Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:10]2=[C:11]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[N:12]=[C:13]([C:15]3[NH:19][N:18]=[N:17][N:16]=3)[CH:14]=[C:9]2[C:8]([CH3:30])=[C:7]1[CH3:31].[C:35](=O)([O-])[O-].[K+].[K+].CN(C)C=O.IC>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:10]2=[C:11]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[N:12]=[C:13]([C:15]3[N:19]([CH3:35])[N:18]=[N:17][N:16]=3)[CH:14]=[C:9]2[C:8]([CH3:30])=[C:7]1[CH3:31]
Reactant: Cc1c(C)n(Cc2cccc(Cl)c2)c2c(N3CCc4ccccc4C3)nc(-c3nnn[nH]3)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1c(C)n(Cc2cccc(Cl)c2)c2c(N3CCc4ccccc4C3)nc(-c3nnnn3C)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.8 %

Procedure:
2-[1-(3-Chlorobenzyl)-2,3-dimethyl-5-(1H-tetrazol-5-yl)-1H-pyrrolo[2,3-c]pyridin-7-yl]-1,2,3,4-tetrahydroisoquinoline (50 mg, 0.11 mmol) prepared in Example 852 and potassium carbonate (22.1 mg, 0.16 mmol) were dripped into anhydrous N,N-dimethylformamide (1 ml). Iodomethane (10 μl, 0.16 mmol) was added to the reaction mixture, which was then stirred overnight at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/3, v/v) to give 18 mg of the titled compound as a white solid (Yield: 34%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([OH:9])[C:3]=1[CH2:10][CH2:11][CH:12]1[O:17][C:16](=[O:18])[CH2:15][CH:14]([OH:19])[CH2:13]1.[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1.ClC1C=C(O)C(=C(Cl)C=1)C=O.C(Br)C1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:30])[F:31])=[CH:29][CH:28]=2)[C:3]=1[CH2:10][CH2:11][CH:12]1[O:17][C:16](=[O:18])[CH2:15][CH:14]([OH:19])[CH2:13]1
Reactant: O=C1CC(O)CC(CCc2c(O)cc(Cl)cc2Cl)O1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: BrCc1ccccc1
Agent: O=Cc1c(O)cc(Cl)cc1Cl
Product: O=C1CC(O)CC(CCc2c(Cl)cc(Cl)cc2OCc2ccc(C(F)(F)F)cc2)O1

Procedure:
By following the procedure of Example 1, step A, but substituting equimolar amounts of 6-{2-(2,4-dichloro-6-hydroxyphenyl)ethyl}-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one and 4-trifluoromethylbenzyl bromide for the 4,6-dichlorosalicylaldehyde and benzyl bromide used therein, the title compound is obtained, m.p. 104°-105° C.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)[NH:4][N:3]=1.[CH3:15]C([O-])(C)C.[K+].IC>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:13])([F:12])[F:14])[CH:9]=2)[N:4]([CH3:15])[N:3]=1
Reactant: FC(F)(F)c1ccc2[nH]nc(I)c2c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1nc(I)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
To a solution of 3-iodo-5-(trifluoromethyl)-1H-indazole (4.0 g, 12.8 mmol) in THF (80 mL) was added t-BuOK (2.0 g, 17.9 mmol) slowly at 0° C. and mixture stirred for 30 minutes, iodomethane (1.1 mL, 17.9 mmol) was added at 0° C., then warmed to room temperature and stirred for 1.5 hours, quenched with water (30 mL) and extracted with EtOAc (3×30 mL), the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was washed with ether (5 mL) and filtered to give 3-iodo-1-methyl-5-(trifluoromethyl)-1H-indazole (3.3 g, 79.3%) as a white solid. LCMS: (M+H)+=327.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH3:23][Si:24]([CH3:53])([CH3:52])[C:25]1[CH:26]=[C:27]([CH:45]=[C:46]([Si:48]([CH3:51])([CH3:50])[CH3:49])[CH:47]=1)[C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34](/[C:37](/[CH3:44])=[CH:38]/[C:39]([O:41]CC)=[O:40])=[CH:33][CH:32]=1)=O>C1(C)C=CC=CC=1>[CH3:23][Si:24]([CH3:53])([CH3:52])[C:25]1[CH:26]=[C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34](/[C:37](/[CH3:44])=[CH:38]/[C:39]([OH:41])=[O:40])=[CH:33][CH:32]=2)=[S:10])[CH:45]=[C:46]([Si:48]([CH3:51])([CH3:50])[CH3:49])[CH:47]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)/C=C(\C)c1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1
Solvent: Cc1ccccc1
Product: C/C(=C\C(=O)O)c1ccc(NC(=S)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1
Yield: 168.1 %

