Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([C@H:17]3[CH2:19][C@H:18]3[CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[C:25]([F:33])[CH:24]=3)[CH2:13][CH2:12]2)=[N:9][CH:10]=1)[CH3:2].Cl.[OH:35][CH:36]1[CH2:39][NH:38][CH2:37]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>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][CH2:4][C:5]1[CH:10]=[N:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([C@H:17]3[CH2:19][C@H:18]3[CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][C:30]([N:38]4[CH2:39][CH:36]([OH:35])[CH2:37]4)=[O:31])=[C:25]([F:33])[CH:24]=3)[CH2:13][CH2:12]2)=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)c(F)c3)CC2)nc1
Reactant: OC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)N4CC(O)C4)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(4-{2-[(1S,2R)-2-{1-[5-(ethoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl]ethoxy}-2-fluorophenyl)acetic acid (50, 0.109 mmol) and 3-hydroxy azetidine hydrochloride (11.97 mg, 0.109 mmol) were dissolved in DMF (1 ml) and HATU (83 mg, 0.219 mmol) and DIEA (0.057 ml, 0.328 mmol) added. The mixture was stirred at RT for 2 hr. The mixture was diluted with ethyl acetate (20 mL), washed with brine, dried over MgSO4, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, Biotage 25M, using a gradient eluant of MeOH/DCM (0-10%) to to provide the title compound. LC/MS (m/z): 513 (M+H)+. GPR119 Human EC50: 1.9 nM
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(Cl)(Cl)Cl.[Br:20]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>CCCCCCC>[Br:20][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCCC
Product: COC(=O)C(Br)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 72 %

Procedure:
A 1-L single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1 (10.6 g, 54.1 mmol), carbon tetrachloride (120 mL), N-bromosuccinimide (10.7 g, 59.9 mmol) and azobisisobutylonitrile (275 mg, 1.67 mmol), and the reaction mixture was heated at reflux for 18 h. After this time the reaction was cooled to room temperature and poured into heptane (120 mL). The resulting suspension was filtered and the filter cake washed with heptane (40 mL). The filtrate was concentrated under reduced pressure and the resulting residue was subjected to flash chromatography to afford 2 in 72% yield (10.7 g) as a clear oil: 1H NMR (500 MHz, CDCl3) δ 8.23 (d, 2H, J=9 Hz), 7.74 (d, 2H, J=9.0 Hz), 5.40 (s, 1H), 3.82 (s, 3H); MS (ESI−) m/z 272 (M−H). Reference: Tetrahedron 2002, 58, 10113.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][O:12][C:13]1[CH:30]=[CH:29][C:28]2[C@@H:27]3[C@H:18]([C@@:19]45[CH2:32][C@@H:20]4[CH2:21][C:22](=[O:31])[C@:23]5([CH2:25][CH2:26]3)[CH3:24])[C@H:17]([CH3:33])[CH2:16][C:15]=2[CH:14]=1.I[CH3:35].[Cl-].[NH4+]>O1CCCC1>[CH3:11][O:12][C:13]1[CH:30]=[CH:29][C:28]2[C@@H:27]3[C@H:18]([C@@:19]45[CH2:32][C@@H:20]4[C@@H:21]([CH3:35])[C:22](=[O:31])[C@:23]5([CH2:25][CH2:26]3)[CH3:24])[C@H:17]([CH3:33])[CH2:16][C:15]=2[CH:14]=1
Reactant: CI
Reactant: COc1ccc2c(c1)C[C@@H](C)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)C[C@H]3C[C@@]312
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C[C@@H](C)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)[C@H](C)[C@H]3C[C@]132
Reaction time: 0.5 h

Procedure:
i)—A solution of lithium bis(trimethylsilyl)amide (20.2 mmol) in tetrahydrofuran (35 ml) was cooled to −40° C. A solution of (7α,14β,15β)-3-methoxy-7-methyl-14,15-methyleneestra-1,3,5 (10)-trien-17-one (Example 1, step ii; 5.60 g) in dry tetrahydrofuran (24 ml) was added dropwise and the reaction mixture was stirred for 30 min. Then, at −30° C., iodomethane (2.4 ml) was added and stirring was continued for 45 min. The mixture was poured into a saturated aqueous solution of ammonium chloride and the product was extracted into ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure, to give (7α,14β,15β,16α)-3-methoxy-7,16-dimethyl-14,15-methyleneestra-1,3,5(10)-trien-17-one (5.99 g). The product was used in the following step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:45]=[CH:44][C:16]([CH2:17][CH:18]2[S:22][C:21](=[O:23])[N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:19]2=[O:43])=[CH:15][CH:14]=1.C(O)(=O)C.O>O1CCOCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][CH:18]2[S:22][C:21](=[O:23])[NH:20][C:19]2=[O:43])=[CH:44][CH:45]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)cc2cccnc21
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)cc2cccnc21
Yield: 96.5 %

