Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>CCOC(C)=O>[I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]
Reactant: CCOP(OCC)OCC
Reactant: BrCc1cccc(I)c1
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1cccc(I)c1)OCC
Temperature: 160 °C
Reaction time: 4 h
Yield: 90.6 %

Procedure:
A mixture of 3-iodobenzyl bromide 12 (5 g, 16.84 mmol) and triethyl phosphite (3.3 g, 20 mmol) was stirred at 160° C. After 4 h, the mixture was cooled to room temperature. The residue was subjected to flash chromatography (EtOAc: Hex, 1:4), and gave 5.4 g of 13 (91%). 1H NMR (200 MHz, CDCl3): δ1.15 (t, J=7.05 Hz, 6H), 2.97 (d, J=21.65 Hz, 2H), 3.92 (m, 4H), 6.93 (t, J=7.76 Hz, 1H), 7.17 (m, 1H), 7.52 (m, 2H); 13C NMR (50 MHz, CDCl3): δ 16.25 (J=5.95 Hz), 33.15 (J=137.60 Hz), 62.19 (J=6.70 Hz), 94.13 (J=3.50 Hz), 128.89 (J=6.35 Hz), 130.07 (J=3.00 Hz), 133.95 (J=9.10 Hz), 135.87 (J=3.55 Hz), 138.51 (J=6.65 Hz).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]2[S:17][C:18]3[CH2:23][N:22]([C:24]([O-:26])=[O:25])[CH2:21][CH2:20][C:19]=3[C:6]=2[CH2:5][NH:4][CH2:3]1.[H-].[Na+].Br[CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33].[Cl-:35].[NH4+]>C(OCC)(=O)C>[Cl:35][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:5]1[N:4]([CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])[CH2:3][C:2](=[O:1])[N:8]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]2[S:17][C:18]3[CH2:23][N:22]([C:24]([O:26][C:6]([CH3:19])([CH3:7])[CH3:5])=[O:25])[CH2:21][CH2:20][C:19]=3[C:6]1=2
Reactant: [Cl-]
Reactant: CC(C)=CCBr
Reactant: O=C([O-])N1CCc2c(sc3c2CNCC(=O)N3CCc2ccccc2)C1
Agent: [H-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)=CCN1CC(=O)N(CCc2ccccc2)c2sc3c(c2C1c1ccccc1Cl)CCN(C(=O)OC(C)(C)C)C3
Temperature: 60 °C
Reaction time: 3 h

Procedure:
0.5 g of t-butyl 5-2-chlorophenyl)-1,2,3,4,5,6,7,9-octahydro-2-oxo-1-(2-phenylethyl)-8H-pyrido[4′,3′:4,5]thieno[2,3-e]-1,4-diazepine-8-carboxylate (1 mmol) is dissolved in anhydrous tetrahydrofuiran (20 ml). Sodium hydride dispersed at 60% (0.028 g, 1.1 mmol) is added by portions. The reaction meum is left until release ends then 1-bromo-3-methyl-2-butene (0.125 ml, 1.1 Immol) is added dropwise. Agitation is carried out for 3 hours at 23° C. and the reaction medium is heated all night at 60° C. then the halogenated derivative (0.125 ml, 1.1 mmol) is added. After heating for 48 hours at 60° C., the reaction medium is poured into a saturated solution of ammonium chloride (30 ml) then ethyl acetate (30 ml) is added. After decanting, the aqueous phase is extracted with ethyl acetate (30ml). The organic phase is dried over magnesium sulphate, filtered and the solvent-is evaporated off. After purification by chromatography on a silica column (eluent: ethyl acetate-heptane: 20-80 to 50-50), the fractions containing only the product are evaporated and the desired product is obtained in the form of a pale yellow amorphous powder (0.47 g, 79%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:12]([NH:14][C:15]2[NH:16][C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[C:18]([CH3:20])[N:19]=2)=[O:13])[C:6]([CH:9]([F:11])[F:10])=[N:7][CH:8]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39].[NH4+].[Cl-]>C(Cl)Cl>[C:38]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:12]([NH:14][C:15]2[NH:16][C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[C:18]([CH3:20])[N:19]=2)=[O:13])[C:6]([CH:9]([F:11])[F:10])=[N:7][CH:8]=1)(=[O:40])[CH3:39]
Reactant: Cc1nc(NC(=O)c2cc(CN)cnc2C(F)F)[nH]c1-c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1cnc(C(F)F)c(C(=O)Nc2nc(C)c(-c3ccc(C(F)(F)F)cc3)[nH]2)c1
Reaction time: 8 h
Yield: 75.9 %

