Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27](=[O:36])[C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([F:35])[CH:29]=4)[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH2:12][NH:11][C:10]1=[O:41].[NH2:42][CH:43]1[CH2:48][C:47]([CH3:50])([CH3:49])[NH:46][C:45]([CH3:52])([CH3:51])[CH2:44]1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:42][CH:43]3[CH2:44][C:45]([CH3:52])([CH3:51])[NH:46][C:47]([CH3:50])([CH3:49])[CH2:48]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27](=[O:36])[C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([F:35])[CH:29]=4)[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH2:12][NH:11][C:10]1=[O:41]
Reactant: Cc1ccc(C(=O)Nc2ccc(C)c(-c3nc(S(C)(=O)=O)nc4c3CNC(=O)N4c3c(F)cccc3F)c2)cc1F
Reactant: CC1(C)CC(N)CC(C)(C)N1
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2ccc(C)c(-c3nc(NC4CC(C)(C)NC(C)(C)C4)nc4c3CNC(=O)N4c3c(F)cccc3F)c2)cc1F
Temperature: 25 °C

Procedure:
The compound N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide (0.070 g, 0.107 mmol) was dissolved in DMF (1.5 mL) and treated with 4-amino-2,2,6,6-tetramethylpiperidine (62 ul, 0.361 mmol). Stirring at room temperature and heating to 70° C. under argon produced no reaction so the mixture was microwaved at 200° C. for 15 min. The solvent was removed in vacuo and the crude product was purified by flash chromatography on silica gel, eluting with CH2C2—10% MeOH/CH2C2. The product was repurified by the same method to afford the title compound as a white solid. mp (dec) 220° C.; LC-MS m/z 659 (M+H)+, 1.94 min (ret. time).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](=[O:8])[CH2:6][CH3:7])[CH3:2].[Br:10]Br>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:9])[C:5](=[O:8])[CH:6]([Br:10])[CH3:7])[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)C(=O)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=O)C(C)Br
Reaction time: 18 h

Procedure:
The 2-oxo-butyric acid ethyl ester prepared above was dissolved in chloroform (100 mL) and bromine (20.964 g, 131.19 mmol) was added dropwise at room temperature. The reaction mixture was allowed to stir for 18 h. Concentration of the reaction mixture under reduced pressure provided 12.0 g of the title compound as an orange oil. 1H NMR (CDCl3) δ 4.39 (q, 2H), 4.32 (q, 1H), 1.88 (d, 3H), 1.39 (t, 3H).
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH2:43]C)=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH3:45][N:46](C)[CH2:47]CN.NC1C=CC=CC=1>>[CH:9]12[O:12][CH:5]([CH2:11][CH2:10]1)[CH2:6][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28][CH2:29][CH2:30][N:46]([CH3:47])[CH3:45])=[O:27])=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH3:43])=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:8]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: CN(C)CCN
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: COC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc(NC(=O)NCCN(C)C)cc4)nc32)CC1

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing N,N-dimethylethylenediamine as the aniline component. (23%, MS=578.3 (M+H))
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([CH2:9][CH:10]([CH3:13])[CH:11]=O)=O)=[CH:5][CH:4]=1.[C:16]([NH:19][S:20]([C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21])(=[O:18])[CH3:17].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[C:16]([NH:19][S:20]([C:23]1[CH:29]=[CH:28][C:26]([N:27]2[CH:11]=[C:10]([CH3:13])[CH:9]=[C:7]2[C:6]2[CH:14]=[CH:15][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21])(=[O:18])[CH3:17]
Reactant: COc1ccc(C(=O)CC(C)C=O)cc1
Reactant: CC(=O)NS(=O)(=O)c1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc(-c2cc(C)cn2-c2ccc(S(=O)(=O)NC(C)=O)cc2)cc1
Yield: 16.1 %

