Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][C:3]([CH2:5][CH2:6]/[CH:7]=[C:8](/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])\[CH3:9])=[CH2:4].[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH:18]=[CH:17]1>C(Cl)(Cl)(Cl)Cl>[CH3:9][C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:14])[CH3:15])=[CH:7][CH2:6][CH2:5][C:3]1[CH2:4][CH:17]2[C:16](=[O:22])[O:21][C:19](=[O:20])[CH:18]2[CH2:1][CH:2]=1
Reactant: C=C(CC)CC/C=C(\C)CCC=C(C)C
Reactant: O=C1C=CC(=O)O1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)=CCCC(C)=CCCC1=CCC2C(=O)OC(=O)C2C1

Procedure:
The (E)-β-farnesene-containing product of Example 1 (6.0 g) and maleic anhydride (2.0 g) in carbon tetrachloride (20 ml) are reacted together at 25° C. for 2 hours. The mixture is then distilled under reduced pressure to give 4-(4,8-dimethyl-3,7-nonadienyl) cyclohex-4-ene-1,2-dioic anhydride as a yellow oil (3.5, 70%; b.p.176°-182° C./0.25τ; nD20 1.5907; M+ (m/z as % base peak): 302 (2.3): δ(CCl4) 1.70 (m, 9H), 2.08 (m, 8H, 2.20-2.70 (m, 4H), 3.36 (m, 2H), 5.16 (m, 2H), 5.70 (br, t, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([CH3:15])[C:9]([F:14])=[C:10]([F:13])[CH:11]=2)[C:6](=[O:16])[C:5]([C:17]([O:19]CC)=[O:18])=[CH:4]1)[CH3:2].Cl>C(O)(=O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([CH3:15])[C:9]([F:14])=[C:10]([F:13])[CH:11]=2)[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2cc(F)c(F)c(C)c2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2c(C)c(F)c(F)cc21
Yield: 80.4 %

Procedure:
Employing ethyl 1-ethyl-5-methyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.55 g), conc. hydrochloric acid (1.5 ml) and 90% acetic acid (6 ml), the procedure of Reference Example 10 is repeated to give 1-ethyl-5-methyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.40 g), as white crystals, m.p.>300° C.
Reaction SMILES: [H-].[Na+].[CH2:3]=[CH:4][CH2:5][CH:6]([OH:10])[CH2:7][CH:8]=[CH2:9].[C:11]([Si:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)Cl)([CH3:14])([CH3:13])[CH3:12]>C1COCC1>[Si:15]([O:10][CH:6]([CH2:7][CH:8]=[CH2:9])[CH2:5][CH:4]=[CH2:3])([C:11]([CH3:14])([CH3:13])[CH3:12])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=CCC(O)CC=C
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(CC=C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 0.92 g, 23 mmol) in THF (10 mL), cooled to 0° C., 1,6-heptadien-4-ol 104 (1 mL, 7.7 mmol) was added dropwise in 10 sec. The resulting suspension was stirred at 0° C. for 30 min and then tert-butyldiphenylchlorosilane (2 mL, 7.9 mmol) was added. The reaction mixture was stirred at 23° C. for 4 h and then quenched with a saturated solution of ammonium chloride. The solvent was removed in vacuo and the aqueous phase was extracted with CH2Cl2. The organic extracts were dried (Na2SO4), the solvent was removed and the residue was purified by flash-chromatography (1:10 EtOAc/Hex) to afford 30 4-(tert-butyldiphenylsilyloxy)hepta-1,6-diene (2.6 g, 96%) as a colorless oil: δH (300 MHz, CDCl3) 7.70 (4H, dd, J1.6, 7.6 Hz, ArH), 7.47-7.38 (6H, m, ArH), 5.83-5.69 (2H, m, 2 CH═CH2), 5.02-4.91 (4H, m, 2.CH═CH2), 3.87-3.80 (1H, m, CHOSi), 2.31-2.12 (4H, m, 3-H2, 5-H2) and 1.08 [9H, s, 35 C(CH3)3]. To a solution of the above compound (2.0 g, 5.7 mmol) in dry CH2Cl2 (20 mL), second generation Grubbs catalyst (4.8 mg, 5.6 μmol) was added and the resulting mixture was heated under reflux for 2 h. Subsequently, the reaction mixture was cooled to 23° C., the solvent was 40 removed under reduced pressure and the residue was purified by flash-chromatography (1:10 EtOAc/Hex) to afford 105 (1.8 g, 98%) as a colorless oil: δH (300 MHz, CDCl3) 7.67 (4H, dd, J1.8, 7.8, ArH), 7.45-7.34 (6H, m, ArH), 5.61 (2 H, s, 1-H, 2-H), 4.57-4.51 (1H, m, 4-H), 2.47-2.33 (4H, m, 3-H2, 5-H2) 45 and 1.05 [9H, s, C(CH3)3].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=O)[NH:9][C:8]=2[CH:14]=1)([O-:3])=[O:2]>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH2:10][NH:9][C:8]=2[CH:14]=1)([O-:3])=[O:2]
Reactant: O=C1COc2ccc([N+](=O)[O-])cc2N1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)NCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
A solution of BH3-Me2S in THF (2 M, 7.75 mL, 15.5 mmol) was added dropwise to a suspension of 6-nitro-4H-benzo[1,4]oxazin-3-one (0.6 g, 3.1 mmol) in THF (10 mL). The mixture was stirred at room temperature overnight. The reaction was quenched with MeOH (5 mL) at 0° C. and then water (20 mL) was added. The mixture was extracted with Et2O and the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give 6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine as a red solid (0.5 g, 89%), which was used without further purification.
Reaction SMILES: [O:1]1C=CC=[C:2]1[C@@H:6]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@H:7]([CH3:15])[CH2:8][O:9][CH2:10][C:11]([OH:14])([CH3:13])[CH3:12].I([O-])(=O)(=O)=[O:26].[Na+]>O.C(Cl)(Cl)(Cl)Cl.CC#N.[Ru](Cl)(Cl)Cl>[C:19]([O:18][C:17]([N:16]([CH3:24])[C@@H:6]([C@H:7]([CH3:15])[CH2:8][O:9][CH2:10][C:11]([OH:14])([CH3:13])[CH3:12])[C:2]([OH:1])=[O:26])=[O:23])([CH3:22])([CH3:21])[CH3:20]
Reactant: C[C@H](COCC(C)(C)O)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: C[C@H](COCC(C)(C)O)[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reaction time: 0.75 h
Yield: 89.5 %

