Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.[Br:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11](O)=[CH:10][C:9]=1[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Br:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:6][C@@H:3]2[CH2:4][CH2:5][O:1][CH2:2]2)=[CH:10][C:9]=1[CH3:16]
Reactant: O[C@H]1CCOC1
Reactant: Cc1cc(O)cc(C)c1Br
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(O[C@@H]2CCOC2)cc(C)c1Br
Temperature: 0 °C
Reaction time: 12 h
Yield: 73.8 %

Procedure:
(S)-Tetrahydrofuran-3-ol 2a (1 g, 11.35 mmol) was dissolved in 30 mL of dichloromethane, followed by addition of 4-bromo-3,5-dimethylphenol (2.28 g, 11.35 mmol). The reaction solution was cooled down to 0° C., followed by addition of triphenylphosphine (3.57 g, 13.62 mmol) and diisopropyl azodicarboxylate (2.75 g, 13.62 mmol) successively. The reaction solution was warmed up to room temperature and stirred for 12 hours. The resulting solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with elution system B to obtain the title compound (R)-3-(4-bromo-3,5-dimethylphenoxy)tetrahydrofuran 35a (2.27 g, yield 73.9%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CS(C)=O.O>[F:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH:12]=[CH:13]2
Reactant: C1CNCCN1
Reactant: O=S(=O)(c1ccc(Cl)cc1)n1ccc2cc(F)ccc21
Solvent: O
Solvent: CS(C)=O
Product: O=S(=O)(c1ccc(N2CCNCC2)cc1)n1ccc2cc(F)ccc21
Yield: 48.9 %

Procedure:
A solution of 1-(4-Chlorobenzenesulfonyl)-5-fluoro-1H-indole (0.210 g, 0.7 mmole) and anhydrous piperazine (0.3 g, 3.4 mmole) in dimethylsulfoxide (3.0 mL) was heated at 100° in a sealed tube for 16 h. The reaction mixture was diluted with 15 mL water and extracted with 20 mL ethyl acetate. The organic phase was washed with three 10 mL portions of water, 10 mL saturated sodium chloride, dried (magnesium sulfate), and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to provide the 5-Fluoro-1-(4-piperazin-1-yl-benzenesulfonyl)-1H-indole (0.123 g), m.p. 77–78°.
Reaction SMILES: Cl.[CH3:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]2[CH:10]=[C:11]([C@@H:15]([NH2:17])[CH3:16])[CH:12]=[CH:13][CH:14]=2)[CH2:4]1.[C:18](O)(=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Cl)CCl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]2[CH:10]=[C:11]([C@@H:15]([NH:17][C:18](=[O:27])[CH:19]=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:16])[CH:12]=[CH:13][CH:14]=2)[CH2:4]1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: CC1CN(c2cccc([C@H](C)N)c2)CCO1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CN(c2cccc([C@H](C)NC(=O)C=Cc3ccccc3)c2)CCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Mixture of (S)-1-[3-(2-methyl-morpholin-4-yl)-phenyl]-ethylamine hydrochloric acid salt, Preparation 41(30 mg, 0.10 mmol), cinnamic acid (17 mg, 0.11 mmol), EDC (40 mg, 0.20 mmol), DMAP (13 mg, 0.10 mmol), triethylamine (0.06 ml, 0.40 mmol) in dichloromethane (0.5 mL) was stirred at room temperature overnight. The reaction mixture was purified by filtering through 2 g silica-gel syringe with 70% ethyl acetate/hexanes. The filtrate was concentrated under vacuum to provide the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([N:4]([C:19]([O:21][CH2:22][C:23]1C=CC=CC=1)=[O:20])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([F:18])[CH:6]=1)C=C.N1C=CC=CC=1.[I:35]I>C(Cl)(Cl)Cl>[I:35][CH2:23][CH:22]1[O:21][C:19](=[O:20])[N:4]([C:5]2[CH:6]=[C:7]([F:18])[C:8]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[C:9]([F:11])[CH:10]=2)[CH2:1]1
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cc(F)c(-c2cccnc2)c(F)c1
Reactant: II
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C1OC(CI)CN1c1cc(F)c(-c2cccnc2)c(F)c1
Reaction time: 1.5 h

