Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])O.[Na+].[CH:6]1([N:12]([CH3:19])[CH2:13][CH2:14][C:15]([CH3:18])([NH2:17])[CH3:16])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C1COCC1.[C:25](ON1C(=O)CCC1=O)([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>O>[CH:6]1([N:12]([CH3:19])[CH2:13][CH2:14][C:15]([NH:17][C:25](=[O:26])[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([CH3:16])[CH3:18])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CN(CCC(C)(C)N)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(CCC(C)(C)NC(=O)OCc1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.9 %

Procedure:
Sodium hydrogen carbonate (15.0 g, 0.18 mol) dissolved in water (200 mL) was added to reaction containing crude N1-cyclohexyl-N1,3-dimethylbutane-1,3-diamine (14.0 g, 46.1 mmol) was dissolved into THF (200 mL). CbzOSu (11.0 g, 1 equiv, 44.2 mmol) was added in one portion to the reaction and left to stir at room temperature for 16 h. The organic solvent was removed and the aqueous residue was extracted with DCM (3×150 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a pale yellow oil (12.7 g). The crude oil was purified on an ISCO purification system with gradient elution from 20-100% ethyl acetate then1-10% methanol in ethyl acetate. The desired fraction was collected and concentrated to give a colorless oil (5.27 g, yield: 34.4%). 1H NMR (CDCl3, 400 MHz): δ 1.0-1.49 (m, 5H), 1.37 (s, 6H), 1.55 (t, 2H), 1.6-1.64 (m, 1H), 1.76 (bs, 4H), 2.21 (s, 3H), 2.32-2.4 (m, 1H), 2.60 (t, 2H), 5.03 (s, 2H), 7.2-7.4 (m, 5H), 7.96 (s, 1H). LRMS (ESI+) for C20H32N2O2 (332.3); Found: 333 (MH+).
Reaction SMILES: Cl.C(OC(=O)[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:46])/[CH:17]=[CH:18]/[C:19]1[CH:20]=[N:21][C:22]([CH:25]([C:36](=[O:45])[NH:37][C:38]2[CH:43]=[CH:42][C:41]([Br:44])=[CH:40][CH:39]=2)[CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][C@@H:33]3[CH2:35][C@H:30]2[CH2:31][O:32]3)=[CH:23][CH:24]=1)(C)(C)C.C([O-])(O)=O.[Na+]>CO>[Br:44][C:41]1[CH:42]=[CH:43][C:38]([NH:37][C:36](=[O:45])[CH:25]([C:22]2[CH:23]=[CH:24][C:19](/[CH:18]=[CH:17]/[C:16](=[O:46])[NH:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH2:8])=[CH:20][N:21]=2)[CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][C@@H:33]3[CH2:35][C@H:30]2[CH2:31][O:32]3)=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccc(C(CCCN2C[C@@H]3C[C@H]2CO3)C(=O)Nc2ccc(Br)cc2)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Nc1ccccc1NC(=O)/C=C/c1ccc(C(CCCN2C[C@@H]3C[C@H]2CO3)C(=O)Nc2ccc(Br)cc2)nc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Hydrochloric acid in methanol (1.25 M, 5 mL) was added to the (E)-[2-(3-{6-[1-(4-Bromo-phenylcarbamoyl)-4-({1S,4S}-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-butyl]-pyridin-3-yl}-acryloylamino)-phenyl]-carbamic acid tert-butyl ester residue, the mixture was stirred at room temperature for about 12 h, and then NaHCO3 was added to the reaction system. After filtration of solids, the crude mixture was purified by preparative HPLC to obtain white solid. MS: calc'd 590 (MH+), exp 590 (MH+). 1H NMR (d4-MeOD, 400 MHz), 8.76 (d, 1H, J=1.6 Hz), 8.09 (dd, 1H, J=2.0, 8.0 Hz), 7.70 (d, 1H, J=15.6 Hz), 7.61 (d, 1H, J=8.0 Hz), 7.57-7.52 (m, 2H), 7.48-7.43 (m, 2H), 7.21 (d, 1H, J=1.6 Hz), 7.10-7.04 (m, 1H), 6.97 (d, 1H, J=15.6 Hz), 6.90 (d, 1H, J=8.0 Hz), 6.77 (t, 1H, J=8.0 Hz), 4.46 (s, 1H), 4.02 (d, 1H, J=8.4 Hz), 3.95 (t, 1H, J=7.6 Hz), 3.76 (broad s, 1H), 3.66 (d, 1H, J=7.3 Hz), 2.95 (d, 1H, J=10.6 Hz), 2.87 (broad s, 1H), 2.77 (broad s, 2H), 2.24 (broad s, 1H), 2.03 (broad s, 1H), 1.95 (d, 1H, J=10.8 Hz), 1.85 (d, 1H, J=10.8 Hz), 1.63 (broad s, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[N:3]=1.[C:11](Cl)(=[O:13])[CH3:12]>C1(C)C(C)=CC=CC=1>[C:11]([NH:1][C:2]1[S:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[N:3]=1)(=[O:13])[CH3:12]
Reactant: Nc1nc(C(F)(F)F)ns1
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1C
Product: CC(=O)Nc1nc(C(F)(F)F)ns1
Yield: 27.5 %

