Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH2:16])[N:15]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:3][CH:2]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[N:24]1([C:21]2[CH:22]=[CH:23][C:18]([NH:16][C:14]3[N:15]=[C:8]4[C:7]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)=[CH:12][CH:11]=[CH:10][N:9]4[N:13]=3)=[CH:19][CH:20]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: Nc1nc2c(-c3ccncc3)cccn2n1
Reactant: Brc1ccc(N2CCOCC2)cc1
Product: c1cc(-c2ccncc2)c2nc(Nc3ccc(N4CCOCC4)cc3)nn2c1

Procedure:
(4-Morpholin-4-yl-phenyl)-(8-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine was prepared from 8-Pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (100.0 mg, 0.4734 mmol) and 4-(4-Bromo-phenyl)-morpholine (160.0 mg, 0.6608 mmol) in an analogous manner to Step 2d. The title compound was isolated as yellow solid (0.035 g, 20%). MP=266-270° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 9.54 (s, 1H), 8.86 (d, J=6.5 Hz, 1H), 8.75-8.70 (m, 2H), 8.23-8.20 (m, 2H), 8.04 (d, J=7.3 Hz, 1H), 7.62-7.57 (m, 2H), 7.14 (t, J=7.0 Hz, 1H), 6.96-6.90 (m, 2H), 3.76-3.72 (m, 4H), 3.05-3.00 (m, 4H). MS=373 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][C:13]([CH2:15][O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[N:12][C:11]=2[CH:26]([CH3:28])[CH3:27])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[OH-].[Na+]>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:29]([N:14]1[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:26]([CH3:28])[CH3:27])[N:12]=[C:13]1[CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(COCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)[nH]2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2Cc2ccccc2)cc1
Yield: 6.5 %

Procedure:
In 10 ml of dry tetrahydrofuran was dissolved 423 mg (1.00 mmol) of 5-(3,5-dichlorophenylthio)-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (16b), followed by addition of 205 mg (1.20 mmol) of benzyl bromide, 48 mg (1.2 mmol) of sodium hydroxide and 5 mg (0.015 mg) of tetrabutylammonium bromide at room temperature wit stirring, and the mixture was stirred at the same temperature for 3 hours. This reaction mixture was concentrated under reduced pressure and the residue was diluted with water and extracted with methylene chloride. The organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure and the residual oil was fractionated by silica gel chromatography (ethyl acetate: methylene chloride=1:9). From the first fraction, 33 mg (yield 6.5%) of the objective position isomer (17f) was obtained. From the subsequent fraction, 450 mg (yield 88%) of 1-benzyl-5-(3,5-dichlorophenylthio)-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (17f) was obtained.
Reaction SMILES: [CH:1]([O:6][CH3:7])([O:4][CH3:5])OC.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C([C:25]1[CH:30]=[CH:29][C:28]([C:31]#[C:32][C:33]2[CH:43]=[CH:42][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:35][CH:34]=2)=[CH:27][CH:26]=1)=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:7][O:6][CH:1]([O:4][CH3:5])[C:25]1[CH:26]=[CH:27][C:28]([C:31]#[C:32][C:33]2[CH:34]=[CH:35][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:42][CH:43]=2)=[CH:29][CH:30]=1
Reactant: COC(OC)OC
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)c1ccc(C#Cc2ccc(C(OC)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
Trimethyl orthoformate (51 g) and (+)-CSA (2.3 g) were added to a methanol (0.40 L)-chloroform (0.10 L) mixed solution of ethyl 4-[(4-formylphenyl)ethynyl]benzoate (27 g) as obtained in Example 10-(1), and the mixture was stirred for 3 hours at room temperature. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and then the desiccant was filtered out. Then, the solvent was distilled off under reduced pressure, and the resulting residue was purified by OH type silica gel chromatography (gradient elution with hexane/ethyl acetate=95/5→80/20) to obtain ethyl 4-{[4-(dimethoxymethyl)phenyl]ethynyl}benzoate (white solid) (21 g, 67%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[Na].[NH2:10][C:11]1[N:16]=[C:15]([C:17](=[O:20])[CH2:18]Br)[CH:14]=[CH:13][N:12]=1.C(N(C(C)C)CC)(C)C>CCO.C1COCC1>[CH2:1]([O:3][C:4](=[O:8])[CH:5]([C:6]#[N:7])[CH2:18][C:17]([C:15]1[CH:14]=[CH:13][N:12]=[C:11]([NH2:10])[N:16]=1)=[O:20])[CH3:2]
Reactant: Nc1nccc(C(=O)CBr)n1
Reactant: CCOC(=O)CC#N
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C#N)CC(=O)c1ccnc(N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.3 %

