Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.C(OP([CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])(OCC)=O)C.CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:46]/[C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:11][N:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
To a mixture of 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-4-carbaldehyde (1.00 g), ethyl diethylphosphonoacetate (0.50 g) and N,N-dimethylformamide (15 mL) was added sodium hydride (60% in oil, 100 mg) at 0° C., and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl (E)-3-(3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazol-4-yl)-2-propenoate (1.08 g, yield 95%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:4, v/v). The crystals were recrystallized from tetrahydrofuran-hexane. melting point: 194-195° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([N+:21]([O-])=O)=[C:10]([C:12]([C:14]2[N:18]([CH3:19])[N:17]=[CH:16][C:15]=2I)=[O:13])[CH:11]=1.ClC1C=CC(CC2C=CC([N+]([O-])=O)=C(C(C3N(C)N=CC=3I)=O)C=2)=CC=1>>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[NH:21][C:15]3[CH:16]=[N:17][N:18]([CH3:19])[C:14]=3[C:12](=[O:13])[C:10]=2[CH:11]=1
Reactant: COc1ccccc1Cc1ccc([N+](=O)[O-])c(C(=O)c2c(I)cnn2C)c1
Agent: Cn1ncc(I)c1C(=O)c1cc(Cc2ccc(Cl)cc2)ccc1[N+](=O)[O-]
Product: COc1ccccc1Cc1ccc2[nH]c3cnn(C)c3c(=O)c2c1

Procedure:
The title compound was prepared according to the procedure of step 5 in EXAMPLE 13 using [5-(2-methoxybenzyl)-2-nitrophenyl](4-iodo-1-methyl-1H-pyrazol-5-yl)methanone (EXAMPLE 21, step 3), instead of [5-(4-chlorobenzyl)-2-nitrophenyl](4-iodo-1-methyl-1H-pyrazol-5-yl)methanone.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:18]=[CH:17][C:12]3[C:13](=[O:16])[O:14][CH2:15][C:11]=3[CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:28]=[C:27]([CH:29]2[CH2:31][O:30]2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>>[OH:30][CH:29]([C:27]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([O:20][CH3:19])[CH:28]=1)[CH2:31][N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][C:9]2[CH:18]=[CH:17][C:12]3[C:13](=[O:16])[O:14][CH2:15][C:11]=3[CH:10]=2)[CH2:2][CH2:3]1
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Reactant: COc1cc(C2CO2)ccc1C#N
Product: COc1cc(C(O)CN2CCN(CCc3ccc4c(c3)COC4=O)CC2)ccc1C#N

Procedure:
4-(1-Hydroxy-2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-2-(methyloxy)benzonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLE 12 starting from 5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one and 2-(methyloxy)-4-oxiran-2-ylbenzonitrile.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1Br
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=Cc1ccccc1-c1ccc(Cl)cc1

Procedure:
2-bromobenzaldehyde (25.05 mL, 40.0 g, 216 mmol) was added to toluene (550 mL) and degassed and flushed with nitrogen. 4-chlorophenylboronic acid (43.9 g, 281 mmol), degassed 2M sodium carbonate (757 mL, 1513 mmol), and tetrakis(triphenylphosphine)palladium(0) (5.00 g, 4.32 mmol) were added. The mixture was refluxed for 2.5 hours, cooled, and the phases were separated. The organic layer was extracted with 2M sodium carbonate, and the aqueous layer was back extracted with ethyl ether. The organic portions were combined, dried with brine and then anhydrous sodium sulfate. The solution was concentrated and purified by flash column chromatography on silica gel with 3% ethyl acetate (in hexanes) increasing to 10% ethyl acetate (in hexanes).
Reaction SMILES: [OH-].[Na+].[N+](C1C=CC(C([O:12][CH2:13][C@H:14]2[O:18][C:17](=[O:19])[N:16]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C@H:15]2[CH3:28])=O)=CC=1)([O-])=O>CO>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([N:16]2[C@@H:15]([CH3:28])[C@@H:14]([CH2:13][OH:12])[O:18][C:17]2=[O:19])=[CH:25][CH:24]=1
Reactant: COc1ccc(N2C(=O)O[C@H](COC(=O)c3ccc([N+](=O)[O-])cc3)[C@@H]2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(N2C(=O)O[C@H](CO)[C@@H]2C)cc1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 69.7 %

