Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH2:21]([O:28][C:29](=[O:37])[CH2:30][C@H:31]([NH2:36])[CH2:32][N:33]([CH3:35])[CH3:34])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:28][C:29](=[O:37])[CH2:30][C@H:31]([NH:36][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:32][N:33]([CH3:34])[CH3:35])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN(C)C[C@@H](N)CC(=O)OCc1ccccc1
Reactant: O=C(O)CCCCCCCCCc1ccccc1
Agent: Cl
Product: CN(C)C[C@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCCCc1ccccc1

Procedure:
The title compound, m/e=377.5 ([M+H]+), was produced in analogy with example 1, steps 3 and 4. Thus, commercially available 10-phenyldecanoic acid was coupled in step 3 with (S)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (S)-4-dimethylamino-3-(10-phenyl-decanoylamino)-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[CH2:12]=O.[H][H]>[Pd].C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:11][CH3:12])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7]
Reactant: C=O
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CNc1cc(F)ccc1C(=O)O

Procedure:
A mixture of 4-fluoroanthranilic acid (2 g), aqueous formaldehyde (37-40% w/v; 6.5 ml) and palladium on charcoal (1 g of 5%) in acetic acid (70 ml) was hydrogenated over 18 hours during which 570 ml hydrogen was taken up. The mixture was filtered, evaporated under reduced pressure and the residue recrystallised from toluene to give 4-fluoro-N-methylanthranilic acid, m.p. 180°-181°. (Compound 7)
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH:9]([CH2:19][O:20][CH2:21][CH:22]1[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]1)[CH2:10][O:11]CC1C=CC=CC=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:29])[N:7]([CH:9]([CH2:19][O:20][CH2:21][CH:22]1[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]1)[CH2:10][OH:11])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)C(COCc1ccccc1)COCC1COC(C)(C)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)C(CO)COCC1COC(C)(C)O1
Reaction time: 1.5 h
Yield: 89.5 %

Procedure:
To a solution of crude [2-Benzyloxy-1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxymethyl)-ethyl]-methyl-carbamic acid tert-butyl ester (1.25 g, 3.06 mmol) in MeOH (10 mL) was added Pd/C (300 mg). The mixture was transferred to an autoclave reactor, charged with 55 psi of hydrogen, and stirred. After 1.5 h, LCMS analysis indicated the completion of the reaction. The reaction mixture was then filtered through celite and concentrated under reduced pressure to give [1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxymethyl)-2-hydroxy-ethyl]-methyl-carbamic acid tert-butyl ester (0.875 g, 95%), which was used without purification. LRMS (M-Boc+H+) m/z 220.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:28])[NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:17]=1.[OH-].[Na+].C(OCC)(=O)C>CO>[CH3:1][C:2]1([CH3:29])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:28])[NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)NS(C)(=O)=O)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(C(=O)NS(C)(=O)=O)c1
Yield: 99.4 %

Procedure:
A mixture of methyl 3,3-dimethyl-2-(3-(methylsulfonylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (58 mg, 0.14 mmol, 1.0 eq.) in methanol (2.5 mL) and 1N sodium hydroxide aqueous solution (2.1 mL, 2.1 mmol, 15.0 eq.) was heated to reflux for 1 h. Thin layer chromatography (petroleum ether:ethyl acetate=1:1) and LC-MS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure and the residual was acidified with 1N hydrochloric acid solution to pH=5. The white solid precipitated was dissolved in ethyl acetate and separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate Removal of the solvent in vacuo gave 56 mg of 3,3-dimethyl-2-(3-(methylsulfonylcarbamoyl)-phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a yellow solid in quantitative yield. MS (ESI+APCI) M+1=403.1.
Reaction SMILES: [CH2:1]=O.[CH2:3]([NH:5][CH3:6])[CH3:4].[F:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][N:14]2[S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:10][C:9]=1[OH:26]>CCO>[CH2:3]([N:5]([CH2:1][C:10]1[C:9]([OH:26])=[C:8]([F:7])[CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][N:14]2[S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH3:6])[CH3:4]
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(O)c(F)cc21
Reactant: CCNC
Reactant: C=O
Solvent: CCO
Product: CCN(C)Cc1c(O)c(F)cc2c1ccn2S(=O)(=O)c1ccccc1

