Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][CH2:14][C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])[CH:10]=2)[CH:5]=[C:4]([OH:20])[C:3]=1[N:21]1[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]1.C(N(CC)CC)C.O.Cl>CS(C)=O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][CH2:14][C:15]([CH:16]=[O:17])([CH3:19])[CH3:18])[CH:10]=2)[CH:5]=[C:4]([OH:20])[C:3]=1[N:21]1[S:25](=[O:26])(=[O:27])[NH:24][C:23](=[O:28])[CH2:22]1
Reactant: CC(C)(CO)CCCc1ccc2cc(O)c(N3CC(=O)NS3(=O)=O)c(F)c2c1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C=O)CCCc1ccc2cc(O)c(N3CC(=O)NS3(=O)=O)c(F)c2c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-[1-fluoro-3-hydroxy-7-(5-hydroxy-4,4-dimethylpentyl)-naphthalen-2-yl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (1.00 g, 2.23 mmol) in anhydrous DMSO (10 ml) at room temperature was added triethylamine (2.17 mL, 15.6 mmol) followed by a slow addition of a solution of sulfur trioxide pyridine complex (1.28 g, 8.02 mmol) in anhydrous DMSO (12 mL). The reaction mixture was stirred for 30 min and cold water (70 mL) was slowly added. The above content was acidified with 3 N HCl to pH 2.5, extracted twice with EtOAc, washed with brine, dried over MgSO4, and concentrated to yield the title compound as a light brown solid. Retention time=1.22 min (Method A); MS (M−H)−=407.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1.Cl[C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]([CH3:23])=[CH:16][N:15]=1>>[CH3:23][C:17]1[CH:18]=[C:19]([N+:20]([O-:22])=[O:21])[C:14]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=2)=[N:15][CH:16]=1
Reactant: CCOC(=O)c1ccc(N)cn1
Reactant: Cc1cnc(Cl)c([N+](=O)[O-])c1
Product: CCOC(=O)c1ccc(Nc2ncc(C)cc2[N+](=O)[O-])cn1
Yield: 53.4 %

Procedure:
Prepared according to General Procedure E starting from ethyl 5-aminopicolinate (14.0 g, 84.2 mmol) and 2-chloro-5-methyl-3-nitropyridine (17.4 g, 101 mmol) to give the title compound as a yellow solid (13.6 g, 53%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]1.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20].ClC1C=CC(C2CC(=O)C(=CN(C)C)C(=O)C2)=CC=1>>[CH3:18][N:19]([CH:21]=[C:11]1[C:12](=[O:14])[CH2:13][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:9][C:10]1=[O:15])[CH3:20]
Reactant: O=C1CC(=O)CC(c2ccccc2F)C1
Reactant: COC(OC)N(C)C
Agent: CN(C)C=C1C(=O)CC(c2ccc(Cl)cc2)CC1=O
Product: CN(C)C=C1C(=O)CC(c2ccccc2F)CC1=O
Temperature: 100 °C
Reaction time: 16 h

Procedure:
The title compound was prepared from 5-(2-fluoro-phenyl)-cyclohexane-1,3-dione (1.03 g, 5.0 mmol), example 1/b stage 2, and N,N-dimethylformamide dimethylacetal (5 ml), following the procedure described for the synthesis of 5-(4-chloro-phenyl)-2-dimethylaminomethylene-cyclohexane-1,3-dione (example 2/a stage 1) except that the reaction was stirred at 100° C. for 16 h.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[I-:22].[K+].[Cl-].[NH4+]>CN(C)P(=O)(N(C)C)N(C)C>[I:22][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: [I-]
Reactant: COC(=O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)CC1CCc2cc(I)cc3[nH]c(=O)c(=O)n1c23
Temperature: 160 °C
Yield: 77.5 %