Procedure:
A solution of 2.82 g (12.8 mmol) of 3-(4-methoxybenzoyl)-2-methylpropionaldehyde [prepared as described in step (i) above] and 2.74 g (12.8 mmol) of 4-acetylaminosulfonylaniline in 30 ml of acetic acid was heated under reflux for 3 hours, after which the acetic acid was removed by distillation under reduced pressure. The residue thus obtained was dissolved in chloroform and a saturated aqueous solution of sodium hydrogencarbonate was added to the resulting solution to separate it into liquid phases. The organic extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate, after which it was concentrated by evaporation under reduced pressure. The residue thus obtained was applied to a silica gel chromatography column and eluted with a 2:3 by volume mixture of hexane and ethyl acetate. It was then recrystallized from ethanol, to give 0.79 g (yield 16%) of the title compound as a white powder, melting at 215-217° C.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:28]=[CH:27][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:26])([CH3:25])[C:20]([O:22]CC)=[O:21])=[CH:15][CH:14]=2)=[O:9])=[CH:6][CH:5]=1>>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:25])([CH3:26])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=2)=[O:9])=[CH:27][CH:28]=1
Reactant: CCOC(=O)C(C)(C)c1ccc(CCNC(=O)c2ccc(Cl)cc2)cc1
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C(=O)O)c1ccc(CCNC(=O)c2ccc(Cl)cc2)cc1
Yield: 96.4 %

Procedure:
13.9 g ethyl 2-{4-[2-(4-chlorobenzamido)-ethyl]-phenyl}-2-methylpropionate 100 ml methanol and 37 ml 2 N aqueous potassium hydroxide solution are maintained at reflux temperature for 9 hours, the methanol is then distilled off in a vacuum and the residue is diluted with water and extracted with diethyl ether. The aqueous phase is filtered and acidified. There are obtained 12.8 g (100% of theory) of crude product. After recrystallization from 130 ml glacial acetic acid, there are obtained 12.4 g (94% of theory) 2-{4-[2-(4-chlorobenzamido)-ethyl]-phenyl}-2-methylpropionic acid; m.p. 234°-235° C.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:18].[Br:19]Br>CC(O)=O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([Br:19])=[CH:4][C:3]=1[CH3:18]
Reactant: Cc1ccc2c(c1N)C(=O)c1ccccc1C2=O
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1cc(Br)c2c(c1N)C(=O)c1ccccc1C2=O
Temperature: 40 °C
Yield: 90 %

Procedure:
1-amino-2-methylanthraquinone (300 g) is slurried with 1500 ml of HOAc in a 5-liter flask. The temperature is raised to 40° C. Neat bromine (405 g) is added over 21/2 hours with stirring at 40°-50° C. The mixture is stirred for 20 additional minutes and filtered. The solids so recovered are washed with HOAc and water and sucked dry with an aspirator and transferred to a reaction flask along with 150 g of NaHSO3 and 1.5 liters of water. The mixture is gradually heated to 90° C. (over two hours) with stirring to give 1-amino-2-methyl-4-bromoanthraquinone as a solid which is recovered from the reaction mixture by filtration in 90% yield, rinsed with water and dried overnight at 155° C. and 1 mm Hg absolute vacuum.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([CH:45]=O)=[CH:41][CH:40]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO.CN(C=O)C.C(Cl)Cl.N>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:45]([C:42]3[CH:41]=[CH:40][C:39]([CH2:38][N:35]4[CH2:34][CH2:33][N:32]([C:30]([O:29][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:31])[CH2:37][CH2:36]4)=[CH:44][CH:43]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C=O)cc2)CC1
Reactant: Cn1cncc1CN1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1cncc1CN1CCN(c2c(Br)cnc3[nH]c(-c4ccc(CN5CCN(C(=O)OC(C)(C)C)CC5)cc4)nc23)CC1
Temperature: 85 °C
Yield: 37.8 %

