Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH:6]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4].[N:23]([C:26]1[CH:27]=[C:28]([CH:39]=[CH:40][CH:41]=1)[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])=[C:24]=[O:25]>O1CCCC1>[CH2:32]([O:31][C:29]([C:28]1[CH:27]=[C:26]([NH:23][C:24](=[O:25])[NH:1][CH2:2][C:3]([N:5]2[CH:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:15][CH2:14][CH:6]2[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4])[CH:41]=[CH:40][CH:39]=1)=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C=Nc1cccc(C(=O)OCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1C(=O)CN
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(C(=O)OCc2ccccc2)c1
Yield: 28.3 %

Procedure:
The operation is carried out in a fashion similar to that described in Example 2, but starting from 1.93 g of tert-butyl (2RS,5SR)-1-(2-aminoacetyl)-5-phenylprolinate and 3.61 g of benzyl 3-isocyanatobenzoate in 50 cm3 of tetrahydrofuran. After treatment, 1 g of tert-butyl (2RS,5SR)-1-{2-[3-(3-benzyloxycarbonylphenyl)-ureido]acetyl)-5-phenylprolinate, melting at 75° C., is obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2C(C(=O)NC3C=CC=CC=3)=CN=C(S(C)(=O)=O)N=2)[CH:9]=1)(C)(C)C.[N-]=[N+]=[N-].[Na+]>CN(C=O)C>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[NH2:7]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2nc(S(C)(=O)=O)ncc2C(=O)Nc2ccccc2)c1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(N)c1
Temperature: 70 °C
Yield: 353 %

Procedure:
To a stirred solution of 7 (0.4 g, 0.69 mmol) in DMF (5 mL) was added sodium azide (0.054 g, 0.83 mmol) and the reaction mixture was heated to 70° C. for 4 h. Then it was treated with ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and with brine, dried over anhydrous Na2SO4, filtered and concentrated to obtain 8 as viscous oil 8 (0.3 g, 82.6%).
Reaction SMILES: O[C@@H:2]1[C@H:7]2[C@H:8]3[C:17]([CH2:18][CH2:19][C@:5]2([CH3:6])[C:4](=[O:21])[CH2:3]1)=[C:16]1[C:11](=[CH:12][C:13](=[O:20])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.C(OC(=O)C(C)(C)C)(=O)C(C)(C)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:6][C@:5]12[CH2:19][CH2:18][C:17]3[C@@H:8]([CH2:9][CH2:10][C:11]4[C:16]=3[CH2:15][CH2:14][C:13](=[O:20])[CH:12]=4)[C@@H:7]1[CH:2]=[CH:3][C:4]2=[O:21]
Reactant: C[C@]12CCC3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1[C@@H](O)CC2=O
Agent: CC(C)(C)C(=O)OC(=O)C(C)(C)C
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Product: C[C@]12CCC3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1C=CC2=O
Reaction time: 72 h
Yield: 78.8 %

Procedure:
A suspension of 19.5 g of 15α-hydroxy-4,9-estradiene-3,17-dione in 300 ml of toluene is mixed, under ice water cooling, successively with 26.5 g of pivalic acid anhydride and 18.6 g of 4-dimethylaminopyridine. Stirring is then performed for 72 hours at room temperature, then the reaction solution is poured into saturated sodium hydrogen carbonate solution, stirred for 30 more minutes at room temperature and extracted with ethyl acetate. The ethyl acetate extracts are washed with saturated ammonium chloride solution and saturated sodium chloride solution, dried with sodium sulfate and concentrated in a water jet vacuum. The crude product, thus obtained, is filtered with aluminum oxide, Merck, neutral, step III, with hexane/ethyl acetate. The main fraction is crystallized from ethyl acetate. 14.4 g (79% of theory) of 4,9,15-estratriene-3,17-dione with a melting point of 182° to 183° C. are obtained.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2.[OH:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[F:14][C:11]1[CH:12]=[CH:13][C:8]2[CH2:7][CH2:6][C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[C:3](=[CH:2][C:22]3[CH:21]=[C:20]([OH:19])[CH:25]=[CH:24][CH:23]=3)[C:9]=2[CH:10]=1
Reactant: Fc1ccc2c(c1)C(=CBr)c1ccccc1CC2
Reactant: OB(O)c1cccc(O)c1
Product: Oc1cccc(C=C2c3ccccc3CCc3ccc(F)cc32)c1

Procedure:
Following the procedures essentially as described in Example 219, below, and using 5-bromomethylene-3-fluoro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (200 mg, 0.660 mmol) and 3-hydroxyphenylboronic acid (100 mg, 0.726 mmol), affords 192 mg (92%) of a mixture of geometric isomers of the title compound as a yellow oil. MS (ES) 339 (M+Na), 315 (M−H); HPLC shows 95% purity.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=[C:2]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:7]=1
Reactant: C1CCNC1
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(N2CCCC2)ccc1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
To a solution of 6-chloro-2-methyl-3-nitropyridine (0.5 g, 2.9 mmol) in pyrrolidine (0.7 mL, 8.7 mmol) was added K2CO3 (0.8 g, 5.8 mmol). The reaction mixture was heated at 110° C. for 2 h. Water (2 mL) was then added and the title compound (0.6 g, 99%) was collected by filtration. LCMS (ES+) 208 (M+H)+, RT 3.019 minutes (method 1).
Reaction SMILES: [CH3:1]/[C:2](/[CH:7]=[CH:8]/[CH:9]=[C:10](\[CH3:21])/[CH:11]=[CH:12]/[C:13]1[C:17]([CH3:18])=[C:16]([CH3:19])[O:15][C:14]=1[CH3:20])=[CH:3]\[C:4]([O-:6])=[O:5].[K+].[CH3:23]/[C:24](/C=C/C=C(\C)/C=C/C1C(C)=C(C)OC=1C)=C\C([O-])=O.[Na+]>>[CH2:23]([O:5][C:4](=[O:6])/[CH:3]=[C:2](\[CH3:1])/[CH:7]=[CH:8]/[CH:9]=[C:10](\[CH3:21])/[CH:11]=[CH:12]/[C:13]1[C:17]([CH3:18])=[C:16]([CH3:19])[O:15][C:14]=1[CH3:20])[CH3:24]
Reactant: CC(/C=C/c1c(C)oc(C)c1C)=C\C=C\C(C)=C\C(=O)[O-]
Reactant: CC(/C=C/c1c(C)oc(C)c1C)=C\C=C\C(C)=C\C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Product: CCOC(=O)/C=C(C)/C=C/C=C(C)/C=C/c1c(C)oc(C)c1C

Procedure:
In a manner similar to that described in Example 11 potassium (E,E,E,E)-3,7-dimethyl-9-(2,4,5-trimethyl-3-furyl)-2,4,6,8-nonatetraenoate m.p. 200°-250° decomposition and sodium (E,E,E,E)-3,7-dimethyl-9-(2,4,5-trimethyl-3-furyl)-2,4,6,8-nonatetraenoate m.p. 210°-260° with decomposition were formed from (E,E,E,E)-3,7-dimethyl-9-(2,4,5-trimethyl-3-furyl)-2,4,6,8-nonatetraenoic acid ethyl ester.
