Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH:15]1([NH2:19])[CH2:18][CH2:17][CH2:16]1>C1COCC1>[CH:15]1([NH:19][CH2:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH3:8])=[O:6])[CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCC1
Reactant: COC(=O)/C=C/CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/CNC1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.5 %

Procedure:
To a solution of (E)-methyl 4-bromobut-2-enoate (5.37 g, 30 mmol) in THF (60 mL) was added potassium carbonate (8.34 g, 60 mmol), followed by cyclobutanamine (2.13 g, 30 mmol, in 30 mL THF) under N2 atmosphere. The resulting reaction mixture was stirred at RT overnight. Excess potassium carbonate was removed by filtration and the filtrate was diluted with EA and water. The organic layer was separated and the aqueous later was extracted with EA. The combined organic phase was dried over Na2SO4. Solvent was removed in vacuum and the crude mixture was purified by flash chromatography (0-5% DCM/MeOH) to provide (E)-methyl 4-(cyclobutylamino)but-2-enoate (19) (1.7 g, 33%) as an oil. LC-MS (ESI): m/z (M+1), 170.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11]O)[CH:5]=[CH:6][C:7]=1[CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(CCCO)cc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(CCCBr)cc1Cl
Yield: 91.8 %

Procedure:
Compound 55-2 (2.34 g) was dissolved in methylene chloride (40 ml), triphenylphosphine (3.66 g) and N-bromosuccinimide (2.48 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.88 g) as a colorless oil.
Reaction SMILES: [CH2:1]([S:8][C@H:9]1[N:12]([CH2:13][C:14]([OH:16])=O)[C:11](=[O:17])[C@@H:10]1[Cl:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:14](=[O:16])[CH2:13][N:12]2[C@H:9]([S:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:10]([Cl:18])[C:11]2=[O:17])=[CH:24][CH:25]=1
Reactant: O=C(O)CN1C(=O)[C@H](Cl)[C@H]1SCc1ccccc1
Reactant: NCCCCCCc1ccc(F)cc1
Product: O=C(CN1C(=O)[C@H](Cl)[C@H]1SCc1ccccc1)NCCCCCCc1ccc(F)cc1
Yield: 85 %

Procedure:
Treatment of (3S,4R)-(4-benzylthio-3-chloro-2-oxoazetidin-1-yl)acetic acid with 6-(4-fluorophenyl)hexylamine under the conditions described for Example 86 gave the title compound as a colourless oil, 85% yield. 1H NMR δ (CDCl3) 1.3-1.6 (8H, m, 4xCH2), 2.56 (2H, t, J=7.6 Hz, CH2Ph), 3.22 (2H, m, NHCH2), 3.51, 3.81 (each 1H, d, J=16.5 Hz, NCH2), 3.83 (2H, s, SCH2), 4.58 (1H, d, J=1.7 Hz, H4), 4.79 (1H, d, J=1.7 Hz, H3), 5.80 (1H, m, NH), 6.95 (2H, m, 4-FPh--H), (2H, m, 4-FPh--H), 7.30 (5H, m. Ph--H)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Li]CCCC.B(OC)(OC)OC.Br[C:21]1[CH:39]=[CH:38][C:24]([C:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:26])=[CH:23][CH:22]=1>C(OCC)C.C1COCC1.O.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>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:25](=[O:26])[C:24]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:39][CH:38]=1)[CH3:37]
Reactant: CCOC(=O)CCCCCCC(=O)c1ccc(Br)cc1
Reactant: Brc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COB(OC)OC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCCCCCC(=O)c1ccc(-c2cccnc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 25.4 %

