Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].Cl.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35]Cl.O>CN(C)C=O>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Reactant: CN(C)CCCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(=O)c1cnc2c(OCCN(C)C)cccc2c1Nc1ccccc1C
Reaction time: 2 h
Yield: 25.5 %

Procedure:
3-Butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (3.2 g, 10 mmol) and potassium t-butoxide (5.0 g, 40 mmol) were stirred in dry dimethylformamide at 80° and 2-dimethylaminoethyl chloride hydrochloride (2.9 g, 20 mmol) added. The mixture was stirred for 2 hours, poured into water and extracted with ether. The extracts were dried and evaporated. Chromatography (silica gel, 3-5% methanolic ammonia in dichloromethane) and recrystallisation from ether gave 3-butyryl-4-(2-methylphenylamino)-8-(2-dimethylaminoethoxy)quinoline (1.0 g, 34%), m.p. 88°-90°.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH2:15][N:16]([CH3:34])[S:17]([C:20]1[CH:29]=[CH:28][C:27]2[NH:26][C:25](=[O:30])[C:24]3[NH:31][CH:32]=[CH:33][C:23]=3[C:22]=2[CH:21]=1)(=[O:19])=[O:18])=[O:14])(C)(C)C.[CH2:35]([C:38]([O-:40])=[O:39])[CH2:36][CH3:37]>ClC(Cl)C>[C:13]([CH2:15][N:16]([CH3:34])[S:17]([C:20]1[CH:29]=[CH:28][C:27]2[NH:26][C:25](=[O:30])[C:24]3[NH:31][CH:32]=[CH:33][C:23]=3[C:22]=2[CH:21]=1)(=[O:19])=[O:18])([OH:14])=[O:12].[CH2:35]([C:38]([O-:40])=[O:39])[CH2:36][CH3:37]
Reactant: CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: CCCC(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: CN(CC(=O)O)S(=O)(=O)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
Trifluoroacetic acid (1 mL) is added slowly to a solution of 95 mg (0.2 mmol) of 8-(tert-butoxycarbonylmethyl-methyl-sulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-propyl carboxylate dissolved in 9 mL of dichloroethane. The solution is stirred at room temperature for 5 hours then the solvents are evaporated. The residue is taken up and triturated in acetonitrile then in diisopropyl ether to give 76 mg (90%) of 8-(carboxymethyl-methyl-sulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-propyl carboxylate in the form of a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=O)[CH:8]=2)[CH:3]=[CH:2]1.N1C=CC=CC=1.Cl.[O:19]([NH2:21])[CH3:20]>O>[CH3:20][O:19][N:21]=[CH:10][C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][NH:1]2)=[CH:5][CH:6]=1
Reactant: O=Cc1ccc2cc[nH]c2c1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CON=Cc1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.6 %

Procedure:
An amount of 1H-Indole-6-carbaldehyde (50 mg, 0.34 mmol) is added to pyridine (2.0 ml) at room temperature, followed by addition of methoxylamine hydrogen chloride (31.6 mg, 0.38 mmol). The mixture is stirred at ambient temperature for 24 h, and 10 mL of water is added. After the solvents were evaporated, the residue is dissolved 10 mL of anhydrous ether, washed successively with 10 mL of aqueous sodium bicarbonate, 10 mL of sodium bisulfite, and 10 mL of brine. Dried over magnesium sulfate, evaporated to give a white solid (49 mg, 0.281 mmol). MS (ESI) m/z 176.3 (M+1)
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([SH:19])[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:21][C:22]1[S:23][CH:24]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[CH:26]=1>>[C:1]12([C:11]3[CH:12]=[C:13]([S:19][CH2:21][C:22]4[S:23][CH:24]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[CH:26]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: COc1ccc(S)cc1C12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)c1csc(CBr)c1
Product: COC(=O)c1csc(CSc2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)c1

