Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Mg+].[C:30]([O:36][CH2:37][CH3:38])(=[O:35])[CH2:31]C([O-])=O.Cl>O1CCCC1.O.C(OCC)(=O)C>[O:14]=[C:12]([C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:16][CH:15]=1)[CH2:31][C:30]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 169.3 %

Procedure:
To a solution of 4-phenoxybenzoic acid (10.4 g, 48.7 mmol) in tetrahydrofuran (150 ml) was added 1,1′-carbonylbis-1H-imidazole (8.68 g, 53.6 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction solution was added monoethyl malonate magnesium salt (7.67 g, 26.8 mmol), and the mixture was stirred at room temperature for 2 hrs. Ethyl acetate (50 ml) and water (50 ml) were added to the reaction solution and conc. hydrochloric acid was added until the aqueous layer showed acidic pH. The reaction solution was extracted with ethyl acetate (200 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl 3-oxo-3-(4-phenoxyphenyl)propionate (12.9 g, 93%) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SC)[NH:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[N:31]1[CH:36]=[C:35]([CH2:37][NH2:38])[CH:34]=[N:33][CH:32]=1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([NH:38][CH2:37][C:35]5[CH:36]=[N:31][CH:32]=[N:33][CH:34]=5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:28])([F:30])[F:29])[CH:3]=1
Reactant: NCc1cncnc1
Reactant: CSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(NCc2cncnc2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(pyrimidin-5-ylmethyl)-amino]-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazolidin-4-one and C-Pyrimidin-5-yl-methylamine following General Procedure B.
Reaction SMILES: C(O[C:4]([C:6]1[S:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23])=[O:5])C.[OH-].[Na+].[CH:26]([O:28][CH2:29][CH2:30][O:31][NH2:32])=[CH2:27].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1.C(O)C>[CH:26]([O:28][CH2:29][CH2:30][O:31][NH:32][C:4]([C:6]1[S:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23])=[O:5])=[CH2:27]
Reactant: CCOC(=O)c1sc2ccncc2c1Nc1ccc(I)cc1F
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: C1CCOC1
Product: C=COCCONC(=O)c1sc2ccncc2c1Nc1ccc(I)cc1F
Temperature: 65 °C
Reaction time: 18 h
Yield: 65.1 %

Procedure:
A mixture of 3-(2-fluoro-4-iodo-phenylamino)-thieno[3,2-c]pyridine-2-carboxylic acid ethyl ester (124 mg, 0.28 mmol), 1N aqueous NaOH solution (0.30 ml, 0.30 mmol) and ethanol (4 ml) was heated at 65° C. for 45 minutes. The reaction mixture was concentrated in vacuo then the resultant residue was azeotroped with toluene (2×2 ml) to give a solid residue. The solid residue was dissolved in anhydrous THF (4 ml) before O-(2-vinyloxy-ethyl)-hydroxylamine (58 mg, 0.56 mmol), EDCI (67 mg, 0.35 mmol), HOBt (53 mg, 0.39 mmol) and DIPEA (147 μl, 0.84 mmol) were added. After stirring for 18 hours at ambient temperature the solvent was evaporated and the resultant residue was diluted with water (20 ml), then extracted with ethyl acetate (30 ml) followed by dichloromethane (30 ml). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give a yellow oil. The resultant yellow oil was purified by flash chromatography (Si-SPE, dichloromethane:methanol, gradient 100:0 to 98:2) to afford the title compound as a yellow solid (91 mg, 65%). LCMS (method B): RT=3.05 min, M+H+=500.
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]>>[Cl:12][C:13]1[CH:18]=[C:17]([C:2]23[CH2:11][CH:6]4[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]4)[CH2:3]2)[CH2:9]3)[CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1Cl
Reactant: BrC12CC3CC(CC(C3)C1)C2
Product: COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1Cl
Yield: 84.4 %

Procedure:
The title compound was prepared from 1-chloro-2-methoxybenzene (10 mL) and 1-bromoadamantane (3.25 g, 15.25 mmol) according to the step 1 of the example 5, which was given 1-(3-chloro-4-methoxyphenyl)adamantane (3.52 g, 84.4% yield).
Reaction SMILES: C(=O)=O.CC(C)=O.[C:8]([S:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)([CH3:11])([CH3:10])[CH3:9].[Br:20]N1C(=O)CCC1=O>C(Cl)Cl>[C:8]([S:12][C:13]1[CH:14]=[CH:15][C:16]([NH2:17])=[C:18]([Br:20])[CH:19]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)Sc1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(C)(C)Sc1ccc(N)c(Br)c1
Reaction time: 8 h

