Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:54]=[C:55]([NH2:62])[C:56]4[CH:57]=[N:58][NH:59][C:60]=4[CH:61]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1>CN(C=O)C.CS(C)=O.CO.CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:62][C:55]2[CH:54]=[C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[C:52]4[C:47]=3[CH:46]=[CH:45][NH:44]4)[CH:61]=[C:60]3[C:56]=2[CH:57]=[N:58][NH:59]3)=[O:10])=[N:6][CH:7]=1
Reactant: Nc1ccc(C(=O)O)nc1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 38 %

Procedure:
To a solution of 5-amino-2-pyridinecarboxylic acid (56 mg, 0.40 mmol, available from ChemPacific) in DMF (2 ml) was added HATU (150 mg, 0.40 mmol) and DIPEA (0.211 ml, 1.21 mmol). The mixture was stirred at room temperature for 20 mins then 6-(1H-indol-4-yl)-1H-indazol-4-amine (50 mg, 0.20 mmol) was added and the mixture stirred at room temperature for 18 h. The reaction mixture was added to the top of a 20 g aminopropyl cartridge that had been preconditioned with MeOH. The reaction mixture remained on the cartridges for 3 h before being eluted with MeOH. The solvent was removed in vacuo to give a crude residue that was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method C). The product was loaded onto a 1 g aminopropyl column, eluted with DCM/MeOH (1:1) and the solvent removed under a stream of nitrogen to give the title compound (28 mg) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][N:12]([CH2:23][C:24]2[CH:29]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:27]=[CH:26][N:25]=2)[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)=[C:7]([CH2:9][OH:10])[CH:8]=1.Cl.[CH2:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][CH:37]([C:45](O)=[O:46])[NH:36]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:30]([C:28]1[CH:27]=[CH:26][N:25]=[C:24]([CH2:23][N:12]([CH2:11][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:45]([CH:37]3[CH2:38][C:39]4[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:35][NH:36]3)=[O:46])=[CH:8][C:7]=2[CH2:9][OH:10])[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)[CH:29]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)c1ccnc(CN(Cc2ccc(CN)cc2CO)C2CCCc3cccnc32)c1
Reactant: O=C(O)C1Cc2ccccc2CN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1ccnc(CN(Cc2ccc(CNC(=O)C3Cc4ccccc4CN3)cc2CO)C2CCCc3cccnc32)c1
Yield: 27.1 %

Procedure:
(5-Aminomethyl-2-{[(4-tert-butyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenyl)-methanol (0.047 g, 0.11 mmol), (±)-1,2,3,4-tetrahydro-3-isoquinoline carboxylic acid hydrochloride (0.027 g, 0.13 mmol), HOBT (0.017 g, 0.13 mmol), EDCI (0.024 g, 0.13 mmol) and DIPEA (40 μL, 0.26 mmol) in CH2Cl2 (8 mL) were reacted according to General Procedure G. Purification by column chromatography on silica gel (CH2Cl2:MeOH:NH4OH, 94:5:1, v/v/v) afforded 1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid 4-{[(4-tert-butyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-3-hydroxymethyl-benzylamide as a white solid (0.018 g, 28%). 1H NMR (CDCl3) δ 1.40 (s, 9H), 1.59 (m, 1H), 1.89-2.02 (m, 2H), 2.22 (m, 1H), 2.69 (m, 1H), 2.79 (m, 1H), 3.22 (dt, 1H, J=12.0, 3.0 Hz), 3.55-3.66 (m, 4H), 3.87 (m, 1H), 3.94 (d, 2H, J=4.5 Hz), 4.06 (d, 2H, J=12.0 Hz), 4.40 (m, 3H), 7.04-7.24 (m, 9H), 7.36 (d, 1H, J=7.5 Hz), 7.52 (br t, 1H), 7.89 (s, 1H), 8.36 (d, 1H, J=6.0 Hz), 8.51 (d, 1H, J=3.0 Hz). HPLC: 89%. ES-MS m/z 604 [M+H]+.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Br:6][C:7]1[S:15][C:14]2[CH:13]=[CH:12][NH:11][C:10](=O)[C:9]=2[CH:8]=1>>[Br:6][C:7]1[S:15][C:14]2[CH:13]=[CH:12][N:11]=[C:10]([Cl:3])[C:9]=2[CH:8]=1
Reactant: O=c1[nH]ccc2sc(Br)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nccc2sc(Br)cc12
Temperature: 135 °C
Yield: 80.7 %

