Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[CH2:12][C:13]([OH:15])=[O:14]>O.N.O>[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([CH2:12][C:13]([OH:15])=[O:14])=[C:3]([S:2][CH3:1])[CH:8]=1
Reactant: CSc1cc([N+](=O)[O-])ccc1CC(=O)O
Agent: N
Solvent: O
Product: CSc1cc(N)ccc1CC(=O)O
Reaction time: 8 h

Procedure:
A solution of [2-(methylsulfanyl)-4-nitrophenyl]acetic acid (230 mg, 1.0 mmol) in 10 mL of water and 0.6 mL of NH3.H2O was added a solution of FeSO4.7H2O (2.25 g, 8.1 mmol) in 10 mL of water and another 1.6 mL of NH3.H2O were added dropwise. The mixture was stirred at 60˜80° C. overnight. The mixture was filtered and the filtrate was acidified to pH 4˜5 with HOAc. Extracted with EtOAc and the combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to afford [4-amino-2-(methylsulfanyl)phenyl]acetic acid.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[CH:7][CH:8]=2)[N:3]=1.[C:17]([O:21][C:22](=[O:28])[NH:23][CH2:24][CH2:25][CH2:26][NH2:27])([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:17]([O:21][C:22]([NH:23][CH2:24][CH2:25][CH2:26][NH:27][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[CH:7][CH:8]=2)[N:3]=1)=[O:28])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: COc1ccc2cc(C(=O)O)c(Cl)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc2cc(C(=O)O)c(NCCCNC(=O)OC(C)(C)C)nc2c1
Temperature: 100 °C

Procedure:
A suspension of 2-Chloro-7-methoxy-quinoline-3-carboxylic acid (60 mg, 0.22 mmol), (3-Amino-propyl)-carbamic acid tert-butyl ester (77 mg, 0.44 mmol), Potassium carbonate (73 mg, 0.46 mmol), and Molecular sieve-4A (300 mg) in dry DMSO (4 ml) was heated at 100° C. for over night. The reaction mixture was purified by chromatography on SCX column using MeOH as eluent and 2-(3-tert-Butoxycarbonylamino-propylamino)-7-methoxy-quinoline-3-carboxylic acid was obtained as white solid after recrystallization from CH2Cl2 and Hexane; 70 mg (85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[N:7]=[C:8]([C:10]3[CH:17]=CC(NC)=C[CH:11]=3)[O:9][C:5]=2[CH:4]=1.BrC1C=[N:23][C:24]([NH:27][CH3:28])=[N:25]C=1>>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[N:7]=[C:8]([C:10]3[CH:11]=[N:23][C:24]([NH:27][CH3:28])=[N:25][CH:17]=3)[O:9][C:5]=2[CH:4]=1
Reactant: CNc1ncc(Br)cn1
Reactant: CNc1ccc(-c2nc3ccc(OC)cc3o2)cc1
Product: CNc1ncc(-c2nc3ccc(OC)cc3o2)cn1

