Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH3:22][C:23]1([CH:26]=[CH2:27])[CH2:25][O:24]1>>[OH:24][C:23]([CH3:25])([CH:26]=[CH2:27])[CH2:22][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: C=CC1(C)CO1
Product: C=CC(C)(O)CN1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 159 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-methyl-2-vinyloxirane and conditions outlined in procedure X. M.p.=74-77° C.; 400 MHz 1H NMR (CDCl3) δ: 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 5.9 (dd, 1H), 5.35 (d, 1H), 5.05 (d, 1H), 3.0-2.7 (m, 4H), 2.6 (m, 4H), 2.45 (d, 1H), 2.1 (t, 2H), 1.9-1.75 (m, 2H), 1.2 (s, 3H); LCMS: 386 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([OH:12])[C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.Cl[C:14](OCC)=[O:15].O>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:9](=[O:10])[NH:11][C:14](=[O:15])[O:12]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: NC(=O)N(O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c(=O)n(-c2ccc(Cl)cc2)o1
Reaction time: 0.5 h

Procedure:
1-(4-Chlorophenyl)-1-hydroxyurea (34 grams; 0.18 mole) dissolved in aqueous sodium hydroxide (200 ml; 2 N) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of 10° to 15°C and ethyl chloroformate (17 ml) is slowly added with stirring. After the addition is completed stirring is continued for a period of about 1/2 hour. Water (200 ml) is then added to the reaction mixture with stirring and the resulting mixture is poured into 3 liters of water. The resulting aqueous solution is then filtered and the filtrate is cooled and acidified with concentrated hydrochloric acid to form a precipitate. The precipitate is recovered by filtration and is dried. The resulting product is then dissolved in a 100:5 mixture of methylene chloride and tetrahydrofuran and the solution is dried over anhydrous magnesium sulfate. The dried solution is then stripped of solvent under reduced pressure to yield the desired product 2-(4-chlorophenyl)-1,2,4-oxadiazolidin-3,5-dione.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[NH:4][N:3]=1.Br[C:15]1[S:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][N:19]=1.O1CCCC1.ClCCl>CO>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([NH:1][C:15]3[S:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][N:19]=3)[NH:3][N:4]=2)=[CH:8][CH:9]=1
Reactant: Nc1n[nH]c(-c2ccc(Cl)cc2)n1
Reactant: O=[N+]([O-])c1cnc(Br)s1
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc(Nc2nc(-c3ccc(Cl)cc3)n[nH]2)s1

Procedure:
The title compound was prepared in a similar manner described in Example 1 by heating 3-amino-5-(4-chlorophenyl)-1,2,4-triazole with 2-bromo-5-nitrothiazole in refluxing tetrahydrofuran followed by silica gel column chromatograph by a solvent mixture of dichloromethane and methanol to yield 3-(4-chlorophenyl)-5-[(5-nitrothiazol-2-yl)amino]-1,2,4-triazole.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.[OH-].[Na+].[Cl:63][CH2:64][C:65](=[O:72])[CH2:66][C:67]([O:69][CH2:70][CH3:71])=[O:68]>>[Cl:63][CH2:64][CH:65]([OH:72])[CH2:66][C:67]([O:69][CH2:70][CH3:71])=[O:68]
Reactant: CCOC(=O)CC(=O)CCl
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Product: CCOC(=O)CC(O)CCl
Temperature: 30 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
The culture of the recombinant Escherichia coli HB101 (pNTRGG1) as obtained in Example 9 was subjected to ultrasonic cell disruption using SONIFIRE 250 (product of BRANSON). To 20 ml of this cell disruption fluid, there were added 4 g of glucose and 3 mg of NADP. While stirring this reaction mixture at 30° C. and adjusting the pH to 6.5 by dropwise addition of 5 M sodium hydroxide, a total of 2 g of ethyl 4-chloroacetoacetate was added to the mixture continuously at a rate of 0.2 g per hour. After completion of the addition, the reaction was further allowed to proceed for 12 hours. After completion of the reaction, this reaction mixture was extracted with ethyl acetate, the solvent was then removed, and the extract was analyzed. Ethyl 4-chloro-3-hydroxybutyrate was obtained in 98% yield. The ethyl 4-chloro-3-hydroxybutyrate formed on that occasion was the R form with an optical purity of 99% ee or more.
Reaction SMILES: CC(C[AlH]CC(C)C)C.CO[C:12](=O)[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[Br:22].[NH2:24][CH2:25][CH2:26][NH:27][S:28]([C:31]1[C:32]2[CH:33]=[CH:34][N:35]=[CH:36][C:37]=2[CH:38]=[CH:39][CH:40]=1)(=[O:30])=[O:29]>>[Br:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[O:14][CH2:13][CH2:12][NH:24][CH2:25][CH2:26][NH:27][S:28]([C:31]1[C:32]2[CH:33]=[CH:34][N:35]=[CH:36][C:37]=2[CH:38]=[CH:39][CH:40]=1)(=[O:30])=[O:29]
Reactant: NCCNS(=O)(=O)c1cccc2cnccc12
Reactant: COC(=O)COc1ccc(F)cc1Br
Agent: CC(C)C[AlH]CC(C)C
Product: O=S(=O)(NCCNCCOc1ccc(F)cc1Br)c1cccc2cnccc12

