Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([SH:22])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[Br:23][CH2:24][CH2:25]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[BrH:23].[CH3:21][S:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:12]3[C:11]([S:22][CH2:24][CH2:25]3)=[N:10][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=2)=[CH:15][CH:16]=1
Reactant: CSc1ccc(-c2nc(S)[nH]c2-c2ccc(SC)cc2)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Br
Product: CSc1ccc(-c2nc3n(c2-c2ccc(SC)cc2)CCS3)cc1
Temperature: 0 °C

Procedure:
A mixture of 19.5 g. (0.06 mole) of 4,5-bis-(p-methylthiophenyl)-2-mercaptoimidazole, 10.7 g. (0.06 mole) of 1,2-dibromoethane and 7.9 g. (0.06 mole) of potassium carbonate in dimethylformamide (250 ml.) was refluxed for 3 hours. The mixture was then poured into 1 liter of ice-water and the yellow precipitate collected and washed with water. This material was then dissolved in chloroform, dried over magnesium sulfate, filtered and the solvent removed at reduced pressure. The residue was then treated with chloroform-ether and the white crystals of 5,6-bis(p-methylthiophenyl)-2,3-dihydroimidazo[2,1-b]thiazole collected. This was then dissolved in methanol and treated with aqueous hydrobromic acid. Filtering and recrystallizing from methanol gave 5,6-bis(p-methylthiophenyl)-2,3-dihydroimidazo[2,1-b]thiazole hydrobromide, m.p. 270° C.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[NH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.Cl.CN(C)CCCN=C=NCC.[Cl:33][C:34]1[CH:55]=[CH:54][C:37]([O:38][C:39]2[C:48]3[C:43](=[CH:44][C:45]([O:52][CH3:53])=[C:46]([C:49](O)=[O:50])[CH:47]=3)[N:42]=[CH:41][CH:40]=2)=[C:36]([F:56])[CH:35]=1>CN(C=O)C.O.C(N(CC)CC)C>[Cl:33][C:34]1[CH:55]=[CH:54][C:37]([O:38][C:39]2[C:48]3[C:43](=[CH:44][C:45]([O:52][CH3:53])=[C:46]([C:49]([NH:11][CH2:12][CH2:13][CH2:14][N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[O:50])[CH:47]=3)[N:42]=[CH:41][CH:40]=2)=[C:36]([F:56])[CH:35]=1
Reactant: NCCCN1CCOCC1
Reactant: COc1cc2nccc(Oc3ccc(Cl)cc3F)c2cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(Cl)cc3F)c2cc1C(=O)NCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-Hydroxybenzotriazole (0.104 g), triethylamine (0.095 ml), N-(3-aminopropyl)morpholine (0.11 ml) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.142 g) were added in turn to a stirred mixture of 4-(4-chloro-2-fluorophenoxy)-7-methoxyquinoline-6-carboxylic acid (0.2 g) in DMF (5 ml). The reaction mixture was stirred at ambient temperature for 16 hours. Water (20 ml) was added and the resultant suspension was transferred onto a C18 reversed-phase silica gel chromatography column and eluted with a decreasingly polar solvent gradient of water and acetonitrile. There was thus obtained the title compound (0.175 g); NMR Spectrum: (DMSOd6) 1.72 (m, 2H), 2.38 (m, 6H), 3.35 (m, 2H), 3.56 (m, 4H), 4.01 (s, 3H), 6.56 (d, 1H), 7.42-7.59 (m, 3H), 7.76 (m, 1H), 8.38 (m, 1H), 8.51 (s, 1H), 8.68 (d, 1H); Mass Spectrum: M+H+ 474 & 476.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[CH:5]=[C:4]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH3:22][CH:23]1[CH:27]([CH3:28])OS(=O)(=O)[N:24]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].O>CN(C=O)C.CCOC(C)=O>[C:34]([O:33][C:31]([NH:24][CH:23]([CH3:22])[CH:27]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[CH:5]=[C:4]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:28])=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2c1
Reactant: CC1OS(=O)(=O)N(C(=O)OC(C)(C)C)C1C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(C(C)C(C)NC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred suspension of 60% NaH dispersion in mineral oil (596 mg, 14.9 mmol) in DMF (14 mL) at 0° C. is added a solution of diethyl 1H-indole-2,6-dicarboxylate (Intermediate A, 3.9 g, 14.9 mmol) in DMF (14 mL). The mixture is stirred for 40 min, then a solution of tert-butyl 4,5-dimethyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (3.8 g, 14.9 mmol) in DMF (7 mL) is added. The reaction mixture is stirred for 30 min at 0° C. and then is warmed to room temperature and stirred for 65 h. Water is added and the mixture is stirred for 15 min before EtOAc (50 mL) is added. Then the organic layer is separated, washed with aqueous NH4Cl solution, water, and brine, dried (MgSO4) and concentrated to afford the crude title compound, which was used directly in the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=O.[C:11](#[N:14])[CH:12]=C.C(C(CCCC)CN(CC(CC)CCCC)CC(CC)CCCC)C>C(#N)CC.[Pd+2]>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH:5]=[CH:12][C:11]#[N:14]
Reactant: C=CC#N
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: [Pd+2]
Agent: CCCCC(CC)CN(CC(CC)CCCC)CC(CC)CCCC
Solvent: CCC#N
Product: N#CC=Cc1cccc(Br)c1
Yield: 9.9 %

