Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]2[C:10]([SH:16])=[C:11]([C:13]([NH2:15])=[O:14])[S:12][C:8]=2[CH:7]=1.C(=O)([O-])O.[Na+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].CN(C=O)C>C1COCC1>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][S:16][C:10]1[C:9]2[CH:17]=[CH:18][C:6]([O:5][CH2:4][C:3]3[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:2]=3[Cl:1])=[CH:7][C:8]=2[S:12][C:11]=1[C:13](=[O:14])[NH2:15])[CH3:35]
Reactant: CCOC(=O)CBr
Reactant: NC(=O)c1sc2cc(OCc3ccc(Cl)cc3Cl)ccc2c1S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)CSc1c(C(N)=O)sc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 6-((2,4-dichlorobenzyl)oxy)-3-sulfanyl-1-benzothiophene-2-carboxamide (40 mg) in THF (dry) (4.0 mL) were added sodium hydrogen carbonate (13.1 mg) and ethyl 2-bromoacetate (0.017 mL). The mixture was stirred overnight at room temperature. To the mixture was added DMF (1.0 mL) and stirred at room temperature over weekend. The mixture was quenched with water and extracted with EtOAc. The combined organic layer was washed successively with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (25.2 mg).
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][NH:16][CH2:17][C:18]=2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[F:39][C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1>C(Cl)Cl>[C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][N:16]([C:44](=[O:45])[C:43]3[CH:47]=[CH:48][C:40]([F:39])=[CH:41][CH:42]=3)[CH2:17][C:18]=2[C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CNCC2(C)C
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CN(C(=O)c1ccc(F)cc1)CC2(C)C
Reaction time: 3 h
Yield: 78.7 %

Procedure:
To a stirred turbid mixture of 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (example 1) (0.0103 g, 0.024 mmol) and Et3N (0.017 ml, 0.120 mmol) in CH2Cl2 (2 mL) was added 4-fluorobenzoyl chloride (8.52 μl, 0.072 mmol) at room temperature. After 3 h, the reaction mixture concentrated and purified by preparative-HPLC (MeCN/H2O/NH4OAc) to afford 2-tert-butoxy-2-(6-(4-fluorobenzoyl)-4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (0.0104 g, 77% yield) as white powder. 1H NMR (500 MHz, CD3OD) δ ppm 6.98-7.59 (8H, m), 4.75-4.87 (1H, br. s.), 4.57 (0.5H, d, J=17.7 Hz), 4.40 (0.5H, d, J=17.7 Hz), 4.31 (0.5H, d, J=17.7 Hz), 4.02 (0.5H, d, J=11.6 Hz), 3.92 (0.5H, d, J=15.3 Hz), 3.73 (0.5H, d, J=12.5Hz), 3.53-3.78 (2H, m), 1.37-1.48 (3H, m), 1.19-1.35 (6H, m), 1.15 (3H, d, J=6.1 Hz), 0.96 (9H, br. s.). LCMS (M+H) calcd for C32H37FN2O4: 551.27. found: 551.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](O)([CH3:13])[O:11][C:10](=O)[C:9]=2[C:16]2[N:17]=[C:18]([CH3:22])[S:19][C:20]=2[CH3:21])=[CH:4][CH:3]=1.O.[NH2:24][NH2:25]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[N:25][NH:24][C:10](=[O:11])[C:9]=2[C:16]2[N:17]=[C:18]([CH3:22])[S:19][C:20]=2[CH3:21])=[CH:4][CH:3]=1
Reactant: NN
Reactant: Cc1nc(C2=C(c3ccc(Cl)cc3)C(C)(O)OC2=O)c(C)s1
Solvent: CCCCO
Solvent: O
Product: Cc1nc(-c2c(-c3ccc(Cl)cc3)c(C)n[nH]c2=O)c(C)s1
Temperature: 0 °C
Yield: 63.5 %

