Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.[N:38]1([C:42](=O)[CH2:43]Cl)[CH2:41][CH2:40][CH2:39]1>>[N:38]1([CH2:42][CH2:43][O:10][C:8]2[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[CH:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:6][CH:7]=2)[CH2:41][CH2:40][CH2:39]1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN3CCC3)cc2)c1
Yield: 37.3 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (26 mg) and 1-azetidin-1-yl-2-chloroethanone (15 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (4.7 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:18]=[C:19](/[CH:23]=[C:24](/[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)\[C:25]#[N:26])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>C(Cl)CCl>[C:1]([O:5][C:6]([CH:7]1[CH:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[CH:18]=2)[C:24]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)([C:25]#[N:26])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C/C(=C\c1cccc(Cl)c1)c1ccc(Cl)cc1
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.8 %

Procedure:
To a solution of [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester (4.26 g, 20.00 mmol) and (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (5.48 g, 20.00 mmol) in ClCH2CH2Cl (100 mL) were added triethyl amine (4.2 g, 40.00 mmol) and AgF (2.53 g, 20.00 mmol) in one portion. The mixture was stirred at rt overnight. The mixture was then quenched with sat. NH4Cl and extracted with CH2Cl2. The organic phase was separated, filtered through Celite and dried over Na2SO4. The mixture was then separated and concentrated. The residue was triturated with EtOAc and nHexane, and the precipitates were collected by filtration and the mother liquid was concentrated and further purified by flash column (SiO2, 1-20% of EtOAc in hexanes) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester (6.65 g, 68.2%; HRMS (ES+) m/z Calcd for C27H32Cl2N2O2+H [(M+H)+]: 487.1914. found: 487.1910.) and rac-(2R,3R,4R,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester (0.86 g, 8.8%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:17])=[C:4]([C:13](=[O:16])[NH:14][CH3:15])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([Cl:9])=[O:8].[C:18]([O:21][CH2:22][C:23](Cl)=[O:24])(=[O:20])[CH3:19]>CN(C)C(=O)C.CN(C)C1C=CN=CC=1>[C:18]([O:21][CH2:22][C:23]([NH:1][C:2]1[C:3]([I:17])=[C:4]([C:13](=[O:16])[NH:14][CH3:15])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([Cl:9])=[O:8])=[O:24])(=[O:20])[CH3:19]
Reactant: CNC(=O)c1c(I)c(N)c(I)c(C(=O)Cl)c1I
Reactant: CC(=O)OCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1c(I)c(NC(=O)COC(C)=O)c(I)c(C(=O)Cl)c1I
Temperature: 0 °C
Reaction time: 16 h
Yield: 103.4 %

Procedure:
To a slurry of (2) (170 g, 0.29 mol) in 350 ml of N,N-dimethylacetamide (DMAc) was added 4-dimethylaminopyridine (DMAP) (1.86 g, 0.015 mol). The mixture was cooled to 0° C. and acetoxyacetyl chloride (62 ml, 78.6 g, 0.58 mol) was added dropwise, keeping the temperature <5° C. The mixture was stirred at 30° C. for 16 hours. The reaction mixture containing the solid white product was immersed in an ice bath for 2 hours, filtered, stirred with cold THF (1100 ml) for 1 hour, filtered and dried under vacuum for 2 days to give 190 g of product 3 (0.30 mol, 95%) as a white solid. 13C NMR (75.5 MHz, DMSO, ref. DMSO at 39.5 ppm): 170.6, 170.2, 169.9, 166.1, 166.0, 151.7, 149.8, 143.6, 143.5, 103.4, 97.0, 88.8, 62.4, 26.0, 20.6.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:66][CH2:67][CH2:68][OH:69]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:66][CH2:67][CH2:68][OH:69])=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: NCCO
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cn3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCO)cn3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reaction time: 0.08 h
Yield: 37.3 %