Procedure:
A solution of 4.3 grams (0.05 mole) 5-amino-3-trifluoromethyl-1,2,4-thiadiazole and 7.0 grams (0.09 mole) acetyl chloride in 50 milliliters xylene was refluxed at about 140° C. for 20 hours. Upon cooling to room temperature 2.9 grams (55% yield) pure product precipitated; m.p. 178.1° C.
Reaction SMILES: [C:1]1([C@H:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:22][CH:21]([O:20][C:18]([N:8]1[CH2:9][CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@@H:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:19])[CH3:23]
Reactant: c1ccc([C@@H]2NCCc3ccccc32)cc1
Reactant: CC(C)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)OC(=O)N1CCc2ccccc2[C@@H]1c1ccccc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A 15.00 g portion of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline and 9.22 g of isopropyl chloroformate were added to a mixture of 75 ml of toluene, 10.43 g of potassium carbonate and 45 ml of water and stirred at 20° C. for 2 hours, and then the organic layer was washed with 50 ml of water. The thus obtained organic layer was concentrated under a reduced pressure and then dried to obtain 21.71 g of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid propan-2-yl ester (1H-NMR (DMSO-d6, tetramethylsilane internal standard, 80° C.): δ 1.18 (3H, d, J=6.4 Hz), 1.22 (3H, d, J=6.4 Hz), 2.73-2.93 (2H, m), 3.25-3.34 (1H, m), 3.83-3.92 (1H, m), 4.80-4.91 (1H, m), 6.22 (1H, s), 7.06-7.33 (9H, m), mass spectrum: m/z=296 [M +H]+ (FAB)).
Reaction SMILES: C[O:2][C:3](=[O:44])[CH2:4][CH:5]1[CH2:10][CH2:9][C@H:8]([C:11](=[O:32])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=[C:23]([CH3:31])[CH:22]=3)=[CH:15][CH:14]=2)[C@@H:7]([C:33](=[O:43])[NH:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:6]1.O.[OH-].[Li+].Cl>C1COCC1>[CH2:36]([O:35][NH:34][C:33]([C@@H:7]1[C@@H:8]([C:11](=[O:32])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=[C:23]([CH3:31])[CH:22]=3)=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH:5]([CH2:4][C:3]([OH:44])=[O:2])[CH2:6]1)=[O:43])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COC(=O)CC1CC[C@H](C(=O)Nc2ccc(OCc3cc(C)nc4ccccc34)cc2)[C@@H](C(=O)NOCc2ccccc2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(COc2ccc(NC(=O)[C@H]3CCC(CC(=O)O)C[C@@H]3C(=O)NOCc3ccccc3)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
To a solution of {3-(S)-benzyloxy carbamoyl-4-(S)-[4-(2-methyl-quinolin-4-ylmethoxy)-phenylcarbamoyl]-cyclohexyl}-acetic acid methyl ester (238 mg, 0.40 mmol) in THF (5 mL) was added water (3 mL) and lithium hydroxide (40 mg, 0.95 mmol). After stirring at ambient temperature for 4 h, the reaction mixture was acidified with 1 N HCl to a pH of ca. 5. The product was extracted with ethyl acetate (4×5 mL) and the combined organic layers were washed with brine (5 mL), dried (NaSO4), and the volatiles were removed in-vacuo to afford 210 mg (90%) of the desired carboxylic acid as a sticky oil that was used without further purification in the following coupling reaction. MS (ESI): 582 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([OH:18])=[O:17])=[CH:5]2.C[C@H](N)C1C=CC=CC=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C@H:7]([C:12]([F:15])([F:13])[F:14])[C:6]([C:16]([OH:18])=[O:17])=[CH:5]2
Reactant: O=C(O)C1=Cc2cc(Cl)ccc2NC1C(F)(F)F
Agent: C[C@H](N)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O)C1=Cc2cc(Cl)ccc2N[C@@H]1C(F)(F)F
Reaction time: 16 h