Procedure:
A 3.8 ml quantity of 8% sodium hydroxide aqueous solution was added to a methanol (20 ml) solution of 2.43 g of (4S, 5S)-(-)-3-(4-methoxyphenyl)-4-methyl-2-oxooxazolidin-5-ylmethyl p-nitrobenzoate obtained in Reference Example 8. The mixture was stirred at 50° C. for 20 minutes. The reaction mixture was concentrated under reduced pressure, and the obtained residue was extracted with ethyl acetate. The extract was washed with water, dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography and purified by hexane-ethyl acetate gradient elution to give 1.04 g of the title compound (yield 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[C:18]([CH3:28])=[N:19][N:20]4[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22][C:21]=34)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)=[CH:4][CH:3]=1.[N:31]1([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[C:18]([CH3:28])=[N:19][N:20]4[CH:25]=[CH:24][C:23]([CH2:26][N:34]5[CH2:35][CH2:36][N:31]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32][CH2:33]5)=[CH:22][C:21]=34)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1nn2ccc(C=O)cc2c1-c1nc(Cc2ccc(Cl)cc2)c(-c2nnc[nH]2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1nn2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2c1-c1nc(Cc2ccc(Cl)cc2)c(-c2nnc[nH]2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.3 %

Procedure:
A mixture of 3-[4-(4-chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridine-5-carbaldehyde (0:0563 g, 0.109 mmol), tert-butyl 1-piperazinecarboxylate (60.8 mg, 0.326 mmol) and acetic acid (0.0800 mL, 1.41 mmol)in dry methylene chloride (10 mL) was stirred at rt for 15 min. Sodium triacetoxyborohydride (69.1 mg, 0.326 mmol) was added and the mixture was stirred at rt for 15 hours. The mixture was washed with saturated NaHCO3 solution and the aqueous layer was extracted with DCM. The DCM extract was washed with water, brine, dried over Na2SO4, filtered and evaporated to give a crude product which was purified by column chromatography on silica gel column using MeOH/DCM (0/100 to 5/95) to give solid product (0.0464 g, yield 70.5%). LCMS: (FA) ES+ 605, 607; ES− 603, 605. 1H NMR (400 MHz, CDCl3 and d4-methanol) δ: 8.23-8.25 (d, J=7.03 Hz, 1H), 8.20 (s, 1H), 7.94 (s, 1H), 7.29-7.31 (d, J=8.28 Hz, 2H), 7.15-7.17 (d, J=8.53 Hz, 2H), 6.86-6.89 (dd, J=7.28, 1.76 Hz, 1H), 4.53 (s, 2H), 3.45 (s, 2H), 3.33-3.36 (m, 4H), 2.62 (s, 3H), 2.35 (s, br, 4H), 1.37 (s, 9H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([C:12]2[C:18]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=3[N:16]3[C:24]([C:27]([NH2:29])=O)=[N:25][N:26]=[C:15]3[CH2:14][N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O>[C:6]1([C:12]2[C:18]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=3[N:16]3[C:24]([C:27]#[N:29])=[N:25][N:26]=[C:15]3[CH2:14][N:13]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NC(=O)c1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
4 ml of phosphorus oxychloride is added to a solution of 1.69 g (0.005 mole) of 6-phenyl-8-chloro-4H-s-triazolo[4,3-a ] [1,4]benzodiazepine-1-carboxamide in 5ml of dimethylformamide, and stirring maintained for 10 minutes at 80°. The reaction mixture is then poured on ice and extracted with ethylene chloride. The extract is washed with water and saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The residue is chromatographed on silica gel with the use of benzene and benzene/ethyl acetate mixtures as eluant. The fractions containing the desired nitrile [Rf = 0.5 in the eluant system benzene/chloroform/ethyl acetate (4:4:2)] are combined and concentrated by evaporation. The residue is crystallised from ethyl acetate/petroleum ether to obtain 6-phenyl-8-chloro-4H-s-triazolo [4,3-a][1,4]benzodiazepine-1-carbonitrile, M.P. 191°-192°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:13])[CH2:9][N:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].O[C:19]1[C:20]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH2:31])=[O:30])[C:21]=2[N:22]=[N:23][N:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C:19]2[C:20]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH2:31])=[O:30])[C:21]=3[N:22]=[N:23][N:24]=2)[CH2:9][N:10]([CH3:11])[CH3:12])=[CH:4][C:3]=1[C:14]([F:15])([F:16])[F:17]
Reactant: NC(=O)c1cccc2c(O)nnnc12
Reactant: CN(C)C[C@@H](N)c1ccc(Cl)c(C(F)(F)F)c1
Product: CN(C)C[C@@H](Nc1nnnc2c(C(N)=O)cccc12)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Compound 13 was prepared following general synthetic scheme 7 wherein (S)-1-(4-Chloro-3-(trifluoromethyl)phenyl)-N2,N2-dimethylethane-1,2-diamine was reacted with 4-hydroxybenzo[d][1,2,3]triazine-8-carboxamide to give the title compound. LC-MS [439 (M+1)], 1H NMR (400 MHz, DMSO-d6): δ 9.61 (brs, 1H), 9.23 (s, 1H), 9.17 (s, 1H), 8.58 (s, 2H), 8.19 (s, 1H), 8.08 (d, J=8.0 Hz, 2H), 7.92 (s, 1H), 7.78 (d, J=7.2 Hz, 1H), 6.34 (s, 1H), 3.83-3.63 (m, 2H), 2.91 (s, 6H).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:9])[CH2:7][NH:6][CH2:5][C@@H:4]1[OH:8].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>C(Cl)Cl>[OH:8][C@H:4]1[CH2:5][N:6]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][C:3]1([CH3:9])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1(C)CNC[C@@H]1O
Agent: Cl
Solvent: ClCCl
Product: CC1(C)CN(C(=O)OCc2ccccc2)C[C@@H]1O
Reaction time: 8 h
Yield: 88.7 %

