Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:41][O:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:16][S:17][CH2:18][C@@H:19]([C:38](O)=[O:39])[NH:20][C:21](=[O:37])[O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl.[NH2:57][CH2:58][CH2:59][CH2:60][C:61]([P:64](=[O:71])([O:68][CH2:69][CH3:70])[O:65][CH2:66][CH3:67])([F:63])[F:62].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH:35]1[C:36]2[CH:24]([CH2:23][O:22][C:21]([NH:20][C@@H:19]([CH2:18][S:17][CH2:16][C@H:15]([O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:41][O:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C:38]([NH:57][CH2:58][CH2:59][CH2:60][C:61]([P:64](=[O:71])([O:68][CH2:69][CH3:70])[O:65][CH2:66][CH3:67])([F:62])[F:63])=[O:39])=[O:37])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: CCOP(=O)(OCC)C(F)(F)CCCN
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCCCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCCC(F)(F)P(=O)(OCC)OCC)OC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5R,9R)-9-(dodecanoyloxy)-1-(9H-fluoren-9-yl)-3,12-dioxo-2,11-dioxa-7-thia-4-azatricosane-5-carboxylic acid (6, 1 eq) in DCM (0.1 M) was added diethyl 4-amino-1,1-difluorobutylphosphonate hydrochloride (1.1 eq), DIEA (3.5 eq) and HBTU (1.1 eq). The reaction mixture was then stirred at room temperature for 2 hours. The mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 30-70% EtOAc/Hex to give the product.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][NH2:43]>>[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][NH:43][C:34](=[O:35])[C:33]1[CH:37]=[CH:38][C:30]([S:27]([CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:29])=[O:28])=[CH:31][CH:32]=1
Reactant: CN(C)CCN
Reactant: O=C(O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Product: CN(C)CCNC(=O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 43.3 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and 2-dimethylaminoethylamine (27 mg, 0.30 mmol, 0.60M in DMF) were combined to give 26 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 601 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([CH2:34][CH2:35][CH2:36][CH3:37])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C(Cl)Cl>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[CH:31][C:32]([CH2:34][CH2:35][CH2:36][CH3:37])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc2c(c1)nc(CCCC)n2Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1ccc2c(c1)nc(CCCC)n2Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2,5-di-n-butyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[C:23]([C:33]([F:36])([F:35])[F:34])[CH:22]=3)[CH:15]=2)[CH2:10]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:36][C:33]([F:34])([F:35])[C:23]1[CH:22]=[C:21]([O:20][CH2:19][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[CH2:10][N:9]([CH2:8][CH2:7][C:6]([OH:37])=[O:5])[CH2:18][CH2:17]3)[CH:26]=[CH:25][C:24]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)CCN1CCc2cc(COc3ccc(-c4ccccc4)c(C(F)(F)F)c3)ccc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCN1CCc2cc(COc3ccc(-c4ccccc4)c(C(F)(F)F)c3)ccc2C1
Temperature: 25 °C

Procedure:
To a solution of 3-[6-(2-trifluoromethyl-biphenyl-4-yloxymethyl)-3,4-dihydro-1H-isoquinolin-2-yl]-propionic acid tert-butyl ester (35 mg, 0.068 mmol) in CH2Cl2 (1 mL) is added TFA (1 mL). The mixture is stirred at room temperature for an hour. All the solvents are evaporated. The mixture is purified by reverse phase preparative LC/MS to give 3-[6-(2-trifluoromethyl-biphenyl-4-yloxymethyl)-3,4-dihydro-1H-isoquinolin-2-yl]-propionic acid:
Reaction SMILES: Br.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:7][C:8]=1[Cl:9].[CH2:14]1[CH2:19][CH2:18][CH:17]([N:20]=[C:21]=[N:22][CH:23]2[CH2:28]CCCC2)CC1.CCN(CC)CC>>[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([N:22]2[CH2:23][CH2:28][N:20]3[CH2:17][CH2:18][CH2:19][CH2:14][C@H:21]23)=[O:13])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: Br
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCN2CCCC[C@@H]21
Yield: 63.5 %