Procedure:
Lawesson's reagent (134 mg) was added to a toluene (5 ml) solution of Compound 19c (300 mg), and the obtained mixture was stirred while refluxing under heating for 20 minutes. After the mixture was allowed to cool, the solvent was distilled off. The obtained residue was purified by column chromatography (6.25% ethyl acetate/n-hexane). Fractions containing the ester body of Compound 19 were collected and concentrated to dryness. As a result, 246 mg of yellow solid was obtained. The obtained yellow solid was, without further purification, dissolved in ethanol (10 ml), and a 2N sodium hydroxide aqueous solution (2.62 ml) was added thereto in a nitrogen atmosphere. The obtained mixture was stirred under heating at 70° C. for 2 hours. After the reaction was over, the mixture was allowed to cool. A 2N hydrochloric acid aqueous solution was added thereto, and the mixture was separated with ethyl acetate and water. The organic layer was washed once with water and once with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and as a result, Compound 19 (112 mg, 48%) was obtained as a yellow solid.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=1)[CH:6]([CH3:8])[CH3:7])C.Cl.[NH2:19]O.C[O-].[Na+]>>[OH:3][C:4]1[C:5]([CH:6]([CH3:8])[CH3:7])=[C:9]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[O:16][N:19]=1
Reactant: NO
Reactant: CCOC(=O)C(C(=O)c1cccnc1)C(C)C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: CC(C)c1c(O)noc1-c1cccnc1
Yield: 22.7 %

Procedure:
2-Nicotinoylisovaleric acid ethyl ester (0.76 g), hydroxylamine hydrochloride (0.46 g) and sodium methoxide (28% methanol solution, 3.1 ml) were subjected to reaction and post-treatment in a similar manner to that described in Reference example 8(b) to obtain the title compound (0.15 g, 23%) as colorless crystals.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[CH:10]=[C:9]4[C:15]5[C:20]([C:21](=O)[C:8]4=[CH:7][C:6]=3[C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:19][CH:18]=[CH:17][CH:16]=5.O.NN.[OH-].[K+]>C(O)COCCO.O>[CH:19]1[C:20]2[CH2:21][C:8]3[CH:7]=[C:6]4[C:5]5[C:13]([CH2:12][C:11]4=[CH:10][C:9]=3[C:15]=2[CH:16]=[CH:17][CH:18]=1)=[CH:1][CH:2]=[CH:3][CH:4]=5
Reactant: O=c1c2ccccc2c2cc3c(=O)c4ccccc4c3cc12
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: c1ccc2c(c1)Cc1cc3c(cc1-2)Cc1ccccc1-3
Temperature: 80 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
A mixture of 17 g (60 mmol) of indeno[1,2-b]fluorene-6,12-dione, 18 g (600 mmol) of hydrazine monohydrate in 350 ml of diethylene glycol was stirred at 80° C. for 3 hours and then refluxed for 1 hour. The resulting mixture was cooled to room temperature, treated with a solution of 33 g (590 mmol) of KOH in 90 mL of water, and refluxed for 3 hours. The resulting mixture was poured into 800 ml of water, and the precipitate was filtered off, washed with water, and dried in air at room temperature to give product 13.1 g (51.6 mmol, 86%) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:3](Cl)=[O:4].[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl>[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][O:19][C:3](=[O:4])[C:2](=[O:1])[C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)[CH2:14][CH2:13]1
Reactant: CN1CCC(CO)CC1
Reactant: O=C(Cl)C(=O)c1cccs1
Solvent: ClC(Cl)Cl
Product: CN1CCC(COC(=O)C(=O)c2cccs2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of oxo-thiophen-2-yl-acetyl chloride (31.5 mmol) at 0 to 5° C. in chloroform (60 ml) is added a solution of (1-Methyl-piperidin-4-yl)-methanol (4.07 g, 31.5 mmol) in chloroform (60 ml), dropwise maintaining the temperature below 5° C. The resulting mixture is stirred for 2 hours at room temperature. Washing with 10% potassium carbonate solution, water and then drying over magnesium sulphate, filtration and evaporation gives the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][O:11][C:12](=[O:37])[CH2:13][CH:14]([C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][C@@H:20]([CH2:23][CH2:24][C:25](=O)[CH3:26])[C:19]1=[O:28].N1CCC[C@H]1C(O)=O.[H][H]>C(O)C.C(OCC)(=O)C.CO.[Pd]>[CH3:10][O:11][C:12](=[O:37])[CH2:13][CH:14]([C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][C@@H:20]([CH2:23][CH2:24][C:25]2[CH:26]=[CH:8][C:7]3[CH2:6][CH2:5][CH2:4][NH:3][C:2]=3[N:1]=2)[C:19]1=[O:28]
Reactant: Nc1ncccc1C=O
Reactant: COC(=O)CC(CCCN1CC[C@@H](CCC(C)=O)C1=O)c1ccc(OC)nc1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CO
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)CC(CCCN1CC[C@@H](CCc2ccc3c(n2)NCCC3)C1=O)c1ccc(OC)nc1
Temperature: 25 °C