Procedure:
N-Allyl-N-carbobenzyloxy-4-(3-pyridyl)-3,5-difluoroaniline (PREPARATION 4, 496 mg 1.31 mmol) in chloroform (25 ml), pyridine (1.58 ml, 19.6 mmol, 15 eq) and iodine (4.97 g, 19.6 mmol, 15 eq) are combined. The resulting mixture is placed under an atmosphere of nitrogen and heated to 50° with stirring. After 1.5 hr, the reaction is decanted into chloroform (70 ml). The remaining sludge is rinsed with chloroform (3×15 ml). The combined organics are washed with sodium thiosulfate (20%), then brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to give a solid. This material is purified by silica gel chromatography (100 g) eluting with methanol/chloroform (0.5/99.5 - 11, 1/99, 11). The appropriate fractions are pooled and concentrated to give the title compound, mp 133°-134°; FTIR (mull) cm-1 3130, 1758, 1650, 1414, 1241, 1017 and 846; NMR (CDCl3) 8.72, 8.62, 7.79, 7.43-7.38, 7.32, 4.84-4.72, 4.19, 3.80, 3.51 and 3.39 δ.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH3:11])[CH2:8][CH2:9][NH2:10].[C:18](OC(=O)C)(=[O:20])C>C(O)=O>[CH:18]([NH:10][CH2:9][CH2:8][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])=[O:20]
Reactant: CC(CCN)c1ccccc1-c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CC(CCNC=O)c1ccccc1-c1ccccc1
Reaction time: 8 h

Procedure:
2.25 g of 3-p-biphenyly-butylamine are dissolved in 30 ml of formic acid, 10 ml of acetic anhydride are added dropwise at 60°, while stirring, and the mixture is allowed to stand overnight and worked up in the customary manner to give 1-formamido-3-p-biphenyly-butane.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=O.[C:17]([CH2:19][C:20]([O:22][CH3:23])=[O:21])#[N:18]>>[C:17](/[C:19](=[C:7]1/[C:8](=[O:13])[NH:9][C:10]2[C:6]/1=[CH:5][C:4]([O:3][C:2]([F:16])([F:15])[F:1])=[CH:12][CH:11]=2)/[C:20]([O:22][CH3:23])=[O:21])#[N:18]
Reactant: COC(=O)CC#N
Reactant: O=C1Nc2ccc(OC(F)(F)F)cc2C1=O
Product: COC(=O)/C(C#N)=C1\C(=O)Nc2ccc(OC(F)(F)F)cc21
Yield: 77 %

Procedure:
Following the general method as outlined for Intermediate 1, starting from 5-(trifluoromethoxy)-isatin and methyl cyanoacetate, the title compound was isolated, after evaporation, as a dark purple solid in 77% yield. This was a 7.5:1 mixture of geometric isomers.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([CH2:8][C:9]([OH:11])=O)=[O:7].[NH2:12][CH:13]1[C:30](=[O:31])[N:15]2[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]3[NH:26][N:25]=[N:24][CH:23]=3)[CH2:18][S:19][C@H:14]12>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([CH2:8][C:9]([NH:12][CH:13]1[C:30](=[O:31])[N:15]2[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]3[NH:26][N:25]=[N:24][CH:23]=3)[CH2:18][S:19][C@H:14]12)=[O:11])=[O:7]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3cnn[nH]3)CS[C@H]12
Reactant: O=C(O)CS(=O)c1ccco1
Product: O=C(CS(=O)c1ccco1)NC1C(=O)N2C(C(=O)O)=C(CSc3cnn[nH]3)CS[C@H]12