Procedure:
In a manner analogous to that of Example 17(a), 800 mg (2.9 mmol) of 3-(1-adamantyl)-4-methoxythiophenol were reacted with 690 mg (2.9 mmol) of methyl 2-bromomethyl-4-thiophenecarboxylate and 700 mg (56%) of the expected methyl ester were recovered in the form of a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:26](O)(=[O:35])[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCN=C=NCCCN(C)C>>[C:29]1([CH2:28][CH2:27][C:26]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(O)CCc1ccccc1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)CCc4ccccc4)c3)c2c1
Yield: 14.4 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (200 mg, 0.56 mmol) with hydrocinnamic acid (0.11 g, 0.71 mmol) and EDCI (0.17 g, 0.89 mmol) furnished 31 mg (13% yield) of the title compound. 1H NMR (DMSO-d6) δ 13.4 (s, 1H), 10.2 (s, 1H), 8.6 (s, 1H), 8.2 (s, 1H), 8.1 (br s, 1H), 7.9 (d, 1H), 7.75 (m, 2H), 7.6 (d, 1H), 7.5 (t, 1H), 7.4–7.1 (m, 5H), 2.95 (t, 2H), 2.68 (t, 2H); ES-MS (m/z) 385 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([F:14])([F:13])[O:7][C:8]2([F:12])[F:11])=[CH:4][C:3]=1[OH:15].[Cl:16][C:17]1[CH:25]=[N:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[Cl:16][C:17]1[CH:25]=[N:24][CH:23]=[CH:22][C:18]=1[C:19]([NH:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[OH:15])[C:6]([F:14])([F:13])[O:7][C:8]2([F:11])[F:12])=[O:20]
Reactant: O=C(O)c1ccncc1Cl
Reactant: Nc1cc2c(cc1O)C(F)(F)OC2(F)F
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cc2c(cc1O)C(F)(F)OC2(F)F)c1ccncc1Cl
Temperature: 80 °C
Yield: 61.5 %

Procedure:
A mixture of 0.68 g of 6-amino-1,1,3,3-tetrafluoro-5-hydroxy-1,3-dihydroisobenzofuran, 0.48 g of 3-chloroisonicotinic acid, 0.76 g of WSC and 7 ml of pyridine was stirred while heating at 80° C. for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.68 g of 3-chloro-N-(1,1,3,3-tetrafluoro-6-hydroxy-1,3-dihydroisobenzofuran-5-yl)isonicotinamide.
Reaction SMILES: Cl[S:2]([C:5]1[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl>[C:14]([NH:18][S:2]([C:5]1[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)N
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)o1
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)(=O)NC(C)(C)C)o1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 5-(chlorosulfonyl)-2-furoate (3.0 g) in DCM (100 mL) was added tert-butylamine (3.6 mL). After stirring at room temperature for 2 days the mixture was filtered through a pad of celite, washing with DCM (2×10 mL). The filtrate was evaporated to dryness in vacuo. The resulting crude residue was purified by column chromatography using EtOAc/isohexane (2:8) as eluent to give the subtitle compound as a foam Yield: 2.75 g.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][C:23]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:26][C:25]2[CH:28]=[CH:29][C:22]([F:21])=[C:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[CH:24]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1ccc(F)c(-c2ccccn2)c1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1ccc(F)c(-c2ccccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with 4-fluoro-3-(pyridin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.74 min.; [M+H]+: 435.13 g/mol.
Reaction SMILES: [CH:1]([O-])([O-])OC.[C:6]([NH:9][C:10]1[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=1)[NH:13][C:14](=[O:19])[CH2:15][C:16](=[O:18])[CH3:17])(=[O:8])[CH3:7].N1C2C(=CC=CC=2)C=CC=1>CO>[C:6]([NH:9][C:10]1[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=1)[NH:13][C:14](=[O:19])/[CH:15]=[C:16](\[O:18][CH3:1])/[CH3:17])(=[O:8])[CH3:7]
Reactant: COC([O-])[O-]
Reactant: CC(=O)CC(=O)Nc1cccc(NC(C)=O)c1
Solvent: CO
Solvent: c1ccc2ncccc2c1
Product: CO/C(C)=C\C(=O)Nc1cccc(NC(C)=O)c1
Temperature: 140 °C
Yield: 58.5 %

