Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:47]=[CH:46][C:16]([CH2:17][N:18]([C:33]3[CH:45]=[CH:44][C:36]4[O:37]C(C)(C)[O:39][C:40](=[O:41])[C:35]=4[CH:34]=3)[C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:23][CH:22]=3)=[O:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CCO>[C:24]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:25]=[CH:26][C:21]([C:19]([N:18]([CH2:17][C:16]2[CH:46]=[CH:47][C:13]([C:12]#[C:11][C:8]3[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:9]=3)=[CH:14][CH:15]=2)[C:33]2[CH:45]=[CH:44][C:36]([OH:37])=[C:35]([CH:34]=2)[C:40]([OH:41])=[O:39])=[O:20])=[CH:22][CH:23]=1
Reactant: CCCCc1ccc(C#Cc2ccc(CN(C(=O)c3ccc(-c4ccccc4)cc3)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)c3ccc(-c4ccccc4)cc3)c3ccc(O)c(C(=O)O)c3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure C using N-{4-[(4-butylphenyl)ethynyl]benzyl}-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-6-yl)biphenyl-4-carboxamide and NaOH 1M aq. in the presence of EtOH as a pale yellow powder (41%).
Reaction SMILES: [C:1](=[O:22])([O:20][CH3:21])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([F:12])=[CH:5][C:4]=1[C:13]1([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C([O-])=O.[NH4+].C(OCC)(=O)C>CO.[Pd]>[C:1](=[O:22])([O:20][CH3:21])[O:2][C:3]1[CH:8]=[C:7]([NH2:9])[C:6]([F:12])=[CH:5][C:4]=1[C:13]1([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1C1(C)CCCCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)Oc1cc(N)c(F)cc1C1(C)CCCCC1
Yield: 82.1 %

Procedure:
To a solution of 4-fluoro-2-(1-methylcyclohexyl)-5-nitrophenyl methyl carbonate 24.1 g, 77.5 mmol) in 220 mL of CH3OH was added Pd/C 10%, 9.6 g, then ammonium formate (26.7 g, 445 mmol) was portion-wise added to the above reaction mixture at room temperature until starting material is consumed. The mixture was filtrated and the filtrate was evaporated under vacuum. The residue was purified by column chromatography on silica gel diluted with hexane:ethyl acetate=50:1 to give 5-amino-4-fluoro-2-(1-methylcyclohexyl)phenyl methyl carbonate as a red brown oil (17.9 g, 82% yield). 1H NMR (400 MHz, CDCl3) δ 6.99 (d, J=13.6 Hz, 1H), 6.51 (d, J=8.4 Hz, 1H), 3.89 (s, 3H), 3.43 (brs, 2H), 1.96-1.91 (m, 2H), 1.58-1.38 (m, 8H), 1.18 (s, 3H): MS m/z: 281.9 [M+H]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH3:33])[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:19][CH:18]=1.C1C(=O)N([Cl:41])C(=O)C1>>[Cl:41][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]([CH3:33])[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)CNC(=O)OC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Cl
Product: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)CNC(=O)OC(C)(C)C)cc1
Yield: 56.5 %

Procedure:
Following General Procedure H, tert-butyl 2-(4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propylcarbamate (180 mg, 0.39 mmol) was reacted with NCS (57 mg, 0.42 mmol) to afford the desired product (110 mg, 56%) as a yellowish solid. ESI MS m/z 499 [C26H27ClN2O4S+H]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[CH:18]1([NH:21][C:22](=[O:36])[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[C:25]([F:35])[CH:24]=2)[CH2:20][CH2:19]1.[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH:18]1([NH:21][C:22](=[O:36])[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][N:32]([CH2:2][C:3]4[CH:12]=[N:11][C:10]5[N:9]6[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]6[C:7](=[O:17])[NH:6][C:5]=5[CH:4]=4)[CH2:31][CH2:30]3)=[C:25]([F:35])[CH:24]=2)[CH2:19][CH2:20]1
Reactant: O=C(NC1CC1)c1ccc(N2CCNCC2)c(F)c1
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)c(F)c1
Temperature: 100 °C
Yield: 86.2 %