Procedure:
To a solution of compound 2.7b (120.0 mg, 0.35 mmol) in water:CCl4:MeCN (3:2:3, 9.6 ml) at room temperature was added sodium periodate (451.0 mg, 2.1 mmol, 6.0 equiv) followed by ruthenium chloride (25.0 mg, 0.12 mmol, 0.34 equiv). After stirring for 45 minutes, the aqueous layer was extracted with ethyl acetate (3×5 ml). Combined organic layer was washed with saturated aqueous NaHSO3 (25 ml), brine, dried with anhydrous sodium sulfate, and concentrated in vacuo to give compound 2.7c (100.0 mg) which was used for the next step without further purification. MS m/z (M+Na) 342.2
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]2[C:26]([NH:27][C:28]([NH:30][CH2:31][CH3:32])=S)=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21][CH3:22])=[O:20])=[CH:11][CH:10]=1)#[N:2].NC1C(NCC2C=CC(C3C=CC=CC=3C#N)=CC=2)=C(C=CC=1)C(OC)=O>>[CH2:31]([NH:30][C:28]1[N:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])=[CH:10][CH:11]=2)[C:17]2[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=[CH:25][C:26]=2[N:27]=1)[CH3:32]
Reactant: CCNC(=S)Nc1cccc(C(=O)OC)c1NCc1ccc(-c2ccccc2C#N)cc1
Agent: COC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2C#N)cc1
Product: CCNc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
The title compound was prepared as colorless crystals (3.2 g, 32%) according to the procedure for Working Example 8 from methyl 2-[[(2′-cyanobiphenyl-4-yl)methyl]amino]-3-(3-ethylthioureido)benzoate (10.5 g), which was synthesized from methyl 3-amino-2-[[(2′-cyanobiphenyl-4-yl)methyl]amino]benzoate in substantially the same manner as Reference Example 5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][C:19](=[O:22])[CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:35]=[N:34][C:33]([Br:36])=[CH:32][N:31]=1.N1C=CC=CC=1>CN(C)C=O.C(Cl)Cl>[Br:36][C:33]1[N:34]=[CH:35][C:30]([NH:29][C:13](=[O:15])[CH:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][C:19](=[O:22])[CH2:18]2)=[N:31][CH:32]=1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)C2)C(=O)O)cc1Cl
Reactant: Nc1cnc(Br)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCC(=O)C2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-propionic acid (prepared as in Example 45, 1.05 g, 3.04 mmol) and N,N-dimethylformamide (5 drops) in methylene chloride (10 mL) cooled to 0° C. was treated with oxalyl chloride (0.39 mL, 4.57 mmol). The reaction mixture was stirred at 0° C. for 1 h and then at 25° C. for 1 h. The solution was then concentrated in vacuo, and the orange-brown gel was dissolved in methylene chloride (5 mL). The resulting solution was added dropwise via an addition funnel at 0° C. to a solution of 2-amino-5-bromopyrazine (0.79 g, 4.57 mmol, prepared according to Tetrahedron 1988, 44, 2977-2983) in methylene chloride (5 mL) and pyridine (0.37 mL, 4.57 mmol). The reaction mixture was stirred at 0° C. for 30 min and then at 25° C. for 3 h. The reaction mixture was quenched with a 1N aqueous citric acid solution (10 mL) and stirred for 15 min. The reaction was then diluted with a 1N aqueous citric acid solution (50 mL) and ethyl acetate (75 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (50 mL), water (50 mL), and a saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 50% ethyl acetate/hexanes) afforded N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-propionamide (0.622 g, 41%) as a yellow-orange foam: mp 97-103° C. (foam to gel); (ES)+-HRMS m/e calcd for C19H19BrClN3O4S (M+H)+ 500.0041. found 500.0048.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([NH:20][CH2:21][C:22]([OH:24])=O)[S:18][CH:19]=2)=[CH:11][CH:10]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[C:17]([NH:20][CH2:21][C:22]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:24])[S:18][CH:19]=2)=[CH:13][CH:14]=1
Reactant: C1CCNCC1
Reactant: O=C(O)CNc1nc(-c2ccc(F)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1nc(-c2ccc(F)cc2)cs1)N1CCCCC1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.27 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylamino]-acetic acid trifluoroacetic acid salt and 46.5 mg (0.54 mmol) of piperidine. Yield: 58 mg.
Reaction SMILES: [C:1]1([N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[Br:30][C:27]1[CH:28]=[CH:29][C:24]([C:11]2[CH:12]=[CH:13][C:8]([N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:9][CH:10]=2)=[CH:25][CH:26]=1
Reactant: OB(O)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: Brc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Brc1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Yield: 87 %