Procedure:
To a mixture of (3R)-4,4-dimethyl-3-pyrrolidinol hydrochloride (0.9920 g, 6.630 mmol) in 1:1 DCM-1 N aq. NaOH (33 mL) was added benzyl chloroformate (0.994 mL, 6.963 mmol). The mixture was vigorously stirred overnight and then diluted with DCM (100 mL). The phases were partitioned, and the organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was then purified by silica gel chromatography (40% EtOAc in hexanes) to afford phenylmethyl (4R)-4-hydroxy-3,3-dimethyl-1-pyrrolidinecarboxylate (1.4654 g, 89% yield) as a colorless oil. LCMS: (M+H)+: 250.1.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:10].[Br:11]Br.O>CN(C)C=O>[Br:11][C:7]1[CH:8]=[C:9]2[O:1][C:2](=[O:10])[NH:3][C:4]2=[N:5][CH:6]=1
Reactant: BrBr
Reactant: O=c1[nH]c2ncccc2o1
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c2ncc(Br)cc2o1
Temperature: 25 °C

Procedure:
After dissolving oxazolo[4,5-b]pyridin-2(3H)-one (5 g, 23.25 mmol) in N,N-dimethylformamide (100 ml), bromine (1.28 ml, 25.58 mmol) is slowly added. Stirring is maintained at room temperature for 2 hours. Water (50 ml) is then added to the reaction mixture; the title product is isolated after having been filtered, rinsed with a little water and dried in vacuo. The yield obtained is 90%. ##STR22##
Reaction SMILES: [NH2:1][C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=O.[OH-].[Na+].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BH4-].[Na+]>C(O)C>[O:7]=[C:5]1[N:1]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4]1
Reactant: O=Cc1ccccc1
Reactant: N[C@H](CCC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCC(=O)N1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
D-glutamic acid (1.47 g, 10 mmol) was dissolved in 2N aqueous sodium hydroxide (10 ml, 20 mmol) and stirred for 15 minutes. The mixture was then treated with a solution of benzaldehyde (1.1 ml, 10 mmol) in ethanol (3 ml) and stirred at room temperature for 30 minutes. The mixture was cooled to 0° C. and treated with sodium borohydride (0.030 g). The mixture was allowed to warm to room temperature with stirring over 4 hrs and then washed with diethyl ether (three times) before acidifying with concentrated hydrochloric acid to pH2. The resulting precipitate was filtered off and washed with diethyl ether before slurrying in ethanol and azeotroping three times with more ethanol. Finally the remaining material was slurried in ethanol (50 ml) and heated at reflux for 16 hrs. The mixture was then cooled to room temperature and evaporated in vacuo. Drying afforded pure 5-oxo-1-(phenylmethyl)proline.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:14]=[C:13](O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:16])[CH:11]=2)[N:6]=1)(=[O:3])[CH3:2].[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1.C(N(C(C)C)CC)(C)C.O=P(Cl)(Cl)Cl>C(#N)C>[C:1]([NH:4][C:5]1[N:14]=[C:13]([C:21]2[N:20]=[CH:19][NH:18][N:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:16])[CH:11]=2)[N:6]=1)(=[O:3])[CH3:2]
Reactant: c1nc[nH]n1
Reactant: CC(=O)Nc1nc(O)c2cc(Br)ccc2n1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(-c2nc[nH]n2)c2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.1 %

