Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:14][C:15]1[CH:16]=[C:17]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH:14][C:15]2[CH:16]=[C:17]([CH:27]=[CH:28][C:29]=2[O:30][CH3:31])[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Yield: 82.4 %

Procedure:
Prepared according to the procedure described for Example 121 using 3-nitrobenzenesulfonyl chloride (2.44 g, 10 mmol) and 3-amino-4-methoxy-N-phenyl-benzamide (2.43 g, 10.0 mmol) to afford the product (3.522 g); m.p. 208-210° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[OH:24][CH2:25][CH2:26][N:27]([CH3:37])[CH2:28][CH2:29][NH:30][C:31]1[CH2:35][S:34][C:33](=[O:36])[N:32]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:35]2/[C:31]([NH:30][CH2:29][CH2:28][N:27]([CH2:26][CH2:25][OH:24])[CH3:37])=[N:32][C:33](=[O:36])[S:34]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CN(CCO)CCNC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CN(CCO)CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 46.1 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.34 g) in 2-propanol (20 mL) were added 4-({2-[(2-hydroxyethyl)(methyl)amino]ethyl}amino)-1,3-thiazol-2(5H)-one (1.71 g) and piperidinium acetate (0.57 g). The reaction mixture was stirred at 60° C. overnight and concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (0.98 g).
Reaction SMILES: [OH:1][C:2]1[C:16]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:15][C:5]([CH2:6][NH:7][N:8]2[CH:12]=[CH:11][N:10]=[C:9]2SC)=[CH:4][C:3]=1[C:21]([CH3:24])([CH3:23])[CH3:22]>C(O)C>[OH:1][C:2]1[C:16]([C:17]([CH3:19])([CH3:18])[CH3:20])=[CH:15][C:5]([CH2:6][NH:7][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][C:3]=1[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CSc1nccn1NCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCO
Product: CC(C)(C)c1cc(CNn2ccnc2)cc(C(C)(C)C)c1O

Procedure:
Variant (b): 600 mg of 1-(4-hydroxy-3,5-di-tert.-butylbenzylamino)-2-methylmercaptoimidazole dissolved in 20 ml of ethanol are heated to 60°-70° for 2 hours while stirring with a 5-fold amount by weight of ethanol-moist Raney-nickel W2. The nickel is then removed by filtration and boiled up twice with 10 ml of ethanol each time. The combined alcoholic filtrates are evaporated, and 1-(4-hydroxy-3,5-di-tert.-butylbenzylamino)imidazole is obtained as the residue in the form of colorless crystals of m.p. 171°-174°.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:7]=1[CH2:20]O.CS(Cl)(=O)=O.[CH2:36]([N:38](CC)CC)C>ClCCl>[C:26]([O:25][C:23](=[O:24])[NH:22][CH:4]1[C:3](=[O:2])[N:38]([CH3:36])[CH2:20][C:7]2[CH:8]=[C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=[CH:11][C:6]=2[CH2:5]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: COC(=O)C(Cc1ccc(OCc2ccccc2)cc1CO)NC(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CN1Cc2cc(OCc3ccccc3)ccc2CC(NC(=O)OC(C)(C)C)C1=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(2-acetoxymethyl-4-benzyloxy-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester (1.85 g, 4.0 mmol) in methanol (40 mL) was added potassium carbonate (560 mg, 4.0 mmol) at room temperature and stirred for 1 h. The reaction mixture was diluted with dichloromethane (150 mL), washed with 1.0 M aqueous hydrogen chloride and dried (Na2SO4) to give the pure 3-(4-benzyloxy-2-hydroxymethyl-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester in almost quantitative yield. To the alcohol (800 mg, 1.93 mmol) in dichloromethane (50 mL) was added methanesulfonyl chloride (0.18 mL, 2.3 mmol) followed by triethylamine (0.38 mL, 2.70 mmol) at 0° C. and then brought to room temperature. After 1 h, the reaction mixture was washed with aqueous sodium hydrogencarbonate, dried (Na2SO4). The solvent was removed, dissolved the crude product in anhydrous THF (20 mL) followed by addition of 2.0 M solution of methylamine in THF (10 mL) in a sealed tube. The sealed tube was heated at 80° C. for a period of 12 h and then removed the solvent. The crude product was purified by flash chromatography using 30% ethyl acetate in hexane to give (8-benzyloxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-carbamic acid tert-butyl ester in 39% overall yield. 1H NMR (500 MHz, CDCl3): in δ 7.40-7.31 (m, 5H), 7.01-7.00 (m, 1H), 6.83-6.82 (m, 1H), 6.66 (s, 1H), 5.91-5.90 (m, 1H), 5.13-5.01 (m, 4H), 3.50-3.46 (m, 1H), 3.03 (s, 3H), 2.85-2.78 (m, 1H), 1.45 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[NH:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([C:29]([F:32])([F:30])[F:31])[CH:22]=2)=[S:28])=[CH:7][CH:6]=1
Reactant: Nc1ccc(Nc2ccc3ccccc3n2)cc1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Nc3ccc4ccccc4n3)cc2)ccc1Cl
Yield: 0.1 %