Procedure:
To a solution of 3-bromopyridine (728 mg, 4.6 mmol) in dry diethyl ether (9 mL) at −78° C. was added n-BuLi (2.5M solution in hexane, 1.8 mL, 4.5 mmol). The reaction mixture was stirred for 20 minutes at 0° C. After a dropwise addition of trimethyl borate (0.5 mL, 4.5 mmol) the mixture was stirred for 1 hour at 0° C. and then a solution of bromoester 49d (1.02 g, 3 mmol) in THF (9 mL) and water (2.3 mL) containing Pd(PPh3)4 (278 mg, 8 mol %, 0.27 mmol) was added. The reaction mixture was refluxed at 70° C. for 24 hours, cooled to room temperature, filtered through a pad of Celite and rinsed with ethyl acetate. The solution was extracted with ethyl acetate (2×30 mL), washed with brine (10 mL), dried (MgSO4) and concentrated. Purification by flash silica gel chromatography (1% methanol in dichloromethane) afforded the corresponding ester 125 (259 mg, 25% yield) as a white solid. MS (ESI)=340 (MH+).
Reaction SMILES: [C:1]1([S:7]([C@H:10]2[CH2:14][C@@H:13]([C:15]([OH:17])=O)[C@H:12]([C:18](=[O:25])[NH:19][C:20]3([C:23]#[N:24])[CH2:22][CH2:21]3)[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]1[C:29]2([CH2:32][NH:31][CH2:30]2)[CH2:28][O:27]1>>[C:23]([C:20]1([NH:19][C:18]([C@@H:12]2[CH2:11][C@@H:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])[CH2:14][C@H:13]2[C:15]([N:31]2[CH2:32][C:29]3([CH2:26][O:27][CH2:28]3)[CH2:30]2)=[O:17])=[O:25])[CH2:21][CH2:22]1)#[N:24]
Reactant: C1NCC12COC2
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3)C[C@H]2C(=O)O)CC1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3)C[C@H]2C(=O)N2CC3(COC3)C2)CC1

Procedure:
The title compound was prepared by reaction of (1R,2R,4R)-4-benzenesulfonyl-2-(1-cyano-cyclopropylcarbamoyl)-cyclopentanecarboxylic acid (example 10) with 2-oxa-6-aza-spiro[3.3]heptane (prepared according to G. Wuitschik et al., Angew. Chem., Int. Ed., 47, 4512, 2008) using a procedure as described in example 1, step 8. Colorless foam. MS: 444.3 (M+H)+.
Reaction SMILES: C(OC(=O)[CH:5]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([CH:22]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])=[N:10][CH:9]=1)[CH3:6])C.C1(NC2CCCC2)CCCCCC1.NC1SC=NC=1.C([O:51][C:52](=[O:55])CS)C>>[CH:22]1([N:16]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:5][CH2:6][C:52]([OH:55])=[O:51])=[CH:9][N:10]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CCOC(=O)C(C)Sc1cnc(NC(=O)N(C2CCCCCC2)C2CCCC2)s1
Reactant: CCOC(=O)CS
Agent: C1CCCC(NC2CCCC2)CC1
Agent: Nc1cncs1
Product: O=C(O)CCSc1cnc(NC(=O)N(C2CCCCCC2)C2CCCC2)s1

Procedure:
[2-(3-Cycloheptyl-3-cyclopentyl-ureido)-thiazol-5-ylsulfanyl]-propionic acid ethyl ester prepared as described in general procedure (A) using cycloheptyl-cyclopentylamine and 5-aminothiazole-2-mercaptoacetic acid ethyl ester. Hydrolysis using general procedure (F) gave the title compound
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:12]3[CH2:13][CH2:14][CH2:15][CH:16]([C:17]([O:19]C(C)C)=[O:18])[C:11]3=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.CO.C(=O)([O-])[O-].[K+].[K+]>O>[F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:12]3[CH2:13][CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:11]3=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)OC(=O)C1CCCn2c(C(=O)c3ccc(F)cc3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(c1ccc(F)cc1)c1ccc2n1CCCC2C(=O)O

Procedure:
A solution of 180 mg. of isopropyl 3-p-fluorobenzoyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate in 5 ml. of methanol is treated with a solution of 200 mg. of potassium carbonate in 1.5 ml. of water. The reaction mixture is refluxed under a nitrogen atmosphere for 24 hours, cooled, and evaporated to dryness. The residue is taken up in water and the resultant mixture extracted with ethyl acetate to remove the neutral impurities. The aqueous phase is made acidic with concentrated hydrochloric acid and the product is extracted with ethyl acetate. The extract is washed with sodium chloride, dried over sodium sulfate and evaporated to dryness under reduced pressure. Crystallization of the residue from acetone hexane affords 3-p-fluorobenzoyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylic acid (XIa, R=H, L=p-F, n=1), m.p. 164° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=4[F:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[CH3:30][NH:31][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[F:29])[C:15]=2[O:14]1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cc(F)ccc4F)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cccc(-c3cc(F)ccc3F)c2O1