Procedure:
To a solution of 6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid (Example 157)(6.75 g, 24.3 mmol) in ethyl acetate (25 mL) was added (S)-(-)-α-methylbenzylamine (1.50 g, 12.2 mmol). To the resulting solution was added hexanes (50 mL) with mixing. Stirring was discontinued and the reaction held static at room temperature for 16 hours during which time yellow crystals formed. The crystals were collected and washed with ethyl acetate-hexanes (100 mL, 1:2). The resulting yellow solid (932 mg) was dissolved in ethyl acetate (20 mL) and extracted with 1 N HCl (3×10 mL). The organic layer was dried over sodium sulfate and solvent removed at reduced pressure. The (s)-6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid was obtained as a yellow solid (648 mg, 10% yield). mp 173-176° C. 1H NMR (acetone-d6, 300 MHz) 7.80 (s, 1H), 7.35(d, 1H, J=2.2 Hz), 7.18 (d, 1H, J=8.0, J=2.2 Hz), 6.86 (d, 1H, J=8.0 Hz), 6.60 (brs, 1H), 5.20 (m, 1H). Anal. Calc'd. for C11H7NO2F3Cl C, 47.40 H, 2.54; N, 5.40. Found C, 47.49; H, 2.60; N, 4.98. The compound was determined to have an optical purity greater than 90% ee. Optical purity was determined by HPLC as described in Example 66.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4][CH2:3]1.[C:28]([O:32][CH3:33])(=[O:31])[NH:29][NH2:30]>CO.ClCCl>[CH3:33][O:32][C:28]([NH:29][N:30]=[C:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:6][CH2:7]1)=[O:31]
Reactant: O=C1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Reactant: COC(=O)NN
Solvent: ClCCl
Solvent: CO
Product: COC(=O)NN=C1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.4 %

Procedure:
3-(4-(4-Oxopiperidin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one (125 mg, 0.33 mmol) was dissolved in MeOH (5 ml) and dichloromethane (5 ml), methyl carbazate (34 mg, 0.37 mmol) added, and the mixture stirred at ambient temperature under nitrogen for 18 hours. The mixture was evaporated, and the residue purified by chromatography on a 5 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 1% MeOH in dichloromethane. Relevant fractions were combined to give the desired product (98 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:32])=[N:15][CH:16]=[C:17]([C:19]2[CH:20]=[N:21][N:22]([CH2:24][CH:25]3[CH2:29][O:28]C(C)(C)[O:26]3)[CH:23]=2)[CH:18]=1)[CH3:11].C(O)(C(F)(F)F)=O>C1COCC1.O>[NH2:32][C:14]1[N:15]=[CH:16][C:17]([C:19]2[CH:20]=[N:21][N:22]([CH2:24][CH:25]([OH:26])[CH2:29][OH:28])[CH:23]=2)=[CH:18][C:13]=1[O:12][CH:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: CC(Oc1cc(-c2cnn(CC3COC(C)(C)O3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: CC(Oc1cc(-c2cnn(CC(O)CO)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Yield: 74.6 %

