Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([CH3:48])=[CH:45][C:46]=2[CH3:47])[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([CH3:48])=[CH:45][C:46]=2[CH3:47])[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Reactant: Cc1cc(C)c(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Product: Cc1cc(C)c(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(4,6-dimethyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K32) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as a light brown foam (388 mg, 83%).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH2:13]([O:15][C:16](=[O:22])[CH2:17][O:18][CH2:19][CH:20]=[CH2:21])[CH3:14].[CH:23]([CH:25]=[CH2:26])=[O:24]>C1COCC1>[CH2:13]([O:15][C:16](=[O:22])[CH:17]([O:18][CH2:19][CH:20]=[CH2:21])[CH:23]([OH:24])[CH:25]=[CH2:26])[CH3:14]
Reactant: C=CCOCC(=O)OCC
Reactant: C=CC=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=CCOC(C(=O)OCC)C(O)C=C
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Under an atmosphere of argon, n-BuLi (3 mmol, 1.2 ml, 2.5 M in hexane) was added dropwise to a solution of diisopropylamine (281 mg, 2.78 mmol) in dry THF (20 ml) at −78° C. After stirring for 20-30 min, a solution of allyloxy-acetic acid ethyl ester (200 mg, 1.38 mmol) in THF (4 ml) was added and the mixture was stirred at −78° C. for 10 min. Acrolein (79 mg, 1.38 mmol) was added into the reaction mixture and stirring was maintained until all starting materials were consumed. The reaction was quenched by addition of EtOH (2 ml) and warmed to room temperature. The solution was diluted with EtOAc (60 ml), washed with H2O (20 ml×2), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography with 20% EtOAc-hexane.
Reaction SMILES: [C:1](=[O:6])([O:4][CH3:5])OC.[H-].[Na+].[C:9]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C([O-])(O)=O.[Na+]>C1COCC1>[O:17]=[C:9]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:1]([O:4][CH3:5])=[O:6]
Reactant: COC(=O)OC
Reactant: O=C1CCCCCCC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1CCCCCCC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of dimethyl carbonate (30 mL, 0.36 mol) in dry THF (600 mL) was added sodium hydride (15 g, 0.36 mol) by portion at 5-10° C. The resulting mixture was stirred at this temperature for 30 min and then was added a solution of cyclooctanone (15.0 g, 0.12 mol) in THF (100 mL) dropwise over 30 min. The resultant mixture was stirred at refluxed for 4 h before cooling to room temperature. The reaction mixture was poured into saturated NaHCO3 solution (100 mL) and ice (500 g), and then the mixture was extracted with PE/EA (4:1, 400 mL×2). The organic layer was washed with brine (400 mL), dried over Na2SO4 and concentrated to give crude product. Then the target product (19.3 g, 88%) was purified by distilling at 60° C. in vacuum.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](OB(O)O)=[CH:27][CH:26]=1)[CH3:20].C(N(CC)CC)C>ClCCl>[CH2:19]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:27][CH:26]=1)[CH3:20]
Reactant: CCOCCCc1ccc(OB(O)O)cc1
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCCCc1ccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.4 g), 4-(3-ethoxypropyl)phenylboric acid (0.65 g), cupric acetate (0.27 g) and molecular sieves 4A (0.8 g) suspended in dichloromethane (15 ml) was added triethylamine (1.0 ml), and the resulting mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the filtrate was evaporated to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain methyl 7-[4-(3-ethoxypropyl)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.28 g) as colorless crystals.
