Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[C:10]1([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccco1
Reactant: Brc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: c1ccc(-c2ccco2)cc1
Temperature: 95 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
To a solution of (furan-2-yl)boronic acid (3.0 g, 26.81 mmol) in dioxane (50.0 mL) and water (1.0 mL) was added bromobenzene (2.10 g, 13.38 mmol), K3PO4 (9.3 g, 43.81 mmol) and Pd(PPh3)4 (767 mg, 0.66 mmol) with stirring for 3 h at 95° C. in an oil bath under an inert atmosphere of nitrogen. The reaction mixture was concentrated under reduced pressure to give the residue, which was purified by silica gel column chromatography (1% ethyl acetate in petroleum ether) to afford 2-phenylfuran as colorless oil (1.20 g, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:4]=1[O:5][CH2:6][C:7]([N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:9])[CH3:8]>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:18]=[C:17]([CH:16]=[CH:15][C:4]=1[O:5][CH2:6][C:7]([CH3:9])([N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)[CH3:8])[NH2:19]
Reactant: COc1cc([N+](=O)[O-])ccc1OCC(C)(C)N1CCCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(N)ccc1OCC(C)(C)N1CCCC1
Reaction time: 18 h
Yield: 93.5 %

Procedure:
1-[2-(2-Methoxy-4-nitrophenoxy)-1,1-dimethylethyl]pyrrolidine (0.075 g, 0.2551 mmol) was dissolved in EtOAc (10 mL). 10% Pd/C (0.007 g) was added and the reaction hydrogenated under 1 atm of H2. The reaction was stirred for 18 h, filtered through celite and the celite washed with EtOAc (3×30 mL). The combined organics were concentrated to afford 0.063 g (0.2386 mmol, 93%) of the product. 1H NMR (CDCl3) δ 6.80 (d, 1H, J=8.4 Hz), 6.22 (s, 1H), 6.18 (d, 1H, J=8.3 Hz), 3.78 (s, 3H), 3.50 (bs, 2H), 2.68 (bs, 6H), 1.78 (bs, 4H), 1.22 (s, 6H).
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[CH3:5][C:6]1[CH:26]=[CH:25][C:9]([C:10]([C:12]2[C:20]3[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=[C:14]([CH2:21][C:22](Cl)=[O:23])[CH:13]=2)=[S:11])=[CH:8][CH:7]=1>C(#N)C.C(N(CC)CC)C>[CH3:5][C:6]1[CH:26]=[CH:25][C:9]([C:10]([C:12]2[C:20]3[O:19][CH:18]=[CH:17][C:16]=3[CH:15]=[C:14]([CH2:21][C:22]([O:4][CH2:1][CH:2]=[CH2:3])=[O:23])[CH:13]=2)=[S:11])=[CH:8][CH:7]=1
Reactant: Cc1ccc(C(=S)c2cc(CC(=O)Cl)cc3c2OCC3)cc1
Reactant: C=CCO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CCOC(=O)Cc1cc(C(=S)c2ccc(C)cc2)c2occc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Allyl alcohol (2.0 ml) was added to a solution of 7-(4-methylthiobenzoyl)-2,3-dihydrobenzofuran-5-ylacetyl chloride (2.0 g) in acetonitrile (100 ml) and triethylamine (2.0 ml). This solution was stirred at room temperature for 12 hours. The solvent was then evaporated to dryness and the residue was taken up in a solution of ethyl acetate/water, washed 3 times with water, the ethyl acetate dried and evaporated to dryness after which the residue was purified by chromatography.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:15])=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[N+:16]([O-])([O-:18])=[O:17].[K+]>>[Cl:1][C:2]1[C:3]([F:15])=[C:4]2[C:9]([NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2)=[C:10]([N+:16]([O-:18])=[O:17])[C:11]=1[F:12]
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2cc(F)c(Cl)c(F)c2[nH]c1=O
Agent: [K+]
Product: O=c1[nH]c2c(F)c(Cl)c(F)c([N+](=O)[O-])c2[nH]c1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 57.4 %

Procedure:
To a solution of 120 mg (5.16 mmol) of 6-chloro-5,7-difluoro-1,4-dihydroquinoxaline-2,3-dione in 1 mL of H2S4 (97%) kept in an ice bath was added portionwise 60 mg (0.59 mmol) of KNO3. The solution was stirred at room temperature for 14 h and 60 mg of KNO3 was added. It was stirred at room temperature for 24 h, then diluted with ice-water (4 mL), filtered, washed with water, and dried to leave a yellow solid (94 mg, 65%). The solid was purified by NaOH/HCl precipitation to leave 63 mg of yellow solid; mp>250° C.; 1H NMR (DMSO-d6), 12.11 (mb, 1), 12.503 (s, 1).
