Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]([CH2:11]Br)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:13]([NH2:16])(=[S:15])[CH3:14].C1C=CC=CC=1>C(N(CC)CC)C>[OH:1][N:2]=[C:3]([C:9]1[N:16]=[C:13]([CH3:14])[S:15][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CC(N)=S
Reactant: CCOC(=O)C(=NO)C(=O)CBr
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)C(=NO)c1csc(C)n1
Reaction time: 1 h

Procedure:
A mixture of ethyl 2-hydroxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (22.0 g.), thioacetamide (7.5 g.) and benzene (100 ml.) was refluxed for 3 hours. After cooling triethylamine (10 g.) was added thereto and the mixture was stirred for 1 hour. An insoluble material was filtered off and the filtrate was concentrated under reduced pressure to give ethyl 2-hydroxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (a mixture of syn and anti isomers) (8.6 g.). This substance was subjected to column chromatography on silica gel (80 g.) using benzene as developing solvent. Firstly the eluate containing anti isomer was eluted, collected and concentrated to give ethyl 2-hydroxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (anti isomer) (2.5 g.), mp 90° to 92° C.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[N:16]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[N:15]=[CH:14][CH:13]=1.[Br:23]N1C(=O)CCC1=O>ClCCl>[Br:23][C:13]1[CH:14]=[N:15][N:16]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:12]=1[C:3]1[C:4]([F:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])c1ccc(F)c(-c2ccnn2C2CCCCO2)c1F
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)c(-c2c(Br)cnn2C2CCCCO2)c1F

Procedure:
A solution of 5-(2,6-difluoro-3-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (1.23 g, 4 mmol) and N-bromosuccinimide (1.25 g, 7 mmol) in dichloromethane (10 mL) was stirred at room temperature for 18 h. The solution was washed with water, dried over anhydrous sodium sulfate and concentrated. Crude 4-bromo-5-(2,6-difluoro-3-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole was obtained.
Reaction SMILES: N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:39][C:40]1[CH:45]=[C:44]([C:46]#[C:47][C:48]2[N:49]=[C:50]([CH3:53])[NH:51][CH:52]=2)[CH:43]=[CH:42][N:41]=1.I[C:55]1[CH:60]=[CH:59][N:58]=[C:57]([O:61][CH3:62])[CH:56]=1>CC1C=CC=CC=1C>[CH3:62][O:61][C:57]1[CH:56]=[C:55]([N:51]2[CH:52]=[C:48]([C:47]#[C:46][C:44]3[CH:43]=[CH:42][N:41]=[C:40]([CH3:39])[CH:45]=3)[N:49]=[C:50]2[CH3:53])[CH:60]=[CH:59][N:58]=1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Reactant: COc1cc(I)ccn1
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1C
Product: COc1cc(-n2cc(C#Cc3ccnc(C)c3)nc2C)ccn1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
Following the Buchwald-protocol [Buchwald et al., Tetrahedron Lett. 40:2657 (1999)], a rigorously dried Schlenk tube was filled with argon and charged with copper(I) trifluoromethanesulfonate benzene complex (101 mg, 0.2 mmol), phenanthroline (720 mg, 4.0 mmol), dibenzylideneacetone (47 mg, 0.2 mmol) and cesium carbonate (2.86 g, 8.8 mmol). 2-Methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine (II-1) (1.18 g, 6.0 mmol), o-xylene (1.6 ml) and 4-iodo-2-methoxypyridine x HCl (1.1 g, 4.0 mmol) [Talik and Plazek, Rocz. Chem. 33:1343 (1959)] was added. The mixture was stirred at 110° C. for 24 hr, cooled to RT and partitioned between CH2Cl2 and saturated aqueous NH4Cl solution. The organic phase was concentrated and purified by chromatography on silica gel (dichloromethane/methanol 100:0→97:3 gradient). The title compound was obtained as a tan semisolid material (44 mg, 4%). The free base was converted to the HCL salt. mp=145–147° C. (MeOH/Et2O), MS: m/e=305.0 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([C:18]2[CH:38]=[CH:37][C:21]3[N:22]([CH3:36])[C:23]([NH:25][C:26]4[S:27][C:28]5[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:29]=5[N:30]=4)=[N:24][C:20]=3[CH:19]=2)=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[ClH:35].[ClH:35].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([C:18]2[CH:38]=[CH:37][C:21]3[N:22]([CH3:36])[C:23]([NH:25][C:26]4[S:27][C:28]5[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:29]=5[N:30]=4)=[N:24][C:20]=3[CH:19]=2)=[O:17])[CH2:10][CH2:9]1
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC3CCNCC3)ccc21
Yield: 305.3 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (piperidin-4-ylmethyl)-amide dihydrochloride (150 mg) was prepared by following General Procedure L starting from 4-({[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}methyl)-piperidine-1-carboxylic acid tert-butyl ester (155 mg) in 4M HCl in dioxane (2 mL).
Reaction SMILES: C1CCCCC=1.[F:7][CH2:8][CH:9]([NH:13][C:14](=[O:17])[O:15][CH3:16])[CH2:10][CH:11]=[CH2:12].[OH-:18].[Na+].OO>CCOCC.O.C(OCC)(=O)C.O1CCCC1>[F:7][CH2:8][CH:9]([NH:13][C:14](=[O:17])[O:15][CH3:16])[CH2:10][CH2:11][CH2:12][OH:18]
Reactant: [OH-]
Reactant: C=CCC(CF)NC(=O)OC
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOCC
Product: COC(=O)NC(CF)CCCO

