Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]1C=CC=C1C=CC(=N)OCC.C(O)C.N#CN.[CH:20]1([NH:26][C:27](=[N:37][C:38]#[N:39])[CH:28]=[CH:29][C:30]2C=C[CH:33]=[CH:32][C:31]=2Cl)CCC[CH2:22][CH2:21]1>C(OCC)(=O)C.C(N(CC)CC)C>[CH2:20]([NH:26][C:27](=[N:37][C:38]#[N:39])[CH:28]=[CH:29][C:30]1[O:2][CH:33]=[CH:32][CH:31]=1)[CH2:21][CH3:22]
Reactant: N#CN=C(C=Cc1ccccc1Cl)NC1CCCCC1
Reactant: CCOC(=N)C=Cc1ccco1
Agent: Cl
Agent: N#CN
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCNC(C=Cc1ccco1)=NC#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl 3-(2-furyl)-2-propenimidate HCl in an amount of 1.34 g. is dissolved in 3 ml. of ethanol and then an equimolar amount of triethylamine is added to the ice-cooled resulting solution. To this solution, cyanamide (0.25 g.) is added and stirring is continued for 1 hour at room temperature. After removal of solvent from the mixture, the resulting residue is dissolved in ethyl acetate. The ethyl acetate layer is washed with water and dried with MgSO4. To the residue, after removal of ethyl acetate, MeOH (3 ml.) and n-butylamine (1.1 g.) are added with slight warming and stirring is continued for 1 hour. The mixture is evaporated and resulting residue is submitted to column chromatography (KIESEL GEL 40 T : ethyl acetate for eluent). The thus obtained crystals, which are recrystallized from acetone have the formula: ##STR11## and the following characteristics:
Reaction SMILES: [CH:1]1([S:7][CH2:8][CH2:9][NH:10][C@H:11]([C:13]([OH:15])=[O:14])[CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[N:20]([O-])=[O:21].[Na+]>O>[CH:1]1([S:7][CH2:8][CH2:9][N:10]([N:20]=[O:21])[C@H:11]([C:13]([OH:15])=[O:14])[CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@H](NCCSC1CCCCC1)C(=O)O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C[C@@H](C(=O)O)N(CCSC1CCCCC1)N=O
Reaction time: 2 h

Procedure:
The N-[2-(cyclohexylthio)ethyl]alanine prepared in Example 2 is suspended in 210 parts of acetic acid and that mixture is treated, over a period of 20 minutes, with a solution containing 7 parts of sodium nitrite and 70 parts of water. The resulting mixture is stirred for 11/2 hours, then filtered. The filtrate is added to 2000 parts of water and extracted with methylene chloride. The organic phase is separated, washed with water, dried over anhydrous sodium sulfate, filtered and then evaporated to dryness under reduced pressure to afford, as an oil, N-[2-(cyclohexylthio)ethyl] -N-nitrosoalanine.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CS(O[CH2:9][CH2:10][C:11]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:12]=1[CH2:13]CS([O-])(=O)=O)(=O)=O.Cl>C(Cl)(Cl)Cl>[CH2:1]([N:3]1[CH2:9][CH2:10][C:11]2[C:12](=[CH:19][CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=2)[CH2:13]1)[CH3:2]
Reactant: CS(=O)(=O)OCCc1cc([N+](=O)[O-])ccc1CCS(=O)(=O)[O-]
Reactant: CCN
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCN1CCc2cc([N+](=O)[O-])ccc2C1
Reaction time: 12 h