Procedure:
Paraformaldehyde (20.6 mg, 0.686 mmol) and N-ethylmethylamine (0.059 ml, 0.686 mmol) in EtOH (1 ml) was heated until a clear solution was obtained. The solution was added to 6-fluoro-1-(phenylsulfonyl)-1H-indol-5-ol (100 mg, 0.343 mmol; Intermediate 95) in EtOH (1 ml) and the mixture was heated in microwave oven at 90 oC for 10 min. Solvent was evaporated and 20% of material was purified on Gilson HPLC using 15-45% MeCN in 50 nM ammonium hydrogencarbonate buffer. Yield: 13 mg; white solid. MS (ESI+) for C18H19FN2O3S m/z 363 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:22]=[CH:21][C:9]2[CH2:10][CH2:11][CH:12]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13][C:8]=2[C:7]=1[CH2:23][CH2:24][CH3:25].[I-:26].[Na+]>C(C(C)=O)C>[I:26][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:22]=[CH:21][C:9]2[CH2:10][CH2:11][CH:12]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13][C:8]=2[C:7]=1[CH2:23][CH2:24][CH3:25]
Reactant: [I-]
Reactant: CCCc1c(OCCCCl)ccc2c1OC(CCC(=O)OCC)CC2
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCI)ccc2c1OC(CCC(=O)OCC)CC2

Procedure:
Ethyl 7-(3-chloropropoxy)-3,4-dihydro-8-propyl-2H-1-benzopyran-2-propanoate (3.2 g, 9.042 mmol) and sodium iodide (13.6 g, 9.042 mmol) were added to 200 ml of methyl ethyl ketone and the reaction mixture was heated to reflux overnight. The solvent was removed under vacuum and 100 ml of water was added. The solution was extracted 3 times with ethyl acetate. The combined extracts were dried and filtered, and the solvent was removed under vacuum to give the product as a brown oil.
Reaction SMILES: C[Si](C)(C)[C:3]([F:6])([F:5])[F:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:27]([N:29]1[C:33]([O:34][C:35]2[CH:40]=[CH:39][C:38]([CH:41]=[O:42])=[CH:37][CH:36]=2)=[CH:32][C:31]([C:43]2[CH:44]=[C:45]([C:49]([NH:52][S:53]([CH2:56][C:57]([F:60])([F:59])[F:58])(=[O:55])=[O:54])([CH3:51])[CH3:50])[CH:46]=[CH:47][CH:48]=2)=[N:30]1)[CH3:28].Cl>O1CCCC1>[CH2:27]([N:29]1[C:33]([O:34][C:35]2[CH:36]=[CH:37][C:38]([CH:41]([OH:42])[C:3]([F:6])([F:5])[F:4])=[CH:39][CH:40]=2)=[CH:32][C:31]([C:43]2[CH:44]=[C:45]([C:49]([NH:52][S:53]([CH2:56][C:57]([F:60])([F:58])[F:59])(=[O:54])=[O:55])([CH3:51])[CH3:50])[CH:46]=[CH:47][CH:48]=2)=[N:30]1)[CH3:28]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C(O)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 2.3 %