Procedure:
Ethylcyanoacetate (5.3 mL, 0.05 mol) was added to a suspension of sodium metal (1.15 g, 0.05 mol) in 150 mL of anhydrous EtOH at 0° C. After sodium dissolution the reaction mixture was concentrated and the resultant solid was added to a solution of 1-(2-amino-pyrimidin-4-yl)-2-bromo-ethanone (15 g, 0.05 mol) in 300 mL of anhydrous THF and diisopropylethylamine (8.8 mL, 0.05 mol). The reaction mixture was stirred overnight at rt, concentrated and the residue was suspended in water and extracted with DCM. The organic extracts were dried (Na2SO4) and concentrated. The crude was purified by flash chromatography (DCM/MeOH 95:5) to give 4.5 g (37%) of the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][C@H:8]([O:21]/[N:22]=[C:23](/[C:27]1[N:28]=[C:29]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[S:30][C:31]=1[Cl:32])\[C:24](O)=[O:25])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:43][C@@H:44]1[C:51](=[O:52])[N:50]2[C@@H:45]1[S:46][CH2:47][C:48]([CH2:69][Cl:70])=[C:49]2[C:53]([O:55][CH:56]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54].P(Cl)(Cl)(=O)OC1C=CC=CC=1.CN1CCOCC1>ClCCl>[CH:56]([O:55][C:53]([C:49]1[N:50]2[C@H:45]([S:46][CH2:47][C:48]=1[CH2:69][Cl:70])[C@H:44]([NH:43][C:24](=[O:25])/[C:23](=[N:22]\[O:21][C@@H:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:41])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:10])/[C:27]1[N:28]=[C:29]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[S:30][C:31]=1[Cl:32])[C:51]2=[O:52])=[O:54])([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: COc1ccc(COC(=O)[C@H](CC(=O)OC(C)(C)C)O/N=C(\C(=O)O)c2nc(NC(=O)OC(C)(C)C)sc2Cl)cc1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Agent: Cl
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(COC(=O)[C@H](CC(=O)OC(C)(C)C)O/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)c2nc(NC(=O)OC(C)(C)C)sc2Cl)cc1
Reaction time: 3 h
Yield: 94.5 %

Procedure:
To a suspension of (S,Z)-2-(((4-(tert-butoxy)-1-((4-methoxybenzyl)oxy)-1,4-dioxobutan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)acetic acid (16.7 g, 27.2 mmol) and (6R,7R)-benzhydryl 7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, Hydrochloride (12.89 g, 28.6 mmol) in Dichloromethane (DCM) (210 mL) at −30° C. was added phenyl phosphorodichloridate (4.95 mL, 32.6 mmol), followed by dropwise N-methylmorpholine (8.97 mL, 82 mmol) over 15 mins. The mixture was stirred at the same temperature over 3 h. LCMS indicated completion of the reaction. The reaction was quenched by addition of 10% aq. citric acid (85 mL), the organic solution was separated and washed with 5% NaHCO3, brine, and dried (Na2SO4), filtered, and concentrated. The residue was purified by CombiFlash automated silica gel chromatography (330 g column, 0-50% EtOAc/Hexanes) to afford (S)-4-tert-butyl 1-(4-methoxybenzyl) 2-(((Z)-(2-(((6R,7R)-2-((benzhydryloxy)carbonyl)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)-2-oxoethylidene)amino)oxy)succinate (26 g, 25.7 mmol, 95% yield) as a light yellow foaming solid. LCMS: (M+H)+: 1010.6
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19].CN(C=O)C>CO>[Si:21]([C@@:3]1([OH:4])[C@@H:5]([CH2:6][O:7][Si:21]([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22])[O:8][C@@H:1]([N:9]2[CH:16]=[CH:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[CH2:2]1)([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(N)nc2=O)C[C@@]1(O)[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2′-deoxycytidine dC (2.85 g, 12.54 mmol), imidiazole (6.49 g, 95.31 mmol), and TBSCl (7.18 g, 47.65 mmol) were added to anhydrous DMF (27 mL) and stirred at room temperature overnight under a N2 atmosphere. Methanol (20 mL) was added, and the mixture was stirred for 30 minutes and then concentrated in vacuo. Ethyl acetate (60 mL) and water (60 mL) were then added. The organic layer was separated and washed twice with water (20 mL), and the combined aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layer was dried with Na2SO4, concentrated in vacuo, and purified by silica gel chromatography to give 3′,5′-O-bis-tert-butyldimethylsilyl-2′-deoxycytidine dC.01 (4.79 g, 84%) as a white foam.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[C:15]([C:16]([O:18]C)=[O:17])=[C:14]([O:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([NH:28][C:29](=[O:41])[CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=5)[CH:22]=4)[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1.CO.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[C:15]([C:16]([OH:18])=[O:17])=[C:14]([O:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([NH:28][C:29](=[O:41])[CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=5)[CH:22]=4)[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: COC(=O)c1c(Oc2ccc(F)c(NC(=O)Cc3cccc(C(F)(F)F)c3)c2)ccc2nc(NC(=O)C3CC3)sc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Cc1cccc(C(F)(F)F)c1)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3c2C(=O)O)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.6 %

