Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C1COCC1>[CH3:27][S:28]([NH:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)S(=O)(=O)NC(C1CCCCC1)=N2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)NC(C1CCCCC1)=N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.3 %

Procedure:
A stirred solution of 7-amino-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (1 g; 3.6 mmol) and triethylamine (1.2 ml; 8 mmol) in dry THF (25 ml) was added methanesulfonylchloride (0.6 ml; 8 mmol) and stirred at rt. for 2 h. The reaction mixture was evaporated to dryness, resuspended in H2O/EtOAc and filtered. The filtrate was adsorbed onto silica gel. Column chromatography (CH2Cl2:acetone=9:1) gave 210 mg of product.
Reaction SMILES: [CH3:1][C:2]([C@@H:10]1[CH2:15][CH2:14][O:13][C:12]([CH3:17])([CH3:16])[O:11]1)([C:4](=[O:9])[CH2:5][CH2:6][CH:7]=[CH2:8])[CH3:3]>C1COCC1.[Pd]>[CH3:3][C:2]([C@@H:10]1[CH2:15][CH2:14][O:13][C:12]([CH3:16])([CH3:17])[O:11]1)([C:4](=[O:9])[CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1]
Reactant: C=CCCC(=O)C(C)(C)[C@@H]1CCOC(C)(C)O1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCC(=O)C(C)(C)[C@@H]1CCOC(C)(C)O1
Yield: 86.6 %

Procedure:
24 g (0.1 mol) of (4S)-4-(2-methyl-3-oxo-hept-6-en-2-yl)-2,2-dimethyl-[1,3]dioxane from Example 17 is dissolved in 480 ml of THF. At room temperature, 4.8 g of palladium on carbon (10%) is added. It is hydrogenated at 10 bar of hydrogen for 2 hours until hydrogen absorption is completed. The catalyst is suctioned off, rewashed with THF, and the product is distilled at 95° C./1 mbar. 21 g of product (87% of theory) is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9]C(C)(C)C)=[O:8].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(COC2CCCCC2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cc(Cl)c(COC2CCCCC2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.1 %

