Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[NH:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([NH2:44])[CH:42]=2)[N:37]([CH:45]2[CH2:50][CH2:49][CH2:48][CH2:47][O:46]2)[N:36]=1>CN(C=O)C>[NH:28]1[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N:26]=[C:27]1[C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([NH:44][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:6])[CH:42]=2)[N:37]([CH:45]2[CH2:50][CH2:49][CH2:48][CH2:47][O:46]2)[N:36]=1
Reactant: O=C(O)C1CC1
Reactant: Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)C1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.4 %

Procedure:
Cyclopropanecarboxylic acid (6.46 mg, 0.075 mmol), HOBT (15.20 mg, 0.112 mmol), EDC (21.56 mg, 0.112 mmol) and sodium bicarbonate (6.30 mg, 0.075 mmol) was added to a solution of 3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (25 mg, 0.075 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash column chromatography (6% CH3OH/CH2Cl2) afforded the title compound (20 mg) as a solid. 1H NMR: (400 MHz, CD3OD): δ 8.50 (d, 1H, J=1.6 Hz), 7.96 (s, 1H), 7.75 (dd, 1H, J=2.0 and 8.8 Hz), 7.65 (m, 2H), 7.26 (m, 2H), 5.86 (dd, 1H, J=2.0 and 9.2 Hz), 3.97 (m, 1H), 3.81 (m, 1H), 2.63 (m, 1H), 2.14 (m, 2H), 1.82 (m, 2H), 1.68 (m, 2H), 0.99 (m, 2H), 0.87 (m, 2H); ESI-MS [M+H]+: 402.22.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([C:17]([OH:19])=O)[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2].O=S(Cl)[Cl:22]>>[C:1]([O:4][C:5]1[CH:6]=[C:7]([C:17]([Cl:22])=[O:19])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(-c2ccccc2)c(C(=O)O)c1
Reactant: O=S(Cl)Cl
Product: CC(=O)Oc1ccc(-c2ccccc2)c(C(=O)Cl)c1
Yield: 114.3 %

Procedure:
5.7 g (2.23×10-2 mol) of p-acetyloxybiphenylcarboxylic acid was added to 20 g (1.68×10-1 mol) of SOCl2 and the mixture was heated at reflux for 3.5 hours. After cooling, the solvent was evaporated to give 7.0 g of p-acetyloxybiphenylcarboxylic acid chloride.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:18])([CH3:17])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=1)(C)(C)C.Cl>CO>[I:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C:8]([NH2:7])([CH3:17])[CH3:18])=[CH:15][CH:14]=1
Reactant: CC(C)(Cc1ccc(I)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CC(C)(N)Cc1ccc(I)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To 1.10 g (2.93 mmol) [2-(4-iodophenyl)-1,1-dimethyl-ethyl]-carbamic acid tert-butyl ester (I52.9) in 8 ml methanol are added 7.04 ml HCl (1.25 mol/l in MeOH) and the solution is stirred at 50° C. for 3 h. The solvent is removed under reduced pressure and the resulting crude product is purified by HPLC (H2O/MeOH/NH3).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:8]1([CH3:13])[O:12][CH2:11][CH2:10][O:9]1)[C:4]([O:6][CH3:7])=[O:5].[N+:14]([C:17]1[CH:27]=[CH:26][CH:25]=[C:19]2[C:20]([O:22][C:23](=O)[C:18]=12)=[O:21])([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:27]=[CH:26][CH:25]=[C:19]2[C:18]=1[C:23](=[O:22])[N:1]([CH2:2][CH:3]([C:8]1([CH3:13])[O:9][CH2:10][CH2:11][O:12]1)[C:4]([O:6][CH3:7])=[O:5])[C:20]2=[O:21])([O-:16])=[O:15]
Reactant: COC(=O)C(CN)C1(C)OCCO1
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Product: COC(=O)C(CN1C(=O)c2cccc([N+](=O)[O-])c2C1=O)C1(C)OCCO1