Procedure:
A mixture of (4-(diphenylamino)phenyl)boronic acid (1.5 g, 5.19 mmol), 4-iodo-1-bromobenzene (1.33 g, 4.71 mmol), Na2CO3 (1.78 g, 16.8 mmol) and Pd(PPh3)4 (0.163 g, 0.141 mmol) in THF/H2O (28 mL/17 mL) was degassed and the resulting mixture was heated at reflux overnight under an argon atmosphere. After cooling, the mixture was poured into dichloromethane (150 mL), then washed with water (2×150 mL) and brine (100 mL). The organic phase was dried over Na2SO4, purified with flash column chromatography (silica gel, hexanes/ethyl acetate 50:1) then recrystallized in dichloromethane/methanol to afford a white solid (Compound 35)(1.64 g, in 87% yield).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[Br:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([Br:31])[CH:30]=1)[CH2:26]Br>>[Br:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([Br:31])[CH:30]=1)[CH2:26][N:8]1[C:9]([C:10](=[O:19])[C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]1=[O:20]
Reactant: BrCc1cc(Br)cc(Br)c1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(Br)cc(Br)c2)c1
Yield: 75.2 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 3,5-dibromobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (402 mg, yield: 75.2%).
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[NH:21])[NH2:20])=[CH:15][CH:14]=1)(C)(C)C.C(Cl)[Cl:24].CO>CO>[ClH:24].[ClH:1].[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([NH2:21])=[NH:20])=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(C(=N)N)cc1
Reactant: ClCCl
Agent: Cl
Solvent: CO
Product: N=C(N)c1ccc(CCCCN)cc1
Reaction time: 2.5 h
Yield: 94 %

