Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])[CH2:10][CH2:9]1.Cl[C:28]1[N:33]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:30][N:29]=1>CN(C)C=O>[C:23]([O:22][C:20]([NH:19][C@@H:15]([CH2:14][CH:11]1[CH2:10][CH2:9][CH:8]([NH:7][C:28]2[N:33]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:31]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[CH:30][N:29]=2)[CH2:13][CH2:12]1)[C:16]([OH:18])=[O:17])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: Clc1ncc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCC(N)CC1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCC(Nc2ncc(-c3ccccc3)c(-c3ccccc3)n2)CC1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.2 %

Procedure:
550 mg (1.69 mmol) of cesium carbonate were added to a solution of 161 mg (0.56 mmol) of (S)-3-(4-aminocyclohexyl)-2-tert-butoxycarbonylaminopropionic acid in 3 ml of dimethylformamide, and the mixture was stirred at room temperature. After 30 minutes, a solution of 100 mg (0.38 mmol) of 2-chloro-4,5-diphenylpyrimidine in 2 ml of dimethylformamide was added, and the mixture was stirred at 90° C. for 6 hours. The solvent was concentrated and the residue was partitioned between ethyl acetate and water. The organic phase was dried and concentrated under high vacuum. The residue was separated by a preparative HPLC (Purosphere, gradient acetonitrile/(water+0.5% TFA), gradient 20% acetonitrile to 100% in 30 minutes). 22 mg of (S)-2-tert-butoxycarbonylamino-3-[4-(4,5-diphenylpyrimidin-2-ylamino)cyclohexyl]propionic acid were obtained. The product obtained in this way was stirred with 50% trifluoroacetic acid in acetonitrile for 16 hours, mixed with water and freeze dried. 17 mg (11%) of the desired product were obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][C:5]([C:8]2[N:9]=[C:10]([N:13]=[C:14]([NH2:16])[NH2:15])[S:11][CH:12]=2)=[CH:6][N:7]=1.[CH3:17][S:18][C:19](SC)=[N:20][C:21]#[N:22]>C(O)C>[C:21]([N:20]=[C:19]([S:18][CH3:17])[NH:1][CH2:2][C:3]1[S:4][C:5]([C:8]2[N:9]=[C:10]([N:13]=[C:14]([NH2:16])[NH2:15])[S:11][CH:12]=2)=[CH:6][N:7]=1)#[N:22]
Reactant: NCc1ncc(-c2csc(N=C(N)N)n2)s1
Reactant: CSC(=NC#N)SC
Solvent: CCO
Product: CSC(=NC#N)NCc1ncc(-c2csc(N=C(N)N)n2)s1

Procedure:
A mixture of 4-(2-aminomethylthiazol-5-yl)-2-(diaminomethyleneamino)thiazole (0.45 g) and dimethyl N-cyanodithioiminocarbonate [(CH3S)2C=N-CN] (0.26 g) in ethanol (10 ml) was refluxed for 5 hours with stirring to give 4-[2-(3-cyano-2-methylisothioureido)methylthiazol-5-yl]-2-(diaminomethyleneamino)thiazole as a crude product. After cooling to ambient temperature, 40% aqueous methylamine by weight (1.4 ml) was added to the suspension and the mixture was stirred for 12 hours at ambient temperature. The solvent was evaporated in vacuo and the residue was mixed with water (5 ml) and ethyl acetate (5 ml). The resulting precipitate was collected and recrystallized from aqueous N,N-dimethylformamide to give 4-[2-(2-cyano-3-methylguanidino)methylthiazol-5-yl]-2-(diaminomethyleneamino)thiazole (0.35 g).
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]2=[N:11][C:10]=1[C:18]([O-:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[CH3:22][CH:23]([CH3:47])[CH2:24][NH:25][C@H:26]1[CH2:31][C@@H:30]([C:32]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[O:33])[CH2:29][N:28]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:27]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.ClC(N(C)C)=[N+](C)C>C(#N)C>[CH3:22][CH:23]([CH3:47])[CH2:24][N:25]([C:18]([C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]2[C:9]=1[CH2:8][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20])[C@H:26]1[CH2:31][C@@H:30]([C:32]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[O:33])[CH2:29][N:28]([C:40]([O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:41])[CH2:27]1
Reactant: CC(C)CN[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: O=C([O-])c1nc2ccccn2c1COc1ccccc1
Agent: CN(C)C(Cl)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(C(=O)c1nc2ccccn2c1COc1ccccc1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.9 %