Procedure:
To a solution of tert-butyl 5-chloro-4-(cyclohexyloxymethyl)-2-fluorobenzoate (1.86 g, 5.43 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid (20 mL). The reaction solution was stirred at ambient temperature for 3 hours, then concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL), washed with brine (3×25 mL), dried over anhydrous sodium sulfate, filtered the solid. The filtrate was concentrated in vacuo to dryness to afford the title compound (0.50 g, 32% crude yield) which was subjected to next step without any further purification: MS (ES+) m/z 287.0, 285.0 (M+1).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[C:11](Cl)([Cl:13])=[O:12]>C(Cl)Cl>[CH:1]1([C:11]([Cl:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: O=C(Cl)Cl
Reactant: c1ccc2c(c1)CCNC2
Solvent: ClCCl
Product: O=C(Cl)C1NCCc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
1,2,3,4-Tetrahydroisoquinoline (0.5 g, 3.76 mmol) was added to a cooled mixture of phosgene (5 ml of 20% phosgene in toluene solution, 9.4 mmol) in methylene chloride (5 ml) at 0° C. The mixture was stirred at 0° C. for 1 hour. The reaction mixture was evaporated in vacuo. The residue was suspended in ethyl ether, filtered and the eluents were condensed to give a pale pink oil. Purification by flash column chromatography (silica gel, 0-10% ethyl acetate/hexane) gave 0.586 g of the desired product. IR (film) 1735.3 cm−1.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][NH2:13]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:13][CH3:12])[CH:7]=1
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Product: CNc1cc(F)ccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To stirred 2,4-difluoronitrobenzene (9.54 g., 60 mmole) was added dropwise an aqueous solution of methylamine (40 wt. %) (11.6 g) in an ice bath. The mixture was stirred for another 1 hour. The yellow precipitate was collected by filtration, washed with water and dried in vacuo to give the compound (7) as yellow crystals (6.1 g., 60%).
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)=[CH:14][C:13]1=[O:26])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)=[CH:14][C:13]2=[O:26])[C:3]([OH:27])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(OC)c2)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(OC2=CC(=O)N([C@@H](CC3CCCCC3)C(=O)O)C2)c1
Temperature: 23 °C
Reaction time: 2 h
Yield: 62.1 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[4-(3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (1.12 g, 0.003 mol) in tetrahydrofuran-water (3:1, 10 mL) was added lithium hydroxide (387 mg, 0.009 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-3-cyclohexyl-2-[4-(3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (670 mg, 62%) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[CH2:20][CH2:21][C:22]#[N:23]>>[Cl:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:21]([CH2:20][C:13]3[C:14]([O:18][CH3:19])=[CH:15][CH:16]=[CH:17][C:12]=3[Cl:11])[C:22]([NH2:23])=[N:1]2)=[CH:6][CH:7]=1
Reactant: Nc1cc(Cl)ccc1C=O
Reactant: COc1cccc(Cl)c1CCC#N
Product: COc1cccc(Cl)c1Cc1cc2ccc(Cl)cc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-4-chlorobenzaldehyde and 3-(2-chloro-6-methoxyphenyl)propionitrile.
Reaction SMILES: [C:1]([O:5][P:6]([O-:13])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:31][CH2:32]I>>[P:6]([O:13][CH2:32][Cl:31])([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: ClCI
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of tetrabutylammonium di-tert-butyl phosphate (57 g, 0.126 mol, Digital Specialty Chemicals) and chloroiodomethane (221 g, 1.26 mol) was stirred at room temperature for four hours before the volatiles were removed under vacuum. 500 ml of ethyl ether was added to the residue and insoluble solid was filtered away. Concentration of the filtrate in vacuo and removal of remaining volatiles using a vacuum pump provided di-tert-butyl chloromethyl phosphate as a light brown or yellow oil, which was utilized in the next step without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:40])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)=[CH:17][CH:16]=3)=[N:10][C:9]=2[N:29]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[CH2:36][CH2:35][CH2:34]3)[CH:30]=1)=O)C.[CH2:41]([NH2:43])[CH3:42]>CO>[CH2:41]([NH:43][C:4]([C:6]1[C:7](=[O:40])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][N:22]4[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]4)=[CH:17][CH:16]=3)=[N:10][C:9]=2[N:29]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[CH2:36][CH2:35][CH2:34]3)[CH:30]=1)=[O:3])[CH3:42]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(CN4CCN(C)CC4)cc3)ncc2c1=O
Reactant: CCN
Solvent: CO
Product: CCNC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(CN4CCN(C)CC4)cc3)ncc2c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 56.9 %

Procedure:
8-Indan-5-yl-2-[4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (9.2 mg, 0.017 mmol) was dissolved in MeOH (1 mL) and ethylamine (1 mL of 1.0 M solution in THF, 1.0 mmol) was added and the reaction mixture was heated at 80° C. After 16 h, the solution was cooled to rt and purified by preparative HPLC (C-18 column, 32 mL/min 5-100% MeCN/H2O gradient over 15 min) and lyophilized to provide 5.2 mg of 8-indan-5-yl-2-[4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethylamide. 1H NMR TFA salt (400 MHz, CDCl3) δ (ppm): 9.38 (br s, 1H), 9.37 (s, 1H), 8.84 (s, 1H), 7.58-7.60 (m, 1H), 7.40-7.47 (m, 2H), 7.16 (dd, 2H, J=2.0 Hz, J=7.9 Hz), 7.05 (br s, 2H), 3.43-3.55 (m, 4H), 3.07 (t, 2H, J=7.3 Hz), 2.99 (t, 2H, J=7.4 Hz), 2.53 (br s, 8H), 2.36 (s, 3H), 2.18-2.27 (m, 2H), 1.15-1.39 (m, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C31H35N7O2: 537.29, Found: 538.3 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:9]1[S:10][C:11](C)=[C:12](C)[N:13]=1.NC1C=CC(N)=CC=1C1SC=C(C2C=CC=CC=2)N=1.NC1C=CC(N)=CC=1C1SC=C(C)N=1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:9]1[S:10][CH:11]=[CH:12][N:13]=1
Reactant: Cc1nc(-c2cc(N)ccc2N)sc1C
Agent: Cc1csc(-c2cc(N)ccc2N)n1
Agent: Nc1ccc(N)c(-c2nc(-c3ccccc3)cs2)c1
Product: Nc1ccc(N)c(-c2nccs2)c1