Procedure:
Methyl 3-(4-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.27 g, 28%) in the same manner as described in the above example 5 (1) from methyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.50 g, 2.64 mmol) and 3-nitrophthalic anhydride (0.57 g, 3.43 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][C:11]1C=CN[N:12]=1.[CH3:17][C:18]1[N:19]=CN[CH:22]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][C:11]1[NH:12][CH:17]=[C:18]([CH3:22])[N:19]=1
Reactant: Cc1c[nH]cn1
Reactant: O=C(Cc1cc[nH]n1)c1ccc(Cl)cc1Cl
Product: Cc1c[nH]c(CC(=O)c2ccc(Cl)cc2Cl)n1

Procedure:
Made using the same procedure as for 1-(2,4-dichlorophenyl)-2-pyrazolylethan-1-one except that 4-methylimidazole (3.7 g, 44.8 mmol) was used in place of pyrazole. The crude residue was purified on silica gel (5% MeOH/CH2Cl2) to yield a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4](Cl)[CH:3]=1.[CH2:24]([NH:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:25]([CH3:27])[CH3:26]>CN1C(=O)CCC1.O>[NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([N:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:24][CH:25]([CH3:27])[CH3:26])[CH:3]=1
Reactant: CC(C)CNCC(C)C
Reactant: Nc1cc(Cl)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)CN(CC(C)C)c1cc(N)c([N+](=O)[O-])cc1C(=O)Nc1ccc2cn[nH]c2c1
Temperature: 25 °C

Procedure:
A solution 4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide (1 mmol; see Example 48) in NMP (2 mL) was added with diisobutylamine (0.5 mL), and the resulting mixture was subjected to microwave irradiation at 140° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with water (20 mL). The solid formed was collected by filtration, washed with water, and dried in vacuo to provide 4-amino-2-diisobutylamino-N-(1H-indazol-6-yl)-5-nitrobenzamide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:19]2[CH:20]=[C:21]([CH:24]=[C:25]([F:27])[CH:26]=2)[C:22]#[N:23])[CH:7]=[C:8]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]12[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([O-])=O.O.O.[Sn](Cl)Cl.CCOCC>C(O)(=O)C.Cl>[NH2:1][C:4]1[CH:5]=[C:6]([C:19]2[CH:20]=[C:21]([CH:24]=[C:25]([F:27])[CH:26]=2)[C:22]#[N:23])[CH:7]=[C:8]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]12[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: N#Cc1cc(F)cc(-c2cc([N+](=O)[O-])c3c(c2)C2(CCCCC2)C(=O)N3)c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: N#Cc1cc(F)cc(-c2cc(N)c3c(c2)C2(CCCCC2)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
To a solution of 3-(7′-nitro-1′,2′-dihydro-2′-oxospiro-[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluorobenzonitrile (1.0 eq, 0.16 g, 0.4 mmol) in glacial acetic acid (4 mL) at room temperature was added a solution of tin (II) chloride dihydrate (0.25 g, 1.1 mmol) in hydrochloric acid (2 mL). The yellow mixture was boiled for 30 min at which point the yellow color disappeared. After cooling to room temperature, 1N HCl (10 mL) and ether (20 mL) were added. The layers were separated and the aqueous phase was extracted with ether (2×20 mL). The organic layers were combined, washed sequentially with water (2×20 mL), saturated aqueous NaHCO3 (20 mL), and brine (20 mL). The solution was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 40% EtOAc/hexane) to give the title compound (70 mg, 50%) as an oil which crystallized upon addition of 10% EtOAc/hexanes, mp 241-3° C. 1H NMR (DMSO-d6; 400 MHz) δ 1.50-1.75 (m, 8H), 1.82-1.95(m, 2H), 4.98 (s, 2H), 6.90 (d, 1H, J=1.8 Hz), 7.09 (d, 1H, J=1.5 Hz), 7.75 (m, 2H), 7.90 (‘s’, 1H), 9.96 (bs, 1H). MS ((+)−APCI) m/z 336 [(M+H)+]. Anal. Calcd for C20H18FN3O: C, 71.63; H, 5.41; N, 12.18. Found: C, 71.16; H, 5.58; N, 12.18.
Reaction SMILES: C([N:8]1[CH2:15][C:14]2([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:10]([CH2:11][CH2:12][O:13]2)[CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[C:21]([O:20][C:18]([NH:17][CH2:16][C:14]12[CH2:15][NH:8][CH2:9][CH:10]1[CH2:11][CH2:12][O:13]2)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NCC12CN(Cc3ccccc3)CC1CCO2
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC12CNCC1CCO2

