Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][N:9]=2)[C:5]([Cl:16])=[CH:4][N:3]=1.[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[F-].[Cs+]>CS(C)=O.CCOC(C)=O>[Cl:16][C:5]1[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][N:9]=2)=[CH:7][C:2]([N:20]2[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]2)=[N:3][CH:4]=1
Reactant: Cc1cnc(-c2cc(Cl)ncc2Cl)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cnc(-c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ncc2Cl)c(C)c1
Temperature: 120 °C
Yield: 78.1 %

Procedure:
To a solution of 2′,5′-dichloro-3,5-dimethyl-2,4′-bipyridine (4.5 g, 17.8 mmol) and tert-butyl piperazine-1-carboxylate (4.0 g, 21.4 mmol) in DMSO (80 mL) was added CsF (5.4 g, 35.6 mmol). Then the mixture was heated at 120° C. for 18 hours. TLC (petroleum ether/EtOAc=2:1) showed that the reaction was complete. It was diluted with EtOAc (200 mL), washed with H2O (70 mL) and brine (70 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (petroleum ether/EtOAc=3:1) to afford title compound (5.6 g, 78%) as white solid.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([O:16]CC)=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][NH2:20]>C(O)C>[C:1]1([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]([NH:19][NH2:20])=[O:16])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CN1CCN(c2ccccc2)CC1
Reactant: NN
Solvent: CCO
Product: NNC(=O)CN1CCN(c2ccccc2)CC1

Procedure:
Synthesized according to General Procedure C: 6{30} (1.23 g, 6.06 mmol, 1 equiv.), anhydrous hydrazine (0.96 mL, 18.2 mmol, 3 equiv.), ethanol (12.1 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{30} (1.23 g, 87%) as a yellow oil. 1H-NMR (500 MHz, CDCl3): δ 8.20 (br s, 1H), 7.29-7.26 (m, 2H), 6.92 (d, 2H, J=8.0 Hz), 6.88 (t, 1H, J=7.0 Hz), 3.51 (br s, 2H), 3.20 (t, 4H, J=5.0 Hz), 3.16 (s, 2H), 2.70 (t, 4H, J=5.0 Hz), 1.23 (t, 3H, J=7.0 Hz). 13C-NMR (125 MHz, CDCl3): δ 170.2, 150.9, 129.1, 120.0, 116.1, 60.5, 53.6, 49.2.
Reaction SMILES: C(OC([N:11]1[CH2:23][C:14]2[S:15][C:16]3[NH:17][CH2:18][N:19]=[C:20](Cl)[C:21]=3[C:13]=2[CH2:12]1)=O)C1C=CC=CC=1.C(OC(N1CCC2C3C(Cl)=NC=NC=3SC=2C1)=O)(C)(C)C.[F:45][C:46]1[CH:52]=[CH:51][C:49]([NH2:50])=[C:48]([O:53][CH:54]2[CH2:59][CH2:58][O:57][CH2:56][CH2:55]2)[CH:47]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[F:45][C:46]1[CH:52]=[CH:51][C:49]([NH:50][C:20]2[C:21]3[C:13]4[CH2:12][NH:11][CH2:23][C:14]=4[S:15][C:16]=3[NH:17][CH2:18][N:19]=2)=[C:48]([O:53][CH:54]2[CH2:59][CH2:58][O:57][CH2:56][CH2:55]2)[CH:47]=1
Reactant: O=C(OCc1ccccc1)N1Cc2sc3c(c2C1)C(Cl)=NCN3
Reactant: Nc1ccc(F)cc1OC1CCOCC1
Agent: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: Fc1ccc(NC2=NCNc3sc4c(c32)CNC4)c(OC2CCOCC2)c1
Temperature: 120 °C
Yield: 10 %