Procedure:
Phosphorus oxychloride (4.08 g, 26.6 mmol) was added dropwise to 2-bromothieno[3,2-c]pyridin-4 (5H)-one (2.04 g, 8.87 mmol) at 0° C. The mixture was heated at 135° C. for 2.5 h, then carefully poured over ice water. The precipitated was collected by filtration and dried to yield 1.78 g (80.7%) of title product. 1H NMR (270 MHz, CH3OH-d4) δ ppm 7.67 (d, 1H) 7.88 (dddd, J=6.33 Hz, 2H) 8.19 (d, J=5.54 Hz, 1H); MS 248.0 (M−H)+; Purity (HPLC) 100
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15]Br)C.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>CN(C=O)C.CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:15][CH2:14][CH2:13][C:12]([OH:17])=[O:11])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(O)CCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
4-Bromo-phenol (172 g, 1 mol), 4-bromo-butyric acid ethyl ester (212 g, 1.1 mol) and K2CO3 (250 g, 1.8 mol) was dissolved in DMF (1000 mL), the mixture was stirred at room temperature overnight. the solvent was removed and water was added to the residue, the mixture was extracted with ethyl acetate, the organic layer was washed with brine, and dried over Na2SO4 the solvent was removed, to the residue was added NaOH (3M, 1000 mol) and CH3OH (600 mL), the mixture was stirred at 70 for 30 minutes and concentrated, the residue was dissolved in H2O and the mixture was washed with diethylether, the aqueous layer was acidified with HCl, and the mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na2SO4, concentrated to give crude 4-(4-bromophenoxy)butanoic acid (239 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([O:24][CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[C:20]([CH:23]=3)[CH:21]=O)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[C:32]([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([O:24][CH2:25][CH2:26][N:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)=[C:20]([C:21]#[CH:32])[CH:23]=3)=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: C#Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
152 mg (0.79 mmol) dimethyl (1-diazo-2-oxo-propyl)-phosphate in 2 mL MeOH are added to a solution of 300 mg (0.66 mmol) 5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (Example 3.55b) and 183 mg (1.32 mmol) K2CO3 in 9 mL MeOH. The reaction solution is stirred for for 3 h at RT and diluted with 20 mL DCM. The organic phase is extracted twice with saturated NaHCO3 solution. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The purification is carried out by HPLC-MS.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[Se:20][C:19]([CH:21]=O)=[CH:18][CH:17]=2)=[C:12]([F:23])[C:11]=1[F:24])[CH3:8]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1COCC1.CC(OC)(C)C.O.Cl>[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[Se:20][C:19]([CH:21]=[CH:1][CH3:2])=[CH:18][CH:17]=2)=[C:12]([F:23])[C:11]=1[F:24])[CH3:8]
Reactant: CCOc1ccc(-c2ccc(C=O)[se]2)c(F)c1F
Reactant: CC(C)(C)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC=Cc1ccc(-c2ccc(OCC)c(F)c2F)[se]1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
7.66 g (20.6 mmol) of ethyltriphenylphosphonium bromide are initially introduced in 80 ml of THF at 0° C., and 2.23 g (19.8 mmol) of potassium tert-butoxide dissolved in 20 ml of THF are added. After 1.5 h at RT, 5.0 g (15.9 mmol) of 5-(4-ethoxy-2,3-difluorophenyl)selenophene-2-carbaldehyde are added in portions with ice-cooling, and the batch is stirred at RT for 3.5 h. The mixture is diluted with MTBE, and water and 2 N hydrochloric acid are added. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:EtOAc=5:1→2:1). Further purification is carried out by recrystallisation from n-heptane; 2-(4-ethoxy-2,3-difluorophenyl)-5-propenylselenophene is obtained as a yellow solid.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[CH2:26]([O:28][C:29]1[CH:30]=[C:31](/[CH:43]=[C:44](\[CH2:50][CH3:51])/[C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:32]=[CH:33][C:34]=1OS(C(F)(F)F)(=O)=O)[CH3:27].[CH3:52][NH:53][C:54]1[CH:59]=[CH:58][CH:57]=[C:56](B2OC(C)(C)C(C)(C)O2)[CH:55]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.[Cl-].[NH4+].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:26]([O:28][C:29]1[CH:30]=[C:31](/[CH:43]=[C:44](\[CH2:50][CH3:51])/[C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:32]=[CH:33][C:34]=1[C:56]1[CH:57]=[CH:58][CH:59]=[C:54]([NH:53][CH3:52])[CH:55]=1)[CH3:27]
Reactant: CNc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCOC(=O)/C(=C/c1ccc(OS(=O)(=O)C(F)(F)F)c(OCC)c1)CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=C/c1ccc(-c2cccc(NC)c2)c(OCC)c1)CC
Temperature: 92.5 °C
Yield: 37.2 %