Procedure:
By following a similar procedure as described in Example 1, DIBAL-H reduction of (2-bromo-4-fluoro-phenoxy)-acetic acid methyl ester, and subsequent reductive amination with isoquinoline-5-sulfonic acid (2-amino-ethyl)-amide gives the free amine of the title compound as a white foam. ESIMS: m/z 468 [(M+H)+, 79Br], 470 [(M+H)+, 81Br].
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]1([C@H:19]([N:21]2[CH2:26][CH2:25][O:24][C@@H:23]([C:27]3[CH:35]=[CH:34][C:30]([C:31]([OH:33])=O)=[CH:29][CH:28]=3)[CH2:22]2)[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>ClCCl>[N:36]1([C:31]([C:30]2[CH:34]=[CH:35][C:27]([C@@H:23]3[O:24][CH2:25][CH2:26][N:21]([C@@H:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH3:20])[CH2:22]3)=[CH:28][CH:29]=2)=[O:33])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(C(=O)O)cc2)C1
Reactant: C1COCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(C(=O)N3CCOCC3)cc2)C1
Reaction time: 2 h
Yield: 61.1 %

Procedure:
1,1′-Carbonyldiimidazole (357 mg, 2.20 mmol) was added to a solution of 4-[(2S)-4-((1R)-1-phenylethyl)-morpholin-2-yl]-benzoic acid (623 mg, 2.00 mmol) in dichloromethane at 0° C. After stirring for 2 hours, morpholine (0.35 ml, 4.0 mmol) was added to the reaction mixture. After stirring over night, the resulting suspension was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford morpholin-4-yl-{4-[(2S)-4-((1R)-1-phenylethyl)-morpholin-2-yl]-phenyl}-methanone (465 mg, 60%.) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](O)=[O:10])=[CH:5][CH:4]=1.O=S(Cl)[Cl:16]>>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([Cl:16])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C=CC(=O)O)cc1
Product: COc1ccc(C=CC(=O)Cl)cc1
Yield: 61.9 %