Procedure:
Dissolve 5-(aminomethyl)-2-(difluoromethyl)-N-[4-methyl-5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]pyridine-3-carboxamide (0.047 g, 0.110 mmol) in DCM (3 mL). Add triethylamine (0.038 mL, 0.276 mmol) followed by acetyl chloride (9.830 μL, 0.138 mmol), and stir overnight. Pour the reaction into saturated aqueous NH4Cl (15 mL) solution, and extract with EtOAc (2×10 mL). Combine the organic extracts; dry the organic extracts over sodium sulfate; filter; collect the filtrate; and concentrate the filtrate under reduced pressure to dryness to give the title compound (0.039 g, 75% yield) as a light yellow solid. LCMS (m/z) 468 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4]([C:33]#[C:34][CH2:35][OH:36])[CH:3]=1.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>ClCCl.C(OCC)(=O)C>[CH3:44][S:45]([O:36][CH2:35][C:34]#[C:33][C:4]1[CH:3]=[C:2]([F:1])[CH:32]=[CH:31][C:5]=1[CH2:6][NH:7][C:8]([C:10]1[N:11]=[C:12]2[N:17]([C:18](=[O:28])[C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][CH2:15][O:14][C:13]2([CH3:30])[CH3:29])=[O:9])(=[O:47])=[O:46]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1C#CCO)c(OCc1ccccc1)c2=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1C#CCOS(C)(=O)=O)c(OCc1ccccc1)c2=O
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
A solution of intermediate 182, N-(4-fluoro-2-(3-hydroxyprop-1-ynyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.280 g, 0.57 mmol) and triethylamine (0.12 ml, 0.86 mmol) in dichloromethane (5 ml) was cooled to 0° C., treated drop wise with methanesulfonyl chloride (0.050 ml, 0.64 mmol) and then stirred for 30 min. The reaction mixture was then diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Chromatography of the residue on silica gel (elution gradient of ethyl acetate in hexane) gave 0.245 g (75% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ ppm: 1.65 (6H, s, 2×CH3), 3.10 (3H, s, SCH3), 4.05 (4H, m, 2×CH2), 4.67 (2H, d, J=6.1 Hz, NCH2), 5.03 (2H, s, CH2), 5.29 (2H, s, OCH2), 7.07 (1H, m, aromatic), 7.18 (1H, dd, J=2.5 Hz and J=9.1 Hz, aromatic), 7.32–7.36 (3H, m, aromatics), 7.38 (1H, dd, J=5.5 Hz and J=8.6 Hz, aromatic), 7.49–7.51 (2H, m, aromatics), 7.77 (1H, broad t, NH). MS (ESI+) m/e 570 [M+H+].
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-:2].[Na+].[Na+].[N+:7]([C:10]1[CH:15]=[CH:14][C:13](O)=[CH:12][CH:11]=1)([O-:9])=[O:8].[CH2:17](OC(NC1C=CNC(=O)N=1)=O)[C:18]1[CH:23]=CC=C[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O1CCOCC1>[C:1](=[O:3])([O:2][C:13]1[CH:14]=[CH:15][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=1)[O:4][C:18]([CH3:23])([CH3:19])[CH3:17]
Reactant: O=C(Nc1cc[nH]c(=O)n1)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Sodium carbonate (29.14 g; 0.275 mol) and 4-nitrophenol (12.75 g; 91.6 mmol) were mixed with dioxane (250 ml). Boc-anhydride (20.0 g; 91.6 mmol) was transferred to the mixture with dioxane (50 ml). The mixture was refluxed for 1 h, cooled to 0° C., filtered and concentrated to ⅓, and then poured into wat.82 ml;82.6 mmol) and a suspension of N4-benzyloxycarbonyl-cytosine (9, 21.0 g;82.6 mmol) and potassium carbonate (11.4 g;82.6 mmol) in dry DMF (900 ml). The mixture was stirred vigorously overnight, filtered, and evaporated to dryness, in vacuo. Water (300 ml) and 4 N hydrochloric acid (10 ml) were added, the mixture was stirred for 15 minutes at 0° C., filtered, and washed with water (2×75 ml). The isolated precipitate was treated with water (120 ml), 2N sodium hydroxide (60 ml), stirred for 30 min, filtered, cooled to 0° C., and 4 N hydrochloric acid (35 ml) was added. The title compound was isolated by filtration, washed thoroughly with water, recrystallized from methanol (1000 ml) and washed thoroughly with ether. This afforded 7.70 g (31%) of pure compound. The mother liquor from the recrystallization was reduced to a volume of 200 ml and cooled to 0° C. This afforded an additional 2.30 g of a material that was pure by tlc but had a reddish color. M.p. 266-274° C. Anal., for C14H13N3O5. Found(calc.); C, 55.41(55.45); H, 4.23(4.32); N, 14.04(13.86) 1H-NMR (90 MHz; DMSO-d6): 8.02 ppm (d,J=7.32 Hz,1H,H-6); 7.39 (s,5H,Ph); 7.01 (d,J=7.32 Hz,1H,H-5); 5.19 (s,2H,PhCH2—); 4.52. (s,2H).
Reaction SMILES: C(CCC([CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)C(O)=O)#N.[CH2:20]([O:22][C:23](=[O:34])[CH:24]([CH2:30][CH2:31][C:32]#[N:33])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:21].[H-].[Na+].ClCC1C2C(=CC=CC=2)C=CC=1>CN(C=O)C>[CH2:28]([O:27][C:25](=[O:26])[C:24]([CH2:30][CH2:31][C:32]#[N:33])([CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)[C:23]([O:22][CH2:20][CH3:21])=[O:34])[CH3:29]
Reactant: CCOC(=O)C(CCC#N)C(=O)OCC
Reactant: N#CCCC(Cc1cccc2ccccc12)C(=O)O
Agent: ClCc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCC#N)(Cc1cccc2ccccc12)C(=O)OCC
Reaction time: 2 h

