Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([OH:13])=O.[NH2:14][C@H:15]([C:19]([NH:21][CH:22]([CH:31]([OH:34])[CH2:32][F:33])[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:20])[CH:16]([CH3:18])[CH3:17].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:14][C@H:15]([C:19]([NH:21][CH:22]([CH:31]([OH:34])[CH2:32][F:33])[CH2:23][C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13]
Reactant: Cn1c(C(=O)O)cc2ccccc21
Reactant: CC(C)[C@H](N)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Temperature: 0 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 1-methylindole-2-carboxylic acid (130 mg, 0.74 mmol) and N-(valinyl)-3-amino-4-hydroxy-5-fluoropentanoic acid, tert-butyl ester in methylene chloride (5 mL) and cooled to 0° C. Solid 4-dimethylaminopyridine (DMAP) (95 mg, 0.78 mmol) and 1-(3′-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (200 mg, 1.04 mmol) were added to the solution at 0° C. The reaction mixture was stirred at 0° C. for 1 h and allowed to warm slowly to room temperature. After 4 h the reaction was partitioned between ethyl acetate (EtOAc) and 5% KHSO4 aqueous solution. The organic layer was washed with 5% KHSO4 solution, saturated sodium bicarbonate solution, brine, dried (Na2SO4) and concentrated to a foam. The crude residue was triturated with diethyl ether and the solid filtered to afford the title compound as a light brown solid (224 mg, 65% yield). TLC(MeOH:CH2Cl2, 1:9): Rf=0.46.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][C@@H:40]([CH3:44])[C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:41](=[O:42])[C@@H:40]([OH:39])[CH3:44])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f37) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:2]=1.C(Cl)(=O)C([Cl:16])=O>C(Cl)Cl.CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][C:10]([Cl:16])=[O:12])[CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCCc1cccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCCc1cccnc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 247 mg (1.49 mmol) of 4-pyridin-3-yl-butyric acid in 10 mL CH2Cl2 was added one drop DMF and 2.3 mL (4.56 mmol) oxalyl chloride and the mixture stirred at rt for 4 h. The volatiles were evaporated under reduced pressure and the material used crude in the following procedure.
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[Cl:9][C:10]1[C:11]2[N:12]([C:16]([CH:19]3[CH2:22][CH:21]([CH2:23][OH:24])[CH2:20]3)=[N:17][CH:18]=2)[CH:13]=[CH:14][N:15]=1>CN(C)C=O.C(Cl)Cl>[Cl:9][C:10]1[C:11]2[N:12]([C:16]([CH:19]3[CH2:20][CH:21]([CH2:23][OH:24])[CH2:22]3)=[N:17][C:18]=2[I:8])[CH:13]=[CH:14][N:15]=1
Reactant: OCC1CC(c2ncc3c(Cl)nccn23)C1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Solvent: CN(C)C=O
Product: OCC1CC(c2nc(I)c3c(Cl)nccn23)C1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of NIS (6.31 g, 28.0 mmol) in anh DMF (100 mL) under Ar was added dry [3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutyl]methanol (6.67 g) dissolved in anh DMF (30 mL). The flask containing [3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutyl]methanol was rinsed with another portion of anh DMF (20 mL) and the rinse was added to the reaction mixture. The reaction was heated to 60° C. (rt→60° C.˜30 min) and the stirred at this temperature for 3 h. The mixture was then cooled to rt, partitioned between 1M aq Na2S2O3 (60 mL), brine (60 mL) and DCM (160 mL). The aq layer was extracted with DCM (3×100 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and purified by flash chromatography on SiO2 (0-8% MeOH in DCM) to provide a material, homogenous by UV on both TLC and HPLC, still containing DMF. The material was dissolved in DCM (200 mL) and washed with water (3×40 mL), dried (Na2SO4) and concentrated under reduced pressure to provide the title compound as a pale yellow solid; HPLC (polar5 min) 2.52 min; MS (ES+): m/z (rel. int.) 364.0 (100, M++1); 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J=4.8 Hz, 1H), 7.49 (d, J=4.8 Hz, 0.22H, minor isomer), 7.29 (d, J=4.8 Hz, 1H), 7.28 (d, J=5.2 Hz, 0.23H, minor isomer), 3.83-3.80 (m, 0.7H), 3.72-3.62 (m, 3H), 2.75-2.55 (m, 4H), 2.42-2.32 (m, 1-2H).
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[N:10]=[C:9]2[Br:21].[C:22]1([C:28](Cl)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C)C=O>[Br:21][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([C:5]3[N:4]=[N:3][N:2]([C:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:1]=3)[CH:7]=2)[N:11]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[N:10]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1nn(C2CCCCO2)c2ccc(-c3nn[nH]n3)cc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Brc1nn(C2CCCCO2)c2ccc(-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc12
Temperature: 25 °C