Procedure:
7.65 mL of ethylamine was dropwise added to a chloroform (15 mL) solution of 1.08 g of 2-{2-[(methylsulfonyl)oxyethyl}-4-nitrobenzylmethanesulfonate, which had been produced according to the method described in Journal of Organic Chemistry, Vol. 63, pp. 4116-4119, and stirred for 12 hours. 1 N hydrochloric acid was added to the reaction solution, and stirred, and then the aqueous layer was separated. Aqueous 5 N sodium hydroxide solution was added to the resulting aqueous layer, extracted with chloroform, and the organic layer was dried with anhydrous sodium sulfate, and the solvent was evaporated away. The crude product was purified through silica gel column chromatography (hexane/ethyl acetate) to obtain 210 mg of 2-ethyl-6-nitro-1,2,3,4-tetrahydroisoquinoline as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=O)[CH2:8]1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl>C(O)C>[ClH:24].[Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[N:23][NH:22][C:19]([NH2:21])=[NH:20])[CH2:8]1
Reactant: N=C(N)NN
Reactant: Cc1ccnc2c1C(=O)CC(c1ccsc1Br)C2
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1ccsc1Br)C2
Temperature: 90 °C
Reaction time: 13 h
Yield: 90.6 %

Procedure:
To a mixture of 7-(2-bromothiophen-3-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.12 g) and aminoguanidine hydrochloride (45 mg) were added ethanol (2 ml) and concentrated hydrochloric acid (0.05 ml), and the mixture was stirred at 90° C. for 13 hours and cooled. Precipitated crystals were filtered, washed with ethanol and dried to give 7-(2-bromothiophen-3-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 123) (0.14 g) as pale yellow crystals.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C(Cl)Cl.[C:10]1([C@H:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][NH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(N(CC)CC)C>[C:10]1([C@H:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][N:17]2[C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc([C@@H]2NCCc3ccccc32)cc1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCc2ccccc2[C@@H]1c1ccccc1
Temperature: 27.5 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
Ethyl chloroformate (5.61 g) was slowly added to a mixture of methylene chloride (100 ml), (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (10 g) and triethylamine (5.32 g) at 5-15° C. over a period of 30 min. Thereafter, the reaction mass was warmed to 25-30° C. and stirred at 25-30° C. for 1 h. The reaction solution was sequentially washed with water (50 ml), 3% w/w hydrochloric acid (50 ml), water (50 ml) and 5% w/w aqueous sodium chloride (50 ml) at 25-30° C. The solvent was removed under reduced pressure at 30-40° C. to produce (1S)-ethyl 1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate (13.0 g) as a pale yellow oil. Chromatographic Purity (By HPLC): 99.22%.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=[N:3]1.[N+:10]([O-])([OH:12])=[O:11].OS(O)(=O)=O.O=S(=O)=O>>[CH3:1][N:2]1[C:6]([C:7]([OH:9])=[O:8])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=[N:3]1
Reactant: O=[N+]([O-])O
Reactant: Cn1nccc1C(=O)O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: Cn1ncc([N+](=O)[O-])c1C(=O)O

Procedure:
18.8 g of 1-methylpyrazole-5-carboxylic acid (mp 227° to 228° C.) are stirred in a mixture consisting of 23.5 of 100% strength nitric acid and 17 ml of 25% strength oleum for 8 hours at from 55° to 60° C. and for 4.5 hours at from 70° to 75° C. The mixture is poured onto ice and extracted with 9:1 methylene chloride/ethanol. The extract is concentrated. This yields 27 g of 1-methyl-4-nitropyrazole-5-carboxylic acid, mp 162° to 164° C., with decomposition (from ethyl acetate).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]([N+:14]([O-])=O)[CH:6]=1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([C:29]3[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=3)=[O:28])[CH:24]=2)[CH:19]=[CH:18]1>>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]2[N:11]=[C:33]([C:32]3[CH:31]=[CH:30][C:29]([C:27]([NH:26][C:23]4[CH:24]=[C:25]5[C:20]([CH:19]=[CH:18][NH:17]5)=[CH:21][CH:22]=4)=[O:28])=[CH:36][CH:35]=3)[NH:14][C:7]=2[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(OCCO)cc1[N+](=O)[O-]
Reactant: O=Cc1ccc(C(=O)Nc2ccc3cc[nH]c3c2)cc1
Product: O=C(Nc1ccc2cc[nH]c2c1)c1ccc(-c2nc3ccc(OCCO)cc3[nH]2)cc1