Procedure:
Trimethyl(trifluoromethyl)silane (0.62 mL, 4.0 mmol, 1.2 equiv) and tetrabutylammonium fluoride (1.0 M in THF, 0.67 mL, 0.67 mmol, 0.20 equiv) were added sequentially to a solution of N-(1-{3-[1-ethyl-5-(4-formylphenoxy)-1H-pyrazol-3-yl]phenyl}-1-methylethyl)-2,2,2-trifluoroethanesulfonamide (1.65 g, 3.33 mmol, 1 equiv) in tetrahydrofuran (3.3 mL) at 0° C. The reaction mixture was stirred for 15 minutes at 0° C., and then was warmed to 22° C. After stirring for 2.5 hours, aqueous hydrochloric acid solution (2 N) was added and the reaction mixture was stirred for an additional 40 minutes. The crude product was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, and the washed solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash-column chromatography (hexanes, grading to 45% ethyl acetate-hexanes) to afford N-[1-(3-{1-ethyl-5-[4-(2,2,2-trifluoro-1-hydroxyethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)-1-methylethyl]-2,2,2-trifluoroethanesulfonamide (43 mg, 2%). Calcd (M+1)+: 566.2. Found: 566.0.
Reaction SMILES: CS(O)(=O)=O.[C:6]([NH:9][CH2:10][C:11]([N:13]([CH2:22][CH:23](OC)OC)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[O:12])(=[O:8])[CH3:7].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[C:6]([N:9]1[CH:23]=[CH:22][N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[C:11](=[O:12])[CH2:10]1)(=[O:8])[CH3:7]
Reactant: COC(CN(Cc1ccc(F)cc1)C(=O)CNC(C)=O)OC
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N1C=CN(Cc2ccc(F)cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methanesulfonic acid (314 g) in dichloromethane (10 L) at room temperature, a solution of N2-acetyl-N1-(2,2-dimethoxyethyl)-N1-(4-fluoro-benzyl)glycinamide (438 g, 1.07 mol) in dichloromethane (2 L) was added slowly over a period of 2 h. The reaction mixture was stirred at room temperature overnight and treated with saturated aqueous sodium carbonate (3 L). The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. To the residual oil, ethyl acetate (1 L) was added and stirred at room temperature. The solid precipitated was filtered to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.[NH4+:17].[OH-]>C(Cl)Cl.CN(C=O)C.C1COCC1>[F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4]([NH2:17])=[O:5]
Reactant: CC(C)(C(=O)O)C(F)(F)F
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C(N)=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
A solution of 3,3,3-trifluoro-2,2-dimethylpropionic acid (0.5 g, 3.20 mmol) in DCM (5 mL) was treated with oxalyl chloride (0.350 mL, 4.00 mmol) and 1 drop of DMF, stirred at RT for 1 h, added drop-wise to a solution of NH4OH (˜15M, 5 mL, ˜75 mmol) in THF (5 mL) and stirred at RT overnight. Solids were removed via filtration through diatomaceous earth, rinsed well with 4:1 DCM/THF, the filtrate saturated with solid NaCl, extracted with 4:1 DCM/THF (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford 3,3,3-trifluoro-2,2-dimethylpropanamide (370 mg, 74%). 1H NMR (400 MHz, DMSO-d6): δ 7.42 (s, 1H), 7.35 (s, 1H), 1.29 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[N:7]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:6]=2[CH:23]=1.[CH3:24][O:25][C:26](=[O:32])[CH2:27][CH2:28][CH2:29][CH2:30]Br>>[CH3:24][O:25][C:26](=[O:32])[CH2:27][CH2:28][CH2:29][CH2:30][O:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[N:7]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:6]=2[CH:23]=1
Reactant: COC(=O)CCCCBr
Reactant: Oc1ccc2nc(-c3cccnc3)n(-c3ccc(F)cc3)c2c1
Product: COC(=O)CCCCOc1ccc2nc(-c3cccnc3)n(-c3ccc(F)cc3)c2c1