Procedure:
To a mixture of 5-bromo-4-(4-((1-methyl-1H-imidazol-5-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.050 g, 0.13 mmol, 1 eq) in EtOH (2.2 mL) and DMF (0.3 mL), tert-butyl-4-(4-formylbenzyl)piperazine-1-carboxylate (0.042 g, 0.14 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.38 mL, 0.38 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 92:8) to give the title compound as a solid (0.032 g, 39%); 1H-NMR (500 Mz, DMSO-d6): 1.39 (s, 9H, C(CH3)3), 2.34 (t, J=5.0 Hz, 4H), 2.56-2.62 (m, 4H), 3.29-3.35 (m, 4H), 3.54 (s, 2H, NCH2), 3.55 (s, 2H, NCH2), 3.61-3.66 (m, 4H), 3.68 (s, 3H, CH3), 6.80 (s, 1H, imidazole 4-H), 7.46 (d, J=8.0 Hz, 2H, ArH, C6H4), 7.57 (s, 1H, imidazole 2-H), 8.14 (d, J=8.5 Hz, 2H, ArH, C6H4), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H); LC (Method B)-MS (ESI, m/z) 2.33 min—650/652 [(M+H)+], Br isotopic pattern]. ESI-HRMS: Found: 650.2565, calculated for C31H41BrN9O2 (M+H)+: 650.2567.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][N:10]=1)=[O:8])C.CO.O.O[Li].O>C1COCC1>[C:15]1([C:12]2[CH:13]=[CH:14][C:9]([C:7]([NH:6][CH2:5][C:4]([OH:21])=[O:3])=[O:8])=[N:10][CH:11]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)CNC(=O)c1ccc(-c2ccccc2)cn1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a stirred solution of 5-phenyl-pyridine-2-carboxylic acid (0.3 g, 0.00151 mol) in DMF (5 mL) was added DIPEA (0.580 g, 0.00452 mol), HOBt (0.243 g, 0.00180 7 mol) and EDCI.HCl (0.346 g, 0.001807 mol) at ambient temperature. After 2 minutes glycine ethyl ester hydrochloride (0.252 g, 0.00181 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 0.32 g (75%) of [(5-phenyl-pyridine-2-carbonyl)-amino]-acetic acid ethyl ester. To a stirred solution of [(5-phenyl-pyridine-2-carbonyl)-amino]-acetic acid ethyl ester (0.32 g, 0.00113 mol) in a mixture of THF (3.2 mL), methanol (2 mL) and H2O (1 mL) was added LiOH.H2O (0.142 g, 0.00338 mol) and the resulting mixture was stirred at ambient temperature overnight. Volatiles were removed by evaporation and the resulting residue was diluted with water and acidified with 10% HCl. The product was extracted with ethyl acetate, which was dried over sodium sulfate and concentrated under reduced pressure to afford 0.24 g (83%) of [(5-phenyl-pyridine-2-carbonyl)-amino]-acetic acid.
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]1[N:11]([CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([C:22]#[N:23])[C:16]=2[CH3:24])O)[CH2:10][CH2:9][N:8]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:7]1)(=[O:3])[CH3:2].S(Cl)([Cl:34])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([S:4][CH2:5][C@H:6]1[N:11]([CH2:12][CH:13]([Cl:34])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([C:22]#[N:23])[C:16]=2[CH3:24])[CH2:10][CH2:9][N:8]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)SC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1CC(O)c1ccc(F)c(C#N)c1C
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)SC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1CC(Cl)c1ccc(F)c(C#N)c1C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of (3S)-tert-butyl 3-(acetylthiomethyl)-4-(2-(3-cyano-4-fluoro-2-methylphenyl)-2-hydroxyethyl)piperazine-1-carboxylate (30.8 mg, 0.0680 mmol) in toluene (0.62 mL) was added thionyl chloride (14.9 μL, 0.205 mmol). The mixture was cooled with an ice bath and then pyridine (22.1 μL, 0.273 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 20 min, and then allowed to warm to room temperature over an hour and finally heated at 70° C. for 30 min. The reaction mixture was concentrated and the residue was diluted with ethyl acetate, washed with a minimum amount of saturated sodium bicarbonate aqueous solution, and then brine. The organic layer was separated, filtered through a pad of anhydrous sodium sulfate and concentrated. Used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23](C4C=CN=CC=4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB(C2C=NN([C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)C=2)O1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([C:44]4[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cnn(-c3cccnc3)c2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(-c3ccncc3)c2)c2ccc(F)cc21
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(-c3cccnc3)c2)c2ccc(F)cc21
Yield: 96 %

Procedure:
Following the general method as outlined in Intermediate 10, starting from 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridine (Intermediate 11; 485 mg; 1.80 mmol), 362 mg (96%) of the title compound was obtained as a brown solid after purification by a silica gel chromatography (petroleum ether/EtOAc=1/1).
Reaction SMILES: Cl.C(OC(=O)[NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:25])[CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[CH2:11][CH2:10]1)(C)(C)C.CCOCC>CO>[NH2:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([NH:15][C:16](=[O:25])[CH2:17][N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[CH2:13][CH2:14]1
Reactant: CN1CCN(CC(=O)N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CN1CCN(CC(=O)N[C@H]2CC[C@H](N)CC2)CC1
Reaction time: 8 h