Procedure:
Seven ml of tetrahydrofuran were placed in a dried, argon-flushed 50 ml flask equipped with a septum, an argon inlet, and a spin bar and 7.0 ml of a 1M solution of borane in tetrahydrofuran was added. Cyclohexene (1.4 ml, 13.8 mmol) was added with stirring and cooling with an ice bath. The bath was removed and the mixture allowed to warm and stir overnight during which time a white precipitate formed. A solution of 1.00 g of methyl 1-(fluoromethyl)-3-butenylcarbamate (6.20 mmol) dissolved in 2.0 ml of ether was added rapidly to the mixture with stirring. The mixture exothermed slightly and the white precipitate dissolved. After 4 hours the solution was cooled with an ice bath and 3.0 ml of 4.0N sodium hydroxide added. There was some gas evolution. Four ml of 30 percent hydrogen peroxide was added dropwise with stirring over several minutes and the mixture was allowed to warm and stir for 20 min at which time it was transferred to a separatory funnel containing 80 ml of ethyl acetate and 20 ml of water. The aqueous layer was removed and the organic layer extracted with 20 ml of aqueous sodium chloride solution. The combined aqueous layers were extracted with ethyl acetate and the organic layers were then combined, dried over magnesium sulfate, and filtered. The volatiles were then removed by evaporation under reduced pressure to obtain the title compound as a clear, viscous oil. This was purified by bulb-to-bulb distillation to obtain 0.89 g of the desired product (80 percent of theory) containing less than 2 percent of isomers and having carbon, fluorine, and proton nmr spectra consistent with the assigned structure.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:17](F)[C:14]=2[C:15]#[N:16])[CH2:7][CH2:6]1.C(=O)(O)O.[NH2:31][C:32]([NH2:34])=[NH:33]>CC(N(C)C)=O>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:14]=2[C:15]([NH2:16])=[N:31][C:32]([NH2:34])=[N:33]3)[CH2:7][CH2:6]1
Reactant: N=C(N)N
Reactant: N#Cc1c(F)cccc1OCC1CCC(Oc2c(F)cccc2F)CC1
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2c(OCC3CCC(Oc4c(F)cccc4F)CC3)cccc2n1
Yield: 9 %