Procedure:
53.5 g of the 4-methoxy cinnamic acid (Aldrich 0.3 mol)) and 124.9 g of SOCl2 (Thionyl Chloride, 1.05 mol) were put into the two-neck flask having the volume of 250 ml, and then reacted with each other at normal temperature for 24 hours. After the reaction was finished, the distillation was performed to remove an excessive amount of SOCl2, and the reactant was diluted with 100 ml of toluene and neutralized by using the NaHCO3 solution. After the neutralization, the resulting substance was dried by using anhydrous MgSO4, and filtered, and the solvent was removed by using the rotary evaporator. Next, the substance was passed through the silica gel to remove the impurity, thus obtaining 36.5 g of the white solid (yield: 62%).
Reaction SMILES: Cl[CH2:2][O:3][CH2:4][C:5]1[CH:9]=[N:8][S:7][N:6]=1.Cl.[Cl:11][C:12]1[CH:13]=[N:14][C:15](=[O:18])[NH:16][CH:17]=1.C(N(CC)CC)C>ClCCl>[S:7]1[N:8]=[CH:9][C:5]([CH2:4][O:3][CH2:2][N:16]2[CH:17]=[C:12]([Cl:11])[CH:13]=[N:14][C:15]2=[O:18])=[N:6]1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: ClCOCc1cnsn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1ncc(Cl)cn1COCc1cnsn1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
3-(Chloromethyl)oxymethyl-1,2,5-thiadiazole (see Preparation 10) (0.18 mmol) in dichloromethane (1 ml) was added dropwise with stirring at room temperature to a solution of 5-chloropyrimidin-2-one hydrochloride (18 mmol) and triethylamine (0.36 mmol) in dichloromethane (3 ml). The mixture was stirred for 11/2 hours at 40° C. before the solvent was distilled off. The residue was triturated with water, extracted into chloroform and the dried (MgSO4) solution evaporated. Trituration of the residue with ether left the title compound in 20% (11 mg) yield, m.p. 106° C. 1H NMR (CDCl3): δ5.00 (CH2Het), 5.40 (OCH2), 7.73 and 8.47 (H-4, H-6, J 3 Hz), 8.50 (H-31).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[CH2:12]([O:19][C:20](=[O:33])[NH:21][CH:22]([C:25]1([CH3:32])[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)[CH2:23][CH3:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:12]([O:19][C:20](=[O:33])[NH:21][CH:22]([C:25]1([CH3:32])[CH2:30][CH2:29][CH:28]([NH:31][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[N:7][CH:6]=[CH:5]3)[CH2:27][CH2:26]1)[CH2:23][CH3:24])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Brc1ccc2cnccc2c1
Reactant: CCC(NC(=O)OCc1ccccc1)C1(C)CCC(N)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCC(NC(=O)OCc1ccccc1)C1(C)CCC(Nc2ccc3cnccc3c2)CC1
Temperature: 100 °C
Yield: 31.8 %

Procedure:
In 2 mL of absolute toluene were dissolved 100 mg (481 μmol) of 6-bromo-isoquinoline, 176 mg (577 μmol) of [1-(4-amino-1-methyl-cyclohexyl)-propyl]-carbamic acid benzyl ester (79), and 235 mg (721 μmol) of cesium carbonate. The solution was degassed twice, then 3.24 mg (14.4 μmol) of palladium acetate and 13.5 mg (21.6 μmol) of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl were added and the reaction mixture was heated to 100° C. until complete conversion could be observed. The mixture was evaporated, the residue dissolved in 50 mL of dichloromethane and washed twice with 50 mL of saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulphate, filtered, concentrated and purified by silica gel chromatography (dichloromethane:methanol) to give 66 mg of the pure desired product. Rt=1.32 min (Method O). Detected mass: 432.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH2:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:15](Cl)(=[O:26])[O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.N1C=CC=CC=1.O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:14][C:15](=[O:26])[O:16][C:17]2[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=2)[C:10]([F:11])([F:12])[F:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NC(c1ccc(Cl)c(Cl)c1)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C(NC(c1ccc(Cl)c(Cl)c1)C(F)(F)F)Oc1ccc([N+](=O)[O-])cc1
Yield: 92.1 %