Procedure:
A solution of 4-chloro-5,7-dihydro-1H-pyrolo[3′,4′:4,5]thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester (prepared in an analogous fashion to 4-chloro-5,8-dihydro-6H-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester, WO2007/109279, 0.135 g, 0.39 mmol), 4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)aniline (0.090 g, 0.39 mmol) and para-toluene sulfonic acid (0.08 g, 0.04 mmol) in 1,4-dioxane (2 mL) was purged with nitrogen and heated at 120° C. for 21 hours. The reaction mixture was diluted with EtOAc, washed with 10% aqueous K2CO3 and brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (100% iso-hexane→100% DCM→3% MeOH/DCM→200:10:1 DCM/MeOH/NH4OH) to afford the title compound as white solid (0.015 g, 10%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:38]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:37][N:21]4[N:22]=[C:23]5[C:28]([C:27]([C:29]6[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=6)=[CH:26][CH:25]=[CH:24]5)=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C>Cl.O1CCOCC1>[NH2:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:38]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:37][N:21]4[N:22]=[C:23]5[C:28]([C:27]([C:29]6[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=6)=[CH:26][CH:25]=[CH:24]5)=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5c(-c6ccc(C#N)cc6)cccc5nn4cc3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cccc3nn4cc(-c5ccccc5)c(-c5ccc(C6(N)CCC6)cc5)nc4c23)cc1
Yield: 25.6 %

Procedure:
235 mg (1-{4-[10-(4-Cyanophenyl)-3-phenylpyrimido[1,2-b]indazol-2-yl]phenyl}-cyclobutyl)carbamic acid tert-butyl ester in 15 mL 4M hydrogen chloride in dioxane were stirred over night at room temperature. The solvent was evaporated and the residue was treated with saturated sodium bicarbonate. After extraction with dichloromethane (trice) the combined organic phases were washed with brine and dried (sodium sulfate). The solvent was evaporated and the residue (189 mg) was purified by HPLC yielding 50 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]#[N:12])[C:5]2[CH:6]=[N:7][NH:8][C:9]=2[CH:10]=1.[OH-].[K+].[I:15]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]#[N:12])[C:5]2[C:6]([I:15])=[N:7][NH:8][C:9]=2[CH:10]=1
Reactant: N#Cc1cc(Cl)cc2[nH]ncc12
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc2[nH]nc(I)c12
Temperature: 50 °C
Yield: 58.8 %

Procedure:
To a solution of 6-chloro-1H-indazole-4-carbonitrile (2.0 g, 11.26 mmol) in DMF (30 mL) was added KOH (1.89 g, 33.78 mmol) and I2 (5.72 g, 22.52 mmol). The mixture was heated at 50° C. overnight. The reaction mixture was quenched with EtOAc (200 mL) and water (100 mL). The organic layer was concentrated in vacuo to afford 6-chloro-3-iodo-1H-indazole-4-carbonitrile as white solid (2.01 g, 58.8%). MS (ESI): m/z=304 [M+1]+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:27]=[C:26]5[C:21]([CH:22]=[CH:23][CH:24]=[N:25]5)=[CH:20][CH:19]=4)=[CH:14][C:13]=3[F:28])[C:8](=[O:11])[NH:9][N:10]=2)[CH2:2]1.[CH3:29][C:30]1([C:33](O)=[O:34])[CH2:32][CH2:31]1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.N1(O)C2C=CC=CC=2N=N1>CN(C)C=O>[F:28][C:13]1[CH:14]=[C:15]([C:18]2[CH:27]=[C:26]3[C:21]([CH:22]=[CH:23][CH:24]=[N:25]3)=[CH:20][CH:19]=2)[CH:16]=[CH:17][C:12]=1[N:7]1[C:6]([CH2:5][CH:3]2[CH2:4][N:1]([C:33]([C:30]3([CH3:29])[CH2:32][CH2:31]3)=[O:34])[CH2:2]2)=[N:10][NH:9][C:8]1=[O:11]
Reactant: CC1(C(=O)O)CC1
Reactant: O=c1[nH]nc(CC2CNC2)n1-c1ccc(-c2ccc3cccnc3c2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C(=O)N2CC(Cc3n[nH]c(=O)n3-c3ccc(-c4ccc5cccnc5c4)cc3F)C2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 9.2 %