Procedure:
A procedure similar to that described in Example 12 was repeated, except that the reaction was conducted using 270 mg of 5-[4-(1-methyl-7-azaindol-2-ylmethoxy) -benzyl]-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 82) and 3 ml of a 2:1:3 by volume mixture of acetic acid, water and 1,4-dioxane. After the period allowed for the reaction had elapsed, the reaction mixture was freed from the solvent by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 157 mg of the title compound, melting at 183-185° C.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[C:10](#[N:12])[CH3:11].[H-].[Na+]>C1COCC1>[F:9][C:2]([F:1])([F:8])[C:3](=[O:5])[CH2:11][C:10]#[N:12]
Reactant: CC#N
Reactant: CCOC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)C(F)(F)F
Temperature: 25 °C
Yield: 109.4 %

Procedure:
A solution of ethyl trifluoroacetate (14.2 g, 0.1 mol) and anhydrous acetonitrile (5.0 g, 0.12 mol) in THF (100 mL) was added dropwise to a suspension of NaH (60%, 6.0 g, 0.15 mol) in THF (100 mL) at 80° C. The resulting mixture was heated to reflux overnight, and then cooled to RT. The reaction mixture was concentrated in vacuo and the residue was diluted with EtOAc and 10% aq HCl. The organic layer was washed with water and brine, dried (MgSO4) and concentrated in vacuo to yield crude 4,4,4-Trifluoro-3-oxo-butyronitrile (15 g), which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[C:9](/[CH3:29])=[CH:10]/[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C@H:20]([O:26][CH2:27][CH3:28])[C:21]([O:23]CC)=[O:22])=[CH:15][CH:14]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.[OH-].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4](/[C:9](/[CH3:29])=[CH:10]/[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C@H:20]([O:26][CH2:27][CH3:28])[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2cc(Br)cc(Br)c2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C=C(\C)c2cc(Br)cc(Br)c2)cc1)C(=O)O
Yield: 98 %

Procedure:
The title compound was prepared from (E)-(S)-ethyl 3-{4-[3-(3,5-dibromophenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate (example 117) (840 mg, 1.60 mmol) and sodium hydroxide (1M, 16 ml, 16 mmol) by a procedure analogous to that described in example 51, yielding (E)-(S)-3-{4-[3-(3,5-dibromophenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic acid (781 mg, 98%) as a colourless gum.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-].[Na+].CN(C)[CH:22]=[O:23]>>[CH3:6][N:7]1[C:13]2[CH:14]=[CH:15][C:16]([CH:22]=[O:23])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CN(C)C=O
Reactant: CN1CCCCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCCCc2cc(C=O)ccc21
Temperature: 70 °C
Reaction time: 5 h