Procedure:
To a stirred solution of 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-4-yl]-pyridin-2-ylamine (150 mg, 0.31 mmol) in THF (3 mL) and H2O (2 mL) was added TFA (2 mL) at 0° C., the mixture was stirred and warmed to room temperature, then heated at 50° C. for 5 hours, LCMS checked that the reaction was completed, remove THF, the residue was purified by prep-HPLC to leave 3-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-propane-1,2-diol (102 mg), yield 74.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH2:13][OH:14])[CH:10]=[CH:11][CH:12]=2)=[C:4]([N+:17]([O-])=O)[CH:3]=1.Cl[Sn]Cl>>[NH2:17][C:4]1[CH:3]=[C:2]([Cl:1])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH2:13][OH:14])[CH:10]=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Oc1cccc(CO)c1
Agent: Cl[Sn]Cl
Product: Nc1cc(Cl)ccc1Oc1cccc(CO)c1
Yield: 82.5 %

Procedure:
The product from Example 176b (1.9 g, 6.8 mmol) was reacted with SnCl2 as described in Example 1f to give the title compound (1.4 g, 83%).
Reaction SMILES: N#N.[CH:3]1[C:20]2=[C:21]3[C:10]([C:11]4[C:22]5[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=5)[CH:14]=[CH:13][CH:12]=4)=[CH:9][CH:8]=[CH:7][C:6]3=[CH:5][CH:4]=1.Cl[Sn](Cl)(Cl)Cl.ClC[CH:30]([O:33]C(CCl)CCl)CCl.Cl>O.ClC1C=CC=CC=1Cl>[CH:18]1[C:19]2=[C:22]3[C:11]([C:10]4[C:21]5[C:6](=[CH:5][CH:4]=[CH:3][C:20]2=5)[CH:7]=[CH:8][CH:9]=4)=[CH:12][CH:13]=[CH:14][C:15]3=[C:16]([CH:30]=[O:33])[CH:17]=1
Reactant: c1cc2cccc3c4cccc5cccc(c(c1)c23)c54
Reactant: ClCC(CCl)OC(CCl)CCl
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: N#N
Solvent: O
Solvent: Clc1ccccc1Cl
Product: O=Cc1ccc2c3cccc4cccc(c5cccc1c52)c43
Reaction time: 16 h

Procedure:
A 3 L 3-neck flask fitted with overhead mechanical stirrer, thermometer, condenser, and N2 line was charged with perylene (Aldrich Chemical Co., Milwaukee, WI, 53201, 25 g, 99 mmol) and o-dichlorobenzene (500 mL). The liquid was warmed until all the large chunks of solid dissolved (80°) and then cooled quickly to give finely divided crystals. After further cooling with a salt-ice bath to 5°, SnCl4 (Aldrich, 98%, 51.2 g, 0.897 mol, 23 mL), was added in one portion. No temperature change occurred. The pot temperature was kept below 5°, and 1,1-dichloromethylmethylether (Aldrich, 14.9 g, 0.13 mol, 11.7 mL) was added dropwise over 1 h. The resulting suspension was warmed slowly to 40° over 2 h and further stirred for 16 h. Considerable HCl gas evolution occurred during the warming and the early part of the reaction at 40°. The reaction mixture was then cooled to 10° and hydrolysed by careful addition of 1 L of cold H2O. After 4 h the layers were separated and the organic layer filtered, dried with anhydrous Na2SO4 (Mallinckrodt Co., 2nd and Mallinckrodt St., St. Louis, MO, 63147, 100 g) and filtered again. The clear yellow solution was passed through a 500 g plug of SiO2 using PhCH3 as the eluting solvent with 500 mL fractions. This chromatography separated unreacted perylene from the aldehyde and a more polar product. Fractions (5 L) containing the aldehyde were combined and the PhCH3 removed. The resulting oily solid was shaken with CH3OH (200 mL) and the orange-brown crystals which formed were collected by filtration to give after drying 23.2 g (83%) of 3-perylenecarbaldehyde mp 223°-233°, (C,H), (lit. mp 236° (darkens >230°), N. P. Buu-Hoi and C. T. Long, Recueil 75 1121 (1956).
Reaction SMILES: [C:1]1([P:7](N=[N+]=[N-])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N12CCCN=[C:24]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2.C1(C)C=CC=CC=1>O1CCCC1.O>[C:1]1([P:7]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(P(c2ccccc2)c2ccccc2)cc1