Procedure:
To a cold (dry ice - acetone bath) stirred solution of 4-tert-butylthioaniline (25.6 g., 0.14 mole) in methylene chloride is added a slurry of N-bromosuccinimide (25.0 g., 0.14 mole) in methylene chloride in three equal portions. The reaction is allowed to come to room temperature with stirring overnight. The methylene chloride solution is washed with dilute aqueous sodium carbonate and water and then evaporated to give the desired product as a brown oil.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.Cl.CCOC(C)=O>O.C1COCC1>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[CH:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:24])=[O:4]
Reactant: COC(=O)CCCCC=C(c1ccccn1)c1ccccn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)CCCCC=C(c1ccccn1)c1ccccn1
Reaction time: 19 h
Yield: 47.1 %

Procedure:
LiOH (10 mg, 0.42 mmol) in water (0.2 mL) was added to III (25 mg, 0.085 mmol) in THF (0.8 mL) at rt. After 19 h, the reaction mixture was neutralized with 2N HCl, poured onto brine (2 mL), and EtOAc (3 mL) was added. The phases were separated and the aqueous phase was extracted with EtOAc (2×3 mL). The organic phases were combined, dried over MgSO4, filtered, and then evaporated under reduced pressure. The resulting residue was then purified by silica gel column chromatography using CH2Cl2/MeOH (100:2 to 100:4) as eluant to furnish IV as a colourless oil (11.3 mg, 46%).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([NH:5][C:6]1[NH:7][C:8](=O)[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[N:18]=1)=[O:4].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:8]1[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[N:18]=[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:21])([CH3:20])[CH3:1])[N:7]=1
Reactant: CC(C)(C)C(=O)Nc1nc2[nH]c3ccccc3c2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)Nc1nc(Cl)c2c(n1)[nH]c1ccccc12
Yield: 59 %

Procedure:
In a 50 mL R.B.F. was placed 5 (56 mg, 0.17 mmol) and phosphoryl trichloride (15 mL). The mixture was stirred and heated at reflux for 4 hours. The phosphoryl trichloride was evaporated under reduced pressure using a vacuum aspirator. The resulting residue was cooled in an ice and water mixture, and neutralized with ammonium hydroxide solution to yield a precipitate that was filtered and dried over P2O5. The filterate was extracted with chloroform and dried over sodium sulfate. The dry precipitate and filterate were combined and evaporated to provide 35 mg of 6 as a brown solid in 59% yield. Compound 6 was used without further purification for the subsequent step. TLC Rf 0.65 (chloroform-methanol 10:1); mp 234° C.; 1H NMR (DMSO-d6) δ 1.24 (s, 9H, C(CH3)3), 7.36-8.17 (m, 4H, Ar—H), 10.25 (s, 1H, 2-NH, exch), 12.55 (s, 1H, 9-NH, exch). Anal. Calculated (C15H15ClN4O. 0.15 H2O): C, 58.98; H, 5.04; N, 18.34; Cl, 11.60. Found: C, 59.00; H, 5.09; N, 17.97; Cl, 11.83.
Reaction SMILES: [CH3:1][SiH:2]([CH3:11])[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([Cl:10])[CH:4]=1.[Br:12]Br>>[CH3:1][Si:2]([CH3:11])([C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([Cl:10])[CH:4]=1)[Br:12]
Reactant: C[SiH](C)c1ccc(Cl)c(Cl)c1
Reactant: BrBr
Product: C[Si](C)(Br)c1ccc(Cl)c(Cl)c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A glass reactor was charged with 19.1 g (0.093 mole) of dimethyl(3,4-dichlorophenyl)silane and 200 ml of petroleum ether. This mixture was cooled to -10° C., at which time a solution containing 14.9 g (0.093 mole) of bromine and 200 ml petroleum ether was gradually added, with agitation, to the reaction mixture. A decolorization of the bromine was observed. The cooling bath was removed as the bromine addition progressed. The resultant reaction mixture was stirred for 1 hour at ambient temperature following completion of the bromine addition. The volatile materials present in the reaction mixture were removed by evaporation under reduced pressure. The residue weighed 26.3 g, which is equivalent to a yield of 100 percent.
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:21]=[C:20]([C:22]3[NH:26][N:25]=[N:24][N:23]=3)[CH:19]=[CH:18][C:17]=2[OH:27])[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(Cl)Cl.[OH-].[Na+].Cl.[C:35](OCC)(=[O:37])C>>[C:1]([NH:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:21]=[C:20]([C:22]3[NH:26][N:25]=[N:24][N:23]=3)[CH:19]=[C:18]([CH:35]=[O:37])[C:17]=2[OH:27])[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)NCc1cccc(-c2cc(-c3nnn[nH]3)ccc2O)c1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)NC(=O)NCc1cccc(-c2cc(-c3nnn[nH]3)cc(C=O)c2O)c1

