Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=1.[CH:18]1[CH:19]=[CH:20][N:21]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[NH:24][CH2:23][C:22]=12.C(N(CC)C(C)C)(C)C>S(Cl)(Cl)=O.ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:24]2[C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[CH2:27][N:21]3[CH:20]=[CH:19][CH:18]=[C:22]3[CH2:23]2)=[O:17])=[CH:13][CH:14]=1
Reactant: COc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 2 h

Procedure:
A suspension of 2′-methoxy-[1,1′-biphenyl]-4-carboxylic acid of Step B (1.0 g, 4.38 mmol) in thionyl chloride (6 mL) was heated at reflux for 30 min. After cooling, the thionyl chloride was removed in vacuo. The residue was dissolved in toluene and concentrated in vacuo to give the crude acid chloride as a yellow solid. The latter was then dissolved in dichloromethane (10 mL) and the solution was slowly added to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.97 g, 5.27 mmol) and N,N-diisopropylethyl amine (1.6 mL, 9.19 mmol) in dichloromethane (30 mL). After stirring for 2 hours, the reaction was quenched with water. The organic layer was washed with 1 N hydrochloric acid, 1 N sodium hydroxide and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow foam. Purification of the residue by flash chromatography using a solvent gradient from 15% to 25% of ethyl acetate in hexane provided the title compound as a white foam which was crystallized by sonication from ethyl acetate/hexane (1.4 g, 81.0%) to give a white solid m.p. 145–147° C.
Reaction SMILES: CS(O[CH:6]1[C:10]([CH3:12])([CH3:11])[C:9](=[O:13])[N:8]([C:14]2[C:18]([NH:19][C:20]([C:22]3[N:23]=[C:24]([C:27]4[CH:32]=[CH:31][N:30]=[C:29]([N:33]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34][C:35]([F:38])([F:37])[F:36])[CH:28]=4)[O:25][CH:26]=3)=[O:21])=[CH:17][N:16]([CH3:46])[N:15]=2)[CH2:7]1)(=O)=O.[N-:47]=[N+:48]=[N-:49].[Na+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.C(OCC)(=O)C>[N:47]([CH:6]1[CH2:7][N:8]([C:14]2[C:18]([NH:19][C:20]([C:22]3[N:23]=[C:24]([C:27]4[CH:32]=[CH:31][N:30]=[C:29]([N:33]([CH2:34][C:35]([F:37])([F:38])[F:36])[C:39](=[O:40])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH:28]=4)[O:25][CH:26]=3)=[O:21])=[CH:17][N:16]([CH3:46])[N:15]=2)[C:9](=[O:13])[C:10]1([CH3:12])[CH3:11])=[N+:48]=[N-:49]
Reactant: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2CC(OS(C)(=O)=O)C(C)(C)C2=O)n1
Reactant: [N-]=[N+]=[N-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2CC(N=[N+]=[N-])C(C)(C)C2=O)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.2 %

Procedure:
1-(4-(((2-(2-((tert-Butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)-1,3-oxazol-4-yl)carbonyl)amino)-1-methyl-1H-pyrazol-3-yl)-4,4-dimethyl-5-oxopyrrolidin-3-yl methanesulfonate (15 mg) was dissolved in DMF (0.50 mL), sodium azide (22 mg) and 18-crown-6 (5.9 mg) were added thereto, and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, and the mixture was washed three times with saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.0 mg).
Reaction SMILES: Cl[C:2]1[C:3](=[O:13])[N:4]([CH2:9][CH2:10][S:11][CH3:12])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[Br:15][C:16]1[CH:17]=[C:18]([O:25][CH3:26])[CH:19]=[C:20]2[C:24]=1[NH:23][CH2:22][CH2:21]2>>[Br:15][C:16]1[CH:17]=[C:18]([O:25][CH3:26])[CH:19]=[C:20]2[C:24]=1[N:23]([C:2]1[C:3](=[O:13])[N:4]([CH2:9][CH2:10][S:11][CH3:12])[CH:5]=[C:6]([Cl:8])[N:7]=1)[CH2:22][CH2:21]2
Reactant: CSCCn1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc(Br)c2c(c1)CCN2
Agent: Cl
Product: COc1cc(Br)c2c(c1)CCN2c1nc(Cl)cn(CCSC)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[2-(methylthio)ethyl]-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. 1H NMR (300 MHz, CDCl3): δ 6.93 (d, J=2.5 Hz, 1 H), 6.88 (s, 1 H), 6.79 (d, J=2.5 Hz, 1H), 4.36 (t, J=7.7 Hz, 2 H), 4.05 (t, J=7.0 Hz, 2 H), 3.78 (s, 3 H), 3.10 (t, J=7.5 Hz, 2 H), 2.90 (t, J=7.0 Hz, 2 H), 2.17 (s, 3 H); HRMS (CI) calcd for C16H17N3O2SBrCl (M+): 428.9913; found m/z 428.9899.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)[CH2:16][N:15]([C:29](OC4C=CC([N+]([O-])=O)=CC=4)=[O:30])[CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:41]1[CH2:45][CH2:44][CH:43]([OH:46])[CH2:42]1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=4)[CH2:16][N:15]([C:29]([N:41]4[CH2:45][CH2:44][CH:43]([OH:46])[CH2:42]4)=[O:30])[CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCNC1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1
Product: O=C(N1CCC(O)C1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1

