Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[CH:2]1N(CC2C=CC=CC=2)C(=O)N(C2C=CC(Cl)=CC=2)[C:3]1=[O:4].[CH2:23]([O:25][C:26](=[O:53])[C@H:27]1[CH2:31][CH:30]([O:32]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:29][N:28]1[S:43]([C:46]1[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=1)(=[O:45])=[O:44])[CH3:24]>C1(C)C=CC=CC=1.C([O-])(=O)C.C[N+](C)(C)C>[CH2:23]([O:25][C:26](=[O:53])[C@H:27]1[CH2:31][CH:30]([O:32][C:3](=[O:4])[CH3:2])[CH2:29][N:28]1[S:43]([C:46]1[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=1)(=[O:44])=[O:45])[CH3:24]
Reactant: CC1C(=O)N(c2ccc(Cl)cc2)C(=O)N1Cc1ccccc1
Reactant: CCOC(=O)[C@H]1CC(OS(=O)(=O)c2ccc(C)cc2)CN1S(=O)(=O)c1ccc(C)cc1
Agent: CC(=O)[O-]
Agent: C[N+](C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@H]1CC(OC(C)=O)CN1S(=O)(=O)c1ccc(C)cc1
Yield: 72.8 %

Procedure:
To 218 g (466 mmol) of allo-1-(4-toluenesulfonyl)-4-(4-toluenesulfonyloxy)-D-proline ethyl ester in 1500 ml of toluene was added 81 g (606 mmol) of tetramethyl ammonium acetate and the mixture was heated to reflux for 2 hours. The reaction was cooled, washed with 2×500 ml of water and dried over sodium sulfate. Evaporation of the solvent and drying the resulting solids in a vacuum oven overnight at 30° C. provided 120.6 g of product (72% yield). M.P.=82°-83° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:17])[N:3]=1.Cl.[OH-].[Na+].[CH2:21]([NH2:23])[CH3:22]>>[CH2:21]([NH:23][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:17])[N:3]=1)[CH3:22]
Reactant: Cc1cccc(C(=O)c2ccc(C)nc2Cl)c1
Reactant: CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCNc1nc(C)ccc1C(=O)c1cccc(C)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
A mixture of 2-chloro-6-methyl-3-(3-methylbenzoyl)pyridine (2.45 g, 10 mmol) and 70% ethylamine aqueous solution (10 ml) was sealed in a tube and stirred for 4 hours at 100° C. The reaction solution was cooled to room temperature and transferred into a separating funnel. This was adjusted to pH 1 with 1 N hydrochloric acid, vigorously shaken, adjusted to pH 10 by adding 1 N sodium hydroxide aqueous solution and then extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, magnesium sulfate was removed by filtration and then the filtrate was concentrated under a reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2-ethylamino-6-methyl-3-(3-methylbenzoyl)pyridine (2.10 g, 83%) as a yellow oily material.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:14][C:15](=O)[C:4]=2[CH:3]=1)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3.B.Cl.[OH-].[Na+]>O1CCCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:14][CH2:15][C:4]=2[CH:3]=1)[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]3
Reactant: O=C1OC2(CCNCC2)c2ccc(F)cc21
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc2c(c1)COC21CCNCC1
Temperature: 0 °C
Yield: 55.9 %