Procedure:
A mixture of 9-bromo-5-methoxycarbonylmethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (530 mg, 1.50 mmol), potassium iodide (4.98 g, 30 mmol) and cuprous iodide (2.0 g, 10.5 mmol) in hexamethylphosphoric triamide (5 mL) was heated at 160° C. for 6.5 h and poured into 1N aqueous ammonium chloride (200 mL). The mixture was extracted with a mixed solvent of THF and ethyl acetate (600 mL). The extract was washed with 1N aqueous ammonium chloride (200 mL×2) and brine (200 mL), dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 0.7 to 1% acetic acid/ethyl acetate to give 465 mg of the title compound (78%): mp 241°~243° C.; 1H NMR (270 MHz, DMSO-d6) δ12.01 (bs, 1H), 7.33 (s, 1H), 7.31 (s, 1H), 5.03~5.14 (m, 1H), 3.62 (s, 3H), 2.93 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.78 (dm, 1H, J=17.1 Hz), 2.54~2.69 (m, 2H), 2.09 (dm, 1H, J=13.5 Hz), 1.79~1.96 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([C:13]([CH3:51])([CH3:50])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:37][CH2:36][N:35]4[CH2:38][CH2:39][CH2:40][C@H:34]4[C@@H:33]3[CH2:41][O:42][Si](C(C)(C)C)(C)C)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.N>CO.Cl>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]([CH3:51])([CH3:50])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:37][CH2:36][N:35]4[CH2:38][CH2:39][CH2:40][C@H:34]4[C@@H:33]3[CH2:41][OH:42])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:52])[F:53])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(N2CCN3CCC[C@H]3[C@@H]2CO[Si](C)(C)C(C)(C)C)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: N
Solvent: CO
Product: Cc1cc(F)ccc1-c1cc(N2CCN3CCC[C@H]3[C@@H]2CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 50.4 %

Procedure:
To a solution of cis-2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-[1-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (D74, 10.5 mg) in dry methanol (1 mL) at 0° C., one drop of concentrated HCl was added. The resulting mixture was stirred at 0° C. for 1.5 hours and then was allowed to reach rt and stirred at this temperature for 2 hours. The solution was then directly charged onto a SCX cartridge (eluting with MeOH and ammonia, 0.5N solution in methanol) to give the desired compound (4.5 mg) as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([OH:14])=[C:7]([CH3:13])[C:8]=2[CH3:12])[N:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[NH:1]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([OH:14])=[C:7]([CH3:13])[C:8]=2[CH3:12])[N:3]=1)[C:15]([CH3:16])=[O:17]
Reactant: Cc1c(O)nc2nc(N)ccc2c1C
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2c(C)c(C)c(O)nc2n1
Yield: 37 %

Procedure:
142 g (0.75 mol) of 2-amino-7-hydroxy-5,6-dimethyl-1,8-naphthyridine and 640 ml of acetic anhydride are boiled under reflux for 30 minutes. After the mixture has been cooled, the product is filtered off and purified by stirring with CH2Cl2 and methanol. There is obtained 64.1 g (37%) of a gray solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[C:4]([N+:21]([O-])=O)[CH:3]=1>CO.Cl.[Fe]>[NH2:21][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[N:8]1[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]1=[O:20]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)cc2[N+](=O)[O-])c1=O
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)cc2N)c1=O
Temperature: 25 °C

Procedure:
To a stirred suspension of 3-(4-choro-2-nitrophenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (1 g) in methanol (20 ml) and conc. hydrochloric acid (10 ml) was added iron (powdered, 0.48 g) unded vigorous stirring. After addition, the mixture was heated at reflux temperature for 1 hr. The oil bath was removed and the solution was allowed to cool to ambient temperature. Ethyl acetate (200 ml) was added, washed with brine (×2) and dried over anhydrous sodium sulfate. After removal of the solvent, the residue was purified by column chromatography on silica gel using ethyl acetate-hexane (1:3) as the eluent to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([CH3:13])[CH:7]=1.[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:17]([CH3:18])[S:19][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([CH3:13])[CH:7]=1)=[O:16]
Reactant: COC(=O)C(=O)C(Cl)c1ccc(C)c(C)c1
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1ccc(C)c(C)c1