Reaction SMILES: [CH3:1][N:2]1[C:7](=O)[CH2:6][CH2:5][C:4]([N+:15]([O-:17])=[O:16])([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH2:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:7](=[S:27])[CH2:6][CH2:5][C:4]([N+:15]([O-:17])=[O:16])([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH2:3]1
Reactant: CN1CC(c2ccncc2)([N+](=O)[O-])CCC1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CN1CC(c2ccncc2)([N+](=O)[O-])CCC1=S
Temperature: 80 °C
Yield: 78.7 %

Procedure:
To a solution of 125 mg (0.531 mmol) rac-1-Methyl-3-nitro-2,3,4,5-tetrahydro-1H-[3,4]bipyridinyl-6-one in 2.5 ml toluene were added 240 mg (0.584 mmol) Lawesson reagent. The suspension was heated in a 80° C. oil bath for 30 minutes. The mixture was concentrated in vacuo. The crude oil was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 105 mg (79%) of the title compound as a light yellow solid. MS (m/e): 252.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[CH:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:30]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:26][CH3:30])[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[CH:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: C#CCOc1ccc(CCNC(=O)C(O)c2ccc(Cl)cc2)cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOc1ccc(CCNC(=O)C(OC)c2ccc(Cl)cc2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(4-Chloro-phenyl)-2-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-acetamide (2.6 g, 7.0 mmol) is dissolved in N,N-dimethylformamide (30 ml). Sodium hydride (0.18 g, 7.5 mmol) is added in portions at +5° C. The mixture is stirred for 30 minutes at room temperature. Subsequently iodomethane (1.1 g, 7.5 mmol) is added dropwise and the resulting mixture is stirred for further 3 hours at room temperature. The reaction mixture is poured on ice/water (200 ml) and extracted with ethyl acetate (2×200 ml). The combined organic layer is washed with brine (200 ml) and dried over magnesium sulfate. After evaporation of the solvent, the residue is purified by chromatography (ethyl acetate/hexane) to yield 2-(4-chloro-phenyl)-2-methoxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-acetamide. 1H-NMR (300 MHz, CDCl3): 2.53 (t, 1H, C≡CH), 2.80 (t, 2H, CH2CH2), 3.34 (s, 3H, OCH3), 3.55 (t, 2H, CH2CH2), 3.84 (s, 3H, OCH3), 4.58 (s, 1H, CHOH), 4.79 (m, 2H, OCH2), 6.68-7.34 (m, 8H, CH arom., NH).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][C:12]=2[CH3:34])=[O:10])[C@H:4]([F:35])[CH2:3]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][C:12]=2[CH3:34])=[O:10])[C@H:4]([F:35])[CH2:3]1)(=[O:38])[CH3:37]
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CC[C@@H](N)C[C@H]1F
Reactant: CC(=O)Cl
Product: CC(=O)N[C@@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)[C@H](F)C1

Procedure:
Starting from N-[(1R*,2R*,4R*)-4-amino-2-fluorocyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (example D.f67) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: FC(F)(F)C(O)=O.ClC1C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)=C2N=C(C3C=CC(CN4CCOCC4)=CC=3)NC2=NC=1.[NH2:42][C:43]1[C:48]([NH2:49])=[C:47]([NH:50][C@@H:51]2[C@@H:56]3[CH2:57][C@@H:53]([CH:54]=[CH:55]3)[C@@H:52]2[C:58]([NH2:60])=[O:59])[C:46]([Cl:61])=[CH:45][N:44]=1.[CH3:62][O:63][C:64]1[CH:71]=[C:70]([O:72][C:73]([F:76])([F:75])[F:74])[CH:69]=[CH:68][C:65]=1[CH:66]=O>>[Cl:61][C:46]1[C:47]([NH:50][C@@H:51]2[C@@H:56]3[CH2:57][C@@H:53]([CH:54]=[CH:55]3)[C@@H:52]2[C:58]([NH2:60])=[O:59])=[C:48]2[N:49]=[C:66]([C:65]3[CH:68]=[CH:69][C:70]([O:72][C:73]([F:74])([F:75])[F:76])=[CH:71][C:64]=3[O:63][CH3:62])[NH:42][C:43]2=[N:44][CH:45]=1
Reactant: COc1cc(OC(F)(F)F)ccc1C=O
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC(F)(F)F)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 60 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 2-Methoxy-4-trifluoromethoxy-benzaldehyde were reacted to produce the title compound (60%). 1H NMR (d-chloroform): 13.94 (br s, 1H), 8.31 (d, J=9 Hz, 1H), 8.20 (d, J=9 Hz, 1H), 7.83 (s, 1H), 6.97 (d, J=9 Hz, 1H), 6.82 (s, 1H), 6.44 (m, 2H), 6.24 (s, 1H), 5.82 (s, 1H), 5.35 (d, J=9 Hz, 1H), 4.11 (s, 3H), 3.17 (s, 1H), 2.97 (s, 1H), 2.74 (d, J=8 Hz, 1H), 2.31 (d, J=9 Hz, 1H), 1.65 (d, J=9 Hz, 1H). MS: 495.00 (M+H). HPLC retention time: 3.12 minutes (G Method).
Reaction SMILES: [C:1]([N:9]([CH2:20][CH2:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:35].CCOC(C)=O>CCOC(C)=O.CCCCCC>[ClH:35].[NH2:12][CH2:11][CH2:10][N:9]([CH2:20][CH2:21][CH:22]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCN(CCC(c1ccccc1)c1ccccc1)C(=O)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: NCCN(CCC(c1ccccc1)c1ccccc1)C(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a suspension of tert-butyl {2-[benzoyl-(3,3-diphenylpropyl)amino]ethyl}carbamate (225 mg) in EtOAc (675 μL) was added 4M HCl/EtOAc (1.23 mL) at ambient temperature and the mixture was stirred at the same temperature for 1 hour. The resulting mixture was diluted with n-hexane (5.0 mL) and the precipitate was collected by filtration followed by washing with n-hexane (10 mL) to afford N-(2-aminoethyl)-N-(3,3-diphenylpropyl)benzamide hydrochloride (166 mg) as colorless crystals.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][C:5]([CH:34]([C:36]2[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][CH:37]=2)[CH3:35])=[CH:4][N:3]=1.[NH2:46][C:47]1[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[N:51][CH:52]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.C(Cl)Cl>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:15]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:10]2[N:9]=[C:8]([C:7]3[C:2]([NH:46][C:47]4[CH:52]=[N:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=4)=[N:3][CH:4]=[C:5]([CH:34]([C:36]4[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:43])=[O:44])=[CH:38][CH:37]=4)[CH3:35])[CH:6]=3)[N:13]=[C:12]([CH3:14])[N:11]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(N)cn1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)c4ccc(S(C)(=O)=O)cc4)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)c4ccc(S(C)(=O)=O)cc4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 51.5 %

Procedure:
4-(2-Fluoro-5-(1-(4-(methylsulfonyl)phenyl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (764.7 mg, 1.218 mmol) and 5-amino-2-methoxypyridine (162.9 mg, 1.312 mmol) were dissolved in THF (12 mL) and the flask was cooled in an ice water bath while being stirred under nitrogen. Then, lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran/ethyl benzene, 3.6 mL, 3.6 mmol) was added via syringe, and the reaction was stirred at 0° C. After 40 min, the reaction was treated with ice water (1.5 mL), diluted with DCM, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (150 mL fritted funnel with about 2 inches of silica gel; DCM to 100:1 DCM/MeOH to 75:1 DCM/MeOH to 40:1 DCM/MeOH). The fractions with product were collected, concentrated, and dried under high vacuum in a water bath (about 40° C.) to give N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)phenyl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (459.4 mg). 1H NMR (CDCl3, 400 MHz) δ 11.57 (s, 1H), 8.65 (d, J=2.35 Hz, 1H), 8.25 (d, J=2.35 Hz, 1H), 8.14 (d, J=2.35 Hz, 1H), 7.89 (dd, J=8.71 Hz, 2.45 Hz, 1H), 7.81 (d, J=8.22 Hz, 2H), 7.40 (d, J=8.02 Hz, 2H), 7.24-7.14 (m, 4H), 6.90-6.81 (m, 4H), 6.70 (d, J=8.80 Hz, 1H), 4.87 (d, J=4.89 Hz, 2H), 4.77 (d, J=5.09 Hz, 2H), 4.23-4.16 (m, 1H), 3.92 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H), 2.98 (s, 3H), 2.57 (s, 3H), 1.66 (d, J=7.24 Hz, 3H). m/z (ESI, pos. ion) 732 (M+H)+.
Reaction SMILES: C([O:5][C:6]1[CH:15]=[C:14]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])[CH2:19][CH2:18]2)[C:13]2[C:8](=[C:9]([NH:46][CH2:47][CH2:48][O:49][CH3:50])[CH:10]=[C:11]([C:30]([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=3)([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)O)[CH:12]=2)[N:7]=1)(C)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH:30]([C:39]2[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=2)[C:11]2[CH:12]=[C:13]3[C:8](=[C:9]([NH:46][CH2:47][CH2:48][O:49][CH3:50])[CH:10]=2)[NH:7][C:6](=[O:5])[CH:15]=[C:14]3[NH:16][CH:17]2[CH2:22][CH2:21][N:20]([S:23]([C:26]([F:29])([F:27])[F:28])(=[O:25])=[O:24])[CH2:19][CH2:18]2)=[CH:33][CH:34]=1
Reactant: COCCNc1cc(C(O)(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc2c(NC3CCN(S(=O)(=O)C(F)(F)F)CC3)cc(OC(C)(C)C)nc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCNc1cc(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc2c(NC3CCN(S(=O)(=O)C(F)(F)F)CC3)cc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To solution of (2-(tert-butoxy)-8-((2-methoxyethyl)amino)-4-((1-((trifluoromethyl) sulfonyl)piperidin-4-yl)amino)quinolin-6-yl)bis(4-chlorophenyl)methanol (12 mg, 0.0159 mmol) and triethylsilane (0.0152 mL, 0.0953 mmol) in CH2Cl2 (1 mL) was added slowly TFA (0.03 mL, 0.392 mmol). The resulting mixture was stirred for 4 hr at room temperature. The reaction was diluted with CH2Cl2 and washed with Na2CO3 to make the aqueous layer basic. The organics were washed with water, dried over anhydrous Na2SO4 and concentrated. The resulting residue was triturated from Et2O/hexanes (1:3) to yield 6-(bis(4-chlorophenyl)methyl)-8-((2-methoxyethyl)amino)-4-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)quinolin-2(1H)-one.