Procedure:
To a suspension of 5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (420 mg, 1.9 mmol) in tetrahydrofuran (4.2 ml) was added dropwise a 1M borane solution in tetrahydrofuran (3.8 ml, 3.8 mmol) at 0° C. The mixture was refluxed overnight and then cooled to 0° C. HCl 5 N (2 ml) was added dropwise. The mixture was refluxed for 5 hours, cooled to 0° C., diluted with water and basified with NaOH 5 N (pH 10). The mixture was extracted 3 times with ethyl acetate. The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was stirred with ether and filtrated. The filtrate was concentrated in vacuo to provide 0.22 g (55%) of 5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidine] as a light yellow oil.
Reaction SMILES: N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=O.[Na+].[F:15][C:16]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:17]=1[NH:23][C:24]1[C:25]([NH:35][S:36]([C:39]2([CH2:42][CH:43]=C)[CH2:41][CH2:40]2)(=[O:38])=[O:37])=[C:26]2[O:34][CH2:33][CH2:32][N:27]2[C:28](=[O:31])[C:29]=1[CH3:30].C[OH:46]>O1CCOCC1.O.C(Cl)Cl.[Os](=O)(=O)(=O)=O>[F:15][C:16]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:17]=1[NH:23][C:24]1[C:25]([NH:35][S:36]([C:39]2([CH2:42][CH:43]=[O:46])[CH2:40][CH2:41]2)(=[O:37])=[O:38])=[C:26]2[O:34][CH2:33][CH2:32][N:27]2[C:28](=[O:31])[C:29]=1[CH3:30]
Reactant: CO
Reactant: C=CCC1(S(=O)(=O)Nc2c(Nc3ccc(I)cc3F)c(C)c(=O)n3c2OCC3)CC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(CC=O)CC2)c2n(c1=O)CCO2
Temperature: 25 °C
Reaction time: 5 h
Yield: 63 %

Procedure:
Osmium tetra oxide (8 mg, 0.035 mmol), 2,6-lutidine (0.08 g, 0.74 mmol) and sodium periodate (0.3 g, 0.001 mol) were added to a solution of 1-allyl-cyclopropanesulfonic acid [7-(2-fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-a]pyridin-8-yl]-amide (0.19 g, 0.35 mmol) in dioxane (7 mL) and water (2 mL). The resulting mixture was stirred at room temperature for 5 hours. The reaction was monitored by TLC (5% MeOH in DCM). The reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with water, brine solution, dried over Na2SO4, filtered and the filtrate was concentrated. Purification by column chromatography on silica gel (2% MeOH in DCM) afforded 0.12 g of the product (63% yield). LCMS: m/z=549 (M+1)
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([C:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=2)=[CH:3]1.C([O-])=O.[NH4+]>[Pd].CO>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([CH:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)=[CH:3]1
Reactant: C1=C(c2coc3ccccc23)CCNC1
Agent: [Pd]
Agent: Cl
Agent: O=C[O-]
Solvent: CO
Product: c1ccc2c(C3CCNCC3)coc2c1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
A stirred mixture of 4-(benzofuran-3-yl)-1,2,3,6-tetrahydropyridine hydrochloride (1.57 g, 6.66 mmol), palladium on carbon (10%, 0.35 g, 0.33 mmol), ammonium formate (2.1 g, 33 3 mmol) and MeOH (61 ml) was heated at reflux conditions for 1 h, cooled to RT, filtrated and evaporated. The residue was diluted with ice-water (20 ml) and 3M NaOH (10 ml) and extracted with dichloromethane/methanol 9:1 (4×50 ml). The combined organic layers were washed with brine (1×25 ml), dried (MgSO4) and evaporated. The crude product (1.37 g) was purified by flash chromatography on silica gel (dichloromethane/methanol/NH4OH 65:10:1) to yield 4-(benzofuran-3-yl)-piperidine as a light yellow oil (1.1 g, 82%), MS (ISP) m/z=202.3 [(M+H)+].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.C(O)C.O1CCCC1.[BH4-].[Na+]>O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([CH2:10][OH:11])=[CH:12][CH:13]=1
Reactant: O=Cc1ccc(-c2nccs2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(-c2nccs2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.9 %

Procedure:
To 4-(thiazol-2-yl)benzaldehyde (see JP 2001-519414A) (1.57 g, 8.30 mmol) were added ethanol (20 ml), tetrahydrofuran (0.46 ml), and then sodium borohydride (157 mg, 4.15 mmol), followed by stirring at room temperature for 1.5 hours. After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=2:1→1:1 (V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (1.49 g) as a white solid. (Yield: 94%)
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH:15]([N:19]([CH2:29][CH2:30][CH3:31])[C:20](=O)[CH2:21][N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH2:16]2)=[CH:11][CH:10]=1.[OH-].[Na+]>C1COCC1>[CH3:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH:15]([N:19]([CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]3)[CH2:29][CH2:30][CH3:31])[CH2:16]2)=[CH:11][CH:10]=1
Reactant: CCCN(C(=O)CN1CCNCC1)C1CCc2ccc(OC)cc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCN(CCN1CCNCC1)C1CCc2ccc(OC)cc2C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 73.5 %