Procedure:
1,4-diamino-2-(4,5-dimethylthiazol-2-yl)benzene; 1,4-diamino-2-(4-phenylthiazol-2-yl)benzene and 1,4-diamino-2-(4-methylthiazol-2-yl)benzene.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].[Cl-].[Li+].N12CCCN=C1CCCCC2.[Cl:34][C:35]([Cl:39])([Cl:38])[C:36]#[N:37]>C(#N)C>[Cl:34][C:35]([Cl:39])([Cl:38])[C:36](=[NH:37])[O:7][C@H:6]1[O:8][C@@H:9]([CH3:20])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:5]1[O:4][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)OC(O)[C@H]1OC(C)=O
Reactant: N#CC(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](OC(=N)C(Cl)(Cl)Cl)O[C@@H](C)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
A mixture of 2,3,4-tri-O-acetyl-L-fucopyranose (anomer mixture) (0.50 g, 1.72 mmol), lithium chloride (73 mg, 1.72 mmol), 1,8-diazabicyclo-[5.4.0]-undec-7-ene (0.20 ml, 1.34 mmol) and trichloroacetonitrile (2.0 ml, 20 mmol) in 20 ml of dry acetonitrile is stirred under nitrogen and at room temperature for about 12 h. After chromatographic purification (petroleum ether/diethyl ether 2:5), a mixture of O-(2,3,4-tri-O-acetyl-α-L-fucopyranosyl) trichloroacetimidate (3) and O-(2,3,4-tri-O-acetyl-β-L-fucopyranosyl) trichloroacetimidate (2) is obtained in a yield of 92% (α:β=6.5:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH2:9].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:20]([O:23][C:24]1[CH:29]=[C:28]([F:30])[C:27]([F:31])=[C:26](F)[C:25]=1[N+:33]([O-:35])=[O:34])[CH:21]=[CH2:22]>C1COCC1>[CH2:20]([O:23][C:24]1[C:25]([N+:33]([O-:35])=[O:34])=[C:26]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[Cl:1])[C:27]([F:31])=[C:28]([F:30])[CH:29]=1)[CH:21]=[CH2:22]
Reactant: C=CCOc1cc(F)c(F)c(F)c1[N+](=O)[O-]
Reactant: Nc1ccc(I)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCOc1cc(F)c(F)c(Nc2ccc(I)cc2Cl)c1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To solution of 2-chloro-4-iodo-phenylamine (1.09 g, 4.3 mmol) in THF (50 mL) was dropwise added LHMDS solution (5.6 mL, 5.6 mmol, 1 M in THF) at −78° C. After stirring for 1 h at −78° C., a solution of 1-allyloxy-3,4,5-trifluoro-2-nitro-benzene (1.1 g, 4.7 mmol) in THF (10 mL) was added dropwise into the reaction mixture, which was stirred at −78° C. for 1 h and at room temperature for 16 h. The progress of reaction was monitored by 1H NMR. After completion, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried over anhydrous Na2SO4 and concentrated. The residue obtained was re-crystallized in hexane to yield (3-allyloxy-5,6-difluoro-2-nitro-phenyl)-(2-chloro-4-iodo-phenyl)-amine as an orange solid (843 mg). 1H-NMR (400 MHz, CDCl3): δ 4.63 (2H, d, J=5.2), 5.37 (1H, d, J=10.4), 5.46 (1H, d, J=17.2) 5.96-6.00 (1H, m), 6.50-6.54 (1H, m), 6.60-6.65 (1H, m), 7.04 (1H, s), 7.43 (1H, d, J=8), 7.68 (1H, d, J=2).
Reaction SMILES: [OH-].[K+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2([CH2:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])[C:4]1=[O:18].[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.Cl>CS(C)=O.O>[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]3([CH2:15][C:14](=[O:16])[NH:13][C:12]3=[O:17])[C:4]2=[O:18])=[CH:22][CH:21]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: O=C1CC2(C(=O)N1)C(=O)Nc1ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C1CC2(C(=O)N1)C(=O)N(Cc1ccc(Br)cc1)c1ccccc12
Reaction time: 4 h
Yield: 8.4 %