Procedure:
Compound 672 was prepared according to the procedure similar to that described in Scheme III from 1-(2-hydroxyethoxy)-3,4-dinitrobenzene and 4-(6-indolylaminocarbonyl)benzaldehyde. [M+H]+ calcd for C24H20N4O3: 413.15; found: 412.96.
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]1[CH:10]=[CH:11][C:12]([C:15]#N)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.C1C[O:43]CC1>>[CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[O:43])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: N#Cc1ccc(N(Cc2ccccc2)Cc2ccccc2)cn1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: O=Cc1ccc(N(Cc2ccccc2)Cc2ccccc2)cn1
Reaction time: 3 h
Yield: 69 %

Procedure:
To a solution of 38 (500 mg, 1.7 mmol) in THF (25 mL) was added 1.6M DIBALH in toluene (3.1 mL, 5.01 mmol) at −78° C. and stirred for 3 h at the same temperature. The reaction mixture was quenched with water (20 mL), extracted with EtOAc (2×50 mL), the combined organic layers were washed with brine (20 mL), dried (Na2SO4) and evaporated. The crude compound was purified by silica gel column chromatography (100-200 mesh, eluted with 20% EtOAc/pet-ether) to obtain compound 39 (350 mg, 69%) as a brown solid. Rf: 0.5 (40% EtOAc/pet-ether); (m/z): 303 [MH]+; 1H NMR (400 MHz, CDCl3): δ 9.85 (1H, S), 8.27 (1H, d, J=2.8 Hz), 7.79 (1H, d, J=8.8 Hz), 7.38-7.20 (10H, m), 7.03 (1H, dd, J=3.2, 8.8 Hz), δ 4.77 (4H, s).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([CH3:17])[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:4].[OH-].[Na+]>C1COCC1.CO.O>[F:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]2[S:8][C:7]([CH3:17])=[N:6][C:5]=2[C:3]([OH:4])=[O:2])=[CH:15][CH:14]=1
Reactant: COC(=O)c1nc(C)sc1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
To a solution of 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid methyl ester (15 g) in a mixture of THF (60 mL) and MeOH (20 mL) was added a solution of sodium hydroxide (2.63 g) in water (60 mL). The reaction mixture was stirred at RT for 30 min. The reaction mixture was then concentrated in vacuo, and the residue was dissolved with water (100 mL) and concentrated again in vacuo. The residue was dissolved in water (250 mL), cooled to 0° C. with a ice-bath. Then was added a solution of conc.HCl (37%)(7.72 g) in water (7.72 g) and stirred at 0° C. for 15 min. The resulting precipitate was filtered off, washed with water and dried in high vacuum pump. to give the title compound as a white solid (13.16 g, 93%).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[C:19]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=4)[CH:16]=[C:11]3[C:10]([CH3:29])=[N:9]2)=CC=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:27][N:26]([CH3:28])[S:23]([C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[CH:16]=[C:11]3[C:10]([CH3:29])=[N:9][NH:8][C:12]3=[N:13][CH:14]=2)[CH:18]=1)(=[O:24])=[O:25]
Reactant: COc1ccc(Cn2nc(C)c3cc(-c4cccc(S(=O)(=O)N(C)C)c4)cnc32)cc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2ncc(-c3cccc(S(=O)(=O)N(C)C)c3)cc12
Temperature: 50 °C