Procedure:
45 mg (0.2 mmol) of palladium acetate and then 140 mg (0.4 mmol) of 2-(dicyclohexylphosphino)biphenyl are added to a mixture of 1.7 g (4 mmol) of ethyl 2-[1-(3-ethoxy-4-trifluoromethanesulfonyloxyphenyl)meth-(E)-ylidene]butyrate, 1.1 g (4.8 mmol) of methyl[3-(4,4,5,5-tetramethyl[1.3.2]dioxaborolan-2-yl)phenyl]amine (prepared according to Example 28a) and 2 mL of aqueous 2 M potassium phosphate solution in 8 mL of dimethylformamide. The reaction mixture is heated at 90-95° C. for 3 hours. The reaction medium is hydrolyzed in saturated ammonium chloride solution and extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent is evaporated off and the brown oil obtained (2.3 g) is purified by chromatography on a column of silica eluted with a 90/10 heptane/ethyl acetate mixture. 526 mg (15%) of ethyl 2-[1-(2-ethoxy-3′-methylaminobiphenyl-4-yl)meth-(E)-ylidene]butyrate are obtained in the form of a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13](=[O:15])[NH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:14][C:13](=[O:15])[NH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: O=c1[nH]cc(-c2ccc([N+](=O)[O-])cc2)o1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(-c2c[nH]c(=O)o2)cc1
Reaction time: 120 h

Procedure:
A solution of 1.1 g (5.4 mmol) of 5-(4-nitrophenyl)-1,3-oxazol-2(3H)-one in 40 ml of ethanol was hydrogenated in the presence of 111 mg of palladium (10% on activated carbon) at RT and standard pressure for 5 d. The reaction mixture was then filtered through Celite and the residue was washed with ethanol. The combined filtrates were concentrated under reduced pressure. The residue was used for the next step without further purification. Yield: 626 mg (purity 88%, 58% of theory)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=1>C1(C)C=CC=CC=1.[O-2].[Mn+2]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=1
Reactant: OCc1csc(-c2ccccn2)n1
Agent: [Mn+2]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: O=Cc1csc(-c2ccccn2)n1
Yield: 87.1 %

Procedure:
5.8 g of the product of Stage D in 60 ml of toluene were refluxed for 2 hours in the presence of 13 g of manganese oxide and filtration was carried out. The solvent was evaporated under reduced pressure to obtain 5 g of the expected product melting at 131° C.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[CH:3]1.C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[CH3:17][N:18]([CH3:20])[CH:19]=[C:8]([N:5]1[CH:4]=[CH:3][C:2](=[O:1])[CH:7]=[CH:6]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)Cn1ccc(=O)cc1
Reactant: CCOC(OCC)N(C)C
Product: CCOC(=O)C(=CN(C)C)n1ccc(=O)cc1