Procedure:
To a solution of methyl 2-[(cyclopropylcarbonyl)amino]-6-[4-fluoro-3-({[3-(trifluoromethyl)phenyl]acetyl}amino)phenoxy]-1,3-benzothiazole-7-carboxylate (1.50 g, 2.68 mmol) produced in Example 54(iv) in tetrahydrofuran (24 mL)/methanol (8 mL) was added a solution of lithium hydroxide monohydrate (1.05 g, 25.7 mmol) in water (8 mL), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and the organic solvent was evaporated under reduced pressure. The obtained residue was collected by filtration, repeatedly washed with water to give the title compound (1.27 g, 83%) as a white powder.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21](Cl)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([C@H:28]1[CH2:33][N:32]([CH:34]2[CH2:37][O:36][CH2:35]2)[CH2:31][CH2:30][N:29]1[C:38]1[CH:39]=[CH:40][C:41]([NH:44][C:45]2[C:46](=[O:61])[N:47]([CH3:60])[CH:48]=[C:49](B3OC(C)(C)C(C)(C)O3)[CH:50]=2)=[N:42][CH:43]=1)[CH3:27].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC([O-])=O.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.CC#N>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:49]3[CH:50]=[C:45]([NH:44][C:41]4[CH:40]=[CH:39][C:38]([N:29]5[CH2:30][CH2:31][N:32]([CH:34]6[CH2:35][O:36][CH2:37]6)[CH2:33][C@@H:28]5[CH2:26][CH3:27])=[CH:43][N:42]=4)[C:46](=[O:61])[N:47]([CH3:60])[CH:48]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3nccc(Cl)c3C=O)ncc2c1
Reactant: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3C=O)cn(C)c2=O)nc1
Temperature: 100 °C
Yield: 49 %

Procedure:
A 50-mL round bottom flask was charged with 2-(6-tert-butyl-8-fluoro-1-oxo-phthalazin-2(1H)-yl)-4-chloronicotinaldehyde 103b (150 mg, 0.43 mmol), (S)-3-(5-(2-ethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (206 mg, 0.43 mmol), PdCl2(dppf) (33 mg, 0.04 mmol), K3PO4 (202 mg, 0.86 mmol), NaOAc (71 mg, 0.86 mmol), and CH3CN (10 mL), H2O (2 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 3 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography eluting with 1:3 petroleum/ethyl acetate to afford 112a as a yellow solid (146 mg, 49%). LCMS: [M+H]+ 693
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][C:12]([C:14]2[CH:36]=[CH:35][C:17]([O:18][C:19]3[CH:28]=[C:27]4[C:22]([CH:23]([C:29]([O:31]CC)=[O:30])[CH2:24][CH2:25][O:26]4)=[CH:21][C:20]=3[Cl:34])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(O)C>C1COCC1.Cl.C(OCC)(=O)C>[C:1]([C:5]1[N:10]=[C:9]([NH:11][C:12]([C:14]2[CH:36]=[CH:35][C:17]([O:18][C:19]3[CH:28]=[C:27]4[C:22]([CH:23]([C:29]([OH:31])=[O:30])[CH2:24][CH2:25][O:26]4)=[CH:21][C:20]=3[Cl:34])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(C(C)(C)C)n4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(Oc3cc4c(cc3Cl)C(C(=O)O)CCO4)cc2)n1
Reaction time: 3 h
Yield: 8.5 %