Procedure:
45 ml of dimethylformamide were treated under an argon atmosphere with 16.2 ml of phosphorus oxychloride. After the reaction had faded away, 7.30 g of 2,3,4,5-tetrahydro-1-methyl-1H-1-benzazepine were added and the reaction mixture was stirred at 70° C. for 5 hours. Thereafter, the mixture was poured on to ice, made alkaline with sodium hydroxide solution, extracted with ether, washed with water, dried and evaporated. Chromatography on silica gel (petroleum ether/ethyl acetate (87:13)) yielded 4.38 g of 2,3,4,5-tetrahydro-1-methyl-1H-1-benzazepine-7-carboxaldehyde.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:11]=2[CH:24]=1)=[O:6].[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC1C=CC=CC=1C>[O:2]=[C:3]([NH:33][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:12][C:11]=2[CH:24]=1)=[O:6]
Reactant: COC(=O)CC(=O)c1ccc2c(c1)CN(C(=O)OC(C)(C)C)CCO2
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1CCOc2ccc(C(=O)CC(=O)NCc3ccccc3)cc2C1
Temperature: 150 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
A mixture of 1,1-dimethylethyl 7-[3-(methyloxy)-3-oxopropanoyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (300 mg, 0.86 mmol) and benzylamine (92 mg, 0.86 mmol) in o-xylene (3 mL) was stirred at 150° C. for one hour. The reaction mixture was cooled and purified directly by silica gel chromatography (50% ethyl acetate in hexanes) to give 1,1-dimethylethyl 7-{3-oxo-3-[(phenylmethyl)amino]propanoyl}-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (220 mg, 60% yield). MS (EI) for C24H28N2O5: 425 (MH+).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:13])=[CH:4][C:3]=2[O:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][CH:27]([CH3:30])[CH2:28][OH:29]>C(Cl)Cl>[OH:13][C:5]1[CH:4]=[C:3]2[O:2][CH2:1][O:12][C:11]2=[CH:10][C:6]=1[C:7]([NH:26][CH:27]([CH3:30])[CH2:28][OH:29])=[O:9]
Reactant: O=C(O)c1cc2c(cc1O)OCO2
Reactant: CC(N)CO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(CO)NC(=O)c1cc2c(cc1O)OCO2
Yield: 52 %

Procedure:
4,5-Methylenedioxysalicylic acid was activated by carbonyldiimidazole in methylene chloride and combined with 2-amino-1-propanol in essentially an identical manner as for Example 1 above. An acidic quench and subsequent purification by flash chromatography (SiO2) using (1:1) hexane-ethyl acetate gave 2-(2-hydroxy-4,5-methylenedioxybenzamido)-1-propanol as a waxy white solid in 52% yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][OH:29])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:4]([F:30])[CH:3]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][S:39]([CH3:38])(=[O:41])=[O:40])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:4]([F:30])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOCCOc1cc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.9 %

Procedure:
Compound 29a (0.035 gram, 0.076 mmol) was dissolved in dichloromethane (4.3 ml) and triethylamine (0.032 gram, 3.82 mmol) was added to the resulting solution. Methanesulfonyl chloride (MsCl, 0.025 gram, 0.022 mmol) was then added and the resulting mixture was stirred at room temperature for 3 hours. The mixture was thereafter extracted twice with CH2Cl2, washed with brine and dried over sodium sulfate. The crude residue was purified by silica gel column chromatography, using a mixture of 2% methanol in dichloromethane as eluent, to give Compound 32a (0.012 gram, 29% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:22]([O-])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1>C(O)(=O)C.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1)[NH2:22]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2Br)CC1
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2Br)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.7 %

Procedure:
To a solution of 3-bromo-4-(1-t-butoxycarbonylpiperidin-4-yloxy)nitrobenzene (3.1 g) in acetic acid (40 ml) was added zinc powder (10.0 g) in ten portions and the mixture was stirred at room temperature for 5 hours. The reaction mixture was filtered through Celite (trade mark) and the filtrate was extracted with ethyl acetate. The extractant was washed with saturated aqueous potassium carbonate, water and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=1/1 as an eluant to give the desired compound (2.0 g, yield 69%) as a brown amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([O:21][CH3:22])=[CH:15][C:14]=2[O:23][CH3:24])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:25]I>>[CH3:1][C:2]1[N:11]=[C:10]([N:12]([C:13]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([O:21][CH3:22])=[CH:15][C:14]=2[O:23][CH3:24])[CH3:25])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1cc(OC)c(Nc2nc(C)nc3ccccc23)c(OC)c1
Reactant: CI
Product: COc1cc(OC)c(N(C)c2nc(C)nc3ccccc23)c(OC)c1