Procedure:
An aqueous solution of HCl (2 M, 15 mL) was added to a solution of trans-{4-[2-(4-methyl-piperazin-1-yl)-acetylamino]-cyclohexyl}-carbamic acid tert-butyl ester (199 mg, 0.56 mmol) in MeOH (15 mL) at RT, and the resulting mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure to give a solid residue. Et2O was added to this material, and the resulting suspension was sonicated. The ether phase was decanted away, leaving a powdery brown solid which was purified by preparative TLC. The resulting oil was dissolved in the minimum quantity of MeOH, and Et2O was added. A solid precipitated; the liquid phase was decanted away to give, after drying, 75 mg of trans-N-(4-amino-cyclohexyl)-2-(4-methyl-piperazin-1-yl)-acetamide as a fine powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1.[CH:18]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C:21](=[O:27])[O:20][C:19]2=O>>[N:17]1[CH:16]=[CH:15][CH:14]=[N:13][C:12]=1[N:9]1[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:1]2[C:19](=[O:20])[CH:18]3[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]3)[C:21]2=[O:27])[CH2:11][CH2:10]1
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Reactant: O=C1OC(=O)C2CCC1CC2
Product: O=C1C2CCC(CC2)C(=O)N1CCCCN1CCN(c2ncccn2)CC1
Reaction time: 0.25 h
Yield: 8.7 %

Procedure:
An intimate mixture of 0.5 g (2.14 mmol) of 1-(4-aminobutyl)-4-(2-pyrimidinyl) piperazine and 0.22 g (1.42 mmol) of 3-oxabicyclo[3.2.2]nonan-2,4-dione was heated in an oil bath at 220°-230° C. for 15 minutes. An additional 0.22 g (1.42 mmol) of 3-oxabicyclo[3.2.2]nonan-2,4-dione was added. Heating in an oil bath at 220°-230° C. was continued for 15 minutes and then an additional 0.22 g (1.42 mmol) of 3-oxabicyclo[3.2.2]-nonan-2,4-dione was added. Heating was continued for 30 minutes at 220°-230° C. and then the reaction mixture was cooled. The resulting product was chromatographed on silica gel, eluting with dichloromethane/methanol (96:4 followed by 94:6), to give 46 mg of the title compound (6% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].[CH2:15]([N:17](CC)CC)C.CN>O1CCCC1.CCCCCC>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:17][CH3:15])=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: CN
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1cnc(SC)nc1NC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
To a solution of 4-chloro-2-methylsulfanyl-5-pyrimidinecarboxylate ethyl ester (18.66 g, 80.4 mmol) in 260 mL of tetrahydrofuran was added triethylamine (34 mL, 244 mmol), followed by 30 mL of a 40% aqueous solution of methylamine. The solution was stirred for 30 minutes at 25° C. then concentrated in vacuo and partitioned between chloroform and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to provide a white solid. The solid was suspended in hexane and filtered to provide 14.70 g (81%) of 4-methylamino-2-methylsulfanyl-5-pyrimidinecarboxylate ethyl ester; mp 91-93° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:3]=1[CH2:4][CH2:5][C:6]1([O:15]2)[CH2:11][CH2:10][N:9]([C:12](=S)[CH3:13])[CH2:8][CH2:7]1.Cl.ClC1C=CC=C2C=1CCC1([O:32]2)CCNCC1.CCN(CC)CC.C(Cl)(=O)C>C(Cl)Cl.O>[C:12]([N:9]1[CH2:10][CH2:11][C:6]2([CH2:5][CH2:4][C:3]3[C:16](=[CH:17][CH:18]=[CH:19][C:2]=3[Cl:1])[O:15]2)[CH2:7][CH2:8]1)(=[O:32])[CH3:13]
Reactant: CC(=S)N1CCC2(CCc3c(Cl)cccc3O2)CC1
Reactant: Clc1cccc2c1CCC1(CCNCC1)O2
Agent: Cl
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N1CCC2(CCc3c(Cl)cccc3O2)CC1
Reaction time: 1 h

Procedure:
5-Chloro-1′-ethanethioyl-3,4-dihydrospiro[chromene-2,4′-piperidine] To a suspension of 5-chloro-3,4-dihydrospiro[chromene-2,4′-piperidine] HCl salt (2 g, 7.3 mmol) and Et3N (3 mL, 21.5 mmol) in CH2Cl2 (25 mL) was added acetyl chloride (0.7 mL, 9.8 mmol). After stirring for 1 h, the mixture was diluted with water and extracted with CH2Cl2. The CH2Cl2 extract was washed with diluted brine, dried (MgSO4) and concentrated. The resulting residue was purified by Combi-Flash™ (40 g, 50-100% EtOAc in hexanes for 20 min, 40 mL/min, 18 mL/fraction) to give 1′-acetyl-5-chloro-3,4-dihydrospiro[chromene-2,4′-piperidine] as an oil, which solidified on standing.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH2:9]=[C:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[C:11]([OH:13])=[O:12]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=1)[C:11]([OH:13])=[O:12]
Reactant: Nc1ccccc1S
Reactant: C=C(C(=O)O)c1ccc(C(F)(F)F)cc1
Solvent: CCO
Product: Nc1ccccc1SCC(C(=O)O)c1ccc(C(F)(F)F)cc1
Yield: 39.4 %