Procedure:
The procedure described in Example 1 is repeated, except that 21.94 g (0.1 mol) of 3-bromobenzoyl chloride, 6.63 g (0.125 mol) of acrylonitrile, 35.37 g (0.1 mol) of tris-(2-ethylhexyl)-amine and 0.3046 g (0.001 mol) of bis-acetylacetonato)-palladium(II) in 50 ml of propionitrile are used. After a reaction time of 3 hours at 100° C., 2.05 g (0.0099 mol) of 3-bromocinnamonitrile are obtained, corresponding to a yield of 9.9% of theory; melting point 62° C. Analysis for C9H6NBr (molecular weight 208): calculated C 51.96%, H 2.91%, N 6.73%; found C 52.29%, H 2.95%, N 6.91%.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[F:25])=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].[C:26]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH2:1]([C:4]1[C:13]([O:14][CH3:26])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[F:25])=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)c(OC)cc2ncnc(Nc3ccc(Br)cc3F)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: C=CCc1c(OC)c(OC)cc2ncnc(Nc3ccc(Br)cc3F)c12
Temperature: 90 °C
Reaction time: 4.5 h

Procedure:
To a solution of 5-allyl-4-(4-bromo-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-ol (0.34 g, 0.84 mmol) (from Example 19, Step D, supra) in acetone (100 mL) was added K2CO3 (0.35 g, 2.52 mmol) and methyl iodide (1.19 g, 8.41 mmol) (Aldrich). The reaction mixture was heated with stirring at 90° C. for 4.5 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:4:0.01) as eluent to give the desired (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-(4-bromo-2-fluoro-phenyl)-amine as a yellow solid. (Yield 0.33 g, 94%).
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=[N:34][O:35][CH3:36])[C:9]([NH:11][C@@H:12]2[C:32](=[O:33])[N:14]3[C:15]([C:29]([O-:31])=[O:30])=[C:16]([CH2:19][N+:20]4[N:21]([CH3:28])[C:22]([NH:25]C=O)=[CH:23][CH:24]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[N:7]=1.C(OCC)C>CO>[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=[N:34][O:35][CH3:36])[C:9]([NH:11][C@@H:12]2[C:32](=[O:33])[N:14]3[C:15]([C:29]([O-:31])=[O:30])=[C:16]([CH2:19][N+:20]4[N:21]([CH3:28])[C:22]([NH2:25])=[CH:23][CH:24]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[N:7]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc(NC=O)n3C)CS[C@H]12)c1csc(N)n1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc(N)n3C)CS[C@H]12)c1csc(N)n1
Reaction time: 3 h

Procedure:
Concentrated hydrochloric acid (0.136 ml) was added to a suspension of 7β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(3-formamido-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (syn isomer) (0.2 g) in methanol (1 ml) at ambient temperature. After being stirred at the same temperature for 3 hours, the mixture was added dropwise to diethyl ether (100 ml), and the precipitate was collected by filtration. The precipitate was dissolved in water and subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20". The desired product was eluted with water, and lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(3-amino-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate.trihydrochloride (syn isomer) (71.20 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([N:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22](=[O:25])[CH2:23][CH3:24])[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH2:6][CH2:5]1.[H][H]>[Ni].CO>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][N:7]2[CH2:6][CH2:5][C:4]([N:21]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:22](=[O:25])[CH2:23][CH3:24])([CH2:3][O:2][CH3:1])[CH2:9][CH2:8]2)=[CH:13][CH:14]=1
Reactant: CCC(=O)N(c1ccccc1)C1(COC)CCN(CCc2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CCC(=O)N(c1ccccc1)C1(COC)CCN(CCc2ccc(N)cc2)CC1