Procedure:
The title compound was prepared from (2-methyl-quinazolin-4-yl)-(2,4,6-trimethoxy-phenyl)-amine (56 mg, 0.17 mmol) and methyl iodide (0.1 ml, 1.6 mmol) by a procedure similar to example 36. 1H NMR (CDCl3): 7.70 (d, J=8.4 Hz, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.09 (d, J=8.7 Hz, 1H), 6.93 (t, J=8.1 Hz, 1H), 6.18 (s, 2H), 3.86 (s, 3H), 3.63 (s, 6H), 3.44 (s, 3H), 2.70 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:17]([O:22][CH3:23])=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:8]=[C:9]([N+:13]([O-])=O)[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.CO.[Pd]>[C:1]([C:5]1[C:10]([O:11][CH3:12])=[C:9]([NH2:13])[CH:8]=[C:7]([C:16]2[C:17]([O:22][CH3:23])=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ncccc1-c1cc([N+](=O)[O-])c(OC)c(C(C)(C)C)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ncccc1-c1cc(N)c(OC)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
step 2—To a solution of 98 (0.98 g, 3.1 mmol) in EtOAc/MeOH (2:1, 30 mL) was added 10% Pd/C (0.10 g). A stream of hydrogen gas was bubbled through the solution for 20 min then the solution was stirred at RT for 16 h. The reaction mixture was filtered and concentrated to afford 3-tert-butyl-2-methoxy-5-(2-methoxypyridin-3-yl)phenylamine (100).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:8]([N:15]([CH2:17][CH2:18]Cl)[CH3:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])(O)=O.[Na+]>CCO>[CH2:8]([N:15]([CH2:17][CH2:18][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN(CCCl)Cc1ccccc1
Reactant: C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CN(CCN1CCCCC1)Cc1ccccc1
Yield: 58.5 %

Procedure:
A solution of piperdine (1.16 g, 13.6 mmol), the title compound of Step 10 (3.0 g, 13.6 mmol) and NaHCO3 (3.94 g, 46.9 mmol) in EtOH (24 mL) was refluxed overnight in a modification of the procedure of Bach, et al. [J. Am. Chem. Soc., 79, 2221-2225 (1957)]. After filtration, the filtrate was concentrated to a yellow murky oil. The oil was dissolved into a 1.0M KOH solution (10 mL) and was extracted with EtOAc (3×5 mL). The organic layer was washed with a 5% NaHCO3, solution (5 mL), H2O (5 mL), and brine (5 mL) and then was dried over MgSO4. The filtrate was concentrated and purified by medium pressure column chromatography on silica gel [eluting NH4OH-EtOH-CHCl3 (1:5:94)] to give 1.85 g (58% yield) of the title compound as an oil. The proton spectral data were consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[CH3:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:13](=[O:15])[CH3:14])[CH:3]=2)[N:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc2cc(N)ccc2n1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2nc(C)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.9 %

Procedure:
6-amino-2-methylquinoline (1.02 g, 6.45 mmol) was dissolved in pyridine (30 ml), acetic anhydride (0.913 ml, 9.67 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and diisopropyl ether was added thereto for crystallization, to obtain N-(2-methyl-6-quinolinyl)acetamide (1.20 g) as white powders.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: Oc1ccc2sccc2c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc2c(c1)CCS2
Temperature: 55 °C
Reaction time: 24 h
Yield: 46.4 %

Procedure:
To a warm mixture of 5-hydroxy benzothiophene (10.0 g, 66.58 mmole) (Fieser & Kennelly, J. Amer. Chem. Soc., Vol. 57, pp 1611-1614, (1935)) in 100 mL TFA was added triethylsilane (19.35 g, 166.45 mmole, 2.5 eq.) The resulting purple solution was heated to 55° C. under N2 overnight. After 24 hours a sample removed for NMR analysis showed the reaction to be about 80% complete. Much of the original purple color had also been discharged at this point. An additional portion of triethylsilane (3.9 g, 0.5 eq) was added and the heating was continued for another 24 hours. NMR analysis at the 48 hour time point showed virtually no change from the 24 hour time point. Most of the TFA was distilled off under reduced pressure (40 mmHg). The residue was taken up in 300 mL H2O and rendered alkaline (pH=10 to pH paper) with 5N NaOH and washed with ether (2×100 mL). The aqueous phase was acidfied with 2N HCI and extracted with ether (3×200 mL). The combined organic extracts were washed with sodium bicarbonate (1×100 mL), H2O (1×100 mL) and brine (1×100 mL). Drying over Na2SO4 and concentration gave 4.7 g (46.5%) gray solids. Purification by preparative chromatography on a Waters 500A prep HPLC using 2 columns and 90/10 vol/vol hexane/EtOAc to elute afforded 3.0 g (30%) pure material (single spot by TLC analysis) mp 87°-89° C.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][N:8]3[C:12](=[O:18])[CH2:13][NH:14][C:15](=[O:17])[CH2:16][CH:7]3[C:6]=2[N:5]=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([Sn](CCCC)(CCCC)CCCC)=[CH:22][N:21]=1.O1CCOCC1>>[F:19][C:20]1[N:21]=[CH:22][C:23]([C:2]2[C:11]3[CH2:10][CH2:9][N:8]4[C:12](=[O:18])[CH2:13][NH:14][C:15](=[O:17])[CH2:16][CH:7]4[C:6]=3[N:5]=[CH:4][CH:3]=2)=[CH:24][CH:25]=1
Reactant: O=C1CC2c3nccc(Cl)c3CCN2C(=O)CN1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(F)nc1
Solvent: C1COCCO1
Product: O=C1CC2c3nccc(-c4ccc(F)nc4)c3CCN2C(=O)CN1
Temperature: 150 °C
Yield: 39.2 %