Procedure:
The title compound was synthesised according to the procedure described for 4-(6-methoxy-1,3-benzoxazol-2-yl)-N-methylaniline starting from 5-bromo-N-methylpyrimidin-2-amine. 1H NMR δ ppm 8.84-9.02 (m, 2H) 7.95 (d, 1H) 7.61 (d, 1H) 7.37 (d, 1H) 6.97 (dd, 1 H) 3.83 (s, 3H) 2.89 (d, 3H); ES-MS m/z 257 (M+H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.CCN(CC)CC.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1>C(Cl)Cl.CCOC(C)=O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[C:22]([CH:19]1[CH2:21][CH2:20]1)=[O:23]
Reactant: O=C(Cl)C1CC1
Reactant: CNc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)C1CC1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of N-methyl-4-nitroaniline (2 g, 13.1 mmol) in DCM (30 mL) was added Et3N (2.75 mL, 20 mmol) and cyclopropanecarbonyl chloride (1.32 mL, 14.4 mmol) at room temperature, after stirring for 1 h at room temperature, the mixture was diluted with EtOAc, the organics was washed with Sat. NaHCO3, brine, dried and concentrated to give N-methyl-N-(4-nitrophenyl)cyclopropanecarboxamide as crude product (3 g).
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[Cl:29])[C:23](Cl)=[O:24]>>[NH2:17][C:11]1[N:10]=[C:9]([NH2:18])[C:8]2[C:13](=[CH:14][CH:15]=[CH:16][C:7]=2[N:1]2[CH2:6][CH2:5][N:4]([C:23]([C:22]3[CH:26]=[CH:27][C:28]([Cl:29])=[C:20]([Cl:19])[CH:21]=3)=[O:24])[CH2:3][CH2:2]2)[N:12]=1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Product: Nc1nc(N)c2c(N3CCN(C(=O)c4ccc(Cl)c(Cl)c4)CC3)cccc2n1
Yield: 63 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 3,4-Dichlorobenzoyl chloride (85.9 mg; 0.41 mmol) to obtain 52.5 mg. (63% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.77 (br s, 1H), 7.75 (m, 2H), 7.47 (m, 1H), 7.4 (t, J=8.0 Hz, 1H), 7.18 (br s, 1H), 6.98 (dd, J=8.4, 0.8 Hz, 1H), 6.85 (dd, J=7.6, 0.8 Hz, 1H), 5.93 (s, 2H), 4.55 (br s, 1H), 3.61 (br s, 1H), 3.45 (br s, 1H), 3.14 (m, 3H), 2.79 (m, 2H). ESIMS+419.3 m/z
Reaction SMILES: [NH2:1][C:2](=[N:36][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH2:32][CH2:33][OH:34])[C:24]=2[F:35])[C:11]2[NH:15][C:14](=[O:16])[N:13]([C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:12]=2)=[CH:5][CH:4]=1.C(=O)([O-])O.[K+].[F:50][C@H:51]1[CH2:56][CH2:55][CH2:54][CH2:53][C@@H:52]1[O:57][C:58](=[O:63])[O:59][CH:60](Cl)[CH3:61].[I-].[Na+]>CN(C=O)C>[F:50][C@H:51]1[CH2:56][CH2:55][CH2:54][CH2:53][C@@H:52]1[O:57][C:58](=[O:63])[O:59][CH:60]([O:16][C:14]1[N:13]([C:17]2[N:18]=[CH:19][CH:20]=[CH:21][N:22]=2)[N:12]=[C:11]([C@H:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([C:2]([NH2:1])=[N:36][C:37](=[O:44])[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:4][CH:5]=2)[C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH2:32][CH2:33][OH:34])[C:24]=2[F:35])[N:15]=1)[CH3:61]
Reactant: CC(Cl)OC(=O)O[C@H]1CCCC[C@@H]1F
Reactant: COc1cc(OCCO)c(F)c([C@@H](Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OCCO)c(F)c([C@@H](Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nc(OC(C)OC(=O)O[C@H]3CCCC[C@@H]3F)n(-c3ncccn3)n2)c1
Temperature: 55 °C
Reaction time: 24 h
Yield: 41.8 %

Procedure:
To a mixture of N-[1-amino-1-(4-{[(R)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]amino}phenyl)methylidene]benzamide (200 mg) and DMF (3 mL), potassium hydrogen carbonate (200 mg), carbonic acid 1-chloroethyl ester (1S,2S)-2-fluorocyclohexyl ester (200 mg), and sodium iodide (100 mg) were sequentially added, and the resulting mixture was stirred at 55° C. for 24 hours. The reaction mixture was crudely purified by NAM silica gel column chromatography (mixed solvent of ethyl acetate-methanol) to obtain the captioned compound (110 mg) as a crudely purified product.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:9]1)=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:34])([CH3:35])[CH3:33])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 100 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 53a (0.4 g, 0.8 mmol) was reacted trifluoroacetic acid in dichloromethane at room temperature to give rac-(2S,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.5 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:12]([NH:15][CH2:16][C:17]1[N:21]([CH2:22][CH2:23][CH3:24])[C:20]2[CH:25]=[CH:26][C:27]([CH2:29][O:30][Si:31]([CH3:37])([CH3:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][C:19]=2[N:18]=1)[CH2:13][CH3:14]>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([N:15]([CH2:12][CH2:13][CH3:14])[CH2:16][C:17]1[N:21]([CH2:22][CH2:23][CH3:24])[C:20]2[CH:25]=[CH:26][C:27]([CH2:29][O:30][Si:31]([CH3:36])([CH3:37])[C:32]([CH3:34])([CH3:33])[CH3:35])=[CH:28][C:19]=2[N:18]=1)=[O:5]
Reactant: CCCNCc1nc2cc(CO[Si](C)(C)C(C)(C)C)ccc2n1CCC
Reactant: O=C(Cl)c1cc(F)ccc1F
Solvent: ClCCl
Product: CCCN(Cc1nc2cc(CO[Si](C)(C)C(C)(C)C)ccc2n1CCC)C(=O)c1cc(F)ccc1F
Yield: 74 %