Procedure:
A solution of 148 (1.00 g, 4.01 mmol), 4-nitrophenyl carbonochloridate (0.9085 g, 4.507 mmol) and pyridine (0.7131 g, 9.015 mmol) in DCM (10 mL) were stirred for 30 min. Water was added and the reaction mixture was extracted with DCM. The organic layer was concentrated and purified by SiO2 chromatography eluting with 20% EtOAc/hexane to afford 1.511 g (90.0%) of 4-nitrophenyl 1-(3,4-dichlorophenyl)-2,2,2-trifluoroethylcarbamate (150).
Reaction SMILES: S([O-])([O-])(=O)=O.C[S+](C)C.C[S+](C)C.[OH-].[Na+].[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21].[CH2:25](Cl)Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+].O.C(OCC)C>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]1[O:21][CH2:25]1
Reactant: O=Cc1cccc(Cl)c1
Reactant: ClCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[S+](C)C
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCOCC
Product: Clc1cccc(C2CO2)c1
Temperature: 50 °C
Yield: 92 %

Procedure:
Synthesis of (±)-1: The aqueous solution of trimethylsulfonium sulfate (20 mL, 1.05×1031 1 mol) was added slowly to a two-phase mixture of 50% NaOH (100 mL), 3-chlorobenzaldehyde (7.03 g, 5.00×10−2 mol), tetrabutylammonium bromide (0.126 g, 3.91×10−4 mol), and CH2Cl2 (132 mL). The reaction was heated at 50° C. for 13 hours and then cooled to room temperature. The reaction was diluted carefully with brine (250 mL) and diethyl ether (350 mL), and then filtered to remove solids. The aqueous layer was extracted with diethyl ether (3×350 mL), and the combined organic layers were washed with brine (200 mL) and dried over Na2SO4, filtered, and concentrated in vacuo to afford a pale yellow liquid. Bulb-to-bulb distillation (70° C., 0.6 mm Hg) from CaH2 afforded 1 (7.12 g, 92%) as a colorless liquid. 1H NMR (CDCl3) δ 7.27 (m, 3H), 7.17 (m, 1H), 3.83 (dd, J=2.5, 4.1 Hz, 1H), 3.15 (dd, J=4.1, 5.5 Hz, 1H), 2.76 (dd, J=2.5, 5.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 139.9, 134.7, 129.9, 128.4, 125.6, 123.8, 51.8, 51.3; IR (thin film, cm−1) 3057, 2994, 2920, 1603, 1576, 1080; CIHRMS calcd for C8H7ClO (M+NH4)+=172.0529, found 172.0527.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[N:14][C:15]=2[NH2:17])[NH:10][N:9]=1.[Cl:18][C:19]1[C:20]([C:41]#[N:42])=[C:21]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([N:38]([CH3:40])[CH3:39])=[O:37])=[N:34][CH:35]=2)[C:22]([O:28][CH3:29])=[C:23]([CH:25](Cl)[CH3:26])[CH:24]=1>CN(C)C=O.CCOC(C)=O>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([CH:25]([C:23]3[C:22]([O:28][CH3:29])=[C:21]([C:30]4[CH:31]=[CH:32][C:33]([C:36]([N:38]([CH3:39])[CH3:40])=[O:37])=[N:34][CH:35]=4)[C:20]([C:41]#[N:42])=[C:19]([Cl:18])[CH:24]=3)[CH3:26])[N:9]=[C:8]([CH3:7])[C:16]=12
Reactant: COc1c(C(C)Cl)cc(Cl)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Reactant: Cc1n[nH]c2ncnc(N)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
Cesium carbonate (3000 mg, 10 mmol) was added to a mixture of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1100 mg, 7.1 mmol) and 5-[3-chloro-5-(1-chloroethyl)-2-cyano-6-methoxyphenyl]-N,N-dimethylpyridine-2-carboxamide (1.8 g, 4.8 mmol) in N,N-dimethylformamide (50 mL). The reaction was stirred at 80° C. for 3 hrs and was allowed to cool to room temperature. The reaction was diluted with EtOAc, washed with water, brine, dried over Na2SO4, filtered and concentrated to give the crude product. This was purified by FCC on silica gel eluting (hexanes/10% EtOH in EtOAc, 0-100%) gradient to give the title compound as light yellow oil (2.0 g, 80%). LCMS calculated for C24H24ClN8O2 (M+H)+: m/z=491.1; found: 491.2. NMR (400 MHz, CD3OD) δ 8.74 (d, J=1.4 Hz, 1H), 8.15 (d, J=2.2 Hz, 1H), 8.13 (s, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.74 (s, 1H), 6.43 (q, J=7.0 Hz, 1H), 3.32 (s, 3H), 3.16 (s, 3H), 3.07 (s, 3H), 2.64 (s, 3H), 1.89 (d, J=7.1 Hz, 3H).
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(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.C(NCC)C>>[C:1]([C:5]1[N:6]=[C:7]([N:22]([CH2:27][CH3:26])[CH2:23][CH3:24])[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])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Solvent: CCNCC
Product: CCN(CC)c1nc(C(C)(C)C)nc2c1nnn2Cc1ccccc1Cl