Procedure:
Ethanolic potassium hydroxide (12 ml., 1M) was added to a stirred solution of spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione (1.0 g.) in dimethyl sulphoxide (10 ml.). 4-Bromobenzyl bromide (1.4 g.) was then added to the clear solution which was stirred for 4 hours. This solution was then added to water (100 ml.). The mixture was acidified (concentrated hydrochloric acid). The precipitate was collected, washed with water, air-dried and recrystallised from ethyl acetate/petrol 60-80 to give 1'-(4-bromobenzyl)-spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione (0.15 g.) m.p. 218°-220° C.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:9][CH2:10][CH2:11][S:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:2]1([S:1][CH2:9][CH2:10][CH2:11][S:12][C:13]2[NH:17][N:16]=[N:15][N:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCSc1nnn[nH]1
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc(SCCCSc2nnn[nH]2)cc1
Yield: 73.7 %

Procedure:
Mercaptobenzene (1.3 g) and 5-(3-bromopropyl)thio-1,2,3,4-tetrazole (1.8 g) are dissolved in acetone (50 ml), and thereto is added potassium carbonate (1.4 g), and the mixture is refluxed for 2 hours. After acetone is distilled off, water is added to the residue, and the mixture is extracted with chloroform. The chloroform layer is washed with 5% aqueous sodium hydroxide and saturated aqueous sodium chloride and dried over magnesium sulfate. After chloroform is distilled off, the residue is purified by column chromatography (Wakogel C-200, eluting agent, chloroform) to give 5-(3-phenylthiopropyl)thio-1,2,3,4-tetrazole (1.5 g) as colorless liquid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[NH:20][C:19](=[O:24])[N:18]([CH3:25])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:26]([O:30][CH2:31]Cl)[CH:27]([CH3:29])[CH3:28].O>CN1CCCC1=O>[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[N:20]([CH2:31][O:30][CH2:26][CH:27]([CH3:29])[CH3:28])[C:19](=[O:24])[N:18]([CH3:25])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Reactant: CC(C)COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)COCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O
Reaction time: 1 h

Procedure:
1.9 g (14.08 mmol) of potassium carbonate were added at 60° C. to a suspension of 2.25 g (8.8 mmol) of 7-benzyl-3-methylxanthine (prepared according to Example 1 a) in 50 ml of N-methylpyrrolidone and the mixture was stirred at this temperature for one hour. 1.4 g (11.44 mmol) of isobutoxymethyl chloride were then added dropwise and the mixture was stirred at 80° C. for 3 hours. A further 0.5 g (4.4 mmol) of isobutoxymethyl chloride was then added and the mixture was stirred again for 2 hours. 50 ml of water were then added and the mixture was extracted three times using 60 ml of methyl tert-butyl ether each time. The combined organic phases were washed twice with 30 ml of water each time, dried using magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column, dichloromethane/methanol (19/0.2).
Reaction SMILES: [CH3:1][C:2]([CH3:63])([CH3:62])[C@H:3]([N:48]1[CH2:52][CH2:51][N:50]([CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([CH3:60])[N:55]=2)[C:49]1=[O:61])[C:4]([NH:6][C@@H:7]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@@H:8]([OH:40])[CH2:9][C@@H:10]([NH:24][C:25]([C@@H:27]([NH:32]C(=O)OC(C)(C)C)[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1)=[O:5].Cl>C1COCC1>[NH2:32][C@@H:27]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:25]([NH:24][C@@H:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1)[CH2:9][C@H:8]([OH:40])[C@@H:7]([NH:6][C:4](=[O:5])[C@@H:3]([N:48]1[CH2:52][CH2:51][N:50]([CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([CH3:60])[N:55]=2)[C:49]1=[O:61])[C:2]([CH3:1])([CH3:63])[CH3:62])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:26]
Reactant: Cc1cccc(CN2CCN([C@H](C(=O)N[C@@H](Cc3ccccc3)[C@@H](O)C[C@H](Cc3ccc(-c4ccccn4)cc3)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C(C)(C)C)C2=O)n1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cccc(CN2CCN([C@H](C(=O)N[C@@H](Cc3ccccc3)[C@@H](O)C[C@H](Cc3ccc(-c4ccccn4)cc3)NC(=O)[C@@H](N)C(C)(C)C)C(C)(C)C)C2=O)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 130D (0.024 g, 0.028 mmol) in a mixture of THF (1 mL) and aqueous HCl (0.050 mL, 4 N) was stirred at 25° C. for 16 hours, and concentrated under reduced pressure. The residue was treated with ethanol and concentrated several times to give the title compound as the hydrochloride salt, which was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:34](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[N:7]=1)[CH3:2].C(O)(=O)C>O>[CH2:1]([C:3]1[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]([C:8]([OH:11])([CH3:9])[CH3:10])[N:7]=1)[CH3:2]
Reactant: CCOC(=O)c1c(C(C)(C)O)nc(CC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C(C)(C)O)nc(CC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Yield: 97.2 %

