Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]2([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:24][CH2:23]2)[N:16]=3)=[C:9]([F:31])[CH:8]=1.Cl.O>C1COCC1>[F:31][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[C:13]1[S:14][C:15]2[C:20]([N:21]=1)=[CH:19][CH:18]=[C:17]([C:22]1([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:23][CH2:24]1)[N:16]=2)[CH:2]=[O:1]
Reactant: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a slurry of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine (22.3 g, 51.6 mmol) in 200 mL THF was added 200 mL 5N HCl. The reaction mixture became warm, was fitted with a water-cooled reflux condenser, and was heated to 65° C. in an oil bath under argon. After 3 h, the reaction was nearly homogeneous. The bath was turned off and the reaction allowed to stir overnight. In the morning a nice yellow precipitate was evident. The THF was removed in vacuo, and the resulting slurry was filtered, rinsing with water, and dried under nitrogen, then dried in vacuo overnight to give 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzaldehyde as a light orange solid. MS (ESI) m/z: Calculated: 374.1; Observed: 375.1 (M++1).
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:6][CH2:5]1>CCO>[OH:3][C@@H:4]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C@H:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:6][CH2:5]1
Reactant: CCOC(=O)[C@@H]1CCC(=O)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)[C@@H]1CC[C@H](O)CN1C(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
NaBH4 (36 g, 1.0 mol) was added in portions to a −40° C. solution of (S)-1-tert-butyl 2-ethyl 5-oxopiperidine-1,2-dicarboxylate (250 g, 0.92 mol) in EtOH (1500 mL). The reaction mixture was then stirred at −40° C. for 0.5 hr then quenched with 10% HOAc solution. After diluting with water, the mixture was extracted with DCM (3×). The combined organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (1:1 petroleum ether/EtOAc) to afford (2S,5S)-1-tert-butyl 2-ethyl 5-hydroxypiperidine-1,2-dicarboxylate (205 g, 80%) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]([CH3:16])=[CH2:15])=[C:10]([O:17][CH3:18])[CH:9]=[C:8](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:27](Cl)(=[O:29])[CH3:28]>>[C:27]([O:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]([CH3:16])=[CH2:15])=[C:10]([O:17][CH3:18])[CH:9]=[C:8](/[CH:19]=[CH:20]/[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:29])[CH3:28]
Reactant: C=C(C)CCc1c(OC)cc(/C=C/c2ccccc2)c(C(=O)OC)c1O
Reactant: CC(=O)Cl
Product: C=C(C)CCc1c(OC)cc(/C=C/c2ccccc2)c(C(=O)OC)c1OC(C)=O
Yield: 82 %

Procedure:
Use compound 8 and acetyl chloride as materials, and follow the method described in Example 180 to obtain a white solid as the target product (82%). 1H NMR (400 MHz, DMSO-d6): 1.79 (s, 3H), 1.83 (s, 3H), 2.08 (s, 3H), 332 (d, J=7.6 Hz, 2H), 3.73 (s, 3H), 3.89 (s, 3H), 5.23 (t, J=7.6 Hz, 1H), 6.72 (s, 1H), 6.79 (d, J=16.0 Hz, 1H), 719 (d, J=16.0 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.43 (d, J=7.6 Hz, 2H), 7.45 (t, J=7.6 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13](OCC)=[O:14])[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([CH2:13][OH:14])[CH:10]=[N:9]2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1cnn(Cc2ccc(OC)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(CO)cn2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
To ethyl 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (8.31 g, 31.9 mmol) in THF (100 mL) at 0° C. was added lithium aluminum hydride (1.45 g, 38.3 mmol). The cold bath was removed and the reaction was stirred for 3 hours. The reaction mixture was diluted with Et2O (200 mL) and Celite (10 g) was added to the reaction mixture. The mixture was cooled to 0° C. and sodium sulfate decahydrate was cautiously added to quench the reaction, which was then filtered, and the filter pad was washed with EtOAc (100 mL) and concentrated to provide the desired product (5.26 g).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:21])=O)=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C[N:23](C)S(N)(=O)=O.Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.CC(N(C)C)=O>[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH2:23])=[O:21])=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)S(N)(=O)=O
Reactant: O=C(O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: NC(=O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[[4-(acetyl)-1-piperazinyl]carbonyl] (400 mg, 0.78 mmol), N,N-dimethylsulfamide (390 mg, 3.13 mmol) and DMAP (380 mg, 3.13 mmol) in dimethylacetamide (6 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (450 mg, 2.34 mmol). The reaction solution was stirred at 50° C. for 3 h, concentrated, purified by preparative HPLC (CH3CN/H2O with NH4OAc buffer) to yield 7H-indolo[2,1-a][2]benzazepine-10-carboxamide, 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-[[4-(acetyl)-1-piperazinyl]carbonyl] (135 mg, 0.22 mol, 28%) as a yellow powder. 1HNMR (500 MHz, DMSO-d6) δ 11.62 (s, 1H), 8.44 (s, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.62-7.55 (m, 4H), 7.04 (s, 1H), 5.19 (br s, 1H), 4.34 (br s, 1H), 3.59-3.30 (m, 8H), 2.91 (s, 6H), 2.85-2.75 (m, 1H), 2.10-1.36 (m, 10H), 1.99 (s, 3H). LCMS: m/e 616 (M−H)−, ret time 1.57 min, column A, 2 minute gradient.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C1C=CC=CN=1)C.[CH2:26]([O:33][C:34]1[C:43]2[C:38](=[C:39]([CH2:44][CH2:45][NH2:46])[CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.O>[CH2:26]([O:33][C:34]1[C:43]2[C:38](=[C:39]([CH2:44][CH2:45][NH:46][C:8]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:10])[CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: NCCc1cccc2c(OCc3ccccc3)cccc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(NCCc1cccc2c(OCc3ccccc3)cccc12)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.6 %