Procedure:
To a flask charged with 6-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)nicotinic acid (for a preparation see Intermediate 7)(90 mg, 0.211 mmol) and HATU (96 mg, 0.253 mmol) was added DMF (3 mL) and the resulting mixture was treated with DIPEA (0.110 mL, 0.632 mmol). After stirring for 5 min, the mixture was treated with 2-aminoethanol (0.013 mL, 0.211 mmol). After stirring for 3 min, the solution was partitioned between EtOAc and saturated aqueous NaHCO3 solution and the layers were separated. The aqueous phase was extracted with EtOAc (×2) and the combined organic layers were washed with saturated aqueous NaHCO3 solution (×3), then dried over MgSO4 and concentrated in vacuo. The residue was purified by MDAP (HpH). The appropriate fractions were collected and concentrated in vacuo. The residue was subsequently dissolved in MeOH and dried (hydrophobic frit). The solvent was removed and the residue triturated in Et2O to give 6-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(2-hydroxyethyl)nicotinamide (37 mg, 0.079 mmol, 37.3% yield) as a white solid. LC/MS (HpH, 2 min), Rt=0.70 min, MH+=501.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:11][C:12](=[CH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][CH3:32])[CH:26]=2)=[CH:21][CH:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)CC)C.O>ClCCl.C(OCC)(=O)C>[CH2:1]([NH:8][C:9](=[O:10])[N:31]([C:27]1[CH:26]=[C:25]([C:22]2[CH:23]=[CH:24][C:19](/[CH:18]=[C:12](\[CH3:11])/[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:20][CH:21]=2)[CH:30]=[CH:29][CH:28]=1)[CH3:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCOC(=O)C(C)=Cc1ccc(-c2cccc(NC)c2)cc1
Reactant: CCCCCCCN=C=O
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\C)C(=O)OCC)cc2)c1
Temperature: 50 °C
Reaction time: 12 h
Yield: 78.8 %

Procedure:
618 μL (3.8 mmol) of heptyl isocyanate are added to a solution of 750 mg (2.5 mmol) of ethyl 2-methyl-3-(3′-methylaminobiphenyl-4-yl)acrylate in 10 mL of dichloromethane in the presence of 2 mL of triethylamine. The reaction mixture is stirred for 12 hours at 50° C. The reaction is stopped by addition of 50 mL of water and extraction with ethyl acetate. The organic phases are washed with sodium chloride solution and dried over magnesium sulfate. The solvents are evaporated off, and the residue is then purified by chromatography on a column of silica eluted with a 7/3 heptane/ethyl acetate mixture. 860 mg (78%) of ethyl (E)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]-2-methylacrylate are obtained.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]2[N:12]=[CH:13][C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)=[CH:15][C:6]1=2.[N:30]1([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:34][CH2:33][CH2:32][CH2:31]1>>[F:1][C:2]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]2[N:12]=[CH:13][C:14]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([N:38]4[CH2:39][CH2:40][CH:35]([N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[CH2:36][CH2:37]4)=[O:21])=[CH:23][CH:24]=3)=[CH:15][C:6]1=2
Reactant: C1CCN(C2CCNCC2)C1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(F)ccc2F)C(=O)CN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(F)ccc2F)C(=O)CN3)cc1)N1CCC(N2CCCC2)CC1
Yield: 30 %

Procedure:
4-[1-(2,5-Difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid (35 mg) was reacted with 4-(1 pyrrolidinyl)piperidine as in General Procedure 8 to give the title compound as a pale yellow solid (30% yield). M.p. 186° C. (dec) m/z=532.30 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.44-1.58 (m, 4H), 1.90-2.06 (m, 2H), 2.28-2.32 (m, 1H), 2.52-2.64 (m, 4H), 2.85-3.11 (m, 3H), 3.70-3.82 (m, 2H), 4.34 (s, 2H), 4.50-4.62 (m, 2H), 5.06 (s, 1H), 5.22 (s, 2H), 6.6.88-6.96 (m, 2H), 7.10-7.22 (m, 1H), 7.20 (s, 1H), 7.40 (dd, J=8.3 Hz, 2H), 8.01 (s, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6](N)=[CH:5][CH:4]=1.[C:10](#[N:13])C=C>C(O)C>[CH3:6][C:8]1[CH:9]=[C:3]([CH:4]([CH3:5])[C:10]#[N:13])[S:2][CH:1]=1
Reactant: CSc1ccc(N)cc1
Reactant: C=CC#N
Solvent: CCO
Product: Cc1csc(C(C)C#N)c1

Procedure:
Dissolve 4-(methylmercapto)aniline (25.7 g, 0.185 mol) and acrylonitrile (11.7 g, 0.22 mol) in ethanol (700 mL) and heat at reflux for 18 hours. Evaporate the solvent in vacuo and purify by distillation to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=O)=[CH:17][CH:16]=2)[N:10]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:33])=[C:30]([CH:32]=1)[NH2:31].C[Al](C)C>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:33])=[C:30]([NH:31][C:19](=[O:21])[C:18]2[CH:23]=[CH:24][C:15]([N:11]3[C:12](=[O:14])[NH:13][C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:10]3)=[CH:16][CH:17]=2)[CH:32]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Reactant: Cc1ccc(Cl)cc1N
Agent: C[Al](C)C
Product: Cc1ccc(Cl)cc1NC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Yield: 46.1 %