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH2:15])[CH:9]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([S:29]([CH2:32][C:33]2[N:34]=[C:35]([C:39]3[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=3)[O:36][C:37]=2[CH3:38])(=[O:31])=[O:30])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][C:43]([C:42]2[CH:41]=[CH:40][C:39]([C:35]3[O:36][C:37]([CH3:38])=[C:33]([CH2:32][S:29]([CH:26]4[CH2:27][CH2:28][N:23]([C:21]([O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:22])[CH2:24][CH2:25]4)(=[O:30])=[O:31])[N:34]=3)=[CH:47][CH:46]=2)=[O:44])[CH:9]=1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: NCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
Triethylamine (440 mg, 4.36 mmol, 3.00 equiv) was added dropwise with stirring to a solution of pyridin-3-ylmethanamine (170 mg, 1.57 mmol, 1.10 equiv), 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-ylsulfonyl)methyl)-5-methyloxazol-2-yl)benzoic acid (670 mg, 1.44 mmol, 1.00 equiv), EDCI (330 mg, 1.73 mmol, 1.20 equiv) and HOBT (230 mg, 1.70 mmol, 1.20 equiv) in N,N-dimethylformamide (10 mL) contained in a 50-mL round-bottom flask. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 30 mL of water/ice. The precipitate was collected by filtration and dried in an oven under reduced pressure to give 0.74 g (93%) of tert-butyl 4-((2-(4-((pyridin-3-ylmethyl)carbamoyl)phenyl)-5-methyloxazol-4-yl)methylsulfonyl)piperidine-1-carboxylate as a yellow solid. LC-MS: (ES, m/z): 555 [M+H]+, 455.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[C:10]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=O.Cl.[NH2:19][OH:20].CN(C)CCO>C(O)C>[ClH:1].[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[C:10]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[N:19][OH:20]
Reactant: NO
Reactant: O=C(c1ccc(F)cc1F)C1CCNCC1
Agent: CN(C)CCO
Agent: Cl
Solvent: CCO
Product: ON=C(c1ccc(F)cc1F)C1CCNCC1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
30 g of 2,4-difluorophenyl(4-piperidinyl)methanone hydrochloride obtained in step B) and 30 g of hydroxylamine hydrochloride were added to 50 ml of ethanol. 29.5 ml of N,N-dimethylethanolamine was added thereto dropwise while stirring at room temperature, and then the mixture was refluxed for 3 hours. The reaction mixture was cooled to room temperature, and the precipitated solid was filtered and dried to obtain 26.4 g of the title compound as a white crystal (yield: 96%).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[C:7]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([OH:16])[CH:11]=1)[CH:6]=[N:5]2.Cl.Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[I-].[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[C:7]([C:10]1[CH:15]=[CH:14][N:13]([CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:12](=[O:16])[CH:11]=1)[CH:6]=[N:5]2
Reactant: ClCCCN1CCCCC1
Reactant: Oc1cc(-c2cnn3ccnc3c2)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CN(C)C=O
Product: O=c1cc(-c2cnn3ccnc3c2)ccn1CCCN1CCCCC1
Temperature: 60 °C

Procedure:
4-Imidazo[1,2-b]pyridazin-7-yl-pyridin-2-ol (1 eq, 0.17 mmol, 36 mg), 1-(3-chloropropyl)piperidine monohydrochloride (1.5 eq, 0.255 mmol, 52 mg) and sodium iodide (1.5 eq, 0.254 mmol, 37.9 mg) are dissolved in DMF (1 ml) and heated at 60° C. for 16 h to give a black solution. The reaction mixture is then poured into aq. sat. NaHCO3 and the organic phase is extracted with CH2Cl2. The organic phase is washed with brine, dried over MgSO4, filtered and evaporated to dryness to afford 4-imidazo[1,2-b]pyridazin-7-yl-1-(3-piperidin-1-yl-propyl)-1H-pyridin-2-one; [M+H]+=338
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][N:15]2[C:19]3=[N:20][C:21](Cl)=[N:22][CH:23]=[C:18]3[CH:17]=[N:16]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:26][C:27]1[CH:28]=[CH:29][C:30]([CH3:37])=[C:31]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:32]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>O1CCOCC1.CCOC(C)=O.O>[C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][N:15]2[C:19]3=[N:20][C:21]([NH:26][C:27]4[CH:28]=[CH:29][C:30]([CH3:37])=[C:31]([S:33](=[O:35])(=[O:34])[NH2:36])[CH:32]=4)=[N:22][CH:23]=[C:18]3[CH:17]=[N:16]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Cn2ncc3cnc(Cl)nc32)CC1