Procedure:
To a suspension of LiAlH4 (1.735 g, 45.73 mmol) in THF (100 ml) at 0° C. was added 7a (3.16 g, 9.15 mmol) in a solution of THF (25 ml). After addition, the mixture was refluxed for 2 h and cooled to 0° C. 15% NaOH was added dropwise to quench the reaction and deactivate the LiAlH4, and the mixture stirred for 20 min, and filtered, washed with ethyl acetate. The solution was dried over Na2SO4, filtered, and concentrated. This crude product was then purified through column chromatography using 20% MeOH in ethyl acetate to get 8a as transparent thick liquid (2.23 g, 74%). 1H NMR (400 MHz, CDCl3) δ ppm 0.91-0.96 (t, 3H, J=10 Hz), 1.40-1.6 (m, 3H), 1.97-2.01 (m, 1H), 2.139 (bs, 1H) 2.41-3.11 (m, 18H), 3.82 (s, 3H), 6.61 (s, 1H), 6.66-6.79 (d, 1H, J=6 Hz), 6.95-6.98 (d, 1H, J=8.8 Hz).
Reaction SMILES: C([O:5][C:6](=[O:30])[C@@H:7]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]2[C:20]3[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)[C:10]1=[O:29])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:28][C:27]1[C:20]2[C:19]([CH2:18][N:11]3[C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[N:9]([C@@H:7]([CH3:8])[C:6]([OH:30])=[O:5])[C:10]3=[O:29])=[CH:23][S:22][C:21]=2[CH:24]=[CH:25][CH:26]=1
Reactant: Cc1cccc2scc(Cn3c(=O)n([C@@H](C)C(=O)OC(C)(C)C)c4ccccc43)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc2scc(Cn3c(=O)n([C@@H](C)C(=O)O)c4ccccc43)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.3 %

Procedure:
To a solution of (S)-2-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionic acid tert-butyl ester (0.12 g, 0.28 mmol) in CH2Cl2 (5 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 3 h. When the reaction was complete, the reaction mixture was diluted with CH2Cl2 and washed with water. The organic phase was dried over Na2SO4 and concentrated. When a small amount of CH2Cl2 (˜3 mL) was added to the resulting residue, a white solid came out of the solution. This solid was filtered and dried to afford 69 mg (66%) of the titled compound. LCMS (ESMS): m/z 367.23 (M+H+).
Reaction SMILES: C(O[C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:22][CH:21]([CH2:23][CH2:24][CH3:25])[CH2:20][O:19][C:11]3=2)[N:6]=1)(C)C.[BH4-].[Na+]>FC(F)(F)C(O)=O>[CH2:23]([CH:21]1[CH2:20][O:19][C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[C:10]2[N:22]1[CH2:13][C:15]([F:18])([F:17])[F:16])[NH:6][CH2:5][CH:14]=[C:13]3[C:15]([F:18])([F:17])[F:16])[CH2:24][CH3:25]
Reactant: CCCC1COc2c(ccc3nc(OC(C)C)cc(C(F)(F)F)c23)N1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCCC1COc2c(ccc3c2C(C(F)(F)F)=CCN3)N1CC(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 284 %

Procedure:
Compound 119 was prepared according to General Method 6 (EXAMPLE 3) from (±)-3,4-dihydro-8-isopropoxy-3-propyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (16 mg, 0.05 mmol) and NaBH4 pellets (>10 equiv) in 11 mL trifluoroacetic acid (0.04 M) stirred at rt for 12 h to afford 27 mg of (+)-3,4-dihydro-3-propyl-4-(2,2,2-trifluoroethyl)-10-(trifluoromethyl)-8H-[1,4]oxazino[2,3-f]quinoline. This material (27 mg, 0.06 mmol) was carried on according to General Method 4 (EXAMPLE 1) by treatment with 1:1 acetic acid:concentrated HCl (0.03M) and heated at 90° C. for 6 h to afford 11 mg (50% for the 2 steps) of Compound 119 after flash chromatography (3:1 hexanes:EtOAc to 1:1 hexanes:EtOAc, gradient elution). 1H NMR (500 MHz, CDCl3) δ 11.78 (bs, 1H), 7.14 (s, 1H), 7.07 (d, J=8.8, 1H), 6.95 (d, J=8.8, 1H), 4.35 (dd, J=10.7, 1.5, 1H), 3.99 (dd, J=10.7, 2.4, 1H), 3.83 (m, 1H), 3.72 (m, 1H), 3.32 (m, 1H), 1.51 (m, 2H), 1.42 (m, 2H), 0.93 (t, J=7.3, 3H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:7]([CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>C(O)C.O>[CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:7]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(CCC(=O)OCC)n1Cc1ccccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCc1ncc(CCC(=O)O)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.4 %