Procedure:
To a solution of 3-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-N,N-dimethylbenzene-sulfonamide (110) (50 mg, 0.114 mmol) dissolved in chloroform (10 mL) was added trifluoroacetic acid (5 mL) and the reaction mixture was heated at 50° C. for 12 h. After completion of the reaction the solvents were removed and diluted with cold water, pH was adjusted to 8 and the aqueous phase extracted with chloroform two times. The organic layer was washed with brine solution and dried over sodium sulphate and the solvents were removed. The crude was passed through 100-200 mesh silica gel eluting the compound at 70% ethyl acetate in hexane as pale yellow solid N,N-dimethyl-3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide 111 (30 mg). MS m/z 316.9 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][CH2:18][CH3:19])=[S:16])=[C:10]([CH3:20])[CH:9]=1>C(Cl)Cl>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:2](=[O:3])[C:1](=[O:5])[N:17]([CH2:18][CH3:19])[C:15]2=[S:16])=[C:10]([CH3:20])[CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCNC(=S)Nc1ccc(Cl)cc1C
Solvent: ClCCl
Product: CCN1C(=O)C(=O)N(c2ccc(Cl)cc2C)C1=S
Yield: 62.2 %

Procedure:
Oxalyl chloride (10.5 g; 0.082 mol) was added dropwise to the stirring solution of N-(4-chloro-2-methylphenyl)-N′-ethylthiourea (17 g; 0.075 mol) in methylene chloride (200 mL). The mixture was heated at reflux for 1 hour then evaporated to dryness. Ethanol (100 mL) was added and the mixture was heated at reflux for 1 hour then evaporated to dryness. The residue was dissolved in ethyl acetate (500 mL) and washed with 2N hydrochloric acid (500 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was crystallized from ethyl acetate/hexane to give 13.2 g of 1-(4-chloro-2-methylphenyl)-3-ethyl-2-thioxo-4,5-imidazolidinedione, m.p. 161–162° C. Mass spectrum; FAB (M+H)+ m/z 283. 1H-NMR (DMSO-d6; 300 MHz): δ 7.49 (d, 1H), 7.39 (m,1H), 7.33 (d, 1H), 3.91 (m, 2H), 2.16 (s, 3H), and 1.23 ppm (t, 3H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[O:13]([C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([NH:25][NH2:26])=[O:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:26][NH:25][C:23](=[O:24])[C:22]1[CH:27]=[CH:28][CH:29]=[C:20]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:21]=1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)c1cccc(Oc2ccccc2)c1
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1cccc(Oc2ccccc2)c1
Temperature: 100 °C
Yield: 83 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 3-phenoxybenzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 403 mg of the title compound (83%) as a yellow solid in 99.5% purity by HPLC (Rt: 6.58, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=2)[C:12]=1[CH3:13])=[O:7])(C)(C)C.Cl.O1CCOCC1>>[Cl:21][C:16]1[CH:15]=[C:14]([N:11]2[C:12]([CH3:13])=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[N:10]2)[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: Cc1c(C(=O)OC(C)(C)C)cnn1-c1ccc(F)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(C(=O)O)cnn1-c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.2 %

Procedure:
1-(3-Chloro-4-fluoro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid tert-butyl ester (2.1 g, 6.8 mmol) is treated with cold HCl in dioxane (4.0 N solution, 10 mL, 40 mmol) and stirred for 16 hours at room temperature. The resultant precipitate is collected by filtration, washed with dioxane (2×1 mL) and dried to afford 1-(3-chloro-4-fluoro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid as a tan solid (540 mg, 31%).
Reaction SMILES: C(OC(=O)[N:10]([CH2:15][CH:16]([OH:37])[CH:17]([NH:25][C:26]([O:28][CH:29]1[CH:36]2[CH:32]([O:33][CH2:34][CH2:35]2)[O:31][CH2:30]1)=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][CH:12]([CH3:14])[CH3:13])C1C=CC=CC=1>C(O)C.[Pd]>[O:31]1[CH:32]2[O:33][CH2:34][CH2:35][CH:36]2[CH:29]([O:28][C:26](=[O:27])[NH:25][CH:17]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:16]([OH:37])[CH2:15][NH:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:30]1
Reactant: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)CNCC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12
Reaction time: 8 h
Yield: 98 %