Procedure:
2,5-difluorobenzoylchloride 1.5 eq is treated with 1.0 eq 1.25 g (3.3 mmole) of propyl({1-propyl-5-[(1,1,2,2-tetramethyl-1-silapropoxy)methyl]benzimidazol-2-yl}methyl) amine in dichloromethane at room temperature for 1 hr. The reaction is quenched with 1 N NaOH and partitioned between dichloromethane and water. The organic layer is dried over anhydrous Na2SO4 and the solvent removed in vacuo. The residue is chromatographed (SiO2) with ethyl acetate to afford 74% of (2,5-difluorophenyl)-N-propyl-N-({1-propyl-5-[(1,1,2,2-tetramethyl-1-silapropoxy)methyl]benzimidazol-2-yl}methyl)carboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([NH2:13])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:14]([CH:17]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:18](OC)=[O:19])(=O)[CH3:15]>CC1C=CC=CC=1C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]3[N:13]=[C:14]([CH3:15])[C:17]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:18]([OH:19])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(-c2cccc(Br)c2)n[nH]1
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Solvent: Cc1ccccc1C
Product: COC(=O)Cc1c(C)nc2cc(-c3cccc(Br)c3)nn2c1O
Temperature: 135 °C
Yield: 93.6 %

Procedure:
A 3-lit three neck flask was fitted with a mechanical stirrer and a heating mantle. A suspension of 3-(3-bromophenyl)-1H-pyrazol-5-amine (84.9 g, 357 mmol), dimethyl 2-acetylsuccinate (73.8 g, 392 mmol) and tosic acid monohydrate (1.357 g, 7.13 mmol) in o-xylene (1500 mL) was heated to refluxed (135° C. measured internal temp) for 3.5 h. The heating was turned off, the reaction was diluted with hexanes (1000 mL) and was allowed to cool slowly overnight. The solids were collected by filtration. The filter cake was washed with hexanes and dried under vacuum overnight to afford methyl 2-(2-(3-bromophenyl)-7-hydroxy-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (132.21 g, 334 mmol, 94% yield) as a white powdery solid. 1H NMR (500 MHz, DMSO-d6) δ: 12.47 (s, 1H), 8.18 (t, J=1.7 Hz, 1H), 8.02 (dt, J=7.1, 1.3 Hz, 1H), 7.65-7.60 (m, 1H), 7.45 (t, J=7.9 Hz, 1H), 6.69 (s, 1H), 3.63 (s, 3H), 3.58 (s, 2H), 2.34 (s, 3H). LCMS (M+H)=376.4.
Reaction SMILES: [CH2:1]1[C:11]2[C:5]([C:6]([C:16](O)=[O:17])=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=[CH:9][CH:10]=2)=[CH:4][CH:3]=[CH:2]1.[NH2:19][C@H:20]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:21]1>>[C:27]1([CH2:26][CH2:25][N:22]2[CH2:23][CH2:24][C@H:20]([NH:19][C:16]([C:6]3[C:5]4=[CH:4][CH:3]=[CH:2][CH2:1][C:11]4=[CH:10][CH:9]=[C:8]4[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=34)=[O:17])[CH2:21]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Reactant: O=C(O)C1=c2ccccc2=CC=C2CC=CC=C21
Product: O=C(N[C@H]1CCN(CCc2ccccc2)C1)C1=c2ccccc2=CC=C2CC=CC=C21