Procedure:
11.7 g of methyl orthoformate were added to a solution of 23.4 g of m-acetamido-acetylacetanilide in 250 ml of anhydrous methanol and the mixture was refluxed for 3 hours and cooled. 0.6 ml of quinoline were added thereto and the methanol was distilled off under reduced pressure. Toluene was added to the residue and the mixture was heated at 140° C. for one hour while distilling a methanol-toluene azeotrope. The mixture was then concentrated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with ethyl acetate yielded 14.5 g of m-acetamido-3-methoxy-crotonanilide melting at 167° C. Crystallization from acetone did not change the melting point.
Reaction SMILES: [NH2:1][C:2]1[CH2:3][C:4]([C:14]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[O:15])=[CH:5][C:6]2[CH:12]=[CH:11][C:10](Br)=[CH:9][C:7]=2[N:8]=1.[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+]>O.CC#N>[NH2:1][C:2]1[CH2:3][C:4]([C:14]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[O:15])=[CH:5][C:6]2[CH:12]=[CH:11][C:10]([C:27]3[CH:28]=[N:23][CH:24]=[N:25][CH:26]=3)=[CH:9][C:7]=2[N:8]=1
Reactant: OB(O)c1cncnc1
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(Br)cc2N=C(N)C1
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3cncnc3)cc2N=C(N)C1

Procedure:
The title compound was prepared by the procedure as described in Example 124 (Step F) using (1E,4E)-2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide, pyrimidin-5-ylboronic acid, and sodium 2′-(dicyclohexylphosphino)-2,6-dimethoxybiphenyl-3-sulfonate in H2O-MeCN. MS APCI (+) m/z 364 (M+1) detected; 1H-NMR (400 MHz, CDCl3) d 9.21 (s, 1H), 9.01 (s, 2H), 7.50 (s, 1H), 7.43 (d, 1H), 7.27-7.29 (m, 1H), 6.84 (s, 1H), 3.47 (br s, 4H), 2.84 (s, 2H), 1.63-1.72 (m, 4H), 0.94 (t, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[O:20][CH3:21].[F:23][C:24]([F:39])([F:38])[C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[N:33]=1)[C:28](O)=[O:29]>>[CH3:1][O:2][C:3](=[O:22])[CH2:4][N:5]([C:28]([C:27]1[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[N:33]=[C:25]([C:24]([F:39])([F:23])[F:38])[CH:26]=1)=[O:29])[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[O:20][CH3:21]
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: COC(=O)CNc1cnccc1-c1cc(F)c(F)cc1OC
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1)c1cnccc1-c1cc(F)c(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4,5-difluoro-2-methoxy-phenyl)-pyridin-3-ylamino]-acetic acid methyl ester (example 172, intermediate a) and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 72 hours. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:80). Colorless solid (48%). MS (ESI): m/z=550.102 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:14]([S:15]CC3C=CC=CC=3)=[N:13][N:12]=[N:11]2)[CH2:4][CH2:3]1.C(O)(=O)C.[BrH:27]>O>[BrH:27].[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]2[C:14]([SH:15])=[N:13][N:12]=[N:11]2)[CH2:6][CH2:7]1
Reactant: CN1CCN(CCn2nnnc2SCc2ccccc2)CC1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CN1CCN(CCn2nnnc2S)CC1