Procedure:
12 N hydrochloric acid (0.71 mL, 8.6 mmol) was added dropwise into a stirring solution of [4-(4-carbamimidoylphenyl)butyl]carbamic acid tert-butyl ester (59) (124 mg, 0.43 mmol) in methanol (2 mL). After stirring for 2.5 h, TLC (methylene chloride/methanol/concentrated ammonium hydroxide, 6:3:1) indicated reaction completion. The reaction mixture was vacuum filtered. The solvent was removed from the filtrate by evaporation. Residual water was further removed as an azeotrope of toluene/methanol (1:1). Placement of the residue under vacuum for 2 h afforded the product 60 (106 mg, 94%) as a yellow foamy solid. 1H NMR (300 MHz, DMSO-d6) δ 1.62 (m, 4H), 2.70 (t, 2H), 2.78 (m, 2H), 3.49 (br s, 1H), 7.47 (d, 2H), 7.82 (d, 2H), 8.13 (br s, 3H), 9.25 (s, 2H), 9.42 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[O:16][CH3:17]>CCO.[Pd]>[F:1][C:2]1[CH:3]=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=1[O:16][CH3:17]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1c(F)cnn1C
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)cc1-c1c(F)cnn1C
Yield: 96.9 %

Procedure:
4-Fluoro-5-(2-methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole (109 mg, 0.434 mmol) in EtOH (10 mL) was treated with Pd—C (10 wt. %, Degussa) and a balloon of H2 was allowed to bubble through the slurry. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure to afford 93 mg (97%) of 3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine as a light brown oil. LCMS m/z (%)=222 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ: 7.38 (d, JH,F=4.4 Hz, 1H), 6.86 (d, J=8.8 Hz, 1H), 6.78 (dd, J1=8.8 Hz, J2=2.8 Hz, 1H), 6.63 (d, J=2.8 Hz, 1H), 3.74 (s, 3H), 3.68 (s, 3H), 3.53 (s, 2H). 19F NMR (376 MHz, CDCl3) δ: −175.50 (d, JH,F=5.3 Hz, 1F).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([N:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)[OH:22])=[O:20])=[CH:14][CH:13]=1)[CH:7]=[CH:6]2.[CH3:34][N:35]([CH3:39])[C:36](Cl)=[O:37]>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([N:21]([OH:22])[C:19](=[O:20])[NH:18][C:15]2[CH:14]=[CH:13][C:12]([N:8]3[C:9]4[C:5](=[CH:4][C:3]([NH:2][C:36](=[O:37])[N:35]([CH3:39])[CH3:34])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)=[CH:17][CH:16]=2)=[CH:24][C:25]=1[C:30]([F:33])([F:32])[F:31]
Reactant: CN(C)C(=O)Cl
Reactant: Nc1ccc2c(ccn2-c2ccc(NC(=O)N(O)c3ccc(Cl)c(C(F)(F)F)c3)cc2)c1
Agent: Cl
Product: CN(C)C(=O)Nc1ccc2c(ccn2-c2ccc(NC(=O)N(O)c3ccc(Cl)c(C(F)(F)F)c3)cc2)c1

Procedure:
The title compound can be synthesized from 1-[4-(5-aminoindol-1-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)-3-hydroxyurea hydrochloride and N,N-dimethyl-carbamic acid chloride by using the same techniques as in Example 41.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]([CH2:13][CH3:14])[CH:9]([C:11]#[N:12])[OH:10])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:17][OH:18]>CO.C[O-].[Na+]>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]([CH:9]([OH:10])[C:11](=[NH:12])[NH:17][OH:18])[CH2:13][CH3:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)C#N
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC[C@H](NC(=O)OC(C)(C)C)C(O)C(=N)NO
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 32.2 %

Procedure:
A solution of (2-cyano-1-ethyl-2-hydroxy-ethyl)-carbamic acid tert-butyl ester (9.53 g, 44 mmol) in methanol (80 mL) is cooled to 0° C. and treated successively with hydroxylamine hydrochloride (3.05 g, 44 mmol) in methanol (80 mL) and 25% sodium methoxide solution in methanol (10.2 mL). After stirring at 0° C. for 5 minutes the reaction mixture stirred at room temperature for 5 hours and then evaporated. The residue is partitioned between ethyl acetate and water. The organic layer is separated, dried over magnesium sulfate and then evaporated under reduced pressure. The residual oil is subjected to mplc, eluting with a mixture of ethyl acetate and heptane to give {(S)-1-[hydroxy-(N-hydroxycarbamimidoyl)-methyl]-propyl}-carbamic acid tert-butyl ester (3.5 g) as a solid. MS: MH+248.
Reaction SMILES: [CH2:1]([CH:3]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[C:8]([OH:16])[CH:7]=1)[CH3:2].[OH-].[K+]>CO>[CH2:1]([CH:3]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[C:8]([OH:16])[CH:7]=1)[CH3:2]
Reactant: CCCCC(CC)COc1ccc(C(=O)OC)c(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCC(CC)COc1ccc(C(=O)O)c(O)c1
Temperature: 25 °C
Yield: 75.4 %

