Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH3:11])=[CH:5][CH:4]=1.[C-:12]#[N:13].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>CN(C)C=O>[CH2:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:12]#[N:13])=[CH:4][CH:5]=1)[CH2:10][CH3:11]
Reactant: CCCc1ccc(CI)cc1
Reactant: [C-]#N
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
Under argon condition, 1-(iodomethyl)-4-propylbenzene (73.6 mg, 0.283 mmol) was dissolved in 1 mL of well-dried N,N-dimethylformamide (dry DMF) and then sodium cyanide (NaCN; 27.7 mg, 0.566 mmol) was added and the reaction mixture was stirred for 2 hours at room temperature. Upon completion of the reaction, the reaction was terminated by adding 3 mL of water and the mixture was extracted with diethyl ether (3 mL×3). The organic layer thus obtained was treated with anhydrous magnesium sulfate to remove water. The precipitate was filtered out and the resulting solution was concentrated by distillation under reduced pressure and purified by column chromatography to obtain 41.0 mg (0.257 mmol, 91%) of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][CH:6]=[N:5][C:4]=2[CH:3]=1.C[O-].[Na+].[CH3:15][O:16][C@@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[C@H:18]1[CH2:29][C:30](=[O:33])[CH2:31]Br>CO>[Cl:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH2:31][C:30](=[O:33])[CH2:29][C@H:18]3[C@H:17]([O:16][CH3:15])[CH2:22][CH2:21][CH2:20][N:19]3[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Reactant: O=c1[nH]cnc2cc(Cl)sc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2cc(Cl)sc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere in a flame dried flask and with magnetic stirring, a solution of 0.80 g (0.0043 mole) of 6-chlorothieno[3,2-d]pyrimidin-4(3H)-one, 3.52 ml of 1.22N sodium methoxide in methanol, and 20 ml of methanol was treated with 1.86 g (0.0056 mole) of allyl trans-3-methoxy-2-(3-bromo-2-oxopropyl)-1-piperidinecarboxylate. The reaction mixture was stirred overnight at room temperature, and was then evaporated under reduced pressure. The residue was taken up in 25 ml of 0.1N aqueous sodium hydroxide, and the resulting solution was extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate, filtered, and evaporated to afford a solid material which was chromatographed under moderate pressure ("flash" chromatography) on a column of silica gel (Woelm 32-63 micrometers, i.d. 2 cm×height 25 cm); the eluant was 7% ethanol in chloroform; after a forerun of 125 ml, 25 ml fractions were taken. Fractions 13-20 were combined and evaporated to furnish the title compound: yield 0.56 g (27%); 1H-nmr (CDCl3) delta ppm 1.2-2.1 (multiplet, 4H, OCHCH2CH2CH2N), 2.7-3.1 (multiplet, peaks, 4H, COCH2CH and NCH2), 3.3 (broad singlet, 1H, CH2CHNCO), 3.4 (singlet, 3H, OCH3), 4.0 (broad doublet, 1H, CHOCH3), 4.6 (broad double, 2H, CH2CH=CH2), 4.8-5.1 (multiple peaks, 2H, NCH2CO), 5.3 (triplet with fine splitting, 2H, CH2 =CH), 5.9 (octet, 1H, CH=CH2), 7.2 (singlet, 1H, thieno H), 8.0 (broad singlet, 1H, N=CH--N).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13](B(O)O)=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:29]1[C:37]2[C:32](=[N:33][CH:34]=[N:35][C:36]=2[NH2:38])[N:31]([CH:39]([CH3:41])[CH3:40])[N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:38][C:36]1[N:35]=[CH:34][N:33]=[C:32]2[N:31]([CH:39]([CH3:41])[CH3:40])[N:30]=[C:29]([C:13]3[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:15]4[C:11]([CH:12]=3)=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:17][CH:16]=4)[C:37]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2cc(OCc3ccccc3)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2cc3cc(OCc4ccccc4)ccc3n2C(=O)OC(C)(C)C)c2c(N)ncnc21
Temperature: 80 °C

Procedure:
A solution of 5-Benzyloxy-1-BOC-indole-2-boronic acid (303 mg, 0.83 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.33 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by silica gel column chromatography [EtOAc-hexanes, 5:95] to yield BA24. ESI-MS (M+H)+ m/z calcd 499.2, found 499.2.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:9]2[N:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]([C@@H:13]([NH2:15])[CH3:14])=[N:12][C:8]=2[CH:7]=[CH:6][C:5]=1[F:22].Cl[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][N:28]2[CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:3][C:4]1[C:9]2[N:10]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:11]([C@@H:13]([NH:15][C:24]3[N:32]=[CH:31][N:30]=[C:29]4[C:25]=3[N:26]=[CH:27][N:28]4[CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[CH3:14])=[N:12][C:8]=2[CH:7]=[CH:6][C:5]=1[F:22]
Reactant: C[C@H](N)c1nc2ccc(F)c(Cl)c2n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(Cl)c2n1-c1ccccc1
Temperature: 90 °C
Yield: 82.3 %

Procedure:
A mixture of (S)-1-(7-chloro-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (150 mg, 0.41 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (118 mg, 0.49 mmol) and DIPEA (280 μL, 1.65 mmol) in n-butanol (3 mL) was heated at 90° C. in a sealed vial for 18 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) to afford the title compound (166 mg, 82%). LCMS (Method B): RT 3.57 min [M+H]+ 492.0/493.8.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si:20]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34]O)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].N1C=CN=C1.[Br:41]Br>C(#N)C.C(OCC)C.CC#N.CCOCC>[Si:20]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][Br:41])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: BrBr
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1CO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1CBr

Procedure:
To a solution of triphenylphosphine (39.5 g, 0.15 mol), (2-((tert-butyldimethylsilyl)-oxy)phenyl)methanol (Ia) (12.23 g, 0.05 mol) and imidazole (10.5 g, 0.15 mol) in acetonitrile and diethyl ether (500 ml, CH3CN/Et2O=1:3, v/v) was added bromine (7.7 mL, 0.15 mol) dropwise at 0° C. with stirring. The reaction mixture was stirred at 0° C. for 20 minutes, during which time a white solid precipitated. The solution was carefully decanted and washed with brine (100 mL). The remaining solid was washed with diethyl ether (2×160 mL). All of the organic solutions were combined and concentrated. Hexane (200 ml) was added to the residue, and the solid was removed by filtration. The hexane solution was concentrated to provide the crude product. The product was purified by vacuum distillation (66-68° C. 0.093 Torr) reduced distillation to provide compound IIa (10.4 g, 67%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.[I:12]N1C(=O)CCC1=O>C(O)(=O)C.O>[I:12][C:10]1[C:2]([CH3:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5](=[O:11])[CH2:4]2
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cccc2c1CC(=O)N2
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(I)ccc2c1CC(=O)N2
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To 2 g of 4-methyl-2-oxindole in 40 mL of glacial acetic acid in an ice bath was added 3.67 g of N-iodosuccinimide. The mixture was stirred for 1 hour, diluted with 100 mL of 50% acetic acid in water and filtered. The resulting white solid was dried under high vacuum to give 3.27 g (88% yield) of the title compound as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:14][NH:15][C@H:16]1[CH2:35][N:20]2[C:21]3[C:26]([C:27]([CH2:28][C:29]([O:31]CCC)=[O:30])=[C:19]2[CH2:18][CH2:17]1)=[CH:25][CH:24]=[CH:23][CH:22]=3>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([N:15]([CH3:14])[C@H:16]3[CH2:35][N:20]4[C:21]5[C:26]([C:27]([CH2:28][C:29]([OH:31])=[O:30])=[C:19]4[CH2:18][CH2:17]3)=[CH:25][CH:24]=[CH:23][CH:22]=5)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(F)cc2)CC1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)C1(c2ccc(F)cc2)CC1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from 1-(4-fluorophenyl)cyclopropanecarboxylic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 321.
