:38][S:37][CH2:36][CH2:35]1.P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C.CN(C)C=O>[O:34]1[C:39]([C:40](=[N:44][O:45][CH2:46][CH2:47][CH3:48])[C:41]([NH:2][CH:3]2[C:24](=[O:25])[N:5]3[C:6]([C:11]([O:13][CH2:14][C:15]4[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=4)=[O:12])=[C:7]([Cl:10])[CH2:8][S:9][C@H:4]23)=[O:42])=[CH:38][S:37][CH2:36][CH2:35]1
Reactant: CCCON=C(C(=O)O)C1=CSCCO1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)C1=CSCCO1
Yield: 98.9 %

Procedure:
A solution of 4-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate hydrochloride (5.0 g.) and trimethylsilylacetamide (11.3 g.) in dryl ethyl acetate (100 ml.) and a solution of 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-propoxyiminoacetic acid (syn isomer, 3.13 g.), dry N,N-dimethylformamide (1.13 ml.) and phosphoryl chloride (1.33 ml.) in ethyl acetate (54.4 ml.) were treated in a similar manner to that of Example 19-(1) to give 4-nitrobenzyl 7-[2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-propoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 7.10 g.).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.CC1NC2C(C=1)=CC=CC=2.Cl[C:23]1NC2C(C=1)=CC=CC=2.[C:32](=[O:34])=[O:33]>>[C:32]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH3:23])=[CH:5]2)([OH:34])=[O:33]
Reactant: O=C=O
Reactant: Cc1cc2cc(Cl)ccc2[nH]1
Reactant: Clc1cc2ccccc2[nH]1
Agent: Cc1cc2ccccc2[nH]1
Product: CCc1cc2cc(C(=O)O)ccc2[nH]1

Procedure:
This synthesis could start with 5-chloro-2-methylindole, which could be alkylated with methyl indole (see 28a). The product chloroindole could then be converted to its Grignard species and exposed to carbon dioxide to finish the synthesis.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:4][CH:3]=1.Cl[C:15]1N=C(C)C(C)=CC=1.[Li+].CC([N-]C(C)C)C.C(=O)(OCC)OCC>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:5]([CH3:15])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)nc1C
Reactant: CCOC(=O)Cc1cccc(Cl)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(=O)OCC
Product: CCOC(=O)Cc1nc(Cl)ccc1C

Procedure:
Following the same procedure described for the preparation of ethyl (6-chloro-2-pyridinyl)acetate (Example 469) and starting from 6-chloro-2,3-dimethylpyridine (0.35 g, 2.5 mmol), LDA (5.17 mmol), and diethyl carbonate (0.75 mL, 6.2 mmol) in THF (10 mL), the title compound was obtained (0.15 g, 29%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.42 (d, 1H), 7.15 (d, 1H), 4.18 (q, 2H), 3.84 (s, 2H), 2.29 (s, 3H), 1.27 (t, 3H); LC-MS: RT=2.30 min, (M+H)+ 214.2.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.C1N=CN([C:23]([N:25]2[CH:29]=N[CH:27]=[CH:26]2)=[O:24])C=1.Cl.[Cl:31][C:32]1[CH:40]=CC=[C:37]2[C:33]=1CN[CH2:36]2.CCN(C(C)C)C(C)C>C1COCC1.CCOC(C)=O>[Cl:31][C:32]1[CH:33]=[CH:37][CH:36]=[C:27]2[C:40]=1[CH2:29][N:25]([C:23]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1)=[O:24])[CH2:26]2
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: Clc1cccc2c1CNC2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(Cl)c3C2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.1 %