Procedure:
The title compound was prepared (0.027 g, 60%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,5-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.060 g, 0.14 mmol) and methylamine (0.045 g, 1.4 mmol). mp 172-174° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:14])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:13]=1.C[O-].[Na+].[C:18](=O)([O:21]C)[O:19][CH3:20]>>[CH3:1][C:2]1[C:3]([CH3:14])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][CH:8]([C:18]([O:19][CH3:20])=[O:21])[C:7](=[O:12])[C:6]=2[CH:13]=1
Reactant: COC(=O)OC
Reactant: Cc1cc2c(cc1C)C(=O)CCCO2
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)C1CCOc2cc(C)c(C)cc2C1=O

Procedure:
A mixture of 7,8-dimethyl-3,4-dihydro-1-benzoxepin5(2H)-one (1.3 g), sodium methoxide (2.0 g) and dimethyl carbonate (30 ml) is heated under reflux for 6 hours with stirring. The reaction mixture is treated in a manner as in Reference Example 11 to give methyl 7,8-dimethyl-5-oxo-2,3,4,5-tetrahydro-1-benzoxepin-4-carboxylate as a colorless oily product (1.3 g). This product (1.2 g) is dissolved in a mixture of methylene chloride (40 ml) and methanol (50 ml). To the solution is added sodium borohydride (0.3 g) in limited amounts, and the mixture is stirred. After addition of water, the reaction mixture is extracted with methylene chloride. The organic layers are combined, washed with water, dried, and concentrated under reduced pressure. To the residue are added methanol (2 ml) and a 1N aqueous solution of sodium hydroxide (10 ml). The mixture is stirred at 60° C. for 15 minutes. To the reaction mixture are added water and ether and the mixture is shaken. Then the aqueous layer is separated. The aqueous layer is acidified with dilute hydrochloric acid, followed by extraction with methylene chloride. The organic layers are combined, washed with water, dried, and concentrated under reduced pressure. To the residue are added dioxane (8 ml) and concentrated hydrochloric acid (1 ml). The mixture is stirred at 100° C. for 40 minutes. To the reaction mixture is added water, followed by extraction with ethyl acetate. The organic layer is washed with water, dried, and evaporated to dryness. The residue is recrystallized from ethyl acetate to afford 7,8-dimethyl-2,3-dihydro-1-benzoxepin-4-carboxylic acid as colorless needles (0.75 g), m.p. 266°-267° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]([OH:14])[C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][C:5]([Cl:15])=[C:4]([Cl:16])[N:3]=1>CC(C)=O.[O-2].[O-2].[Mn+4]>[NH2:1][C:2]1[C:7]([C:8]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[O:14])=[N:6][C:5]([Cl:15])=[C:4]([Cl:16])[N:3]=1
Reactant: Nc1nc(Cl)c(Cl)nc1C(O)c1nccs1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: Nc1nc(Cl)c(Cl)nc1C(=O)c1nccs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 66.4 %

Procedure:
In 2 ml of acetone there was dissolved 2-amino-5,6-dichloro-3-[hydroxy(thiazol-2-yl)methyl]-pyrazine (44 mg) prepared in Step C above, after which manganese dioxide (120 mg) was added, and the reaction mixture was stirred for 5 hours at room temperature. The manganese dioxide was filtered off, the remaining precipitate washed twice with acetone, and the filtrate concentrated to dryness to give a crystalline product (29 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][CH:3]=1.[CH3:12][N:13]([CH3:16])[CH:14]=O.COC(OC)N(C)C>CO>[Cl:1][C:2]1[C:7](/[CH:8]=[CH:12]/[N:13]([CH3:16])[CH3:14])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(Cl)cccc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: COC(OC)N(C)C
Solvent: CO
Product: CN(C)/C=C/c1c(Cl)cccc1[N+](=O)[O-]