Reaction SMILES: [F:1][C:2]([F:26])([C:7]1[CH:8]=[CH:9][C:10]2[O:15][CH:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20]([O:22]CC)=[O:21])=[CH:12][C:11]=2[CH:25]=1)[C:3]([F:6])([F:5])[F:4].[OH-].[Na+]>C1COCC1.CCO.O>[F:26][C:2]([F:1])([C:7]1[CH:8]=[CH:9][C:10]2[O:15][CH:14]([C:16]([F:17])([F:18])[F:19])[C:13]([C:20]([OH:22])=[O:21])=[CH:12][C:11]=2[CH:25]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: CCOC(=O)C1=Cc2cc(C(F)(F)C(F)(F)F)ccc2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C(O)C1=Cc2cc(C(F)(F)C(F)(F)F)ccc2OC1C(F)(F)F
Reaction time: 16 h

Procedure:
To a stirred solution of the ethyl ester (Step 1) (0.090 g, 0.231 mmol) in THF:EtOH:H2O (7:2:1) (4 mL) was added aqueous NaOH solution (0.11 mL, 2.5 M). After stirring 16 hours, the reaction was partially concentrated in vacuo to remove the organic solvents, diluted with H2O, and washed with diethyl ether. The resulting aqueous phase was acidified with concentrated HCl, extracted with diethyl ether, dried over MgSO4, filtered and concentrated in vacuo yielding an oil. The oil was purified by flash chromatography (silica, hexanes-ethyl acetate, 3:1 with 5% acetic acid). This procedure yielded the title acid (0.020 g, 24%) as a white powder: mp 162.3–164.7° C. 1H NMR (acetone-d6/300 MHz) 8.05 (s, 1H), 7.90 (s, 1H), 7.74 (d, 1H, J=8.7 Hz), 7.29 (d, 1H, J=8.7 Hz), 5.97 (q, 1H, J=6.8 Hz). FABLRMS m/z 361 (M−H). ESHRMS m/z 361.0111 (M−H, Calc'd 361.0094).
Reaction SMILES: [N:1](OCCC(C)C)=[O:2].Cl.[F:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[CH2:15][CH2:14]2>CO>[F:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[C:15](=[N:1][OH:2])[CH2:14]2
Reactant: CC(C)CCON=O
Reactant: O=C1CCc2cc(F)ccc21
Agent: Cl
Solvent: CO
Product: O=C1C(=NO)Cc2cc(F)ccc21

Procedure:
15 ml of isoamyl nitrite and then 7.5 ml of concentrated hydrochloric acid are added dropwise to a solution, heated to 40° C., of 11.2 g of 5-fluoro-1-indanone in 185 ml of methanol. After reaction for 45 minutes at 40° C., the reaction mixture is cooled with ice. A precipitate is formed, which is filtered off and then dried in vacuo, allowing the expected product to be isolated.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:5][N:4]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17].[Cl:29][CH:30]([CH3:34])[C:31](Cl)=[O:32].[OH-].[Na+]>O1CCCC1.O>[Si:9]([O:8][C@H:6]1[CH2:5][N:4]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[O:17])[C@H:3]([CH2:2][NH:1][C:31](=[O:32])[CH:30]([Cl:29])[CH3:34])[CH2:7]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(Cl)C(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CN)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(Cl)C(=O)NC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
To a solution of (2S,4R)-2-aminomethyl-4-(t-butyldimethylsilyloxy)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (15 g) in a mixture of tetrahydrofuran (100 ml) and water (50 ml) was added dropwise 2-chloropropionylchloride (4.27 ml) with stirring under ice-cooling, keeping the pH 9-10 with 4N sodium hydroxide. The mixture was stirred at the same temperature for 1 hour. The reaction mixture was evaporated in vacuo to remove the organic layer. The resulting residue was extracted twice with ethyl acetate (100 ml). The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo to give (2S,4R)-4-(t-butyldimethylsilyloxy)-2-(2-chloropropionyl)aminomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (18.36 