Procedure:
In a round bottom flask under nitrogen, a solution of 5-(3-azetidinylmethyl)-4-[2-fluoro-4-(7-quinolinyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (1.07 mmol) in N,N-dimethylformamide (5 mL) was treated with 1-methylcyclopropanecarboxylic acid (1.285 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (2.14 mmol), N,N-diisopropylethylamine (3.21 mmol) and then 1H-1,2,3-benzotriazol-1-ol (2.14 mmol). The reaction mixture was stirred at room temperature for 1.5 h and then concentrated in vacuo. Purification of the residue by reverse phase HPLC (10-70% acetonitrile/water with 0.1% NH4OH) and subsequent silica gel chromatography (0-3% methanol/ethyl acetate) followed by trituration in ethanol provided the title compound as a white solid (45 mg, 9.2%). MS(ES)+ m/e 458.2 [M+H]+.
Reaction SMILES: CCN(CC)CC.[NH2:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([O:14]CC)=[O:13].N1P(Cl)(Cl)=NP(Cl)(Cl)=NP=1(Cl)Cl.[Br:32][C:33]1[C:34]([CH3:51])=[N:35][O:36][C:37]=1[NH:38][S:39]([C:42]1[CH:46]=[CH:45][S:44][C:43]=1[C:47](OC)=[O:48])(=[O:41])=[O:40]>C1COCC1.O>[Br:32][C:33]1[C:34]([CH3:51])=[N:35][O:36][C:37]=1[NH:38][S:39]([C:42]1[CH:46]=[CH:45][S:44][C:43]=1[C:47]([NH:8][C:9]1[CH:19]=[CH:18][CH:17]=[C:11]([C:12]([OH:14])=[O:13])[CH:10]=1)=[O:48])(=[O:40])=[O:41]
Reactant: COC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Br
Reactant: CCOC(=O)c1cccc(N)c1
Agent: ClP1(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=N1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1noc(NS(=O)(=O)c2ccsc2C(=O)Nc2cccc(C(=O)O)c2)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.9 %

Procedure:
Et3N (2.27 ml. 16. mmol), ethyl 3-aminobenzoate (836 ml, 5.44 mmol) and phosphonitrilic chloride trimer (1.89 g, 5.44 mmol) were sequentially added to a solution of N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carbonyl)thiophene-3-sulfonamide (Example 12) (1 g, 2.27 mmol) in dry THF (20 ml). The reaction was stirred at room temperature for 1 hour and cooled. Water (5 ml) was added to quench the reaction. The resulting solution was concentrated on a rotavap. The residue was diluted with EtOAc and washed with 2 N HCl (2×150 ml). The organic layer was dried (MgSO4). The solid was filtered off and the filtrate was concentrated. The residue was treated with 1 N NaOH (200 ml) and stirred at 0° C. for 15 minutes. The mixture was then acidified with conc. HCl to pH ˜1. The resulting yellow precipitate was filtered off and recrystallized from CH3CN/H2O to give N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(3-carboxyphenyl)aminocarbonyl]thiophene-3-sulfonamide (153 mg., 11.6%) as a yellowish powder, m.p. 183-185° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[N:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:22]2[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)C(CC1CCCC1)c1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.8 %

Procedure:
A slurry of dichlorobis(triphenylphosphine)palladium(II) (119 mg, 0.17 mmol) in 1,2-dimethoxyethane (10 mL) was treated with 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (1.00 g, 2.79 mmol). The reaction slurry was stirred at 25° C. for 10 min and then treated with a solution of pyridine-4-boronic acid (515 mg, 4.19 mmol) and a 2M aqueous sodium carbonate solution (2.8 mL, 5.58 mmol) in water (5 mL). The resulting reaction mixture was heated under reflux for 8 h. The reaction mixture was allowed to cool to 25° C. where it was stirred for 3 d. The reaction mixture was partitioned between water (75 mL) and methylene chloride (75 mL), and the layers were separated. The aqueous layer was further extracted with methylene chloride (75 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-(4-pyridin-4-yl-phenyl)-propionic acid methyl ester (240 mg, 28%) as a brown oil that was used without further purification and characterization.
Reaction SMILES: [Cl:1][C:2]([Cl:32])([Cl:31])[CH2:3][O:4][C:5]([O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20])[O:14][CH:13]=[C:12]([C:27]([OH:29])=O)[C:11]2=[O:30])=[O:6].S(Cl)([Cl:35])=O>C1C=CC=CC=1>[Cl:1][C:2]([Cl:31])([Cl:32])[CH2:3][O:4][C:5]([O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:24])[Cl:25])=[O:20])[O:14][CH:13]=[C:12]([C:27]([Cl:35])=[O:29])[C:11]2=[O:30])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(OCC(Cl)(Cl)Cl)Oc1cc2occ(C(=O)O)c(=O)c2cc1OC(=O)OCC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: O=C(OCC(Cl)(Cl)Cl)Oc1cc2occ(C(=O)Cl)c(=O)c2cc1OC(=O)OCC(Cl)(Cl)Cl
Reaction time: 3 h