Procedure:
12.2 g (34.5 mmol) of 7-benzyl-1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]octane are hydrogenated in 200 ml of ethanol on 7 g of palladium-active charcoal (10% Pd) at 100° C. and 100 bar. The catalyst is filtered off with suction and the filtrate is concentrated and distilled. Yield: 5.7 g (68% of theory) Boiling point: 120°-130° C./0.01 mbar.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[N:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:24])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:25][NH:26][CH2:27][CH2:28][C:3]1=2.[C:29]1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:41].Cl>>[ClH:41].[ClH:41].[CH3:29][N:26]1[CH2:27][CH2:28][C:3]2[N:2]([CH3:1])[C:10]3[CH:9]=[C:8]([N:11]4[CH:16]=[CH:15][C:14]([C:17]5[N:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=5)=[CH:13][C:12]4=[O:24])[CH:7]=[CH:6][C:5]=3[C:4]=2[CH2:25]1
Reactant: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCNC5)c(=O)c2)nn1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Cl
Product: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCN(C)C5)c(=O)c2)nn1
Yield: 74 %

Procedure:
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-methylpyridazin-3-yl)pyridin-2(1H)-one (77 mg, 0.21 mmol) was reacted according to the procdure of Example 47 to provide the free-base. Conversion to the dihydrochloride salt using the procedure of Example 30 (step g) provided the title compound (60 mg, 74%) as a yellow solid: mp 285-288° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.32 (d, J=8.8 Hz, 1H), 7.85 (d, J=7.2 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.64 (d, J=1.5 Hz, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.25 (d, J=1.7 Hz, 1H), 7.14-7.11 (m, 2H), 4.65 (d, J=12.1 Hz, 1H), 4.31 (dd, J=14.2, 7.5 Hz, 1H), 3.81-3.74 (m, 1H), 3.71 (s, 3H), 3.55-3.45 (m, 1H), 3.26-3.15 (m, 2H), 2.98 (s, 3H), 2.72 (s, 3H); ESI MS m/z 386 [M+H]+; HPLC (Method B)>99% (AUC), tR=9.4 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:30][CH2:31][O:32][C:33](=[O:35])[CH3:34])([S:14][C:15]2[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:18]([OH:25])=[C:17]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:36]>O1CCOCC1>[ClH:36].[C:26]([C:17]1[CH:16]=[C:15]([S:14][C:11]2([CH2:30][CH2:31][O:32][C:33](=[O:35])[CH3:34])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:18]=1[OH:25])([CH3:27])([CH3:28])[CH3:29]
Reactant: CC(=O)OCCC1(Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)OCCC1(Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CCNCC1
Reaction time: 3 h
Yield: 100 %