Procedure:
2-(4-aminophenylamino)quinoline (5.0 moles, 1.15 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (5.0 moles, 1.20 g) were reacted according to procedure C of to yield the title compound 1.60 g, 68%. Mass Spec (FD) 473. Calculated for C23H16C1F3N4S: C,; H,; N, Found: C,; H,; N,.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=3)=[CH:18][CH:17]=2)[N:3]=1.[Br:30][CH2:31][CH2:32]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:30][CH2:31][CH2:32][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]4[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=4)=[CH:20][CH:21]=3)[CH:5]=2)=[CH:9][CH:10]=1
Reactant: BrCCBr
Reactant: Cc1cc(Oc2ccc(Nc3cc(-c4ccc(O)cc4)nc(N)n3)cc2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(Nc3cc(-c4ccc(OCCBr)cc4)nc(N)n3)cc2)ccn1
Temperature: 25 °C

Procedure:
To a solution of Step 2 product (1 equiv) in DMF is added 1,2-dibromoethane (1 equiv) and K2CO3 (3 equiv). The mixture is refluxed overnight. After cooling to rt, the mixture is diluted with EtOAc and washed sequentially with 1N NaOH, water and brine. The organic layer is dried (Na2SO4) and concentrated to afford a crude product which is to be used in next step without further purification.
Reaction SMILES: [I:1][C:2]1[C@H:3]([OH:12])[C@@H:4]2[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]2[CH:11]=1.N1C=CN=C1.[Si:18](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C.CCOC(C)=O>[C:31]([Si:18]([O:12][C@@H:3]1[C@H:4]2[C@H:5]([O:6][C:7]([CH3:9])([CH3:10])[O:8]2)[CH:11]=[C:2]1[I:1])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC1(C)O[C@@H]2[C@@H](C=C(I)[C@@H]2O)O1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)O[C@@H]2[C@@H](C=C(I)[C@@H]2O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3aS,4R,6aR)-5-iodo-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (5-3) (1.5 g, 5.3 mmol, 1 equiv) was dissolved in DMF (6 mL) and imidazole (1.3 g, 18/4 mmol, 3.5 equiv) was added followed by TBDPS-Cl (3.0 mL, 11.6 mmol, 2.2 equiv). The resulting mixture was stirred at ambient temperature for 30 minutes. Upon disappearance of starting material, the mixture was diluted with 50 mL EtOAc and washed with water (2×50 mL). The organic layer was dried over MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography (120 g SiO2, 0-20% EtOAc in hexanes) to yield tert-butyl((3aR,4R,6aR)-5-iodo-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)diphenylsilane (5-4) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.82 (t, J=8 Hz, 4H); 7.34-7.44 (m, 6H); 6.33 (s, 1H); 4.61 (dd, J=5.5, 2.0 Hz, 1H); 4.46 (dd, J=5.5, 2.0 Hz, 1H); 3.91 (t, J=5.5 Hz, 1H); 1.40 (s, 3H); 1.21 (s, 3 II); 1.16 (s, 9H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Br[CH2:57][C:58]#[C:59][C:60]([CH3:70])([O:62][Si:63]([CH2:68][CH3:69])([CH2:66][CH3:67])[CH2:64][CH3:65])[CH3:61]>O1CCCC1.O>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:57][C:58]#[C:59][C:60]([CH3:61])([O:62][Si:63]([CH2:68][CH3:69])([CH2:66][CH3:67])[CH2:64][CH3:65])[CH3:70])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC[Si](CC)(CC)OC(C)(C)C#CCBr
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC[Si](CC)(CC)OC(C)(C)C#CCO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 100.1 %