Procedure:
The title compound was prepared in a manner similar to Example Preparation 10 using ethyl 2-(4-oxopyridin-1(4 H)-yl)acetate and 1,1-diethoxy-N,N-dimethylmethanamine to give the title compound. MS m/z 237 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (t, J=7.1 Hz, 3 H) 2.86 (br. s, 6 H) 4.06 (q, J=7.1 Hz, 2 H) 6.01-6.11 (m, 2 H) 7.43-7.47 (m, 2 H) 7.48 (s, 1 H).
Reaction SMILES: C(S[S:8]([CH2:11][CH:12]([NH2:16])[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])C(N)C(O)=O>C(O)=O>[CH2:11]([S:8]([OH:10])=[O:9])[C@H:12]([NH2:16])[C:13]([OH:15])=[O:14]
Reactant: NC(CSS(=O)(=O)CC(N)C(=O)O)C(=O)O
Solvent: O=CO
Product: N[C@@H](CS(=O)O)C(=O)O
Yield: 113.6 %

Procedure:
This cystine disulfoxide (13.6 g, 0.05 mols) was dissolved in 250 ml of formic acid. The solution was passed through 150 ml of a Diaion SK1B column, and washed with 300 ml of water. A solution of 11.4 g of sodium hydroxide in 200 ml of water was passed through this resin column, and then washed with 150 ml of water. Subsequently, a solution of 17.5 g of a 25% aqueous ammonia in 200 ml of water was passed through the resin column, and then washed with water. This eluate was passed through 150 ml of a Diaion WK-10 column. The resulting eluate was concentrated, crystallized, filtered and dried to obtain 8.7 g of cysteinesulfinic acid (yield: 85%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[N:8]([O-:10])=[O:9].CN([S+](N(C)C)N(C)C)C.OC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O.[N+](CCCCCC)([O-])=O>C(#N)C>[N:8]([O:10][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:9]
Reactant: O=N[O-]
Reactant: CCCCCCBr
Agent: CCCCCC[N+](=O)[O-]
Agent: CN(C)[S+](N(C)C)N(C)C
Agent: OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: CC#N
Product: CCCCCCON=O
Reaction time: 0.25 h

Procedure:
A 165-mg (1 mmole) sample of 1-bromohexane was added to 0.5 ml (1 mmole) of 2M tris(dimethylamino)sulfonium nitrite in acetonitrile. The course of the reaction was followed by glc analysis. No further reaction occurred after 15 min. Glc analysis showed that 1-nitrohexane and 1-hexyl nitrite were formed in a 70:30 ratio.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:19]O>>[Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(CC(=O)O)s1
Reactant: CO
Product: COC(=O)Cc1ccc(CO[Si](C)(C)C(C)(C)C)s1
Reaction time: 0.5 h

Procedure:
To 2-(5-((tert-butyldimethylsilyloxy)methyl)thiophen-2-yl)acetic acid (E231) in MeOH at 0° C. was added TMS-CH2N2 until the solution persisted in a yellow color and TLC indicated completion of the reaction. The solution stirred for 30 min and then was quenched with a few drops of AcOH. The solvents were evaporated and column chromatography (SiO2, 0-15% EtOAc/Hexanes) gave pure methyl 2-(5-((tert-butyldimethylsilyloxy)methyl)thiophen-2-yl)acetate (E232).
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]([C:15](=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)=[N:8][CH:7]=[C:6]2[C:25]([OH:27])=O.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[OH:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>C(OCC)(=O)C.CN(C)C=O>[OH:43][CH:44]1[CH2:49][CH2:48][N:47]([C:25]([C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)=[O:24])=[N:8][CH:7]=2)=[O:27])[CH2:46][CH2:45]1
Reactant: OC1CCNCC1
Reactant: COc1cccc(C(=O)c2ncc(C(=O)O)c3cc(OC)c(OC)cc23)c1
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)c2ncc(C(=O)N3CCC(O)CC3)c3cc(OC)c(OC)cc23)c1
Temperature: 25 °C
Yield: 3.4 %