Procedure:
A mixture of 0.86 g of 4-(4-chlorophenyl)-3-(2,5-dimethyl-4-thiazolyl)-5-hydroxy-5-methyl-2(5H)-furanone, 0.18 g of hydrazine monohydrate and 8 ml of 1-butanol was heated under reflux for 5 hours. The reaction mixture was cooled to 0° C. The deposited solid was collected by filtration. The solid was washed with a mixed solvent of hexane and t-butyl methyl ether, and dried under reduced pressure to obtain 0.54 g of 5-(4-chlorophenyl)-4-(2,5-dimethyl-4-thiazolyl)-6-methyl-2H-pyridazin-3-one.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:12]([C:14]1[N:18]2[N:19]=[C:20]([C:23](=O)[CH3:24])[CH:21]=[CH:22][C:17]2=[N:16][CH:15]=1)[CH3:13].Cl.[NH2:27][NH:28][C:29]([NH2:31])=[O:30].C(N(CC)CC)C>CO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:12]([C:14]1[N:18]2[N:19]=[C:20](/[C:23](=[N:27]/[NH:28][C:29]([NH2:31])=[O:30])/[CH3:24])[CH:21]=[CH:22][C:17]2=[N:16][CH:15]=1)[CH3:13]
Reactant: CC(=O)c1ccc2ncc(C(C)c3cc4cccnc4cc3F)n2n1
Reactant: NNC(N)=O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: C/C(=N\NC(N)=O)c1ccc2ncc(C(C)c3cc4cccnc4cc3F)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
To a solution of 1-(3-(1-(7-fluoroquinolin-6-yl)ethyl)imidazo[1,2-b]pyridazin-6-yl)ethanone (60 mg, 0.18 mmol) in methanol (10 ml) was added semicarbazide hydrochloride (40 mg, 0.36 mmol). Triethyl amine was added dropwise to adjust the pH to 5-6. The reaction mixture was stirred at room temperature overnight. The precipitate was collected by filtration and dried over vacuum pump to afford 38 mg (yield: 54%) title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.62 (s, 1H), 8.84 (d, 1H), 8.26 (d, 1H), 8.15 (d, 1H), 7.96 (d, 1H), 7.77 (m, 3H), 7.44 (q, 1H), 6.69 (b, 2H), 5.03 (t, 1H), 2.07 (s, 3H), 1.83 (d, 3H). LCMS (method A): [MH]+=392, tR=4.88 min.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]([CH2:11][C:12]([OH:14])=[O:13])[C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C>>[CH3:1][C:2]1[S:6][C:5]([CH:7]2[CH2:11][C:12](=[O:13])[O:14][C:8]2=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(CC(=O)O)C(=O)O)s1
Solvent: CC(=O)Cl
Product: Cc1ccc(C2CC(=O)OC2=O)s1
Yield: 69.1 %

Procedure:
15.8 g of (5-methyl-2-thienyl) succinic acid was added to 75 cc of acetyl chloride and the mixture was refluxed for 1 hour 30 minutes. The excess acetyl chloride was evaporated under reduced pressure. Bidistillation of the residue provided 10 g (yield=69%) of (5-methyl-2-thienyl) succinic anhydride. Bp1=155°-160° C.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([Cl:27])=[C:6]([C:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[N:16]([C:19]4[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=4[F:26])[N:17]=[CH:18][C:10]=3[CH:9]=2)[CH:7]=1.[I:28]I.[I-].[Cs+].N(OCCC(C)C)=O>COCCOC.[Cu]I>[Cl:27][C:5]1[CH:4]=[CH:3][C:2]([I:28])=[CH:7][C:6]=1[C:8]1[C:13](=[O:14])[N:12]([CH3:15])[C:11]2[N:16]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[N:17]=[CH:18][C:10]=2[CH:9]=1
Reactant: II
Reactant: Cn1c(=O)c(-c2cc(N)ccc2Cl)cc2cnn(-c3c(F)cccc3F)c21
Agent: [Cu]I
Agent: CC(C)CCON=O
Agent: [Cs+]
Solvent: COCCOC
Product: Cn1c(=O)c(-c2cc(I)ccc2Cl)cc2cnn(-c3c(F)cccc3F)c21
Reaction time: 4 h