Procedure:
A 2-liter flask fitted with a 30-cm. vacuum-jacketed Vigreux column, downward condenser, and receiver with a nitrogen inlet was charged with 171.6 g. of 6-chloro-2-nitrotoluene, 500 ml. of dimethylformamide, and 149.0 g. of N,N-dimethylformamide dimethyl acetal and then heated to 140°-156° for 13 hours. The pot temperature was maintained by continuous distillation of the methanol as it was formed.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([CH3:13])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.[OH-].[Na+].CN(C)[CH:23]=[O:24]>O>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:23]=[O:24])[C:10]([CH3:13])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccn(Cc2ccccc2)n1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1nn(Cc2ccccc2)cc1C=O
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 1-benzyl-3-methyl-1H-pyrazole (compound 314.1, 1.00 g, 5.81 mmol) in N,N-dimethylformamide (3 mL) was added POCl3 (493 μL, 5.28 mmol) dropwise. The reaction mixture was stirred for 3 h at 90° C. under nitrogen. The reaction mixture was diluted with 50 mL of H2O. The pH of the solution was adjusted to 7 with sodium hydroxide (2 M). The aqueous phase was extracted with 3×20 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 1.42 g (crude) of the title compound as a brown oil.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[S:10][C:11](Br)=[CH:12][N:13]=2)[CH:5]=[CH:4][CH:3]=1.[C:15]([C:18]1[CH:19]=[C:20]([SH:25])[CH:21]=[CH:22][C:23]=1[CH3:24])([OH:17])=[O:16].C[O-].[Na+]>CO.C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[S:10][C:11]([S:25][C:20]3[CH:21]=[CH:22][C:23]([CH3:24])=[C:18]([CH:19]=3)[C:15]([OH:17])=[O:16])=[CH:12][N:13]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S)cc1C(=O)O
Reactant: Brc1cccc(Nc2ncc(Br)s2)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(Sc2cnc(Nc3cccc(Br)n3)s2)cc1C(=O)O
Temperature: 54 °C
Yield: 81.3 %

Procedure:
A suspension of 2-[(6-bromo-2-pyridinyl)amino]-5-bromothiazole (100 mg, 0.3 mmol), 3-carboxy-4-methylthiophenol (170 mg, 0.98 mmol) and sodium methoxide (210 μL, 25% w/w solution in methanol, 0.9 mmol) in methanol (4.9 mL) and THF (2 mL) was heated to 54° C. for 5.5 h. Supplemental sodium methoxide solution (1.42 mL) was added in portions over a period of 5 h. The mixture was heated to 54° C. for 16 h and concentrated. The residue was diluted with 1 N aqueous HCl solution at 0° C. and stirred for several minutes. The precipitated solid was filtered, washed several times with water and ether, and dried in vacuo over P2O5. Trituration with ether afforded the titled compound (103 mg, 81%) as an off-white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[CH3:13][S:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([NH:21][NH2:22])=[O:20])=[CH:17][CH:16]=1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:22][NH:21][C:19](=[O:20])[C:18]1[CH:17]=[CH:16][C:15]([S:14][CH3:13])=[CH:24][CH:23]=1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: CSc1ccc(C(=O)NN)cc1
Solvent: CC(=O)O
Product: CSc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 94 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-(methylsulfanyl)benzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 411 mg of the title compound (94%) as a yellow solid in 99.3% purity by HPLC (Rt: 5.75, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: C([C:4]1[C:9]([NH:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:8]([N+:16]([O-:18])=[O:17])[CH:7]=[CH:6][CH:5]=1)(O)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:26])C=CC=CC=1.C([N:39]([CH2:43]C)C(C)C)(C)C>C(O)(C)(C)C>[N+:16]([C:8]1[C:9]2[N:10]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:43](=[O:26])[NH:39][C:4]=2[CH:5]=[CH:6][CH:7]=1)([O-:18])=[O:17]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)CNc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Product: COC(=O)Cn1c(=O)[nH]c2cccc([N+](=O)[O-])c21
Temperature: 90 °C

Procedure:
A mixture of methyl N-(6-carboxy-2-nitrophenyl)glycinate from Step A (6.08 g, 23.9 mmol), diphenyl phosphoryl azide (7.90 g, 28.7 mmol) and N,N-diisopropylethylamine (12.5 mL, 71.8 mmol) in tert-BuOH (40 mL) was heated at 90° C. for 90 min, then solvent was removed in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 90:10, to give the title compound in sufficient purity for use in subsequent steps. MS: m/z=252 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[Cl:22])=[C:4]([C:11]([O:13]C)=[O:12])[NH:5][C:6]=1[C:7]([O:9]C)=[O:8].[OH-].[Na+].O>C(O)C>[Cl:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[Cl:22])=[C:4]([C:11]([OH:13])=[O:12])[NH:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1[nH]c(C(=O)OC)c(-c2cccc(Cl)c2Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1[nH]c(C(=O)O)c(-c2cccc(Cl)c2Cl)c1Cl
Yield: 100.8 %