Procedure:
348 mg. of 2-furylsulfinylacetic acid of the R form and 7-amino-3-(1H-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 109 mg. of 7-(2-furylsulfinylacetamido)-3-(1H-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid of the R form were obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[SH:14]>CC[O-].[Na+]>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[S:14][C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1
Reactant: Sc1cccs1
Reactant: Clc1cnc(Cl)nc1
Agent: CC[O-]
Agent: [Na+]
Product: Clc1cnc(Sc2cccs2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
2,5-Dichloropyrimidine (11.3 mmol) was added to a solution of thiophene-2-thiol (12.3 mmol) in ethanolic (50 ml) 0.246 M NaOEt. The reaction mixture was stirred at room temperature for 15 min and heated under reflux for 2 h. The solvent was then evaporated, the residue extracted with chloroform, the chloroform solution washed with 2 M NaOH and the dried (MgSO4) solution evaporated to leave the sulfide; yield 89%, m.p. 65° C. (pet. ether b.p. 100° C.). 1 H NMR (CDCl3); δ7.03, 7.26, 7.53 (thiophene), 8.40 (H-4, H-6).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[C:5]2=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Brc1cnc2[nH]ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2nc(Br)cnc21
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To a stirred solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (from Ark Pharm, cat# AK-23813, 1.00 g, 5.05 mmol) in tetrahydrofuran (10 mL), NaH (60% w/w dispersion form in mineral oil, 283 mg, 7.07 mmol) was added at 0° C. After 0.5 hour, benzenesulfonyl chloride (644 μL, 5.05 mmol) was added dropwise. After another 1 hour, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with methylene chloride. The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified on silica gel (eluting with 0 to 50% ethyl acetate (EtOAc) in hexanes) to give the desired product (1.50 g, 88%). LCMS calculated for C12H9BrN3O2S (M+H)+: m/z=339.2. Found: 339.2.
Reaction SMILES: CS(O[CH:6]1[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1)(=O)=O.[NH:16]1[CH:20]=[C:19]([C:21]2[C:22]3[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:23]=3[N:24]=[CH:25][N:26]=2)[CH:18]=[N:17]1.[H-].[Na+]>CN(C=O)C>[O:13]1[C:9]2([CH2:14][CH2:15][CH:6]([N:16]3[CH:20]=[C:19]([C:21]4[C:22]5[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:23]=5[N:24]=[CH:25][N:26]=4)[CH:18]=[N:17]3)[CH2:7][CH2:8]2)[O:10][CH2:11][CH2:12]1
Reactant: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4CCC5(CC4)OCCO5)c3)ncnc21
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A mixture of 1,4-dioxaspiro[4.5]dec-8-yl methanesulfonate (0.50 g, 0.0015 mol) with 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.36 g, 0.0011 mol) and sodium hydride (0.082 g, 0.0020 mol) was cooled at −78° C. and DMF (2.0 mL) was added. The reaction was allowed to warm to 25° C. and was then stirred for 20 minutes and was then heated to 55° C. for 24 hours. The reaction was then extracted with ethyl acetate. The organic extracts were washed with water and saturated NaCl, then dried (MgSO4) and concentrated in vacuo. The concentrate was chromatographed on silica gel using 1:1 EtOAc/hexanes to give the product. LC/MS (M+H)+: 456, 1H NMR (CDCl3): 8.89 (s, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 7.44 (d, 1H), 6.87 (d, 1H), 5.73 (s, 2H), 4.38 (m, 1H), 4.06 (s, 4H), 3.60 (m, 2H), 2.22-2.31 (m, 4H), 2.00 (m, 2H), 1.86 (m, 2H), 0.98 (m, 2H), 0.00 (s, 9H)
Reaction SMILES: C1O[C:4]2([C:12]3[C:7](=[CH:8][C:9]([N+:22]([O-])=O)=[C:10]([S:13][C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=4[F:21])[CH:11]=3)[CH2:6][CH2:5]2)[O:3]C1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:22][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[S:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])[C:4](=[O:3])[CH2:5][CH2:6]2
Reactant: O=[N+]([O-])c1cc2c(cc1Sc1ccc(F)cc1F)C1(CC2)OCCO1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc2c(cc1Sc1ccc(F)cc1F)C(=O)CC2
Yield: 88.5 %