Procedure:
A solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5 (10 μl) and 1-bromo-4-methyl-4-triethylsilyloxy-2-pentyne (109 mg, 0.375 mmol) in tetrahydrofuran (1 ml) was stirred at 60° C. for 2 hours. The solution was cooled to room temperature and then taken into water and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) to give the title compound as a colorless oil (82.4 mg, 99%).
Reaction SMILES: [C:1]([N:4]([CH2:17][CH2:18][O:19][C:20](=[C:28]1[CH:35]2[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:37][CH:29]1[CH2:30]3)[CH2:34]2)[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=1)[C:5]([C:7]1[S:8][C:9]2[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:6])(=[O:3])[CH3:2].[OH:38][C:39]1C=CC2N=C(C(NCCOC(=C3C4CC5CC(CC3C5)C4)C3C=CC=C(O)C=3)=O)SC=2[CH:40]=1>C(OCC)(=O)C.CCCCCC>[C:39]([O:27][C:23]1[CH:22]=[C:21]([C:20](=[C:28]2[CH:35]3[CH2:36][CH:31]4[CH2:32][CH:33]([CH2:37][CH:29]2[CH2:30]4)[CH2:34]3)[O:19][CH2:18][CH2:17][N:4]([C:1](=[O:3])[CH3:2])[C:5]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:6])[CH:26]=[CH:25][CH:24]=1)(=[O:38])[CH3:40]
Reactant: CC(=O)N(CCOC(=C1C2CC3CC(C2)CC1C3)c1cccc(O)c1)C(=O)c1nc2ccc(O)cc2s1
Reactant: O=C(NCCOC(=C1C2CC3CC(C2)CC1C3)c1cccc(O)c1)c1nc2ccc(O)cc2s1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)Oc1cccc(C(OCCN(C(C)=O)C(=O)c2nc3ccc(O)cc3s2)=C2C3CC4CC(C3)CC2C4)c1

Procedure:
The second product was obtained with 35% ethyl acetate/hexane and was found to be {[2-(N-acetyl-N-(6-hydroxybenzothiazole-2-carbonyl)amino)ethoxy][3-hydroxyphenyl]methylene}adamantane (3a): 1H NMR (CDCl3) δ1.80-1.96 (m, 12H), 2.18 (s, 3H), 2.67 (bs, 1H), 3.33 (bs, 1H), 3.65 (m, 4H), 6.74 (bs, 1H), 6.96-7.92 (m, 7H), 7.79 (bs, 1H).; 13C NMR (CDCl3) δ20.97, 28.22, 30.53, 32.35, 37.07, 39.01, 39.14, 39.97, 67.79, 107.09, 117.16, 120.75, 122.35, 125.13, 126.71, 129.10, 133.50, 136.72, 138.86, 140.98, 147.39, 150.65, 155.72, 160.34, 160.43, 169.36. The third product was identified as {[2-(N-(6-hydroxybenzothiazole-2-carbonyl)amino)ethoxy][3-hydroxyphenyl]methylene}adamantane ##STR35##
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[C:8]([CH:22]=1)[C:9]([NH:11][CH2:12][C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[CH:14]=1)=[O:10])([O-:3])=[O:2].[C:30](O)(=[O:32])[CH3:31].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:30]([N:27]1[CH2:28][CH2:29][CH:24]([NH:23][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:22][C:8]=2[C:9]([NH:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]3[O:17][CH2:18][O:19][C:15]=3[CH:14]=2)=[O:10])[CH2:25][CH2:26]1)(=[O:32])[CH3:31]
Reactant: O=C(NCc1ccc2c(c1)OCO2)c1cc([N+](=O)[O-])ccc1NC1CCNCC1
Reactant: CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(Nc2ccc([N+](=O)[O-])cc2C(=O)NCc2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
A mixture of 5-nitro-2-(4-piperidinylamino)-N-(1,3-benzodioxol-5-ylmethyl)benzamide (80.0 mg), acetic acid (13.3 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (57.7 mg) and 1-hydroxybenzotriazole (40.7 mg) in anhydrous dimethylformamide (1 mL) was stirred for 3 hours at ambient temperature. The mixture was partitioned between water and ethyl acetate. The organic layer was separated and washed with an aqueous saturated sodium bicarbonate solution, water and brine. Then, the resultant was dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 2-(1-acetyl-4-piperidinylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide as yellow powders (81.1 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:14])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].Br[CH2:16][CH:17]1[CH2:22][CH2:21][Si:20]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])(C2C=CC=CC=2)[CH2:19][CH2:18]1>>[F:1][C:2]1[CH:3]=[C:4]([O:14][CH2:16][C@H:17]2[CH2:22][CH2:21][Si@H:20]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:19][CH2:18]2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:12])([F:13])[F:11]
Reactant: Oc1ccc(OCC(F)(F)F)c(F)c1
Reactant: CCCCCCC[Si]1(c2ccccc2)CCC(CBr)CC1
Product: CCCCCCC[Si@H]1CC[C@H](COc2ccc(OCC(F)(F)F)c(F)c2)CC1