Procedure:
6.7-Bis(2,2,2-trichloroethoxycarbonyloxy)-chromone-3-carboxylic acid (57.3 mg) was dissolved in benzene (10 ml). To the solution was added with stirring at room temperature thionyl chloride (0.5 ml). The mixture was refluxed with stirring for three hours, and the reaction solution was concentrated. To the concentrate was added n-hexane (5 ml) to cause crystallization of the reaction product. The resulting product was recovered by filtration and washed with n-hexan and dried. There were thus obtained 34.8 ml of the desired product (34.8 mg).
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])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.[C:23]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].ClCCl>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(N(CC)CC)C>[C:23]([C:27]1[CH:32]=[CH:31][C:30]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][CH:18]=2)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(Nc4ccc(C(C)(C)C)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (689 mg) (starting compound A) and 4-t-butylphenylboronic acid (450 mg) (starting compound B) were dissolved in a mixed solution composed of dichloromethane (50 ml) and triethylamine (0.7 ml) to prepare a solution. Copper(II) acetate (450 mg) was added to the solution, and the mixture was stirred at room temperature for 16 hr. The mixture was filtered, and the filtrate was then concentrated to give a crude which was then purified by chromatography on silica gel to give the title compound (500 mg, yield 50%).
Reaction SMILES: [CH2:1]([NH:19][C:20]([O:22][CH2:23][C:24](=[CH2:37])[CH2:25][O:26][C:27](=[O:36])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH:38]1[CH:42]=[CH:41][N:40]=[CH:39]1>C1(C)C=CC=CC=1>[CH2:1]([NH:19][C:20]([O:22][CH2:23][C:24](=[CH2:37])[CH2:25][O:26][C:27](=[O:36])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:38]1[CH:42]=[CH:41][N:40]=[CH:39]1)=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C=C(COC(=O)CCCCCCCBr)COC(=O)NCCCCCCCCCCCCCCCCCC
Reactant: c1c[nH]cn1
Solvent: Cc1ccccc1
Product: C=C(COC(=O)CCCCCCCn1ccnc1)COC(=O)NCCCCCCCCCCCCCCCCCC

Procedure:
1-Octadecylaminocarbonyloxy-3-(8-bromooctanoyloxy)-2-methylenepropane (from Preparation 11) (1.18 g) and imidazole (0.68 g) were stirred in toluene (20 ml) at 104° C. for 14 hours. The mixture was cooled and evaporated in vacuo. The residue was chromatographed on silica gel 60 (70-230 mesh, 40 g) with ether/chloroform/triethylamine (1:1:0.04) as eluent to give the desired product.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:14]#[N:15])=[C:7]([OH:13])[N:8]=[C:9]2[SH:12])=[CH:4][CH:3]=1.[CH3:16]N(C=O)C.[OH-].[Na+].IC>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:14]#[N:15])=[C:7]([OH:13])[N:8]=[C:9]2[S:12][CH3:16])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: N#Cc1c(O)nc(S)c2cc(F)ccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Product: CSc1nc(O)c(C#N)c2ccc(F)cc12
Reaction time: 2 h
Yield: 79 %