Procedure:
20.41 g of aminothiophenol were added all at once to a solution of 43 g of α-methylene-4-(trifluoromethyl)-benzene acetic acid [J. Med. Chem. (1969), Vol. 12 (3), p. 477 to 480] in 300 ml of ethanol, and the mixture was refluxed for 2 hours. The ethanol was evaporated off and the residue was taken up in 600 ml of ethyl ether and partially concentrated to 300 ml. 200 ml of isopropyl ether were added with concentration to 100 ml and cooled for 30 minutes in ice-cooled water. The crystallized product was separated off, washed with isopropyl ether and dried under reduced pressure at 100° C. to obtain 21.9 g of expected product melting at approx. 138° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH3:29])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[Cl:28][C:24]1[CH:23]=[C:22]([C:21]2[C:15]3[O:14][CH:13]([CH2:12][NH:31][CH3:30])[CH2:17][C:16]=3[CH:18]=[C:19]([CH3:29])[CH:20]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C)cc(-c4cccc(Cl)c4)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(C)cc(-c3cccc(Cl)c3)c2O1

Procedure:
The title compound was prepared (0.016 g, 13%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(3-chlorophenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.16 g, 0.37 mmol) and methylamine (0.115 g, 3.7 mmol). mp 181-182° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([C@H:18]2[CH2:22][CH2:21][O:20][CH2:19]2)([C:14]([O:16]C)=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].C(OC(C)(C)C)=O>O1CCCC1.CO.O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([C@H:18]2[CH2:22][CH2:21][O:20][CH2:19]2)([C:14]([OH:16])=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@]1([C@H]2CCOC2)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Agent: CC(C)(C)OC=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1C=C[C@@](C(=O)O)([C@H]2CCOC2)C1

Procedure:
To a solution of methyl (1R,4S)-4-[(tert-butoxycarbonyl)amino]-1-[(3R)-tetrahydrofuran-3-yl]cyclopent-2-ene-1-carboxylate (1.60 g, 5.14 mmol) in tetrahydrofuran (27.8 mL), methanol (27.8 mL) and water (6.0 mL) was added lithium hydroxide, monohydrate (0.346 g, 8.25 mmol). The pink mixture was heated to reflux for 18 h. The organic solvents were removed in vacuo and the aqueous layer was extracted once with ether and then acidified slowly with 6 M HCl until the pH reached 3-4. The resulting suspension was extracted with CH2Cl2 three times. The combined organic layers were dried over MgSO4, filtered and concentrated to give the product as a mixture of two cis/trans isomers (1.59 g) as a light yellow solid. MS calculated for C15H24NO5: (M+H) 298.2; found 198.2 (M+H-Boc).
Reaction SMILES: C[O-].[Na+].[S:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6](=[O:14])[CH2:5]1.[NH:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH:20]=O.O>CN(C)C=O>[NH:15]1[CH:19]=[CH:18][CH:17]=[C:16]1/[CH:20]=[C:5]1\[S:4][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]\1=[O:14]
Reactant: O=C1CSc2ccccc2N1
Reactant: O=Cc1ccc[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2ccccc2S/C1=C\c1ccc[nH]1
Temperature: 120 °C

Procedure:
Sodium methoxide (0.28 g, 5.2 mmol) was added to a solution of 2H-1,4-benzothiazin-3(4H)-one (0.60 g, 4 mmol) and pyrrol-2-carboxaldehyde (0.49 g, 5.2 mmol) in dry N,N-dimethylformamide (3.5 ml) (hereinafter “DMF”). The mixture was heated at 120° C. for 6.5 h, allowed to cool and poured into water (60 ml). The precipitate was collected by filtration and washed with water. The precipitate was dissolved in ethyl acetate and the insoluble black residue was filtered out. The filtrate was concentrated, then chromatographed on a silica column using a gradient of 100% dichloromethane to (100:1) dichloromethane:ethanol as the mobile phase. The first eluted product was the (E)-isomer.