Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[C:7]([OH:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=1.[C:16]([O:20][C:21](=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br)([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:16]([O:20][C:21](=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:14][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:3]([O:2][CH3:1])=[O:15])[CH:13]=[CH:12]2)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)CCCCCBr
Reactant: COC(=O)c1ccc2cccc(O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cccc(OCCCCCC(=O)OC(C)(C)C)c2n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 82.6 %

Procedure:
To a solution of 8-hydroxyquinaldic acid methyl ester (406 mg, 2 mmol, 1 eq.) and t-butyl-6-bromohexanoate (754 mg, 3 mmol, 1.5 eq.) in DMF (5 mL) was added potassium carbonate (828 mg, 6 mmol, 3 eq.). The mixture was stirred vigorously for 3 h at 60° C., and then concentrated in vacuo. The residue was diluted with ethyl acetate, washed with NaH2PO4 buffer (pH 5, 1M) and brine, dried over Na2SO4 and concentrated in vacuo. Crude product was purified by flash chromatography on silica using ethyl acetate:hexanes gradient to provide 617 mg of 1. Yield 86%. MS m/z 374 (M+H)+
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20](=[O:23])[CH2:21][NH3+:22])[CH:14]=[CH:13]2.[Cl-].[CH3:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](Cl)=[O:36])=[CH:27]1>C(Cl)Cl>[CH3:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35]([NH:22][CH2:21][C:20]([C:15]2[CH:14]=[CH:13][C:12]3[C:17](=[CH:18][CH:19]=[C:10]([O:9][CH3:8])[CH:11]=3)[CH:16]=2)=[O:23])=[O:36])=[CH:27]1
Reactant: Cn1cc(C(=O)Cl)c2ccccc21
Reactant: COc1ccc2cc(C(=O)C[NH3+])ccc2c1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2cc(C(=O)CNC(=O)c3cn(C)c4ccccc34)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
Triethylamine (3.2 mL, 22.8 mmol) in 30 mL of methylene chloride was added dropwise over 2 h to a mixture of 2-(6-methoxy-naphthalen-2-yl)-2-oxo-ethyl-ammonium; chloride (2.47 g, 11.4 mmol), prepared in step 3 of Example 1, and 1-methyl-1H-indole-3-carbonyl chloride (2.21 g, 11.4 mmol), prepared in the previous step, in 100 mL of methylene chloride at room temperature. After the addition of the reaction was stirred at room temperature for 16 h (overnight). The reaction was diluted with methylene chloride, extracted twice with 1N HCl, dried (MgSO4), filtered and the solvent removed under reduced pressure to give 1-methyl-N-[2-(6-methoxy-2-naphthyl)-2-oxoethyl]-1H-indole-3-carboxamide (3.86 g, 91%) as a yellow solid, mp 177-180° C. Elemental Analysis for C23H20N2O3 Calc'd: C, 74.18; H, 5.41; N, 7.52. Found: C, 72.68; H, 5.34; N, 7.29
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:20][C:21](=[O:39])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33](Br)[CH:32]=2)=[CH:26][C:25]=1[CH3:38]>>[CH3:38][C:25]1[CH:26]=[C:27]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:18][C:9]3[CH:10]=[C:11]([C:14]([F:15])([F:16])[F:17])[CH:12]=[CH:13][C:8]=3[O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:32]=2)[CH:28]=[CH:29][C:24]=1[CH2:23][CH2:22][C:21]([OH:39])=[O:20]
Reactant: COC(=O)CCc1ccc(Oc2cccc(Br)c2)cc1C
Reactant: Oc1cc(C(F)(F)F)ccc1Oc1ccccc1
Product: Cc1cc(Oc2cccc(Oc3cc(C(F)(F)F)ccc3Oc3ccccc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared according to Example 85 by using 2-phenoxy-5-trifluoromethyl-phenol and 3-[4-(3-bromo-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester to afford about 35 mg (11%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C29H23O5F3 508, found 509 (M+1, 100%).
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH2:6][O:7]2.[N+](=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N-]>ClCCCl>[CH2:22]([O:21][C:19]([CH:18]1[CH:4]2[CH:5]1[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12](=[O:15])[CH2:13][CH3:14])=[C:2]([OH:1])[C:3]=12)=[O:20])[CH3:23]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CCC(=O)c1ccc2c(c1O)C=CCO2
Solvent: ClCCCl
Product: CCOC(=O)C1C2COc3ccc(C(=O)CC)c(O)c3C21
Reaction time: 0.25 h
Yield: 41.3 %