Procedure:
Alternatively, compounds of formula (16) can be (a) treated with diphenylphosphorylazide and 1,8-diazabicyclo[5.4.0]undec-7-ene in a solvent such as, but not limited to toluene, at a temperature of about 0° C. to about 50° C.; and (b) treated with the asides obtained from step (a) with triphenylphosphine in a mixture of tetrahydrofuran and water and at about the reflux temperature of the solvent, to provide compounds of formula (18).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9].N1C=CC=CC=1.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>ClCCl>[CH2:20]([O:19][C:17](=[O:18])[NH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(F)cc1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.7 %

Procedure:
To 2,4-difluoroaniline (42, 7.0 mL, 0.070 mol) in 100 mL of dichloromethane was added pyridine (11 mL, 0.14 mol) and benzyl chloroformate (11.9 mL, 0.0834 mol). The reaction mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and KHSO4 solution. The organic layer was dried (MgSO4), concentrated and crystallized from hexanes to give compound 613 (15.6 g, 85%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15]C(=O)[CH2:13][CH:12]1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:28]([O:31][CH3:32])[O:29][CH3:30]>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:28]([O:29][CH3:30])([O:31][CH3:32])[CH2:13][CH:12]1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[CH3:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)OC
Reactant: Cc1cc(F)ccc1C1CC(=O)CCN1C(=O)OCc1ccccc1
Solvent: CO
Product: COC1(OC)CCN(C(=O)OCc2ccccc2)C(c2ccc(F)cc2C)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 132 g of 1-benzyloxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxopiperidine were added 650 ml of methanol, 84 ml of trimethoxymethane and 2 g of strongly acidic resin IR-120 (manufactured by Japan Organo Co., Ltd.), and the mixture was stirred at room temperature for 3 days. From the reaction mixture was removed insoluble matters by filtration, and the solvent was removed by distillation under reduced pressure, to give 146 g of 1-benzyloxycarbonyl-2-(4-fluoro-2-methylphenyl)-4,4-dimethoxypiperidine as shown in Table 125 below.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9](=O)[NH:10][CH:11]=[N:12]2)[CH3:5].[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25][N:26]1[C:34]2[C:29](=[CH:30][C:31]([NH2:35])=[CH:32][CH:33]=2)[CH:28]=[N:27]1>>[CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]([NH:35][C:31]1[CH:30]=[C:29]3[C:34](=[CH:33][CH:32]=1)[N:26]([CH2:25][C:21]1[S:20][CH:24]=[CH:23][N:22]=1)[N:27]=[CH:28]3)=[N:10][CH:11]=[N:12]2)[CH3:5]
Reactant: Nc1ccc2c(cnn2Cc2nccs2)c1
Reactant: C[C@@H](Oc1cccc2nc[nH]c(=O)c12)C(=O)N(C)C
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12)C(=O)N(C)C
Yield: 77.1 %

Procedure:
Using the same procedure as in Example 18, (2R)—N,N-dimethyl-2-[(4-oxo-3,4-dihydroquinazolin-5-yl)oxy]propanamide (150 mg, 0.57 mmol) and 1-(1,3-thiazol-2-ylmethyl)-1H-indazol-5-amine (138 mg, 0.6 mmol) were reacted to give the title compound as a white solid (208 mg, 77%); NMR Spectrum (CDCl3) 1.73 (d, 3H), 3.06 (s, 3H), 3.14 (s, 3H), 5.43 (q, 1H), 5.92 (s, 2H), 6.82 (d, 1H), 7.26 (m, 1H), 7.50 (d, 2H), 7.61 (t, 1H), 7.75 (d, 1H), 7.87 (dd, 1H), 8.11 (s, 1H), 8.45 (s, 1H), 8.62 (s, 1H); Mass spectrum 474.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14](B(O)O)=[CH:13][C:12]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH2:27][N:26](C(=O)C(F)(F)F)[CH2:25][CH2:24]2.BrC1C=CC=C2C=1CN(C(=O)C(F)(F)F)CC2.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.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.C1(C)C=CC=CC=1>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:13][C:12]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N1CCc2cc(Br)ccc2C1)C(F)(F)F
Reactant: OB(O)c1cc2cc(Cc3ccccc3)ccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(N1CCc2cccc(Br)c2C1)C(F)(F)F
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1ccc(Cc2ccc3oc(-c4ccc5c(c4)CCNC5)cc3c2)cc1
Yield: 56 %