Procedure:
A mixture of 1-[2-(4-methyl-1-piperazinyl)ethyl]-5 benzylthio-1H-tetrazole (5.4 g), acetic acid (40 ml) and conc. hydrobromic acid (40 ml) was heated at 70° to 80° C. for 8 hours. After the concentration of the reaction mixture, the concentrate was diluted with water. The mixture was washed with diethyl ether twice and evaporated under reduced pressure. The residue was recrystallized from methanol. A solution of the obtained crystals in a little amounted of water was adjusted to pH 6.0 with 1 N aqueous solution of potassium hydroxide., washed with ethyl acetate and then evaporated under reduced pressure. To the residue was added hot ethanol and insoluble materials were filtered out. The filtrate was cooled and the precipitated crystals were collected by filtration to give 1-[2-(4-methyl-1-piperazinyl)ethyl]-1H-tetrazole-5-thiol hydrobromide (1.1 g), mp 216° to 222° C.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([F:30])([F:29])[F:28])[O:23][CH2:22][C:21]2[N:16]3[C@H:17]([CH3:32])[C:18](=[O:31])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[NH:8]1[CH2:9][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([F:30])([F:28])[F:29])[O:23][CH2:22][C:21]2[N:16]3[C@H:17]([CH3:32])[C:18](=[O:31])[NH:19][N:20]=2)[CH2:11]1
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(C(F)(F)F)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1C(=O)NN=C2COc3cc(C(F)(F)F)c(NC4CNC4)cc3N21

Procedure:
A solution of 3-(4(R)-methyl-3-oxo-7-trifluoromethyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester ((Enantiomer 2, SFC (Table 1, Method 6), Rt=10.53 min., 0.260 g, 0.57 mmol) in DCM (10 mL) and TFA (2 mL) was stirred at ambient temperature for 1 h. The solvent was removed in vacuo to give 6-(azetidin-3-ylamino)-4(R)-methyl-7-trifluoromethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid as a pale yellow solid (Example #53-2, Enantiomer 2, SFC (Table 1, Method 7), Rt=7.98 min, 0.260 g, 97%). LC/MS (Table 1, Method 5) Rt=2.068 min.; MS m/z: 356 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][C@@H:9]1[CH2:11][O:10]1)([CH3:4])([CH3:3])[CH3:2].O.[NH3:14]>C(O)C>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][C@@H:9]([OH:10])[CH2:11][NH2:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CO1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC[C@@H](O)CN
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(R)-1-Oxiranylmethylcarbamic acid tert-butyl ester (2.26 g, 13.05 mmol) obtained in Step 2 above was dissolved in ethanol (15 ml), and then 28% ammonia water (6 ml) was added thereto at room temperature. After the solution was stirred at room temperature for 1.5 hour, the solvent was distilled off under reduced pressure. After the resulting residue was dissolved in methanol, the solvent was distilled off under reduced pressure to give a crude product of ((S)-3-amino-2-hydroxypropyl)carbamic acid tert-butyl ester (2.38 g) as a yellow oily material.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][C:6](=[O:8])[O:5][C:3]1=O.[NH2:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18]C)=[O:16])=[CH:13][CH:12]=1.CC1(C)CC(=O)OC(=O)C1>>[CH3:9][C:2]1([CH3:1])[CH2:7][C:6](=[O:8])[N:10]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:20][CH:21]=2)[C:3]1=[O:5]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CC1(C)CC(=O)OC(=O)C1
Product: COC(=O)c1ccc(N2C(=O)CC(C)(C)C2=O)cc1