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:37]=[CH:36][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[CH:24][CH:23]=2)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:40].C(N([CH2:53][CH3:54])CC)C>C(Cl)(Cl)Cl>[CH2:42]([O:41][C:39]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:37]=[CH:36][C:18]([C:19]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[CH:26][CH:27]=2)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[N:13]([C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:53][CH3:54])=[O:40])[CH:12]=[CH:11][N:10]=1)=[O:40])[CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)cc1
Reactant: CCCCCCOC(=O)Cl
Reactant: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCOC(=O)n1ccnc1CN(Cc1ccc(C(=O)Nc2ccc(CN(CCC)CCC)cc2)cc1)Cc1nccn1C(=O)OCCCCCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The compound obtained in Example 19-3 was treated with an anion-exchange resin. The treated product was dissolved in chloroform (4.0 ml) and added with n-hexyl chloroformate (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (0.054 ml) and triethylamine (0.060 ml), followed by stirring at room temperature for 16 hours. After completion of the reaction, the solvent was distilled off. The residue was added with chloroform, washed with water and saturated saline solution, and dried with anhydrous sodium sulfate, followed by distilling the solvent off. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (66.6 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=3)[N:13]=1)[CH2:8][CH2:7]2.[N:23]1([CH2:28][C:29](O)=[O:30])[CH:27]=[N:26][CH:25]=[N:24]1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:29](=[O:30])[CH2:28][N:23]4[CH:27]=[N:26][CH:25]=[N:24]4)[CH:18]=3)[N:13]=1)[CH2:8][CH2:7]2
Reactant: Nc1ccc2nc(NC3CCc4cccc(F)c43)ccc2c1
Reactant: O=C(O)Cn1cncn1
Product: O=C(Cn1cncn1)Nc1ccc2nc(NC3CCc4cccc(F)c43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method described in example 6 from rac-N2-(7-fluoro-indan-1-yl)-quinoline-2,6-diamine and 1,2,4-triazol-1-acetic acid; MS: m/e=401.5 (M−H+).
Reaction SMILES: [H-].[Na+].O1CCC[CH2:4]1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][C@H:18](/[CH:21]=[CH:22]/[CH2:23][OH:24])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.CI>O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:15]2[CH2:16][CH2:17][C@H:18](/[CH:21]=[CH:22]/[CH2:23][O:24][CH3:4])[CH2:19][CH2:20]2)=[CH:13][CH:14]=1
Reactant: OC/C=C/[C@H]1CC[C@H](c2ccc(Br)cc2)CC1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COC/C=C/[C@H]1CC[C@H](c2ccc(Br)cc2)CC1
Reaction time: 2 h

Procedure:
A mixture of 0.5 g of sodium hydride and 50 ml of tetrahydrofuran was treated with 2.6 g of 1-bromo-4-[trans-4-[(E)-3-hydroxypropenyl]cyclohexyl]benzene while gassing with nitrogen, stirred for 2 hours, treated with 1.6 g of methyl iodide and subsequently stirred at room temperature overnight. The reaction mixture was treated with 500 ml of water and extracted four times with 50 ml of hexane each time, the combined organic phases were washed twice with 500 ml of water each time, dried over magnesium sulphate, the suspension was filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel with hexane and the product obtained was recrystallized from hexane at -78° C. to give 2.4 g of 1-bromo-4-[trans-4-[(E)-3-methoxypropenyl]cyclohexyl]benzene, m.p. (C-I) 47° C.