Procedure:
A mixture of [3-(hexahydro-furo[2,3-b]furan-3-yloxycarbonylamino)-2-hydroxy-4-phenyl-butyl]-isobutyl-carbamic acid benzyl ester 18 (5.5 g, 10.4 mmol) and 550 mg of 10% Pd/C in 130 ml of ethanol was stirred under a hydrogen atmosphere overnight. The catalyst was removed by filtration through Celite®, and the solution was evaporated to dryness to yield (1-benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester 19 (4.0 g, 97%) as a white solid. TLC: Rf 0.36 (5:15:85 triethylamine:methanol:ethyl acetate). MS 393 (MH)+.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[C@@H:16]([OH:17])[C:15](=[O:18])[N:14]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:13]3[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:12]=3[S:11]2)=[CH:6][CH:5]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(O)(=O)C>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]2[C@@H:16]([O:17][C:30](=[O:32])[CH3:31])[C:15](=[O:18])[N:14]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:13]3[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:12]=3[S:11]2)=[CH:8][CH:9]=1
Reactant: COc1ccc([C@@H]2Sc3ccc(OC)cc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc([C@@H]2Sc3ccc(OC)cc3N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
A mixture of 1 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-7-methoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride, 1.5 ml of acetic anhydride and 1.5 ml of acetic acid is stirred at 110° C. for 4 hours. After the reaction is completed, the mixture is evaporated under reduced pressure to remove acetic anhydride and acetic acid. Benzene is added to the residue, and the mixture is evaporated under reduced pressure to remove acetic anhydride and acetic acid. The residue thus obtained is recrystallized from a mixture of ethanol and ether. 0.87 g of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-7-methoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride 1/2 hydrate is obtained. Yield: 78%
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]([N+:27]([O-])=O)[CH:14]=[C:15]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]([CH:14]=[C:15]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:16]=1)[NH2:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)c1cc(C(=O)OCc2ccccc2)cc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(C(=O)OCc2ccccc2)cc(C(=O)OCc2ccccc2)c1
Yield: 0.1 %

Procedure:
3,5-dibenzyloxycarbonyl-nitrobenzene (3.91 g, 10 mol) was dissolved in ethyl acetate (50 ml) and tin(II)chloride dihydrate (11.27 g, 50 mmol) was added and the mixture stirred and heated at 70° under an atmosphere of nitrogen for 1 h. The mixture was poured carefully onto 5% sodium hydrogencarbonate solution (200 ml) and a further aliquot of ethyl acetate (100 ml) was added. After shaking the organic layer was separated and the aqueous layer was extracted with more ethyl acetate (50 ml). The combined organic layers were washed with brine, and dried, filtered and evaporated to leave a pale yellow solid (3.25 g, 90%), 1H NMR (CDCl3) δ 8.1 (1H, d), 7.5 (12H, m), 5.4 (4H, s), 3.8 (2H, bs).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[CH:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>O.[Cl-].C([N+](CCCCCCCC)(CCCCCCCC)C)CCCCCCC.C1(C)C=CC=CC=1>[C:9]1([CH:8]([OH:15])[C@@H:2]([C:3]([OH:5])=[O:4])[NH2:1])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: NCC(=O)O
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: N[C@H](C(=O)O)C(O)c1ccccc1
Reaction time: 20 h
Yield: 86.5 %