Procedure:
6-Hydroxy-1-(4-fluorophenyl)-2-(3-pyridinyl)-1H-benzimidazole was reacted with 5-bromo-pentanoic acid methyl ester according to general operating instructions 3.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:17][CH2:16][C:15]3[C:14]([NH:18][C:19]4[CH:27]=[C:26]5[C:22]([C:23]([CH3:29])([CH3:28])[CH2:24][NH:25]5)=[CH:21][CH:20]=4)=[N:13][CH:12]=[N:11][C:10]=3[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[C:31]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([N:8]2[CH2:17][CH2:16][C:15]3[C:14]([NH:18][C:19]4[CH:27]=[C:26]5[C:22]([C:23]([CH3:29])([CH3:28])[CH2:24][N:25]5[CH3:31])=[CH:21][CH:20]=4)=[N:13][CH:12]=[N:11][C:10]=3[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)CNc2cc(Nc3ncnc4c3CCN(c3ncccc3Cl)C4)ccc21
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CC(C)(C)c2ccc(Nc3ncnc4c3CCN(c3ncccc3Cl)C4)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of compound of Example 69 hydrogen chloride (20 mg) in DMF (5 mL) was added K2CO3 (50 mg), followed by MeI (50 μL). The mixture was stirred at room temperature for 2 h, and then treated with water, extracted with EtOAc (50 mL). The organic layer was separated, washed with brine, dried (Na2SO4), and evaporated. The residue was purified by flash chromatography over silica ghel to give a light yellow solid (10 mg).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH2:19]O)[C:3]=1[C:21]#[N:22].C(N(S(F)(F)[F:29])CC)C>ClCCl>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH2:19][F:29])[C:3]=1[C:21]#[N:22]
Reactant: CCN(CC)S(F)(F)F
Reactant: N#Cc1c(CO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Solvent: ClCCl
Product: N#Cc1c(CF)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 5-amino-4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-hydroxymethylpyrazole (1.25 g) in dichloromethane (10 ml) was added slowly to a stirred solution of diethylaminosulphur trifluoride (0.66 g) in dichloromethane (6 ml) cooled to -78° C. After 30 minutes at this temperature the solution was warmed to room temperature and stirred for 2 hours. The mixture was then poured onto water (20 ml) and the dichloromethane layer was separated, dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo. The product was purified by chromatography on silica (Merck, 40-230 mesh, 0.7 kg cm-2) eluting with a mixture of dichloromethane and ethyl acetate (98:2), and subsequent recrystallization from dichloromethane-petroleum ether to give 5-amino-4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-fluoromethylpyrazole as a white solid m.p. 139°-141° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]([O:20]C)=[O:19])=[CH:16][N:17]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[Li+].[OH-]>CO>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]([OH:20])=[O:19])=[CH:16][N:17]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2ncc(C(=O)OC)s2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCNC(=O)Nc1ccc(-c2ncc(C(=O)O)s2)cn1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
Methyl-2-(6-{[(ethylamino)carbonyl]amino}pyridin-3-yl)-1,3-thiazole-5-carboxylate (Example 1, 0.185 g, 0.60 mmol) was taken in MeOH (6 mL) and 2N LiOH (1 mL) was added to it. The resulting mixture was stirred at 45° C. for two hours. The solvent was removed and the aqueous was diluted with water and acidified with 1N HCl. The precipitated product was collected by filtration and washed with water and dried (0.17 g). MS (ESP): 293 (M+H+) for C12H12N4O3S; NMR: 1.09 (t, 3H), 3.16-3.22 (m, 2H), 7.60 (d, 1H), 7.81 (t, 1H), 8.26 (dd, 1H), 8.38 (s, 1H), 8.81 (s, 1H), 9.54 (s, 1H), 13.54 (brs, 1H).
Reaction SMILES: [CH:1]1([O:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClCCl.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(N(CC)CC)C>[CH3:15][S:16]([O:11][CH2:10][CH2:9][CH2:8][O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCOC1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCOC1CCCCC1
Temperature: 25 °C
Reaction time: 9 h
Yield: 57.8 %

Procedure:
To a solution of 10 parts of 3-(cyclohexyloxy)-1-propanol in 160 parts of dichloromethane there were added 11.2 parts of N,N-diethylethanamine and dropwise 8.14 parts of methanesulfonyl chloride. The whole was stirred for 9 hours at room temperature. The reaction mixture was washed with Na2CO3 (aq.) and water and was then dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 99:1). The eluent of the desired fraction was evaporated and the residue was co-evaporated with methylbenzene. The product was filtered off and dried, yielding 8.6 parts (57.8%) of 3-(cyclohexyloxy)-1-propanol methanesulfonate (ester) (interm. 21).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[CH2:16][CH2:17][CH2:18][OH:19]>C(O)C>[OH:19][CH2:18][CH2:17][CH2:16][S:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(S)cc1
Reactant: OCCCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: OCCCSc1ccc(O)cc1
Reaction time: 8 h