Procedure:
Dibenzo[a,d]cycloheptene-5-carboxylic acid and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)dibenzo[a,d]cycloheptene-5-carboxamide.
Reaction SMILES: [CH3:1][C:2]([O:24][Si:25]([CH3:28])([CH3:27])[CH3:26])([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:3][CH2:4]S(C1N(C2C=CC=CC=2)N=NN=1)(=O)=O.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[CH:39]([C@H:41]1[C@H:45]([CH3:46])[O:44][C:43](=[O:47])[N:42]1[CH2:48][CH2:49][S:50][C:51]1[S:52][CH:53]=[C:54]([C:56]([O:58][CH2:59][CH2:60][CH2:61][CH3:62])=[O:57])[N:55]=1)=O.C(=O)(O)[O-].[Na+]>C(COC)OC>[CH3:46][C@@H:45]1[O:44][C:43](=[O:47])[N:42]([CH2:48][CH2:49][S:50][C:51]2[S:52][CH:53]=[C:54]([C:56]([O:58][CH2:59][CH2:60][CH2:61][CH3:62])=[O:57])[N:55]=2)[C@H:41]1/[CH:39]=[CH:4]/[CH2:3][C:2]([CH3:1])([O:24][Si:25]([CH3:27])([CH3:26])[CH3:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCC(C)(CCS(=O)(=O)c1nnnn1-c1ccccc1)O[Si](C)(C)C
Reactant: CCCCOC(=O)c1csc(SCCN2C(=O)O[C@@H](C)[C@@H]2C=O)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [K+]
Solvent: COCCOC
Product: CCCCCC(C)(C/C=C/[C@H]1[C@H](C)OC(=O)N1CCSc1nc(C(=O)OCCCC)cs1)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.9 h
Yield: 48.8 %

Procedure:
To a solution of the compound 41 (10.1 g) in dimethoxyethane (79 mL) was slowly added dropwise potassium hexamethyldisilazide (0.5M in toluene, 47.5 mL) at −78° C. and the solution was stirred at −78° C. for 54 minutes. To the reaction solution was slowly added dropwise a solution of the compound 42 (9.84 g) in dimethoxyethane (79 mL) and the solution was stirred at −78° C. for 25 minutes. The solution temperature was risen to 0° C. and the solution was stirred for 50 minutes. To the reaction solution was added an aqueous saturated sodium bicarbonate solution and the solution was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate. The reaction solution was filtrated through Celite (Brand name) and concentrated. The obtained residue was purified by Yamazen Parallel Prep (Brand name; column: 3 L, inject column: 2 L, n-hexane:ethyl acetate=84:16) to give the title compound (6.62 g) having the following physical data.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[CH2:4][CH2:5][CH2:6][N:7]([CH3:28])[C:8]([NH:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:19]=2[F:27])[CH:14]=[CH:13][N:12]=1)=[O:9])[CH3:2].O1CCCC1>CO.[Pd]>[CH2:29]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:28])[C:8]([NH:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=2[F:27])[CH:14]=[CH:13][N:12]=1)=[O:9])[CH3:30]
Reactant: CCN(CC)CCCN(C)C(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(CC)CCCN(C)C(=O)Nc1cc(Oc2ccc(N)cc2F)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a solution of 1-(3-diethylaminopropyl)-3-[4-(2-fluoro-4-nitrophenoxy)pyridin-2-yl]-1-methylurea (503 mg) in methanol (40 ml)-tetrahydrofuran (20 ml) was added 10% palladium on carbon (200 mg), followed by stirring under a hydrogen atmosphere at room temperature for 12 hr. The catalyst was removed by filtration and washed with methanol, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol=10:1) to provide the titled compound as a yellow oil (467 mg, 85.6%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:25][CH2:24][C:23]([F:27])([F:26])[CH2:22]2)=[O:20])=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(N(C(C)C)CC)(C)C.CN(C(ON1N=[N:52][C:47]2[CH:48]=[CH:49][CH:50]=[N:51][C:46]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NC1C=NC=CC=1>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:25][CH2:24][C:23]([F:26])([F:27])[CH2:22]2)=[O:20])=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:6]([CH:10]=1)[C:7]([NH:52][C:47]1[CH:46]=[N:51][CH:50]=[CH:49][CH:48]=1)=[O:8]
Reactant: O=C(O)c1cc(Cl)c(C(=O)N2CCC(F)(F)C2)cc1OCc1ccccc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cc(Cl)c(C(=O)N2CCC(F)(F)C2)cc1OCc1ccccc1
Reaction time: 18 h