Procedure:
Ethyl 3-(phenoxymethyl)imidazo[1,2-a]pyridine-2-carboxylate (889 mg) was dissolved in ethanol (50 ml), 2N aqueous sodium hydroxide solution (3 ml) was added, and the mixture was stirred at room temperature for 15 hr. The precipitated crystals were collected by filtration, and washed with ethanol to give sodium 3-(phenoxymethyl)imidazo[1,2-a]pyridine-2-carboxylate (680 g). The obtained sodium 3-(phenoxymethyl)imidazo[1,2-a]pyridine-2-carboxylate (290 mg), tert-butyl (3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (370 mg) and N,N-diisopropylethylamine (862 μl) were dissolved in acetonitrile (20 ml), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (561 mg) was added and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, and the residue was diluted with aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (9:1) was concentrated under reduced pressure to give the object product (563 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[F:8][C:5]1[CH:4]=[N:3][C:2]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]2)=[N:7][CH:6]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: OCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: OCC1CCN(c2ncc(F)cn2)CC1
Temperature: 100 °C
Yield: 95.3 %

Procedure:
A solution of 2-chloro-5-fluoropyrimidine (1.1 g, 8.05 mmol) and 4-piperidinemethanol (1.14 g, 9.66 mmol) in DMSO (20 mL) was treated with K2CO3 (2.23 g, 16.10 mmol). The reaction mixture was heated at 100° C. overnight. The mixture was cooled to ambient temperature and poured into water and extracted with CH2Cl2 (60 mL×3). The organic extracts were combined and washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give crude product as a brown oil. The crude product was purified by chromatography on an ISCO silica gel column using 0 to 40% EtOAc/hexanes to give 1.62 g (95%) of [1-(5-fluoro-2-pyrimidinyl)-4-piperidinyl]methanol as a white solid upon standing. 1H NMR (400 MHz, CDCl3): δ 8.18 (s, 2H), 4.75-4.65 (m, 2H), 3.51 (d, 2H, J=6.1 Hz), 2.95-2.80 (m, 2H), 1.85-1.70 (m, 3H), 1.30-1.15 (m, 2H); LRMS (ESI), m/z 212 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:20](=O)[NH2:21])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CO>C1COCC1>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([CH2:20][NH2:21])[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CCCC(NC(=O)OC(C)(C)C)C(N)=O)cc1
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CCCC(CN)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C

Procedure:
A solution of [1-carbamoyl-4-(4-methoxy-phenyl)-butyl]-carbamic acid tert-butyl ester (0.5 g, 1.48 mmol) in THF (15 mL) is treated dropwise with 1M borane-THF complex (4.47 mL, 4.47 mmol) and then heated at reflux for 2 h. After cooling to RT, MeOH (20 mL) is added and the mixture is heated again at reflux for 2 h. The solvent is removed in vacuo and the resulting oil is dissolved in DCM (10 mL) and filtered through Celite® (filter material). The filtrate is concentrated in vacuo to afford the title compound as a colourless oil. [M+H]+ 308.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[C:4]([O:16][CH:17]([F:19])[F:18])[CH:3]=1.C(O)CCC.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:36][CH2:37][CH:38]([OH:41])[CH2:39]O>C1(C)C=CC=CC=1>[F:18][CH:17]([F:19])[O:16][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[C:8]1([CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[O:41][CH:38]([CH2:37][Cl:36])[CH2:39][O:15]1
Reactant: OCC(O)CCl
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1OC(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCCCO
Product: FC(F)Oc1cc(Cl)ccc1C1(Cn2cncn2)OCC(CCl)O1
Temperature: 60 °C