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]([C:15]([O:17][CH3:18])=[O:16])[CH:8]([CH3:19])[CH2:7][C:6]2=[O:20].[CH:21](OCC)=[O:22].[O-]CC.[Na+].[H-].[Na+]>C(O)C.C1C=CC=CC=1>[OH:22][CH:21]=[C:7]1[C:6](=[O:20])[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]([C:15]([O:17][CH3:18])=[O:16])[CH:8]1[CH3:19]
Reactant: CCOC=O
Reactant: COC(=O)N1c2cc(OC)c(OC)cc2C(=O)CC1C
Agent: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: COC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CO)C1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methyl 6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline-1-carboxylate (13.8 g.) in 140 ml. of benzene containing 19 ml. of ethyl formate is added to sodium ethoxide freshly prepared from 4.8 g. of sodium hydride and 6 ml. of ethanol over a period of 45 min. After stirring at room temperature for 4 hrs. the reaction mixture is poured onto 250 ml. of ice-water. The aqueous layer is retained and the organic layer washed with 1N aqueous sodium hdyroxide. The washings are combined with the aqueous extracts and backwashed with benzene. The aqueous layer is then made acid with 12N hdyrochloric acid and extracted with chloroform. The organic phase is separated, dried over magnesium sulfate and evaporated in vacuo to dryness. The residue is employed in subsequent reactions without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([OH:19])=O)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O.C(Cl)Cl>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([Cl:23])=[O:19])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cn(Cc2ccccc2)c2ccccc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cn(Cc2ccccc2)c2ccccc12
Yield: 100 %

Procedure:
A mixture of 1-benzyl-1H-indole-3-carboxylic acid (3.36 g, 13.37 mmol), oxalyl chloride (5.83 mL, 66.85 mmol), 100 mL methylene chloride and a catalytic amount of DMF was stirred at room temperature under nitrogen for 18 h (overnight). The solvent was removed under reduced pressure. To remove excess oxalyl chloride benzene was added and the solvent removed under reduced pressure to give 1-benzyl-1H-indole-3-carbonyl chloride as a brown oil (13.37 mmol) which was immediately used in step 2 without additional purification.
Reaction SMILES: ClC1C(N)=CC=CN=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][N:35]=[C:36]=[S:37])[CH2:29][CH2:28]2)=[CH:12][CH:11]=1.[CH2:38]([OH:40])[CH3:39]>>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][NH:35][C:36](=[S:37])[O:40][CH2:38][CH3:39])[CH2:31][CH2:32]2)=[CH:12][CH:11]=1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCN=C=S)CC3)nc3ccccc32)cc1
Reactant: CCO
Agent: Nc1cccnc1Cl
Product: CCOC(=S)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1

Procedure:
A mixture of 1.3 parts of 2-chloro-3-pyridinamine, 4.1 parts of 1-(4-fluorophenylmethyl)-N-[1-(2-isothiocyanatoethyl)-4-piperidinyl]-1H-benzimidazol-2-amine and 80 parts of ethanol was stirred and refluxed overnight. The reaction mixture was evaporated. Water and ammonia were added to the residue and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.4 parts of ethyl [2-[4-[[1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]carbamothioate; mp. 148.6° C. (compound 35).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[S:30][C:29]([CH3:31])=[N:28][C:27]=4[CH3:32])[CH2:23][CH2:22][C:21]([C:33]([O:35]C)=[O:34])=[CH:20][C:19]=3[CH:37]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[S:30][C:29]([CH3:31])=[N:28][C:27]=4[CH3:32])[CH2:23][CH2:22][C:21]([C:33]([OH:35])=[O:34])=[CH:20][C:19]=3[CH:37]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2sc(C)nc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2sc(C)nc2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