Procedure:
prepared by reaction of 3-chloro-3-(3,4-dimethyl-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.96 min; [M+H]+=262.3.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[C@@H:12]4[CH2:17][N:16](C([O-])=O)[CH2:15][CH2:14][C@@H:13]4[N:5]([C:6]=23)[CH2:4][CH2:3]1.[OH-].[K+].[CH2:23](O)[CH2:24]CC>>[CH2:23]([CH:4]1[N:5]2[C@H:13]3[CH2:14][CH2:15][NH:16][CH2:17][C@H:12]3[C:7]3[C:6]2=[C:11]([CH:10]=[CH:9][CH:8]=3)[N:2]([CH3:1])[CH2:3]1)[CH3:24]
Reactant: CN1CCN2c3c(cccc31)[C@@H]1CN(C(=O)[O-])CC[C@@H]12
Reactant: CCCCO
Agent: [K+]
Agent: [OH-]
Product: CCC1CN(C)c2cccc3c2N1[C@H]1CCNC[C@@H]31
Temperature: 120 °C

Procedure:
(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido-[3′,4′:4,5]-pyrrolo[1,2,3-de]quinoxaline-8-carboxylate (ca. 18.5 g, 57 mmol), KOH (12.7 g, 226 mmol) and n-butanol are placed in a 300 ml pressure bottle and heated in an oil bath at 120° C. for 3 hours. n-butanol is removed in vacuo and 300 ml of water is added and then extracted with DCM. The DCM layers are combined and washed with brine and dried (Na2SO4). Evaporation of the solvent gives (6bR,10aS)-ethyl-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido-[3′,4′:4,5]-pyrrolo[1,2,3-de]quinoxaline.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]Cl)=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2].[CH2:16]([SH:19])[CH2:17][CH3:18]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][S:19][CH2:16][CH2:17][CH3:18])=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2]
Reactant: CCCS
Reactant: O=[N+]([O-])c1ccc(SCl)c(C(Cl)(Cl)Cl)c1
Product: CCCSSc1ccc([N+](=O)[O-])cc1C(Cl)(Cl)Cl
Yield: 90.8 %

Procedure:
Similarly, 61 g of 4-nitro-2-trichloromethylbenzenesulfenyl chloride is reacted with 15 g of 1-propylmercaptan. There is obtained 62 g (89% of theory) of (4-nitro-2-trichloromethylphenyl)-n-propyl disulfide as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.B1(C=C)OB([CH:26]=[CH2:27])OB(C=C)O1.C1C=CN=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:3]([CH:26]=[CH2:27])=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(Cl)c(I)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C=Cc1cc2c3ccnc(C)c3c(=O)n(C)c2cc1Cl
Temperature: 90 °C
Yield: 52.8 %

Procedure:
A solution of 8-chloro-9-iodo-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (1.2 g, 2.71 mmol), 2,4,6-trivinylcyclotriboroxane pyridine complex (0.784 g, 3.26 mmol), tetrakis(triphenylphosphine)palladium (0.157 g, 0.136 mmol) and Na2CO3 (0.575 g, 5.43 mmol) in toluene (30 mL) and water (0.5 mL) was purged with nitrogen and heated at 90° C. for 16 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was taken up in ethyl acetate and filtered through diatomaceous earth (Celite®). The EtOAc layer was washed with brine and water. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography using EtOAc-hexane as the eluent to afford 8-chloro-4,6-dimethyl-9-vinylbenzo[c][2,7]naphthyridin-5(6H)-one (0.6 g, 1.43 mmol, 68% yield)) as brown gummy solid. LC/MS (ESI) m/e 285.0 [(M+H)+, calcd for C16H14ClN2O, 285.1]; LC/MS retention time (method B): tR=2.25 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([CH2:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=[CH:17][C:9]=3[O:8]2)[CH2:4][CH2:3]1>C(O)(=O)C.[Ni]>[NH2:18][C:15]1[CH:16]=[CH:17][C:9]2[O:8][C:5]3([CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH2:12][C:11](=[O:13])[C:10]=2[CH:14]=1
Reactant: CN1CCC2(CC1)CC(=O)c1cc([N+](=O)[O-])ccc1O2
Agent: [Ni]
Solvent: CC(=O)O
Product: CN1CCC2(CC1)CC(=O)c1cc(N)ccc1O2
Yield: 75.1 %