Procedure:
To a mixture of 2-acetamido-6-bromo-4-hydroxy-quinazoline (2.82 g, 10 mmol) and 1,2,4-triazole (6.9 g, 100 mmol) in acetonitrile (100 ml) was added diisopropylethylamine (3.5 ml, 30 mmol) and POCl3 (2.8 ml, 30 mmol). The mixture was stirred at room temperature for 12 hours. The precipitate was collected, washed with ethanol, diethylether, and dried over P2O5 in a vacuum dessicator to yield the title compound as yellow solid (3.3 g). The crude product was used in the following reaction without further purification and was characterized by its mass spectrum as follows: MS (m/z): 333 ([M+H]+, 100).
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].O=S(Cl)Cl.[C:13]([C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[S:23])=[C:17]([CH2:24][CH3:25])[CH:16]=1)#[N:14]>>[C:13]([C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]2[NH:8][C@@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:23]2)=[C:17]([CH2:24][CH3:25])[CH:16]=1)#[N:14]
Reactant: CC(C)C[C@H](N)CO
Reactant: CCc1cc(C#N)ccc1N=C=S
Solvent: O=S(Cl)Cl
Product: CCc1cc(C#N)ccc1N=C1N[C@@H](CC(C)C)CS1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was reacted with SOCl2 followed by 4-cyano-2-ethylphenyl isothiocyanate according to Method C2a to give (4S)-2-(4-cyano-2-ethylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-cyano-2-ethylphenylimino)-3,4-diisobutyl-1,3-thiazolidine.
Reaction SMILES: C(=O)=O.[C:4]([NH:7][CH:8]([C:12]1([CH3:17])[CH2:16][CH:15]=[CH:14][O:13]1)[C:9]([OH:11])=O)(=[O:6])[CH3:5].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:4]([NH:7][CH:8]([C:12]1([CH3:17])[CH2:16][CH:15]=[CH:14][O:13]1)[C:9]([NH:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:11])(=[O:6])[CH3:5]
Reactant: CC(=O)NC(C(=O)O)C1(C)CC=CO1
Reactant: NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: O=C=O
Solvent: CN1CCOCC1
Product: CC(=O)NC(C(=O)NCc1ccccc1)C1(C)CC=CO1
Yield: 42.6 %