Procedure:
To a solution of diphenylacetic acid (0.171 g) in methylene chloride (10 ml), dimethylaminopyridine (0.01 g) and 1-benzyloxy-5-(2-aminoethyl)naphthalene (0.196 g) were added at room temperature. After 10 minutes, EDC·HCl (0.154 g) was added to the mixture solution. The mixture was stirred overnight at room temperature for 1 night. After termination of reaction, water and methylene chloride were added to the reaction mixture. The organic layer was washed with a saturated aqueous solution of ammonium chloride, water and a saturated aqueous solution of sodium chloride, dried over and concentrated under reduced pressure. The residue was purified on silica gel chromatography to give the title compound (0.172 g) having the following physical data.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH3:7])=[O:3].[NH2:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[NH:12][C:13](=[O:19])/[CH:14]=[C:15](\[O:17][CH3:18])/[CH3:16].O1CCCC1>C(N(CC)CC)C>[CH2:5]([O:4][C:2]([NH:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[NH:12][C:13](=[O:19])/[CH:14]=[C:15](\[O:17][CH3:18])/[CH3:16])=[O:3])[CH2:6][CH3:7]
Reactant: CCCOC(=O)Cl
Reactant: CO/C(C)=C\C(=O)Nc1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCOC(=O)Nc1cccc(NC(=O)/C=C(/C)OC)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 68.5 %

Procedure:
27 g of propyl chloroformate were slowly added to a mixture of 41.2 g of m-amino-3-methoxy-crotonanilide, 300 ml of tetrahydrofuran and 22.2 g of triethylamine and the mixture was stirred for 16 hours at 20° C. The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8- 2 methylene chloride-acetone mixture to obtain 40 g of m-(n-propyloxycarbonylamino)-3-methoxy-crotonanilide melting at 115° C. Crystallization from chloroform did not change the melting point.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:31][C@@H:30]2[C@:25]([CH3:39])([CH2:26][CH2:27][C@H:28]([O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[CH2:29]2)[C@@H:24]2[C@@H:10]1[C@H:11]1[C@:21]([CH3:40])([CH2:22][CH2:23]2)[C@@H:14]([C@H:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[O:19])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:41]([Mg]Cl)([CH3:43])[CH3:42].[NH4+].[Cl-]>C1COCC1>[CH2:1]([O:8][C@@H:9]1[CH2:31][CH:30]2[C@:25]([CH3:39])([CH2:26][CH2:27][C@H:28]([O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[CH2:29]2)[C@@H:24]2[C@@H:10]1[C@H:11]1[C@:21]([CH3:40])([CH2:22][CH2:23]2)[C@@H:14]([C@H:15]([CH3:20])[CH2:16][CH2:17][CH:18]([OH:19])[CH:41]([CH3:43])[CH3:42])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](CCC=O)[C@H]1CC[C@H]2[C@@H]3[C@H](OCc4ccccc4)C[C@H]4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C(O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](OCc4ccccc4)CC4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 77.2 %