Procedure:
The title compound was prepared according to the procedure described in Example-31, by using methyl 4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoate (step-2 of Intermediate-9, 0.100 g, 0.28 mmol), 5-chloro-2-methyl aniline (0.062 g, 0.43 mmol) and trimethyl aluminium (2M solution in toluene) (0.5 mL) to afford 0.059 g of desired product. 1HNMR (DMSO-d6): δ 2.23 (s, 3H), 7.23 (d, J=6.9 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.53 (m, 2H), 7.59 (m, 1H), 7.71 (m, 1H), 8.10 (br s, 4H), 9.98 (br s, 1H), 12.76 (br s, 1H); MS (m/z): 457.18 [M]+.
Reaction SMILES: BrC1C=C2C(C=CN2)=CC=1OC.[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18]([C:25]1[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[CH:28][NH:29]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18]([C:25]1[CH:26]=[C:30]2[C:31]([CH:27]=[CH:28][NH:29]2)=[CH:32][C:33]=1[O:34][CH3:35])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:14]
Reactant: CCOC(=O)C=C(c1ccccc1)c1c(OC)ccc2[nH]ccc12
Agent: COc1cc2cc[nH]c2cc1Br
Product: CCOC(=O)C=C(c1ccccc1)c1cc2[nH]ccc2cc1OC

Procedure:
3-(5-Methoxy-1H-indol-6-yl)-3-phenyl-acrylic acid ethyl ester CXXXIII was prepared from 6-bromo-5-methoxyindole XLVII using the procedure described above for preparation of 3-(5-Methoxy-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester XLVIII (Example 12).
Reaction SMILES: [CH3:1][CH:2]([C@H:4]([NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:5]([O:7]C1C=CC([N+]([O-])=O)=CC=1)=O)[CH3:3].[NH2:28][CH2:29][C:30]([NH:32][C@H:33]([C:35]([N:37]1[CH2:48][CH2:47][CH2:46][C@H:38]1[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:36])[CH3:34])=[O:31]>C(OCC)(=O)C>[NH:17]([C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[C@H:4]([C:5]([NH:28][CH2:29][C:30]([NH:32][C@H:33]([C:35]([N:37]1[CH2:48][CH2:47][CH2:46][C@H:38]1[C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])=[O:36])[CH3:34])=[O:31])=[O:7])[CH:2]([CH3:1])[CH3:3]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: C[C@H](NC(=O)CN)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C

Procedure:
3.73 g of Z-Val-ONP and 2.99 g of H-Gly-Ala-Pro-OtBu in 12 ml of ethyl acetate are stirred for one hour at 0° C. and 20 hours at room temperature. After dilution with ethyl acetate the mixture is washed with 50% saturated potassium carbonate solution and water, dried over sodium sulphate and evaporated at 30° C. in a waterpump vacuum. The oil is crystallised from methanol-water. Melting point 73°-75° C. In a thin layer chromatogram on silica gel Rf = 0.42 in the system toluene-acetone (1:1) and Rf = 0.46 in the system chloroform-methanol (9:1).
Reaction SMILES: C(O[C:6](=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[C:14]([CH3:22])([CH3:21])[C:13]2=[O:23])[CH2:9]1)(C)(C)C.BrC1[S:27][C:28]([CH3:31])=[CH:29][N:30]=1>>[CH3:22][C:14]1([CH3:21])[C:15]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[N:12]([C@H:10]2[CH2:9][C@H:8]([NH:7][C:6]3[S:27][C:28]([CH3:31])=[CH:29][N:30]=3)[CH2:11]2)[C:13]1=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](N2C(=O)C(C)(C)c3cccnc32)C1
Reactant: Cc1cnc(Br)s1
Product: Cc1cnc(N[C@H]2C[C@H](N3C(=O)C(C)(C)c4cccnc43)C2)s1