Procedure:
To a mixture of 1-(5-hydroxy-2H-chromen-6-yl)-propan-1-one (511 mg, 2.5 mmol) and (Rh(II)Ac2)2 (11 mg, 0.025 mmol) in 1,2-dichloroethane (8 mL) at 20° C., was added dropwise (3 h) a solution of ethyl diazoacetate (571 mg, 5 mmol) in 1,2-dichloroethane (2 mL). After 15 min at 20° C., the reaction mixture was washed with H2O (10 mL). The H2O phase was washed with CH2Cl2 (10 mL) and the solvent of the combined organic phases was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, 1→5% MeOH in CH2Cl2), to give 300 mg (41%) of 7-hydroxy-6-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylic acid ethyl ester (a 33/64 mixture of cis and trans isomers).
Reaction SMILES: [F:1][CH2:2][CH:3]([OH:5])[CH3:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]>C1COCC1.O.CCOC(C)=O>[F:23][C:21]1[CH:22]=[CH:17][C:18]([N+:24]([O-:26])=[O:25])=[C:19]([O:5][CH:3]([CH3:4])[CH2:2][F:1])[CH:20]=1
Reactant: CC(O)CF
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(CF)Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.29 g (3.77 mmol) 1-fluoro-propan-2-ol in 20 mL THF is cooled down to 0° C. 4.90 mL (1 M in THF; 4.90 mmol) LiHMDS is added drop wise. After 60 minutes of stirring at 0° C. 0.60 g (3.77 mmol) 2,4-difluoro-1-nitro-benzene is added. The mixture is stirred for 2 h. The mixture is diluted with water and EtOAc. The organic layer is washed with brine, separated, dried and evaporated giving rise to the crude 4-fluoro-2-(2-fluoro-1-methyl-ethoxy)-1-nitro-benzene. 80.0 mg palladium on charcoal (10%) and MeOH are added hydrogenated in a Parr apparatus (RT; 50 psi; 5 h). The catalyst is filtered off and the solvent is evaporated.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24]([OH:26])=O)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH2:37][CH:36]([CH2:40][NH2:41])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH2:37][CH:36]([CH2:40][NH:41][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[C:8]5[O:12][CH2:11][O:10][C:9]=5[CH:13]=[CH:14][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:16]=3[NH:23][CH:22]=2)=[O:26])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C(O)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(C)(C)OC(=O)N1CCCC(CN)C1
Product: CC(C)(C)OC(=O)N1CCCC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A67) and 3-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)=[C:4]([Cl:15])[C:3]=1[O:16]CC1C=CC=CC=1>CCO.[Pd]>[NH2:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)=[C:4]([Cl:15])[C:3]=1[OH:16]
Reactant: Nc1c(OCc2ccccc2)c(Cl)c2c(c1C(=O)O)CCCC2
Agent: [Pd]
Solvent: CCO
Product: Nc1c(O)c(Cl)c2c(c1C(=O)O)CCCC2
Reaction time: 2 h
Yield: 86.9 %

Procedure:
7-Amino-6-benzyloxy-8-carboxy-5-chlorotetralin (33 mg, 0.10 mmol) was dissolved in EtOH (3 mL) and 5% Pd/C (4 mg) was added. Hydrogenation at room temperature and atmospheric pressure for 2 h, filtration, evaporation and vacuum-drying gave the title compound (21 mg). Mp: 147° C. (dec); 1H NMR (DMSO-d6): δ 7.9 (br, NH, OH), 2.66 (t, J=6.0 Hz, 2 H), 2.54 (t, J=6.7 Hz, 2 H), 1.70-1.64 (m, 2 H) , 1.63-1.57(m, 2 H) ; 13C NMR (DMSO-d6): δ 169.73, 138.12, 136.45, 128.13, 123.32, 121.36, 115.15, 27.86, 26.91, 22.45, 22.25; MS (EI, 70 eV): m/z (rel.int.) 243/241 (M+, 21/65), 225/223 (35/100), 197/195 (61/100).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]#[C:8][CH2:9][OH:10])=[CH:3][CH:2]=1>[Rh]>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:3][CH2:2]1
Reactant: OCC#Cc1ccncc1
Agent: [Rh]
Product: OCCCC1CCNCC1