In THF (5.0 ml)/methanol (2.5 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(2,4-dimethyl-1,3-thiazol-5-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.25 g). To the solution was added 1N sodium hydroxide solution (2.5 ml), and the mixture was stirred at room temperature for 16 hours. pH was adjusted to approximate with 1N hydrochloric acid, and the solvent was concentrated to half under reduced pressure. The concentrated material was extracted with ethyl acetate/THF, and the extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was washed with hexane/ethyl acetate (8/1) to give 7-(4-(2-butoxyethoxy)phenyl]-1-(2,4-dimethyl-1,3-thiazol-5-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (190 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:19])([C@H:16]([SH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[CH3:20][N:21]([CH3:25])[C:22](Cl)=[S:23].C(N(CC)CC)C>ClCCl>[CH3:20][N:21]([CH3:25])[C:22](=[S:23])[S:18][C@@H:16]([C@:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([OH:19])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)[CH3:17]
Reactant: C[C@@H](S)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CN(C)C(=S)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](SC(=S)N(C)C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 61.3 %

Procedure:
(2R,3R)-2-(2,4-difluorophenyl)-3-mercapto1-[1H-1,2,4-triazol-1-yl]-2-butanol (0.10 g) was allowed to react with N,N-dimethylthiocarbamoyl chloride (0.13 g) in dichloromethane (3.0 ml) in the presence of triethylamine (49 ml) by the same manner as in Example 2. The compound (32), i.e., [(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl] N,N-dimethyldithiocarbamate (0.08 g) was obtained as colorless oil.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([NH:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1.C(N(CC)CC)C.[Br:27][C:28]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:29]=1[C:30](Cl)=[O:31]>C(Cl)Cl>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([N:14]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:30](=[O:31])[C:29]4[CH:33]=[C:34]([N+:37]([O-:39])=[O:38])[CH:35]=[CH:36][C:28]=4[Br:27])=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Br
Reactant: CN(C)CCNc1ccnc2cc3c(cc12)OCO3
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCN(C(=O)c1cc([N+](=O)[O-])ccc1Br)c1ccnc2cc3c(cc12)OCO3

Procedure:
To a solution of compound 7 (259 mg, 1.0 mmol) and triethylamine (0.5 mL) in dry CH2Cl2 (20 mL) was added a solution of 2-bromo-5-nitrobenzoic acid chloride in 20 mL of CH2Cl2 (which was prepared by refluxing of 295 mg, 1.2 mmol of 2-bromo-5-nitrobenzoic acid in 10 mL of thionyl chloride for 3 h.) and reaction mixture was heated to reflux for 4 h. The reaction mixture was washed with saturated NaHCO3 solution, water and brine and dried over Na2SO4. The solvent was removed in vacuo to give a yellow solid; yield 350 mg (71.8%); mp 204–5° C.; 1H NMR (CDCl3) δ (2.3, s, 6H), 2.53–2.64 (m, 2H), 3.67–3.81 (m, 1H), 4.42–4.55 (m, 1H), 6.19 (s, 2H), 7.31 (s, 1H), 7.34 (d, 1H, J=4.8), 7.43 (s, 1H), 7.52 (d, 1H, J=8.8), 7.76 (dd, 1H, J=2.6, 8.4), 7.87 (d, 1H, J=2.6), 8.53 (d, 1H, J=4.8); 13C NMR (CDCl3) δ 45.4, 46.6, 56.4, 97.9, 102.4, 106.6, 119.4, 122.3, 122.8, 124.6, 127.2, 134.0, 139.0, 144.5, 145.9, 148.1, 148.5, 149.6, 151.5, 166.5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][N:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:15][C:16]1[N:17]=[CH:18][C:19]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccc(Cl)nc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Reaction time: 18 h
Yield: 45.7 %

Procedure:
To a mixture of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (15.5 g, 77 mmol), 2-Chloro-5-hydroxy-pyridine (9.9 g, 77 mmol) and triphenylphosphine (24.24 g, 92.4 mmol) in THF, diisopropylazodicarboxylate (18.6 g, 92.4 mmol) was added at 0° C. and stirred for 18 h. The reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was concentrated in vacuo, resulting residue was purified by flash column chromatography to give tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (11 g, 45%); MS: 335.2 (M+23).