Procedure:
At RT, a mixture of 5-(5-amino-2-chlorophenyl)-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (230 mg, 0.59 mmol), iodine (151 mg, 0.59 mmol), copper(I) iodide (34 mg, 0.18 mmol) and cesium iodide (154 mg, 0.59 mmol) in DME (4.40 mL) was treated with isoamyl nitrite (0.48 mL, 3.57 mmol) drop wise over 3 min. The reaction mixture was stirred for 4 h, and filtered through a pad of celite washing with EtOAc (100 mL). The organic layer was washed sequentially with ˜2% NH4OH (20 mL), a solution of sodium thiosulfate (20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified on the ISCO 12 g column (10-60% EtOAc in hexanes) affording the title compound as a white crystalline solid. MS (ESI, pos.ion) m/z: 497.9 (M+1).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([N+:28]([O-:30])=[O:29])=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31]I.[OH-].[Na+].O>CN(C=O)C>[CH3:31][N:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:19]1[CH:20]=[C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:14][CH2:13]2)[CH:16]=[CH:17][C:18]=1[N+:28]([O-:30])=[O:29]
Reactant: CI
Reactant: O=C(c1ccccc1)N1CCN(c2ccc([N+](=O)[O-])c(Nc3ccccc3)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1ccccc1)c1cc(N2CCN(C(=O)c3ccccc3)CC2)ccc1[N+](=O)[O-]
Yield: 86.4 %

Procedure:
A solution of 5-(4-benzoylpiperazin-1-yl)-2-nitro-N-phenylbenzenamine (2.0 g, 5.00 mmol), methyl iodide (0.31 ml, 5.00 mmol) and sodium hydroxide (0.26 g, 6.5 mmol) in 25 ml DMF was stirred at 0° C. for 2 hours. 100 ml water was added to the mixture to quench the run, and the mixture was extracted with ethyl acetate (2×20 ml). The extraction was washed with water (3×30 ml) and dried over anhydrous sodium sulfate. N-methyl-5-(4-benzoylpiperazin-1-yl)-2-nitro-N-phenylbenzenamine (1.8 g, 90%) was obtained after remove of solvents. 1H NMR (500 MHz, CDCl3) δ (ppm) 3.38 (s, 3H), 3.37-3.87 (m, 8H), 6.72 (m, 4H), 6.84 (m, 1H), 7.21 (m, 2H), 7.45 (m, 5H), 8.07 (d, J=9.9 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 40.5, 47.7, 47.9, 111.1, 114.6, 115.3, 119.8, 127.6, 129.1, 129.2, 129.6, 130.7, 135.6, 137.3, 145.4, 148.4, 155.1, 171.0.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=O)=[CH:16][CH:15]=1>O>[C:14]1([CH3:13])[CH:22]=[CH:21][C:17]([C:18]2[O:12][C:3]3[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=3[N:1]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1cccc(N)c1O
Reactant: Cc1ccc(C(=O)O)cc1
Solvent: O
Product: COC(=O)c1cccc2nc(-c3ccc(C)cc3)oc12
Temperature: 180 °C
Yield: 30.2 %