Procedure:
100 mg (0.18 mmol) of the compound from Example 187A and 47 mg (0.54 mmol) of 3-pyrrolidinol were reacted according to the General Method 6. Yield: 25 mg (26% of theory)
Reaction SMILES: [Si]([O:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][C@H:21]([CH2:25][CH:26]=[C:27]([CH2:35][CH3:36])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:35]([C:27](=[CH:26][CH2:25][C@H:21]1[CH2:22][CH2:23][CH2:24][C@@H:19]([OH:18])[CH2:20]1)[C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])[CH3:36]
Reactant: CCC(=CC[C@H]1CCC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(=CC[C@H]1CCC[C@@H](O)C1)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
1.3.11 g of tert-butyl 4-[cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]-2-ethylbut-2-enoate are dissolved in 20 ml of tetrahydrofuran, and 15.7 ml of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran are added. The mixture is stirred at 60° C. for 2 hours. The reaction mixture is concentrated under reduced pressure and purified on silica gel using the mobile phase n-heptane:ethyl acetate=30:1=>ethyl acetate. This gives 1.65 g of tert-butyl 2-ethyl4-(cis-3-hydroxycyclohexyl]but-2-enoate as an oil. C16H28O3 (268.40), Rf(n-heptane:ethyl acetate=5:1)=0.07.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[Br:26][C:27]1[N:32]2[CH:33]=[CH:34][N:35]=[C:31]2[C:30](Br)=[N:29][CH:28]=1>C(O)(C)C>[Br:26][C:27]1[N:32]2[CH:33]=[CH:34][N:35]=[C:31]2[C:30]([NH:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)=[N:29][CH:28]=1
Reactant: Brc1ncc(Br)n2ccnc12
Reactant: Nc1ccc(OCCN2CCOCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Brc1cnc(Nc2ccc(OCCN3CCOCC3)cc2)c2nccn12
Yield: 86.3 %

Procedure:
In the same way as described in the general procedure for amine displacement using 4-(2-morpholin-4-yl-ethoxy)-phenylamine (600 mg, 2.7 mmol), N,N-diisopropylethylamine (0.470 mL, 2.7 mmol) and a solution of 5,8-dibromo-imidazo[1,2-a]pyrazine (0.500 g, 1.80 mmol) in isopropanol (6 mL). Purification by silica gel column chromatography eluting with a mixture 97:3 DCM:MeOH affords the title compound as a pale yellow solid (650 mg, 86%). 1H-NMR (400 MHz, CDCl3) δ (ppm) 2.51-2.62 (4H, m), 2.75-2.83 (2H, t), 3.71-3.78 (4H, m), 4.09-4.18 (2H, m), 6.90 (2H, d), 7.51 (1H, s), 7.61 (1H, s), 7.64 (2H, d), 7.70 (1H, s), 7.90 (1H, s). LCMS: Rt 2.09 min (97%).
Reaction SMILES: C(OC(=O)[CH:5]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[C@H:17]2[CH2:22][CH2:21][C@H:20](C)[CH2:19][CH2:18]2)=[O:15])=[N:10][CH:9]=1)[CH3:6])C.C1(N[C@H]2CC[C@H](C)CC2)CCCC1.NC1SC=NC=1.C([O:51][C:52](=[O:56])C(S)C)C>>[CH:17]1([N:16]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:5][CH2:6][C:52]([OH:56])=[O:51])=[CH:9][N:10]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CCOC(=O)C(C)S
Reactant: CCOC(=O)C(C)Sc1cnc(NC(=O)N(C2CCCC2)[C@H]2CC[C@H](C)CC2)s1
Agent: C[C@H]1CC[C@H](NC2CCCC2)CC1
Agent: Nc1cncs1
Product: O=C(O)CCSc1cnc(NC(=O)N(C2CCCCC2)C2CCCC2)s1