Reaction SMILES: Br[C:2]1[C:3]([O:16][CH3:17])=[C:4]([C:14]#[N:15])[C:5](=[O:13])[N:6]([CH:8]([CH:10]2[CH2:12][CH2:11]2)[CH3:9])[CH:7]=1.[CH3:18][N:19]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[N:20]1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH:10]1([CH:8]([N:6]2[CH:7]=[C:2]([C:21]3[CH:22]=[CH:23][N:19]([CH3:18])[N:20]=3)[C:3]([O:16][CH3:17])=[C:4]([C:14]#[N:15])[C:5]2=[O:13])[CH3:9])[CH2:12][CH2:11]1
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: COc1c(Br)cn(C(C)C2CC2)c(=O)c1C#N
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+]
Solvent: O
Solvent: COCCOC
Product: COc1c(-c2ccn(C)n2)cn(C(C)C2CC2)c(=O)c1C#N
Temperature: 100 °C
Yield: 39.2 %

Procedure:
A mixture of 5-bromo-1-(1-cyclopropylethyl)-4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step B of Example 163 (66 mg), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (69 mg), tetrakis(triphenylphosphine)palladium(0) (26 mg), aqueous sodium carbonate solution (2 M, 0.666 mL) and 1,2-dimethoxyethane (3.0 mL) was heated with microwave irradiation at 100° C. for 1 hr under argon atmosphere. The reaction mixture was cooled to room temperature, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and then silica gel column chromatography (basic silica gel, hexane/ethyl acetate) to give the title compound (26 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][S:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[OH:30]OS([O-])=O.[K+]>CO.O>[C:1]([O:5][C:6](=[O:29])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][S:12](=[O:30])[CH:11]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:20]=2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S([O-])OO
Reactant: CC(C)(C)OC(=O)CCN1CCSC(c2ccc(OCc3ccccc3)cc2)C1
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)CCN1CCS(=O)C(c2ccc(OCc3ccccc3)cc2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[2-(4-benzyloxy-phenyl)-thiomorpholin-4-yl]-propionic acid tert-butyl ester (0.85 g; 1.77 mmol) in MeOH (25 mL) was added dropwise a solution of Oxone® (0.54 g; 0.89 mmol) in water (25 mL), at 0° C. The resulting mixture was stirred for 2 hours at 0° C., and subsequently, overnight at RT. The resulting mixture was treated with water and a 25% aqueous solution of NH4OH, and extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2/MeOH 97.5:2.5) to afford 3-[2-(4-benzyloxy-phenyl)-1-oxo-thiomorpholin-4-yl]-propionic acid tert-butyl ester (0.65 g).
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:27])[CH2:6][O:7][C:8]([CH3:26])([CH3:25])[C:9]#[C:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH:14]=[CH:15][C:16]=1[CH3:17]>O1CCOCC1.O>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:13]2[CH:14]=[CH:15][C:16]([CH3:17])=[C:11]([C:10]#[C:9][C:8]([CH3:26])([CH3:25])[O:7][CH2:6][C:5]([OH:27])=[O:4])[CH:12]=2)=[CH:23][CH:22]=1
Reactant: COC(=O)COC(C)(C)C#Cc1cc(-c2ccc(Cl)cc2)ccc1C
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1C#CC(C)(C)OCC(=O)O
Temperature: 20 °C
Reaction time: 4 h
Yield: 69.8 %

Procedure:
Potassium hydroxide (1.105 g, 19.7 mmol) is added to a solution of [3-(4′-chloro-4-methyl-biphenyl-3-yl)-1,1-dimethylprop-2-ynyloxy]acetic acid methyl ester (6.7 g, 18.8 mmol) in dioxane (20 ml) and water (20 ml). After stirring for four hours at 20° C., the reaction mixture is extracted twice with dichloromethane. The aqueous layer is acidified at 0° C. to pH 2-3 using 1N aqueous hydrochloric acid and extracted twice with ethyl acetate. The combined organic extracts are dried over anhydrous sodium sulfate, filtered and the filtrate evaporated in vacuo. The residue is stirred in hexane and filtered to afford [3-(4′-chloro-4-methylbiphenyl-3-yl)-1,1-dimethylprop-2-ynyloxy]acetic acid (4.50 g) as a white solid (m.p. 125° C.).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[S:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1.[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>>[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:6]1[S:5][CH:9]=[CH:8][CH:7]=1)=[O:16]
Reactant: c1ccsc1
Reactant: O=C(Cl)CCCCCl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCCCl)c1cccs1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
16 g (0.120 mol) of aluminium chloride are introduced portionwise over 15 min into a solution, maintained at about +5°, of 20.2 g (0.240 mol) of thiophene and 15.5 g (0.100 mol) of 5-chlorovaleryl chloride and the mixture is stirred for 5 h at room temperature. After removal of the supernatant by means of separating the phases by settling, the reaction medium is taken up in 120 ml of 3N hydrochloric acid solution and extracted with chloroform.