Procedure:
A stirred solution of 2-amino-3-formylpyridine (1.40 mmol), 1-13 (420 mg, 1.08 mmol) and proline (162 mg, 1.40 mmol) in ethanol (10 mL) was heated at reflux for 14 h, and the cooled to ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The reaction mixture was filtered and concentrated at reduced pressure. The resulting oil was purified by flash column chromatography (silica gel, 3:0.3:0.3 to 8:0.8:0.8% ethanol/ammonium hydroxide/water in ethyl acetate) to give 1-14 as an inseparable mixture of diastereomers. To a stirred solution of this mixture in methanol (20 mL) was added a slurry of 10% palladium on carbon (80 mg) in ethanol (2 mL). The resulting suspension was stirred under a slight overpressure of hydrogen for 16 h. The reaction mixture was filtered through Celite and concentrated at reduced pressure. The resulting oil was purified by flash column chromatography (silica gel, 3:0.3:0.3 to 8:0.8:0.8% ethanol/ammonium hydroxide/water in ethyl acetate) to give 1-15 as an inseparable mixture of diastereomers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[C:13]3[NH:25][C:26]2[CH:27]=[CH:28][C:29]([N:32]3[CH2:37][CH2:36][CH2:35][C@@H:34]([NH:38]C(=O)OC(C)(C)C)[CH2:33]3)=[N:30][CH:31]=2)[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].C(O)(C(F)(F)F)=O>>[ClH:1].[ClH:1].[ClH:1].[NH2:38][C@@H:34]1[CH2:35][CH2:36][CH2:37][N:32]([C:29]2[N:30]=[CH:31][C:26]([NH:25][C:13]3[C:12]4[C:17](=[CH:18][CH:19]=[C:10]([C:4]5[CH:5]=[C:6]([F:9])[C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=5)[N:11]=4)[N:16]=[CH:15][C:14]=3[C:20](=[O:24])[CH:21]([CH3:22])[CH3:23])=[CH:27][CH:28]=2)[CH2:33]1
Reactant: CC(C)C(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@@H](N)C2)nc1
Product: Cl
Yield: 262.6 %