Procedure:
The 3,4-dihydro-1'-methyl-6-nitro-spiro[2H-1-benzopyran-2,4'-piperdin]-4-one (11.2 g, 0.04 mol) was dissolved in acetic acid (200 ml) and was hydrogenated using two "lab spoon" spatulas of Raney nickel catalyst in a Parr shaker. The theoretical amount of hydrogen was absorbed in 4 hours. The reaction mixture was filtered under nitrogen and the acetic acid was removed in vacuo. The residual oil was taken up in 3N HCl (150 ml), washed with ethyl acetate and neutralized with solid sodium bicarbonate. The product was extracted into ethyl acetate (3×100 ml), washed with sat'd. NaCl, dried, filtered and concentrated in vacuo to yield 7.4 g (75%) of product.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[CH2:21][NH2:22])[CH2:13][CH2:12]1)[CH3:3].[CH2:26]1[CH2:30][C:29]2([CH2:37][C:35](=O)[O:34][C:32](=[O:33])[CH2:31]2)[CH2:28][CH2:27]1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:3][CH:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:19]=[C:20]([CH2:21][N:22]3[C:35](=[O:34])[CH2:37][C:29]4([CH2:30][CH2:26][CH2:27][CH2:28]4)[CH2:31][C:32]3=[O:33])[CH:23]=[CH:24][CH:25]=2)[CH2:13][CH2:12]1)[CH3:1]
Reactant: CC(C)Oc1ccccc1N1CCN(Cc2cccc(CN)c2)CC1
Reactant: O=C1CC2(CCCC2)CC(=O)O1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(C)Oc1ccccc1N1CCN(Cc2cccc(CN3C(=O)CC4(CCCC4)CC3=O)c2)CC1

Procedure:
A solution of 3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]-benzyl amine (2.50 g, 7.37 mmol), prepared as described above, 3,3-tetramethyleneglutaric anhydride (1.12 g, 6.66 mmol), and toluene (30 mL) was heated to reflux, cooled slightly, and treated with thionyl chloride (9.72 mL, 13.32 mmol). The resulting slurry was refluxed for 30 min, cooled and the solid collected by filtration. This material was partitioned between CH2Cl2 /3N NaOH and the organic layer was separated, dried, filtered and evaporated giving 8-[[3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]phenyl]methyl]-8-azaspiro[4.5]decane-7,9-dione as a crude oil. The oil was converted to the maleate salt in i-PrOH. The isolated residue was converted back to the free base which was obtained as an oil (2.10 g). Chromatography of this material on flash silica using EtOAc/hexane of varying proportions gave an oil which was dissolved in ether and added to ethereal HCI causing formation of a solid. Filtration afforded 8-[[3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]phenyl]methyl]-8-azaspiro[4.5]decane-7,9-dione dihydrochloride (0.94 g, 25%), m.p. 212°-216° C. (dec). 1H NMR and mass spectral analysis supported the assigned structure.
Reaction SMILES: [OH-].[Na+:2].C[O:4][C:5](=[O:21])[CH2:6][C:7]1[NH:8][C:9](=[O:20])[C:10]([Cl:19])=[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:12]=1>C1COCC1>[Cl:19][C:10]1[C:9](=[O:20])[NH:8][C:7]([CH2:6][C:5]([O-:21])=[O:4])=[N:12][C:11]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1.[Na+:2]
Reactant: COC(=O)Cc1nc(N2CCOCC2)c(Cl)c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C([O-])Cc1nc(N2CCOCC2)c(Cl)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.4 ml of 2N sodium hydroxide are added to a solution of 410 mg of (5-chloro-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetic acid methyl ester in 3.6 ml of THF. The reaction medium is stirred at ambient temperature for 24 hours. The reaction medium is concentrated under reduced pressure. The residue obtained is oven-dried under vacuum in the presence of P2O5, so as to give 400 mg of sodium (5-chloro-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate, the characteristics of which are the following:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([F:12])[CH:6]=1)[OH:4].C(N(C(C)C)CC)(C)C.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]1[CH:35]=[C:36]([S:40]([NH2:43])(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1>CN(C)C=O>[CH:8]([OH:11])=[O:29].[F:12][C:7]1[CH:6]=[C:5]([C@@H:3]([OH:4])[CH2:2][NH:1][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:35]=[C:36]([S:40]([NH2:43])(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=2)[CH:10]=[CH:9][C:8]=1[OH:11]
Reactant: NS(=O)(=O)c1cccc(CCCCOCCCCCCBr)c1
Reactant: NC[C@H](O)c1ccc(O)c(F)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1cccc(CCCCOCCCCCCNC[C@H](O)c2ccc(O)c(F)c2)c1
Product: O=CO
Yield: 62.1 %