Procedure:
4-Hydroxythiophenol (6.31 g, 50 mmol) was dissolved in ethanol (100 mL) and potassium tert-butoxide (6.72 g, 60 mmol) was added. The mixture was stirred until a clear, yellow solution was obtained. Then 3-chloro-1-propanol (4.20 ml, 50 mmol) was added with a syringe. The reaction mixture was stirred overnight at room temperature, the potassium chloride precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (150 mL) and the organic layer was extracted with water (2×100 mL) and brine (100 mL), dried over sodium sulphate and concentrated under reduced pressure. The resulting oil was dissolved in dichloromethane (50 mL) and hexane (100 mL) and left standing open overnight. The solid product was filtered off and dried under high vacuum. Yield: 5.34 g (58%) pale yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([NH:6][C:7]1[C:12]([NH2:13])=[C:11]([C:14]2[C:15]([CH3:22])=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[N:10]=[CH:9][N:8]=1)[CH3:5].[C:23](OCC)(=[O:27])[C:24]([CH3:26])=O>C(O)C>[CH3:1][O:2][CH2:3][C@H:4]([N:6]1[C:7]2[N:8]=[CH:9][N:10]=[C:11]([C:14]3[C:15]([CH3:22])=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[C:12]=2[N:13]=[C:24]([CH3:26])[C:23]1=[O:27])[CH3:5]
Reactant: COC[C@@H](C)Nc1ncnc(-c2ccc(OC)nc2C)c1N
Reactant: CCOC(=O)C(C)=O
Solvent: CCO
Product: COC[C@@H](C)n1c(=O)c(C)nc2c(-c3ccc(OC)nc3C)ncnc21
Reaction time: 18 h

Procedure:
(R)-N4-(2-Methoxy-1-methyl-ethyl)-6-(6-methoxy-2-methyl-pyridin-3-yl)-pyrimidine-4,5-diamine (0.22 g, 0.74 mmol) was diluted in ethanol (8 ml) and ethyl pyruvate was added (0.82 ml, 7.4 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. After concentrating the solution the product was purified by preparative TLC eluting with 35% ethyl acetate in hexanes to yield 5.0 mg of (R)-8-(2-methoxy-1-methyl-ethyl)-4-(6-methoxy-2-methyl-pyridin-3-yl)-6-methyl-8H-pteridin-7-one (Example 650a). 1H NMR (300 MHz, CDCl3) δ ppm 8.99 (s, 1 H), 7.65 (d, J=8.42 Hz, 1 H), 6.68 (d, J=8.42 Hz, 1 H), 5.71 (m, 1H), 3.99 (s, 3 H), 3.59 (m, 2 H), 3.31 (s, 3 H), 2.50 (s, 3H), 2.50 (s, 3H), 2.50 (s, 3H), 0.85 (d, J=7.69 Hz, 3 H). MS (EI) 356.3 [(M+H)+, 100].
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12]([C@H:13]([OH:17])[CH2:14]2)[N:11]1C(OC(C)(C)C)=O)=[O:9])#[N:2].[ClH:25]>O1CCOCC1.O>[ClH:25].[OH:17][C@H:13]1[C@H:12]2[CH2:16][C@H:15]([C@@H:10]([C:8]([N:4]3[CH2:5][CH2:6][CH2:7][C@H:3]3[C:1]#[N:2])=[O:9])[NH:11]2)[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2O)[C@H]1C(=O)N1CCC[C@H]1C#N
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: N#C[C@@H]1CCCN1C(=O)[C@H]1N[C@@H]2C[C@H]1C[C@H]2O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solid of tert-butyl (1R,3S,4S,6R)-3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl}-6-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 42-8 (796 mg), was added a mixture of 4N hydrochloride in dioxane (1.87 mL) and water (0.13 mL). The mixture was stirred at room temperature for 5 minutes. The resulting mixture was evaporated in vacuo and the residual solid was washed with isopropyl alcohol. The solid was recrystalized from ethanol-water to give the target compound as a white crystal (367 mg)
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][CH:25]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([C:19](=[O:22])[CH2:20][SH:21])[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].Cl[C:27]1[C:28]([C:33]#[N:34])=[N:29][CH:30]=[CH:31][N:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[NH2:34][C:33]1[C:28]2[C:27](=[N:32][CH:31]=[CH:30][N:29]=2)[S:21][C:20]=1[C:19]([C:14]1[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]2[CH:23]=[CH:24][CH:25]=[C:6]([C:3]([C:1]#[N:2])([CH3:4])[CH3:5])[CH:7]=2)[CH:17]=[CH:16][C:15]=1[CH3:18])=[O:22]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1C(=O)CS
Reactant: N#Cc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1C(=O)c1sc2nccnc2c1N
Yield: 21 %