Procedure:
4-Cyano-2(R,S)-α-naphthylmethylbutyric acid: 2.13 g of 2-cyanoethylmalonic acid diethyl ester are added to a suspension of 0.48 g of sodium hydride dispersion in 25 ml of DMF. The reaction mixture is stirred for 2 hours at 80° and then, at room temperature, 1.77 g of α-chloromethylnaphthalene in 5 ml of DMF are added. The mixture is further stirred for 16 hours at 50° and then concentrated by evaporation. The residue is dissolved in ethyl acetate, washed with 0.1N hydrochloric acid and water, dried over sodium sulphate and concentrated by evaporation, leaving 2-cyanoethyl-α-naphthylmethylmalonic acid diethyl ester.
Reaction SMILES: COC1C=CC(C[NH:8][CH2:9][C:10]2[C:11]([C:21]3[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=3[F:29])=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:20])=CC=1.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>CC#N.O>[F:29][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:21]=1[C:11]1[C:10]([CH2:9][NH2:8])=[CH:19][C:18]2[C:13](=[C:14]([CH3:20])[CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: COc1ccc(CNCc2cc3cccc(C)c3nc2-c2c(F)cccc2OC)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COc1cccc(F)c1-c1nc2c(C)cccc2cc1CN

Procedure:
Prepared according to Procedure G using N-(4-methoxybenzyl)(2-(2-fluoro-6-methoxyphenyl)-8-methylquinolin-3-yl)methanamine (1.1795 g, 2.8320 mmol, 1 eq) and ammonium cerium(iv) nitrate (5.434 g, 9.912 mmol, 3.5 eq) in CH3CN—H2O (2:1, 13 mL). After purification, (2-(2-fluoro-6-methoxyphenyl)-8-methylquinolin-3-yl)methanamine was obtained as yellow sticky solid. 1H NMR (DMSO-d6) δ ppm 8.41 (1H, s), 7.82 (1H, d, J=7.4 Hz), 7.55-7.60 (1H, m), 7.45-7.54 (2H, m), 7.03 (1H, d, J=8.2 Hz), 6.92-7.00 (1H, m), 3.71 (3H, s), 3.59 (2H, q, J=16.6 Hz), 2.64 (3H, s), 1.88 (2H, br. s.). Mass Spectrum (ESI) m/e=297.1 (M+1).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1>C1(C)C=CC=CC=1.CO.C(Cl)Cl>[CH3:8][N:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([O:22][CH3:1])=[O:21])=[CH:18][CH:17]=2)[CH2:13][CH2:14]1
Reactant: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CN2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.2 %