Procedure:
A stirred solution of 4-[(1R)-2-amino-1-hydroxyethyl]-2-fluorophenol (45 mg), diisopropylethylamine (0.06 ml) and 3-{4-[(6-bromohexyl)oxy]butyl}benzenesulfonamide (86 mg) in N,N-dimethylformamide (1 ml) under nitrogen was heated to 50° for 18 h. The mixture was cooled to 20°, the solvent evaporated in vacuo and the residue purified by mass-directed autopreparative HPLC to give the title compound (36 mg). LCMS RT=2.37 min, ES+ve 483 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[CH3:2].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][NH:11]2)[CH3:2]
Reactant: CCOC(=O)COc1cccc2[nH]ccc12
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)COc1cccc2c1CCN2
Temperature: 25 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
To a solution of commercially available 4-hydroindole (compound 1, 0.226 g, 1.7 mmol) and potassium carbonate (0.704 g, 5.1 mmol) in acetone was added ethyl bromoacetate (0.3 mL, 2.6 mmol). The reaction mixture was stirred at RT for 18 h, and then filtered. The solvent was removed and the green oil was purified by flash chromatography [hexanes-ethyl acetate (4:1)] to give ethyl(indol-4-yloxy)acetate. NMR: δ (300 MHz, CDCl3) 8.2 (br s, 1H), 7.13 (dd, J=5.6, 2.3 Hz, 1H), 7.1-7.06 (m, 2H), 6.73 (t, J=2.4 Hz), 6.43 (dd, J=5.9, 2.7 Hz, 1H), 4.78 (s, 2H), 4.28 (q, J=7.4 Hz, 2H), 1.31 (t, J=7.4 Hz, 3H). To a solution of this indole in acetic acid (10 mL) was added sodium cyanoborohydride (0.302 g, 4.8 mmol) as a solid. The reaction mixture was stirred at RT for 18 h, then neutralized with aqueous sodium bicarbonate and extracted with diethyl ether. The solvent was removed to give compound 2a (0.308 g, 88% yield) as a colorless oil. NMR: δ (300 MHz, CDCl3) 6.98 (d, J=7.9 Hz, 1H), 6.39 (t, J=7.9 Hz, 1H), 6.18 (d, J=7.9 Hz, 1H), 4.62 (s, 2H), 4.28 (q, J=7.0, Hz, 2H), 3.58 (t, J=8.4 Hz, 2H), 3.07 (t, J=8.4 Hz, 2H), 1.30 (t, J=7.0 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([C:19]3([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=4)[C:27]4[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:29])[CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([O-])=O.NN>C(O)C.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([C:19]3([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=4)[C:27]4[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:29])[CH2:14]2)=[O:12])=[CH:8][CH:9]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Agent: [Ni]
Agent: NN
Solvent: CCO
Product: Nc1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.1 %