Procedure:
To a solution of (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (0.50 g, 2.04 mmol) in dry THF (6 mL) was added CDI (430 mg, 2.65 mmol) in one portion and the mixture was stirred at rt for 6 h. 4-chloroisoindoline hydrochloride (0.89 g, 4.69 mmol) was then added in portions, followed by slow addition of DIEA (1.07 mL, 6.12 mmol). The reaction was stirred at rt for overnight. The reaction was diluted with 120 mL EtOAc, washed with 1N HCl (2×50 mL), water and brine (50 mL each), and dried over Na2SO4 and concentrated down to a thick brownish oil. The crude was purified by silica chromatography (eluent=hexanes/EtOAc 2:1), giving (2S,4R)-1-tert-butyl 2-methyl 4-(4-chloroisoindoline-2-carbonyloxy)pyrrolidine-1,2-dicarboxylate as a light pinkish foamy solid (0.79 g, 91% yield).
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]2([C:20]([C:22]2(Br)[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]2[C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][O:36]C(=O)C)=[CH:30][CH:29]=2)=[O:21])Br)=[CH:9][CH:8]=1)(=O)C.[OH-:41].[Na+].[OH2:43]>COCCOC>[OH:36][CH2:35][CH2:34][C:31]1[CH:30]=[CH:29][C:28]([CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][C:22]2([C:20]([C:14]2([OH:43])[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]2[C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][OH:4])=[CH:8][CH:9]=2)=[O:21])[OH:41])=[CH:33][CH:32]=1
Reactant: CC(=O)OCCc1ccc(C2CCCCC2(Br)C(=O)C2(Br)CCCCC2c2ccc(CCOC(C)=O)cc2)cc1
Reactant: [OH-]
Reactant: O
Agent: [Na+]
Solvent: COCCOC
Product: O=C(C1(O)CCCCC1c1ccc(CCO)cc1)C1(O)CCCCC1c1ccc(CCO)cc1

Procedure:
A mixture of 8.19 g (23.2 mmol) of 4-(2-acetyloxyethyl)phenyl1-bromo-cyclohexyl ketone, 6.26g (15.65 mmol) of sodium hydroxide, 20 ml of water, and 50 ml of 1,2-dimethoxyethane is heated at reflux for 16 hours. The reaction is concentrated, and then acidified with 25 ml of 1.5 N hydrochloric acid. Ethyl acetate (200 ml) is added, and the organic layer is washed with distilled water, dried over sodium sulfate, and concentrated. The crude product is passed through a pad of silica gel with ethyl acetate as the eluant to give 5.50 g of the title compound which is further purified by recystallization. Mass spectrum: m/z=249 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[S:5][CH:4]=1.C(N(CC)CC)C.[CH2:38]([S:41](Cl)(=[O:43])=[O:42])[CH2:39][CH3:40]>CN(C)C=O>[CH:27]1([CH2:26][NH:25][N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]([OH:24])=[C:14]([C:8]3[NH:7][C:6]4[S:5][CH:4]=[C:3]([CH2:2][NH:1][S:41]([CH2:38][CH2:39][CH3:40])(=[O:43])=[O:42])[C:11]=4[S:10](=[O:12])(=[O:13])[N:9]=3)[C:15]2=[O:30])[CH2:28][CH2:29]1
Reactant: CCCS(=O)(=O)Cl
Reactant: NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 48 %

Procedure:
To a solution of the product of Example 353E (16.7 mg, 0.037 mmol) in N,N-dimethylformamide (0.4 mL) was added triethylamine (0.011 mL, 0.079 mmol). The mixture was cooled to 0° C. and 1-propane sulfonyl chloride was added (0.005 mL, 0.041 mmol). The mixture was warmed to 23° C. and stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with a gradient of 10% acetonitrile/0.1% trifluoroacetic acid in water to 95% acetonitrile/0.1% trifluoracetic acid in water to give the title compound (9.9 mg, 48%). 1H NMR (300 MHz, DMSO-d6) δ 0.15 (d, J=4.04 Hz, 2 H) 0.42 (d, J=7.35 Hz, 2 H) 0.99 (m, 4 H) 1.69 (m, 2 H) 2.84 (d, J=7.35 Hz, 2 H) 3.06 (m, 2 H) 4.27 (d, J=6.25 Hz, 2 H) 6.35 (bs, 1 H) 7.37 (s, 1 H) 7.42 (t, J=7.54 Hz, 2 H) 7.75 (t, J=6.07 Hz, 1 H) 7.87 (t, J=7.17 Hz, 1 H) 8.07 (d, J=8.46 Hz, 1 H) 8.15 (dd, 1 H) 14.52 (bs, 1 H).
Reaction SMILES: C[O:2][C:3](=[O:22])/[CH:4]=[CH:5]/[CH:6]=[C:7](\[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)/[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[OH-].[Na+]>CO>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14](/[C:7](/[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6]\[CH:5]=[CH:4]\[C:3]([OH:22])=[O:2])=[CH:19][CH:18]=1
Reactant: COC(=O)/C=C/C=C(\c1ccc(OC)cc1)c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C(=C\C=C\C(=O)O)c2cccnc2)cc1
Yield: 83.6 %