Reaction SMILES: [Cl:1]C1C(C(F)(F)F)=CC=CC=1CNCC(C1C=CC=CC=1Cl)C.Cl[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]([CH3:61])[CH2:32][N:33]([CH2:46][CH2:47][CH2:48][O:49][C:50]1[CH2:51][C:52](=[CH:56][C:57]([O:59][CH3:60])=[O:58])[CH:53]=[CH:54][CH:55]=1)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[C:36]=1[Cl:45]>>[Cl:1][C:30]1[CH:25]=[C:26]([CH:31]([CH3:61])[CH2:32][N:33]([CH2:46][CH2:47][CH2:48][O:49][C:50]2[CH2:51][C:52](=[CH:56][C:57]([O:59][CH3:60])=[O:58])[CH:53]=[CH:54][CH:55]=2)[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[C:36]=2[Cl:45])[CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)C=C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(C)c2ccccc2Cl)C1
Reactant: CC(CNCc1cccc(C(F)(F)F)c1Cl)c1ccccc1Cl
Product: COC(=O)C=C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(C)c2cccc(Cl)c2)C1
Yield: 49 %

Procedure:
The titled compound was prepared from N-(2-Chloro-3-trifluoromethylbenzyl)-2-(2-chlorophenyl)propylamine in 49% yield in the same manner as the preparation of N-(2-[2-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylamine in Example 184f. MS (ESI) 568 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([OH:27])=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[CH:12][C:11]([CH3:28])=[C:10]([CH3:29])[N:9]=2)[S:5][C:6]=1[CH3:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][OH:39]>CN(C)C=O>[CH3:1][C:2]1[N:3]=[C:4]([C:8]2[C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:27][CH2:37][CH2:38][OH:39])=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[CH:12][C:11]([CH3:28])=[C:10]([CH3:29])[N:9]=2)[S:5][C:6]=1[CH3:7]
Reactant: OCCBr
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3nc(C)c(C)s3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3nc(C)c(C)s3)ccnc2cc1OCCO
Temperature: 70 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
4-[2-(4,5-Dimethyl-thiazol-2-yl)-5,6-dimethyl-pyridin-3-yloxy]-6-methoxy-quinolin-7-ol (compound 455) (41 mg) was suspended in N,N-dimethylformamide (2 ml). Potassium carbonate (42 mg) and 2-bromoethanol (0.02 ml) were added to the suspension, and the mixture was stirred at 70° C. overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (47 mg, yield 100%).
Reaction SMILES: O.[Cl:2][C:3]1[CH:26]=[C:25]([F:27])[C:24]([N:28]2[C:33](=[O:34])[CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[N:30]([CH3:39])[C:29]2=[O:40])=[CH:23][C:4]=1[O:5][C:6]1[N:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([N+:20]([O-])=O)=[CH:8][CH:7]=1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:20][C:9]1[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:11][C:6]([O:5][C:4]2[CH:23]=[C:24]([N:28]3[C:33](=[O:34])[CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[N:30]([CH3:39])[C:29]3=[O:40])[C:25]([F:27])=[CH:26][C:3]=2[Cl:2])=[CH:7][CH:8]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc([N+](=O)[O-])c(OCc4ccccc4)n3)c(Cl)cc2F)c1=O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc(N)c(OCc4ccccc4)n3)c(Cl)cc2F)c1=O
Temperature: 35 °C
Yield: 89.7 %

Procedure:
To a mixed solution of 3.0 g of an iron powder, 15 ml of acetic acid and 1.5 ml of water was added a solution of 3.0 g of 6-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-benzyloxy-3-nitropyridine in 10 ml of acetic acid and 10 ml of ethyl acetate dropwise while maintaining the temperature of the reaction solution at 35° C. or lower. After completion of the addition, the mixture was stirred over night, then, the reaction solution was filtrated through Celite, and the solvent was removed at reduced pressure. The residue was diluted with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The resulted residue was subjected to silica gel chromatography to obtain 2.55 g of 3-amino-6-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-benzyloxypyridine