Procedure:
{2-[3-Cyclopentyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester prepared as described in general procedure (A) using cyclopentyl-(trans-4-methyl-cyclohexyl)-amine and 5-aminothiazole-2-mercaptopropionic acid ethyl ester. Hydrolysis using general procedure (F) gave the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5](C=O)=[CH:4][CH:3]=1.[C:10]([O:15][CH2:16][CH3:17])(=[O:14])[CH:11]([CH3:13])[OH:12].S(C1C=CC(C)=CC=1)([O-])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([O:12][CH:11]([CH3:13])[C:10]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOC(=O)C(C)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)Oc1ccc(O)cc1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
12.2 g of 4-hydroxybenzaldehyde, 30 g of (-)-ethyl lactate-tosylate ([α]D25 =-34.2°, optical purity: 96%), 20 g of potassium carbonate and 100 g of acetonitrile, were mixed, and the mixture was refluxed for 5 hours and then cooled to room temperature. The reaction mixture was treated in the same manner as in Reference Example 3, whereby 20.0 g of (+)-ethyl 2-(4-hydroxyphenoxy)propionate was obtained as a colorless transparent liquid. The boiling point was from 130° to 140° C./1 mmHg. [α]D25 =+51.5°, optical purity: 93%.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>O1CCCC1.CN(C)C=O>[Si:17]([N:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)N1c2ccccc2Oc2ccccc21

Procedure:
5 Grams of phenoxazine was dissolved in 100 ml of dry tetrahydrofuran, then 1.63 g of 50% sodium hydride in mineral oil was added and the mixture refluxed for 30 minutes. Then 6.19 g of t-butyldimethylsilyl chloride in dimethylformamide (2 ml) and tetrahydrofuran (8 ml) was added and reflux was continued for five more minutes. The reaction was quenched by the addition of water, the organic layer was separated and dried over sodium sulfate. Then the solvent was removed under reduced pressure and the residue purified by column chromatography (silica as solid phase, hexane:ethylacetate (95:5) as mobile phase). N-t-butyldimethylsilylphenoxane had a melting point of 57° C. after crystallization from pentane.
Reaction SMILES: C(O[CH:4](OCC)[C:5]#[C:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10]2)C.[C:20]1([NH:26][NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>C(#N)C.O>[C:20]1([N:26]2[C:6]([C:7]3[CH:8]=[C:9]4[C:13](=[CH:14][CH:15]=3)[NH:12][C:11](=[O:16])[CH2:10]4)=[CH:5][CH:4]=[N:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(C#Cc1ccc2c(c1)CC(=O)N2)OCC
Reactant: NNc1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C1Cc2cc(-c3ccnn3-c3ccccc3)ccc2N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.1 %

Procedure:
To a solution of 5-(3,3-diethoxyprop-1-ynyl)indolin-2-one (100 mg, 0.39 mmol) in acetonitrile (5 ml) were added phenyl hydrazine (38 μL, 0.38 mmol) and sulfuric acid (52 μL, 0.98 mmol), and the mixture was stirred for 3 h at room temperature, then the mixture was stirred for 2 h at 50° C. The reaction mixture was poured into water (50 mL), and the resulting precipitate was filtered and dried. The precipitated was dissolved in acetonitrile (5 mL), then water (52 μL, 3.9 mmol) and sulfuric acid (93 μL, 1.75 mmol) were added. The mixture was heated at 80 C for 4 h. The mixture was cooled to room temperature, and then neutralized with sat. NaHCO3. The mixture was extracted with CHCl3/EtOAc 3 times. The combined organic extracts were washed with sat. NaCl, dried over Na2SO4, and evaporated in vacuo. The residue purified by column chromatography (EtOAc/n-hexane) to give the title compound as a brown solid (44 mg, 41%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)[CH3:27]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1ccccc1Cl
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4ccccc4Cl)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(2-chloro-phenyl)-1-methyl-propyl]-amine and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [OH:1][C:2]([CH3:22])([CH3:21])[C@H:3]([NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:23]=[S:24](Cl)Cl.N1C=CC=CC=1>C1COCC1>[CH3:21][C:2]1([CH3:22])[O:1][S@:24](=[O:23])[N:10]([S:11]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)(=[O:13])=[O:12])[C@@H:3]1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)C(C)(C)O)cc1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)N2[C@H](c3ccccc3)C(C)(C)O[S@@]2=O)cc1
Reaction time: 2 h
Yield: 86.9 %