Procedure:
A solution of 6,7-dimethoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid (30.0 mg, 61.75 mmol) in dry, N,N-dimethylformamide (2 mL) was chilled in an ice bath under argon. With stirring, triethylamine (14.4 uL, 102 mmol) and isobutylchloroformate (13.4 uL, 102 mmol) were added. The solution was stirred for 30 min and then 4-hydroxypiperidine (165 mg, 1.633 mmol) was added. The solution was allowed to warm to room temperature with stirring for 1 hr. and then diluted with ethyl acetate (30 mL). The ethyl acetate solution was washed sequentially with saturated aqueous sodium bicarbonate solution (2×5 mL), water (5 mL), and saturated aqueous sodium chloride solution (5 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford 35 mg of an off white solid. This crude material was purified by flash chromatography eluting with 50% ethyl acetate in hexanes (containing 1% acetic acid) and then increasing gradually to 80% ethyl acetate in hexanes. After tlc analysis, fractions were pooled and evaporated to yield 25 mg (68%) of product as an acetic acid salt: APCI-MS m/e calcd for C25H26N2O6 (M+H) 451.5, found 451, H NMR (300 MHz) compatible.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6]1[C:7]([OH:14])=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10])[CH3:4]>Br.CC(O)=O>[Br:1][C:12]1[CH:13]=[C:6]([O:5][CH2:3][CH3:4])[C:7]([OH:14])=[C:8]([CH:11]=1)[CH:9]=[O:10]
Reactant: CCOc1cccc(C=O)c1O
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Product: CCOc1cc(Br)cc(C=O)c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 39.9 %

Procedure:
Bromine (2.95 g, 15.95 mmol) was added to a stirring solution of 3-ethoxy-2-hydroxybenzaldehyde (5.30 g, 31.9 mmol), which was dissolved in 30% HBr/HOAc The solution was stirred for 1.5 hrs at r.t. The reaction was quenched with H2O and extracted with ethyl acetate. The organic layer was washed with sat. ammonium chloride and dried over anhydrous sodium sulfate. Upon filtration the filtrate was concentrated in vacuo and purified by flash chromatography (silica gel) and eluted with 5% EtOAc/hexanes to yield 1.56 g (20%) of the title compound as a colorless oil: ESHRMS m/z 242.9657 (M−H, C9H9O3Br, Calc'd 242.9662).
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:43]=[CH:44][CH:45]=1)[C:9]([NH:11][C:12]1[S:13][C:14]2[CH2:42][CH2:41][CH2:40][CH2:39][C:15]=2[C:16]=1[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)=[CH:22][CH:21]=1)=[O:18])=[O:10])([CH3:3])[CH3:2].[CH3:46][O:47][C:48]([C:50]1[N:55]=[C:54]([C:56](O)=[O:57])[CH:53]=[CH:52][CH:51]=1)=[O:49]>>[CH:1]([N:4]([CH2:5][C:6]1[CH:45]=[CH:44][CH:43]=[C:8]([C:9](=[O:10])[NH:11][C:12]2[S:13][C:14]3[CH2:42][CH2:41][CH2:40][CH2:39][C:15]=3[C:16]=2[C:17](=[O:18])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:37][CH:38]=3)=[CH:22][CH:21]=2)[CH:7]=1)[C:56]([C:54]1[N:55]=[C:50]([C:48]([O:47][CH3:46])=[O:49])[CH:51]=[CH:52][CH:53]=1)=[O:57])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cccc(C(=O)O)n1
Reactant: COC(=O)c1ccc(CCCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CNC(C)C)c4)sc4c3CCCC4)cc2)cc1
Product: COC(=O)c1ccc(CCCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CN(C(=O)c5cccc(C(=O)OC)n5)C(C)C)c4)sc4c3CCCC4)cc2)cc1
Yield: 78.6 %