Procedure:
1-(4-Pyridyl)-1-propine-3-ol was hydrogenated with rhodium on alumina as catalyst.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[CH3:52][C:53]1[CH:60]=[CH:59][C:56]([C:57]#[N:58])=[CH:55][C:54]=1[NH:61][CH:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1>CN(C=O)C.O>[C:57]([C:56]1[CH:59]=[CH:60][C:53]([CH3:52])=[C:54]([NH:61][CH:62]2[CH2:67][CH2:66][N:65]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]3[CH:17]=[C:16]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:20][N:19]=3)=[O:22])[CH2:64][CH2:63]2)[CH:55]=1)#[N:58]
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: Cc1ccc(C#N)cc1NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C#N)cc1NC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Reaction time: 8 h
Yield: 20.5 %

Procedure:
DIPEA (426 mg, 3.3 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (285 mg, 1.1 mmol) in DMF (3 mL) followed by HOBt (175 mg, 1.3 mmol) and EDCI.HCl (252 mg, 1.3 mmol). After 2 minutes 4-methyl-3-(piperidin-4-ylamino)-benzonitrile dihydrochloride (250 mg, 1.1 mmol) (prepared according to the method used for the synthesis of Intermediate 3) was added and the stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure. Purification by column chromatography (using 60-120 silica gel and 5% MeoH in CHCl3 as eluent) afforded 100 mg (22.7% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(5-cyano-2-methyl-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 443.31, 91.96%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (s, 1H), 8.1 (t, 1H), 7.8 (d, 2H), 7.4 (m, 4H), 7.2 (m, 2H), 7.0 (s, 1H), 6.9 (d, 1H), 5.0 (d, 1H), 4.4 (m, 1H), 4.2 (m, 2H), 3.9 (m, 1H), 3.7 (m, 1H), 3.2 (m, 1H), 2.8 (m, 1H), 2.2 (s, 3H), 2.0 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[O:20][C:19](=[O:21])[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[Br:28][CH2:29][CH2:30][CH2:31]Br>CN(C)C=O>[Br:28][CH2:29][CH2:30][CH2:31][N:18]1[N:17]=[C:16]([C:7]2[CH:8]=[C:9]([C:12]([CH3:14])([CH3:15])[CH3:13])[C:10]([OH:11])=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=2)[O:20][C:19]1=[O:21]
Reactant: CC(C)(C)c1cc(-c2n[nH]c(=O)o2)cc(C(C)(C)C)c1O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(-c2nn(CCCBr)c(=O)o2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.5 %

Procedure:
To a solution of 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3,4-oxadiazol-2(3H)-one (0.50 g) in dimethylformamide (8 ml) were added sodium carbonate (0.36 g) and 1,3-dibromo-propane (1.74 g), followed by stirring at room temperature for 5 hours. After completion of the reaction, the reaction mixture was poured into ice-water, and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform) and then recrystallized from chloroform/n-hexane to afford 0.45 g (63%) of the title compound as colorless crystals. mp 130-131° C. NMR (CDCl3) (200 MHz) δ: 1.46 (18H, s), 2.1-2.6 (2H, m), 3.46 (2H, t, J=6.6 Hz), 3.93 (2H, t,J=6.6 Hz), 5.60 (1H, s), 7.63 (2H, s)
Reaction SMILES: [CH:1]12[CH2:10][CH:7]([CH2:8][CH2:9]1)[C:5](=[CH2:6])[C:2]2([CH3:4])[CH3:3].[CH:11](=[O:13])[CH3:12].CC1C=CC(C)=CC=1C>>[CH3:3][C:2]1([CH3:4])[CH:1]2[CH2:10][CH:7]([CH2:8][CH2:9]2)[CH:5]1[CH2:6][C:11](=[O:13])[CH3:12]
Reactant: C=C1C2CCC(C2)C1(C)C
Reactant: CC=O
Agent: Cc1ccc(C)c(C)c1
Product: CC(=O)CC1C2CCC(C2)C1(C)C
Yield: 40.5 %

Procedure:
A 1 liter water jacketed photochemical reaction vessel equipped with magnetic stirrer and pyrex immersion well is charged with 418 g camphene (807, Aldrich) and 372 g acetaldehyde and 30 g diacetyl (photochemical hydrogen abstractor). The mixture is irradiated with a 450 medium pressure mercury lamp (Hanovia) for 55 hours, during which time five 30 g portions of diacetyl are added at varying intervals. The reaction mixture is combined with 150 g of 1,2,4-trimethyl benzene and washed with water. The material is distilled without fractionation and then redistilled through a 5 foot Vigreux column to yield 224 g colorless product, b.p. 70°-72° (55 mm Hg).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:7][C:8](OC)=O)[C:3](OC)=O.[NH2:12][CH2:13][CH2:14][OH:15]>>[CH3:1][C@H:2]1[CH2:7][CH2:8][N:12]([CH2:13][CH2:14][OH:15])[CH2:3]1
Reactant: COC(=O)C[C@H](C)C(=O)OC
Reactant: NCCO
Product: C[C@H]1CCN(CCO)C1