Procedure:
The desired product was prepared by substituting methyl 4-aminobenzoate and 2,2-dimethylsuccinic anhydride for ethyl 4-aminobenzoate and 3,3-dimethylglutaric anhydride, respectively, in Example 119A. MS (DCI) mle 262 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>O.CO.[Pd]>[C:14]1([C@H:12]2[C@@H:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:10][CH2:9][NH:8][CH2:13]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C1=C(c2ccccc2)CN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CCOC(=O)[C@H]1CCNC[C@H]1c1ccccc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a mixture of 9.98 g of ethyl 1-benzyl-5-phenyl-1,2,3,6-tetrahydropyridine-4-carboxylate, 10.31 g of ammonium formate, and 90 mL of methanol was added 1.49 g of 10% palladium/carbon while suspending it in 10 mL of water and 10 mL of methanol. The reaction mixture was vigorously stirred at 60° C. for 2 hours. After cooling to room temperature, the insolubles were filtered on a celite layer, and the filtrate was concentrated under reduced pressure. To the obtained residue was added chloroform, followed by washing with saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and dried to obtain 7.09 g of a pale yellow oily substance of ethyl rel-(3R,4S)-3-phenylpiperidine-4-carboxylate as a crude product. ESI+: 234
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:21]3[O:20][C:19]([CH2:22][CH3:23])=[N:18][C:17]=3[C:16]([O:24][CH:25]([F:27])[F:26])=[CH:15][CH:14]=2)=[O:12])=CC=1)([O-])=O.[CH3:28][N:29]1[C:33]([NH2:34])=[CH:32][CH:31]=[N:30]1.C(OCC)C>CCCCCC>[CH3:28][N:29]1[C:33]([NH:34][C:11]([C:13]2[C:21]3[O:20][C:19]([CH2:22][CH3:23])=[N:18][C:17]=3[C:16]([O:24][CH:25]([F:26])[F:27])=[CH:15][CH:14]=2)=[O:12])=[CH:32][CH:31]=[N:30]1
Reactant: Cn1nccc1N
Reactant: CCc1nc2c(OC(F)F)ccc(C(=O)Oc3ccc([N+](=O)[O-])cc3)c2o1
Solvent: CCOCC
Solvent: CCCCCC
Product: CCc1nc2c(OC(F)F)ccc(C(=O)Nc3ccnn3C)c2o1
Yield: 15.7 %

Procedure:
Starting from 4-difluoromethoxy-2-ethylbenzooxazole-7-carboxylic acid 4-nitro-phenyl ester (100 mg) and 2-methyl-2H-pyrazole-3-ylamine (51 mg). Purification by column chromatography on silica eluting with ethyl acetate afforded, after trituration with a mixture of diethyl ether and hexane, the title compound as a pale yellow solid (14mg).
Reaction SMILES: C(OC(C)(C)C)(=O)[NH:2][NH2:3].[CH3:10][C:11]1[O:15][C:14]([C:16](Cl)=[O:17])=[CH:13][CH:12]=1>C(Cl)Cl>[CH3:10][C:11]1[O:15][C:14]([C:16]([NH:2][NH2:3])=[O:17])=[CH:13][CH:12]=1
Reactant: Cc1ccc(C(=O)Cl)o1
Reactant: CC(C)(C)OC(=O)NN
Solvent: ClCCl
Product: Cc1ccc(C(=O)NN)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl carbazate (549 mg, 4.15 mmol) was added to a methylene chloride (10 mL) solution of commercially available 5-methylfuran-2-carbonyl chloride (500 mg, 3.46 mmol) under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and then, the residue was dissolved in methylene chloride (10 mL). To the solution, trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated to obtain 5-methylfuran-2-carbohydrazide.
Reaction SMILES: CSC.B.[F:5][C:6]1([F:25])[O:23][C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH2:9][NH:8][C:7]1=O.CN(C)CCN.O1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH2:33]([N:8]1[CH2:7][C:6]([F:25])([F:5])[O:23][C:10]2([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[CH2:9]1)[C:34]#[C:35][CH3:36]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)C(F)(F)O2
Agent: B
Agent: CN(C)CCN
Solvent: CSC
Product: CC#CCN1CC(F)(F)OC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 55 °C