Procedure:
To 4-(2-acetoxy-ethyl)-4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester (Ex. 1b, 420 mg) was added 5 mL of 4 N HCl in dioxane. The mixture was stirred for 3 h and then concentrated under reduced pressure. The resulting solid was washed with Ethyl acetate/hexanes (1:3, 20 mL) and dried under high vacuum to afford acetic acid 2-[4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-piperidin-4-yl]-ethyl ester hydrochloride as a white solid (370 mg, 100%). ESI/CI-MS m/z 408 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.CCN(C(C)C)C(C)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:26]([O:16][C:7]1[N:8]=[C:9]([CH3:15])[C:10]2[C:5]([CH:6]=1)=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2cc(OC(C)=O)nc(C)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (3.11 g, 14.19 mmol) in dry CH2Cl2 (230 mL) in a 500 mL round-bottomed flask equipped with a magnetic stirrer was added DIEA (2.46 mL, 14.88 mmol), DMAP (173 mg, 1.42 mmol) and acetic anhydride (1.39 mL, 14.80 mmol) and the reaction mixture was stirred overnight at RT. The organic solution was then washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was finally purified by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 50:50) to give 6,7-dimethoxy-1-methylisoquinolin-3-yl acetate SIL 32158 as an off-white solid (3.26 g, 88% yield).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:17]1[N:22]=[N:21][C:20]([N:23]2[CH2:28][C@@H:27]([CH3:29])[NH:26][CH2:25][C@@H:24]2[CH3:30])=[C:19]2[CH:31]=[N:32][CH:33]=[CH:34][C:18]=12>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:30][C@H:24]1[CH2:25][NH:26][C@H:27]([CH3:29])[CH2:28][N:23]1[C:20]1[N:21]=[N:22][C:17]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:18]2[CH:34]=[CH:33][N:32]=[CH:31][C:19]=12
Reactant: C[C@@H]1CN(c2nnc(Cl)c3ccncc23)[C@@H](C)CN1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[C@@H]1CN(c2nnc(-c3ccccc3)c3ccncc23)[C@@H](C)CN1
Temperature: 100 °C
Yield: 93.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium (146 mg, 126 μmol), phenylboronic acid (461 mg, 3.78 mmol), 2 M sodium carbonate (2520 μl, 5.04 mmol), and 1-chloro-4-(trans-2,5-dimethylpiperazine-1-yl)pyrido[3,4-d]pyridazine 43 (700 mg, 2.52 mmol) were added to a round bottom flask. The reaction vessel was purged with nitrogen and toluene (25 mL) was added. The reaction was heated to 100° C. overnight. After cooling to RT, the reaction was diluted with 250 mL of ethyl acetate and washed with 1×50 mL of sat. NaHCO3 and 1×50 mL of brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by column chromatography (10:0.5:0.1 CH2Cl2:MeOH, Et3N) afforded racemic 4-(trans-2,5-dimethylpiperazine-1-yl)-1-phenylpyrido[3,4-d]pyridazine 44 (750 mg, 93% yield). 1H-NMR (400 MHz, CDCl3): δ 9.76 (d, J=1.2 Hz, 1H), 8.94 (d, J=5.5 Hz, 1H), 7.84 (dd, J=5.9, 1.2 Hz, 1H), 7.78 (m, 2H), 7.57 (m, 2H), 3.83 (dqd, J=10.2, 5.9, 3.1 Hz, 1H), 3.47 (dd, J=12.1, 2.7 Hz, 1H), 3.30 (dqd, J=9.8, 6.3, 2.7 Hz, 1H), 3.25 (dd, J=12.5, 3.1 Hz, 1H), 2.94 (dq J=12.1, 10.2 Hz, 1H), 2.73 (dd, J=12.1, 9.8 Hz, 1H), 1.17 (d, J=6.3 Hz, 1H), 1.11 (d, J=6.6 Hz, 1H). MS 319.2 (calc'd) 320.2 (M+H, found).
Reaction SMILES: O=[C:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O.[NH2:10][C:11]1[CH:12]=[C:13]([C:15]([CH3:19])=[CH:16][C:17]=1[CH3:18])[NH2:14]>CO.[Ni]>[NH2:10][C:11]1[CH:12]=[C:13]([N:14]2[CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])[C:15]([CH3:19])=[CH:16][C:17]=1[CH3:18]
Reactant: Cc1cc(C)c(N)cc1N
Reactant: CC(=O)CCCC(=O)O
Agent: [Ni]
Solvent: CO
Product: Cc1cc(C)c(N2C(=O)CCCC2C)cc1N