Procedure:
The mixture of 1 g of dimethyl 4-chloro-3-(2,3-dichlorophenyl)pyrol-2,5-dicarboxylate, 1 g of sodium hydroxide, 30 ml of ethanol and 18 ml of water was heated for 90 minutes under reflux. After the reaction, ethanol was removed by distillation under reduced pressure and the residue was washed with ether. The aqueous layer was acidified with hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dehydrated and evaporated to dryness under reduced pressure to obtain 0.93 g of 4-chloro-3-(2,3-dichlorophenyl)pyrol-2,5-dicarboxylic acid (white crystal, d.p. 273° C.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16](F)=[CH:15][CH:14]=2)[CH:3]=1.[NH:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1>C(O)C>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:3]=[C:2]2[N:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1
Reactant: Fc1ccc(-c2cc(Cl)c3cc(Cl)ccc3n2)cc1
Reactant: NC(=O)C1CCNCC1
Solvent: CCO
Product: NC(=O)C1CCN(c2cc(-c3ccccc3)nc3ccc(Cl)cc23)CC1

Procedure:
The named compound was made in a manner analogous to that of Example 4(c) using 4,6-dichloro-2-(4-fluorophenyl)quinoline and isonipecotamide as starting materials. It was obtained as white needles, mp 253°-255° dec on recrystallization from ethanol.
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23](=[O:31])OC4C=CC=CC=4)[N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.Cl.[O:40]([NH2:42])[CH3:41]>O1CCCC1>[CH2:1]([NH:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]([NH:42][O:40][CH3:41])=[O:31])[N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)=[O:5])[CH3:2]
Reactant: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)Oc4ccccc4)n3)ccc21
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)NOC)n3)ccc21
Temperature: 25 °C
Yield: 21.5 %

Procedure:
Similarly to Production example 27-2, a crude product of phenyl N-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy-2-pyrimidyl)carbamate (546 mg, 1.31 mmol, 56.3%) was obtained as pale brown powder from N1-ethyl-5-(2-amino-4-pyrimidyl)oxy-1H-1-indolecarboxamide (691 mg, 2.32 mmol) and phenyl chlorocarbonate. The crude carbamate product (273 mg, 0.65 mmol) was dissolved in tetrahydrofuran (7.0 ml); and triethylamine (0.91 ml, 6.53 mmol) and methoxylamine hydrochloride (273 mg, 3.27 mmol) was added thereto while stirred at room temperature. After the reaction mixture was stirred overnight, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and was dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate:hexane=1:1). The crystals were precipitated from ethyl acetate-hexane (1:10), filtered off, and dried under aeration to yield the title compound (52.5 mg, 0.14 mmol, 21.7%) as white crystals.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][Cl:24]>CCO>[ClH:24].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Reactant: Fc1cccc(CCl)c1
Solvent: CCO
Product: Cl
Product: Fc1cccc(CSC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)c1
Temperature: 25 °C
Yield: 53.9 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 3-fluorobenzyl chloride (0.190 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 169 mg of the product 219. 1H NMR (DMSO-d6) δ 11.39 (s, 2 H), 7.65-7.40 (m, 3 H), 7.35-7.20 (m, 1 H), 7.20-6.90 (m, 6 H), 6.90-6.65 (m, 4 H), 5.80 (s, 2 H), 4.85 (s, 2 H); MS: m/z 363 (M++1).
Reaction SMILES: [C:1](=[O:4])([O-:3])O.[Na+].[C:6](=O)([O:14]C1C=CC=CC=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:6]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:14])[C:1]([O:3][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: O=C([O-])O
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: [Na+]
Product: O=C(Oc1ccccc1)C(=O)Oc1ccccc1
Yield: 85 %

Procedure:
400 parts of an aqueous solution of sodium hydrogencarbonate having a pH of 8 were added to 200 parts of diphenyl carbonate, obtained through the decarbonylation reaction of diphenyl oxalate using tetraphenyl phosphonium chloride as a catalyst, and the mixture was heated to 90° C. and stirred for 1 hour. The obtained heavy solution (diphenyl carbonate layer) was purified by distillation in the same manner as in Example 3 at an yield of 85% to obtain diphenyl carbonate containing 0.8 ppm of hydrolyzable chlorine.
Reaction SMILES: CS/[C:3](/[NH2:6])=[N:4]/[NH2:5].[IH:7].[NH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>O>[IH:7].[NH2:5][NH:4][C:3]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])=[NH:6]
Reactant: CCCCN
Reactant: CS/C(N)=N/N
Agent: I
Solvent: O
Product: CCCCNC(=N)NN

Procedure:
S-Methylisothiosemicarbazide hydroiodide (46.6 g) and 1-aminobutane (48 ml) and water (100 ml) were heated under reflux for 1 hour. The resulting solution was evaporated to an oil which was crystallised from amyl alcohol/80-100 PE, to give the title compound (a).