Procedure:
A solution of 5-benzylbenzofuran-2-ylboronic acid (252 mg, 1.0 mmole) in ethanol (3 ml) was added to a mixture of 1-(6-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone and 1-(8-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone (308 mg, 1.0 mmole), Pd(PPh3)4, toluene, and 2 M Na2CO3(3.5 ml). The resulting mixture was heated at reflux overnight. The reaction was concentrated in vacuo, and the residue was diluted with water. The aqueous phase was extracted with EtOAc (3×50 ml). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified on ISCO column (5% to 10% MeOH/CH2Cl2) to provide the title compounds (189 mg, 56%). 1H NMR (400 MHz, CDCl3) δ 7.60 (m, 2H), 7.39 (dd, 1H), 7.37 (s, 1H), 7.25 (m, 5H), 7.10 (dd, 2H), 6.90 (s, 1H), 4.10 (s, 2H), 3.40 (s, 2H), 3.18 (m, 2H), 2.94 (m, 2H). MS (ESI) m/z: Calculated: 339.16; Observed: 340.10 (M++1).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:7])=[CH:5][N:6]=1.BrN1C(=O)CCC1=O.C1(C(OOC(=O)C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:34][C:35]1[N:40]=[C:39]([SH:41])[N:38]=[C:37]([OH:42])[CH:36]=1>C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl>[CH3:34][C:35]1[N:40]=[C:39]([S:41][CH2:1][C:2]2[S:3][C:4]([CH3:7])=[CH:5][N:6]=2)[N:38]=[C:37]([OH:42])[CH:36]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Cc1cnc(C)s1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(O)nc(SCc2ncc(C)s2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 37.9 %

Procedure:
To CCl4 (100 mL) in a 250 mL round bottom flask were added 2,5-dimethyl-1,3-thiazole (1.7 g, 15 mmol), 1-bromopyrrolidine-2,5-dione (2.94 g, 16.5 mmol), and benzoyl benzenecarboperoxoate (180 mg, 0.75 mmol). The reaction mixture was heated at 80° C. for 4 hours. The solvent was then removed under vacuum. The crude product was dissolved in ethanol (30 mL). 6-methyl-2-sulfanylpyrimidin-4-ol (700 mg, 5 mmol) and triethylamine (1.4 mL) were added, and the mixture was stirred at room temperature for 2 hours. After removal of the solvent, the crude product was purified by column chromatography (0-8% methanol in DCM) to provide the title compound as a white solid (480 mg, 40% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.25 (s, 3H), 2.50 (s, 3H), 4.56 (s, 2H), 6.03 (br, 1H), 7.55 (s, 1H); M+ 254.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:11][C@H:10]([NH:12][OH:13])[CH2:9]2)=[CH:4][CH:3]=1.[C:14]1([CH3:26])[CH:19]=[CH:18][C:17]([S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[CH:16][CH:15]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:11][C@H:10]([N:12]([OH:13])[C:24]([NH:23][S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:26])=[CH:15][CH:16]=3)(=[O:22])=[O:21])=[O:25])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: ON[C@H]1C[C@@H](c2ccc(F)cc2)C1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(=O)N(O)[C@H]2C[C@@H](c3ccc(F)cc3)C2)cc1
Yield: 148 %

Procedure:
To a stirred solution of cis-3-(4-fluorophenyl)cyclobutylhydroxylamine (0.9 g, 3 mmol) in THF (20 ml) was added p-toluenesulfonyl isocyanate (1.085 g, 5.5 mmol) at room temperature. The resultant precipitates were collected by filtration and recrystallized from ethyl acetate/EtOH to provide 1.68 g (89% yield) of the title compound as a colorless solid, m.p. 177-178° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][CH2:31][CH2:32][CH2:33][OH:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][CH2:31][CH2:32][CH2:33][OH:34])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: NCCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNCCCO)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 3-amino-1-propanol (0.015 mL, 0.20 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(3-hydroxypropylaminomethyl)indol-2-yl]isoindolinone.