Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=O)=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]>P(Cl)(Cl)(Cl)=O>[N:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[NH:1][C:15]=1[C:14]1[CH:18]=[CH:19][C:11]([O:10][CH3:9])=[C:12]([N+:20]([O-:22])=[O:21])[CH:13]=1
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1cccnc1N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2nc3cccnc3[nH]2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
2,3-Diaminopyridine (10 g, 91.6 mmol) and 18.07 g of 4-methoxy-3-nitro benzoic acid were mixed together, and the mixture was added in portions to 200 mL of phosphorous oxychloride at. room temperature. The resulting mixture was heated to reflux for 4 hours, and then cooled to room temperature and allowed to stir overnight. The reaction was rotary evaporated in vacuo, and the residue was carefully quenched with saturated sodium bicarbonate solution, filtered, and dried on the vacuum filter overnight to give a brown solid. The solid was washed with several fractions of ethyl acetate to yield 21.36 g of 5-(3H-imidazo[4,5-b]pyridin-2-yl)-2-methoxy-nitrobenzene as a dark brown solid that was used without further purification. 1H-NMR (DMSO-d6); δ 8.71 (d, 1H), 8.48 (dd, 1H), 8.31 (dd, 1H), 7.99 (d, 1H), 7.58 (d, 1H), 7.23 (dd, 1H), 4.00 (s, 3H) ppm.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[C:20]([S:23]([O:26]C3C(F)=C(F)C(F)=C(F)C=3F)(=[O:25])=O)[CH:21]=[CH:22][C:14]1=2)#[N:2].Cl.[S:39]1[CH:43]=[C:42]([NH2:44])[N:41]=[CH:40]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[C:20]([S:23]([NH:44][C:42]3[N:41]=[CH:40][S:39][CH:43]=3)(=[O:25])=[O:26])[CH:21]=[CH:22][C:14]1=2)#[N:2]
Reactant: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Nc1cscn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Nc3cscn3)ccc21
Reaction time: 0.08 h
Yield: 33.7 %

Procedure:
A 10-mL round-bottom flask was charged with perfluorophenyl 4-(2-cyano-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate (INTERMEDIATE AB) (48.92 mg, 0.089 mmol), thiazol-4-amine hydrochloride (Accel Pharmatech, East Brunswick, N.J., 15.78 mg, 0.116 mmol), and THF (889 μl) to give a suspension. The flask was cooled in a dry ice-acetone bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (293 μl, 0.293 mmol) was added dropwise over 30 s to give a bright orange mixture. The mixture was stirred for 5 min, then the flask was lowered into an ice-water bath. After 2 h, additional portions of thiazol-4-amine hydrochloride (15.78 mg, 0.116 mmol) and lithium bis(trimethylsilyl)amide (1M in THF) (293 μl, 0.293 mmol) were added in sequence. Following an additional 1 h of stirring, the mixture was quenched with glacial acetic acid (1 drop), diluted with MeOH, and concentrated in vacuo. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-10% MeOH/DCM) to give 4-(2-cyano-4-(trifluoromethyl)phenyl)-N-(thiazol-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (14.11 mg, 0.030 mmol, 34.0% yield) as a tan solid: 1H NMR (400 MHz, DMSO-d6) 6=10.96 (s, 1 H), 8.88 (d, J=2.2 Hz, 1 H), 8.41 (d, J=1.7 Hz, 1 H), 8.09 (dd, J=1.9, 8.8 Hz, 1 H), 7.72 (d, J=8.7 Hz, 1 H), 7.30 (d, J=2.2 Hz, 1 H), 7.20 (dd, J=2.2, 8.6 Hz, 1 H), 6.99 (d, J=2.2 Hz, 1 H), 6.79 (d, J=8.6 Hz, 1 H), 4.38-4.28 (m, 2 H), 3.90-3.81 (m, 2 H); m/z (ESI) 467.2 (M+H)+.
Reaction SMILES: ClC(Cl)C.CN([CH:8]=[O:9])C.P(Cl)(Cl)(Cl)=O.[CH:15]1[C:16]([C:24]([O:26][CH3:27])=[O:25])=[CH:17][N:18]2[C:23]=1[CH2:22][CH2:21][CH2:20][CH2:19]2>C(#N)C>[CH:8]([C:17]1[N:18]2[C:23]([CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:15][C:16]=1[C:24]([O:26][CH3:27])=[O:25])=[O:9]
Reactant: COC(=O)c1cc2n(c1)CCCC2
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: CC#N
Product: COC(=O)c1cc2n(c1C=O)CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
A 100-mL round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with anhydrous dichloroethane (20 mL) and anhydrous DMF (0.70 mL, 9.0 mmol). To the mixture at 0° C. was added phosphorus oxychloride (0.70 mL, 7.3 mmol) over a period of 2 min, while maintaining the reaction temperature between 0° C. and 10° C. The cooling bath was removed and the reaction was stirred at room temperature for 1 hour. A solution of 193c (1.0 g, 5.6 mmol) in acetonitrile (10 mL) was added and the reaction mixture was stirred at room temperature for 3 hours. After this time, it was concentrated under reduced pressure. The oily residue was taken up with saturated aqueous NaHCO3 (20 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with water (50 mL), dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:5 ethyl acetate/petroleum ether to afford 193d as a white solid (703 mg, 58%). MS-ESI: (M+H)+ 208.3. 1H NMR (500 MHz, DMSO-d6) δ 10.14 (s, 1H), 6.40 (s, 1H), 4.27 (t, J=6.0 Hz, 2H), 3.78 (s, 3H), 2.78 (t, J=6.0 Hz, 2H), 1.94-1.85 (m, 2H), 1.78-1.69 (m, 2H).
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[C@@H:10]([C@@H:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=2)[CH3:22])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][C@H:21]([C@@H:10]2[C@@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=3)[CH2:12][NH:8][CH2:9]2)[CH3:22])=[N:25][CH:26]=1
Reactant: C[C@H](Oc1ccc(Cl)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(F)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Oc1ccc(Cl)cn1)[C@H]1CNC[C@@H]1c1ccc(Cl)c(F)c1
Temperature: 100 °C
Yield: 96 %