Procedure:
Glycine (60 g) and 48 g of sodium hydroxide were dissolved in 500 g of water. Then, 0.5 g of trioctylmethyl ammonium chloride was added, and with stirring at 25° to 30° C., a solution of 169.6 g of benzaldehyde in 150 g of toluene was added dropwise over the course of about 1 hour. The reaction was further carried out at 25° to 35° C. for 20 hours. After the reaction, 209 g of 35% hydrochloric acid was added dropwise at a temperature of less than 40° C. The mixture was stirred at room temperature for 1 hour. After standing, the lower aqueous layer was separated, neutralized with 45% sodium hydroxide to a pH of 6 at room temperature, stirred at 0° to 5° C. for 1 hour, filtered, washed with cold water, and dried to give 125.3 g of β-phenylserine. The purity of the product was 90.6%. The yield based on glycine was 78.3%.
Reaction SMILES: C([O:8][C:9]([C:11]1[N:12]=[C:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:14][C:15]=1[CH:16]([CH3:18])[CH3:17])=[O:10])C1C=CC=CC=1.O1CCCC1.CO.[H-].[OH-].[Li+]>O>[CH:16]([C:15]1[O:14][C:13]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:12][C:11]=1[C:9]([OH:10])=[O:8])([CH3:18])[CH3:17]
Reactant: CC(C)c1oc(-c2ccccc2)nc1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)c1oc(-c2ccccc2)nc1C(=O)O
Yield: 41.2 %

Procedure:
Solution of 5-isopropyl-2-phenyl-oxazole-4-carboxylic acid benzyl ester (830 mg, 2.59 mmol) in a mix of tetrahydrofuran, methanol and water (3:1:1, 10 mL) was treated with lithium hydroxide monohydride (258 mg, 6.5 mmol) at room temperature for an hour. After the reaction was complete, solvent was removed. To the residue, water and dichloromethane were added, and white precipitate formed. After filtering off the solid, filtrate was collected and the phases were separated. The pH of the aqueous layer was adjusted to 1˜2 with dilute hydrochloride acid (1N). Then the aqueous layer was extracted with ethyl acetate three times. The ethyl acetate layers were collected, dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (Merck silica gel 60, 230-400 mesh, 0-80% ethyl acetate in hexane for 20 min) gave 5-isopropyl-2-phenyl-oxazole-4-carboxylic acid (247 mg, 41%) as a white solid. LCMS calcd for C13H13NO3 (m/e) 231, obsd 232 (M+H).
Reaction SMILES: [OH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[O:11]1[C:15]2[CH:16]=[CH:17]C=CC=2N=C1>>[O:11]1[CH2:15][CH:16]1[CH2:17][O:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Oc1nc2ccccc2s1
Reactant: c1ccc2ocnc2c1
Product: c1ccc2sc(OCC3CO3)nc2c1

Procedure:
Compound 44 was prepared in the manner of compound 6 substituting 2-hydroxy-benzothiazole for compound 8 in partC-5 of Example 1.
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[CH:10][C:11]([F:23])=[C:12]([C:14]3[CH:22]=[N:21][CH:20]=[CH:19][C:15]=3[C:16]([NH2:18])=[O:17])[CH:13]=2)OC1.Br[C:26]1[N:30]2[CH:31]=[CH:32][C:33]([C:35]([F:38])([F:37])[F:36])=[N:34][C:29]2=[N:28][CH:27]=1>>[F:23][C:11]1[CH:10]=[CH:9][C:8]([C:26]2[N:30]3[CH:31]=[CH:32][C:33]([C:35]([F:36])([F:37])[F:38])=[N:34][C:29]3=[N:28][CH:27]=2)=[CH:13][C:12]=1[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([NH2:18])=[O:17]
Reactant: CC1(C)COB(c2ccc(F)c(-c3cnccc3C(N)=O)c2)OC1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Product: NC(=O)c1ccncc1-c1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccc1F

Procedure:
3-[5-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-2-fluorophenyl]isonicotinamide (100 mg, 0.41 mmol) was coupled to 3-bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine (121 mg, 0.46 mmol) using the method in Example 1. Purification by chromatography on silica gel eluting with dichloromethane containing 4% methanol, then recrystallisation from toluene, gave 3-[2-fluoro-5-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)phenyl]isonicotinamide as a yellow solid: δH (400 MHz, d6-DMSO) 7.50-7.60 (3H, m), 7.65 (1H, s), 7.80-7.86 (2H, m), 8.02 (1H, s), 8.30 (1H, s), 8.73-8.76 (2H, m), 9.33 (1H, d, J 7); m/z (ES+) 402 (M++H).