Procedure:
A mixture of 5-nitro-6-(2,4-difluorophenylthio)-1-indanone ethylene ketal (580 mg, 1.59 mmol), iron powder (500 mg, 8.9 mmol) and ammonium chloride (50 mg, 0.93 mmol) in 30 mL of ethanol:water (2:1) was refluxed for 1 h. The hot mixture was filtered through celite. The solvente was evaporated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The ethyl acetate extract was dried over anhydrous MgSO4 and concentrated to give the title compound (410 mg, 81%) as a light brown solid. 1H NMR (CDCl3) δ7.95 (s, 1H), 7.00 (m, 1H), 6.80 (m, 2H), 6.72 (s, 1H), 4.95 (br s, 2h), 3.05 (t, 2H), 2.65 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[C:24](=[O:35])NC2CCN(C(C)C)CC2)=[O:10])=[N:6][CH:7]=1.CNCC[OH:40]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[C:24]([OH:35])=[O:40])=[O:10])=[N:6][CH:7]=1
Reactant: CNCCO
Reactant: CC(C)N1CCC(NC(=O)c2nc3ccc(C(=O)O)cc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Product: O=C(Cn1c(C(=O)O)nc2ccc(C(=O)O)cc21)Nc1ccc(Cl)cn1

Procedure:
5-[(2-hydroxy-ethyl)-methyl-amide]2-[(1-isopropyl-piperidin-4-yl)-amide]3-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-3H-benzoimidazole-2,5-dicarboxylic acid 5-[(2-hydroxy-ethyl)-methyl-amide]2-[(1-isopropyl-piperidin-4-yl)-amide] was prepared by a procedure according to example 22 starting from 50 mg (0.10 mmol) 3-[(5-chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H-benzoimidazole-5-carboxylic acid and 8.3 mg (0.11 mmol) N-methyl-2-aminoethanol. The title compound was obtained as its formiate in form of a white amorphous solid. Yield: 32 mg MS (ES+): m/e=556, chloro pattern.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:17]1[CH2:18][CH2:19][CH2:20][CH:15]([O:14][C:10]2[CH:9]=[N:8][CH:13]=[CH:12][CH:11]=2)[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCCC(Oc2cccnc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cncc(OC2CCCNC2)c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 99.7 %

Procedure:
To 130 mg of 3-(1-t-butoxycarbonyl-3-piperidinyloxy)-pyridine was added 10 mL of solution containing 5 mL of TFA and 5 mL of CH2Cl2 at ice-bath temperature. The reaction solution was slowly warmed to room temperature and allowed to stir 50 min at room temperature. After 50 min, solvents were removed in vacuo and the crude product was purified by flash chromatography (9:1: 0.05, CHCl3:MeOH:conc. NH4OH) to obtain 83 mg (quantitative yield) of a clear oil: 1H NMR (300 MHz, CD3OD) δ 8.27 (1H, d, J=2.7 Hz), 8.13 (1H, d, J=4.0 Hz), 7.49-7.34 (2H, m), 4.52 (1H, m), 3.20-2.80 (4H, m), 2.05-1.55 (4H, m); Mass spectrum (ESI) m/z 179.6 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>O1CCCC1>[C:16]([Si:13]([CH3:15])([CH3:14])[O:10][CH2:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCc1ccc([N+](=O)[O-])cc1
Reaction time: 24 h
Yield: 98 %

Procedure:
4-nitrophenethylalcohol (1.0 g, 5.98 mmol) was dissolved in tetrahydrofuran (20 ml), sequentially added with t-butyldimethylsilyl chloride (990 mg, 6.58 mmol) and imidazole (450 mg, 6.58 mmol). The resulting mixture was stirred for one day and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was then purified by flash column chromatography (ethylacetate:hexane=1:8) to obtain the title compound (1.65 g, yield: 98%, yellow oil).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][O:12][CH2:13][CH2:14][CH2:15][NH2:16]>>[CH3:11][O:12][CH2:13][CH2:14][CH2:15][NH:16][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COCCCN
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: COCCCNc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
1-Fluoro-4-nitrobenzene (10 g, 70.8 mmoles) is refluxed for 5 hours with 36.5 g (410 mmoles) of 3-methoxy-propylamine. After that, the reaction product is poured onto 400 g of ice/water and the dye obtained is filtered off. A yellow dye with a melting point of 57°-59° C. is obtained.
Reaction SMILES: [C@@H:1]12[CH2:6][C@@H:5]1[C:4](=[O:7])[O:3][C:2]2=[O:8].[CH3:9][C:10]([OH:13])([CH3:12])[CH3:11]>>[C:10]([O:13][C:4]([C@H:5]1[CH2:6][C@H:1]1[C:2]([OH:8])=[O:3])=[O:7])([CH3:12])([CH3:11])[CH3:9]
Reactant: CC(C)(C)O
Reactant: O=C1OC(=O)[C@@H]2C[C@H]12
Product: CC(C)(C)OC(=O)[C@H]1C[C@H]1C(=O)O
Temperature: 110 °C
Reaction time: 60 h