Procedure:
(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (150 mg, 0.643 mmol), N-cyclopropyl-3-fluoro-4-(piperazin-1-yl)benzamide (203 mg, 0.772 mmol), (cyanomethyl)trimethylphosphonium iodide (250 mg, 1.029 mmol) and N,N-diisopropylethylamine (562 μl, 3.22 mmol) were suspended in Propiononitrile (Volume: 1931 μl) and heated in a closed vial at 100° C. for 4 h. The reaction mixture became a dark brown solution with precipitate. It was cooled to room temperature and the precipitate was filtered off, washed with MeCN (2 mL) and suspended in MeCN with heating and sonication. The suspension was cooled to ambient temperature, and the precipitate was filtered off, washed with MeCN (2 mL) and dried in vacuum to afford (S)-N-cyclopropyl-3-fluoro-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (265 mg, 0.554 mmol, 86% yield) as a white solid. 1H NMR (DMSO-d6) δ 10.48 (s, 1H), 8.31 (d, J=4.3 Hz, 1H), 7.53-7.69 (m, 4H), 7.02 (t, J=8.8 Hz, 1H), 6.97 (d, J=2.0 Hz, 1H), 4.50 (br. d, J=12.9 Hz, 1H), 3.84 (dd, J=11.2, 2.7 Hz, 1H), 3.37 (s, 2H), 3.01-3.13 (m, 4H), 2.80 (tq, J=7.4, 3.9 Hz, 1H), 2.60 (td, J=12.6, 2.5 Hz, 1H), 2.44-2.51 (m, 4H), 2.04 (br. d, J=12.9 Hz, 1H), 1.85 (br. d, J=12.4 Hz, 1H), 1.64 (br. d, J=12.6 Hz, 1H), 1.33-1.56 (m, 3H), 0.61-0.71 (m, 2H), 0.50-0.60 (m, 2H); [M+H] calc'd for C26H31FN6O2, 479; found, 479.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C@@H:25]([OH:27])[CH3:26])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25](=[O:27])[CH3:26])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: C[C@H](O)c1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(=O)c1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2)cc1
Reaction time: 0.33 h
Yield: 84.9 %

Procedure:
(1S)-1-[2-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)phenyl]ethanol (Example 135; 100 mg, 0.26 mmol), N-methylmorpholine-N-oxide (46 mg, 0.39 mmol), 4 Å activated molecular sieves (100 mg) and CH2Cl2 (2.6 mL) were combined under N2 and stirred for 20 minutes prior to addition of tetra(n-propyl)ammonium perruthenate (4.6 mg, 0.013 mmol). After a further 20 minutes, the mixture purified by flash chromatography (eluant 40% EtOAc/isohexane) to afford 1-[2-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)phenyl]ethanone as a white solid (84 mg). δH (400 MHz, d6 DMSO): 8.10 (1H, d, J 7.8), 7.88 (2H, d, J 8.5), 7.80 (3H, dd, J 0.0, 8.7), 7.72–7.68 (3H, m), 7.62 (1H, d, J 6.6), 7.46 (1H, d, J 16.5), 7.32–7.22 (3H, m), 2.61 (3H, s). m/z (ES+) 380 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.Cl[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Oc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1
Reactant: CCOC(=O)CCl
Product: CCOC(=O)COc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1

Procedure:
The title compound was prepared from 4-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)phenol and ethyl chloroacetate using the method described in Example 41.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[Br-:13].[Li+]>CC(C)=O>[Br:13][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: Cc1ccc(CCl)cc1[N+](=O)[O-]
Reactant: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Product: Cc1ccc(CBr)cc1[N+](=O)[O-]
Yield: 85.5 %

Procedure:
4-Chloromethyl-1-methyl-2-nitro-benzene (5 g) was dissolved in 50 ml of acetone and 23.4 g of lithium bromide was added. The reaction mixture was heated at reflux for 18 hr. The solvent was evaporated off and the residue was tritrated with hexane to give 5.3 g of 4-bromomethyl-1-methyl-2-nitro-benzene as a tan solid. ##STR109##
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:13])[CH3:12])=[N:7][C:6]=1[CH3:14])=O.[C:15]([NH2:19])(=[S:18])[CH2:16][CH3:17].O>CO.[OH-].[O-2].[P-3].[Mo]>[CH2:16]([C:15]1[S:18][CH:2]=[C:3]([C:5]2[S:9][C:8]([NH:10][C:11](=[O:13])[CH3:12])=[N:7][C:6]=2[CH3:14])[N:19]=1)[CH3:17]
Reactant: CC(=O)Nc1nc(C)c(C(=O)CBr)s1
Reactant: CCC(N)=S
Agent: [Mo]
Agent: [O-2]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1nc(-c2sc(NC(C)=O)nc2C)cs1