Procedure:
Following general procedure IV-2, (R)-tert-butyl (1-(5-((6-(3-chloro-5-fluoro-4-hydroxyphenyl)-3-isobutyryl-1,5-naphthyridin-4-yl)amino)pyridin-2-yl)piperidin-3-yl)carbamate (168 mg, 0.26 mmol) was reacted with TFA (2 mL) followed by formation of the trihydrochloride salt to afford the desired product (110 mg, 78%) as an orange solid: 1H NMR (500 MHz, CD3OD) δ 9.31 (s, 1H), 8.35 (s, 2H), 8.18 (d, J=2.5 Hz, 1H), 7.64 (d, J=9.0, 2.5 Hz, 1H), 7.38 (bs, 1H), 7.22-7.12 (m, 1H), 7.02 (d, J=9.0 Hz, 1H), 4.44-4.32 (m, 1H), 3.98-3.90 (m, 1H), 3.82-3.70 (m, 1H), 3.46-3.22 (m, 3H), 2.22-2.12 (m, 1H), 2.01-1.88 (m, 1H), 1.80-1.68 (m, 2H), 1.36-1.20 (m, 6H); ESI MS m/z 535 [M+H]+; HPLC>99% (AUC), tR=10.07 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[NH:9][N:8]=1.[H-].[Na+].[CH3:20][N:21]([CH3:25])[C:22](Cl)=[O:23]>O1CCCC1>[CH3:20][N:21]([CH3:25])[C:22]([N:8]1[C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[N:11][C:10]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=[N:9]1)=[O:23]
Reactant: c1cnc(-c2n[nH]c(-c3cnccn3)n2)cn1
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)n1nc(-c2cnccn2)nc1-c1cnccn1

Procedure:
To 2.25 g. (0.01 mole) of 3,5-dipyrazinyl-1,2,4-triazole in 200 ml. of tetrahydrofuran is added 57% sodium hydride (0.42 g., 0.01 mole). The reaction mixture is heated at reflux for one hour, cooled, and a solution of dimethylcarbamoyl chloride (1 gram, 0.01 mole) in 10 ml. of tetrahydrofuran is added dropwise. The reaction mixture is then refluxed four hours, cooled, filtered and concentrated to a solid. After recrystallization from benzene 1-dimethylcarbamoyl-3,5-dipyrazinyl-1,2,4-triazole is obtained.
Reaction SMILES: IC.[Cl:3][C:4]1[CH:5]=[C:6]([SH:11])[CH:7]=[CH:8][C:9]=1[F:10].[C:12](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:12][S:11][C:6]1[CH:7]=[CH:8][C:9]([F:10])=[C:4]([Cl:3])[CH:5]=1
Reactant: Fc1ccc(S)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1ccc(F)c(Cl)c1
Reaction time: 8 h

Procedure:
Iodomethane (1.15 ml) was added to a stirred mixture of 3-chloro-4-fluoro-benzenethiol (3.0 g), potassium carbonate (2.48 g) in DMF (20 ml) and left overnight. The reaction was diluted with water and extracted with diethylether, the organics were dried and evaporated under reduced pressure, yield 4.3 g.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:15][C:14]3[C:9](=[C:10]([CH3:23])[CH:11]=[C:12]([C:16]4[O:20][N:19]=[C:18]([CH2:21]Cl)[N:17]=4)[CH:13]=3)[C:8]2=[O:24])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C(OC([N:40]1[CH2:45][C@@H:44]2[CH2:46][C@H:41]1[CH2:42][NH:43]2)=O)(C)(C)C>CC#N.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:15][C:14]3[C:9](=[C:10]([CH3:23])[CH:11]=[C:12]([C:16]4[O:20][N:19]=[C:18]([CH2:21][N:40]5[CH2:45][CH:44]6[CH2:46][CH:41]5[CH2:42][NH:43]6)[N:17]=4)[CH:13]=3)[C:8]2=[O:24])=[CH:25][CH:26]=1
Reactant: Cc1cc(-c2nc(CCl)no2)cc2c1C(=O)N(Cc1ccc(Cl)cc1)C2
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(-c2nc(CN3CC4CC3CN4)no2)cc2c1C(=O)N(Cc1ccc(Cl)cc1)C2
Temperature: 60 °C
Yield: 58.3 %