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[CH2:22]([O:24][C:25]([C:27]1[CH:28]=[CH:29][C:30]([C:37]2[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[C:39]([O:45][CH3:46])[CH:38]=2)=[C:31]2[C:36]=1[N:35]=[CH:34][CH:33]=[CH:32]2)=[O:26])[CH3:23]>CC#N>[CH2:22]([O:24][C:25]([C:27]1[CH:28]=[CH:29][C:30]([C:37]2[CH:38]=[C:39]([O:45][CH3:46])[CH:40]=[C:41]([O:43][CH3:44])[C:42]=2[F:21])=[C:31]2[C:36]=1[N:35]=[CH:34][CH:33]=[CH:32]2)=[O:26])[CH3:23]
Reactant: CCOC(=O)c1ccc(-c2cc(OC)cc(OC)c2)c2cccnc12
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CCOC(=O)c1ccc(-c2cc(OC)cc(OC)c2F)c2cccnc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 34.4 %

Procedure:
SelectFluor (2.04 g, 5.8 mmol, 2 equiv) was added to a cold (−5° C.) solution of 5-(3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid ethyl ester (Step 174.2) (970 mg, 2.9 mmol) in CH3CN (40 mL), under an argon atmosphere. The reaction mixture was allowed to warm to rt, stirred at that temperature for 6 h, quenched by addition of a saturated aqueous solution of NaHCO3, and concentrated. The residue was diluted in EtOAc and a saturated aqueous solution of NaHCO3. The aqueous phase was separated and extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (Hex/EtOAc, 3:2) followed by trituration in Et2O to provide 355 mg of the title compound: ESI-MS: 356.2 [M+H]+; tR=3.80 min (System 1); TLC: Rf=0.18 (Hex/EtOAc, 3:2).
Reaction SMILES: [Li+].CCC[CH2-].C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[CH:20](OCC)=[O:21]>C1COCC1>[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH:20]=[O:21]
Reactant: Clc1cccnc1
Reactant: CCOC=O
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1ccncc1Cl
Temperature: -70 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
THF (200 mL) is chilled to −70° C. in a dry flask under N2, and N-butyllithium (24.4 mL, 55.0 mmol) is added drop-wise. The reaction is placed in an ice bath and diisopropyl amine (7.71 mL, 55.0 mmol) in THF (20 mL) is added drop-wise. The solution is again chilled to −70° C., and 3-chloropyridine (4.75 mL, 50.0 mmol) in THF (20 mL) is added drop-wise. The reaction is allowed to stir for 4 h at −70° C. and ethyl formate (4.44 mL, 55.0 mmol) in THF (20 mL) is added. The reaction is stirred for an additional 3 h at −70° C. and quenched with H2O (500 mL). The layers are allowed to separate, and the aqueous layer is extracted with EtOAc (3×250 mL). The combined organic layer is dried over MgSO4, filtered, and concentrated to a dark brown solid. The crude material is chromatographed over 250 g slurry-packed silica, eluting with 50% EtOAc/hexane. The fractions with the desired compound are collected and concentrated to give 3-chloroisonicotinaldehyde (C120) as an off-white solid (55% yield). MS (EI) for C6H4ClNO, m/z: 141 (M)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[Br:19][C:20]1[S:24][C:23]([S:25](Cl)(=[O:27])=[O:26])=[CH:22][CH:21]=1>>[Br:19][C:20]1[S:24][C:23]([S:25]([NH:18][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:7]([F:8])[C:6]=2[NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])(=[O:27])=[O:26])=[CH:22][CH:21]=1
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Product: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)c1ccc(Br)s1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with 5-bromothiophene-2-sulfonyl chloride to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ 7.39-7.29 (m, 2H), 7.20-7.05 (m, 3H), 6.96 (d, J=3.6 Hz, 1H), 5.85 (dt, J=2.1, 9.0 & 17.4 Hz, 1H), 5.54 (br s, 1H).