Procedure:
To a solution of 2-{(S)-1-[(3R,4S)-1-benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-ethoxy}-5-chloro-pyridine 98 mg (0.22 mmol) dissolved in toluene (5 mL) were added 0.072 mL (0.66 mmol) of 1-chloroethyl chloroformate and 0.11 mL (0.66 mL) of Hunig's base. The reaction mixture was heated at 100° C. for one hour. After cooling down to RT, volatiles were removed under vacuo and the crude was dissolved in MeOH (5 mL). The reaction mixture was heated at 85° C. for 30 minutes and after cooling down to RT, volatiles were removed under vacuo and the residue was directly purified on column chromatography (SiO2, CH2Cl2/MeOH 9:1) yielded 75 mg (95%) of the title compound as a light yellow oil. ES-MS m/e: 355.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]([Cl:10])=[C:8]([C:11]3[NH:12][CH2:13][CH2:14][N:15]=3)[S:7][C:6]=2[CH:16]=1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1B(O)O>>[Cl:10][C:9]1[C:5]2[CH:4]=[CH:3][C:2]([C:18]3[S:17][CH:21]=[CH:20][CH:19]=3)=[CH:16][C:6]=2[S:7][C:8]=1[C:11]1[NH:12][CH2:13][CH2:14][N:15]=1
Reactant: OB(O)c1cccs1
Reactant: Clc1c(C2=NCCN2)sc2cc(Br)ccc12
Product: Clc1c(C2=NCCN2)sc2cc(-c3cccs3)ccc12

Procedure:
The compound was prepared in manner similar to that of Example 45 from 2-(6-bromo-3-chlorobenzo[b]thiophen-2-yl)-4,5-dihydro-1H-imidazole and thiophen-2-boronic acid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C@@:21]([F:26])([CH3:25])[C:22](O)=[O:23])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]([F:41])([F:40])[CH2:38][NH2:39]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C@@:21]([F:26])([CH3:25])[C:22]([NH:39][CH2:38][C:37]([F:41])([F:40])[F:36])=[O:23])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@](F)(C(=O)O)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: NCC(F)(F)F
Product: C[C@@](F)(C(=O)NCC(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (S)—N—[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-2-fluoro-2-methyl-malonamic acid and 2,2,2-trifluoroethylamine, the title compound was prepared in the same manner as described for example 1c. Colorless, viscous oil (73%). MS: m/e=558(M+H+).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([OH:17])=O)[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:26][C@H:27]1[CH2:33][CH2:32][S:31][C@H:30]2[CH2:34][CH2:35][CH2:36][C@@H:37]([C:38]([NH:40][C:41]3[S:42][CH:43]=[CH:44][N:45]=3)=[O:39])[N:29]2[C:28]1=[O:46]>>[CH2:18]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:26][C@H:27]1[CH2:33][CH2:32][S:31][C@H:30]2[CH2:34][CH2:35][CH2:36][C@@H:37]([C:38](=[O:39])[NH:40][C:41]3[S:42][CH:43]=[CH:44][N:45]=3)[N:29]2[C:28]1=[O:46])=[O:11])[C:15]([NH:26][C@@H:27]1[CH2:33][CH2:32][S:31][C@H:30]2[CH2:34][CH2:35][CH2:36][C@@H:37]([C:38](=[O:39])[NH:40][C:41]3[S:42][CH:43]=[CH:44][N:45]=3)[N:29]2[C:28]1=[O:46])=[O:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N[C@H]1CCS[C@H]2CCC[C@@H](C(=O)Nc3nccs3)N2C1=O
Reactant: O=C(O)[C@H](CC[C@H](Cc1ccccc1)C(=O)O)Cc1ccccc1
Agent: Cl
Product: O=C(N[C@H]1CCS[C@H]2CCC[C@@H](C(=O)Nc3nccs3)N2C1=O)[C@H](CC[C@H](Cc1ccccc1)C(=O)N[C@@H]1CCS[C@H]2CCC[C@@H](C(=O)Nc3nccs3)N2C1=O)Cc1ccccc1