Procedure:
3,3-Dimethyl-1-(trans-3-((5-methylthiazol-2-yl)amino)cyclobutyl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one was prepared by Method B7 using starting materials 1-(trans-3-aminocyclobutyl)-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one hydrochloride (intermediate 26, 0.100 g, 0.329 mmol) and 2-bromo-5-methylthiazole (0.0585 g, 0.329 mmol) at 120° C. for 192 h. M+1: 329.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31 (s, 6 H) 2.23 (d, J=1.17 Hz, 3 H) 2.24-2.33 (m, 2 H) 3.16-3.27 (m, 2 H) 4.23-4.33 (m, 1 H) 5.14 (quin, J=8.41 Hz, 1 H) 6.71 (br. d, J=1.20 Hz, 1 H) 7.08 (dd, J=7.24, 5.28 Hz, 1 H) 7.76 (dd, J=7.24, 1.56 Hz, 1 H) 7.81 (d, J=6.26 Hz, 1 H) 8.21 (dd, J=5.18, 1.66 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-])=[O:12])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O.[OH-].[Na+]>C(OCC)(=O)C.Cl>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([NH:11][OH:12])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: Cc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C1c2ccccc2C(=O)C1(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1c([N+](=O)[O-])cc(NO)cc1[N+](=O)[O-]
Yield: 38.1 %

Procedure:
To a stirred solution of TNT (1.4 g, 6.16 mmol) in ethyl acetate (20 ml) was added a solution/suspension of stannous chloride (4.2 g, 22.22 mmol) in HCl (7.5 ml). An immediate yellow colour resulted. Stirring was continued until TLC (A) and ninhydrin development indicated the conversion of starting materials. The acidic solution was made basic by addition of NaOH solution (1M) and then extracted with saturated potassium chloride solution (4×10 ml). The organic layer was dried over sodiumsulphate and purified by column chromatography, eluting with dichloromethane to afford [7] as a yellow/orange solid (500 mg, 38%). Crystallisation from-chloroform afforded [7] as fine orange needles (220 mg). Rf (B) 0.18; δH(400 MHz; Acetone-d6) 2.29 (3H, s, CH3) 8.04 (1H, s, Ar—H) 8.19 (1H, s, Ar—H) 8.39 (1H, s, NOH) 8.42 (1H, s, NOH); m/z (EI−LR) 213 [(M) calc. for C7H7N3O5 213]; (Found C, 38.02; H, 2.07; N, 18.84. C7H7N3O5 requires C, 39.43; H, 3.28; N, 19.72%).
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:9]([NH2:14])[CH2:10][CH2:11][CH2:12][CH3:13]>C(Cl)Cl>[CH2:9]([NH:14][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCN
Reactant: CCCCCC(=O)Cl
Solvent: ClCCl
Product: CCCCCNC(=O)CCCCC
Reaction time: 4 h

Procedure:
275 g of caproyl chloride are added dropwise within 30 minutes to a solution of 500 ml of n-pentylamine in 1.4 l of methylene chloride while cooling with ice and stirring. After standing at room temperature for 4 hours the reaction solution is washed in succession with 1 l of 0.1N HCl, 1 l of 0.1N NaOH and 1.5 l of NaCl solution. The organic phase is concentrated on a rotary evaporator and dried in a high vacuum and gives 370 g of a crystalline mass (98% of theory). M.p. 37° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:30])[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=O)=O)=CC=1.[N-:31]=[N+:32]=[N-:33].[Na+]>CN(C=O)C>[N:31]([CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH:17]=[C:18]([F:23])[CH:19]=2)[O:14]1)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3cc(F)cc(-c4ccccc4Cl)c3O2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H]1CCc2cc(F)cc(-c3ccccc3Cl)c2O1
Reaction time: 0.17 h
Yield: 83.9 %

Procedure:
A solution ((R)-8-(2-chlorophenyl)-6-fluoro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate (400 mg, 0.90 mmol) and sodium azide (0.29 g, 4.5 mmol) in anhydrous DMF (20 mL) was heated to 90° C. under nitrogen for 20 hours. The cooled reaction mixture was quenched by the addition of water (30 mL) and the resulting suspension stirred vigorously for 10 minutes. The mixture was then partitioned between ethyl acetate (100 mL) and water (100 mL), the organic phase separated, washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Chromatography with 0–30% ethyl acetate in hexanes afforded 240 mg (88%) of (R)-2-azidomethyl-8-(2-chloro-phenyl)-6-fluoro-chroman as a colorless oil. MS (APPI) m/z 288 ([M−N2+H]+).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:27])[C@@H:12]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.Cl>O1CCCC1.O>[CH:14]1([CH2:13][C@H:12]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[CH:5][N:6]=2)=[O:27])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(Cl)c(Cl)c2)nc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(Cl)c(Cl)c2)nc1
Temperature: 60 °C
Yield: 4.4 %