Procedure:
The HBr salt of the title product of Example 4 (1.00 g, 3.3 mmol) and 3,4-dichlorophenylacetic acid (1.07 g, 5.2 mmol, 1.5 eq) and DCC (1.43 g, 6.9 mmol, 2.0 eq) were reacted by addition of Et3N (2.4 mL, 5.0 eq) to give the title compound (0.84 g, 92%) as a colorless crystalline solid. The reaction was-conducted as follows. To a stirred solution of the dichlorophenylacetic acid in CH2Cl2 (100 mL) was added a solution of the DCC in CH2Cl2 (100 mL) and the solution was stirred for 10 min at rt. To the precipitated complex was added the salt of the title compound of Example 4 followed by the Et3N and stirring was continued until TLC (solvent system A) indicated the reaction to be complete. The precipitated DCU was removed by filtration and the filter cake was washed with Et20 (50 mL). The filtrate was diluted with enough Et20 to render the organic layer less dense than the aqueous layer, and the organic extract was then extracted with 10% aqueous citric acid (200 mL) and discarded. The aqueous layer was washed with Et20 (2×200 mL) and the combined washings were discarded. The aqueous layer was basified by addition of excess concentrated aqueous NH3 solution and extracted with CH2Cl2 (2×200 mL). The combined organic layer was washed with water, dried (Na2SO4) and evaporated to give the desired product: mp 102.5-103.5° C. (2-propanol); 1H-NMR (CDCl3) σ 7.39 (d, J=7.9 Hz, 1H), 7.35 (d, J=2.0 Hz, 1H), 7.09 (d, J=2.0, 7.9 Hz, 1H), 4.67 (dd, Jgem=39 Hz, J=13 Hz, 1H), 3.81 (dd, Jgem=44, J=13 Hz, 1H), 3.68 (d, J=3.8 Hz, 2H), 2.73-3.28 (complex m, 3H), 1.98-2.48 (complex m, 3H), 1.64-1.93 (complex m, 4H), 1.32-1.48 (m, 1H); Anal (calcd for C15H18Cl2N2O): C 57.52, H 5.79, N 8.94. Found: 57.60, H 5.76, N 8.94.
Reaction SMILES: Br[C:2]1[C:3]([Cl:10])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:11][N:12]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[N:13]1>>[Cl:10][C:3]1[C:2]([C:15]2[CH:14]=[N:13][N:12]([CH3:11])[CH:16]=2)=[CH:7][N:6]=[C:5]([O:8][CH3:9])[CH:4]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1cc(Cl)c(Br)cn1
Product: COc1cc(Cl)c(-c2cnn(C)c2)cn1

Procedure:
Alternative way to prepare Compound 543: first, 5-bromo-4-chloro-2-methoxypyridine was reacted with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole under the standard Suzuki-Coupling condition to form 4-chloro-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridine; then it was subject to HBr hydrolysis, followed by a second Suzuki-Coupling with (4-ethoxy-2-methylphenyl)boronic acid, then reaction with BnNH2 as described herein. Hydrogen chloride salt: 1H NMR (DMSO-d6, 400 MHz) 1H NMR (DMSO-d6, 400 MHz) δ 8.01 (s, 1H), 7.64 (s, 1H), 7.46 (s, 1H), 7.41-7.35 (m, 5H), 7.28 (m, 1H), 7.18 (d, J=8.8 Hz, 1H), 6.93 (s, 1H), 6.83 (d, J=8.8 Hz, 1H), 5.87 (s, 1H), 4.45 (s, 2H), 4.04 (q, J=6.8 Hz, 2H), 3.89 (s, 3H), 2.00 (s, 3H), 1.32 (t, J=6.8 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:7](/[CH:8]=[CH:9]/N2CCCC2)=[C:6]([N+:15]([O-])=O)[C:5]([O:18][CH3:19])=[CH:4][CH:3]=1.NN>C1COCC1.CO.[Ni]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]2[C:7]=1[CH:8]=[CH:9][NH:15]2
Reactant: COc1ccc(Br)c(/C=C/N2CCCC2)c1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Br)c2cc[nH]c12
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[(E)-2-(6-bromo-3-methoxy-2-nitrophenyl)vinyl]pyrrolidine (1.3 g, 3.97 mmol) in THF (6 mL) and methanol (6 mL) was added Raney Ni (≈500 mg) followed by hydrazine (0.19 mL). (CAUTION: Exothermic reaction with vigorous gas evolution). Hydrazine (0.19 mL) was added again, two times, after 30 min and 1 h. The reaction was stirred at 45° C. for 2 h, filtered through a pad of celite. The filtrate was concentrated in vacuo and the residue purified by chromatography over silica gel eluting with EtOAc/hexane to afford pure 4-bromo-7-methoxy-1H-indole. 1H NMR (400 MHz, CDCl3) δ=3.94 (s, 3H), 6.52 (d, J=8.08 Hz, 1H), 6.56 (dd, J=3.16, 2.40 Hz, 1H), 7.17 (d, J=8.08 Hz, 1H), 7.22 (t, J=2.78 Hz, 1H) and 8.47 (br. s., 1H); MS (ES+): m/z 226.12 [MH+].
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[F:11][C:12]([F:22])([F:21])[C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.O>O1CCCC1>[F:11][C:12]([F:21])([F:22])[C:13]1[CH:20]=[CH:19][C:16]([CH2:17][S:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:3])=[CH:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: FC(F)(F)c1ccc(CCl)cc1
Reactant: Nc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(SCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.2 %