Procedure:
14.2 parts of 1-(4-chloro-2-difluoromethoxyphenyl)-2-(1H-1,2,4-triazolyl)ethan-1-one and 100 ml of n-butanol in 450 ml of abs. toluene are heated in the presence of 9.4 parts of p-toluenesulfonic acid for 5 hours under reflux, while removing the water of reaction with a water separator. After cooling to 60° C., 33 parts of 3-chloro-1,2-propanediol and a further 18 parts of p-toluenesulfonic acid are added and the batch is refluxed for 80 hours while removing the water of reaction with a water separator. The reaction mixture is cooled to room temperature, washed twice with saturated aqueous sodium carbonate solution and with 2×200 ml of water, dried over sodium sulfate and filtered. The solvent is removed in a rotary evaporator and the oily residue is chromatographed through a 50 cm column of silica gel with a 1:1 mixture of methylene chloride/diethyl ether as eluant. The solvent mixture is removed by evaporation, affording the title compound in the form of a pale yellow oil with a refractive index nD22 : 1.5336.
Reaction SMILES: [Cl:1][C:2]([Cl:31])([Cl:30])[CH2:3][O:4][C:5]([O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20])[O:14][CH:13]=[C:12]([CH:27]=[O:28])[C:11]2=[O:29])=[O:6].S(=O)(=O)([OH:34])N.Cl([O-])=O.[Na+]>ClCCl.O>[Cl:31][C:2]([Cl:1])([Cl:30])[CH2:3][O:4][C:5]([O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][C:19]([O:21][CH2:22][C:23]([Cl:24])([Cl:25])[Cl:26])=[O:20])[O:14][CH:13]=[C:12]([C:27]([OH:34])=[O:28])[C:11]2=[O:29])=[O:6]
Reactant: NS(=O)(=O)O
Reactant: O=Cc1coc2cc(OC(=O)OCC(Cl)(Cl)Cl)c(OC(=O)OCC(Cl)(Cl)Cl)cc2c1=O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: ClCCl
Product: O=C(OCC(Cl)(Cl)Cl)Oc1cc2occ(C(=O)O)c(=O)c2cc1OC(=O)OCC(Cl)(Cl)Cl
Temperature: 10 °C
Yield: 79.4 %

Procedure:
The compound (838.4 mg) obtained in Example 4, (b) was dissolved in 16 ml of dichloromethane, and with stirring at 10° C., a solution of 525 mg of sulfamic acid in 9.5 ml of water was added, followed by addition of a solution of 262.8 mg of sodium chlorite in 0.6 ml of water. The mixture was stirred for 1 hour at the same temperature. The reaction mixture was allowed to separate. The dichloromethane layer was washed with water and then with a saturated aqueous solution of sodium chloride, and then dried over magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from ethyl ether to afford 685 mg of the desired product.
Reaction SMILES: Cl[CH:2]([O:6][C:7]([NH:9][CH2:10][C:11]1([CH2:17][C:18]([OH:20])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:8])[CH:3]([CH3:5])[CH3:4].N12CCCN=C1CCCCC2.[C:32]([OH:40])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[N:35][CH:34]=1>CC(C)=O>[C:32]([O:40][CH:2]([O:6][C:7]([NH:9][CH2:10][C:11]1([CH2:17][C:18]([OH:20])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:8])[CH:3]([CH3:5])[CH3:4])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[N:35][CH:34]=1
Reactant: CC(C)C(Cl)OC(=O)NCC1(CC(=O)O)CCCCC1
Reactant: O=C(O)c1cccnc1
Solvent: CC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)C(OC(=O)NCC1(CC(=O)O)CCCCC1)OC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 14.5 %

Procedure:
A mixture of (93) (268 mg, 0.88 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (158 μL, 1.01 mmol), and nicotinic acid (637 mg, 5.2 mmol) in acetone was stirred at room temperature for 48 h. After filtration, the filtrate was concentrated in vacuo and the resulting residue was purified by reverse phase preparative HPLC to afford 50 mg (14%) of the title compound. 1H NMR (CD3OD, 400 MHz): δ 1.07 (d, J=6.8 Hz, 3H), 1.09 (d, J=6.8 Hz, 3H), 1.32-1.58 (m, 10H), 2.19 (m, 1H), 2.26 (s, 2H), 3.23 (m, 2H), 6.78 (d, J=4.8 Hz, 1H), 7.58 (m, 1H), 8.39 (d, J=6.4 Hz, 1H), 8.76 (d, J=4.4 Hz, 1H), 9.10 (s, 1H). MS (ESI) m/z 393.42 (M+H+).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Cl:19])[CH:13]=3)[C:5]=2[N:6]=1.Cl.Cl.[CH3:22][C:23]1[N:28]=[CH:27][N:26]=[C:25]([N:29]2[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]2)[CH:24]=1>>[Cl:19][C:14]1[CH:13]=[C:12]([C:7]2[C:5]3[N:6]=[C:2]([NH:35][CH:32]4[CH2:33][CH2:34][N:29]([C:25]5[CH:24]=[C:23]([CH3:22])[N:28]=[CH:27][N:26]=5)[CH2:30][CH2:31]4)[S:3][C:4]=3[CH:10]=[C:9]([CH3:11])[CH:8]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: Cc1cc(-c2ccc(F)c(Cl)c2)c2nc(Br)sc2c1
Reactant: Cc1cc(N2CCC(N)CC2)ncn1
Agent: Cl
Product: Cc1cc(-c2ccc(F)c(Cl)c2)c2nc(NC3CCN(c4cc(C)ncn4)CC3)sc2c1