Procedure:
A solution of 65 g (0.5 mol) of 5-oxo-caproic acid and 70 g (0.51 mol) of 3-amino-4,6-dimethylaniline in 300 ml of methanol is hydrogenated at 130°-140° in the presence of Raney nickel. Yield: 110 g.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[Cl:18][C:19]1[CH:20]=[C:21]([SH:26])[CH:22]=[CH:23][C:24]=1[Cl:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([S:26][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: Sc1ccc(Cl)c(Cl)c1
Reactant: O=C1CCc2cc(OCCCCCl)ccc2N1
Product: O=C1CCc2cc(OCCCCSc3ccc(Cl)c(Cl)c3)ccc2N1

Procedure:
Prepared analogous to Example 1 from 6-(4-chloro-butoxy)-3,4-dihydro-carbostyril (m.p. 147°-148° C.) and 3,4-dichloro-thiophenol.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]([O:20][C:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:7](=[O:19])[CH2:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([CH:8]2[CH2:2][CH2:3][CH2:4][CH2:5][N:6]([O:20][C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:7]2=[O:19])(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: O=C(CS(=O)(=O)c1ccc(F)cc1)N(CCCCBr)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1C(S(=O)(=O)c2ccc(F)cc2)CCCCN1OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
N-(4-Bromo-butyl)-2-(4-fluoro-benzenesulfonyl)-N-trityloxy-acetamide prepared from step E (170.2 mg, 0.279 mmol) and Cs2CO3 (187.3 mg, 0.575 mmol) in anhydrous DMF (6 mL) was stirred at room temperature for overnight.). The reaction mixture was diluted with EtOAc and washed sequentially with water and saturated NaCl solution. The organic phase was then dried over anhydrous Na2SO4 and concentrated under reduced pressure to gave a crude material, which was then purified by a column chromatography (0˜30% EtOAc in hexane). MS: 552.2 (M+Na)+.
Reaction SMILES: O[C@H:2]([C:22]1[CH:23]=[CH:24][C:25]2[O:30][C@H:29]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:34][CH:33]=3)C=C[C:26]=2[CH:46]=1)[C@H:3]([O:19][CH2:20][CH3:21])C(N1[C@@H](CC2C=CC=CC=2)COC1=O)=O.C([SiH](CC)CC)C.FC(F)(F)[C:56]([OH:58])=[O:57]>>[CH2:39]([O:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][CH2:29][O:30][C:25]2[CH:24]=[CH:23][C:22]([CH2:2][C@H:3]([O:19][CH2:20][CH3:21])[C:56]([OH:58])=[O:57])=[CH:46][CH:26]=2)=[CH:33][CH:34]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc2c(c1)C=C[C@@H](Cc1ccc(OCc3ccccc3)cc1)O2
Agent: CC[SiH](CC)CC
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(OCc3ccccc3)cc2)cc1)C(=O)O

Procedure:
(R) -6-{(1R, 2S)-1-Hydroxy-2-ethoxy-3-[(S)-4-benzyl-2-oxo-3-oxazolidinyl ]-3 -oxopropyl}-2-(4-benzyloxybenzyl)-2H-benzopyran (18.8 g, 31 mmol) was dissolved in trifluoroacetic acid (200 ml) and triethylsilane (49 ml, 0.31 mmol) was added. After 45 minutes the volatile components were evaporated and the oily residue was triturated with isopropyl alcohol. The product was purified by flash-chromatography (hexanes/ethyl acetate, 2:) and obtained as a thick oil (8.9 g).
Reaction SMILES: [Cl:1][C:2]1[S:28][C:5]2=[N:6][C:7](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[O:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:8](I)[C:9](=[O:10])[N:4]2[CH:3]=1.[C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)#[N:30].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[Cl:1][C:2]1[S:28][C:5]2=[N:6][C:7](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[O:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:8]([C:34]3[CH:35]=[CH:36][C:31]([C:29]#[N:30])=[CH:32][CH:33]=3)[C:9](=[O:10])[N:4]2[CH:3]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: COc1cccc(/C=C/c2nc3sc(Cl)cn3c(=O)c2I)c1OCC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3sc(Cl)cn3c(=O)c2-c2ccc(C#N)cc2)c1OCC(C)(C)C
Yield: 149.6 %