Procedure:
A mixture of 14.8 parts of N-{4-(methoxymethyl)-1-[2-(4-nitrophenyl)ethyl]-4-piperidinyl}-N-phenylpropanamide and 200 parts of methanol is hydrogenated at normal pressure and at room temperature with 3 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is triturated in petroleumether. The product is filtered off and crystallized from a small amount of 2,2'-oxybispropane. It is filtered off and dried, yielding 8.23 parts of N-{1-[2-(4-aminophenyl)ethyl]-4-(methoxymethyl)-4-piperidinyl}-N-phenylpropanamide; mp. 106.2° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:18])[CH:15]([CH3:17])[CH3:16])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[OH:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][C:31]=1[O:39][CH3:40]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:18][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][C:30]([O:29][CH2:28][CH2:27][CH2:26][OH:25])=[C:31]([O:39][CH3:40])[CH:32]=2)[CH:15]([CH3:17])[CH3:16])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](N)C(C)C)c2c1N
Reactant: COc1cc(C(=O)O)ccc1OCCCO
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](NC(=O)c3ccc(OCCCO)c(OC)c3)C(C)C)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-amino-3-methylbutoxy)-2-methylquinoline-3-carboxylate (Example 95b) and 4-(3-hydroxypropoxy)-3-methoxybenzoic acid (Baraldi, P. G. et al. J. Med. Chem. 1999, 42, 5131.) as brown solid (29%). MS 540 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:20]([OH:23])(=[O:22])=[O:21])[CH:5]=[C:6]2[C:11]=1[C:10]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9][C:8]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:7]2.C1C(N=NC2C(=O)N(C3C=CC(S([O-])(=O)=O)=CC=3)N=C2C([O-])=O)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[N+:64]([C:67]1[CH:72]=[C:71]([CH3:73])[C:70]([S:74](Cl)(=[O:76])=[O:75])=[CH:69][CH:68]=1)([O-:66])=[O:65]>O>[N+:64]([C:67]1[CH:72]=[C:71]([CH3:73])[C:70]([S:74]([NH:1][C:2]2[CH:3]=[C:4]([S:20]([OH:23])(=[O:22])=[O:21])[CH:5]=[C:6]3[C:11]=2[C:10]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9][C:8]([S:16]([OH:19])(=[O:17])=[O:18])=[CH:7]3)(=[O:76])=[O:75])=[CH:69][CH:68]=1)([O-:66])=[O:65]
Reactant: Cc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Reactant: Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c12
Agent: O=C([O-])C1=NN(c2ccc(S(=O)(=O)[O-])cc2)C(=O)C1N=Nc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1S(=O)(=O)Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 841.4 %

Procedure:
A mixture of 17.0 g of 8-amino-1,3,6-naphthalenetrisulfonic acid, trisodium salt, 17.5 g of the preceding compound and 7.8 g of anhydrous sodium carbonate in 210 ml of water is stirred at room temperature for 18 hours, then an additional 0.5 g of sodium carbonate and 1.0 g of 5-nitro-o-toluenesulfonyl chloride is added and stirring is continued for 18 hours longer. The reaction mixture is evaporated and 100 ml of water is added with stirring. The mixture is filtered and 900 ml of absolute ethanol is added to the filtrate with stirring. The mixture is stirred for 2 hours, then the precipitate is collected and is washed with ethanol and ether and is dried to yield 20.8 g of 8-(5-nitro-o-toluenesulfonamido)-1,3,6-naphthalenetrisulfonic acid, trisodium salt.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][NH:14][C:15](=O)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[O:23][C:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)=[CH:25][N:26]=3)[CH:17]=2)=O)=[CH:6][CH:5]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:38].O>O1CCOCC1>[CH3:1][O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[S:38][C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[O:23][C:24]([C:27]5[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=5)=[CH:25][N:26]=4)[CH:17]=3)=[N:14][N:13]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CC(=O)NNC(=O)c2cccc(-c3ncc(-c4ccc(OC)cc4)o3)c2)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Cc2nnc(-c3cccc(-c4ncc(-c5ccc(OC)cc5)o4)c3)s2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To a suspension of 0.25 g (0.51 mmol) 4-[2-(N′-{3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-benzoyl}-hydrazino)-2-oxo-ethyl]-benzoic acid methyl ester from Preparation 8 in 10 mL dry dioxane was added P2S5 in one portion. The resulting mixture was warmed to 50° C. for 1 hour before cooling to room temperature and adding about 20 mL water. Stirred 2 hours and then filtered off solid product. Triturated in hot MeOH and filtered. Dissolved in THF and filtered through a plug of flash silica gel with THF eluent. Concentration gave 0.18 g (73%) desired product. Used directly in the procedure of Example B3 without characterization.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH:18]([C:21]1[CH:22]=[CH:23][C:24]([CH3:28])=[C:25]([CH:27]=1)[NH2:26])([CH3:20])[CH3:19].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:26][C:25]2[CH:27]=[C:21]([CH:18]([CH3:19])[CH3:20])[CH:22]=[CH:23][C:24]=2[CH3:28])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Cc1ccc(C(C)C)cc1N
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)CC2
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(C)C)cc1Nc1nc(Cl)nc2c1CCC2c1ccccc1
Reaction time: 2 h
Yield: 30.9 %