Procedure:
To a 50 mL round bottom flask was added 7-fluoro-3-hydroxy-1-mercaptoisoquinoline-4-carbonitrile (400 mg, 2.27 mmol), DMF (10 mL), NaOH (10 mL, 2 N), followed by iodomethane (322 mg, 2.27 mmol). After stirring for 2 h, the solution was diluted with a solution of citric acid (200 mL, 10% w/v) and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and filtered. The solvent was concentrated to yield 7-fluoro-3-hydroxy-1-(methylthio)isoquinoline-4-carbonitrile (420 mg, 1.79 mmol, 79%) as a pale yellow solid which was suitably clean for the next step. LC/MS m/z 235 [M+H].
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:7]([Cl:15])=[N:8][CH:9]=[C:10]([CH:14]=1)[C:11]([OH:13])=O.C(N(CC)CC)C.[CH3:23][N:24]([CH3:30])[CH2:25][CH2:26][CH2:27][NH:28][CH3:29]>O.O1CCCC1>[Cl:5][C:6]1[C:7]([Cl:15])=[N:8][CH:9]=[C:10]([CH:14]=1)[C:11]([N:28]([CH2:27][CH2:26][CH2:25][N:24]([CH3:30])[CH3:23])[CH3:29])=[O:13]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: CNCCCN(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)CCCN(C)C(=O)c1cnc(Cl)c(Cl)c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
Thionyl chloride (15 ml) was added to 5,6-dichloronicotinic acid (2.0 g, 10.4 mmol), and stirred under a nitrogen atmosphere at 90° C. for 30 minutes. The reaction solution was concentrated under reduced pressure, and with cooling with ice, triethylamine (4.36 ml, 31.3 mmol) and N,N,N′-trimethylpropane-1,3-diamine (2.39 ml, 15.6 mmol) were added to a tetrahydrofuran solution (30 ml) of the obtained residue, and stirred at room temperature for 3 minutes. Saturated saline water was added to the reaction solution, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amine-type silica gel column chromatography (Biotage NH, hexane:ethyl acetate=4:1 to 1:1) to obtain 5,6-dichloro-N-[3-(dimethylamino)propyl]-N-methylnicotinamide (3.21 mg) as an orange oil.
Reaction SMILES: O=[O+][O-].[CH3:4][C:5]12[O:11][CH:8]([CH2:9][CH2:10]1)[C:7]([CH3:13])([CH3:12])[CH2:6]2.[I-].[Na+].S([O-])([O-])(=[O:18])=S.[Na+].[Na+].II.C([O-])(O)=O.[Na+]>O=O.C(O)(=O)C.CO>[CH3:4][C:5]12[O:11][CH:8]([CH2:9][CH2:10]1)[C:7]([CH3:13])([CH3:12])[C:6]2=[O:18]
Reactant: O=S([O-])([O-])=S
Reactant: CC12CCC(O1)C(C)(C)C2
Agent: II
Agent: O=C([O-])O
Agent: O=O
Solvent: CC(=O)O
Solvent: CO
Product: CC12CCC(O1)C(C)(C)C2=O