Reaction SMILES: O[C:2]([C:4](F)(F)F)=O.[Cl:8][C:9]1[S:21][C:12]2[NH:13][C:14](=[O:20])[C:15]([C:18]#[N:19])=[C:16]([OH:17])[C:11]=2[C:10]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2([OH:36])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:24][CH:23]=1.C(=O)C.CS(C)=O.CO>CC(O)=O>[Cl:8][C:9]1[S:21][C:12]2[NH:13][C:14](=[O:20])[C:15]([C:18]#[N:19])=[C:16]([OH:17])[C:11]=2[C:10]=1[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][C:30]2([OH:36])[CH2:35][CH2:34][N:33]([CH2:2][CH3:4])[CH2:32][CH2:31]2)=[CH:26][CH:27]=1
Reactant: N#Cc1c(O)c2c(-c3ccc(OCC4(O)CCNCC4)cc3)c(Cl)sc2[nH]c1=O
Reactant: O=C(O)C(F)(F)F
Agent: CC=O
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CCN1CCC(O)(COc2ccc(-c3c(Cl)sc4[nH]c(=O)c(C#N)c(O)c34)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-chloro-4-hydroxy-3-{4-[(4-hydroxypiperidin-4-yl)methoxy]phenyl}-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile TFA salt (40 mg, 0.073 mmol), acetaldehyde (0.006 mL, 0.110 mmol), and MS-CNBH3 (88 mg, 0.110 mmol, 1.25 mmol/g loading) in a 1:1 mixture of DMSO/MeOH (1 mL) containing 2% v/v AcOH was shaken in a 1 dram vial at rt for 18 h. The mixture was then filtered and purified by RP-HPLC to give the title compound. MS (ESI) m/e 460 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.24 (t, J=7.29 Hz, 3H), 1.83 (m, 2H), 1.98 (m, 2H), 3.15 (m, 4H), 3.32 (d, J=7.29 Hz, 2H), 3.87 (s, 2H), 5.22 (s, 1H), 6.92 (d, J=8.82 Hz, 2H), 7.20 (d, J=8.82 Hz, 2H), 8.91 (s, 1H), 10.77 (s, 1H).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].Br.Br[CH:11]1[CH2:20][CH2:19][C:18]2[CH:17]=[N:16][CH:15]=[CH:14][C:13]=2[C:12]1=[O:21].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:7]([O:6][C:4](=[O:5])[CH:3]([C:1]#[N:2])[CH:11]1[CH2:20][CH2:19][C:18]2[CH:17]=[N:16][CH:15]=[CH:14][C:13]=2[C:12]1=[O:21])[CH3:8]
Reactant: O=C1c2ccncc2CCC1Br
Reactant: CCOC(=O)CC#N
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C#N)C1CCc2cnccc2C1=O
Reaction time: 4 h
Yield: 95 %

Procedure:
To a stirred, cold (4° C.) solution of ethyl cyanoacetate (52.2 mmol) and 6-bromo-7,8-dihydro-6H-isoquinolin-5-one 8B (6.5 mmol) in DMF (10 mL), DIEA (19.5 mmol) was added. The mixture was brought to rt and stirred for 4 h. Solvent was removed and the residue, dissolved in DCM, was repeatedly washed with water. The organic layer was dried (Na2SO4) and concentrated. Purification by chromatography on silica gel (DCM/MeOH 98:2) provided the title compound in 95% yield. ESI (+) MS: m/z 259 (MH+). 1H NMR: 1.15-1.32 (m, 3H), 1.98-2.44 (m, 2H), 3.59-3.82 (m, 3H), 4.20-4.28 (m, 2H), 4.70 (s, 1H), 7.67-7.73 (m, 1H), 8.64-8.68 (m, 1H), 8.75-8.78 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][CH2:19][C:11]2[N:12]=[C:13](Cl)[N:14]=[C:15]([O:16][CH3:17])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[CH2:20][CH2:19][C:11]2[N:12]=[C:13]([C:23]3[C:24]([CH3:28])=[CH:25][CH:26]=[CH:27][C:22]=3[CH3:21])[N:14]=[C:15]([O:16][CH3:17])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C)c1B(O)O