Procedure:
Prepared in analogy to example 207d, starting from 2-bromo-4-(3-chloro-4-fluorophenyl)-6-methylbenzo[d]thiazole and 1-(6-methyl-pyrimidin-4-yl)-piperidin-4-ylamine dihydrochloride. The title compound was obtained as a white solid.
Reaction SMILES: [NH:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:12]([N:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C1CCC2(CC1)CCCCN2
Solvent: c1ccncc1
Product: O=C(c1ccccc1)N1CCCCC12CCCCC2

Procedure:
The 1-azaspiro[5.5]undecane starting material can be prepared by the method described by H. Hodjat, et al., in J. Heterocyclic Chem., 9, 1081 (1972). This starting material is treated with benzoyl chloride in pyridine to form the N-benzoyl-1-azaspiro-[5.5]undecane, shown at the beginning of step 2.
Reaction SMILES: BrCBr.[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[NH:11][N:12]=[CH:13][C:6]=12.N(OCCC(C)C)=O.C(N(CC)CC)C.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40]N[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][N:4]([C:5]2[N:10]=[CH:9][N:8]=[C:7]3[NH:11][N:12]=[CH:13][C:6]=23)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1ncnc2[nH]ncc12
Agent: CC(C)CCON=O
Solvent: CCN(CC)CC
Solvent: BrCBr
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3[nH]ncc23)CC1
Reaction time: 3 h
Yield: 2.3 %

Procedure:
A dibromomethane suspension (5 mL) of commercially available 4-aminopyrazolo[3,4-d]pyrimidine (420.8 mg, 3.11 mmol) was heated to 80° C., and isoamyl nitrite (0.43 mL, 3.20 mmol) was added thereto, followed by stirring at the same temperature for 3 hours. Isoamyl nitrite (0.43 mL, 3.20 mmol) was further added thereto, followed by heating under reflux for 3.5 hours, and then the insoluble matter was removed by filtration. The filtrate was concentrated, the resulting residue was dissolved in dimethylformamide (5 mL), and then triethylamine (2.00 mL, 14.3 mmol) and N-tert-butoxycarbonylpiperazine (1.00 g, 5.37 mmol) were added thereto, followed by stirring at room temperature overnight. After the reaction solution was concentrated, the resulting residue was purified by silica gel column chromatography to give the target compound (20.4 mg, 0.07 mmol).
Reaction SMILES: [NH2:1][CH:2]([CH3:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[NH:6][CH:5]=1.C([O-])(O)=O.[Na+].O.ClC([O:24][CH2:25][CH:26]1C2C=CC=CC=2C2[C:27]1=CC=CC=2)=O>O1CCOCC1>[NH2:1][CH:2]([CH3:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:25](=[O:24])[CH2:26][CH3:27])[CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(N)Cc1c[nH]c2ccc(O)cc12
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCC(=O)Oc1ccc2[nH]cc(CC(C)N)c2c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 162.4 %