Procedure:
In the manner described in Example 99, (E,E)-5-(4-methoxyphenyl)-5-(3-pyridinyl)-2,4-pentadienoic acid methyl ester (0.295 g) was saponified in a refluxing mixture of methanol (1.5 mL) and 1N NaOH 1.5 mL). After the cooled reaction was neutralized with 1N HCI (1.5 mL), the crude acid was filtered off and crystallized from methanol to afford 0.235 g of (E,E)-5-(4-methoxyphenyl)-5-(3-pyridinyl)-2,4-pentadienoic acid as its 0.33 molar hydrate, mp 173°-175° C. Anal. Calcd for C17H15NO3 0.33 H2O: C, 71.08: H, 5.49:, N, 4.88. Found: C, 71.01: H, 5.59: N, 4.85.
Reaction SMILES: [OH:1][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48]>CN(C)C=O.O>[C:47]([O:49][CH2:50][CH2:51][O:38][C:35]1[CH:36]=[CH:37][C:32]([CH:2]([OH:1])[CH:3]([NH:18][C:19]([C:21]2[C:26]3[CH:27]=[CH:28][CH2:29][CH2:30][CH2:31][C:25]=3[CH:24]=[CH:23][CH:22]=2)=[O:20])[CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:16])([F:17])[CH:13]([F:15])[F:14])[CH:6]=2)=[CH:33][CH:34]=1)(=[O:48])[CH3:46]
Reactant: CCOC(=O)CBr
Reactant: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(O)cc1)c1cccc2c1C=CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCCOc1ccc(C(O)C(Cc2cccc(OC(F)(F)C(F)F)c2)NC(=O)c2cccc3c2C=CCCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{(1RS,2SR)-2-hydroxy-2-(4-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide (600 mg, 1.13 mmol) in N,N-dimethylformamide (20 ml) were added potassium carbonate (470 mg, 3.40 mmol) and ethyl bromoacetate (570 mg, 3.40 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1). Recrystallization from ethyl acetate-hexane gave the objective substance (167 mg, 24%).
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.Cl.[CH3:12][NH:13][CH:14]1[C:19]2=[C:20]([CH3:27])[C:21]3[C:26]([N:18]2[CH2:17][CH2:16][CH2:15]1)=[CH:25][CH:24]=[CH:23][CH:22]=3>O1CCCC1>[CH3:27][C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:18]2[CH2:17][CH2:16][CH2:15][CH:14]([N:13]([CH3:12])[CH:1]=[O:3])[C:19]=12
Reactant: O=CO
Reactant: CNC1CCCn2c1c(C)c1ccccc12
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: Cc1c2n(c3ccccc13)CCCC2N(C)C=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Formic acid (7 mL) and acetic anhydride (14 mL) were mixed and heated at 60° C. for 4 hours. A solution of 6,7,8,9-tetrahydro-N,10-dimethylpyrido[1,2-a]indol-9-amine hydrochloride (7.49 g, 35 mmol) in tetrahydrofuran (40 mL) was added, and the mixture was stirred at room temperature overnight. The resultant solution was poured onto ice, and products were extracted with ether. The combined extracts were washed with 5% hydrochloric acid, 5% bicarbonate, and water. After drying (MgSO4) and filtration, the solvent was removed, and the residual oil was rapidly filtered through a silica gel column packed in chloroform/methanol 50:1. The title formamide was obtained as a yellowish oil 6.3 g (74%).
Reaction SMILES: [CH3:1][N:2]([C:12]1[S:13][C:14]2[N:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16](=[O:18])[N:17]=1)[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=[O:10])=[CH:5][CH:4]=1.[H][H]>[Pd].CN(C=O)C>[OH:10][NH:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([C:12]2[S:13][C:14]3[N:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16](=[O:18])[N:17]=2)[CH3:1])=[CH:4][CH:5]=1
Reactant: CN(c1ccc([N+](=O)[O-])cc1)c1nc(=O)c2cccnc2s1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: CN(c1ccc(NO)cc1)c1nc(=O)c2cccnc2s1
Temperature: 25 °C
Yield: 6.8 %