Procedure:
The general procedure of Example 9 was repeated using 3-fluoro-4-(2,2,2-trifluoroethoxy)phenol and 4-bromomethyl-1-n-heptyl-1-phenyl-1-silacyclohexane, thereby obtaining the intended compound.
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[NH2:11][C@H:12]1[C:25](=[O:26])[N:24]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:23][C:15]2[C:16]3[CH:17]=[N:18][NH:19][C:20]=3[CH:21]=[CH:22][C:14]=2[CH2:13]1.[CH3:32][N:33]1[C:37]2([CH2:46][CH2:45][C:44]3[C:39](=[CH:40][CH:41]=[C:42]([C:47](O)=[O:48])[CH:43]=3)[CH2:38]2)[C:36](=[O:50])[NH:35][C:34]1=[O:51].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH3:29][C:28]([CH3:31])([CH3:30])[CH2:27][N:24]1[C:25](=[O:26])[C@H:12]([NH:11][C:47]([C:42]2[CH:43]=[C:44]3[C:39](=[CH:40][CH:41]=2)[CH2:38][C:37]2([C:36](=[O:50])[NH:35][C:34](=[O:51])[N:33]2[CH3:32])[CH2:46][CH2:45]3)=[O:48])[CH2:13][C:14]2[CH:22]=[CH:21][C:20]3[NH:19][N:18]=[CH:17][C:16]=3[C:15]=2[CH2:23]1
Reactant: CC(C)(C)CN1Cc2c(ccc3[nH]ncc23)C[C@@H](N)C1=O
Reactant: CN1C(=O)NC(=O)C12CCc1cc(C(=O)O)ccc1C2
Agent: CS(=O)(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN1C(=O)NC(=O)C12CCc1cc(C(=O)N[C@@H]3Cc4ccc5[nH]ncc5c4CN(CC(C)(C)C)C3=O)ccc1C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 7-(R)-amino-9-(2,2-dimethylpropyl)-6,7,9,10-tetrahydro-3H-2,3,9-triazacyclohepta[e]inden-8-one bis-methanesulfonate (110 mg, 0.23 mmol) [Chaturvedula et al. WO 2006/052378], (±)-3-methyl-2,5-dioxo-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-6′-carboxylic acid (77 mg, 0.28 mmol) [Bell et al. WO 2004/082605], HOBT (43 mg, 0.28 mmol), and EDC (54 mg, 0.28 mmol) in DMF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (2×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [Si]([O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][CH:14]([C:22]([OH:24])=[O:23])[C:15]([CH2:20][CH3:21])(O)[C:16]([OH:18])=O)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:27]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C:14]2[C:22]([O:23][C:16](=[O:18])[C:15]=2[CH2:20][CH3:21])=[O:24])=[CH:25][CH:26]=1)(=[O:29])[CH3:28]
Reactant: CCC(O)(C(=O)O)C(Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCC1=C(Cc2ccc(OC(C)=O)cc2)C(=O)OC1=O
Temperature: 115 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To the crude 3-(4-t-butyldimethylsilyloxybenzyl)-2-ethyl-2-hydroxysuccinic acid thus obtained was added acetic anhydride (5 mL), and the mixture was stirred at 115° C. for 3 h. The acetic anhydride was evaporated under reduced pressure, and the residue thus obtained was subjected to silica gel column chromatography (toluene-ethyl acetate 19:1→16:1) to give the title compound as oil in an amount of 210 mg (2 step yield: 79%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6](Cl)[CH:5]=1.[CH3:14][S-:15].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:5]=[C:6]([S:15][CH3:14])[N:7]=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: C[S-]
Reactant: COC(=O)c1cc(Cl)nc(OC)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)nc(SC)c1
Reaction time: 18 h