Procedure:
To a solution of 2-(5-(2H-1,2,3,4-tetrazol-5-yl)-3-bromo-1H-indazolyl)perhydro-2H-pyran (0.554 g, 1.59 mmol) in dimethyl formamide (5 mL) was added triphenylmethyl chloride (0.662 g, 2.38 mmol), and triethyl amine (1.110 mL, 7.95 mmol). The reaction was heated to reflux temperature for 3.5 hours and maintained at room temperature overnight. The solvent was removed under reduced pressure. The resulting solid was dissolved in 20 mL of ethyl acetate and was washed with 10 ml-portions of water. The title compound was purified by column chromatography (SiO2, 20% ethyl acetate in hexanes) (0.754 g, 70%): ES-MS (m/z) mass not detected.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[O:16][CH2:15][CH2:14][O:13][C:5]2=[C:6]2[C:11]=1[NH:10][CH:9]=[CH:8][C:7]2=[O:12].[OH-].[Na+]>O.O1CCOCC1.[Pd]>[O:13]1[C:5]2=[C:6]3[C:11](=[CH:2][CH:3]=[C:4]2[O:16][CH2:15][CH2:14]1)[NH:10][CH:9]=[CH:8][C:7]3=[O:12]
Reactant: O=c1cc[nH]c2c(Br)cc3c(c12)OCCO3
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=c1cc[nH]c2ccc3c(c12)OCCO3
Reaction time: 8 h
Yield: 114.8 %

Procedure:
A suspension of 6-bromo-2,3-dihydro-7H-[1,4]dioxino[2,3-f]quinolin-10-one (3.4 g, 12 mmol) in water/dioxane (150 mL/80 mL) was treated with 1M aqueous sodium hydroxide solution then hydrogenated over 10% palladium on charcoal (1.5 g) for 20 hours. The mixture was filtered then acidified with 5M aqueous hydrochloric acid. On concentrating to ca 100 mL, a solid began to crystallise out. The mixture was stored at 5° C. overnight. Filtration and drying afforded a pale yellow solid (2.8 g, 100%). LC/MS (ES) m/z 203 (MH+ 92%); 1H-NMR (400 MHz, d6-DMSO), 11.4 (1H, s, NH), 7.64 (1H, d, J=7.2, CHNHC), 7.15 (1H, d, J=9.2, CHCO), 6.95 (1H, d, J=8.8, CHCN), 5.80 (1H, d, J=7.2, CH═CO), 4.26-4.27 (4H, m, 2×(CH2O)).
Reaction SMILES: [C:1]1(=O)[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1.Cl.[NH2:16]O.C([O-])(=O)C.[Na+]>C(O)C.O>[CH:1]1([NH2:16])[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCc2c1[nH]c1ccccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC1CCCc2c1[nH]c1ccccc21
Reaction time: 0.25 h