Procedure:
Cyclization of 2-[4-(2,6-difluorophenoxy)cyclohexylmethoxy]-6-fluorobenzonitrile was carried out using Method F (95 mg; 0.26 mmol) and guanidine carbonate (43 mg; 0.26 mmol) in 1.5 mL of dimethylacetamide. Material was purified using C18 reverse phase silica and 0-100% acetonitrile in water gradient to give 9 mg of title compound. (9% yield. 1HNMR (400 MHz, DMSO-d6) δ 7.37 (m, 1H), 7.14 (m, 5H), 6.77 (m, 1H), 6.51 (m, 1H), 5.96 (br s, 2H), 5.7 (s, 1H), 4.02 (m, 3H), 2.02 (m, 4H), 1.62 (m, 4H). MS m/z (ESI) 401 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:14]2[N:6]([N:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH2:5][CH2:4][N:3]1[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22](OC(C)(C)C)=[O:23])[CH2:18][CH2:17]1.[C:29]1([CH2:35]C(Cl)=O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:29]1([CH2:35][C:22]([N:19]2[CH2:20][CH2:21][CH:16]([CH2:15][N:3]3[CH2:4][CH2:5][N:6]4[N:7]=[C:8]5[C:13]([CH:12]=[CH:11][CH:10]=[CH:9]5)=[C:14]4[C:2]3=[O:1])[CH2:17][CH2:18]2)=[O:23])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCn3nc4ccccc4c3C2=O)CC1
Product: O=C(Cc1ccccc1)N1CCC(CN2CCn3nc4ccccc4c3C2=O)CC1

Procedure:
The product was prepared using the method described in example 2e), using tert-butyl 4-[(1-oxo-3,4-dihydropyrazino[1,2-b]indazol-2(1H)-yl)methyl]piperidine-1-carboxylate (example 1d) and benzeneacetyl chloride as reagents. The product was purified by flash chromatography on silica gel, using the mixture chlorofom:methanol in a ratio of 9:1 as eluent. Thus, 104 mg of 2-{[1-(phenylacetyl)piperidin-4-yl]methyl}-3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one were obtained.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]([OH:24])[CH2:14][NH:15][C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl.[OH-].[K+]>ClCCl>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]2[CH2:14][N:15]([C@@H:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH3:17])[C:3](=[O:4])[CH2:2][O:24]2)=[CH:11][CH:12]=1
Reactant: C[C@@H](NC[C@@H](O)c1ccc(Br)cc1)c1ccccc1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N1C[C@H](c2ccc(Br)cc2)OCC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 115 %

Procedure:
A solution of chloroacetyl chloride (19.5 ml, 245 mmol) in dichloromethane (100 ml) was added dropwise to a ice-cooled solution of (1S)-1-(4-bromophenyl)-2-((1R)-1-phenylethylamino)ethanol (intermediate 11, 71.0 g, 222 mmol) and triethylamine (34 ml, 245 mmol) in dichloromethane (600 ml). After the mixture was stirred for 2 hours, 1 M hydrochloric acid was added and the mixture was partitioned between water and chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in 2-propanol (600 ml). The solution was added with potassium hydroxide (85%, 18.3 g, 278 mmol). The mixture was stirred at room temperature for 15 hours. The solvent was evaporated under reduced pressure and the residue was added with ethyl acetate. The mixture was partitioned between water and ethyl acetate, and the organic layer was washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give (6S)-6-(4-bromophenyl)-4-((1R)-1-phenylethyl)morpholin-3-one (intermediate 12, 92 g) as a brown oil. This crude product was used for next reaction without purification.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]1[CH2:11][CH:10]([CH:12]2[CH2:14][CH2:13]2)[C:9]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=[O:4].[Br:23]N1C(=O)CCC1=O>C(#N)C>[F:22][C:2]([F:1])([F:21])[C:3]([N:5]1[CH2:11][CH:10]([CH:12]2[CH2:14][CH2:13]2)[C:9]2[CH:15]=[C:16]([Br:23])[C:17]([O:19][CH3:20])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2C1CC1
Solvent: CC#N
Product: COc1cc2c(cc1Br)C(C1CC1)CN(C(=O)C(F)(F)F)CC2
Reaction time: 2 h
Yield: 44.6 %