Procedure:
To a solution of 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (500 mg, 1.886 mmol) in NMP (Volume: 7543 n1) was added 5-isopropyl-2-methylaniline (281 mg, 1.886 mmol) and DIPEA (329 μl, 1.886 mmol). The resulting mixture was brought to 120° C. and stirred for 2 h. The mixture was then diluted with EtOAc (25 mL), washed with water (2×10 mL), brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash chromatography (Silica, Thomson 40 g, 0-35% EtOAc/Hexanes) gave 2-chloro-N-(5-isopropyl-2-methylphenyl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (81421-078-01) (220 mg, 0.582 mmol, 30.9% yield). LC-MS (M+H)+=378.1. 1H NMR (500 MHz, MeOD) δ ppm 7.30-7.41 (3H, m), 7.19-7.26 (3H, m), 7.16 (2H, d, J=7.93 Hz), 7.11 (1H, d, J=7.63 Hz), 4.27 (1H, t, J=7.63 Hz), 2.91 (1H, ddd, J=13.89, 6.87, 6.71 Hz), 2.77-2.86 (1H, m), 2.61-2.76 (2H, m), 2.24 (3H, s), 2.03-2.13 (1H, m), 1.27 (5H, dd, J=7.02, 1.53 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[NH2:9][C:10]1[S:11][C:12]([C:20]([F:23])([F:22])[F:21])=[CH:13][C:14]=1[C:15](OCC)=O.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:15]1[C:14]2[CH:13]=[C:12]([C:20]([F:21])([F:22])[F:23])[S:11][C:10]=2[N:9]=[C:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[N:2]=1
Reactant: CCOC(=O)c1cc(C(F)(F)F)sc1N
Reactant: N#Cc1ccncc1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cc2c(Cl)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 477, the reaction of 4-cyanopyridine and 2-amino-5-trifluoromethyl-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(pyridin-4-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]2)C=CC=CC=1.O[C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[C:32]([CH3:39])[CH:31]=1>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:16][C:30]2[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[C:32]([CH3:39])[CH:31]=2)[N:10]=[CH:9]1
Reactant: CC(=O)c1ccc(O)cc1C
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: CC(=O)c1ccc(OCCCc2c[nH]cn2)cc1C

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 6 mmol of (4-hydroxy-2-methylphenyl)ethanone are treated as described in Example 56, but isolated in the form of the free base.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]=[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])[N:9]=2)[CH2:4]1.C1COCC1.C(N(CC)CC)C.Cl[C:39]([O:41][CH2:42][CH:43]([CH3:45])[CH3:44])=[O:40]>C(Cl)Cl>[OH:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:10]1[N:9]=[C:8]([N:5]2[CH2:6][CH2:7][C@@H:3]([CH2:2][NH:1][C:39](=[O:40])[O:41][CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:4]2)[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[N:11]=1
Reactant: Cc1ccc2c(N3CC[C@@H](CN)C3)nc(-c3ccccc3O)nc2c1
Reactant: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CC[C@@H](CNC(=O)OCC(C)C)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
A mixture of 2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (200 mg, 0.6 mmol), THF (6.0 mL), and CH2Cl2 was stirred under an N2 atmosphere. Triethylamine (0.166 mL, 1.2 mmol) was added, and the reaction was cooled in an ice bath. To this was added 1 M isobutyl chloroformate solution (78 μL in 600 μL THF, 0.6 mmol). After allowing the reaction mixture to warm to room temperature, CH2Cl2 was added, and the organic solution washed twice with water, then dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 0-20% EtOAc in CH2Cl2/hexanes (1:1) gave isobutyl ((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate (183 mg, 70%). LC/MS: m/z 435.5 (M+H)+ at 2.63 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). LC/MS: m/z 435 (M+H)+ at 2.63 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.43 (dd, J=8.2, 1.8 Hz, 1H), 8.22 (d, J=8.7 Hz, 1H), 7.58 (s, 1H), 7.42-7.31 (m, 3H), 6.93-6.89 (m, 2H), 4.17-3.91 (m, 3H), 3.80-3.69 (m, 3H), 3.34-3.30 (m, 1H), 3.21-3.07 (m, 2H), 2.49 (s, 3H), 2.16-2.08 (m, 1H), 1.88-1.74 (m, 2H), 0.88 (d, J=6.7 Hz, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Si:11]([O:18][CH2:19][CH2:20][CH2:21][CH2:22]O)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O>O1CCCC1>[Si:11]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][O:10][C:3]1[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6])([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:12])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OCCCCO
Reactant: O=Cc1cccc(Cl)c1O
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCOc1c(Cl)cccc1C=O
Reaction time: 0.33 h
Yield: 24.8 %