Procedure:
To a solution of 2-(4-chloro-benzyl)-5-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-7-methyl-2,3-dihydroisoindol-1-one (40 mg, 0.103 mmol) in MeCN (4 mL) was added K2CO3 (0.309 mmol) and (1s, 4s)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (31 mg, 0.154 mmol). The mixture was heated at 60° C. overnight. The reaction was cooled and diluted with water, then extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. Column chromatography on silica (1% 2M NH3 in MeOH/CH2Cl2) provided 2-(4-chlorobenzyl)-5-[3-(2,5-diazabicyclo[2.2.1]hept-2-ylmethyl)-[1,2,4]oxadiazol-5-yl]-7-methyl-2,3-dihydroisoindol-1-one as a brown solid (27 mg). 1H NMR (300 MHz, CDCl3) δ 8.04 (s, 1H), 7.99 (s, 1H), 7.37 (d, 2H), 7.26 (d, 2H), 4.77 (s, 2H), 4.30 (s, 2H), 3.94 (dd, 2H), 3.58 (d, 2H), 3.26 (d, 1H), 3.11 (d, 1H), 2.89 (d, 1H), 2.84 (s, 3H), 2.63 (d, 1H), 1.88 (d, 1H), 1.66 (d, 1H).
Reaction SMILES: [OH:1][CH:2]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][NH:4][CH2:5][CH2:6][NH:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10].[ClH:21]>CCOCC>[Cl-:21].[OH:1][CH:2]([CH2:13][O:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:3][NH2+:4][CH2:5][CH2:6][NH:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10]
Reactant: Cl
Reactant: CC(C)C(=O)NCCNCC(O)COc1ccccc1
Solvent: CCOCC
Product: CC(C)C(=O)NCC[NH2+]CC(O)COc1ccccc1
Product: [Cl-]

Procedure:
A solution of (-)-N-(2-[2-hydroxy-3-phenoxypropyl]aminoethyl)isobutyramide (0.7 g) in anhydrous ether (10 ml) was treated with an excess of a saturated solution of hydrogen chloride in anhydrous ether. The solid which formed was collected and recrystallised twice from a mixture of methanol and anhydrous ether to give (-)-N-[2-hydroxy-3-phenoxypropyl]-N-(2-isobutyramidoethyl)ammonium chloride, m.p. 137°-139° C; 25 [α]D -19.7° [c, 1.135; methanol]; microanalysis C15H24N2O3.HCl requires: C, 56.87; H, 7.90; N, 8.84; Cl, 11.20%; found: C, 56.80; H, 8.0; N, 8.6; Cl, 11.1%.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[Cl-].[K+].C(#N)C.[OH-].[K+]>O.C(OCC)(=O)C>[C:1]([NH:4][C@H:5]([CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(Cc1cccnc1)NC(C)=O
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCOC(=O)[C@@H](Cc1cccnc1)NC(C)=O
Reaction time: 0.5 h