Procedure:
A solution of ethyl 3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]propanoate (179 mg, 0.513 mmol) in ethanol (10 mL) was treated with sodium hydroxide (62 mg, 1.54 mmol) dissolved in water (2 mL). The solution was stirred for one hour at 25° C., cooled, acidified with 10% aqueous hydrochloric acid solution to pH 4.2 and concentrated to near dryness in vacuo. Water (3 mL) was added, and the resulting white solid was filtered, washed with water and dried to give 32 mg (20%) of 3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]propanoic acid; mp 163.5°-164.5° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:12][N:11]=[C:10]([CH3:13])[CH:9]=2)=[CH:6][CH:7]=1.[NH2:14][NH2:15]>C(O)(CC)C.O>[CH3:13][C:10]1[CH:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([NH:14][NH2:15])=[CH:7][CH:6]=2)[S:12][N:11]=1
Reactant: Cc1cc(-c2ccc(Cl)nn2)sn1
Reactant: NN
Solvent: CCC(C)O
Solvent: O
Product: Cc1cc(-c2ccc(NN)nn2)sn1
Temperature: 130 °C

Procedure:
A mixture of 3-chloro-6-(3-methylisothiazol-5-yl)pyridazine (0.85 g, 4.0 mmol) and anhydrous hydrazine (3.8 ml, 120 mmol) in 30 mL of sec-BuOH was heated at 130° C. for 3 hours. The mixture was cooled to 23° C. and diluted with 5 mL of water. The solid was collected by filtration and was washed by 2 mL of water to produce a yellow solid. MS (ESI pos. ion) m/z: 208 (MH+). Calc'd exact mass for C8H6ClN3S: 207.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][C:17]=2[C:18]#[C:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[CH:21]=2)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1.[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][C:17]=2[C:18]#[C:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:34]([NH:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:35])[CH:21]=2)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1cc(-c2cnn(C)c2)cn2ncc(C#Cc3ccnc(N)c3)c12
Solvent: ClCCl
Product: COc1cc(-c2cnn(C)c2)cn2ncc(C#Cc3ccnc(NC(=O)Nc4ccccc4)c3)c12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-{[4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]ethynyl}pyridin-2-amine (24 mg, 0.07 mmol) in dichloromethane (1400 μl) was added phenyl isocyanate (9.09 μl, 0.084 mmol) and the mixture was allowed to stir for 72 hours at room temperature. The precipitated solid was filtered was filtered and the washed with 10 mL of dichloromethane. The solid was dried in vacuo to afford N-(4-{[4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]ethynyl}pyridin-2-yl)-N′-phenylurea. 1H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H); 9.46 (s, 1H); 8.69 (s, 1H); 8.28 (s, 1H); 8.23-8.21 (m, 2H); 8.01 (s, 1H); 7.56 (s, 1H); 7.47 (d, 2H); 7.26 (t, 2H); 7.04 (s, 1H); 6.98-6.96 (m, 2H); 4.05 (s, 3H); 3.82 (s, 3H). LRMS (ESI) calculated for C26H21N7O2 [M+H]+, 464.2; found 464.1.
Reaction SMILES: Cl.[S:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.Br[CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])[C:13]([OH:15])=[O:14].[OH-].[K+].Cl>O.CO>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH:12]([N:7]1[CH2:8][CH2:9][C:10]2[S:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)[C:13]([OH:15])=[O:14]
Reactant: c1cc2c(s1)CCNC2
Reactant: O=C(O)C(Br)c1ccccc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 40 °C
Yield: 93.3 %