Procedure:
To a solution of 5-chloro-4-[(3,3-difluoro-1-pyrrolidinyl)carbonyl]-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 65; 90 mg, 0.23 mmol) in N,N-dimethylformamide (3 ml) was added diisopropylethylamine (0.08 ml, 0.46 mmol), HATU (156 mg, 0.41 mmol) and 3-aminopyridine (25.7 mg, 0.27 mmol). The solution was stirred for 18 hours. The solvent removed in vacuo to give a gum. Purification by MDAP gave the title compound as a white solid. 65 mg.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH3:13])=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][NH:6][CH3:7].CNCC1C=CC2C(=CC=CC=2)C=1CCC.Cl.[N:31]1([CH2:37][CH2:38][N:39]2[CH2:44][C:43]3[CH:45]=[C:46](/[CH:49]=[CH:50]/[C:51]([OH:53])=O)[CH:47]=[N:48][C:42]=3[NH:41][C:40]2=[O:54])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[ClH:1].[Cl:1][C:2]1[C:3]([O:11][CH2:12][CH3:13])=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][N:6]([CH3:7])[C:51](=[O:53])/[CH:50]=[CH:49]/[C:46]1[CH:47]=[N:48][C:42]2[NH:41][C:40](=[O:54])[N:39]([CH2:38][CH2:37][N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[CH2:44][C:43]=2[CH:45]=1
Reactant: CCOc1c(Cl)cccc1CNC
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)C(=O)N2
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: Cl
Product: CCOc1c(Cl)cccc1CN(C)C(=O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)C(=O)N2
Yield: 60 %

Procedure:
According to the procedure of Example 1, except substituting 3-chloro-2-ethoxy-benzyl-methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-[3-(2-morpholin-4-yl-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3,-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.15 g, 60%) was prepared as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 10.82-10.69 (m, 1H), 10.11-10.09 (m, 1H), 8.41-8.33 (m, 1H), 8.01-7.91 (m, 1H), 7.58-7.48 (m, 1H), 7.47-7.36 (m, 1H), 7.28-7.01 (m, 3H), 4.86-4.68 (m, 2), 4.60-4.51 (m, 2H), 4.07-3.91 (m, 4H), 3.82-3.71 (m, 4H), 3.59-3.49 (m, 2H), 3.40-3.30 (m, 2H), 3.13-2.88 (m, 4H), 1.38 (t, J=7.0 Hz, 3H); MS (ESI) m/e 514 (M+I—)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[CH:4]=1.[Li]CCCC.[C:18](=[O:20])=[O:19].O>C1COCC1.CCCCCC>[CH3:12][O:11][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[C:6]=1[C:18]([OH:20])=[O:19]
Reactant: COc1cc(OC)cc(OC)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COc1cc(OC)c(C(=O)O)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
To a stirred solution of 1,3,5-trimethoxybenzene (10.0 g, 59.4 mmol) in 150 mL of dry THF at 0° C. in nitrogen atmosphere was added 27.3 mL (68.31 mmol) of 2.5 M n-BuLi in hexane dropwise via syringe. The resulting solution was stirred at room temperature overnight. The mixture was cooled to -20° C. and 30 g of dry ice was added. Stirring was continued for 1 hr before hydrolysis with 200 mL of water. The mixture was evaporated under reduced pressure to remove THF. The aqueous phase was extracted with ether, acidified with hydrochloric acid to pH 3 and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and concentrated. The solid residue was washed with ether and dried in vacuo to give 6.7 g of the title compound: mp 152-153° C. dec (lit.: 147° C. dec.; Beilsteins, 10, 1988). 1H NMR (CDCl3): 6.16 (2 H, s), 3.91 (6 H, s), 3.86 (3 H, s).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH:7]([OH:27])[C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:11]3[C:16](=[O:17])[N:15]([CH3:18])[C:14](=[O:19])[N:13]([CH3:20])[C:12]=23)[S:5][CH:6]=1.[F:28]C1C=C(C2NC(C=O)=C3C=2C(=O)N(C)C(=O)N3C)C=CC=1.C(C1C=C(C2N(CCC(N(OC)C)=O)C=C3C=2C(=O)N(C)C(=O)N3C)C=CC=1)#N>>[Cl:1][C:2]1[N:3]=[C:4]([CH:7]([OH:27])[C:8]2[NH:9][C:10]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=3)=[C:11]3[C:16](=[O:17])[N:15]([CH3:18])[C:14](=[O:19])[N:13]([CH3:20])[C:12]=23)[S:5][CH:6]=1
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]c(C=O)c2n(C)c1=O
Reactant: Cn1c(=O)c2c(-c3ccccc3)[nH]c(C(O)c3nc(Cl)cs3)c2n(C)c1=O
Agent: CON(C)C(=O)CCn1cc2c(c1-c1cccc(C#N)c1)c(=O)n(C)c(=O)n2C
Product: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]c(C(O)c3nc(Cl)cs3)c2n(C)c1=O