Procedure:
1-tert-Butyl-3-[2′-hydroxy-5′-(1H-tetrazol-5-yl)-biphenyl-3-ylmethyl]-urea (0.56 g, 1.5 mmol) was dissolved in a mixture of chloroform (0.2 mL, 3 mmol) and sodium hydroxide (10% aqueous, 5 mL, 12 mmol) and the mixture was refluxed for 5 days. The mixture was worked up with 1N hydrochloric acid and ethyl acetate. Some solids precipitated out of solution and were filtered and dried. The organic layer from the extraction was dried and combined with the solids above gives 1-tert-butyl-3-[3′-formyl-2′-hydroxy-5′-(1H-tetrazol-5-yl)-biphenyl-3-ylmethyl]-urea as a 3:1 mixture of starting material to product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[NH2:19].CCCCCC.CCOC(C)=O>O1CCOCC1.O>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:19][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(N)cc1OC
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1OC
Yield: 54.7 %

Procedure:
A mixture of 2-nitrobenzenesulfonyl chloride (3.0 g, 13.5 mmol) and 3,4-dimethoxyaniline (2.1 g, 14.9 mmol) in 1,4-dioxane (30 mL) in a sealed reaction tube was heated at 80° C. for 24 h with TLC monitoring (hexane: EtOAc, 1:1). The reaction mixture was diluted with H2O (30 mL), extracted with EtOAc (3×100 mL) and the combined organic phases dried over Na2SO4, filtered and concentrated in vacuo. Purification by gradient flash chromatography, eluting with 20-25% EtOAc in hexane yielded the title compound (2.5 g, 7.39 mmol).
Reaction SMILES: O.[C:2]([NH:4][C:5](=[N:8][CH2:9][CH2:10][S:11][CH2:12][C:13]1[N:14]=[CH:15][NH:16][C:17]=1[CH3:18])SC)#[N:3].[CH3:19][NH2:20]>O>[CH3:19][NH:20][C:5]([NH:8][CH2:9][CH2:10][S:11][CH2:12][C:13]1[N:14]=[CH:15][NH:16][C:17]=1[CH3:18])=[N:4][C:2]#[N:3]
Reactant: CN
Reactant: CSC(=NCCSCc1nc[nH]c1C)NC#N
Solvent: O
Product: CNC(=NC#N)NCCSCc1nc[nH]c1C
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
N-cyano-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-S-methylisothiourea monohydrate (14.35 g; 0.05 mole) is suspended in distilled water (50 ml), stirred and heated. At a bath temperature of 50° C., aqueous methylamine solution (18.5 ml containing 411 g/liter of methylamine, i.e. 0.245 mole equal to 4.9 equivalents) is added. The evolving gas is led to an equipment for destruction (annihilation). The reaction mixture is kept in a bath of 50°-55° C. for 2.5 hours. Initially, the mixture becomes considerably thinner, then, in most cases, N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidine begins to precipitate without appearing of a complete solution. The mixture becomes thicker and eventually the stirring is stopped. After 2.5 hours the mixture is rapidly heated to 90° C. and stirred at this temperature for 30 minutes. The solution should not contain undissolved material. The solution is poured without cooling onto stirred ice (70 g). A clear solution of 0° to 10° C. is formed which becomes turbid and granular, and well-settling crystals separate. The solution is kept in a refrigerator for 2 hours, then filtered and washed with distilled water (2×10 ml). The wet weight of this precipitate is 14.8 g. After drying at 40° C., the dry weight of N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidine H is 12.27 g (90.82%); m.p. 73°-75° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[CH2:9]([Mg]Br)[CH3:10].[Cl-].[NH4+]>C(OCC)C.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]([OH:8])[CH2:9][CH3:10])[S:5][CH:6]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)c1cc(Br)cs1
Reaction time: 2 h