Procedure:
A solution of (trimethylsilyl)diazomethane ((0.611 mL, 3.84 mmol) 2.0M in diethyl ether) was added dropwise to a stirred suspension of 4-((4-methylpiperazin-1-yl)methyl)benzoic acid (0.75 g, 3.20 mmol) in toluene (21 mL) and methanol (7 mL) over a period of 10 mins under nitrogen. The resulting suspension was stirred at room temperature for 3 h. A further aliquot of (trimethylsilyl)diazomethane (1.222 mL, 7.68 mmol) was added dropwise and the solution was stirred at room temperature for a further 18 h. The reaction mixture was evaporated to dryness to afford the crude product (0.723 g) as a white solid. This was taken up in DCM and the insolubles were filtered off. The filtrate was evaporated to dryness to afford the crude product. This was taken up in DCM again and more insolubles were filtered off to afford methyl 4-((4-methylpiperazin-1-yl)methyl)benzoate (0.351 g, 44.2%), which was used without purification.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=1)(C)C.C(=O)([O-])[O-].[K+].[K+].O.CCOC(C)=O>CO>[C:6]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=1)#[CH:5]
Reactant: COC(=O)CCc1ccc(C#C[Si](C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: C#Cc1ccc(CCC(=O)OC)cc1
Temperature: 25 °C

Procedure:
Methyl 3-(4-((trimethylsilyl)ethynyl)phenyl)propanoate (225 mg, 0.86 mmol) and potassium carbonate (234 mg, 1.69 mmol) was dissolved in MeOH (9 mL) and stirred vigorously for 2½ hours at room temperature. The reaction was added water and extracted with EtOAc. The organic phases were combined, washed with brine, dried over MgSO4 before concentrated under vacuum to give 138 mg (90%) of a brown, oily product. Rf: 0.31 (EtOAc:hexanes, 1:5); 1HNMR (CDCl3) δ 7.43-7.40 (m, 2H), 7.17-7.14 (m, 2H), 3.66 (s, 3H), 3.04 (s, 1H), 2.97-2.92 (t, 2H, J=7.7 Hz), 2.65-2.59 (t, 2H, J=7.8 Hz); 13CNMR (CDCl3) δ 173.0, 141.4, 132.3, 128.3, 120.2, 83.5, 76.8, 51.6, 35.3, 30.8; ESI-MS m/z 287.1 (MNa+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[CH2:22]([CH2:24][NH2:25])[OH:23]>C(Cl)Cl.CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([NH:25][CH2:24][CH2:22][OH:23])=[O:8])#[N:2]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: NCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)Oc1ccc(C(=O)NCCO)cc1C#N
Temperature: 50 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a stirring suspension of 3-cyano-4-isopropoxybenzoic acid (1.0 g, 4.8 mmol) in DCM (20 mL) was added oxalyl chloride (3.7 g, 29.2 mmol) followed by two drops DMF. The reaction mixture was stirred at 50° C. for 2 h. The mixture was concentrated and the residue re-dissolved in DCM (10 mL). Ethanolamine (0.6 g, 9.7 mmol) and TEA (1.45 g, 14.4 mmol) were added and the reaction mixture was stirred overnight at room temperature. The resulting solid was filtered, washed with water, and dried to afford 1.0 g (83%) of 3-cyano-N-(2-hydroxyethyl)-4-isopropoxybenzamide which was used in the next step without purification. LCMS-ESI (m/z) calculated for C13H16N2O3: 248.3; found 249.0 [M+H]+, tR=2.41 min. 1H NMR (400 MHz, CDCl3) δ 8.02-7.79 (m, 2H), 6.97-6.87 (m, 1H), 6.71 (s, 1H), 4.65 (dt, J=12.1, 6.1 Hz, 1H), 3.82-3.70 (m, 2H), 3.56 (dd, J=10.2, 5.5 Hz, 2H), 1.96 (d, J=10.0 Hz, 1H), 1.40-1.29 (m, 6H).
Reaction SMILES: C[O-].[Na+].[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]2[C:23]3[C:24]([C:28]([O:30][CH2:31]C)=[O:29])=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]2[O:33][CH3:34])=[CH:14][CH:13]=1)#[N:5]>CO>[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]2[C:23]3[C:24]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]2[O:33][CH3:34])=[CH:16][CH:17]=1)#[N:5]
Reactant: CCOC(=O)c1cccc2nc(OC)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc2nc(OC)n(Cc3ccc(-c4ccccc4C#N)cc3)c12