Procedure:
A mixture of rel-(1R,5S)-3-oxabicyclo[3.1.0]hexane-2,4-dione (1.1 g) and 2-methyl-2-propanol (10 ml) was stirred at 110° C. for 2.5 days. The reaction mixture was concentrated under reduced pressure to obtain rel-(1R,2S)-2-(tert-butoxycarbonyl)cyclopropanecarboxylic acid (1.8 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31].O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:7]1[C:6]2[CH:21]=[C:2]([NH:1][C:30](=[O:31])[N:29]([CH3:33])[CH3:28])[CH:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=1
Reactant: CN(C)C(=O)Cl
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc(N)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CN(C)C(=O)Nc1ccc2c(c1)C(c1ccccc1F)=NCC(=O)N2C
Temperature: 20 °C
Reaction time: 336 h

Procedure:
4.2 g (0.015 M) of 7-amino-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one are suspended in 60 ml of absolute methylene chloride, treated with 2.1 g of powdered potassium carbonate and 1.6 ml of dimethylcarbamoyl chloride and stirred at 20° C. for 14 days. The mixture is then poured on to a mixture of ice and water, extracted with methylene chloride and the organic phase is washed 2-3 times with water, dried with sodium sulphate, filtered and concentrated. The residue is purified on a 200 g silica gel column using ethyl acetate as the eluting agent and crystallised from ethanol/petroleum ether. There is obtained 3-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-1,1-dimethylurea which crystallises with 0.5 mol of ethanol and melts at 97° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:22]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18](O)=[O:19])[CH:8]=1)=[O:5].C([N:39]1[CH2:44][CH2:43][O:42][C@H:41]([CH2:45][NH2:46])[CH2:40]1)C1C=CC=CC=1>>[Cl:1][C:2]1[CH:24]=[CH:23][C:22]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([NH:46][CH2:45][C@H:41]2[O:42][CH2:43][CH2:44][NH:39][CH2:40]2)=[O:19])[CH:8]=1)=[O:5]
Reactant: NC[C@@H]1CN(Cc2ccccc2)CCO1
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Product: O=C(NC[C@@H]1CNCCO1)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1

Procedure:
The title compound was prepared according to the method described for Example 52 using 5-(2-chloro-5-(3-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 105) and (R)-(4-benzylmorpholin-2-yl)methanamine.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][CH2:5][NH:6][C:7]1[C:8]([NH2:16])=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1)[CH3:2].[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1)[CH3:20].C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>ClCCl>[CH2:17]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[NH:16][C:29](=[O:30])[CH2:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:19][CH3:20])=[CH:23][CH:24]=1)[CH3:18]
Reactant: CCN(CC)CCNc1ccc([N+](=O)[O-])cc1N
Reactant: CCOc1ccc(CC(=O)O)cc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClCCl
Product: CCOc1ccc(CC(=O)Nc2cc([N+](=O)[O-])ccc2NCCN(CC)CC)cc1
Temperature: 35 °C