Reactant: Cc1ccc(N)cc1S(N)(=O)=O
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(Nc2ncc3cnn(C[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c3n2)cc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
A solution of tert-butyl-cis-4-((6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate (1.66 g, 4.53 mmol, prepared using A from Preparation #2 and tert-butyl-cis-(4-hydroxymethyl)cyclohexylcarbamate [AMRI]), 5-amino-2-methylbenzenesulfonamide (1.10 g, 5.89 mmol, Waterstone), and sodium tert-butoxide (1.306 g, 13.59 mmol) in 1,4-dioxane (15 mL) was stirred at ambient temperature for about 30 min. In a separate 10 mL nitrogen purged vial charged with Pd2(dibenzylideneacetone)3 (0.415 g, 0.453 mmol) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.789 g, 1.86 mmol) was added 1,4-dioxane (2 mL) followed by heating to about 80° C. for about 2 min. The mixture was subsequently cooled to ambient temperature. The catalyst solution was added to the reaction mixture at ambient temperature and the reaction mixture was heated to about 80° C. for about 16 h. The reaction mixture was cooled to ambient temperature then water (100 mL) and EtOAc (50 mL) were added and the organic layer was separated. The aqueous layer was further extracted with EtOAc (2×50 mL) and the combined organic extracts were dried over anhydrous MgSO4, filtered through a silica gel pad, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with 50% EtOAc in heptane to provide tert-butyl-cis-4-((6-(4-methyl-3-sulfamoylphenylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate (0.58 g, 25%) as a light yellow solid. LC/MS (Table 2, Method a) Rt=1.38 min; MS m/z: 516 (M+H)+.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[C:11](Br)=[N:10][N:9]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[N:8]=1.BrC1N=NN(C2CCN(C(OC(C)(C)C)=O)CC2)C=1Br.[Cl-].[NH4+]>O1CCCC1>[Br:6][C:7]1[CH:11]=[N:10][N:9]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[N:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(Br)c(Br)n2)CC1
Agent: CC(C)(C)OC(=O)N1CCC(n2nnc(Br)c2Br)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2ncc(Br)n2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 2.92 mL, 7.30 mmol) was added dropwise to a −78° C. solution containing a mixture of tert-butyl 4-(4,5-dibromo-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate and tert-butyl 4-(4,5-dibromo-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (3.00 g, 7.35 mmol) in tetrahydrofuran (20 mL). The resulting solution stirred for 1 hour at −78° C., and then the reaction mixture was poured into saturated aqueous ammonium chloride solution (20 mL). The aqueous phase was separated and extracted with ethyl acetate (3×20 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 2:1, ethyl acetate/petroleum ether) to afford tert-butyl 4-(4-bromo-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate (0. 800 g, 33%) as a colorless oil. MS (ESI, pos. ion) m/z 331, 333 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[O:13]1[CH:17]=[CH:16][C:15]([C:18]2[S:22][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:20][CH:19]=2)=[N:14]1>>[O:13]1[CH:17]=[CH:16][C:15]([C:18]2[S:22][C:21]([S:23]([NH:1][C:2]3[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=3)(=[O:25])=[O:24])=[CH:20][CH:19]=2)=[N:14]1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccon2)s1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(-c3ccon3)s2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 5-isoxazol-3-ylthiophene-2-sulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (15.9 mg) with purity >90%. MS (pos) m/z 400.3.