Procedure:
To a solution of (1R)-N-(2-hydroxy-2-methyl-1-phenyl-propyl)-4-methyl-benzene sulfonamide (2.0 g, 6.3 mmol) in THF 8 mL at −45° C. was added SOCl2 (1.12 g, 9.4 mmol), followed by slow addition of pyridine (1.24 g, 12.9 mmol) in THF (8 mL) over a period of 2 h. The reaction was monitored on TLC. The reaction was quenched by addition of saturated aqueous NaHCO3 and the mixture was extracted with EtOAc (30 ml), and organic phase washed with brine (20 mL) and evaporated to dryness. The residue was added hexane (40 mL) and stirred at ambient for 2 h. The precipitate formed was filtered and wet cake washed with hexane to afford the title compound (2.0 g, 87.5%) with 99% de.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:28](C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CCCCC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH2:28][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Solvent: C1CCNCC1
Product: CC(C)(C)c1nc(N2CCCCC2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and piperidine and isolated as light-yellow solid (10.0 mg, 55%). MS(m/e): 385.4 (MH+).
Reaction SMILES: CN(C)C=[CH:4][C:5]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:8]([C:9]#[N:10])=[C:7]([O:16][CH2:17][CH3:18])[N:6]=1.O.I([O-])(=O)(=O)=[O:22].[Na+]>O1CCCC1>[CH2:17]([O:16][C:7]1[N:6]=[C:5]([CH:4]=[O:22])[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:8]=1[C:9]#[N:10])[CH3:18]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCOc1nc(C=CN(C)C)c([N+](=O)[O-])cc1C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1nc(C=O)c([N+](=O)[O-])cc1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.6 %

Procedure:
To a stirred solution of the compound prepared in Example 445 (1.07 g) in tetrahydrofuran (20 mL) at ambient temperature was added water (20 mL), and to the resulting mixture was added sodium periodate (2.62 g). The resulting mixture was stirred at ambient temperature for 18 hours. There was a significant amount of precipitate present in the reaction mixture, and it was collected by filtration and washed with 50% aqueous tetrahydrofuran. The combined filtrate and wash were concentrated to remove most of the tetrahydrofuran, and the residue was extracted with chloroform. The organic layers were combined and dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 1/1 hexanes/ethyl acetate, to provide the title compound (0.61 g) with the following physical data.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](O)=[O:41])=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C:47]([CH3:55])([CH3:54])[C:48]([NH:50][CH2:51][CH2:52][OH:53])=[O:49].NC(C)(C)C(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:41])[NH:46][C:47]([C:48](=[O:49])[NH:50][CH2:51][CH2:52][OH:53])([CH3:55])[CH3:54])=[CH:33][CH:32]=3)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(C)(N)C(=O)NCCO
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(C)(N)C(N)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OCCC(=O)NC(C)(C)C(=O)NCCO)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 78 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole and 2-(2-amino-2-methylpropionyl-amino)ethanol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methyl-propionamide, respectively.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:12]([NH2:13])=[C:11]([CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[O:29]1[CH2:34][CH2:33][CH:32]([C:35](Cl)=[O:36])[CH2:31][CH2:30]1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:12]([NH:13][C:35]([CH:32]2[CH2:33][CH2:34][O:29][CH2:30][CH2:31]2)=[O:36])=[C:11]([CH3:19])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1CCOCC1
Reactant: Cc1cc(OCc2ccccc2)cc([N+](=O)[O-])c1N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCc2ccccc2)cc([N+](=O)[O-])c1NC(=O)C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.22 g (0.85 mmol) 4-(benzyloxy)-2-methyl-6-nitroaniline were placed in 5 mL DCM. 0.17 mL (1.00 mmol) DIPEA and 0.10 mL (1.00 mmol) tetrahydro-2H-pyran-4-carbonyl chloride were added and the mixture was stirred for 2 h at RT. A further 0.10 mL (1.00 mmol) tetrahydro-2H-pyran-4-carbonyl chloride were added and the mixture was stirred overnight at RT. The reaction mixture was diluted with DCM and washed with water. The organic phase was evaporated down i.vac.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[CH2:4]/[CH:5]=[CH:6]\[CH2:7][NH:8][C:9]1[CH2:13][S:12][C:11](=[O:14])[N:10]=1)[CH3:2].[F:17][C:18]([F:39])([F:38])[C:19]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:39][C:18]([F:17])([F:38])[C:19]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25](/[CH:28]=[C:13]2/[C:9]([NH:8][CH2:7]/[CH:6]=[CH:5]\[CH2:4][N:3]([CH2:1][CH3:2])[CH2:15][CH3:16])=[N:10][C:11](=[O:14])[S:12]/2)[CH2:24][CH2:23]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CCN(CC)C/C=C\CNC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CCN(CC)C/C=C\CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 16 %