Reactant: COc1nc(Cl)nc2c1CN(Cc1ccccc1)CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1nc(-c2c(C)cccc2C)nc2c1CN(Cc1ccccc1)CC2
Temperature: 100 °C

Procedure:
To a suspension of 6-benzyl-2-chloro-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (6.52 g, 22.5 mmol) and 2,6-dimethylphenylboronic acid (3.90 g, 26.0 mmol) in 1,2-dimethoxyethane (175 mL), was added 2 M aqueous Na2CO3 (35.2 mL, 70.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.751 g, 0.651 mmol). The reaction was flushed with nitrogen, then heated to 100° C. for 48 h. The reaction mixture was cooled to r.t., then ethyl acetate and brine were added. The aqueous layer was extracted by ethyl acetate twice. The combined ethyl acetate layers were dried over Na2SO4, filtered, and concentrated. The resulting residue was purified via silica gel FCC (0-40% EtOAc/heptane) to give 6-benzyl-2-(2,6-dimethylphenyl)-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. 1H NMR (400 MHz, CD2Cl2) δ ppm 7.23-7.46 (m, 5 H), 7.12-7.21 (m, 1 H), 7.04-7.10 (m, 1 H), 6.97 (d, J=7.6 Hz, 1 H), 3.94 (d, J=10.1 Hz, 3 H), 3.73 (d, J=16.4 Hz, 2 H), 3.36-3.56 (m, 2 H), 2.91 (d, J=4.8 Hz, 1 H), 2.84 (br. s., 2 H), 2.77 (t, J=5.4 Hz, 1 H), 2.35 (s, 3 H), 2.08 (s, 3 H). MS (ESI+) m/z 360.3 (M+H)+.
Reaction SMILES: CO[C:3]([C:5]1[S:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4].[NH2:25][CH:26]1[CH2:30][CH2:29][O:28][CH2:27]1>>[CH:13]([NH2:14])([CH3:18])[CH3:12].[O:28]1[CH2:29][CH2:30][CH:26]([NH:25][C:3]([C:5]2[S:9][N:8]=[C:7]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:6]=2)=[O:4])[CH2:27]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)ns1
Reactant: NC1CCOC1
Product: CC(C)N
Product: Cc1onc(-c2ccc(F)cn2)c1COc1cc(C(=O)NC2CCOC2)sn1
Yield: 55.3 %

Procedure:
As described for example 38b, 3-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-isothiazole-5-carboxylic acid methyl ester (120 mg, 0.34 mmol), was converted, using 3-aminotetrahydrofuran (36 mg, 0.41 mmol), instead of isopropyl amine, to the title compound (38 mg, 27%) which was obtained as a white solid after purification by chromatography (silica, heptane:ethyl acetate=75:25 to 25:75). MS: m/e=405.3 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=2)=[O:8])[CH:2]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:14][CH2:13][C:12]1[CH:11]=[CH:10][C:9]([C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:8])=[CH:16][CH:15]=1)(=[O:27])=[O:26]
Reactant: O=C(c1ccc(CO)cc1)c1cccnc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(C(=O)c2cccnc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
Dissolve 4-(pyridine-3-carbonyl)-benzyl alcohol (85 mg, 0.399 mmol) in dichloromethane (5 mL). Cool to 0° C. and add triethylamine (0.056 mL, 0.438 mmol) and methanesulfonyl chloride (0.033 mL, 0.438 mmol). Allow the mixture to warm to room temperature and stir for 2 h. Dilute the reaction mixture with dichloromethane and wash with saturated aqueous NaHCO3. Dry the organic phase over Na2SO4, filter and concentrate in vacuo to provide the title compound as oil (115 mg, 100%). GC-MS m/z: 291 (M+).