Procedure:
Sodium hydride [0.153 g (50% in mineral oil), 3.2 mmol] was added to a solution of 4-aminothiophenol (0.20 g, 1.6 mmol) in 5 ml anhydrous tetrahydrofuran. The resulting mixture was stirred at room temperature under nitrogen for 15 min, then 4-trifluoromethylbenzyl chloride (0.236 ml, 1.6 mmol) was added. The reaction mixture was stirred overnight at room temperature under nitrogen. Water (50 ml) was then added and the resulting mixture was extracted with 2×50 ml ethyl acetate. The combined ethyl acetate extracts were washed sequentially with 60 ml saturated aqueous sodium bicarbonate solution, 60 ml water and 60 ml brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The solid residue was purified by flash column chromatography (silica gel, 15 g), eluting with 85:15 hexane/ethyl acetate to yield the title compound as an off-white solid (0.318 g, 70% yield). MS: 284.1 (M+1)
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH3:14])=[C:8](B(O)O)[CH:9]=1)([CH3:3])[CH3:2].Br[C:16]1[CH:17]=[C:18]([CH:22]([C:27]2[O:28][C:29]([CH3:32])=[N:30][N:31]=2)[CH2:23][C:24]([OH:26])=[O:25])[CH:19]=[CH:20][CH:21]=1>CN(C=O)C.O.[NH4+].[Cl-]>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH3:14])=[C:8]([C:20]2[CH:21]=[CH:16][CH:17]=[C:18]([CH:22]([C:27]3[O:28][C:29]([CH3:32])=[N:30][N:31]=3)[CH2:23][C:24]([OH:26])=[O:25])[CH:19]=2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: Cc1nnc(C(CC(=O)O)c2cccc(Br)c2)o1
Reactant: COc1ccc(C(C)C)cc1B(O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(C)C)cc1-c1cccc(C(CC(=O)O)c2nnc(C)o2)c1
Yield: 57 %

Procedure:
12.83 g (66.11 mmol) of 5-isopropyl-2-methoxybenzeneboronic acid, 48.97 g (150.3 mmol) and 18.7 g (60.1 mmol) of 3-(3-Bromo-phenyl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionic acid are heated together with 3 mmol of bis(triphenylphosphine)palladium (II)dichloride in 200 ml of DMF and 30 ml of water for 10 hours at 100° C. The reaction mixture is diluted with conc. NH4Cl solution (200 ml) and extracted with methyl-tetrahydrofurane. The organic phase is filtrated over Celite and 100 g of SiO2 and the solvent is removed in vacuo. The obtained crude 3-(5′-Isopropyl-2′-methoxy-biphenyl-3-yl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionic acid is used directly in the next step. (Yield=57%, 28 g)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:40]1[S:41][CH:42]=[CH:43][CH:44]=1)CCC>C1(C)C=CC=CC=1.CO.C(Cl)Cl.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:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:40]3[S:41][CH:42]=[CH:43][CH:44]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2cccs2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Yield: 54.7 %

Procedure:
A solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (50 mg, 0.1 mmol), tributyl(thiophen-2-yl)stannane (44.7 mg, 0.12 mmol) and tetrakis(triphenylphosphine)palladium(0) (115 mg, 0.1 mmol) in toluene (3 mL) was heated to 102° C. for 24 h. The solid was filtered though a pad of Celite, and resulting crude material was reconstituted in MeOH/DCM (20 mL) and purified via preparative HPLC. The collected fractions were combined and stripped to dryness via rotary evaporation to yield the title compound (30 mg, 55%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][N:11]1[C:15](=[O:16])[CH2:14][S:13][C:12]1=[S:17].[CH:18](=O)[CH2:19][CH2:20][CH2:21][CH3:22]>C(O)(=O)C.N1CCCCC1.C(COC)OC>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][N:11]1[C:15](=[O:16])[C:14](=[CH:18][CH2:19][CH2:20][CH2:21][CH3:22])[S:13][C:12]1=[S:17]
Reactant: O=C1CSC(=S)N1N=c1sc2ccccc2s1
Reactant: CCCCC=O
Solvent: COCCOC
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCCCC=C1SC(=S)N(N=c2sc3ccccc3s2)C1=O