Procedure:
To a solution of 2,3,4,9-tetrahydro-1H-carbazol-1-one (1.5 g, 8.10 mmol) in ethanol (20 mL) was added a solution of hydroxylamine hydrochloride (1.13 g, 16.2 mmol) in water (10 mL) and a solution of sodium acetate (2.19 g, 26.7 mmol) in water (10 mL). The reaction mixture was heated at reflux for 2 h, cooled, and concentrated. The residue was diluted with water and extracted with ethyl acetate (2×100 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated to a brown solid. The oxime was dissolved in THF (80 mL) and lithium aluminum hydride (1.0 M in THF, 24.3 mL) was added dropwise. The reaction was heated at reflux for 7 h and cooled in an ice bath. Methanol was added dropwise until bubbling ceased. The mixture was diluted with aqueous Na/K tartrate, stirred vigorously for 15 min and extracted with ethyl acetate (2×100 mL). The extracts were combined, dried over sodium sulfate, filtered and concentrated. The crude amine was purified by flash chromatography on silica (2% to 5% methanol/methylene chloride gradient) to provide 2,3,4,9-tetrahydro-1H-carbazol-1-amine as a brown oil. The oil was diluted in diethyl ether and HCl (1.0 M in diethyl ether) was added. The resulting precipitate was collected by filtration to provide 2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride (760 mg, 42%) as a light brown solid. 1H-NMR (CD3OD): δ 7.54 (d, 1H), 7.42 (d, 1H), 7.22 (t, 1H), 7.09 (t, 1H), 4.66 (t, 1H), 2.95-2.73 (m, 2H), 2.39-2.28 (m, 1H), 2.18-2.03 (m, 3H); MS m/z (M+1) 170.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([S:18][CH3:19])=[N:16][N:15]=[N:14]2)=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Li+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([S:18][CH3:19])=[N:16][N:15]=[N:14]2)=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(-n2nnnc2SC)ccc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-n2nnnc2SC)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine methyl 2-methoxy-5-(5-methylthio-1H-tetrazol-1-yl)benzoate (0.51 g, 1.81 mmol) and lithium hydroxide (0.065 g, 2.71 mmol) and tetrahydrofuran/water (5 mL/5 mL). Heat to reflux. After 1 hour, cool to ambient temperature, separate the layers, and extract the organic layer 2 times with 1 M aqueous sodium hydroxide solution. Combine the aqueous layers and extract with diethyl ether. Acidify the aqueous layer using aqueous 1 M hydrochloric acid solution to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[CH:7][C:4]=1[CH:5]=O.[C:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)(=[O:21])[CH3:20]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[CH:7][C:4]=1/[CH:5]=[CH:20]/[C:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)=[O:21]
Reactant: COc1cc(OC)c(-c2cncnc2)cc1C=O
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: COc1cc(OC)c(-c2cncnc2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Yield: 26 %

Procedure:
The title compound was prepared by condensing 2,4-dimethoxy-5-pyrimidin-5-yl-benzaldehyde (Ex-31A) and 4-acetylbezoic acid in a similar manner as described in Ex-3. Yellow solid, mp>260° C., 26% yield. 1H-NMR (DMSO-d6) δ 9.11 (s, 1H), 8.96 (s, 2H), 8.13–8.16 (m, 3H), 8.01–8.09 (m, 3H), 7.90 (d, J=15 Hz, 1H), 6.85 (s, 1H), 3.99 (s, 3H), MS m/z=391 ([M+H]+, 100%). HRMS (ES+) Calcd. for C22H18N2O5: 391.1294. Found: 391.1295.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:14][CH2:13][O:12][C:9]=3[CH:10]=2)[CH:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:4][C:3]1=[O:21].[O-][Mn](=O)(=O)=O.[K+]>O1CCOCC1>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:14][CH2:13][O:12][C:9]=3[CH:10]=2)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:4][C:3]1=[O:21]
Reactant: CN1C(=O)NC(c2ccccc2)c2cc3c(cc21)OCO3
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1c(=O)nc(-c2ccccc2)c2cc3c(cc21)OCO3
Yield: 42.9 %