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 diethylamine and isolated as colorless gum (11.5 mg, 65%). MS (m/e): 373.4 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([OH:8])=O.[NH2:9][C@@H:10]([CH3:26])[CH2:11][N:12]1[CH:16]=[CH:15][C:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([Cl:25])[CH:18]=2)=[N:13]1>>[Cl:25][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][N:12]([CH2:11][C@@H:10]([NH:9][C:6]([C:2]3[NH:1][CH:5]=[CH:4][N:3]=3)=[O:8])[CH3:26])[N:13]=2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: O=C(O)c1ncc[nH]1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1ncc[nH]1
Yield: 76 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-imidazole-2-carboxamide was prepared using the method of Example 34(d) starting from 1H-imidazole-2-carboxylic acid (0.206 g, 1.841 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.4 g, 1.534 mmol). The crude product was washed with 0.1 M HCl, 1M NaCO3, water and brine. Yield 76%. 1H-NMR (400 MHz; DMSO): δ 1.23 (d, 3H), 4.31 (dd, 1H), 4.38 (dd, 1H), 4.41-4.50 (m, 1H), 6.94 (d, 1H), 7.07 (s, 1H), 7.24 (dd, 1H), 7.84 (d, 1H), 7.96 (dd, 1H), 7.99 (dd, 1H), 8.17 (dd, 1H), 8.65 (d, 1H), 12.95 (s, 1H).
Reaction SMILES: [CH3:1][CH:2](OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]3[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]3)[N:12]=2)=[CH:7][CH:6]=1.[N-:39]=[N+:40]=[N-:41].[Na+]>CN(C=O)C>[N:39]([CH:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]3[CH2:19][C:20]([CH3:27])([CH3:26])[NH:21][C:22]([CH3:24])([CH3:25])[CH2:23]3)[N:12]=2)=[CH:7][CH:6]=1)=[N+:40]=[N-:41]
Reactant: Cc1ccc(S(=O)(=O)OC(C)CCc2ccc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(CCc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cc1)N=[N+]=[N-]

Procedure:
The title compound was prepared from toluene-4-sulfonic acid 1-methyl-3-{4-[2-(2,2,6,6-tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-phenyl}-propyl ester and sodium azide in DMF. Yield 96 mg (82%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)=[O:6]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCC(NC(=O)c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.6 %