Procedure:
A solution of compound 2009 (0.374 g, 0.679 mmol) in anhydrous THF (10 ml) under argon was treated with isopropylmagnesium chloride (2 ml, 2M in THF, 5.43 mmol) at room temperature. The reaction was stirred until no starting material remained by TLC. Aqueous NH4Cl solution (10%, 15 ml) was added to quench the reaction and the THF was removed in vacuo. Distilled H2O (5 ml) was added and the solution extracted 3× with 15 ml CH2Cl2. The combined organic layers were washed with aqueous saturated NaCl solution (15 ml), dried over anhydrous MgSO4, filtered and the solvent removed in vacuo. Flash chromatography (SiO2, 12:1 hexanes:EtOAc) gave compound 2010 (0.3117 g, 77%) as a white foam. 1H NMR (500 MHz, CDCl3) δ: 7.35-7.34 (m, 5H, benzyl Ar—H), 4.71-4.69 (m, 1H, THP ether methine H), 4.585 (d, J=11.9 Hz, 1H, benzyl-CH2), 4.31 (d, J=12.0 Hz, 1/2H, benzyl-CH2), 4.295 (d, J=12.0 Hz, 1/2H, benzyl-CH2), 3.94-3.91 (m, 1H, THP, OCH2), 3.62-3.58 (m, 1H, THP OCH2), 3.50-3.48 (m, 1H, C-3 H), 3.45 (s, 1H, C-7 H), 3.32-3.31 (m, 1H, C-24 H), 0.81 (s, 3H, C-19 H), 0.63 (d J=2.4 Hz, 3H, C-18 H) (Note: product is a mixture of diastereomers); IR (CHCl3) 3605, 2900 cm−1; MS (CI/isobutane) m/z 595 (M+1, 10%), 401 (M+1-THP-Bn-H2O, 25%), 385 (M+1-THP-HOBn, H2O, 100%); m.p. 55-59° C.; Anal. calcd. for C39H62O4: C=78.74; H=10.50. Found: C=78.65; H=10.54.
Reaction SMILES: Cl[CH2:2][C:3]#[C:4][CH2:5][NH:6][C:7](=[O:22])[C:8]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[I-].[Na+].[CH3:25][NH:26][CH3:27]>O1CCOCC1>[CH3:25][N:26]([CH3:27])[CH2:2][C:3]#[C:4][CH2:5][NH:6][C:7](=[O:22])[C:8]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CNC
Reactant: O=C(NCC#CCCl)C(O)(c1ccccc1)C1CCCCC1
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(C)CC#CCNC(=O)C(O)(c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(4-chloro-2-butynyl)-2-cyclohexyl-2-hydroxy-2-phenylacetamide (0.5 g), sodium iodide (0.1 g), and 50% aqueous dimethylamine (1.5 ml) in 1,4-dioxane (5 ml) was stirred at room temperature overnight. After removal of the solvent, saturated sodium bicarbonate aqueous solution and ethyl acetate were added to the residue. The organic layer was separated, washed with sodium chloride aqueous solution, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of chloroform =nd methanol (20:1) as an eluent to give N-(4-dimethylamino-2-butynyl)-2-cyclohexyl -2-hydroxy-2-phenylacetamide (0.49 g) as oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CN(C=O)C>[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:2]=1)([OH:12])=[O:11]
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCn1cc(C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 49 %

Procedure:
Indole 3-carboxylic acid (3 g, 18.62 mmol) was added to a suspension of sodium hydride (60% in oil) (1.11 g, 1.5 eq) in dry DMF (30 ml) under a nitrogen atmosphere. The mixture was stirred at room temperature for 45 min (H2 evolving has ceased) and to this was added 1-bromopentane (4.62 ml, 2 eq) in dry DMF (10 ml) dropwise. The mixture was stirred at room temperature overnight. The solvents were removed in vacuo and to the residue was added water (30 ml) and ethyl acetate (30 ml). The ethyl acetate portion was separated, dried over sodium sulphate, filtered and evaporated to dryness. The crude residue was purified by column chromatography (silica gel: 20% ethyl acetate in hexane) to give the title compound (2.12 g, 49%) as a cream solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[N:40][N:39]=[CH:38]2)[CH:32]=1)CCC>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:38]=[N:39][N:40]=[CH:41]2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Reactant: CCCCOC(=O)CC(=O)c1cccc(-n2cnnc2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2cnnc2)c1