Procedure:
10 g (52 mmol) of 4-bromothiophene-2-carbaldehyde are dissolved in 200 mL of ethyl ether and 20 mL of THF. 26.6 mL (78 mmol) of 3.0M ethylmagnesium bromide are added slowly. After 2 hours at room temperature, the reaction medium is poured into saturated ammonium chloride solution. After extraction, a yellow oil is obtained (m=11.5 g, Y=99%).
Reaction SMILES: [OH-:1].[Na+].[OH:3][CH:4]([C:8]1[N:9]=[C:10]([CH2:34][CH2:35][CH3:36])[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([C:30]([O:32]C)=[O:31])=[O:29])=[CH:18][CH:17]=2)[C:12]=1[C:13]#[N:14])[CH:5]([CH3:7])[CH3:6]>C(O)C>[OH:3][CH:4]([C:8]1[N:9]=[C:10]([CH2:34][CH2:35][CH3:36])[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([C:30]([OH:32])=[O:31])=[O:29])=[CH:18][CH:17]=2)[C:12]=1[C:13]([NH2:14])=[O:1])[CH:5]([CH3:7])[CH3:6]
Reactant: [OH-]
Reactant: CCCc1nc(C(O)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)C(=O)OC)cc1
Agent: [Na+]
Solvent: CCO
Product: CCCc1nc(C(O)C(C)C)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)C(=O)O)cc1

Procedure:
4 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 170 mg of 4-(1-hydroxy-2-methylpropyl)-1-[(2'-methoxalylbiphenyl-4-yl)methyl]-2-propylimidazole-5-carbonitrile [prepared as described in step (a) above] dissolved in 3 ml of hot ethanol, and the resulting mixture was stirred under reflux for 2.5 hours. At the end of this time, the ethanol was removed by evaporation under reduced pressure, and ethyl aceate was added to the residual aqueous solution. 4 ml of 1N aqueous hydrochloric acid were added to the mixture, after which the ethyl acetate layer was separated. This extract was then dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation under reduced pressure to give 140 mg of the title compound as crystals, softening at 150° C., and melting at 165°-170° C. (with decomposition).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][CH3:13])=[N:4][CH:3]=1.[CH3:14][Zn]C.[Cl-].[NH4+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C1(C)C=CC=CC=1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:13][O:12][C:5]1[C:6]([C:8]([O:10][CH3:11])=[O:9])=[N:7][C:2]([CH3:14])=[CH:3][N:4]=1
Reactant: C[Zn]C
Reactant: COC(=O)c1nc(Br)cnc1OC
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(C)cnc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
After dissolving 300 mg of methyl 6-bromo-3-methoxypyrazine-2-carboxylate in 10 ml of tetrahydrofuran, 32 mg of [1,3-bis(diphenylphosphino)propane]dichloronickel(II) was added, a solution of 0.73 ml of dimethyl zinc in toluene (2.0 M) was added dropwise under a nitrogen atmosphere and the mixture was stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride solution and aqueous sodium carbonate solution were added to the reaction solution in that order, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (161 mg, 73% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Br[CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[CH2:14]([O:13][C:11](=[O:12])[C@H:10]([CH3:16])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:15]
Reactant: CCOC(=O)C(C)Br
Reactant: Nc1ccc(Cl)cc1
Product: CCOC(=O)[C@H](C)Nc1ccc(Cl)cc1

Procedure:
This compound was prepared in a manner analagous to the process described in synthesis example 14, except using 4-chloroaniline and ethyl 2-bromoproprionate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]([C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32].N1C=CC=CC=1>C(Cl)Cl>[CH2:34]([O:33][C:31](=[O:32])[NH:20][C:17]1[CH:16]=[CH:15][C:14]([C:13](=[O:21])[C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:22])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:19][CH:18]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)c1ccc(N)cc1)C(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)c1ccc(NC(=O)OCc2ccccc2)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.9 %