Procedure:
A stream of 3-5% ozone in oxygen was passed through a solution of (±)-1,3,3-trimethyl-7-oxabicyclo[2.2.1]heptane from step (3) (1.20 g., 0.007 moles) in 35 ml. of methanol at -78° C. until the solution became light blue (ozone saturation). The excess ozone was removed by purging the cold reaction mixture with oxygen for 15 minutes. The cold reaction mixture was then poured into a stirred solution of 15 ml. of methanol, 4 ml. of glacial acetic acid, and 8 g. of sodium iodide and stirred for 30 minutes. Sodium thiosulfate solution (0.1N) was added to decompose the liberated iodine. Saturated NaHCO3 solution was then added until the mixture was slightly basic (pH 7.5). The aqueous mixture was extracted with ether, the extract washed with brine, and then dried over Na2SO4. Evaporation of the solvent afforded the product which was characterized by NMR. Yield: 1.12 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]([NH:19][CH2:20][C:21]#[CH:22])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]>C(NC(C)C)(C)C.C(OCC)(=O)C.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]I>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:22]#[C:21][CH2:20][NH:19][C:9](=[O:10])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C#CCNC(=O)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: O=C(NCC#Cc1ccc(Br)cn1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
A mixture of 2,5-dibromopyridine (1.19 g), N-Cbz-propargylamine (1.04 g), Pd(PPh3)2Cl2 (73 mg), and CuI (10 mg) in diisopropylamine (20 mL) was stirred at ambient temperature for 3 hours under nitrogen. The mixture was diluted with ethyl acetate (50 mL). The mixture was filtered and washed with ethyl acetate (20 mL). The filtrate and wash were combined, concentrated under reduced pressure and triturated in MTBE to give crystalline 7-1 (1.28 g). The mother liquor was further purified by silica gel column chromatography using a mixture of MTBE: hexanes (1:1) to give an additional 280 mg of 7-1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@:9]1([CH3:15])[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC1C=CC(C(N2CC[C@]2(C)C(O)=O)=O)=CC=1.ClC(N(C)C)=C(C)C.Cl.[CH3:42][O:43][C:44](=[O:57])[CH2:45][CH2:46][CH2:47][NH:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[CH:51]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@@:9]1([C:12](=[O:14])[N:48]([CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[CH:51]=1)[CH2:47][CH2:46][CH2:45][C:44]([O:43][CH3:42])=[O:57])[CH3:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@]1(C)C(=O)O
Reactant: COC(=O)CCCNCc1cccc(Cl)c1
Agent: CC(C)=C(Cl)N(C)C
Agent: C[C@]1(C(=O)O)CCN1C(=O)c1ccc(Br)cc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)CCCN(Cc1cccc(Cl)c1)C(=O)[C@@]1(C)CCN1C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-2-methyl-azetidine-1,2-dicarboxylic acid 1-tert-butyl ester, Intermediate 33 (13 g, 1 eq.) in 300 mL of dry DCM under nitrogen was added dropwise a solution of 1-chloro-N,N,2-trimethylpropenylamine (16 mL, 2 eq.) in 50 mL of DCM. The solution was stirred at 20° C. for 30 min, then cooled to −5° C. A solution of 4-(3-chloro-benzylamino)-butyric acid methyl ester hydrochloride, Intermediate 80 (18.5 g, 1.1 eq.) and TEA (25 mL, 3 eq.) in 200 mL of DCM was added slowly to the previous mixture. The reaction was stirred at 20° C. for 2.5 h. The mixture was added to 500 mL of a saturated aqueous solution of NaHCO3. The crude was extracted three times with DCM. The organic layers were combined, washed with brine, dried over MgSO4, filtered, concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 90/10 to 50/50) to afford (R)-2-[(3-chloro-benzyl)-(3-methoxycarbonyl-propyl)-carbamoyl]-2-methyl-azetidine-1-carboxylic acid tert-butyl ester (27 g, yield=quantitative).
Reaction SMILES: [CH2:1]([C:7]1[S:11][C:10]([CH:12]=[O:13])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([OH:16])C.[OH-].[Na+]>O.[N+]([O-])([O-])=O.[Ag+]>[CH2:1]([C:7]1[S:11][C:10]([C:12]([OH:16])=[O:13])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(C=O)s1
Reactant: CCO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCc1ccc(C(=O)O)s1
Reaction time: 1.5 h
Yield: 76.6 %

Procedure:
In a 5 liter-four-necked flask, 90.0 g (4.59×10-1 mol) of 5-hexylthiophene-2-carbaldehyde, 540 ml of ethanol and a solution of 171.0 g of AgNO3 in 540 ml of water were placed. A solution of 91.8 g of NaOH in 270 ml of water was added dropwise to the mixture in 30 min. at room temperature, followed by stirring for 1.5 hours. After the reaction, the reaction mixture was subjected to filtration, and the filtrate was acidified with 6N--HCl to precipitate a crystal. The crystal was recovered by filtration to provide a crude product. The product was subjected to recrystallization from 50% hydrous ethanol to obtain 74.5 g of a pure product (yield: 76.6%).