Procedure:
Methyl 3-amino-2-hydroxybenzoate (4.4 g, 26 mmol) and 4-methylbenzoic acid (3.6 g, 26.0 mmol) were added to the polyphosphoric acid (20 g). The mixture was heated at 180° C. for 2 hr, and then cooled, poured into water, extracted with ethyl acetate, washed with saturated sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and condensed to obtain methyl 2-p-tolylbenzo[d]oxazole-7-carboxylate as a white solid (2.1 g, yield 30%). LC-MS (ESI) m/z 268 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:23][C:22]([CH3:24])=[C:21]([C:25](O)=[O:26])[C:20]=2[CH3:28])/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH:43]1([CH2:46][NH:47][CH2:48][C@@H:49]2[CH2:53][CH2:52][CH2:51][NH:50]2)[CH2:45][CH2:44]1>CN(C=O)C.C(Cl)Cl>[CH:43]1([CH2:46][NH:47][CH2:48][C@@H:49]2[CH2:53][CH2:52][CH2:51][N:50]2[C:25]([C:21]2[C:20]([CH3:28])=[C:19](/[CH:18]=[C:10]3\[C:11](=[O:17])[NH:12][C:13]4[C:9]\3=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH:16]=[CH:15][CH:14]=4)[NH:23][C:22]=2[CH3:24])=[O:26])[CH2:44][CH2:45]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)c(C)c1C(=O)O
Reactant: C1CN[C@H](CNCC2CC2)C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1[nH]c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)c(C)c1C(=O)N1CCC[C@H]1CNCC1CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (70 mg, 0.185 mmol), EDC (70 mg, 0.37 mmol), HOBt (26 mg, 0.19 mmol) in DMF (4 mL) was added TEA (0.08 mL) and cyclopropylmethyl-(S)-1-pyrrolidin-2-ylmethyl-amine (0.05 mL, 0.37 mmol). The mixture was stirred at rt for 20 hours. The reaction was diluted with DCM, washed with water, NaHCO3, dried and concentrated. The residue was purified on a silica gel column to give the titled compound.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH3:27][C:28]([CH3:33])([CH3:32])[C:29](O)=[O:30]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:29](=[O:30])[C:28]([CH3:33])([CH3:32])[CH3:27])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: CC(C)(C)C(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: CC(C)(C)C(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, white solid (76 mg, 74%), MS (ISP) m/z=411.5 [(M+H)+], mp 157° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 2,2-dimethyl-propionic acid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]2[O:10][CH2:11][O:12][C:4]=2[CH:3]=1.[Mg].Br[CH2:15][CH2:16][CH3:17].[Cl-].[NH4+]>O1CCCC1>[CH3:1][C:2]1[C:7]([CH:8]([OH:9])[CH2:15][CH2:16][CH3:17])=[CH:6][C:5]2[O:10][CH2:11][O:12][C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1C=O)OCO2
Reactant: CCCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC(O)c1cc2c(cc1C)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
A solution of 5.0 g of (6-methyl-1,3-benzodioxol-5-yl)-carboxaldehyde in 20 ml of tetrahydrofuran was dropwise added at a room temperature to a Grignard reagent prepared from 0.86 g of magnesium ribbon, 10 ml of tetrahydrofuran and 4.4 g of 1-bromopropane. The obtained mixture was stirred at a room temperature for one hour, followed by the addition of a saturated aqueous solution of ammonium chloride. The obtained mixture was extracted with ether. The organic layer was washed with an aqueous solution of common salt, dried over magnesium sulfate and distilled to remove the solvent. 5.6 g of (6-methyl-1,3-benzodioxol-5-yl)-butan-1-ol was obtained.
Reaction SMILES: C([O:8][CH2:9][C@@:10]1([O:24][CH3:25])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C@H:11]1[F:23])C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].CO>[F:23][C@H:11]1[C@:10]([CH2:9][OH:8])([O:24][CH3:25])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]1
Reactant: CO[C@]1(COCc2ccccc2)CCN(C(=O)OC(C)(C)C)C[C@H]1F
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CO[C@]1(CO)CCN(C(=O)OC(C)(C)C)C[C@H]1F
Yield: 110.6 %

Procedure:
20% palladium hydroxide on carbon powder (102 mg) was suspended in a MeOH (29 ml) solution of tert-butyl rel-(3R,4S)-4-[(benzyloxy)methyl]-3-fluoro-4-methoxypiperidine-1-carboxylate (971 mg), and stirring was performed at room temperature under a flow of hydrogen gas for 4 hours. After filtration through Celite, the filtrate was concentrated to obtain tert-butyl rel-(3R,4S)-3-fluoro-4-(hydroxymethyl)-4-methoxypiperidine-1-carboxylate (800 mg).
Reaction SMILES: Cl[Si:2]([C:5]1[CH2:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([CH3:4])[CH3:3].[CH:14]1([Na])[CH:18]=[CH:17][CH:16]=[CH:15]1.O>C(OCC)C.O1CCCC1>[CH:14]1([Si:2]([C:5]2[CH2:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)([CH3:3])[CH3:4])[CH:18]=[CH:17][CH:16]=[CH:15]1
Reactant: C[Si](C)(Cl)C1=Cc2ccccc2C1
Reactant: [Na]C1C=CC=C1
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C1=Cc2ccccc2C1)C1C=CC=C1
Temperature: 0 °C
Reaction time: 15 h
Yield: 45.8 %