Procedure:
2-Fluoro-4-nitrobenzoic acid (Aldrich; 3 g, 16.21 mmol), 4-Amino-1-methylpiperidine (Fluorochem; 2.03 g, 17.83 mmol), HATU (6.77 g, 17.83 mmol), DIPEA (8.5 mL, 48.63 mmol) and DMF (30 mL) were combined and stirred at ambient temperature for 18 hrs. Solvents evaporated and partitioned between DCM (200 ml) and water (100 ml). The aqueous phase was re-extracted with DCM (100 ml). The combined organic phases were dried (MgSO4) and evaporated. The resultant material was taken up in DCM and purified on silica eluting with a gradient of 0-5% 2M ammonia in MeOH/DCM then 5% 2M ammonia in MeOH/DCM. Fractions containing product were combined and evaporated to give the title compound as a yellow solid (2.67 g, 59%)
Reaction SMILES: C([Li])CCC.[O:6]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[N:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[S:19][CH:20]=3)=[CH:15][C:10]=2[CH2:9][CH2:8][CH2:7]1.[C:27]([O:31][CH2:32][CH3:33])(=[O:30])[CH:28]=[O:29].C1(C)C=CC=CC=1>O1CCCC1.O>[O:6]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[N:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[S:19][C:20]=3[CH:28]([OH:29])[C:27]([O:31][CH2:32][CH3:33])=[O:30])=[CH:15][C:10]=2[CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)C=O
Reactant: c1ccc(-c2nc(-c3ccc4c(c3)CCCO4)cs2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(O)c1sc(-c2ccccc2)nc1-c1ccc2c(c1)CCCO2
Reaction time: 0.33 h
Yield: 29 %

Procedure:
Butyl lithium (1.6M, 930 μL, 1.5 mmol) was added at −78° C. to a solution of 4-(3,4-dihydro-2H-1-benzopyran-6-yl)-2-phenyl-1,3-thiazole (9c) (330 mg, 1.12 mmol) in anhydrous tetrahydrofuran (10 mL). After 20 minutes, ethyl glyoxylate 50% in toluene (400 μL, 2 mmol) was added at −78° C. and the mixture was stirred for 2 hours, hydrolyzed with water and concentrated in vacuo. The residue was diluted with ethyl acetate (20 mL) and the organic layer was washed with water (10 mL), brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 80/20) to afford the desired alcohol (9d) as a white solid (130 mg, 0.33 mmol, 29%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][C@@H:11]([CH2:15][OH:16])[NH:12][CH2:13][CH:14]=2)=[CH:5][CH:4]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][C@@H:11]([CH2:15][OH:16])[N:12]([S:23]([C:20]3[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=3)(=[O:25])=[O:24])[CH2:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(C2=CCN[C@H](CO)C2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(C2=CCN(S(=O)(=O)c3ccc(C)cc3)[C@H](CO)C2)cc1
Reaction time: 8 h

Procedure:
To a solution of 72.0 g of [(S)-4-(4-methoxy-phenyl)-1,2,3,6-tetrahydro-pyridin-2-yl]-methanol in 1.5 l of ethyl acetate and 1.5 l of 2N aqueous sodium carbonate are added 57.7 g of p-toluenesulfonyl chloride at 0° C. The reaction mixture is stirred overnight, extracted with ethyl acetate and the combined organic phases are dried over sodium sulfate and concentrated under reduced pressure. The crude product is used for the next step without any further purification. Rf=0.1 (EtOAc-heptane 1:1); Rt=4.20.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH3:18][N:19]([CH3:28])[C:20]1[CH:21]=[C:22]([CH2:26]O)[CH:23]=[CH:24][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:18][N:19]([CH3:28])[C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[CH2:26][O:17][C:14]1[CH:13]=[CH:12][C:11]([CH:4]([O:3][CH2:1][CH3:2])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:16][CH:15]=1
Reactant: CCOC(=O)CC(OCC)c1ccc(O)cc1
Reactant: CN(C)c1cccc(CO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(OCC)c1ccc(OCc2cccc(N(C)C)c2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 76.3 %

Procedure:
Ethyl 3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.420 mmol) produced in Example 1 (1C) and [3-(dimethylamino)phenyl]methanol (95 mg, 0.630 mmol) were dissolved in tetrahydrofuran (10 mL), and triphenylphosphine (178 mg, 0.680 mmol) and a 40% diethyl azodicarboxylate toluene solution (309 μL, 0.680 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 50° C. for 4 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a white solid (119 mg, yield: 76%).