Procedure:
A solution of 3-(2-cyanopropan-2-yl)-N-(3-(2-mercaptoacetyl)-4-methylphenyl)benzamide 115 (0.094 mmol, 33 mg), 3-chloropyrazine-2-carbonitrile (0.094 mmol, 13 mg) and sodium carbonate (0.112 mmol, 12 mg) in ethanol (1 mL) was stirred 2 h at 50° C. Quenched in 1N HCl solution and extracted with CH2Cl2. Organic layer was dried and evaporated. Purification by HPLC gave N-(3-(7-aminothieno[2,3-b]pyrazine-6-carbonyl)-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide 116 (9 mg, 21%). NMR (400 MHz, DMSO-d6) 1.74 (s, 6H), 2.27 (s, 3H), 7.37 (d, J=8.6 Hz, 1H), 7.60 (t, J=7.8 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.81 (dd, J=8.2 Hz and 2.3 Hz), 7.95 (m, 2H), 8.04 (m, 3H), 8.82 (s, 2H), 10.44 (s, 1H). (m/z)=457 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][N:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=C(C=CC=1Cl)N.C(#N)CC#N.O.[NH2:31][NH2:32]>>[NH2:15][C:14]1[C:11](=[N:10][NH:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[C:12]([NH2:13])=[N:32][N:31]=1
Reactant: N#CC(C#N)=NNc1ccc(Cl)c(Cl)c1
Reactant: NN
Agent: Nc1ccc(Cl)c(Cl)c1
Solvent: O
Solvent: N#CCC#N
Product: NC1=NN=C(N)C1=NNc1ccc(Cl)c(Cl)c1
Yield: 39 %

Procedure:
This compound was prepared using 120 mg (0.5 mmol) of 2-[(3,4-dichlorophenyl)-hydrazono]malononitrile, which was derived from 3,4-dichloroaniline (162 mg, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. Precipitate formed in the reaction tube immediately after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, precipitated from an ethyl acetate solution by the addition of hexanes, and dried to yield 53 mg (39%) of the title compound as a yellow solid. 1H NMR (ppm, DMSO-d6): 6.30 (br, s, 4H), 7.55-7.79 (m, 2H), 7.95 (s, 1H), 10.80 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH:17]1[CH2:19][CH2:18]1)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1>[CH:17]1([CH2:16][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][OH:14])[CH2:18][CH2:19]1
Reactant: O=C(N[C@@H](CC1CC1)C(=O)O)OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(N[C@H](CO)CC1CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.4 %

Procedure:
A solution of (S)-2-(benzyloxycarbonylamino)-3-cyclopropylpropanoic acid (0.292 g, 1.11 mmol) in THF (2 mL) was cooled to 0° C. and treated with borane-THF complex (1.44 mL, 1.44 mmol). The mixture was stirred at ambient temperature for 4 hours and then treated with 1N HCl until bubbling ceased. After stirring at ambient temperature overnight, the organic solvent was concentrated. The residue is treated with EtOAc, aqueous phase removed, organic phase washed with 1N NaOH, dried (phase separator silicone treated filter paper), concentrated to provide (S)-benzyl 1-cyclopropyl-3-hydroxypropan-2-ylcarbamate (0.156 g, 56% yield) as a white gum.