Procedure:
Employing the mixed carbonic anhydride coupling procedure with 18 (2.40 g, 12.2 mmol), 4-methylmorpholine (1.23 g, 12.2 mmol), isobutylchloroformate (1.83 g, 13.4 mmol), and benzylamine (1.43 g, 12.7 mmol) gave 4 (1.50 g, 43%) as a thick oil: Rf 0.29 (2% MeOH/CHCl3); 1H NMR (CDCl3) δ 1.94 (s, CH3), 1.98 (s, C(O)CH3), 4.40 (d, J=5.6 Hz, CH2), 6.20 (br s, NH), 6.34-6.37 (m, C3H, C4H), 7.05-7.36 (m, NH, C5H, 5 PhH); 13C NMR (CDCl3) 22.31 (C(O)CH3), 23.81 (CH3), 43.77 (CH2), 58.50 (C(CH3)), 107.94 (C4), 110.67 (C3), 126.99 (2C2 ' or 2C3 '), 127.41 (C4 '), 128.60 (2C2 ' or 2C3 '), 137.52 (C1 '), 142.38 (C5), 152.94 (C2), 169.03 (C(O)NH), 171.16 (COCH3) ppm; mass spectrum, m/e (relative intensity) 287 (M+ +1, 4), 228 (4), 153 (99), 152 (96), 138 (15), 111 (63), 110 (100), 91 (75); Mr (EI) 286.13074 (calcd for C16H18N2O3, 286.13174).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][S:15][CH2:16][CH:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.Cl.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[CH:39][CH:38]=1>C(#N)CC.O>[Cl:36][C:37]1[CH:38]=[CH:39][C:40]([N:43]2[CH2:48][CH2:47][N:46]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][S:15][CH2:16][CH:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:45][CH2:44]2)=[CH:41][CH:42]=1
Reactant: O=C1Nc2cc(CO)cnc2N2CCSCC12
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C1Nc2cc(CN3CCN(c4ccc(Cl)cc4)CC3)cnc2N2CCSCC12
Temperature: 90 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one (Compound 86C; 100 mg, 0.36 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (123.0 mg, 0.51 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). To the stirred mixture was then added 1-(4-chlorophenyl)piperazine hydrochloride (104.9 mg, 0.45 mmol). The reaction was heated to 90° C. with stirring for 2 h. The reaction was then cooled to room temperature and diluted with water (3 mL) and filtered. The solids were collected and refluxed in ethanol (5 mL) for 1 h. The suspension was cooled back to room temperature and filtered. The solids were collected to afford the title compound (86.1 mg, 56%) as a white solid. 1H NMR (DMSO-d6) δ: 10.66 (s, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.16-7.26 (m, 2H), 7.00 (d, J=2.0 Hz, 1H), 6.86-6.96 (m, 2H), 4.88 (dt, J=13.6, 2.7 Hz, 1H), 4.26 (dd, J=10.7, 2.9 Hz, 1H), 3.34-3.42 (m, 2H), 3.07-3.16 (m, 4H), 3.02 (td, J=12.8, 2.3 Hz, 1H), 2.65-2.83 (m, 3H), 2.43-2.48 (m, 5H). [M+H] calc'd for C, 21; H, 24; ClN, 5; OS, 430; found, 430.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11](=[O:17])[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C1COCC1>[C:21]([Si:24]([CH3:26])([CH3:25])[N:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11](=[O:17])[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)([CH3:23])([CH3:22])[CH3:20]
Reactant: CCN(CC)C(=O)Oc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)Oc1ccc2c(ccn2[Si](C)(C)C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Diethyl-carbamic acid 1H-indol-5-yl ester (5.72 g, 24.6 mmol) is dissolved in THF (200 mL) and cooled to 0° C. The flask is purged with nitrogen and then 60% NaH (1.1 g, 27.5 mmol) is added and the mixture stirred in aen ice bath for 30 minutes. At that point TBDMSCl (0.210 g, 1.39 mmol) is added and the reaction is allowed to stir overnight (14 hours). The reaction is quenched with a saturated solution of ammonium chloride and the mixture is diluted with ethyl acetate and water. The organic layer is removed, dried (sodium sulfate) and concentrated to obtain the title compound as an oil that is used without further purification. MS (ESI) m/z 347.21 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH2:18][OH:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[CH:26][C:27](=O)[NH:28][CH:29]=1>COCCOC>[CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH2:18][O:19][C:27]1[CH:26]=[CH:25][C:24]([C:23]([F:32])([F:31])[F:22])=[CH:29][N:28]=1)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:6]=1
Reactant: CC(C)(C)CN(CCO)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: O=c1ccc(C(F)(F)F)c[nH]1
Solvent: COCCOC
Product: CC(C)(C)CN(CCOc1ccc(C(F)(F)F)cn1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 27B from 4-[(2,2-dimethylpropyl)(2-hydroxyethyl)amino]-2-(trifluoromethyl)benzonitrile (Example 61C) and 5-(trifluoromethyl)-2(1H)-pyridinone, using dry DME as the reaction solvent: 1H NMR (400 MHz, CDCl3) δ 8.43 (m, 1H), 7.79 (app. dd, J=8.8, 2.6 Hz, 1H), 7.56 (d, J=8.9 Hz, 1H), 7.27 (d, J≈2.6 Hz, 1H; partially obscured by solvent), 6.97 (dd, J=9.0, 2.8 Hz, 1H), 6.78 (partially resolved ddd, J=8.7, ˜0.6, ˜0.6 Hz, 1H), 4.52 (t, J=6.6 Hz, 2H), 3.90 (t, J=6.7 Hz, 2H), 3.34 (s, 2H), 1.00 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[OH-].[K+].[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23]Br>C(O)C>[CH3:14][O:15][C:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)=[O:25]
Reactant: COC(=O)c1ccccc1CBr
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)c1ccccc1COc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
4-Hydroxyphenylacetic acid (760 mg, 4.995 mmol) was dissolved in ethanol (99.5%, 20 ml). Potassium hydroxide (560.5 mg, 9.99 mmol) was added. The mixture was stirred at room temperature for 30 minutes. 2-Bromomethylbenzoic acid methyl ester (1144.2 mg, 4.995 mmol) was then dropped in. The resulting mixture was heated to reflux for 2 hours and then evaporated in vacuum to dry. Water and ethyl acetate were added into the residue and the phases were separated. The water phase was acidified with 10% hydrochloric acid, pH˜5, and then extracted with ethyl acetate. The organic phase was dried with magnesium sulphate and evaporated in vacuum to dry. Chromatography of the residue on a column (ISOLUTE® SI, 5 g/6 ml) using DCM, MeOH/DCM (1:99) as eluant gave the desired product (262 mg), yield 17.5%.