Procedure:
To a solution of 1-methyl-6,7-methylenedioxy-4-phenyl-3,4-dihydroquinazolin-2(1H)-one (47 mg) in dioxane (3 mL) was added an aqueous solution of KMnO4 (33 mg in 3 mL of water) at 10° C. After the addition, the mixture as extracted with EtOAc (3×10 mL). The organic phase was concentrated in vacuo. To the residue, water (70 mL) was added. The resulting solid was collected by filtration, washed with water, dried in vacuo to provide the title compound as a yellow solid (20 mg, 42%), mp: 253-255° C. 1H NMR (CDCl3): 7.69-7.66 (m, 2H), 7.53-7.51 (m, 3H), 7.18 (s, 1H), 6.86 (s, 1H), 6.11 (s, 2H), 3.76 (s, 3H). Anal. calcd. for C16H12N2O3: C, 68.27; H, 4.32; N, 9.99. Found: C, 67.99; H, 4.17; N, 9.73.
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15]([OH:17])=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][NH:21]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15]([N:21]3[CH2:22][C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20]3)=[O:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)O)CCN(C)C1
Reactant: c1ccc2c(c1)CNC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2Cc3ccccc3C2)CCN(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.1 %

Procedure:
A mixture of 2-(1, 2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetic acid (50 mg, 0.205 mmol), Isoindoline (23 mg, 0.205 mmol), DCC (46 mg, 0.22 mmol), and DMAP (27 mg, 0.22 mmol) in dry DCM (2.0 mL) was stirred at room temperature for 3 h. The reaction mixture was filtered through Celite and concentrated using rotary evaporator afforded 16.3 mg of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(isoindolin-2-yl)ethanone as TFA Salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [CH2:1]([S:7][S:8][CH2:9][C@H:10]([NH2:14])[C:11]([OH:13])=O)[C@H:2]([NH2:6])[C:3]([OH:5])=O.[CH3:15][N:16]=[C:17]=[O:18]>[OH-].[Na+]>[CH3:15][N:16]1[C:11](=[O:13])[C@H:10]([CH2:9][S:8][S:7][CH2:1][C@@H:2]2[C:3](=[O:5])[N:16]([CH3:15])[C:17](=[O:18])[NH:6]2)[NH:14][C:17]1=[O:18]
Reactant: CN=C=O
Reactant: N[C@@H](CSSC[C@H](N)C(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CN1C(=O)N[C@@H](CSSC[C@H]2NC(=O)N(C)C2=O)C1=O
Reaction time: 2 h

Procedure:
To a mixture of L-cystine (12 g) and 2 molar sodium hydroxide solution (50 ml), cooled to 0°-5° C. in an ice bath, was added, dropwise, methyl isocyanate (8.55 g). The clear solution was stirred at 0° for 2 hours, and then at room temperature over night.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:15][C@H:14](OS(C)(=O)=O)[CH2:13][C@H:12]2[CH2:21][NH:22][S:23](=[O:26])(=[O:25])[NH2:24])=[O:10])=[CH:5][CH:4]=1.[C:29]([O-:32])(=[S:31])[CH3:30].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:15][C@@H:14]([S:31][C:29](=[O:32])[CH3:30])[CH2:13][C@H:12]2[CH2:21][NH:22][S:23](=[O:25])(=[O:26])[NH2:24])=[O:10])=[CH:27][CH:28]=1
Reactant: COc1ccc(COC(=O)N2C[C@H](OS(C)(=O)=O)C[C@H]2CNS(N)(=O)=O)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)N2C[C@@H](SC(C)=O)C[C@H]2CNS(N)(=O)=O)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 45 %