Procedure:
A slurry of 2.0 g of 3-[(1,3-benzodithiol-2-ylidene)amino]-2-thioxo-4-thiazolidinone (see example 37), valeraldehyde (10 ml, excess) and acetic acid/piperidine (2:1) (10 drops) in anhydrous glyme (400 ml) is heated at reflux for 18 hours. The reaction mixture is chilled in an ice bath and the resultant precipitate collected by filtration. This precipitate (1.6 g) is recrystallized from 50 ml of dimethylformamide to yield 1.1 g of the title compound, melting point 210°-212° C.
Reaction SMILES: O=[C:2]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]#[N:5].O.[NH2:16][NH2:17]>CCO>[C:9]1([C@@H:7]2[CH2:8][C@H:6]2[C:2]2[CH:3]=[C:4]([NH2:5])[NH:17][N:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NN
Reactant: N#CCC(=O)[C@@H]1C[C@H]1c1ccccc1
Solvent: O
Solvent: CCO
Product: Nc1cc([C@@H]2C[C@H]2c2ccccc2)n[nH]1
Temperature: 80 °C
Reaction time: 6 h
Yield: 127.5 %

Procedure:
To a stirred solution of 39 (28.5 g, 153.87 mmol, 1.00 equiv) in EtOH (300 mL) under N2 was added 85% hydrazine hydrate (5.7 g, 100 mmol, 0.65 equiv), and the reaction mixture was stirred at 80° C. for 6 h. The reaction was cooled to RT, and concentrated in vacuo. The crude residue was purified by SiO2 chromatography eluting with DCM/MeOH gradient (1 to 5% MeOH) to afford 25.4 g (83%) of trans-3-(2-phenylcyclopropyl)-1H-pyrazol-5-amine (41) as a light yellow oil: 1H NMR (400 MHz, DMSO-d6): δ 7.30-7.10 (m, 5H), 5.15 (s, 1H), 4.90-4.20 (br s, 2H), 2.10-2.07 (m, 1H), 2.00-1.95 (m, 1H), 1.35-1.31 (m, 2H), 1H not seen; MS (ESI+) m/z=200 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14]C)=[O:13])=[O:9])=[CH:4][C:3]=1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[H-].[Na+].I[CH3:31].Cl>O1CCCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([OH:14])=[O:13])=[O:9])=[CH:4][C:3]=1[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH3:31]
Reactant: COC(=O)c1ccccc1C(=O)c1ccc(N)c(NC(=O)OC(C)(C)C)c1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(C(=O)c2ccccc2C(=O)O)ccc1N
Reaction time: 1.1 h