Procedure:
N-[5-(2-Bromo-acetyl)-4-methyl-thiazol-2-yl]-acetamide (71.6 mg) (prepared by the procedure of WO 2005/068444) is dissolved in CH3OH (5 mL) at RT, followed by addition of thiopropionamide (21.4 mg) and ammonium phosphomolybdate×H2O (37.5 mg). After completion of the reaction, water is added (25 mL) and the precipitate is filtered off to obtain the title compound as a dark green powder. Title compound: HPLC (Method F) RT 4.86 minutes; MS (Method D) M+H 268.2 and M−H 266.2.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[C:14]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[NH2:25])[NH:15]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].C(O)(=O)C.[Cl:41][CH2:42][C:43](Cl)=[O:44]>O1CCCC1>[C:1]([NH:5][S:6]([C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)=[C:14]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[NH:25][C:43](=[O:44])[CH2:42][Cl:41])[NH:15]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2[nH]c3cc(S(=O)(=O)NC(C)(C)C)ccc3c2C2CCCCC2)c(N)c1
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1ccc(-c2[nH]c3cc(S(=O)(=O)NC(C)(C)C)ccc3c2C2CCCCC2)c(NC(=O)CCl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a suspension of N-tert-butyl-2-(2-amino-4-methylphenyl)-3-cyclohexyl-1H-indole-6-sulfonamide (2.14 g, 4.86 mmol), sodium acetate (472 mg, 5.75 mmol) and acetic acid (0.33 ml, 5.76 mmol) in tetrahydrofuran (20 ml) was added dropwise chloroacetyl chloride (0.45 ml, 5.64 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. the reaction mixture was concentrated under reduced pressure, and water was added to the residue. The precipitated solid was collected by filtration and dried in vacuo. A suspension of the obtained solid in diethyl ether was stirred at room temperature for 1 hr. The solid was collected by filtration and dried in vacuo to give N-tert-butyl-2-[2-(chloroacetylamino)-4-methylphenyl]-3-cyclohexyl-1H-indole-6-sulfonamide (2.22 g, yield 89.9%). The obtained crude product was used for Step 10 without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([CH:18]([C:20]3[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=3[CH:27]([CH3:29])[CH3:28])O)[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SiH](CC)(CC)CC.B(F)(F)F.CCOCC>ClCCl>[CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([CH2:18][C:20]3[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=3[CH:27]([CH3:29])[CH3:28])[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(Br)cc1C(O)c1ccc2c(c1)N(Cc1ccccc1)CCO2
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)c1ccc(Br)cc1Cc1ccc2c(c1)N(Cc1ccccc1)CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To an ice cold solution of (4-Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-(5-bromo-2-isopropyl-phenyl)-methanol (1.3 g, 2.87 mmol) in dichloromethane (25 mL) was added Et3SiH (4.8 mL, 5.70 mmol) followed by BF3.OEt2 (0.74 mL, 5.7 mmol). The reaction mixture was stirred at room temperature overnight then quenched by the addition of aq. NaHCO3. The reaction mixture was extracted with ethyl acetate (3×30 mL), and the combined organic layers were washed with brine (30 mL) and dried over sodium sulfate. Crude product obtained after evaporation of the solvent was purified by silica gel column chromatography to furnish 4-Benzyl-6-(5-bromo-2-isopropyl-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine (1.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:32]2[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:28][CH:27]=3)[CH2:34][CH2:33]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Reactant: COc1ccc(N2CCNCC2)cc1
Product: COc1ccc(N2CCN(C(=O)Nc3nc4cc(OC)ccc4nc3OC)CC2)cc1
Yield: 81 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(4-methoxyphenyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 81%). 1H NMR (200 MHz, CDCl3): δ 3.16 (s, 4H), 3.78-3.88 (m, 9H), 4.12-4.17 (m, 4H), 6.84-6.97 (m, 4H), 7.16-7.32 (m, 3H), 7.62-7.66 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][Si](C=[N+]=[N-])(C)C>CO.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:14]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)C1
Yield: 96 %

Procedure:
1-Benzyloxycarbonyl-3-azetidinecarboxylic acid (from step (i); 9.3 g, 39.6 mmol) was dissolved in methanol (100 mL) and toluene (100 mL), and cooled to 0° C. A solution of 2M trimethylsilyldiazomethane in hexanes was then added dropwise until bubbling had ceased and the yellow colour persisted. Acetic acid was then added dropwise until the yellow colour disappeared. Concentration of the solution yielded the title compound as an oil (9.48 g, 38 mmol, 96%).
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]([O:32]C)=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([C:7]2[N:16]=[C:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]([OH:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccccc1-c1ccc(Cc2nc(-c3ccccc3)nc3ccccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccccc1-c1ccc(Cc2nc(-c3ccccc3)nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.6 %