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) (302 mg, 1.0 mmol) and 3-oxo-3-(3-[1,2,4]triazol-4-yl-phenyl)-propionic acid butyl ester (Example H11) (345 mg, 1.2 mmol) according to the general procedure K. Obtained as a yellow amorphous substance (207 mg).
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH:10]=[N:9][CH:8]=[CH:7][C:6]=2[C:5]([NH2:12])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[CH2:28][N:29]=[C:30]=[O:31]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:30]([NH:29][CH2:28][C:22]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=2[Cl:20])=[O:31])=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2
Reactant: Nc1ccc(Br)c2cnccc12
Reactant: O=C=NCc1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(Cl)cc1Cl)Nc1ccc(Br)c2cnccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.5 %

Procedure:
The product from Example 73A (120 mg, 0.52 mmol) in THF:toluene (1.4, 5 mL) was treated with a solution of 2,4-dichloro-1-(isocyanatomethyl)benzene (108 mg, 0.52 mmol) in THF (0.5 mL). After stirring for 16 hours at room temperature, the mixture was filtered and the filter cake dried under reduced pressure to provide the title compound as a white solid (178 mg, 78%). The hydrochloride salt was obtained by dissolving the product in hot THF and adding HCl in diethyl ether (2M). The yellow precipitate was collected by filtration and dried under reduced pressure. MS (ESI+) m/z 426 (M+H)+; MS (ESI−) m/z 424 (M−H)−; 1H NMR (DMSO-d6, 300 MHz) δ 4.42 (d, 5.8, 2H), 7.22 (t, J 5.8, 1H), 7.65 (m, 1H), 7.91 (d, J 8.5, 1H), 8.02 (d, J 6.1, 1H), 8.22 (d, J 8.5, 1H), 8.69 (d, J 5.8, 1H), 9.01 (s, 1H), 9.44 (s, 1H); Anal. Calcd for C17H12BrCl2N3O HCl 0.25 EtOH: C, 44.41; H, 3.14; N, 8.88. Found: C, 44.80; H, 2.76; N, 8.84.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:5]=2[N:6]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2sc(C)nc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nc2cc(CBr)ccc2s1

Procedure:
8.16 g of 2,5-dimethylbenzothiazole was dissolved in 50 ml of carbon tetrachloride. To the solution were added 8.9 g of N-bromosuccinimide and 82 mg of benzoyl peroxide. The mixture was refluxed for 3 hours. The resulting insolubles were removed by filtration. The solvent of the filtrate was removed by distillation under reduced pressure to obtain 5-bromomethyl-2-methylbenzothiazole. It was suspended in 100 ml of 50% acetic acid. To the suspension was added 14.00 g of hexamethylenetetramine, and the mixture was refluxed for 1 hour. The reaction mixture was mixed with 200 ml of water. The resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution, water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: n-hexane/ethyl acetate=3/1) to obtain 3.54 g of colorless crystals of 2-methyl-5-formylbenzothiazole having a melting point of 92°-94° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:15])([CH3:14])[NH:9][CH:10]2[CH3:13])=[CH:5][C:4]=1[OH:16].[CH3:17][CH:18]([Si:20](Cl)([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH3:19].N1C=CN=C1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:15])([CH3:14])[NH:9][CH:10]2[CH3:13])=[CH:5][C:4]=1[O:16][Si:20]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:19])[CH3:17]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COc1cc2c(cc1O)CC(C)(C)NC2C
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COc1cc2c(cc1O[Si](C(C)C)(C(C)C)C(C)C)CC(C)(C)NC2C
Yield: 105.9 %