Procedure:
50.0 g of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride and 74.6 g of α-bromo-(2-chlorophenyl)acetic acid were successively added to a mixture of 275 ml of water and 75 ml of methanol, and the resulting solution was cooled to below 10° C. while stirring. 63.9 g of 85.0% KOH dissolved in 142 ml of water was slowly added to the above solution while maintaining the temperature at below 15° C. The resulting transparent solution was heated to 40° C. and stirred at that temperature for 3 hrs. The pH of the reaction solution was adjusted to 3.5 with 6N-HCl, cooled to room temperature and stirred for 2 hrs. Then, the reaction mixture was further cooled to below 5° C. and stirred for 2 hrs. The precipitated crystals were filtered, washed sequentially with 150 ml of water and 100 ml of n-hexane, and dried at 40° C. to obtain 81.7 g of the title compound (yield: 88%) as a white-yellow monohydrate.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:11]1([CH:17]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:18][NH2:19])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[C:20]1[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=1)=[O:6]
Reactant: NCC(c1ccncc1)N1CCOCC1
Reactant: Cc1ccccc1C(=O)O
Product: Cc1ccccc1C(=O)NCC(c1ccncc1)N1CCOCC1

Procedure:
From 2-methylbenzoic acid and (2-morpholin-4-yl-2-pyridin-4-ylethyl)amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH2:9][CH3:10])[CH:8]=1)[NH2:5].[CH2:11]([O:13][C:14]([C:16]#[C:17][C:18](OCC)=[O:19])=[O:15])[CH3:12]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:6]([C:18](=[O:19])[CH:17]=[C:16]([C:14]([O:13][CH2:11][CH3:12])=[O:15])[NH:5]2)=[C:7]([CH2:9][CH3:10])[CH:8]=1
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: CCc1cc(N)cc(Cl)c1
Product: CCOC(=O)c1cc(=O)c2c(CC)cc(Cl)cc2[nH]1

Procedure:
Reaction of 3-chloro-5-ethylaniline (0.9 g) with diethylacetylene dicarboxylate (0.93 ml) as described in Example 1b gave a mixture of the two 5,7-regioisomers (800 mg). The isomers were separated by silica chromatography to give ethyl 7-chloro-5-ethyl-4-oxo-1,4-dihydroquinoline-2 -carboxylate (250 mg), mp 222°-3° C.; δ (360 MHz, DMSO-d6) 1.15 (3H, t, CH2CH3), 1.36 (3H, t, CO2CH2CH3), 3.25 (2H, q, CH2CH3), 4.42 (2H, q, CO2CH2) 6.57 (1H, s, 3-H), 7.12 (1H, d, 8-H), 7.87 (1H, d, 6-H) and 11.75 (1H, bs, NH); and ethyl 5-chloro-7-ethyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (200 mg), mp 182°-3° C.; δ (360 MHz, DMSO-d6) 1.21 (3H, t, CH2CH3), 1.35 (3H, t, CO2CH2CH3), 2.67 (2H, q, CH2CH3), 4.40 (2H, q, CO2CH2) 6.56 (1H, s, 3-H), 7.28 (1H, d, 6-H), 7.73 (1H, d, 8-H) and 11.78 (1H, bs, NH).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[N:22][C:23]([N:26]2[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27]2)=[N:24][CH:25]=1>>[OH:31][C@H:28]1[CH2:29][CH2:30][N:26]([C:23]2[N:24]=[CH:25][C:20]([NH:19][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:21][N:22]=2)[CH2:27]1
Reactant: Nc1cnc(N2CC[C@H](O)C2)nc1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: O=C(Nc1cnc(N2CC[C@H](O)C2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a method similar to example 43 above, (S)-2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid-[2-(3-hydroxypyrrolidin-1-yl)pyrimidin-5-yl]amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (S)—N-(5-aminopyrimidin-2-yl)-pyrrolidin-3-ol. LCMS calcd for C19H16F3N5O3 m/e 419.37, obsd 420.1 (ES, M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.O>CN(C=O)C.CCCCCCC.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[N:7]([CH2:26][C:25]1[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=1)[CH:6]=[CH:5]2
Reactant: Cc1cc2c(=O)[nH]ccc2cc1F
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: COc1ccc(Cn2ccc3cc(F)c(C)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 9.17 g (51.8 mmol) of 6-fluoro-7-methyl-2H-isoquinolin-1-one in 80 ml of DMF were added 20.2 g (62.1 mmol) of cesium carbonate and then 8.92 g (56.9 mmol) of 4-methoxybenzylchloride. After stirring at room temperature for 90 minutes the reaction mixture was poured into 600 ml of water, stirred for 1 h, and then the precipitated product was isolated by suction. From the mother liquor additional producted was isolated by chromatography with heptane/ethyl acetate (80:20). The combined products were recrystallized from ethyl acetate and 8.39 g 6-fluoro-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one were received.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:34]=[CH:33][C:16]([C:17]([O:19][C:20]([CH3:32])([CH3:31])[C:21]([O:23]CC2C=CC=CC=2)=[O:22])=[O:18])=[CH:15][C:14]=1[O:35][CH2:36][CH:37]1[CH2:39][CH2:38]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:34]=[CH:33][C:16]([C:17]([O:19][C:20]([CH3:32])([CH3:31])[C:21]([OH:23])=[O:22])=[O:18])=[CH:15][C:14]=1[O:35][CH2:36][CH:37]1[CH2:38][CH2:39]1)[S:9]([CH3:12])(=[O:10])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(c1ccc(C(=O)OC(C)(C)C(=O)OCc2ccccc2)cc1OCC1CC1)S(C)(=O)=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N(c1ccc(C(=O)OC(C)(C)C(=O)O)cc1OCC1CC1)S(C)(=O)=O
Yield: 96 %