Reaction SMILES: [C-:1]1([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8](O)=[O:9])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[Fe+2:20].P(Cl)(Cl)[Cl:22]>N1C=CC=CC=1.C1C=CC=CC=1>[C-:1]1([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([Cl:22])=[O:9])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[Fe+2:20]
Reactant: ClP(Cl)Cl
Reactant: O=C(O)c1ccccc1-[c-]1cccc1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(Cl)c1ccccc1-[c-]1cccc1
Reaction time: 3 h
Yield: 83 %

Procedure:
To a solution of o-ferrocenylbenzoic acid (1.75 g) and pyridine (3 drops) in 10 cm3 of dry benzene was slowly added 5 cm3 of phosphorous trichloride. The resulting mixture was then stirred for 3 hours at 60° to 70° C. After this time the solution was decanted off and the solvent removed under vacuum. The residue was twice more evaporated from dry benzene and then taken up in light petroleum (40° to 60° ). Removal of the solvent under vacuum afforded 1.54 g (83%) of o-ferrocenylbenzoyl chloride, a dark-red, viscous oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](Br)[C:9]2[N:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[C:27]1([Sn](CCCC)(CCCC)CCCC)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]2[N:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c1ccccc1n2-c1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(-c2ccccc2)c2c(c1O)c1ccccc1n2-c1ccccc1
Temperature: 130 °C
Reaction time: 0.67 h

Procedure:
A mixture of 1-bromo-4-hydroxy-9-phenyl-9H-beta-carboline-3-carboxylic acid ethyl ester (91 mg, 0.221 mmol), phenyltributyltin (98 mg, 0.265 mmol), and Pd(PPh3)2Cl2 (8 mg, 0.011 mmol) in DMF (1 mL) was stirred at 130° C. for 40 min. The mixture was then diluted with EtOAc, washed with water and saturated NaCl aqueous solution, respectively; the EtOAc phase was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column to give a white solid, the desired title compound. The title compound, ESI MS (m/z): 409 (M+H+).
Reaction SMILES: [CH3:1][Mg+].[Br-].[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=3[CH2:30][N:31]3[C@@H:35]([CH3:36])[C@@H:34]([C:37]4[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[C:39]([C:47]([F:50])([F:49])[F:48])[CH:38]=4)[O:33][C:32]3=[O:51])[C:16]([Cl:19])=[CH:17][CH:18]=2)=[C:9]([CH3:52])[CH:8]=1)(=[O:6])[CH3:5].[Cl-].[NH4+]>C1COCC1>[F:44][C:43]([F:46])([F:45])[C:41]1[CH:42]=[C:37]([C@H:34]2[O:33][C:32](=[O:51])[N:31]([CH2:30][C:21]3[CH:22]=[C:23]([C:26]([F:27])([F:28])[F:29])[CH:24]=[CH:25][C:20]=3[C:15]3[C:16]([Cl:19])=[CH:17][CH:18]=[C:13]([C:10]4[CH:11]=[CH:12][C:7]([C:4]([OH:6])([CH3:1])[CH3:5])=[CH:8][C:9]=4[CH3:52])[CH:14]=3)[C@H:35]2[CH3:36])[CH:38]=[C:39]([C:47]([F:49])([F:50])[F:48])[CH:40]=1
Reactant: C[Mg+]
Reactant: CC(=O)c1ccc(-c2ccc(Cl)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(C(C)(C)O)ccc1-c1ccc(Cl)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