Procedure:
A solution of N-trifluoroacetyl-1-cyclopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.025 g, 0.08 mmol) in acetonitrile (1 mL) was treated with N-bromosuccinimide (0.032 g, 0.18 mmol) and stirred for 2 hrs. at 50 C. The product mixture was concentrated and then purified by flash chromatography (10% EtOAc in hexanes, silica) resulting in 0.014 g of a white solid. MS calculated for C15H15BrF3NO2+H: 378, observed: 378.
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[C:24](I)[CH:23]=2)[C:10]=1[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])C.C([Sn](CCCC)(CCCC)[C:46]1[S:47][CH:48]=[CH:49][N:50]=1)CCC.[OH-].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.C(O)C.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>[C:35]([CH2:34][CH2:33][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:46]3[S:47][CH:48]=[CH:49][N:50]=3)[CH:25]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:3])=[O:40])([OH:37])=[O:36]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2nccs2)c1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
To a solution containing 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-iodo-5-methanesulfonyl-phenoxy)-hexyl]-phenoxy}-butyric acid ethyl ester (90 mg, 0.14 mmol) and 2-(tributylstannyl)thiazole (0.088 mL, 0.28 mmol) in toluene (4 mL) was added Pd(PPh3)4 (8 mg, 5 mol %). The reaction mixture was stirred at 110° C. for 12 h, then diluted with EtOAc. The resulting solution was washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude sample which was dissolved in hot ethanol (4 mL). To this solution, 1 N sodium hydroxide (1 mL) was added and the reaction mixture was stirred at 60° C. for 3 h. Once the hydrolysis was completed as determined by LCMS, the reaction mixture was diluted with EtOAc and washed with 10% HCl and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude sample which was purified by preparative HPLC. HR-ES(+) m/e calcd for C29H35NO8S2 (M+H)+ 590.1877, found 590.1876.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][NH:8][CH:7]2[CH2:10][CH2:11][N:12]([C:13](=[O:29])[CH:14]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:6]12)=[O:4].[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][N:8]([C:33]([CH:30]2[CH2:32][CH2:31]2)=[O:34])[CH:7]2[CH2:10][CH2:11][N:12]([C:13](=[O:29])[CH:14]([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:6]12)=[O:4]
Reactant: COC(=O)C1CNC2CCN(C(=O)C(NC(=O)OC(C)(C)C)C3CCCCC3)C21
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)C2CC2)C2CCN(C(=O)C(NC(=O)OC(C)(C)C)C3CCCCC3)C12
Reaction time: 2 h
Yield: 99.5 %

Procedure:
A solution of 27 (500 mg, 1.22 mmol) in DCM (10 mL) was cooled to 0° C. and treated with TEA (0.26 mL, 1.83 mmol) and cyclopropanecarbonyl chloride (0.13 mL, 1.46 mmol). After 2 h, the reaction mixture was diluted with DCM, washed successively with 1M HCl, and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 44 (580 mg) as a pale yellow-colored foam that was used without further purification. Mass spectrum, m/z [478.6] (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][NH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.Cl[C:16]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[O:17].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:22][O:21][CH2:20][CH2:19][O:18][C:16]([N:5]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1)[CH2:4][CH2:3][N:2]([CH3:14])[CH3:1])=[O:17]
Reactant: CN(C)CCNc1ccc(C=O)cc1
Reactant: COCCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COCCOC(=O)N(CCN(C)C)c1ccc(C=O)cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 63 %