Procedure:
To a mixture of 1-(benzyloxy)-2-methyl-1-oxopropan-2-yl 4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoate (0.5 g, 0.890 mmol) and 10% Pd/C (0.100 g) in MeOH (30 ml), ammonium formate (0.337 g, 5.34 mmol) was added, and the mixture was heated to reflux for 1 hour. After cooling the catalyst was filtered off and the solvent was evaporated; the residue was dissolved in ethyl acetate and washed with 0.5N HCl and brine. The organic phase was dried over Na2SO4, filtered and evaporated to give 2-(4-(N-(tert-butoxycarbonyl)-methylsulfonamido)-3-(cyclopropylmethoxy)benzoyloxy)-2-methylpropanoic acid as a white powder (0.402 g, 0.853 mmol, 96% yield, MS/ESI+ 493.9 [MNa]+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]([C:9]([F:12])([F:11])[F:10])[CH:4]([C:6]([OH:8])=[O:7])[NH2:5].[Si](C=[N+]=[N-])(C)(C)[CH3:16].C[Si](C)(C)C.CO.C(Cl)(Cl)Cl>C(Cl)Cl.CO>[NH2:5][CH:4]([CH:3]([C:9]([F:11])([F:10])[F:12])[C:2]([F:13])([F:14])[F:1])[C:6]([O:8][CH3:16])=[O:7]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: NC(C(=O)O)C(C(F)(F)F)C(F)(F)F
Solvent: C[Si](C)(C)C
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)C(N)C(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4,4,4,4′,4′,4′-hexafluoro-DL-valine (2.00 g, 8.89 mmol) in CH2Cl2:MeOH (4:1, 50 mL) was stirred under nitrogen at 0° C. Tetramethylsilane (TMS) diazomethane (5.33 mL, 2.0 M in hexane) was added dropwise, and the resulting solution stirred for 3 h at 25° C. After this time period, the reaction was complete by TLC (10% MeOH:chloroform). After concentration, the resulting residue (1.34 g, 63%) was used directly in the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[O:6]CCO1.[C:17]1([C:23]2[O:27][CH:26]=[N:25][C:24]=2[C:28](O)=[O:29])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13]([NH:16][C:28]([C:24]2[N:25]=[CH:26][O:27][C:23]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:29])=[N:12]1
Reactant: CC1(CCCCn2ccc(N)n2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)CCCCn1ccc(NC(=O)c2ncoc2-c2ccccc2)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-3-ylamine and 5-phenyl-oxazole-4-carboxylic acid.