Procedure:
The title compound was prepared from Intermediate 19 (100 mg, 0.181 mmol) and 4-cyanophenylboronic acid (30 mg, 0.200 mmol) using Pd[(C6H5)3P]4 (9 mg, 0.007 mmol) in toluene (5 ml) and ethanol (2 ml) followed by sodium carbonate (119 mg, 1.110 mmol) in water (2 ml) according to the procedure outlined in Example 1 to afford 137 mg of the desired compound; 1H NMR (300 MHz, DMSO-d6) δ 1.01 (s, 9H), 3.52 (s, 2H), 3.76 (s, 3H), 6.75 (d, J=15.6 Hz, 1H), 6.96-7.02 (m, 3H), 7.53 (d, J=8.4 Hz, 2H), 7.93 (d, J=8.4 Hz, 2H), 8.22 (d, J=15.6 Hz, 1H), 8.28 (s, 1H); ESI-MS (m/z) 506.55, 508 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[C:5]#[N:6].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:9]([F:10])=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[C:4]([CH:3]=1)[C:5]#[N:6]
Reactant: O=[N+]([O-])O
Reactant: N#Cc1ccc(F)c(Br)c1
Agent: O=S(=O)(O)O
Product: N#Cc1cc(Br)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
3-Bromo-4-fluorobenzonitrile (25 g, 0.125 mol) was dissolved in concentrated sulfuric acid (200 ml), and at 0° C., fuming nitric acid was dropwise added at 0° C., taking 1 hour. After stirred for 30 minutes at the same temperature, this was heated up to room temperature, taking 1.5 hours. This was gradually poured into ice. The formed precipitate was collected by filtration with washing with water, and dried under reduced pressure. The collected yellow powder was fractionated with chloroform and aqueous 1 M sodium hydroxide solution. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was well dried under reduced pressure to obtain the entitled compound (14.7 g, 48%) as a yellow powder.
Reaction SMILES: [C:1]([C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1)([OH:3])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>C1(C)C=CC=CC=1.FC(F)(F)S(O)(=O)=O>[O:3]=[C:1]1[C:4]2[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=2[CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][C:9]1=2
Reactant: O=C(O)Cc1ccc(OCc2ccccc2C(=O)O)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 75 °C
Yield: 73.1 %

Procedure:
To a suspension of 4-(2-carboxybenzyloxy)phenylacetic acid (Olo-IM1) (300.09 g, 1.04 mol; assay: 99.0%) and trifluoromethane sulfonic acid (4.77 g, 0.03 mol; assay: 98.0%) in toluene (1122 g) was added slowly trifluoroacetic anhydride (255.18 g, 1.20 mol; assay: 99.0%) at 20-35° C. The brown solution was stirred after complete addition of trifluoroacetic anhydride for 1 hour at 20-25° C. and the mixture was then hydrolyzed with water (99.0 g). Afterwards, the mixture was distilled under normal pressure until the steam temperature was 105-110° C. (1191 g two-phase distillate). The residue was diluted with toluene (261 g) and the suspension was heated to reflux. The dark solution was then cooled to 75° C. and seeded with crystals of 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-acetic acid (Olo-IM2). The suspension was stirred after cooling to 20-25° C. for additional 1-2 hours at this temperature. The product was filtered off, washed with cyclohexane (600 g) and water (390 g) and dried under vacuum (20 h, 50° C.) to give 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-acetic acid (Olo-IM2) (yield: 203.21 g, 0.76 mol, 73.0%; HPLC assay >99.5%, HPLC purity: 99.62%). This product was then recrystallized from a mixture of cyclohexane (700 g) and toluene (1892 g). After filtration the wet product was washed with cyclohexane (466 g) and dried under vacuum (15 h, 70° C.) to give slightly gray colored 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-acetic acid (Olo-IM2) (yield: 198.4 g, 0.74 mol, 97.6%; HPLC assay >99.5%, HPLC purity: 99.90%; overall yield: 71.3%).