Procedure:
A 35 mL round bottom flask was charged with 3-(2-aminopropyl)-1H-indol-5-ol (0.20 g, 0.65 mmol) was added NaHCO3 (0.9 g, 11 mmol), water (2 mL) and 1,4-dioxane (8 mL). 9-Fluorenylmethyl chloroformate (0.20 g, 0.82 mmol) was added and the mixture stirred for 16 h at 23° C. TLC analysis indicated that the reaction was complete and the solution decanted into aqueous NaHCO3, then extracted with ether (2×30 mL). The combined organic extracts were washed with water (20 mL), dried over MgSO4 and concentrated. The crude product was purified by chromatography (silica, 65:35 hexanes:ethyl acetate) to furnish the title compound (0.26 g, 97%): 1H NMR (CDCl3) δ 7.88 (bs, 1H), 7.76 (d, J =6 Hz, 2H), 7.57 (d, J=6 Hz, 2H), 7.44-7.19 (m, 6H), 7.07 (s, 1H), 6.94 (s, 1H), 6.77 (dd, J=8, 2 Hz, 1H), 4.8 (m. 1H), 4.45 (m, J=8 Hz, 2H), 4.20 (m, J=8 Hz, 1H), 2.81 (bm, 2H), 1.15 (d, J=8 Hz); MS(ESI) m/z 430 (M+NH4)+, 413 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>CS(C)=O>[O:14]1[CH2:15][CH2:16][N:11]([C:2]2[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=2)[CH2:12][CH2:13]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cccc(F)c1
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccc(N2CCOCC2)c1

Procedure:
Using 1-fluoro-3-nitrobenzene (10 g, 0.07M) and morpholine (33.5 g, 0.38M) in DMSO (116 ml) is prepared using the method described by Brown G. R. et al., Tet. Lett. 40 (1999) 1219-1222. Filtration of the precipitated product yields the product; mp 113.8-115.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][S:9][CH2:10][CH2:11][C:12]#[N:13])[N:3]=1.[F:14][C:15]([F:21])([F:20])[CH2:16][N:17]=[C:18]=[S:19]>C(#N)C>[F:14][C:15]([F:21])([F:20])[CH2:16][NH:17][C:18](=[S:19])[NH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][S:9][CH2:10][CH2:11][C:12]#[N:13])[N:3]=1
Reactant: FC(F)(F)CN=C=S
Reactant: N#CCCSCc1nccc(N)n1
Solvent: CC#N
Product: N#CCCSCc1nccc(NC(=S)NCC(F)(F)F)n1

Procedure:
To a solution of 3-(4-aminopyrimid-2-ylmethylthio)propionitrile (1.7 g.) in acetonitrile (40 ml.) was added 2,2,2-trifluoroethylisothiocyanate (2 ml.) and the solution heated under reflux for 17 hours. The acetonitrile was evaporated in vacuo and the residue dissolved in EtOAc, treated with decolourising carbon, filtered and evaporated to give 3-[4-(3-[2,2,2-trifluoroethyl]thioureido)pyrimid-2-ylmethylthio]propionitrile as an orange solid, m.p. 108°-110°.
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:6]([CH2:14][CH3:15])[C:4]1=[O:5])[CH3:2].Cl[CH2:17][CH2:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22]>>[CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22])[CH:9]=[N:8][C:7]=2[N:6]([CH2:14][CH3:15])[C:4]1=[O:5])[CH3:2]
Reactant: CCn1c(=O)c2[nH]cnc2n(CC)c1=O
Reactant: CC(=O)CCCCCl
Product: CCn1c(=O)c2c(ncn2CCCCC(C)=O)n(CC)c1=O

Procedure:
1,3-Diethyl-7-(5-oxohexyl)xanthine (melting point 68-69° C.) is prepared from 1,3-diethylxanthine and 1-chloro-hexan-5-one.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:34]=[CH:35][C:36]([CH3:40])=[C:37]([OH:39])[CH:38]=1>C1COCC1>[OH:39][C:37]1[CH:38]=[C:33]([NH:32][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:31])[CH:34]=[CH:35][C:36]=1[CH3:40]
Reactant: CC(=O)c1ccc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)s1
Reactant: Cc1ccc(N)cc1O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(C)c(O)c3)c2)s1
Temperature: 65 °C
Reaction time: 24 h
Yield: 71.9 %