Procedure:
N1-(2-Diethylamino-ethyl)-4-nitro-benzene-1,2-diamine 4a (0.47 g, 1.863 mmol) was dissolved in anhydrous dichloromethane (110 mL) in a small, argon purged flask fitted with an condenser and magnetic stirbar. (4-Ethoxy-phenyl)-acetic acid 5 (0.352 g, 1.956 mmol) followed by 2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (0.552 g, 2.235 mmol) are added quickly as solids and resulting solution heated in an oil bath at 35° C. for 18 hours. After cooling to room temperature the solvent was removed under reduced pressure and the resulting residue partitioned between H2O and chloroform and 3M ammonium hydroxide solution added to adjust pH to 11-12. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with chloroform and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and concentrated to afford crude solid. Recrystallization of the crude solid from ethyl acetate yielded a yellow powder 6a N-[2-(2-Diethylamino-ethylamino)-5-nitro-phenyl]-2-(4-ethoxy-phenyl)-acetamide. Yield: 0.305 grams (39.5%). 1H NMR (DMSO) δ: 0.94 (t, 6H, J=7.1), 1.31 (t, 3H, J=6.9), 2.50 (m, 4H), 2.59 (t, 2H, J=6.5), 3.26 (m, 2H), 3.55 (s, 2H), 4.02 (q, 2H, J=6.9), 6.21 (br s, 1H), 6.75 (d, 1H, J=9.9), 6.87 (d, 2H, J=8.4), 7.24 (d, 2H, J=8.4), 7.97 (m, 2H), 9.54 (br s, 1H); MS (ESI): 415 (MH+, 100%)
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[C:12](=O)[C:13]([Cl:19])=[C:14]([Cl:18])[C:15]([OH:17])=[O:16])=[CH:9][C:8]([CH3:21])=[CH:7][CH:6]=2)[CH3:2].[CH2:22]([N:29]1[C:37]2[C:32](=[CH:33][C:34]([F:38])=[CH:35][CH:36]=2)[CH:31]=[CH:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CN1C2C(=CC=CC=2)C=C1C>>[CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[C:12]1([C:31]3[C:32]4[C:37](=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=4)[N:29]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:30]=3)[O:16][C:15](=[O:17])[C:14]([Cl:18])=[C:13]1[Cl:19])=[CH:9][C:8]([CH3:21])=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCc1[nH]c2ccc(C)cc2c1C(=O)C(Cl)=C(Cl)C(=O)O
Reactant: Fc1ccc2c(ccn2Cc2ccccc2)c1
Agent: Cc1cc2ccccc2n1C
Product: CCc1[nH]c2ccc(C)cc2c1C1(c2cn(Cc3ccccc3)c3ccc(F)cc23)OC(=O)C(Cl)=C1Cl

Procedure:
Following a procedure similar to that described above in part B of this example except that 4-(2-ethyl-5-methyl-3-indolyl)-2,3-dichloro-4-oxo-2-butenoic acid is used in place of 4-(1,2-dimethyl-3-indolyl)-2,3-dichloro-4-oxo-2-butenoic acid and 1-benzyl-5-fluoroindole is substituted for 1,2-dimethylindole, there is obtained 5-(2-ethyl-5-methyl-3-indolyl)-5-(1-benzyl-5-fluoro-3-indolyl)-3,4-dichloro-2(5H)-furanone (Formula V: R=R3 =H; R1 =CH3CH2 ; R2 =C6H5CH2 ; Y=5-CH3 ; Y1 =5-F).
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19]N=3)=[CH:13][CH:14]=2)[C:9]1=[O:26])[C:4]([O:6][CH3:7])=[O:5].CC(C)[C@H](N1CC2C(=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)C1=O)C(OC)=O.BrC1C=CC([N+]([O-])=O)=C[C:57]=1[C:65]([F:68])([F:67])[F:66]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:1][CH:2]([CH3:27])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:57]=3[C:65]([F:68])([F:67])[F:66])=[CH:13][CH:14]=2)[C:9]1=[O:26])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc([N+](=O)[O-])cn3)cc2C1=O
Reactant: O=[N+]([O-])c1ccc(Br)c(C(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1=O
Solvent: ClCCl
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc([N+](=O)[O-])cc3C(F)(F)F)cc2C1=O
Yield: 85 %

Procedure:
The compound of example 413 was prepared analogous to the compound of example 391 by reaction of the compound of example 390, 1-bromo-4-nitro-2-(trifluoromethyl)benzene and Pd(dppf)Cl2: CH2Cl2.