Procedure:
To a solution of 4-{[(2Z)-4-(diethylamino)but-2-en-1-yl]amino}-1,3-thiazol-2(5H)-one (440 mg) in 2-propanol (5 mL) were added 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (617 mg) and piperidinium acetate (264 mg) at room temperature, and the reaction mixture was stirred at 60° C. for 4 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (164 mg).
Reaction SMILES: C(OC([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C@@H:13]1[O:23][CH3:24])=O)C1C=CC=CC=1>CO.Cl.[Pd].C>[NH2:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C@@H:13]1[O:23][CH3:24]
Reactant: CCOC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@@H](OC)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOC(=O)N1CC[C@@H](N)[C@@H](OC)C1
Reaction time: 3 h
Yield: 117 %

Procedure:
ethyl (3S,4R)-4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidine-1-carboxylate (Intermediate 24; 3.98 g) was dissolved in MeOH (100 ml) and 1N HCl (50 ml). 10% Pd-charcoal (600 mg) was added, degassed and hydrogenolysed under an atmosphere of H2 gas at room temperature for 3 h. The catalyst was filtered through a bed of celite, concentrated in vacuo and lyophilized giving the title compound (2.8 g). MS (ES) MH+: 202 for C9H18N2O3.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.Br[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1>>[CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH:6][C:16]2[CH:15]=[CH:14][CH:19]=[CH:18][C:17]=2[CH2:20][CH2:21][OH:22])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: Cc1cc(N)c([N+](=O)[O-])cc1C
Product: Cc1cc(Nc2ccccc2CCO)c([N+](=O)[O-])cc1C

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 45 from 4,5-dimethyl-2-nitroaniline and 4-bromophenylethyl alcohol.
Reaction SMILES: [F:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:4]=2[CH:3]=1.S(Cl)([Cl:15])=O.CN(C)C=O>ClCCCl>[Cl:15][C:9]1[C:4]2[CH:3]=[C:2]([F:1])[N:12]=[CH:11][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=c1[nH]cnc2cnc(F)cc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Fc1cc2c(Cl)ncnc2cn1
Yield: 91 %

Procedure:
A stirred suspension of 30.0 g (182 mmol) of 6-fluoropyrido[3,4-d]pyrimidin-4(3H)-one in 182 mL of 1,2-dichloroethane was treated successively with 182 mL of thionyl chloride, then ca. 1 mL of N,N-dimethyl-formamide. The mixture was heated at reflux for 2.5 hours, then concentrated to a solid that was coevaporated twice with 1,2-dichloroethane. The residual dark brown solids were dissolved in dichloromethane, and the solution was filtered through a short pad of silica gel eluting with dichloromethane. Concentration of product fractions afforded 30.5 g (91%) of pure product after drying. Crystallization of a small sample from tert-butyl methyl ether gave product of mp 75-76° C. 1H NMR (CDCl3): δ9.29 (s, 1H, 9.16 (s, 1H), and 7.65 (dd, J=0.7 Hz, 2.0 Hz, 1H).