Procedure:
Chloro-2-indenyldimethylsilane (4.6 g, 0.022 mol.) from Example 1 was dissolved in 20 ml of diethyl ether. The solution was cooled to 0° C., and a solution of cyclopentadienylsodium (1.94 g, 0.022 mol.) in 20 ml of tetrahydrofuran was added dropwise. The mixture was stirred for 15 hours at 25° C. 50 ml of water were then added, and the organic phase was washed with water again and dried over Na2SO4. After removal of the solvents under an oil pump vacuum, the light-yellow oil that remained was purified by means of column chromatography. The solvent was removed to yield 2.4 g (46%) of cyclopentadienyl-2-indenyl-dimethylsilane in the form of a colorless oil.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Cl:14]Cl>C1(C)C=CC=CC=1.O>[Cl:14][CH:2]([C:3]([CH3:5])=[O:4])[C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: CC(=O)CC(=O)Nc1ccccc1
Reactant: ClCl
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)C(Cl)C(=O)Nc1ccccc1
Temperature: 6 °C
Yield: 63.9 %

Procedure:
A suspension of 177 g (1.0 mole) of acetoacetanilide in 1440 ml of toluene and 167 ml of water, in a chlorinator (2000 ml 3-neck flask), was cooled to approximately 6° C. and chlorine gas was added at about the rate of 1.5 g/minute, while maintaining the temperature at 6° C. until 82.6 g (1.16 moles) of chlorine had been added (about 56 minutes). The resultant mixture was stirred for an additional 36 minutes and then heated to 70° C. for 15 minutes. The mixture was then cooled and the product was precipitated. The precipitate was filtered from the toluene/aqueous HCl mixture to give 134.8 g (63.9%) of α-chloroacetoacetanilide, mp 132°-134° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:15][C:16]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:18]2[C:19]([O:21][C:22](=O)[C:17]=12)=[O:20]>>[Cl:15][C:16]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:18]2[C:17]=1[C:22](=[O:21])[N:1]([CH2:2][CH:3]([C:9]1([CH3:14])[O:10][CH2:11][CH2:12][O:13]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:19]2=[O:20]
Reactant: O=C1OC(=O)c2c(Cl)ccc(Cl)c21
Reactant: CCOC(=O)C(CN)C1(C)OCCO1
Product: CCOC(=O)C(CN1C(=O)c2c(Cl)ccc(Cl)c2C1=O)C1(C)OCCO1

Procedure:
Ethyl 3-(4,7-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (1.10 g, 74%) in the same manner as described in the above example 5 (20) from ethyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.80 g, 3.94 mmol) and 3,6-dichlorophthalic anhydride (0.94 g, 4.33 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: CO.[C:3](O)(=[O:5])C.[C-]#N.[Na+].[Cl:10][C:11]1[C:12]([CH2:20][N:21]2[C:25]([CH:26]=[O:27])=[C:24]([S:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[N:23]=[C:22]2[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:13][C:14]2[O:18][CH2:17][O:16][C:15]=2[CH:19]=1>C(Cl)Cl.[O-2].[Mn+2]>[Cl:10][C:11]1[C:12]([CH2:20][N:21]2[C:25]([C:26]([O:5][CH3:3])=[O:27])=[C:24]([S:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[N:23]=[C:22]2[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:13][C:14]2[O:18][CH2:17][O:16][C:15]=2[CH:19]=1
Reactant: COc1ccc(CSc2nc(-c3ccccc3)n(Cc3cc4c(cc3Cl)OCO4)c2C=O)cc1
Reactant: CC(=O)O
Agent: [Mn+2]
Agent: [C-]#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1c(SCc2ccc(OC)cc2)nc(-c2ccccc2)n1Cc1cc2c(cc1Cl)OCO2
Reaction time: 96 h