Procedure:
The title compound was synthesized as described in Intermediate 11 using (S)-dimethyl 2-methylsuccinate and 2-aminoethanol as starting materials. 1H NMR (CDCl3): δ 3.66 (t, 1H), 2.93 (dd, 1H), 2.81 (m, 1H), 2.73 (m, 1H), 2.66 (m, 1H), 2.63 (m, 1H), 2.29 (m, 1H), 2.18 (dd, 2H), 2.05 (m, 1H), 1.40 (m, 1H), 1.04 (d, 3H); MS: 130.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[NH:10][C:9]2=[O:15])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:19]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:12][C:11]([CH3:13])([CH3:14])[N:10]([CH3:19])[C:9]2=[O:15])=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC1(C)CN(c2ccc(Cl)nn2)C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2ccc(Cl)nn2)CC1(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-(6-chloropyridazin-3-yl)-4,4-dimethylimidazolidin-2-one (Example 154, step 2) (140 mg, 618 μmol) in DMF (3 ml) was added 60% sodium hydride suspension (37.1 mg, 926 μmol, 1.5 equiv.). After stirring at room temperature for 10 min, iodomethane (132 mg, 57.9 μl, 926 μmol, 1.5 equiv.) was added and the suspension was stirred for 1 hour at room temperature. The solvent was removed in vacuo and the residue was worked up with ethyl acetate/water. The title compound was obtained as a crystalline light brown solid (129 mg, 87% yield), MS: m/e=241.2, 243.4 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1[N+:21]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)=[CH:11][C:10]=1[NH2:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(-c2ccncc2)ccc1OCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(-c2ccncc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.8 %

Procedure:
To a solution of 4-(4-(benzyloxy)-3-nitrophenyl)pyridine 13.0 (1.52 g, 4.97 mmol) in ethyl acetate (20 mL) was added tin(II) chloride dihydrate (4.49 g, 19.87 mmol). The mixture was heated to reflux for 2 hours, then quenched with 100 ml 1N NaOH. The resulting mixture was stirred overnight at room temperature, then partitioned between AcOEt and water. The organic phase was dried on MgSO4 and concentrated to afford 2-(benzyloxy)-5-bromobenzenamine 13.D (1.59 g, 115% yield) which was used in the next step without any further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[C:28]=1[C:29](Cl)=[O:30].O=C1CC(=O)N(C2C=CC(C(O)=O)=CC=2)C2C=CC3C(C=2N1)=CC=CC=3>>[CH3:37][O:36][C:32]1[CH:33]=[CH:34][CH:35]=[C:27]([O:26][CH3:25])[C:28]=1[C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:30]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(c2ccc(C(=O)O)cc2)c2ccc3ccccc3c2N1
Product: COc1cccc(OC)c1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 71 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and 2,6-dimethoxybenzoyl chloride, the title compound (yield 71%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](=O)[CH3:18])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br-].[C:21]1([CH3:47])[CH:26]=[CH:25][CH:24]=[C:23](C[P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:22]=1.C[C:49](O)=[O:50]>C1COCC1>[C:4]([Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([CH3:18])=[CH:47][C:21]2[CH:26]=[CH:25][C:24]([O:50][CH3:49])=[CH:23][CH:22]=2)=[CH:11][CH:10]=1)([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(=O)O
Reactant: Cc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CC(=O)CCc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1ccc(C=C(C)CCc2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Potassium f-butylat (45 mL, 45 mmol, 1.0 equiv., 1M in THF) and 4-[4-(tert-butyldimethylsilyloxy)phenyl]butan-2-one (12.5 g, 45 mmol, 1.0 equiv.) in THF (23 mL) were added simultaneously to a solution of (m-tolyl)methyltriphenylphosphonium bromide (20.1 g, 45 mmol, 1.0 equiv.) in THF (45 mL) at 70° C. The mixture was stirred at 70° C. for 16 h. After addition of 20% aq. AcOH-solution at 25° C., the aqueous layer was extracted with hexane. The combined organic phases were washed with MeOH/H2O (4:1; 2-3×), dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 (cyclohexane/EtOAc 99:1) to yield tert-butyl{4-[4-(4-methoxyphenyl)-3-methylbut-3-en-1-yl]phenoxy}-dimethylsilane as a light yellow oil. This compound was dissolved in THF (32 mL), n-Bu4NF (35 mL, 35 mmol, 0.8 equiv., 1.0 M in THF) was added, and the mixture was stirred at 25° C. for 1 h. After addition of H2O, the aqueous layer was extracted with MTBE (2×), the combined organic phases were washed with brine, dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 (hexane/EtOAc 9:1→4:1) to yield 7.40 g (65% over 2 steps) of the title compound as a light yellow oil.
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C1(C)C=CC=CC=1>[C:1]1([N:7]2[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]2=[S:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc(=O)n(-c2ccccc2)c1
Solvent: Cc1ccccc1
Product: Cc1ccc(=S)n(-c2ccccc2)c1