Procedure:
Methyl 2-{[4-amino-3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)phenyl]carbonyl}benzoate (0.217 g, 0.586 mmol) was dissolved in tetrahydrofuran (3 mL) and cooled in an ice bath. Sodium hydride (60 wt. % dispersion in oil; 0.024 g, 0.600 mmol) was added followed by dropwise addition of iodomethane (0.037 mL, 0.594 mmol). The mixture was stirred for 1.1 h and then iodomethane (0.100 mL, 1.61 mmol) was added dropwise. The mixture was stirred for a further 1 h and then sodium hydride (60 wt. % dispersion in oil; 0.019 g, 0.475 mmol) was added and the mixture was stirred for a further 0.25 h. The mixture was quenched with 1 N hydrochloric acid. The aqueous portion was extracted with ethyl acetate (2×). The combined organic portion was washed with saturated sodium bicarbonate solution. The ethyl acetate portion was dried over sodium sulfate, filtered and concentrated in vacuo to afford a mixture of 4:1 mono-N-methylated: di-N-methylated material (0.115 g). The aqueous portion was acidified with 1 N hydrochloric acid and extracted with ethyl acetate (2×). The organic portion was washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-({4-amino-3-[{[(1,1-dimethylethyl)oxy]carbonyl}(methyl)amino]phenyl}carbonyl)benzoic acid as an orange oil which was dissolved in methanol (0.5 mL) and toluene (4.5 mL), cooled in an ice-bath and treated with (trimethylsilyl)diazomethane (2.0M solution in hexanes; 0.200 mL, 0.400 mmol). The mixture was stirred for 0.1 h and then was quenched with 0.5 N hydrochloric acid and partitioned with ethyl acetate. The organic portion was washed with saturated sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow foam (0.120 g). This yellow foam was combined with the 4:1 mixture of mono- and di-methylated material isolated above (0.115 g) and was purified by column chromatography (ethyl acetate-hexanes 1:1) to afford methyl 2-({4-amino-3-[{[(1,1-dimethylethyl)oxy]carbonyl}(methyl)amino]phenyl}carbonyl)benzoate as a yellow foam (0.167 g, 0.435 mmol, 74% yield). 1H NMR (4100 MHz, CDCl3): 8.02 (dd, 1H), 7.65-7.30 (m, 5H), 6.69 (d, 1H), 4.24 (s, 2H), 3.65 (s, 3H), 3.13 (s, 3H), 1.56 (s, 9H); MS (EI) for C21H24N2O5: 407 (MNa+).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[C:3]1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH2:16](N(CC)CC)C.[H][H]>C1COCC1.CO>[O:1]=[C:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][C:8]([O:10][CH3:16])=[O:9])[C@@H:3]1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: [H][H]
Reactant: CCN(CC)CC
Reactant: CCCCCC1=C(CC(=O)O)CCC1=O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCC[C@@H]1C(=O)CC[C@@H]1CC(=O)OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 252 mg (1.20 mmole) 3-oxo-2-pentyl-1 cyclopentene-1-acetic acid, in a mixture of 7 ml of THF and 21 ml of methanol, there were added 2 ml of the catalyst solution obtained in a) (0.025 mmole, 0.021 eq.) and 10.4 μl of triethylamine (0.075 mmole, 3 eq.) under stirring at r.t. This solution, prepared in the glass container of a standard autoclave, was introduced in this autoclave, which was locked, put under a pressure of 45×105Pa of hydrogen and stirred at r.t. The reaction was followed by gas chromatography and was completed in about 4 h. After 1 night, the contents were evaporated under vacuum at r.t., the residue taken in ether, washed with HCl 10.1N and then water, dried over MgSO4 and filtered. The thus obtained (+)-(1R)-3-oxo-2-pentyl-1-cyclopentaneacetic acid was esterified by means of diazomethane to yield methyl (+)-(1R)-cis-3-oxo-2-pentyl-1-cyclopentaneacetate, the chromatographic analysis (GC) of which indicated 97% purity, 96:4 cis/trans ratio and 95:5 (+)-(1R)-cis/(-)-(1S)-cis ratio.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1([CH3:16])[NH:10][CH2:9][C:8](=[O:11])[N:7]1[CH2:12][C:13]([O-:15])=[O:14].[Na+].[CH2:18](O)[CH3:19]>>[CH3:5][C:6]1([CH3:16])[NH:10][CH2:9][C:8](=[O:11])[N:7]1[CH2:12][C:13]([O:15][CH2:18][CH3:19])=[O:14]
Reactant: CCO
Reactant: CC1(C)NCC(=O)N1CC(=O)[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CN1C(=O)CNC1(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(1) To an ice-cold solution of thionyl chloride (5 ml) in dry ethanol (50 ml) a solution of sodium 2,2-dimethyl-5-oxo-1-imidazolidineacetate (4 g) in dry ethanol (50 ml) was added dropwise. The mixture was stirred at 0° C. for 1 hour, then at room temperature overnight. After evaporation under reduced pressure, the residue was taken up with a saturated solution of sodium hydrogen carbonate and extracted with 3×100 ml of dichloromethane. The organic layer was dried and evaporated, to yield ethyl 2,2-dimethyl-5-oxo-1-imidazolidineacetate (2.57 g) as a colorless oil (Rf. 0.49, methanol/acetone 1:1; silica gel plates). Oxalate salt m.p. 109°-113° C. (ethanol/diethyl ether).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19])C(OC)=O.Cl(O)(=O)(=O)=O.C(OCC)(=O)C.CO>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19]
Reactant: COC(=O)C(C(=O)OC)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 125 °C
Reaction time: 1.5 h
Yield: 54.6 %

Procedure:
10.08 g (33.8 mmol) of dimethyl-2-(2,6-dinitrophenyl)-malonate is mixed in 54 ml of glacial acetic acid with 2.7 ml of perchloric acid and refluxed at 125° C. In this case, the ethyl acetate that is produced is distilled off. After 90 minutes, the reaction is brought to a halt, since starting material is no longer present according to TLC. The reaction mixture is poured into ice water and extracted three times with ethyl acetate. The combined organic extracts are shaken with 5% sodium bicarbonate solution, with water and with brine. After the organic phase is dried, the desiccant is filtered off and the solvent is spun off, a residue remains that is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 4.69 g of the (2,6-dinitrophenyl)-acetic acid, which then is esterified with methanol (16 ml) and concentrated sulfuric acid (0.4 ml), is isolated. To this end, the acid and the reagents are refluxed for seven hours. The methanol is spun off, and the residue is worked up in the usual way. After chromatography on silica gel (mobile solvent:ethyl acetate/hexane), 4.43 g (89%) of the desired ester is obtained.