Procedure:
To a solution of 4-[[2-(dimethylamino)ethyl]amino]benzaldehyde (300 mg) in methylene chloride (4 mL) is added 2-methoxyethyl chloroformate (234 μL) and thereto is added dropwise pyridine (252 μL) under ice-cooling. The mixture is stirred at 50° C. for 2 days. The reaction mixture is diluted with chloroform (5 mL) and thereto is added a saturated sodium hydrogencarbonate solution (10 mL). After stirring, the organic layer is separated and concentrated. The residue is purified by column chromatography on silica gel (Solvent; chloroform:methanol=100:0→90:10) to give 4-[N-[(2-methoxyethoxy)carbonyl]-N-[2-(dimethylamino)ethyl]amino]benzaldehyde (290 mg, yield; 63%) as an amorphous powder. MS (APCI) m/z: 294 [M+H]+
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]([C:11](=O)[CH3:12])[C:6](OCC)=[O:7])#[N:2].C(=O)(O)O.[NH2:18][C:19]([NH2:21])=[NH:20]>N1C=CC=CC=1>[NH2:21][C:19]1[N:20]=[C:6]([OH:7])[C:5]([CH2:4][CH2:3][C:1]#[N:2])=[C:11]([CH3:12])[N:18]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C(CCC#N)C(C)=O
Agent: O=C(O)O
Solvent: c1ccncc1
Product: Cc1nc(N)nc(O)c1CCC#N
Reaction time: 8 h
Yield: 64.5 %

Procedure:
A mixture of ethyl 2-(2-cyanoethyl)-3-oxobutanoate (9 g, 49 mmol), guanidine carbonate (5.30 g, 29.4 mmol) and pyridine (49 ml) was kept at 100° C. for 8 hours. The procedure according to pro-treatment of Reference-example 6 was carried out to give the object compound (3.38 g, 38.6%).
Reaction SMILES: O.O.O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:11].[Mg+2].[F:21][C:22]1[CH:27]=[CH:26][C:25]([C@H:28]([NH:30][C:31]([C@H:33]2[CH2:38][CH2:37][C@H:36]([NH:39][S:40]([C:43]3[CH:48]=[CH:47][C:46]([C:49]4[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=4)=[CH:45][CH:44]=3)(=[O:42])=[O:41])[CH2:35][CH2:34]2)=[O:32])[CH3:29])=[CH:24][CH:23]=1>CO.C(Cl)Cl>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C@H:28]([NH:30][C:31]([C@H:33]2[CH2:34][CH2:35][C@H:36]([NH:39][S:40]([C:43]3[CH:44]=[CH:45][C:46]([C:49]4[CH:54]=[CH:53][N+:52]([O-:11])=[CH:51][CH:50]=4)=[CH:47][CH:48]=3)(=[O:41])=[O:42])[CH2:37][CH2:38]2)=[O:32])[CH3:29])=[CH:24][CH:23]=1
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: C[C@@H](NC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(-c3ccncc3)cc2)CC1)c1ccc(F)cc1
Agent: [Mg+2]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: C[C@@H](NC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(-c3cc[n+]([O-])cc3)cc2)CC1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Magnesium monoperoxyphthalate hexahydrate (66.8 mg, 0.135 mmol) was suspended in MeOH (0.5 ml) and cooled to 0° C. Trans-4-(4-pyridin-4-yl-benzenesulfonylamino)-cyclohexanecarboxylic acid [(R)-1-(4-fluoro-phenyl)-ethyl]-amide (Example 284, 50 mg, 0.097 mmol) in DCM (0.5 ml) was added dropwise and the reaction mixture was left to stir overnight at 23° C. LCMS indicated that the reaction was complete, and the mixture was concentrated in vacuo to a residue which was purified by reverse phase chromatography on prep-HPLC (150 mm, C8 luna, 15-20 min run, 10%-100% MeCN in water containing 0.1% TFA). Product containing fractions were lyophilized to yield the title compound (10 mg, 21%). MS MH+ 498.1
Reaction SMILES: C([NH:4][C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[C:7]([O:18][CH3:19])[CH:6]=1)(=O)C.[OH-].[Na+]>C(O)C>[NH2:4][C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[C:7]([O:18][CH3:19])[CH:6]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(NC(C)=O)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(N)c([N+](=O)[O-])cc1C(=O)O