Procedure:
239 (183 mg, 0.83 mmol), TIPS-Cl (237 mg, 3.5 mmol) and imidazole (237 mg, 3.5 mmol) in DCM (10 ml) were stirred at rt for 24 h. The reaction mixture was quenched with water (5 ml) and extracted with DCM (3×10 ml). The combined organic extracts were washed with brine (10 ml), dried (MgSO4) and concentrated in vacuo. Purification (personal flashmaster: 20 g, EtOAc:MeOH:TEA; 100:10:1) afforded the title compound (332 mg) as a yellow oily solid. 1H NMR (270 MHz; CDCl3) 1.07 (18H, d, J=6.4 Hz, 6×CH3CH), 1.08 (3H, s, CH3), 1.15-1.28 (3H, m, 3×CHCH3), 1.25 (3H, s, CH3), 1.21 (3H, d, J=6.4 Hz, CH3CH), 2.44 (1H, d, J=15.8 Hz, CHH), 2.65 (1H, d, J=15.8 Hz, CHH), 3.74 (3H, s, OCH3), 4.0 (1H, q, J=6.4 Hz, CHCH3), 6.46 (1H, s, CH), 6.67 (1H, s, CH). LC/MS (ES+) tr=1.8 min, m/z 378.24 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][CH2:22][C:23]1[O:24][CH:25]=[C:26]([C:28](O)=[O:29])[N:27]=1>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:16])([F:17])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:26]3[N:27]=[C:23]([CH2:22][F:21])[O:24][CH:25]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: O=C(O)c1coc(CF)n1
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Product: C[C@@]1(c2cc(NC(=O)c3coc(CF)n3)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1

Procedure:
The coupling of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1) and 2-(fluoromethyl)oxazole-4-carboxylic acid [D. Banner et al. WO2011069934 (2011)] following General Procedure F yielded the title compound as a colorless solid. MS: m/z=419.5 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([OH:15])=[O:14]>[Cl-].[Al+3].[Cl-].[Cl-]>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[C:9]([C:13]([OH:15])=[O:14])=[CH:10][CH:11]=[CH:12]2
Reactant: Fc1ccccc1
Reactant: O=C(O)c1ccco1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)c1cccc2cc(F)ccc12
Temperature: 95 °C
Reaction time: 16 h
Yield: 6.1 %

Procedure:
To a 1 liter round-bottomed flask equipped with condenser and N2 inlet were added 345 ml (3.68 mol) of fluorobenzene and 48 g (0.428 mol) of furoic acid. To the stirring suspension was added in portions 120 g (0.899 mmol of aluminum chloride. The reaction mixture was stirred at 95° C. for 16 hours and then quenched by addition to ice/water/1N HCl. After stirring 1 hour, the aqueous layer was decanted, and benzene and a saturated aqueous solution of sodium bicarbonate were added. After stirring 1 hour, the layers were separated, the aqueous layer washed with benzene, acidified, and extracted into ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over sodium sulfate, and evaporated to a solid. The solid was triturated with isopropyl ether to give 5.0 g (6.1%) of a white solid, NMR (DMSO-d6): 7.0-8.0 (m, 5H), 8.6 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[CH:11][N:10]=2)[C:5]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:17][CH2:16]2)=[C:6]([C:13]#[N:14])[C:7]1=[O:12])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)cnc2[nH]c1=O
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)cnc2n(Cc2ccccc2)c1=O

Procedure:
This compound was prepared from 6-fluoro-2-oxo-4-[4-(thiophene-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (98) and benzyl bromide according to General Procedure B. Yield 317 mg (43%), MP 173° C.; 1H-NMR (DMSO-d6): δ 3.73 (m, 4H), 3.92 (m, 4H), 5.53 (s, 2H), 7.22-7.30 (m, 6H), 7.49 (d, J=3.6 Hz, 1H), 7.80 (dd, J=1.2, 5.2 Hz, 1H), 8.16 (dd, J=2.8, 9.2 Hz, 1H), 8.77 (d, J=2.8 Hz, 1H); EIMS: 474 (M+1). Anal. (C25H20FN5O2S) C, H, N.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH2:18][CH3:19])=[O:11]
Reactant: CCO
Reactant: Cc1cccc(CC(=O)O)c1Br
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cccc(C)c1Br

Procedure:
2-(2-bromo-3-methylphenyl)acetic acid (7.9 g, 0.034 mol) and sulfuric acid (0.1 ml) were added to ethanol (25 ml) and the mixture was refluxed overnight. The solvent was evaporated and to the residue was added saturated sodium carbonate. The aqueous solution was extracted twice with diethyl ether, the organic extracts were combiened, washed twice with water, dried and evaporated under reduced pressure to give the desired product as an oil. (8.5 g,97.7%).