Procedure:
To a solution of crude (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-methanesulfonyloxy-2-sulfamoylaminomethylpyrrolidine (2.26 g) obtained in Step 5 in dimethylformamide (12 ml), potassium thioacetate (1.7 g) is added. The mixture is stirred at 60° C. for 5 hours. The reaction mixture is diluted with ethyl acetate, successively washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography (toluene:ethyl acetate=1:2) to give (2S,4S)-1-p-methoxybenzyloxycarbonyl-4-acetylthio-2-sulfamoylaminomethylpyrrolidine (971 mg). NMR δ(CDCl3) ppm: 1.8(br s, 1H), 2.33(s, 3H), 2.4 to 2.7(m, 1H), 3.1 to 3.5(m), 3.81(s, 3H), 3.9 to 4.2(m, 2H), 5.05(s, 2H), 6.89(d, J=8.8 Hz, 2H), 7.30(d, J=8.8 Hz, 2H). IR ν (CHCl3) cm-1 : 3414, 3276, 1688.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:19]=1[N:18]=[C:9]([C:10]([NH:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1)=[O:11])[CH:8]=[C:7]2[O:20][CH3:21].COC1C2C(=C([N+]([O-])=O)C=CC=2)N=C(C([NH:29]C2NN=NN=2)=O)C=1>>[NH2:29][C:4]1[CH:5]=[C:6]2[C:19](=[CH:2][CH:3]=1)[N:18]=[C:9]([C:10]([NH:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1)=[O:11])[CH:8]=[C:7]2[O:20][CH3:21]
Reactant: COc1cc(C(=O)Nc2nnn[nH]2)nc2c([N+](=O)[O-])cccc12
Reactant: COc1cc(C(=O)Nc2nnn[nH]2)nc2c(N)cccc12
Product: COc1cc(C(=O)Nc2nnn[nH]2)nc2ccc(N)cc12

Procedure:
8-Amino-4-methoxy-N(1H-tetrazol-5-yl)quinaldamide, m.p. 276° (d), was prepared by the hydrogenation of 4-methoxy-8-nitro-N(1H-tetrazol-5-yl)quinaldamide.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[Se](=O)=[O:14]>O1CCOCC1>[O:12]=[C:8]1[NH:9][C:10]2[N:11]=[C:2]([CH:1]=[O:14])[CH:3]=[CH:4][C:5]=2[CH:6]=[CH:7]1
Reactant: O=[Se]=O
Reactant: Cc1ccc2c(n1)NC(=O)CC2
Solvent: C1COCCO1
Product: O=Cc1ccc2ccc(=O)[nH]c2n1
Reaction time: 240 h
Yield: 49.7 %

Procedure:
A solution of 0.90 g of 7-methyl-3,4-dihydro-1,8-naphthyridin-2(1H)-one in 150 mL of dioxane was heated under reflux while dividedly adding 25.7 g of selenium dioxide, and the mixture was stirred for 10 days. The insoluble substance was filtered off with celite, and the solvent was distilled off under reduced pressure. To the resultant residue, 2-propanol was added, and the solid was filtered off. The solid thus obtained was purified by silica gel column chromatography using an eluent of chloroform:methanol=20:1, and ethyl acetate was added thereto, and the solid was filtered off to obtain 0.48 g of 7-oxo-7,8-dihydro-1,8-naphthyridine-2-carbaldehyde as a light orange solid.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([S:12](Cl)(=O)=O)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[O:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([SH:12])=[CH:10][CH:11]=2)=[CH:4][N:3]=[CH:2]1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Sc1ccc(-c2cnco2)cc1
Reaction time: 0.33 h
Yield: 89.4 %