Procedure:
240 mg of the product of Example 22 were introduced into 2 ml of ethanol and 0155 ml of 2N sodium hydroxide were added. The solution was stirred for 2 days at ambient temperature and then was refluxed for 2 hours. The solution was evaporated to dryness and the residue was taken up in water and neutralized with concentrated hydrochloric acid. The precipiate was filtered, dried and crystallized from a water-isopropyl alcohol mixture 10-90 to obtain 150 mg of the expected product melting at 210° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:12])[NH:11][C:5]=2[CH:4]=1.C1C(=O)N([Br:22])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:22][C:14]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1
Reactant: COc1ccc2c(c1)NC(=O)CCC2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc2c(cc1Br)CCCC(=O)N2
Temperature: 25 °C

Procedure:
A suspension of 8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (100 mg, 0.52 mmol), NBS (103 mg, 0.57 mmol) and BPO (ca. 5 mg) in carbon tetrachloride (1.5 mL) was heated at reflux for 3 hrs. The reaction mixture was allowed to cool to room temperature, diluted with DCM (20 mL), washed with water and dried over Na2SO4. Filtration and evaporation of the organic layer provided a solid residue, which was washed with n-hexane and dried in high vacuum. The title compound was obtained as a white crystalline product (140 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].Cl[CH2:11][C:12](Cl)=[O:13].C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:12](=[O:13])[CH2:11][O:9][C:3]=2[CH:4]=1
Reactant: Nc1ccc(Cl)cc1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1COc2cc(Cl)ccc2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-amino-5-chloro-phenol (27) (2.0 g, 14 mmol, 1 equiv) in 30 ml of THF, chloroacetyl chloride (1.26 ml, 16.8 mmol, 1.2 equiv), and saturated aqueous NaHCO3 50 mL was stirred at RT for 2 hrs and then heated at 80° C. overnight. The reaction mixture was diluted with EtOAc, and washed with water. Purification of the crude product by flash chromatography provided 7-chloro-4H-benzo[1,4]oxazin-3-one (28): LCMS Retention time: 1.48 min.; LCMS observed (M+H)+: 184.
Reaction SMILES: Cl.C([NH:6][S:7]([C:10]1[C:11]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][CH2:23][C:24]3[CH:25]=[N:26][C:27](C)=[C:28]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([C:40]#[N:41])[CH:35]=4)[C:29]=3[CH2:30][OH:31])=[CH:18][CH:17]=2)=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:9])=[O:8])(C)(C)C.[NH3:43].CO>C(O)C>[OH:31][CH2:30][C:29]1[C:24]([CH2:23][NH:22][C:19]2[CH:20]=[CH:21][C:16]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:7](=[O:9])(=[O:8])[NH2:6])=[CH:17][CH:18]=2)=[CH:25][N:26]=[CH:27][C:28]=1[O:32][CH2:33][C:34]1[CH:35]=[C:36]([CH:37]=[CH:38][CH:39]=1)[C:40]([NH2:41])=[NH:43]
Reactant: N
Reactant: Cc1ncc(CNc2ccc(-c3ccccc3S(=O)(=O)NC(C)(C)C)cc2)c(CO)c1OCc1cccc(C#N)c1
Agent: Cl
Solvent: CCO
Solvent: CO
Product: N=C(N)c1cccc(COc2cncc(CNc3ccc(-c4ccccc4S(N)(=O)=O)cc3)c2CO)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Hydrogen chloride gas was bubbled into a suspension of 4′-{[5-(3-cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl]-amino}-biphenyl-2-sulfonic acid tert-butylamide (13) (100 mg, 0.17 mmol) in absolute ethyl alcohol (30 mL) at 0° C. for 30 minutes. The septum was replaced and the reaction mixture was stirred at room temperature overnight. Hydrogen chloride gas was purged with nitrogen gas for 2 hours and the solvent evaporated to give the crude amide ester as a solid. Ammonia in methyl alcohol (30 mL, 7 M, 350 mmol) was added to the crude amide ester and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated and the product purified on a silica gel column using a mixture of dichloromethane:methyl alcohol (4:1) as eluant to give the corresponding 3-{4-hydroxymethyl-5-[(2′-sulfamoyl-biphenyl-4-ylamino)-methyl]-pyridin-3-yloxymethyl}-benzamidine (14) (90 mg, 97% yield) as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][CH:38]=[CH:37][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH:18]2[O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:33]=2[NH:32][C:31](=O)[C:30]3([CH3:36])[CH3:35])=[CH:13][CH:12]=1.COCCO[AlH2-]OCCOC.[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:40]=[CH:39][CH:38]=[CH:37][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH:18]2[O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:33]=2[NH:32][CH2:31][C:30]3([CH3:36])[CH3:35])=[CH:15][CH:16]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCNCC2OCc2cccc3c2NC(=O)C3(C)C)cc1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccccc1COCCCOc1ccc(C2CCNCC2OCc2cccc3c2NCC3(C)C)cc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
The solution of 0.055 g of 7-(4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidin-3-yloxymethyl)-3,3-dimethyl-1,3-dihydroindol-2-one (Example 218) and 1.0 ml of toluene is admixed with 0.072 ml of Vitride and stirred at 110° C. over 1 hour. The reaction mixture is cooled to 10° C., admixed slowly with 1M NaOH and extracted with tert-butyl methyl ether (2×30 ml). The organic phases are washed successively with 1M NaOH (30 ml), water (30 ml) and brine (30 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][C:5](=[O:7])[CH2:4][C@H:3]1[C:8]([O:10]C)=[O:9].[I-].[Na+].C[Si](C)(C)Cl.O>C(#N)C>[CH3:1][C@H:2]1[CH2:6][C:5](=[O:7])[CH2:4][C@H:3]1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)[C@@H]1CC(=O)C[C@@H]1C
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: C[C@H]1CC(=O)C[C@H]1C(=O)O
Temperature: 25 °C
Yield: 32.3 %