Reaction SMILES: C[C:2]1[C:3](=[CH:7][C:8](=[CH:12][CH:13]=1)[N:9]=[C:10]=[O:11])[N:4]=[C:5]=[O:6].[C:14]([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>C(C(CCCC)CO)C>[CH3:14][C:7]1[C:3]([N:4]=[C:5]=[O:6])=[CH:2][CH:13]=[CH:12][C:8]=1[N:9]=[C:10]=[O:11]
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Reactant: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCCCC(CC)CO
Product: Cc1c(N=C=O)cccc1N=C=O

Procedure:
In another reactor, a fully blocked diurethane of 80/20 2,4/2,6-toluene diisocyanate mixture was prepared by slowly adding 87.1 parts of 80/20 toluene diisocyanate to 142 parts of 2-ethylhexanol containing 1 drop of dibutyl tin dilaurate with external cooling to maintain the reaction mixture below 100°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:12]1[CH2:16][CH2:15][C@@H:14]([OH:17])[CH2:13]1.Cl[Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:12]1[CH2:16][CH2:15][C@@H:14]([O:17][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH2:13]1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COc1cc([N+](=O)[O-])ccc1N1CC[C@@H](O)C1
Solvent: c1ccncc1
Product: COc1cc([N+](=O)[O-])ccc1N1CC[C@@H](O[Si](C(C)C)(C(C)C)C(C)C)C1
Temperature: 0 °C
Yield: 99.4 %

Procedure:
Dissolve the crude (R)-1-(2-methoxy-4-nitro-phenyl)-pyrrolidin-3-ol (10.9 g, 45.5 mmol) in dry pyridine (50 mL) and chill to 0° C. Add chloro-triisopropyl-silane (19.8 mL, 91 mmol) dropwise and then heat to 80° C. overnight. Remove the pyridine via reduced pressure and then wash the crude material with NaHSO3 solution and extract with EtOAc (3×100 mL). Combine the organic solutions, then dry and concentrate to give the crude product. Purify over a silica plug with hexanes (300 mL) and flush with 10% EtOAc in hexanes (800 mL) to give the title compound as a reddish oil (17.85 g, 99%). MS/ES m/z 395.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24](/[CH:28]=[CH:29]/[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=3)[CH:23]=2)=[O:20])=[CH:14][C:13]=1[O:37][CH3:38])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.C(O)(=O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=3)[CH:23]=2)=[O:20])=[CH:14][C:13]=1[O:37][CH3:38])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(CC(=O)Nc2cccc(/C=C/c3cccc(C)c3)c2)ccc1OCCNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(CC(=O)Nc2cccc(CCc3cccc(C)c3)c2)ccc1OCCNC(=O)OC(C)(C)C
Yield: 79.7 %

Procedure:
4-[2-(tert-Butoxycarbonylamino)ethoxy]-3-methoxy-N-[3-[(E)-2-(3-methylphenyl)vinyl]phenyl]phenylacetamide (100 mg) is dissolved in methanol (10 ml) and acetic acid (1 ml), and thereto is added 10% palladium on carbon (10 mg), and the mixture is subjected to catalytic hydrogenation at 50° C. The catalyst is removed by filtration, and the solvent is evaporated to give 4-[2-(tert-butoxycarbonylamino)ethoxy]-3-methoxy-N-[3-[2-(3-methylphenyl)ethyl]phenyl]phenylacetamide (80 mg). This product is treated with 10% hydrogen chloride-methanol to give the desired compound (50 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([CH3:12])[C:7]([O:9]CC)=[O:8].[OH-].[Na+]>CO>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([CH3:12])[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(C)c1nccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)O)c1nccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a solution of 0.26 g (1.5 mmol) of ethyl 2-(1,3-thiazol-2-yl)propanoate from step A above in 15 mL of methanol was added 3.0 mL (15 mmol) of an aqueous 5.0 M sodium hydroxide solution. The resulting mixture was stirred at ambient temperature overnight. The reaction mixture was evaporated in vacuo to remove the methanol and the aqueous phase was acidified with a 2 N hydrochloric acid solution until a pH of 4 was achieved. The aqueous solution was purified by reverse phase HPLC (TMC Pro-Pac C18; 0-25% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). The pure fractions were lyophilized overnight to afford the title compound as a white solid (0.17 g, 71%). LC-MS: m/z (ES) 158 (MH)+.