Procedure:
A mixture of 1.181 g (3.76 mmol) of 2-[N-methyl-N-(4-nitrophenyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one obtained in Example 63, 100 ml of DMF and 250 mg of 10% Pd on carbon was stirred in an atmosphere of hydrogen for 6 days. The reaction mixture was then heated so that the compound thus precipitated was dissolved. The insoluble matters were hot-removed by filtration. The solution thus obtained was then allowed to cool to room temperature. The resulting crystal was collected by filtration, washed with THF and then with ethanol, and then dried under reduced pressure to obtain 77 mg of 2-[N-(4-hydroxyaminophenyl)-N-methylamino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:14]([C:17]4([C:20]5[CH:21]=[C:22]6[C:27](=[CH:28][CH:29]=5)[N:26]=[CH:25][CH:24]=[CH:23]6)[CH2:19][CH2:18]4)=[N:15][N:16]=3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:30][O:31][C:32]1[N:33]=[CH:34][C:35]([C:2]2[CH:3]=[C:4]([C:8]3[CH:9]=[N:10][C:11]4[N:12]([C:14]([C:17]5([C:20]6[CH:21]=[C:22]7[C:27](=[CH:28][CH:29]=6)[N:26]=[CH:25][CH:24]=[CH:23]7)[CH2:19][CH2:18]5)=[N:15][N:16]=4)[N:13]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:36][CH:37]=1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1cccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2cccc(-c3cnc4nnc(C5(c6ccc7ncccc7c6)CC5)n4n3)c2)cn1
Temperature: 120 °C
Yield: 58.9 %

Procedure:
To a mixture of 6-{1-[6-(3-bromophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl]cyclopropyl}quinoline (16 mg, 0.036 mmol), 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (10 mg, 0.043 mmol), and potassium phosphate (30 mg, 0.14 mmol) in 1,4-dioxane (0.5 mL) was added tetrakis(triphenylphosphine)palladium(0) (3 mg) and water (0.1 mL). The resulting mixture was heated at 120° C. overnight. The reaction mixture was cooled to RT and concentrated. The residue was dissolved in MeOH and purified by RP-HPLC (pH=10) to afford the desired compound 10 mg (60%). Analytical LCMS: (M+H)+=472.2.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][NH2:11].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:11][CH3:10])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1ccc(F)cc1
Reaction time: 1 h

Procedure:
To 4-fluorobenzaldehyde (2.48 g) in MeOH was added methylamine (40% aqueous solution, 2.0 mL). The reaction mixture was stirred at RT for 12 h at which time NaBH4 (0.38 g) was added. After stirring for 1 h the reaction was quenched with H2O and extracted with ethyl acetate. The combined extracts were dried, filtered, and concentrated to yield (4-fluorobenzyl)-methylamine (2.30 g) which was used without further purification.
Reaction SMILES: C[C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4](C)[NH:3]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([N:3]1[CH2:4][CH2:5][NH:6][CH2:7][CH2:2]1)(=[O:19])=[O:18]
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of cis-2,6-dimethylpiperazine and triethylamine in DCM at 0° C. was added dropwise methanesulphonyl chloride and the reaction mixture stirred at room temperature overnight. After quenching with water, extraction into DCM and being washed with brine, the organics were dried and the solvent removed under reduced pressure to yield 1-Methanesulfonyl-piperazine as a pale yellow solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][CH:31]=1)[CH:16]=[N:17][C:18]1[CH:28]=[CH:27][C:21]2[NH:22][C:23](=[O:26])[CH2:24][S:25][C:20]=2[CH:19]=1.CN(C=O)C.[BH4-].[Na+]>CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][CH:31]=1)[CH2:16][NH:17][C:18]1[CH:28]=[CH:27][C:21]2[NH:22][C:23](=[O:26])[CH2:24][S:25][C:20]=2[CH:19]=1
Reactant: O=C1CSc2cc(N=Cc3cccc(OCc4ccc5ccccc5n4)c3)ccc2N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1CSc2cc(NCc3cccc(OCc4ccc5ccccc5n4)c3)ccc2N1
Yield: 79.8 %

Procedure:
7-[3- (2-Quinolinylmethoxy)benzylidenamino]-3,4-dihydro-2H-1,4-benzothiazin-3-one (6.383 g, 15 mmol) obtained in Example 91 was dissolved in a mixed solvent consisting of 200 ml of DMF and 50 me of MeOH, followed by the addition of 2.26 g (60 mmol) of NaBH4 in small portions. After the resultant mixture was stirred for 30 minutes at room temperature, the solvent was distilled off under reduced pressure. Water was added to the residue, followed by extraction with CHCl3. The extract was washed with water, dried over MgSO4 and then concentrated. The concentrate was recrystallized from MeOH-AcOEt, whereby 5.117 g of the title compound were obtained as white powder (yield: 79.8%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][CH:22]1[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][CH2:25][CH2:24][NH:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:23]3[CH2:24][CH2:25][CH2:26][CH:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:22]3[CH3:21])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC1NCCCC1c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1C(c2ccccc2)CCCN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 2-methyl-3-phenylpiperidine (70769-67-4) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=442.5 [MH+].