Procedure:
In acetonitrile (5 ml) were dissolved methyl cis-2-methyl-4-oxocyclopentanecarboxylate [K. Kojima et al., Chem. Pharm. Bull., 33, 2750 (1985)] (827 mg) and sodium iodide (3.175 g), and trimethylchlorosilane (2.69 ml) was added to the solution at room temperature. The mixture was refluxed under nitrogen atmosphere for one day. After the temperature was cooled to room temperature, water was added and the mixture was extracted with ether, followed by washing with an aqueous solution of sodium thiosulfate. The water layer was further extracted with ether. The organic layers were combined, dried over magnesium sulfate and concentrated to dryness. The residue was subjected to silica gel column chromatography with ethyl acetate:chloroform (1:1), and the eluted fractions were combined and concentrated to dryness to yield the title compound (243 mg).
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([OH:8])[C@H:6]([OH:9])[C@H:5]([CH3:10])[O:4][C@H:3]1[O:11][CH2:12][CH2:13][NH:14][C:15]([C@@H:17]1[C@H:22]([C:23]([NH:25][CH2:26][CH2:27][O:28][C@H:29]2[C@@H:34]([OH:35])[C@H:33]([OH:36])[C@H:32]([OH:37])[C@H:31]([CH3:38])[O:30]2)=[O:24])[CH2:21][CH2:20][NH:19][CH2:18]1)=[O:16].O=[CH:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1.O>[OH:1][C@H:2]1[C@H:7]([OH:8])[C@H:6]([OH:9])[C@H:5]([CH3:10])[O:4][C@H:3]1[O:11][CH2:12][CH2:13][NH:14][C:15]([C@@H:17]1[C@H:22]([C:23](=[O:24])[NH:25][CH2:26][CH2:27][O:28][C@H:29]2[C@@H:34]([OH:35])[C@H:33]([OH:36])[C@H:32]([OH:37])[C@H:31]([CH3:38])[O:30]2)[CH2:21][CH2:20][N:19]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:46])[CH2:18]1)=[O:16]
Reactant: C[C@@H]1O[C@@H](OCCNC(=O)[C@H]2CNCC[C@H]2C(=O)NCCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)[C@@H](O)[C@H](O)[C@@H]1O
Reactant: O=CCCCCC(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1O[C@@H](OCCNC(=O)[C@H]2CN(CCCCCC(=O)OCc3ccccc3)CC[C@H]2C(=O)NCCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(3R,4R)—N3,N4-bis(2-(((2R,3S,4R,5S,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)ethyl)piperidine-3,4-dicarboxamide (118 mg, 0.214 mmol) was dissolved in THF (2 mL), to which benzyl 6-oxohexanoate (70.7 mg, 0.321 mmol) in THF (0.5 mL) was added, followed by sodium triacetoxyborohydride (136 mg, 0.642 mmol) and acetic acid (3.67 μL, 0.064 mmol) were added, and the mixture was stirred at room temperature for 3 h. The product was isolated by preparative reverse-phase chromatography on C-18 column, using a gradient of 0-30% of AcN in water. UPLC Method F: m/e=756.4241 [M+1]; Rt=3.05 min