Procedure:
A solution of 1.9 g of ethyl 2-ethyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above] in 28 ml of 75% v/v aqueous acetic acid was stirred at 60° C. for 2 hours. At the end of this time, the reaction mixture was diluted with 7 ml of water and cooled to room temperature. Precipitated trityl alcohol was removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure. The syrupy residue was crystallized in diisopropyl ether, to give 1.21 g of the title compound, melting at 166°-167° C.
Reaction SMILES: [C:1]1([C:7]2[S:11][CH:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([S:20][CH2:21][CH2:22][C:23](Cl)=[O:24])(=[O:19])[CH3:18]>C1(C)C=CC=CC=1>[C:17]([S:20][CH2:21][CH2:22][C:23]([N:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[S:11][CH:10]1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:24])(=[O:19])[CH3:18]
Reactant: CCOC(=O)C1NN=C(c2ccccc2)S1
Reactant: CC(=O)SCCC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C1SC(c2ccccc2)=NN1C(=O)CCSC(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.6 %

Procedure:
A solution of the product of step (a) (2.36g) in toluene (100ml) was treated with polyvinylpyridine (2.0g) and 3-acetylthiopropanoyl chloride (1.7g) and the mixture stirred at room temperature for 4 hours. The mixture was filtered and the filtrate stirred with a saturated solution of sodium bicarbonate (100ml) for 1 hour. The organic phase was separated, washed with water, dried and evaporated to a gum. The residue was purified by flash chromatography to give the sub-title product (2.62g) as an oil.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[C:28]1[O:32][CH:31]=[N:30][CH:29]=1)[C:22](O)=[O:23]>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:27]([C:28]3[O:32][CH:31]=[N:30][CH:29]=3)=[C:19]([F:18])[CH:20]=2)[CH2:2][CH2:3]1
Reactant: Cc1cnc(N2CCC(NC3CC3)CC2)cn1
Reactant: O=C(O)c1ccc(-c2cnco2)c(F)c1
Product: Cc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)c(F)c3)C3CC3)CC2)cn1

Procedure:
The title compound is prepared from cyclopropyl-[1-(5-methyl-pyrazin-2-yl)-piperidin-4-yl]-amine and 3-fluoro-4-oxazol-5-yl-benzoic acid following a procedure analogous to that described in Example 17. LC (method 1): tR=1.20 min; Mass spectrum (ESI+): m/z=422 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14]Cl)=[CH:7][CH:6]=1)[CH3:2].[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][N:21]2[C:17](=[O:27])[C:18]3[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:20]2=[O:22])=[CH:7][CH:6]=1)[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOC(=O)c1ccc(OCCCCl)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 135 °C
Yield: 56 %

Procedure:
To a stirred solution of 22.5 g (0.092 mole) of 4-(3-chloropropoxy)benzoic acid ethyl ester in 150 mL of dimethylformamide was added 17.6 g (0.093 mole) of potassium phthalimide (98%, Aldrich) and the mixture was heated (135° C.) under a nitrogen atmosphere for 8 hr. The solvent was evaporated under reduced pressure to leave a semi-solid residue. The residue was triturated with 100 mL of water and the resulting solid was collected by filtration. The solid was recrystallized from isopropyl alcohol to yield 18.2 g (55%) of title compound as an off-white solid, mp 106°-108° C.