Procedure:
94-10. To a degassed solution of 4-chloro-5,6,9,10,12,12a-hexahydro-[1,4]diazepino[1,7-h][1,7]naphthyridine-8,11-dione (66 mg, 0.25 mmol) and 2-fluoro-5-(tributylstannyl)pyridine (120 mg, 0.31 mmol) in dioxane (2 mL) Pd(PPh3)4 (15 mg, 0.012 mmol) was added and the mixture was heated in the microwave at 150° C. for 5 h. The solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera Four, eluent: from 2% MeOH in AcOEt to 20% MeOH in AcOEt in 21 min) to yield the title compound as a beige solid (32 mg). UPLC-MS: MS 327.2 (M+H+); UPLC rt 0.58 min.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([S:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:10]([CH3:19])=[CH:9][C:8]=2[F:20])[N:5]=[C:4]([O:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[CH:3]=1.[Br:30]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([S:13][CH2:14][C:15]([F:16])([F:17])[F:18])[C:10]([CH3:19])=[CH:9][C:8]=2[F:20])[N:5]=[C:4]([O:21][CH2:22][C:23]([F:28])([F:29])[C:24]([F:25])([F:27])[F:26])[C:3]=1[Br:30]
Reactant: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)cc2N)cc1SCC(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)c(Br)c2N)cc1SCC(F)(F)F
Reaction time: 0.17 h
Yield: 85.2 %

Procedure:
2.0 g of 5-amino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole was dissolved in 50 mL of acetonitrile, and 0.8g of N-bromosuccinimide was added under cooling with ice. After stirring for 10minutes under cooling with ice, the solvent was distilled off under reduced pressure, extraction with ethyl acetate was carried out, and the organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 2.0 g of 5-amino-4-bromo 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole.
Reaction SMILES: C(OC1C=CC(C([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[C:24](=[O:47])[C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:46])[CH2:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=4[C:42]([F:45])([F:44])[F:43])=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)=O)=CC=1)CCCCCC.CO.[OH-].[Na+].CC(O)=O>C1COCC1>[OH:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:23]([CH2:48][C:49]([O:51][C:52]([CH3:53])([CH3:54])[CH3:55])=[O:50])[C:24](=[O:47])[C:25]2[CH:26]=[CH:27][C:28]([NH:31][C:32](=[O:46])[CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=3[C:42]([F:44])([F:45])[F:43])=[CH:29][CH:30]=2)=[CH:20][CH:21]=1
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc(NC(=O)Cc4ccc(OC)cc4C(F)(F)F)cc3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(O)cc3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
Prepared using General Procedure 9: To a stirring solution of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-6 (2.53 g, 3.20 mmol) in THF (10 mL) and MeOH (50 mL) was added 2N NaOH (3.2 mL). The reaction mixture was stirred at room temperature for 10 min. The reaction mixture was acidified with AcOH. The crude mixture was concentrated then diluted with DCM (150 mL) and washed with brine (200 mL). The organic layer was concentrated and purified by chromatography (EA/hexanes) to afford 1.64 g (88%) of tert-butyl 2-(N-(4-hydroxybenzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate INT-9. LCMS-ESI (m/z) calculated for C30H31F3N2O6: 572; found 571 [M−H]−, tR=2.30 min. (Method 3).