Procedure:
A solution of 5.2M sodium methoxide in methanol (0.5 ml) was added to a solution of ethyl 1-[(2′-cyanobiphenyl-4-yl)methyl]-2-methoxybenzimidazole-7-carboxylate (1.3 g) in methanol (50 ml). The mixture was heated for 4 hours under reflux. The reaction mixture was concentrated, and the precipitated crystals were collected by filtration. Recrystallization from methanol afforded colorless prisms (1.1 g, 85%), m.p. 149-150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:21][O:22][C:23](=[O:36])[C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[C:27]([O:33][CH3:34])=[CH:26][C:25]=1F>C1COCC1>[CH3:21][O:22][C:23](=[O:36])[C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[C:27]([O:33][CH3:34])=[CH:26][C:25]=1[NH:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(OC)cc1F
Reactant: Nc1ccc(CCCCCc2ccc(Cl)c(Cl)c2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc([N+](=O)[O-])c(OC)cc1Nc1ccc(CCCCCc2ccc(Cl)c(Cl)c2)cc1
Yield: 37.3 %

Procedure:
The title compound was prepared from 4-[5-(3,4-dichlorophenyl)pentyl]phenylamine (231 mg, 0.75 mmol), LHDMS (6.28 mL, 1 M in THF, 6.28 mmol) and 2-fluoro-4-methoxy-5-nitrobenzoic acid methyl ester (172 g, 0.75 mmol) in THF (5 mL) using the procedure described in Example 13. Purification by flash chromatography (silica gel, 10% EtOAc/hexane) yielded 145 mg (0.28 mmol, 37%) of the desired product
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[CH3:30][O:31][CH2:32][CH2:33][NH2:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:34][CH2:33][CH2:32][O:31][CH3:30])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: COCCN
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COCCNCc1ccc2c(c1)cc(-c1ccc(Cl)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C

Procedure:
In a similar manner to Step. 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 2-methoxyethylamine (0.017 mL, 0.20 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-[(2-methoxyethyl)aminomethyl]indol-2-yl]isoindolinone.
Reaction SMILES: [CH2:1]([N:4]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)[CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1)[CH2:2][CH3:3].[C:24]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.OCCCCNC(=O)C1C=CC=CC=1>>[C:24]1([N:30]2[CH2:35][CH2:34][N:33]([C:19]([C:18]3[CH:22]=[CH:23][C:15]([CH2:14][N:4]([CH2:1][CH2:2][CH3:3])[CH:5]4[CH2:13][CH2:12][C:8]5[N:9]=[CH:10][S:11][C:7]=5[CH2:6]4)=[CH:16][CH:17]=3)=[O:20])[CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCCN(Cc1ccc(C(=O)Cl)cc1)C1CCc2ncsc2C1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C(NCCCCO)c1ccccc1
Product: CCCN(Cc1ccc(C(=O)N2CCN(c3ccccc3)CC2)cc1)C1CCc2ncsc2C1
Yield: 59 %