Procedure:
Ethyl 7-(4-(6-tert-butylpyridin-2-ylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (10 mg, 0.020 mmol) was diluted with THF (200 μL) followed by the addition of NaOH (98 μL, 0.098 mmol) and ethanol (100 μL). After stirring for 3 hours, the reaction was diluted with 0.5N HCl and ethyl acetate. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a 0.5 mm preparative TLC plate, eluting with 10% methanol/DCM to yield the desired compound (0.8 mg, 0.0017 mmol, 8.5% yield). MS (ESI)=481.2 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:11])=[CH:3][C:4]1[S:8][C:7]([C:9]#[N:10])=[CH:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]([CH3:11])=[CH:3][C:4]1[S:8][C:7]([CH2:9][NH2:10])=[CH:6][CH:5]=1
Reactant: CC(C)=Cc1ccc(C#N)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=Cc1ccc(CN)s1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
5-(2-Methylpropenyl)-thiophene-2-carbonitrile described in Preparation Example 144 (15 mg, 0.092 mmol) was dissolved in tetrahydrofuran (2 mL), lithium aluminum hydride (10 mg, 0.26 mmol) was added under stirring at room temperature, the solution was heated to 70° C., followed by stirring for 2 hours. The reaction solution was cooled on an ice bath, then, water (0.01 mL), an aqueous solution of 15% sodium hydroxide (0.01 mL) and water (0.03 mL) were sequentially added, then, the solid was filtered, and washed with tetrahydrofuran (5 mL). The filtrate and the washings were combined, and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo, and the title compound (14 mg, 0.083 mmol, 91.1%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[N+:24]([O-])([O-:26])=[O:25].[Na+].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([N+:24]([O-:26])=[O:25])=[CH:14][C:13]=3[CH2:18][N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1
Reactant: O=[N+]([O-])[O-]
Reactant: Cn1nnc2ccc(Oc3ccccc3Cn3cncn3)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cn1nnc2ccc(Oc3ccc([N+](=O)[O-])cc3Cn3cncn3)cc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 26.2 %

Procedure:
The suspension of 1-methyl-6-[2-(1H-1,2,4-triazol-1-ylmethyl)phenoxy]-1H-benzotriazole (0.5 g) from Example 44, sodium nitrate (0.28 g) and trifluoroacetic acid (5 ml) was stirred at room temperature for 3 days. Stirring was done for another day after further addition of sodium nitrate (0.28 g), and the reaction solution was neutralized with sodium hydrogen carbonate solution, prior to extraction in ethyl acetate. The organic layer was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate, prior to removal of the solvent under reduced pressure. The resulting crude crystal in pale yellow was washed with ethyl acetate to give white crystal, which was then recrystallized three times for methanol to give the title compound (0.15 g; 25%). The purity of the compound was 98.8% by HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH3:30])=[O:28])=[CH:22][CH:21]=3)[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38]([C:41]1[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:56])OC2C=CC=CC=2)=[CH:43][CH:42]=1)(=[O:40])[NH2:39]>CN(C=O)C>[CH3:30][NH:29][C:27]([NH:26][C:23]1[CH:22]=[CH:21][C:20]([C:10]2[N:11]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:48]([NH:47][C:44]4[CH:43]=[CH:42][C:41]([C:38]([NH2:39])=[O:40])=[CH:46][CH:45]=4)=[O:56])=[CH:7][CH:6]=3)[N:9]=2)=[CH:25][CH:24]=1)=[O:28]
Reactant: NC(=O)c1ccc(NC(=O)Oc2ccccc2)cc1
Reactant: CNC(=O)Nc1ccc(-c2nc(-c3ccc(N)cc3)nc(N3CCOCC3)n2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)Nc1ccc(-c2nc(-c3ccc(NC(=O)Nc4ccc(C(N)=O)cc4)cc3)nc(N3CCOCC3)n2)cc1
Temperature: 90 °C
Yield: 5.3 %

Procedure:
To a solution of 1-(4-(4-(4-aminophenyl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea (0.6 g, 1.5 mmol) and triethylamine (4-5 mL) in dry DMF (10 mL), phenyl 4-carbamoylphenylcarbamate (1.15 g, 4.5 mmol).) was added at room temperature and mixture was heated to 90° C. for 10 hours under nitrogen atmosphere. After cooling to room temperature reaction mixture was quenched with ice water and resulting solid was filtered to get crude product. Crude product was purified by Preparative HPLC to give 4-({[4-(4-{4-[(methylcarbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide (45 mg, 5.3% yield).
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[O:8])(=O)C.[OH-].[Na+].O.Cl>CO.[Zn]>[SH:4][CH2:5][CH:6]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[O:8]
Reactant: COC(=O)CCCCCCNC(=O)C(CSC(C)=O)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)CCCCCCNC(=O)C(CS)Cc1ccccc1
Temperature: 25 °C