Procedure:
A solution of [1(S)-(4-aminobenzoyl)-2,2-dimethylpropyl]-carbamic acid tert-butyl ester (67 mg, 0.22 mmol) and triethylamine (95 μL, 0.69 mmol) in DCM (3 mL) was cooled on an ice bath prior to addition of benzyl chloroformate (98 μL, 0.69 mmol). The reaction was warmed to room temperature and left for 15 hours. Examination by T.l.c. suggested minimal conversion to product hence pyridine (0.10 mL, 1.2 mmol) was added and the reaction left for a further 2 hours. Solvent was removed in vacuo and the residue taken up in ethyl acetate (20 mL). The organic phase was washed with 1M HCl (1×20 mL), brine (1×20 mL), 1M Na2CO3 (1×20 mL) and brine (1×20 mL, dried over MgSO4, filtered and the solvent removed in vacuo, giving a yellow solid. Purification by column chromatography (SiO2, 9:1 isohexane:ethyl acetate) afforded the title compound as a yellow solid (90 mg, 90%).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[O:33]=[C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:43]3[CH:48]=[CH:47][C:46]([NH:49][C:50](=[O:62])[C:51]4[CH:56]=[CH:55][C:54]([O:57][C:58]([F:61])([F:60])[F:59])=[CH:53][CH:52]=4)=[CH:45][CH:44]=3)[CH:41]=2)[CH2:36][N:35]1[C:63]1([C:68]([O:70]C)=[O:69])[CH2:67][CH2:66][CH2:65][CH2:64]1>>[O:33]=[C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:43]3[CH:48]=[CH:47][C:46]([NH:49][C:50](=[O:62])[C:51]4[CH:52]=[CH:53][C:54]([O:57][C:58]([F:60])([F:59])[F:61])=[CH:55][CH:56]=4)=[CH:45][CH:44]=3)[CH:41]=2)[CH2:36][N:35]1[C:63]1([C:68]([OH:70])=[O:69])[CH2:67][CH2:66][CH2:65][CH2:64]1
Reactant: COC(=O)C1(N2Cc3ccc(-c4ccc(NC(=O)c5ccc(OC(F)(F)F)cc5)cc4)cc3C2=O)CCCC1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: O=C(Nc1ccc(-c2ccc3c(c2)C(=O)N(C2(C(=O)O)CCCC2)C3)cc1)c1ccc(OC(F)(F)F)cc1
Yield: 70 %

Procedure:
The compound of example 535 was prepared analogous to compound of example 98 by hydrolysis of compound of example 534.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[C:6]([CH3:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[CH3:14][O:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:10][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[N:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][O:15][CH3:14])[CH2:19][CH2:20]1
Reactant: COCCN1CCNCC1
Reactant: COc1cc(F)c(C)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COCCN1CCN(c2cc(OC)c([N+](=O)[O-])cc2C)CC1
Temperature: 130 °C
Yield: 86.1 %

Procedure:
To 1-fluoro-2-methyl-5-(methyloxy)-4-nitrobenzene (prepared according to Example 113, Step B) (1 g, 5.4 mmol) in 10 mL of DMSO was added, 1-[2-(methyloxy)ethyl]piperazine (1 g, 7 mmol), and K2CO3 (1.27 g, 4.2 mmol). The mixture was heated to 130° C. for 24 h. The mixture was then poured into 100 mL of H2O and extracted with EtOAc. The product was isolated by flash chromatography to give the title compound of step A (1.44 g, 4.65 mmol, 86%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.74 (s, 1H), 6.68 (s, 1H), 3.88 (s, 3H), 3.44 (t, J=5.68 Hz, 2H), 3.22 (s, 3H), 2.95-3.01 (m, 4H), 2.50-2.58 (m, 6H), 2.17 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH:17]2[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)=[N+]=[N-])[CH3:2].[OH:21][CH:22]1[CH2:26][CH2:25][O:24][CH2:23]1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH:17]2[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)[O:21][CH:22]1[CH2:26][CH2:25][O:24][CH2:23]1)[CH3:2]
Reactant: CCOC(=O)C(=[N+]=[N-])c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: OC1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C(OC1CCOC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.9 %

Procedure:
(4-Cyclopropanesulfonyl-phenyl)diazo acetic acid ethyl ester (2 gm, 6.74 mmol) was dissolved in DCM (33 mL) under argon atmosphere. To this solution, 3-hydroxy tetrahydrofuran (1.36 mL, 16.87 mmol) was added followed by rhodium(II)acetate dimer (62 mg, 0.14 mmol). Mixture was stirred at 25° C. for 3 hr. Reaction mixture was diluted with DCM (25 mL), organic layer was washed with water followed by brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product which was purified by column chromatography using 35-40% ethyl acetate in hexane as eluent to provide (4-cyclopropanesulfonyl-phenyl)-[(tetrahydro-furan-3-yloxy)]-acetic acid ethyl ester (1 gm).