Procedure:
30 ml of methanol, 120 ul of acetic acid, 2.25 g of manganese oxide and 300 mg of sodium cyanide are added respectively to a solution of 600 mg of the product of Example 7 in methylene chloride. The reaction medium is left under agitation at ambient temperature for 96 hours, followed by filtering, washing with ethyl acetate and evaporating. 410 mg of expected product is obtained M.p.=158° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C@@H:9]2[C@@H:4]([CH2:5][C@@H:6]([C:16]([OH:18])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>O1CCCC1>[OH:1][C@H:2]1[CH2:11][CH2:10][C@@H:9]2[C@@H:4]([CH2:5][C@@H:6]([C:16]([OH:18])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1
Reactant: COC(=O)N1C[C@@H]2CCC(=O)C[C@@H]2C[C@H]1C(=O)O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)N1C[C@@H]2CC[C@H](O)C[C@@H]2C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
To a slurry of 17.3 g of (3S, 4aS, 8aR)6-oxo-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (46 mmol) in 240 mL of tetrahydrofuran is added 106 mL if 1.0 M L-Selectride in tetrahydrofuran. The mixture is stirred for 1 hour at room temperature, then quenched with 130 mL of 1.4 M hydrochloric acid. The layers are separated and the aqueous phase extracted with 50 mL of tert-butyl methyl ether. The organic phases are combined and extracted with 75 mL of saturated aqueous sodium carbonate. The aqueous phase is washed twice with 30 mL portions of tert-butyl methyl ether then acidified to pH 1 with 6 M hydrochloric acid. The product is extracted into 75 mL of tert-butyl methyl ether. The organic mixture is dried with sodium sulfate, and concentrated to 8.17 g of yellow solid. The product is crystallized from 20 mL of tert-butyl methyl ether to provide 6.92 g of the title compound (59% yield).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:15][C:16]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=1[OH:27].O[CH:29]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>>[Cl:15][C:16]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=1[O:27][CH:33]1[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: N#Cc1cc(O)c(Cl)c([N+](=O)[O-])c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(C#N)cc([N+](=O)[O-])c2Cl)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
DIAD (0.309 mL, 1.495 mmol) was added to a solution of 4-chloro-3-hydroxy-5-nitrobenzonitrile (Example 425B) (223 mg, 1.122 mmol), (+/−)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (200 mg, 1.068 mmol) and triphenylphosphine resin (3 mmol/g loading, 560 mg, 2.136 mmol) in THE (5 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 0-20% ethyl acetate/dichloromethane). (+/−)-tert-butyl 3-(2-chloro-5-cyano-3-nitrophenoxy)pyrrolidine-1-carboxylate (272 mg) was obtained as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=[N:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[C:12]=1[O:18][CH3:19])[C:6](=[O:8])[CH3:7])[CH3:2].[C:21]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)([OH:23])=[O:22].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([O:3][C:4]([C:5](=[N:9][NH:10][C:11]1[C:12]([O:18][CH3:19])=[C:13]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([C:21]([OH:23])=[O:22])[CH:29]=2)[CH:14]=[CH:15][CH:16]=1)[C:6](=[O:8])[CH3:7])=[O:20])[CH3:2]
Reactant: CCOC(=O)C(=NNc1cccc(Br)c1OC)C(C)=O
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=NNc1cccc(-c2cccc(C(=O)O)c2)c1OC)C(C)=O
Reaction time: 20 h

Procedure:
A mixture of ethyl-2-[(3-bromo-2-methoxyphenyl)hydrazono]-3-oxobutanoate (4 g) prepared as in Example 1, 3-carboxyphenylboronic acid (2.30 g), bis(triphenylphosphine)palladium(II)chloride [PdCl2(PPh3)2] (0.30 g), potassium carbonate (4.023 g) in ethanol (100 mL) and water (30 mL) was heated to about reflux temperature and stirred for about 20 hours. The hot mixture was filtered to remove the catalyst. The clear filtrate was concentrated under vacuum. To the residue, water (100 mL) was added, acidified to pH 3-5 using hydrochloric acid and stirred for about 30 minutes at about room temperature. The slurry was filtered, washed with water (25 ml) and dried in an oven at about 55° C. to about 60° C. for about 12 hours.
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:13][C:12]([CH2:14][CH:15]=[CH2:16])=[CH:11][C@H:10]1[C:17]([OH:19])=[O:18])=[O:8])(=O)C.N>>[CH2:14]([C:12]1[CH2:13][N:9]([C:7](=[O:8])[CH2:6][CH2:5][SH:4])[C@H:10]([C:17]([OH:19])=[O:18])[CH:11]=1)[CH:15]=[CH2:16]
Reactant: C=CCC1=C[C@@H](C(=O)O)N(C(=O)CCSC(C)=O)C1
Agent: N
Product: C=CCC1=C[C@@H](C(=O)O)N(C(=O)CCS)C1

Procedure:
The product from part (b) is treated with concentrated ammonia according to the procedure of Example 4 to yield (2S)-4-allyl-2,5-dihydro-1-(3-mercapto-1-oxopropyl)-1H-pyrrole-2-carboxylic acid.