Procedure:
A solution of 6-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionylamino]-nicotinic acid methyl ester (prepared as in Example 45, 188 mg, 0.45 mmol) in tetrahydrofuran (3 mL) was treated with a 3N aqueous hydrochloric acid solution (3 mL). The resulting reaction mixture was heated under reflux at 60° C. for 4 h. After such time, the reaction was cooled to 25° C., diluted with water (5 mL), and then extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate with 1% acetic acid) afforded 6-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionylamino]-nicotinic acid (8 mg, 4%) as a white solid: [α]23589=−41.4° (c=0.099, chloroform); FAB-HRMS m/e calcd for C20H20Cl2N2O3 (M+H)+ 407.0930, found 407.0928.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[N:18]1([C:2]2[N:3]([C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: O=Cc1c(Cl)n(-c2ccsc2)c2ccccc12
Reactant: C1CNCCN1
Product: O=Cc1c(N2CCNCC2)n(-c2ccsc2)c2ccccc12
Yield: 78 %

Procedure:
2-Chloro-1-(thien-3-yl)-1H-indole-3-carboxaldehyde as prepared above is reacted with piperazine as described in Example 3 to give the title compound as a pale yellow solid (78% yield). MS 409 (M+H)
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=O.[OH-].[Na+].[CH3:14][C:15]([CH3:17])=[O:16]>O>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1/[CH:4]=[CH:14]/[C:15](=[O:16])[CH3:17]
Reactant: CC(C)=O
Reactant: O=Cc1c(Cl)ccc(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)/C=C/c1c(Cl)ccc(Cl)c1Cl
Reaction time: 4 h
Yield: 92.3 %

Procedure:
Using the method of Example 1 step 1: To 5.0 g (23.9 mmole) of 2,3,6-trichloro benzaldehyde in 20 ml acetone, was added 2.3 g 50% aqueous NaOH (28.7 mmole) in 100 ml water; After 4 hours the reaction mixture was worked u to give 5.5 g of the trans-4-(2,3,6-trichlorophenyl)-3-buten-2-one as a yellow oil with solid in a 92.3% yield (99% purity by GLC).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][N:5]2[CH:11]=1.Br[C:13]1[S:17][C:16]([C:18]2[N:22]([CH3:23])[N:21]=[CH:20][N:19]=2)=[CH:15][C:14]=1[Cl:24].C([O-])([O-])=O.[Cs+].[Cs+].N#N.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[Cl:24][C:14]1[CH:15]=[C:16]([C:18]2[N:22]([CH3:23])[N:21]=[CH:20][N:19]=2)[S:17][C:13]=1[C:11]1[N:5]2[N:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:4]2=[N:3][C:2]=1[CH3:1]
Reactant: Cc1cn2nc(C)ccc2n1
Reactant: Cn1ncnc1-c1cc(Cl)c(Br)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc2nc(C)c(-c3sc(-c4ncnn4C)cc3Cl)n2n1
Temperature: 135 °C
Yield: 38.7 %

Procedure:
A solution of 2,6-dimethyl-imidazo[1,2-b]pyridazine (0.32 g, 2.17 mmol), 5-(5-bromo-4-chloro-thiophen-2-yl)-1-methyl-1H-[1,2,4]triazole (0.72 g, 2.61 mmol), Cs2CO3 (1.49 g, 4.57 mmol) and DMF (6 mL) is de-gassed for 15 minutes with N2. Pd(OAc)2 (0.024 g, 0.11 mmol) and PPh3 (0.057 g, 0.22 mmol) are added and the solution is heated at 135° C. for 4 hours. The solution is diluted with CH2Cl2 (50 mL), washed with sat. NH4Cl (2×50 mL), water (50 mL), filtered and concentrated. The residue is purified by ISCO flash chromatography (30%-100% EtOAc gradient) furnish the title compound (0.29 g, 0.84 mmol, 39%). 1H NMR (CDCl3) δ 2.49 (s, 3H), 2.50 (s, 3H), 4.10 (s, 3H), 6.92 (d, J=9.2 Hz, 1H), 7.44 (s, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.85 (s, 1H). LC/MS (m/z): calcd. for C15H13ClN6S (M+H)+: 345.1; found: 345.2.