MeMgBr (0.168 ml, 0.168 mmol, 1 M solution) was added to a solution of ketone from Example 52 (80 mg, 0.112 mmol) in THF (3 ml) at −78° C. The solution was stirred at −78° C. for 2 h. Saturated ammonium chloride solution was added. The mixture was extracted with EtOAc (3×10 ml). The combined EtOAc layers were washed with brine, and dried over sodium sulfate. The residue was purified by flash column on silica gel, eluting with EtOAc/hexane (30:70) to give the title compound as a colorless solid. 1H NMR (CDCl3, 500 MHz): δ a mixture of 1:1 atopoisomers 7.89 (s, 2H), 7.83 (d, J=8 Hz, 1H), 7.72 (m, 4H), 7.63 (d, J=8.5 Hz, 1H), 7.51 (d, J=8.0 Hz, 0.5H), 7.46 (d, J=8.0 Hz, 0.5H), 7.40-7.34 (m, 2H), 7.27 (d, J=2.0 Hz, 0.5H), 7.21 (d, J=2.5 Hz, 0.5H), 5.64 (d, J=8.0 Hz, 0.5H), 5.63 (d, J=8.0 Hz, 0.5H), 5.02 (d, J=16.0 Hz, 0.5H), 4.83 (d, J=16.0 Hz, 0.5H), 4.08 (d, J=16.0 Hz, 0.5H), 4.01 (d, J=15.5 Hz, 0.5H), 4.00 (m, 0.5H), 3.90(m, 0.5H), 2.41 (s, 1.5H), 2.39 (s, 1.5H), 1.60 (m, 3H), 1.28 (m, 3H), 0.64 (d, J=6.5 Hz, 1.5H), 0.62 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.I[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.C(O)CO>[Cu]I.CCCCCC.C(OCC)(=O)C.CC(O)C>[CH2:9]([NH:16][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(I)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: OCCO
Product: COc1ccc(NCc2ccccc2)cc1
Yield: 90 %

Procedure:
The general procedure under argon was followed using copper(I) iodide (10 mg, 0.05 mmol), K3PO4 (425 mg, 2.00 mmol), benzylamine (131 μL, 1.20 mmol), 4-iodoanisole (234 mg, 1.00 mmol), ethylene glycol (111 μL, 2.00 mmol) and 2-propanol (1.0 mL). Column chromatography using a solvent mixture (hexane/ethyl acetate=10/1, Rf=0.4) afforded N-benzyl-4-methoxyaniline (192 mg, 90% isolated yield) as light yellow solid. The spectral data (1H NMR) matched with the literature references and GC analysis indicated >95% purity.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([NH:10][C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=2[N+:19]([O-])=O)[CH2:8][C@H:7]([CH2:22][O:23]C(=O)C)[C@@H:6]1[O:27]C(=O)C)(=O)C.[CH2:31](O)[CH2:32]C>[Ni]>[Cl:18][C:14]1[C:15]([Cl:17])=[CH:16][C:11]2[N:10]([C@H:9]3[C@@H:5]([OH:4])[C@@H:6]([OH:27])[C@@H:7]([CH2:22][OH:23])[CH2:8]3)[C:31]([CH3:32])=[N:19][C:12]=2[CH:13]=1
Reactant: CC(=O)OC[C@H]1C[C@@H](Nc2cc(Cl)c(Cl)cc2[N+](=O)[O-])[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CCCO
Agent: [Ni]
Product: Cc1nc2cc(Cl)c(Cl)cc2n1[C@@H]1C[C@H](CO)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 26 %

Procedure:
(1R, 2S, 3R, 5R)-3-(Acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyl diacetate (1.29 g, 2.78 mmol) in n-propanol (100 mL) was shaken with Raney nickel (Aldrich, slurry in water, 200 mg wet) under hydrogen (40 psi) on a Parr shaker for 4 hours. Catalyst was filtered off with Celite and the volatiles were evaporated in vacuo. The residual oil was refluxed in 96% formic acid (45 mL) for 5 hours. Concentrated hydrochloric acid (5 mL) was added and reflux continued for an additional 4 hours. Volatiles were evaporated in vacuo and the residue was dissolved in 1N sodium hydroxide (10 mL). The solution was stirred at ambient temperature for 18 hours, neutralized with acetic acid, and concentrated in vacuo. The residue was chromatographed on silica gel. Elution with 15% methanol-chloroform gave (1R, 2S, 3R, 5R)-5-(5,6-dichloro-2-methyl-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol as white powder (236 mg, 26%), m.p. 198°-200° C.; 1H-NMR(DMSO-d6)δ: 8.30 and 7.72 (both s, 1 each, 2 aromatic CH), 5.0-4.8 (m, 3, 2 OH and NCH), 4.56 (t, J=5.1 Hz, 1, CH2OH), 4.2-4.1 (m, 2, 2 OCH), 3.8-3.5 (m, 2, CH2O), 2.58 (s, 3, CH3), 2.4-2.2 (m, 1, CH), 2.2-1.9 (m, 2, CH2); mass spectrum(CI): 331(M+1); [α]20589 -13.5°, [α]20578 -13.9°, [α]20546 -15.9°, [α]20436 -30.3° (c=0.251, methanol).