Procedure:
To a suspension of rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-nitro-phenyl)-amide (0.15 g, 0.28 mmol) (from Example 76a supra) in ethanol (15 mL) was added Rani-nickel, followed by the addition of hydrazine (35 mg, 0.84 mmol) (Aldrich). The mixture was stirred at room temperature for 20 minutes. The crude was filtered through the celite pad. The filtrate was concentrated and the residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-amino-phenyl)-amide as a white solid (Yield 90 mg, 64%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12]([OH:14])=[O:13].[N+](=[CH2:23])=[N-]>C1COCC1>[CH3:23][O:13][C:12](=[O:14])[CH:11]([S:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)C(Sc1nc2ccccc2s1)c1ccccc1
Reactant: C=[N+]=[N-]
Solvent: C1CCOC1
Product: COC(=O)C(Sc1nc2ccccc2s1)c1ccccc1

Procedure:
1 g of 2-(benzothiazol-2-ylthio)-2-phenylacetic acid is dissolved in 20 ml of THF, an ethereal solution of diazomethane is added dropwise until a yellow coloration is produced and the mixture is evaporated to give 2-(benzothiazol-2-ylthio)-2-phenylacetic acid methyl ester, in the form of an oil.
Reaction SMILES: [CH:1]([CH:4]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[CH2:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:13]([Mg]Br)#[CH:14]>C1COCC1>[C:13]([C:9]1([OH:10])[CH:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][CH2:7][C:8]1([CH3:12])[CH3:11])#[CH:14]
Reactant: CC(C)C1CCCC(C)(C)C1=O
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC1(O)C(C(C)C)CCCC1(C)C
Temperature: 60 °C
Reaction time: 48 h
Yield: 81 %

Procedure:
A solution of 6-isopropyl-2,2-dimethylcyclohexanone (12.6 g, 75.0 mmol) in THF (50 ml) was added within 10 min at room temperature to a stirred solution of ethynyl magnesium bromide in THF (0.5 M, 180 ml, 90 mmol), and the reaction mixture was stirred for 2 d at 60° C. The reaction mixture was allowed to cool to room temperature, quenched with satd. aq. NH4Cl solution (500 ml) and extracted with Et2O (3×300 ml). The combined organic extracts were dried (Na2SO4) and evaporated. Purification of the resulting residue by silica gel FC (pentane/Et2O, 98:2, Rf 0.21) furnished 1-ethynyl-6-isopropyl-2,2-dimethylcyclohexanol (11.8 g, 81%) as a colorless liquid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[S:23][N:22]=[C:21]([N:24]4[CH2:29][CH2:28][CH:27]([C:30](O)=[O:31])[CH2:26][CH2:25]4)[N:20]=3)[CH2:15][CH2:14]2)=[O:12])=[N:2]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:55][CH2:56][CH2:57][NH:58][C:59](=[O:65])[O:60][C:61]([CH3:64])([CH3:63])[CH3:62]>CN(C)C=O.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[S:23][N:22]=[C:21]([N:24]4[CH2:25][CH2:26][CH:27]([C:30]([NH:55][CH2:56][CH2:57][NH:58][C:59](=[O:65])[O:60][C:61]([CH3:63])([CH3:62])[CH3:64])=[O:31])[CH2:28][CH2:29]4)[N:20]=3)[CH2:17][CH2:18]2)=[O:12])=[N:2]1
Reactant: O=C(O)C1CCN(c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)CC1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCNC(=O)C1CCN(c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)CC1
Yield: 84.5 %

Procedure:
A solution of 1-(5-{4-[(1,2-benzisoxazol-3-ylamino)carbonyl]piperazin-1-yl}-1,2,4-thiadiazol-3-yl)piperidine-4-carboxylic acid (100 mg, 0.219 mmol), 1-hydroxybenzotriazole (29.6 mg, 0.219 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (84.0 mg, 0.438 mmol) and tert-butyl N-(2-aminoethyl)carbamate (35.0 mg, 0.219 mmol) in N,N-dimethylformamide (2 ml) was stirred at room temperature for 12 hours. The reaction mixture was poured to water, and a solid was separated by filtration, which was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to give 111 mg (84.7%) of the desired product as a solid.