Procedure:
To a stirred solution of 2-chloro-6-methoxy-isonicotinic acid methyl ester (8.5 g, 42 mmol) in DMF (100 mL) was added sodium thiomethoxide (3.22 g, 41.6 mmol), resulting in a yellow colored solution. After 18 hours, the mixture was quenched with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (4×50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate and concentrated in vacuo to afford 2-methoxy-6-methylsulfanyl-isonicotinic acid methyl ester.
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.C(N(CC)CC)C.Cl[S:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>ClCCl>[O:2]1[C:10]2[CH2:9][CH2:8][N:7]([S:19]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:29][CH:30]=3)(=[O:21])=[O:20])[CH2:6][C:5]=2[CH:4]=[CH:3]1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: c1cc2c(o1)CCNC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)c1ccc(S(=O)(=O)N2CCc3occc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.900 g (18.169 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride and 12.7 ml (90.8 mmol) of triethylamine in 100 ml of dichloromethane, 4.81 g (21.8 mmol) of 4-chlorosulfonylbenzoic acid was added under ice-cooling, followed by overnight stirring at room temperature. After the solvent was distilled off under reduced pressure, 1 N hydrochloric acid was added; the resulting precipitate was filtered, washed with 1 N hydrochloric acid and dried to yield the desired product.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:9]1[C:20]([O:22]CC)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>CO>[CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[C:9]1[C:20]([OH:22])=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)ccn1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1c(-c2ccc(Cl)cc2)ccn1Cc1ccccc1

Procedure:
Ethyl 1-benzyl-3-(4-chlorophenyl)-1H-pyrrole-2-carboxylate (8 g, 23.54 mmol) was dissolved in MeOH (33.4 mL) and THF (33.4 mL) followed by addition of aqueous 6M NaOH (33.4 mL, 200 mmol) and the reaction mixture was stirred at reflux for 18 h. The volatile solvents were evaporated under reduced pressure. The remaining aqueous phase was acidified with aqueous 1M HCl until pH=4 and a solid precipitated. The solid was filtered off and washed with cold H2O. The collected solid was dissolved in EtOAc, dried over Na2SO4, filtered and the solution evaporated to dryness to give 6.69 g (91%) of ACI-01.
Reaction SMILES: [C:1]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.O>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:8]
Reactant: O=C(c1ccccc1)c1cccc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC(c1ccccc1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
To a solution of benzoylnaphthalene (5.00 g, 21.5 mmol) in methanol (30 mL) was added sodium borohydride (400 mg, 10.8 mmol) with ice-cooling and the mixture was stirred at room temperature for 30 minutes. This reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over MgSO4, and filtered and the filtrate was concentrated under reduced pressure to provide 4.80 g of (2-naphthyl)phenylmethanol. To a solution of this compound (4.80 g, 20.5 mmol) in diisopropyl ether (30 mL) was added phosphorus tribromide (3.70 g, 13.7 mmol) with ice-cooling and the mixture was stirred at room temperature for 1 hour. This reaction mixture was diluted with water and extracted with diisopropyl ether. The organic layer was washed with water and saturated aqueous sodium hydrogen carbonate solution, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure and the solid residue was recrystallized from diisopropyl ether-hexane to provide 4.10 g of the title compound. Yield 64%.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@H:9]1[C:14](=[O:16])[NH2:15])=O)(C)(C)C.Cl>C(O)CCC>[F:13][C@@H:11]1[CH2:12][NH:8][C@H:9]([C:14]([NH2:15])=[O:16])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(N)=O
Agent: Cl
Solvent: CCCCO
Product: NC(=O)[C@@H]1C[C@H](F)CN1
Temperature: 50 °C
Reaction time: 60 h

Procedure:
A mixture of (2S,4S)-2-carbamoyl-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g), conc. HCl (0.6 ml) and 1-butanol (10 ml) was heated for 48 h at 50° C. The RM was evaporated and partitioned DCM and aqueous NaHCO3, the DCM layers were dried over Na2SO4 and evaporated. A solution of 7 M ammonia in methanol (10 ml) was added to the residue and the mixture was stood for 60 h at it in a sealed vessel. Evaporation and trituration with EtOH gave the title compound as a white solid.