Procedure:
A suspension of 54.7 g of ethyl 2-(acetylamino)-3-(3-pyridyl)propanoate in 420 cm3 of water, to which has been added 18.5 g of potassium chloride, is dissolved by adding 100 cm3 of acetonitrile. An orange-colored solution of neutral pH is obtained, 0.168 g of α-chymotrypsin is then added and the pH falls. Aqueous 2N potassium hydroxide solution is added dropwise, with stirring, to remain at a constant pH of 7.2. After 1 hour 30 min, with the pH showing little change, the mixture is stirred for 48 hours at room temperature. The pH of the solution is then approximately 5.6 and, on adding aqueous 2N potassium hydroxide solution, it is thereby adjusted to about 7. 0.084 g of α-chymotrypsin is introduced and the pH is adjusted to 7.2 by a further addition of aqueous 2N potassium hydroxide solution, and the mixture is left stirring for 1 hour 30 min. The pH of the reaction medium does not change. 400 cm3 of ethyl acetate are added and the mixture is stirred for 30 min and then filtered through Celite. The filtrate is separated out after settling has taken place and the aqueous phase is extracted with 3 times 400 cm3 of ethyl acetate. The organic phases are combined, washed with 400 cm3 of saturated sodium chloride solution and dried over magnesium sulfate. After filtration and concentration under reduced pressure (2 kPa) at a temperature in the region of 40° C., 20.77 g of ethyl (2R)-2-(acetylamino)-3-(3-pyridyl)propanoate are obtained in the form of a beige-colored solid melting at 80° C. [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 1.13 (t, J=7 Hz: 3H); 1.81 (s: 3H); 2.92 (dd, J=14 and 9.5 Hz: 1H); 3.05 (dd, J=14 and 5.5 Hz: 1H); 4.07 (q, J=7 Hz: 2H); 4.48 (mt: 1H); 7.33 (dd, J=8 and 5 Hz: 1H); 7.66 (dt, J=8 and 2 Hz: 1H); 8.36 (d, J=8 Hz: 1H); 8.44 (mt: 2H)].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C(N(CC)CC)C>CCO>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:7]=1
Reactant: C1COCCN1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Clc1cc(N2CCOCC2)ncn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
To a solution of 4,6-dichloropyrimidine (1.0 equiv.) in EtOH (0.44 M) was added morpholine (1.0 equiv.) followed by triethylamine (1.10 equiv.). The resulting mixture was stirred at RT for 16 hours. The reaction mixture was then concentrated in vacuo and dried under high vacuum over 20 h to yield 4-(6-chloropyrimidin-4-yl)morpholine as a white solid in 93% yield. LCMS (m/z) (M+H)=200.0/201.8, Rt=0.35 min. 1H NMR (400 MHz, <cdcl3>) δ ppm 3.53-3.71 (m, 4H) 3.72-3.83 (m, 4H) 6.51 (s, 1H) 8.39 (s, 1H) 11.75 (br. s., 1H).
Reaction SMILES: C[N:2](/[CH:4]=[N:5]/[C:6](=[S:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])C.N1C=CC=CC=1.NOS(=O)(=O)O>C(O)C>[S:12]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][CH:4]=[N:2]1
Reactant: CCOC(=O)C(=S)/N=C/N(C)C
Agent: NOS(=O)(=O)O
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1ncns1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To ethyl {[(1E)-(dimethylamino)methylidene]amino}(thioxo)acetate (I78) (1.42 g, 7.54 mmol) and pyridine (1.220 mL, 15.09 mmol) dissolved in Ethanol (20 mL) was added (aminooxy)(hydroxy)sulfane dioxide (0.938 g, 8.30 mmol) dissolved in Ethanol (18 ml) and the mixture stirred at 25° C. for 48 hr. The solvents were concentrated in vacuo and the residue was dissolved in ethyl acetate (50 mL). The solution was washed with saturated sodium bicarbonate solution (25 mL), aqueous phase back extracted with ethyl acetate (25 mL) and the organic extracts were combined. The solution was washed with brine (25 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The crude oil was purified by flash chromatography (Isolera, 50 g, 0-100% ethyl acetate/iso-hexane, 15 column volumes) to afford product in 246 mg.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.FC(F)(F)S(O[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Si](C)(C)C)(=O)=O.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1>[C:12]1([C:11]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:18][CH:2]3[CH:3]=[CH:4][C:5]4[C:10]([N:1]3[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]2=3)=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc2ncccc2c1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: C1=CC2OC(c3ccccc3)(c3ccccc3)c3ccccc3N2c2ccccc21
Yield: 54.2 %

Procedure:
Following the general procedure, treatment of quinoline (0.064 g, 59 μL, 0.50 mmol) and benzophenone (0.136 g, 0.75 mmol) with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.179 g, 146 μL, 0.60 mmol) in the presence of KF (0.070 g, 1.2 mmol) and 18-crown-6 (0.317 g, 1.2 mmol) in THF (2.0 mL) at −10° C. to room temperature for 12 hrs followed by flash column chromatography (Pet. ether/EtOAc=95/05) of the crude reaction mixture afforded 5,5-diphenyl-5H,6aH-benzo[4,5][1,3]oxazino[3,2-a]quinoline as a yellow solid (0.105g, 54% yield).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.S(=O)(=O)(O)O.[CH3:20]O>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:20])=[O:7])=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1C(F)(F)F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(F)cc1C(F)(F)F

Procedure:
To a solution of 4-fluoro-2-(trifluoromethyl)benzoic acid in MeOH were added concentrated sulfuric acid at 0° C. The reaction mixture was heated and refluxed for 2 days. The reaction mixture was concentrated under reduced pressure and the residue was diluted with EtOAc. The organic layer was washed with a saturated aqueous NaHCO3 solution, dried over MgSO4, and then concentrated under reduced pressure to obtain methyl 4-fluoro-2-(trifluoromethyl)benzoate as a colorless oily substance.