Procedure:
A small screw cap test tube was charged with 5-Acetyl-thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 54, 100 mg, 0.231 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methylphenol (31.33 mg, 0.254 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 72% (89 mg, 0.166 mmol) of the title compound.
Reaction SMILES: [CH2:1]1[C@:6]([OH:9])([CH2:7][OH:8])[C@@H:5]([OH:10])[C@H:4]([OH:11])[C@@H:3]([OH:12])[C@H:2]1N.C(C1C(=O)C(=[O:28])C=C(C(C)(C)C)C=1)(C)(C)C.C(O)(=O)C(O)=O.[OH-].[NH4+]>CO.O>[CH2:1]1[C@:6]([OH:9])([CH2:7][OH:8])[C@@H:5]([OH:10])[C@H:4]([OH:11])[C@@H:3]([OH:12])[C:2]1=[O:28]
Reactant: CC(C)(C)C1=CC(=O)C(=O)C(C(C)(C)C)=C1
Reactant: N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: O=C(O)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 1.5 h
Yield: 52.9 %

Procedure:
To a stirred solution of valiolamine (80 mg, 0.414 mmol), in 96% aq. methanol (5.2 mL) was added 3,5-di-t-butyl-1,2-benzoquinone (92 mg, 0.418 mmol) dissolved in methanol (2 mL) at room temperature. After stirring for 90 min, water (1 mL) was added, the pH lowered to 5.0 (pH paper control) with an aqueous solution of oxalic acid, and the mixture shaken vigorously for 45 min. Subsequently, the pH was adjusted to 8 with ammonium hydroxide. The mixture was diluted with water (80 mL) and extracted with chloroform (4×40 mL). The water phase was concentrated to approximately 5 mL in a vacuum and loaded onto an IRA-68 anion exchange column (40 mL, OH- -form). Elution with water gave a fraction containing the product. This solution was concentrated to 1 mL and further purified by chromatography on a weak cation exchanger (Wk-100, 40 mL, NH4+ -form, mobile phase: water) to give pure valiolone (42 mg, 0.219 mmol, 53% yield). 1H NMR (300 MHz, D2O), δ(ppm): 2.39 (d, 1H, J=14.6 Hz, HCH--C=O); 2.79 (d, 1H, J=14.6 Hz, HCH--C=O); 3.3 (d, 1H, J=11.5 Hz, HCH--C--OH); 3.62 (d, 1H, J=11.3 Hz, HCH--C--OH); 3.63 (t, 1H, J=9.5 Hz, HC-3); 3.84 (d, 1H, J=9.4 Hz, HC-4) and 4.19 (d, 1H, J=9.7 Hz, Hc-2). 13C NMR (75 MHz, D2O), δ (ppm): 45.45, 64.37, 72.91, 75.79, 76.01, 78.62 and 209.43.
Reaction SMILES: [SH:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.[H-].[Na+].[C:9]([O:13][C:14]([N:16]1[CH2:22][CH2:21][C:20]2[C:23]([CH2:28]Cl)=[C:24]([Cl:27])[CH:25]=[CH:26][C:19]=2[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:22][CH2:21][C:20]2[C:23]([CH2:28][S:1][C:2]3[S:3][CH2:4][CH2:5][N:6]=3)=[C:24]([Cl:27])[CH:25]=[CH:26][C:19]=2[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCl)c2CC1
Reactant: SC1=NCCS1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSC3=NCCS3)c2CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.1 %

Procedure:
To a solution of 2-mercaptothiazoline (0.3 g, 2.5 mmol) in anhydrous DMF (8.5 mL) at room temperature add sodium hydride (0.1 g, 2.6 mmol, 60% dispersion in mineral oil) in portions. After stirring at room temperature for 10 min, add a solution of 3-tert-butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.74 g, 2.3 mmol) in anhydrous DMF (5.6 mL). Stir at room temperature overnight and quench the reaction mixture with 10% aqueous NaHCO3 (14 mL). Extract the mixture twice with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Dissolve the residue in DCM, load the solution on to a RediSep® column (40 g) and purify the crude mixture by preparative liquid chromatography (100:0 to 95:5 hexane/EtOAc over 30 min; 95:5 hexane/EtOAc over 3 min; 95:5 to 75:25 hexane/EtOAc over 30 min; 75:25 hexane/EtOAc over 3 min; 35 mL/min) to afford 3-tert-butoxycarbonyl-7-chloro-6-(4,5-dihydro-thiazol-2-ylthiomethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.77 g, 83%). MS (ES+) m/z: 413.1 (M+H)+.