Procedure:
Borane dimethylsulfide (36.3 μL, 0.408 mmol) was added dropwise to a solution of tert-butyl 10,10-difluoro-9-oxo-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (125 mg, 0.408 mmol) in tetrahydrofuran (3 mL). The reaction mixture was heated at 55° C. for 2 h then cooled to room temperature. The mixture was quenched with the careful dropwise addition of methanol (˜2 mL). N,N-dimethylethane-1,2-diamine (33.3 μL, 0.313 mmol) was then added and the mixture heated at 70° C. for 40 min. The reaction was concentrated, and silica gel chromatography (4 g silica, 1% triethylamine/4% methanol/dichloromethane)) provided tert-butyl 8-but-2-ynyl-10,10-difluoro-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate which was taken directly to the next reaction.
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1CC(CC[Si](OC)(OC)OC)[CH2:5][CH2:6]2.COC([SiH3])(OC)OC.C1([Si](OC)(OC)OC)C=CC=CC=1.[C:38](O)(=O)[C:39]([OH:41])=[O:40]>CO.O>[C:39]([O:41][CH:6]([CH3:5])[CH2:7][O:1][CH3:2])(=[O:40])[CH3:38]
Reactant: O=C(O)C(=O)O
Reactant: CO[Si](CCC1CCC2OC2C1)(OC)OC
Agent: COC([SiH3])(OC)OC
Agent: CO[Si](OC)(OC)c1ccccc1
Solvent: CO
Solvent: O
Product: COCC(C)OC(C)=O
Temperature: 40 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
In a 1000 ml glass flask, to a mixture of 150 g of methanol, 22 g of 2-(3,4-epoxycyclohexyl) ethyl trimethoxy silane, 77 g of trimethoxymethyl silane, 14 g of phenyl trimethoxy silane, and 1.5 g of oxalic acid was added dropwise a mixed solution of 40 g of deionized water and 20 g of methanol at a liquid temperature of 40 degrees C. After that, this solution was stirred for 12 hours at 40 degrees C. After the reaction finished, the solvent was removed under a reduced pressure. Thus-obtained residue was dissolved in 1000 ml of ethyl acetate, and washed with deionized water for washing. After the water layer was separated, the organic layer was washed twice with deionized water. To this organic layer was added 600 g of propylene glycol monomethyl ether acetate (PGMEA), and the contents were heated up to a liquid temperature of 40 degrees C. under a reduced pressure to remove ethyl acetate and to give a PGMEA solution of a polymer.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[NH:8][C:7](=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:24])=O.C(N(CCC)CCC)CC>>[C:1]([C:5]1([Cl:24])[NH:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])=[N:8][CH:7]=[CH:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(=O)[nH]c(-c2ccccc2C(F)(F)F)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: CCCN(CCC)CCC
Product: CC(C)(C)C1(Cl)C=CN=C(c2ccccc2C(F)(F)F)N1
Temperature: 115 °C
Yield: 65.5 %

Procedure:
A solution of 6-tert-butyl-2-(2-trifluoromethyl-phenyl)-3H-pyrimidin-4-one (0.47 g, 1.59 mmol) in phosphorous oxychloride (1.65 mL, 15.9 mmol) was treated with tri-n-propylamine (0.61 mL, 3.17 mmol) and heated at 110-120° C. for 1 hour. The solvent was removed by evaporattion then azeotroped three times with toluene. The residue was taken up in ethyl acetate, washed sequentially with 1 N sodium hydroxide, water and brine, then dried over sodium sulfate and concentrated. Purification by flash chromatography [SiO2, ethyl acetate:hexanes (1:9)] provided the title compound (0.33 g, 66% yield) as a yellow oil. 1H NMR (CDCl3, 500 MHz) δ 1.31 (9H, s), 7.25 (s, 1H), 7.51 (t, J=7.6 Hz, 1H), 7.58 (t, J=7.5 Hz, 1H), 7.74 (t, J=8.5 Hz, 2H) ppm; MS (FIA) 314.9 (M+H); Rt (Method A) 4.156 minutes.