Procedure:
By using 116 mg of methyl 4-{3-[4-({[2-({3-[(isopropylamino)methyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]propyl}benzoate and 50 mg of 6-(methoxycarbonyl)pyridine-2-carboxylic acid as starting materials, the reaction similar to Preparation Example 33 was performed, thereby obtaining 115 mg of methyl 6-{isopropyl[3-({3-[(4-{3-[4-(methoxycarbonyl)phenyl]propyl}phenyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl}carbamoyl)benzyl]carbamoyl}pyridine-2-carboxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>C(N(CC)CC)C.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]>[F:10][C:5]1[CH:4]=[CH:3][C:2]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)C#Cc1ccc(F)c(C#N)c1
Temperature: 100 °C

Procedure:
5-Bromo-2-fluorobenzonitrile (5.01 g, 25.0 mmol), dichlorobis(triphenylphosphine)palladium(II) (652 mg, 0.929 mmol), and copper (J) iodide (413 mg, 2.17 mmol) were combined in triethylamine (15 mL) under an atmosphere of nitrogen. Trimethylsilyl acetylene (4.2 mL, 29.7 mmol) was added and the mixture was heated to 100° C. The mixture solidified and was monitored by LC/MS. After completion, the mixture was diluted with methylene chloride and washed with 1 N HCl. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of ethyl acetate in hexanes (5-45%) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.09 (dd, J=6.10, 2.03 Hz, 1H) 7.77-7.97 (m, 1H) 7.54 (t, J=9.15 Hz, 1H) 0.15-0.32 (m, 9H).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][CH:6]([CH3:13])[CH2:7][O:8][CH2:9][C:10](O)=[O:11]>C(Cl)(Cl)Cl>[CH3:5][CH:6]([CH3:13])[CH2:7][O:8][CH2:9][C:10]([Cl:3])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: CC(C)COCC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)COCC(=O)Cl

Procedure:
2-Methylpropoxyacetyl chloride may be obtained in the following manner: thionyl chloride (5 cc) is added in the course of 15 minutes to a solution of 2-methylpropoxyacetic acid (8.3 g) in chloroform (50 cc). The mixture is heated for 5 hours under reflux and then evaporated to dryness under reduced pressure (2.7 kPa). 2-Methylpropoxyacetyl chloride (7.5 g) is thereby obtained in the form of an oil, which is employed in the crude state in the subsequent syntheses.
Reaction SMILES: [CH3:1][C:2](=[CH2:13])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[C:14]1([S:20]([CH2:23][C:24]#[N:25])(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1CCCCC1>C(O)C>[C:14]1([S:20]([C:23](=[CH:9][C:8]2[CH:11]=[CH:12][C:5]([O:4][CH2:3][C:2]([CH3:1])=[CH2:13])=[CH:6][CH:7]=2)[C:24]#[N:25])(=[O:21])=[O:22])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C=C(C)COc1ccc(C=O)cc1
Reactant: N#CCS(=O)(=O)c1ccccc1
Solvent: CCO
Solvent: C1CCNCC1
Product: C=C(C)COc1ccc(C=C(C#N)S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 77 %

Procedure:
A solution of 4-(2-methylallyloxy)-benzaldehyde (7.03 g, 40 mmol) and of (phenylsulfonyl)acetonitrile (7.24 g, 40 mmol) in 70 ml absolute ethanol is heated under reflux in the presence of a catalytic quantity of piperidine (0.5 ml) for 48 hours. The reaction medium is cooled to room temperature and the precipitate formed is filtered and washed with cold ethanol. After drying in a dessicator, 10.45 g (yield 77%) of 2-benzenesulfonyl-3-[4-(2-methylallyloxy)phenyl]acrylonitrile are obtained in the form of a very pale yellow solid which is used as it is in the next step.