Procedure:
Prepared analogously to example 547b from methyl 4-acetylamino-2-methoxy-5-nitro-benzoate with NaOH in ethanol.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.C(OC([NH:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[N:36][C:35]=1[C:45](O)=[O:46])=O)(C)(C)C>>[NH2:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[N:36][C:35]=1[C:45]([NH:23][C:18]1[CH:19]=[N:20][N:21]([CH3:22])[C:17]=1[C@@H:5]1[CH2:6][CH2:7][C@@H:8]([NH2:9])[C@H:2]([F:1])[CH2:3][O:4]1)=[O:46]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2)nc1C(=O)O
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3)sc2N)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 5-((tert-butoxycarbonyl)amino)-2-phenylthiazole-4-carboxylic acid (Example 6) gave 320. 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 7.89-7.81 (m, 2H), 7.50-7.34 (m, 4H), 7.01-6.59 (m, 1H), 4.83 (dd, J=10.7, 3.5 Hz, 1H), 4.57-4.39 (m, 1H), 4.37-3.99 (m, 2H), 3.80-3.70 (m, 3H), 2.04 (d, J=13.7 Hz, 1H), 2.00-1.66 (m, 4H). LCMS (ES+) m/z 431 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7](Cl)=[O:8])[O:5][CH:6]=1.Cl.[CH3:11][NH:12][O:13][CH3:14].C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:14][O:13][N:12]([CH3:11])[C:7]([C:4]1[O:5][CH:6]=[C:2]([Br:1])[CH:3]=1)=[O:8]
Reactant: CNOC
Reactant: O=C(Cl)c1cc(Br)co1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cc(Br)co1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.9 %

Procedure:
The crude 4-bromofuran-2-carbonyl chloride (157 mmol theoretical) was dissolved in CH2Cl2 (500 mL) in a 1 L round bottomed flask. The flask was immersed in an ice bath and N,O-dimethyl-hydroxylamine hydrochloride (19.5 g, 200 mmol) was added. The cold suspension was then treated with N,N-diisopropylethylamine (75 mL, 430 mmol), and a small amount of 4-(N,N-dimethylamino)pyridine (catalytic). Several minutes after the addition of the 4-(N,N-dimethylamino)pyridine the ice bath was removed and the pale orange solution was allowed to warm to ambient temperature. After standing at ambient temperature for ˜16 hours the pale brown reaction mixture was quenched with water (100 mL) and diluted with CH2Cl2 (500 mL). The layers were separated and the organic layer was washed with 1N HCl (2×100 mL), H2O (100 mL), and saturated NaHCO3 (50 mL). The organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 4-bromo-furan-2-carboxylic acid methoxy-methyl-amide (25.7 g, 70% yield from crude acid) as a pale brown solid. 1H NMR of the material showed it to be very clean. 1H-NMR (400 MHz, CDCl3): δ 7.60 (1H, d, J=0.8 Hz), 7.14 (1H, d, J=0.8 Hz), 3.77 (3H, s), 3.35 (3H, s).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][OH:7])=[CH:2]1.[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([N:17]([CH3:19])[CH3:18])[CH:14]=[C:13](Cl)[N:12]=1>O1CCCC1>[Cl:10][C:11]1[CH:16]=[C:15]([N:17]([CH3:19])[CH3:18])[CH:14]=[C:13]([O:7][CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[N:12]=1
Reactant: OCc1ccsc1
Reactant: CN(C)c1cc(Cl)nc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)c1cc(Cl)nc(OCc2ccsc2)c1

Procedure:
To a solution of 3-thiophenemethanol (0.526 g, 0.0042×1.1 mol) in 10 ml of dry tetrahydrofuran, sodium hydride (0.335 g, (ca.60% in mineral oil), 0.0042×2.0 mol) was added. After the bubbling ceased, a solution of 2,6-dichloro-4-dimethylaminopyridine (0.8 g, 0.0042 mol) in 20 ml of dry tetrahydrofuran was added dropwise at room temperature.