Procedure:
(±)-7-[[2-[(Acetylthio)methyl]-1-oxo-3-phenylpropyl]amino]heptanoic acid, methyl ester (1.43 g., 3.77 mmole) is dissolved in methanol (30 ml.) by warming, and then chilled in an ice bath under nitrogen. 1N Sodium hydroxide (3.77 ml., 1.0 eq.) is added dropwise over 10 minutes to this solution. The mixture is stirred at 0° for ten minutes and then allowed to warm to room temperature and stirred for one hour. The mixture is concentrated in vacuo to remove all the methanol. The residue is diluted with water (20 ml.) and extracted with ethyl acetate (3×15 ml.). These organic layers are combined, washed with water and brine (15 ml. each), dried (Na2SO4) and concentrated to yield 1.26 g. of a white solid. This solid is dissolved in 25 ml. of a 1:1 mixture of methanol: water and adjusted to pH of about 1.0 with concentrated hydrochloric acid. Zinc dust (80 mg.) is added to this solution and the mixture is stirred at room temperature for 30 minutes. The remaining zinc is filtered off and the filtrate is concentrated in vacuo to remove all the methanol. The residue is diluted with water (20 ml.) and then extracted with ethyl acetate (3×25 ml.). These organic layers are combined, washed with 5% sodium bicarbonate, water and brine (2×20 ml. each), dried (Na2SO4), and concentrated to yield 1.23 g. of a white solid. This material is purified by flash chromatography on 50 g. of Merck silica gel (230-400 mesh) eluting with ethyl acetate to yield 980 mg. of a white solid. This solid is taken up in methanol, filtered through a cellulose microfilter, and concentrated in vacuo to yield (±)-7-[[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]amino]heptanoic acid, methyl ester, m.p. 68°-70°. TLC (silica gel, benzene/acetic acid 4:1) Rf =0.44.
Reaction SMILES: [Cl-].[Li+].[BH4-].[Na+].COCCOCCOC.C[O:15][C:16]([C:18]1[N:19]=[CH:20][C:21]2[C:26]([CH:27]=1)=[C:25]([N:28]=[C:29]1[N:33]3[CH2:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=4[CH2:41][C@H:32]3[CH2:31][S:30]1)[CH:24]=[CH:23][CH:22]=2)=O>O>[OH:15][CH2:16][C:18]1[N:19]=[CH:20][C:21]2[C:26]([CH:27]=1)=[C:25]([N:28]=[C:29]1[N:33]3[CH2:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=4[CH2:41][C@H:32]3[CH2:31][S:30]1)[CH:24]=[CH:23][CH:22]=2
Reactant: COC(=O)c1cc2c(N=C3SC[C@@H]4Cc5ccccc5CN34)cccc2cn1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: COCCOCCOC
Solvent: O
Product: OCc1cc2c(N=C3SC[C@@H]4Cc5ccccc5CN34)cccc2cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
Lithium chloride (1.01 g), sodium borohydride (0.91 g) and diglyme (diethylene glycol dimethyl ether) (100 cc) are mixed at 0° C. The mixture is stirred for 30 minutes at 0° C. and (S)-3-[(3-methoxycarbonylisoquinol-5-yl)imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]-isoquinoline (4.7 g) is added. Stirring is continued for 1 hour at 0° C. and then for 2 hours at 20° C. Water (1 liter) is added and the mixture is extracted with methylene chloride (3×150 cc). The organic extracts are combined, washed with water, dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (40 mm Hg; 5.3 kPa) at 40° C. The residue is dissolved in methylene chloride (20 cc) and the solution is poured onto a column of diameter 3 cm, containing silica gel (120 g) in methylene chloride. Elution is carried out with an ethyl acetate/cyclohexane mixture (70/30 by volume), 300 cc fractions being collected. Fractions 7 to 11 are combined and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue is recrystallised from butyl acetate (100 cc). After filtration, washing with diisopropyl ether and drying, (S)-3-[(3-hydroxymethylisoquinol-5-yl)-imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (2 g) is obtained, as a white solid, m.p.=210° C.