Procedure:
Compound 43 is prepared from 42C and 1-phenyl-piperazine as described for 1D.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:37]([OH:38])[C@@H:36]([CH3:39])[C@@H:35]([OH:40])[C@@H:34]([CH3:41])[C@H:33]([O:42][C:43]([CH3:45])=[O:44])[C@H:32]([CH3:46])[C@@H:31]([O:47][CH3:48])[CH:30]=[CH:29][O:28][C@:25]2([CH3:49])[C:26](=[O:27])[C:15]3[C:16]([O:24]2)=[C:17]([CH3:23])[C:18]([OH:22])=[C:19]2[C:20](=[O:21])[C:10](=[C:11](Br)[C:12]([C:14]=32)=[O:13])[NH:9][C:7](=[O:8])[C:6]([CH3:51])=[CH:5][CH:4]=[CH:3]1.C[N:53](C)C=O>>[CH3:1][C@@H:2]1[C@H:37]([OH:38])[C@@H:36]([CH3:39])[C@@H:35]([OH:40])[C@@H:34]([CH3:41])[C@H:33]([O:42][C:43]([CH3:45])=[O:44])[C@H:32]([CH3:46])[C@@H:31]([O:47][CH3:48])[CH:30]=[CH:29][O:28][C@:25]2([CH3:49])[C:26](=[O:27])[C:15]3[C:16]([O:24]2)=[C:17]([CH3:23])[C:18]([OH:22])=[C:19]2[C:20](=[O:21])[C:10](=[C:11]([NH2:53])[C:12]([C:14]=32)=[O:13])[NH:9][C:7](=[O:8])[C:6]([CH3:51])=[CH:5][CH:4]=[CH:3]1
Reactant: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C(Br)=C(NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Reactant: CN(C)C=O
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C(Br)=C(NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C(N)=C(NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Product: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C(N)=C(NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Temperature: 20 °C
Reaction time: 5 h

Procedure:
540 g of 3-bromo-rifamycin S are dissolved in 1500 ml of N,N-dimethyl formamide at 20° C. A steam of N2 is bubbled through the solution for 20', then 60 g of sodium nitrite are added portionwise allowing the temperature to rise to 39° C. while stirring under nitrogen atmosphere. The temperature is kept at 40° C. with a water bath for 30', then cooled at 20° C.; 10 g of urea are added and 70 ml of acetic acid are added dropwise. The steam of N2 is stopped and 130 g of zinc powder are added portionwise with vigorous stirring and cooling with an ice bath to keep the temperature below 60° C. The reaction mixture is stirred allowing the temperature to decrease to room temperature, and stirring is continued for 5 hours. The reaction mixture is filtered and the solution is diluted with 3000 ml of dichloromethane and washed with water several times. The dichloromethane solution is treated with manganese dioxide in order to oxidize 3-amino-rifamycin SV to 3-amino-rifamycin S. After filtration and evaporation to dryness, raw material such obtained is crystallized from 600 ml of 2-methoxy-ethanol to give 440 g of TLC pure 3-amino-rifamycin S in black crystals. U.V.; I.R. and PMR are identical to an authenic sample prepared according to W. Kump, H. Bickel, Helv. Chem. Acta, 56(7), 2348 (1973).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]C(=O)N(C)C)=[C:4]([Cl:15])[CH:3]=1.[OH-].[K+].Cl>C(O)C.O>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([SH:9])=[C:4]([Cl:15])[CH:3]=1
Reactant: CN(C)C(=O)Sc1c(Cl)cc(N)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc(Cl)c(S)c(Cl)c1
Temperature: 95 °C
Yield: 68.7 %

Procedure:
A solution of dimethyl-thiocarbamic acid S-(4-amino-2,6-dichloro-phenyl)ester (81) (2.0 g, 7.5 mmol) in ethanol was treated with a 3N aqueous potassium hydroxide solution. The reaction was heated to 95° C. for 2 d. At this time, the reaction was cooled to 25° C. and was then acidified to pH=2 with a 3N aqueous hydrochloric acid solution. This solution was diluted with water (500 mL) and then was extracted with ethyl acetate (2×250 mL). The organics were dried with magnesium sulfate, filtered, and concentrated under vacuum to an orange solid. The solid was slurried in chloroform, collected by filtration and washed with chloroform. The filtrate was concentrated under vacuum and purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 85:15 petroleum ether/ethyl acetate) to afford 4-amino-2,6-dichloro-benzenethiol (82) (1.0 g, 69%) as a white solid; EI(+)-HRMS m/e calcd for C6H5Cl2NS (M+) 192.9520, found 192.9519. Exact Mass=192.9520; Molecular weight=194.08