Procedure:
1-phenyl-5-methyl-2-pyridinone (555.7 mg, 3 mmol) was reacted with Lawesson's reagent (606.7 mg, 1.5 mmol) in toluene (5 ml) at 90° C. Reaction mixture was evaporated and the target compound was isolated by column chromatography (20-30% ethyl acetate-hexane) followed by crystallization from methyl-tert-butyl ether. Yield 403 mg (67%), yellow solid. The 1H NMR spectra was consistent with the structure of Compound 18.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:35])=[N:4][O:5][C:6]=1[N:7](COCCOC)[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[CH3:28])(=[O:10])=[O:9].Cl>CO>[Cl:1][C:2]1[C:3]([CH3:35])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[CH3:28])(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(Cc2ccc(C)cc2C)sc2ncccc12
Agent: Cl
Solvent: CO
Product: Cc1ccc(Cc2sc3ncccc3c2S(=O)(=O)Nc2onc(C)c2Cl)c(C)c1
Yield: 72.6 %

Procedure:
The title compound was prepared by the method of Example 4(D) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-(2,4-dimethylbenzyl)thieno[2,3-b]pyridine-3-sulfonamide (87 mg, 0.16 mmoles), methanol (3 ml) and 4N HCl (1 ml). Recrystallization from chloroform/hexane provided 52 mg (72%) of the title compound as a white crystalline solicl, m.p. 123-125° C.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:5]([C@@H:6]2[CH2:10][O:9][C:8]([CH3:12])([CH3:11])[O:7]2)[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[O:22][CH3:23])[C:3]1=[O:24].C([O-])(O)=O.[Na+].Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>>[CH3:23][O:22][C:15]1[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=1[CH2:13][N:4]1[C:3](=[O:24])[C@@H:2]([NH:1][C:31](=[O:32])[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:5]1[C@@H:6]1[CH2:10][O:9][C:8]([CH3:12])([CH3:11])[O:7]1
Reactant: COc1ccc(CN2C(=O)[C@@H](N)[C@H]2[C@@H]2COC(C)(C)O2)c(OC)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2[C@@H]2COC(C)(C)O2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To the crude organic solution from step 3 (EtOAc, 4 L) cooled to 0° C. was added saturated NaHCO3 (aq, 2.05 L) followed by benzyl chloroformate (205 mL, 1.43 mol), drop-wise over 1 h. After stirring at rt for 2 h the layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was treated with MeOH (2 L), filtered and washed with MeOH (2×200 mL) to afford pure title compound (155 g) as a white solid. The mother liquor was cooled to −20° C. for 12 h and the resulting precipitate was collected by filtration, affording additional title compound (90 g) for a combined 45% yield over 4 steps. LCMS: m/z=471.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23]Cl)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][NH:35]1>CC(=O)CC.O>[CH3:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][N:35]1[CH2:23][CH2:22][CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: CC1CCCCN1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(OCCCCl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CC1CCCCN1CCCOc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 88.2 %

Procedure:
1,1-Dimethylethyl 4-{4-[(3-chloropropyl)oxy]phenyl}-1-piperazinecarboxylate (D9) (1.6 g), was dissolved in 2-butanone (10 ml). Potassium carbonate (1.38 g) and a catalytic amount of potassium iodide were added, followed by 2-methylpiperidine (0.99 g). The mixture was heated at reflux for 72 h under nitrogen. The reaction mixture was diluted with water and extracted with dichloromethane. The organic phases were separated using a hydrophobic frit, combined and evaporated in vacuo. The residue was purified on a 100 g silica SPE bond elut cartridge, eluting with a gradient of 0% to 20% [0.880 ammonia-methanol (1:9)]-dichloromethane mixtures, to give the title compound (1.66 g). LCMS RT=2.48 min.