Procedure:
The title compound was prepared by an analogous method to 7-((4-chlorothiazol-2-yl)(hydroxy)methyl)-1,3-dimethyl-5-phenyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (Example 21 Step 1) from 5-(3-fluorophenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidine-7-carbaldehyde (Intermediate Nc) and 2-bromo-4-chlorothiazole (Intermediate Q, step 2);
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH3:11][OH:12]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([O:12][CH3:11])[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: CO
Product: COc1cc(Cl)ccc1CN

Procedure:
The title compound is synthesized by coupling followed by reduction of 4-chloro-2-fluoro-benzonitrile and methanol analogously to the preparation of Intermediate 98.1 as a colorless oil; HPLC: AtRet=2.24 min; 1HNMR (CDCl3) δ 7.20-7.10 (m, 1H), 7.00-6.80 (m 2H), 3.90-3.80 (m, 5H), 1.80 (bs, 2H).
Reaction SMILES: CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:12])=O.[N:15]1([CH2:21][CH2:22][NH:23][C:24]2[NH:25][C:26](=O)[C:27]3[N:28]=[CH:29][NH:30][C:31]=3[N:32]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[Cl:12][C:26]1[N:25]=[C:24]([NH:23][CH2:22][CH2:21][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:32]=[C:31]2[C:27]=1[N:28]=[CH:29][NH:30]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(NCCN2CCCCC2)nc2[nH]cnc12
Solvent: CN(C)c1ccccc1
Product: Clc1nc(NCCN2CCCCC2)nc2[nH]cnc12
Yield: 88.7 %

Procedure:
A mixture of N,N-dimethylaniline (4 ml, 31 mmol) and phosphorus oxychloride (30 ml, 314 mmol) was stirred at ambient temperature for 10 min before Intermediate 37 (5.5 g, 20 mmol) was added portionwise and was then refluxed for 15 min. On cooling the phosphorus oxychloride was evaporated in vacuo, the residue obtained was azeotroped with toluene (3×50 ml). Purification using flash column chromatography with a Biotage column (90 g, SiO2) eluting with 10% methanol/chloroform 1% ammonia gave the title compound as a pale yellow solid (4.980 g). LC/MS SYSTEM C Rt=1.61 min, m/z=281 MH+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:6]=1.[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]1[C:25](O)=[O:26].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([NH:1][C:25]([C:17]3[N:16]([CH3:15])[C:24]4[C:19]([CH:18]=3)=[CH:20][CH:21]=[CH:22][CH:23]=4)=[O:26])[S:3][CH:4]=2)=[CH:12][CH:11]=1
Reactant: Cn1c(C(=O)O)cc2ccccc21
Reactant: COc1ccc(-c2csc(N)n2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(-c2csc(NC(=O)c3cc4ccccc4n3C)n2)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
1 g of 2-amino-4-(4-methoxyphenyl)thiazole is dissolved in 20 ml of dimethylformamide and, successively, 0.6 g of 1-methylindole-2-carboxylic acid, then 1.6 g of 1-benzotriazolyl-oxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) and then 0.7 g of triethylamine are added to the reaction mixture at ambient temperature. The reaction mixture is left at ambient temperature for about 12 hours, while stirring well, before pouring into 100 ml of ice-water; the aqueous phase obtained is then extracted with twice 50 ml of ethyl acetate. The organic extracts are dried over anhydrous magnesium sulphate and evaporated to dryness. The residual solid is purified by chromatography on a silica column (eluant: CH2Cl2). Yield