Procedure:
To a solution of 4-oxazol-5-yl-benzenesulfonyl chloride (1 g) in THF (20 ml) was added triphenylphosphine (4.3 g). After stirring at RT for 10 minutes water (2 ml) was added and the reaction was stirred for a further 20 minutes. The reaction was evaporated under reduced pressure and the residue dissolved in EtOAc. The EtOAc solution was extracted with 1M NaOH (×3), the basic extractions were combined, the pH adjusted to 3 using 1M HCl and then re-extracted with EtOAc (×3). The EtOAc fractions were combined and washed with brine, dried (MgSO4) and evaporated under reduced pressure to give the subtitle compound as a green solid (0.65 g).
Reaction SMILES: C(O[C:4](=[O:11])[CH2:5][C:6](=O)[CH:7]([CH3:9])[CH3:8])C.Cl.[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[C:17]([NH2:19])=[NH:18]>>[Cl:13][C:14]1[CH:15]=[C:16]([C:17]2[N:19]=[C:4]([OH:11])[CH:5]=[C:6]([CH:7]([CH3:8])[CH3:9])[N:18]=2)[CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: N=C(N)c1cc(Cl)cc(Cl)c1
Agent: Cl
Product: CC(C)c1cc(O)nc(-c2cc(Cl)cc(Cl)c2)n1

Procedure:
The title compound was prepared from 4-methyl-3-oxo-pentanoic acid ethyl ester and 3,5-dichloro-benzamidine hydrochloride according to general procedure 1. 1H NMR (DMSO-d6, 400 MHz) δ 1.20-1.26 (m, 6H), 2.80-2.90 (m, 1H), 6.34 (s, 1H), 7.82(s, 1H), 8.18 (s, 2H), 12.50 (br s,1H); MS: m/z (ESI) 283 (M+H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[F:12][C:13]([F:19])([F:18])[C:14]([CH3:17])([NH2:16])[CH3:15].C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:16][C:14]([CH3:17])([CH3:15])[C:13]([F:19])([F:18])[F:12])=[O:7]
Reactant: CC(C)(N)C(F)(F)F
Reactant: O=C(Cl)c1cccc(CCl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)c1cccc(CCl)c1)C(F)(F)F
Reaction time: 2 h
Yield: 46.4 %

Procedure:
3-(Chloromethyl)benzoyl chloride (38.5 mmol, 5.48 mL, 7.29 g) was dissolved in dichloromethane (100 mL) and stirred. To this was added a mixture of 1,1,1-trifluoro-2-methylpropan-2-amine (39.3 mmol, 5 g) and triethylamine (59.0 mmol, 8.22 mL, 5.97 g) (dropwise) and stirring continued for 2 hours. The reaction was diluted with dichloromethane and this organic mixture was washed with saturated sodium chloride, water, and saturated sodium chloride. The organic phase was dried with sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica chromatography (eluting with dichloromethane) to give the title compound (5 g).
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]([OH:18])[CH2:14][N+:15]([O-])=O)[CH:10]=[CH:11][CH:12]=1>O1CCCC1.CO.[C].[Pd]>[NH2:15][CH2:14][CH:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][CH3:5])[CH:8]=1)[OH:18]
Reactant: COc1cccc(C(O)C[N+](=O)[O-])c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(C(O)CN)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.6 %

Procedure:
Palladium-carbon (10%, 0.64 g) and ammonium formate (4.8 g) were added to a mixed solution of the compound of Example B142 (3.0 g, 15 mmol) in tetrahydrofuran (43 ml) and methanol (43 ml), and this mixture was stirred at room temperature for 18 hours. The catalyst was removed by filtration, the filtrate was diluted with ether, precipitates were removed by filtration, and the obtained filtrate was concentrated to give the title compound (1.82 g). This compound was used in the following reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].S(=O)(=O)(O)O.[C:17]([O-])(O)=O.[Na+]>CO>[CH3:17][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([CH3:11])[CH:4]=1
Reactant: O=C([O-])O
Reactant: Cc1cc(C(=O)O)ccc1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(Br)c(C)c1

Procedure:
4-Bromo-3-methylbenzoic acid (10 g) was suspended in methanol (50 ml) containing conc. sulphuric acid (2 ml). The mixture was heated to reflux for 18 h. On addition of 8% NaHCO3 (100 ml) to the cooled reaction, a flocculent solid was filtered off and dried in vacuo at 40°-45° to give the title compound as a liquid which recrystallised on cooling (10.25 g) m.p. 39.5°-40.5°.