Procedure:
In 100 ml of methanol was dissolved 6.44 g (23.1 mmol) of methyl 4-(2-ethylhexyloxy)-2-hydroxybenzoate (compound 1 obtained in Example 1), and an aqueous solution of 3.0 g (53.5 mmol) of KOH was added thereto at room temperature to obtain a reaction mixture. The resulting reaction mixture was heated under reflux for 4 hours, followed by cooling to room temperature, and methanol was evaporated. The residue was poured into 200 ml of dilute hydrochloric acid to be rendered acidic and then extracted with 200 ml of ethyl acetate. The extract was washed successively with two 200 ml portions of water and two 200 ml portions of a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated. Recrystallization of the resulting crude product from ethyl acetate/hexane gave 4.64 g (76%) of 4-(2-ethylhexyloxy)-2-hydroxybenzoic acid represented by the following chemical formula (hereinafter referred to as compound 14) as white crystals. The analytical results of the product are shown below. ##STR35##
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+].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>[C:2]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(Br)cc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2ccccc2)cc1

Procedure:
Heat in a sealed tube with stirring propane-2-sulfonic acid [2-(4-bromo-phenyl)-thiophen-3-yl]-amide (0.5 mmol), phenyl boronic acid (0.75 mmol), 2M Na2CO3 water solution (0.2 mL) and Pd(PPh3)4(0.05 mmol) in 4.0 ml of an anhydrous and deoxygenated 2:1 DME/EtOH mixture to 80° C.-100° C. for 24 h. Filter mixture through a small silica pad and elute with EtOAc. Evaporate the filtrate. Purify the product by flash chromatography (Silica gel-hexane/EtOAc) to obtain the title compound. MS (ES−): 356 (M−1).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([NH2:16])[CH:10]=1)([CH3:8])[CH3:7])(=[O:3])[CH3:2].ClCCl.[CH3:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=O)=[CH:23][CH:22]=1>C(N(CC)CC)C>[C:1]([NH:4][CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]2[N:15]=[C:20]([C:21]3[CH:29]=[CH:28][C:24]([CH3:25])=[CH:23][CH:22]=3)[NH:16][C:11]=2[CH:10]=1)([CH3:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)NCC(C)(C)c1ccc(N)c(N)c1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCC(C)(C)c1ccc2nc(-c3ccc(C)cc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 4.4 g. of the 4-(2-acetamidomethylpropan-2-yl)-1,2-diaminobenzene (prepared in Example 1f) in 120 ml. dry dichloromethane are added 3.3 ml. triethylamine and then, with ice cooling, 3.06 g. 4-methylbenzoic acid chloride. After stirring the reaction mixture for 3 hours at ambient temperature, the solvent is removed in a vacuum. The residue is dissolved in water and extracted three times with dichloromethane, the organic phase is dried over anhydrous sodium sulphate, filtered and the solvent is removed in a vacuum. The residue (6.7 g.) is dissolved in glacial acetic acid and stirred for 3 hours at 70° C. The solvent is removed in a vacuum and the residue is purified by column chromatography (silica gel; dichloromethane containing 5% methanol). There is obtained 1.55 g. of the title compound; m.p. 230°-232° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH2:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+]>C1COCC1>[CH2:15]([O:22][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Yield: 78.7 %

Procedure:
To a solution of 2-fluoro-5-nitrobenzotrifluoride (500 mg, 2.48 mmol) and benzyl alcohol (267 mg, 2.48 mmol) in THF was added sodium hydride (95.1 mg, 2.48 mmol) at 0° C. The reaction was followed by TLC and quenched with saturated ammonium chloride solution after 0.5 h. The mixture was extracted with dichloromethane three times. The combined organic layer was dried over sodium sulfate and concentrated. The residue was triturated with 2.5 mL of hexanes and ethyl acetate (7:1) and a yellow precipitate was collected by filtration to give 1-benzyloxy-4-nitro-2-trifluoromethylbenzene (580 mg, 79%).