Procedure:
To 3-chloro-2-hydroxybenzaldehyde (313 mg, 2 mmol) in tetrahydrofuran (4 mL) was added 4-(tert-butyldimethylsilyloxy)butan-1-ol (409 mg, 2 mmol), triphenylphosphine (524 mg, 2 mmol), and (E)-di-tert-butyl diazene-1,2-dicarboxylate (460 mg, 2 mmol). The mixture was stirred for 20 minutes and was purified by silica gel column chromatography eluting with hexanes and ethyl acetate (4:1) to afford the titled compound (170 mg; 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:10](=[CH:18][N:19]([CH3:22])[C:20]=2[CH3:21])[N:11]([CH3:17])[C:12](=[O:16])[CH:13](O)[N:14]=1.S(Cl)(Cl)=O.Cl.[CH2:28]([O:30][C:31](=[O:36])[CH2:32][CH2:33][CH2:34][NH2:35])[CH3:29]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:10](=[CH:18][N:19]([CH3:22])[C:20]=2[CH3:21])[N:11]([CH3:17])[C:12](=[O:16])[CH:13]([NH:35][CH2:34][CH2:33][CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:36])[N:14]=1
Reactant: Cc1c2c(cn1C)N(C)C(=O)C(O)N=C2c1ccccc1Cl
Reactant: CCOC(=O)CCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCCNC1N=C(c2ccccc2Cl)c2c(cn(C)c2C)N(C)C1=O
Reaction time: 24 h
Yield: 70.3 %

Procedure:
A mixture of 5-(2-chlorophenyl)-1,7-dihydro-3-hydroxy-1,6,7-trimethyl-pyrrolo[3,4-e][1,4]diazepin-2(3H)-one (6.3 g, 0.0198 mole) and thionyl chloride (18 mole) is allowed to stand at room temperature for one night. The 3-chloro derivative which forms is precipitated by the addition of ethyl ether, recovered by filtration and washed on filter with ethyl ether. The obtained intermediate is dissolved in chloroform (100 ml) and triethylamine (8 g) and γ-aminobutyric acid ethyl ester hydrochloride (6.4 g, 0.0382 mole) are gradually added to the obtained solution. The reaction mixture is allowed to stand, at room temperature for one day, then chloroform is evaporated, the residue is taken up with water acidified with HCl and the undissolved oil is extracted with chloroform. The chloroform solution is neutralized by washing with aqueous NaHCO3, dried over Na2SO4, filtered and concentrated to dryness yielding 6 g of an oily residue.
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]2[CH:7]=[C:8]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:10][CH:11]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:21]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>CN(C)C=O>[C:21]([C:25]1[CH:26]=[CH:27][C:28]([CH2:29][N:4]([CH2:5][C:6]2[CH:7]=[C:8]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:10][CH:11]=2)[CH:1]2[CH2:2][CH2:3]2)=[CH:31][CH:32]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CC(=O)c1cccc(CNC2CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cccc(CN(Cc2ccc(C(C)(C)C)cc2)C2CC2)c1
Temperature: 25 °C
Yield: 39.5 %

Procedure:
3′-(N-cyclopropylaminomethyl)acetophenone (0.30 g; 1.59 mmol) and potassium carbonate (0.31 g; 2.27 mmol) were added to N,N-dimethylformamide (15 ml). While the mixture was stirred at room temperature, 4-tert-butylbenzyl bromide (0.29 g; 1.51 mmol) in N,N-dimethylformamide (5 ml) was added dropwise. The mixture was stirred for 1 hour at room temperature, and the reaction was stopped by pouring the mixture into ice+saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=15:1), to thereby yield 0.20 g of the target compound as colorless transparent oily matter (yield: 39.5%).