Procedure:
(2R,5R)-2,5-Dibenzyl-N1-((4R,7S,10aS)-5-oxo-7-(thiazol-2-ylcarbamoyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)-N6-((4S,7S,10aS)-5-oxo-7-(thiazol-2-ylcarbamoyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)hexanediamide was synthesized as described in General Procedure F using Intermediate 3 (10 mg, 0.031 mmol) and Intermediate 37 (25 mg, 0.069 mmol) to give a white solid (14 mg, 46% yield). Anal. Calcd. for C46H54N8O6S4 m/z 942.7. found: 943.5 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.21-7.11 (m, 14H), 5.38 (br s, 2H), 5.11 (m, 4H), 3.15 (m, 2H), 2.76 (m, 6H), 2.36 (m, 4H), 2.12 (m, 4H), 1.85-1.40 (m, 14H).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:30])[C:13]([NH:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:14][N:15]3[CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:10][C:9]=2[F:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:40](=[O:49])[CH2:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45].O>C1COCC1>[CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:30])[C:13]([N:23]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:40](=[O:49])[CH2:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:14][N:15]3[CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:10][C:9]=2[F:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CNc1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reactant: CCOC(=O)CCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CCCC(=O)N(CC(=O)OCC)c1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg of ethyl {[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]amino}acetate was dissolved in 3.0 ml of THF, and 0.060 ml of triethylamine and 0.060 ml of ethyl 5-chloro-5-oxopentanoate were added, followed by overnight stirring at room temperature. Water was added to the reaction mixture, followed by extraction with chloroform. The resulting organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then concentrated under a reduced pressure. By purifying the resulting residue by silica gel column chromatography, 199 mg of ethyl 5-[[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl](2-ethoxy-2-oxoethyl)amino]-5-oxopentanoate was obtained.
Reaction SMILES: [CH2:1]([C:8]1[C:9]2[CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29][C:10]=2[N:11]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]3)=[C:17]([O:27][CH3:28])[CH:16]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[CH2:1]([C:8]1[C:9]2[CH2:32][NH:31][CH2:30][CH2:29][C:10]=2[N:11]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]3)=[C:17]([O:27][CH3:28])[CH:16]=2)[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(Nc2nc3c(c(Cc4ccccc4)n2)CN(C(=O)OC(C)(C)C)CC3)ccc1-n1cnc(C)c1
Agent: Cl
Solvent: CO
Product: COc1cc(Nc2nc3c(c(Cc4ccccc4)n2)CNCC3)ccc1-n1cnc(C)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-benzyl-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (1.0 g, 1.90 mmol) was dissolved in methanol (10 mL). Hydrochloric acid (0.156 mL, 1.90 mmol) was added and the reaction mixture was stirred at 80° C. for 1 h. The solvent was evaporated under reduced pressure and the crude was used in the subsequent step as such. MS (ES+) m/z 427.0 (M+H)+
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH2:16])[CH3:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:18][C:19](=O)[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:27]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:26][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:20]=1[C:19](=[O:18])[N:16]([CH:14]([C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:12]=1)[CH3:15])[CH2:27]2
Reactant: COC(=O)c1c(Cl)cccc1CBr
Reactant: CC(N)c1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(c1ccc(Oc2ccccc2)cc1)N1Cc2cccc(Cl)c2C1=O
Reaction time: 16 h
Yield: 33.8 %

Procedure:
A mixture of 1-(4-phenoxyphenyl)ethylamine (121 mg, 0.57 mmol), 2-bromomethyl-6-chloro-benzoic acid methyl ester (150 mg, 0.57 mmol), and K2CO3 (1 g, 7.2 mmol) in toluene (10 mL) was heated at reflux with stirring for 16 h. Workup and silica gel column chromatography using a gradient of hexanes to 30% ethyl acetate in hexanes afforded 7-chloro-2-[1-(4-phenoxyphenyl)-ethyl]-2,3-dihydroisoindol-1-one (70 mg, 34%). GC/MS gave: m/z (rel.int.) 365 (M+, 9), 363 (M+23), 350 (25), 348 (63), 211 (32), 196 (65), 168 (33), 152 (54), 141 (27), 124 (27), 115 (27), 89 (35), and 77 (100). 1H NMR (300 MHz, CDCl3): δ 1.68 (d, 3H), 3.99 (d, 1H), 4.15 (d, 1H), 5.79 (q, 1H), 6.98 (br t, 4H), 7.13 (t, 1H), 7.26-7.10 (br m, 7H).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([CH3:25])[CH:24]=1>>[CH3:18][C:19]1[CH:20]=[C:21]([N:15]2[C:13]3=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]3[N:17]=[CH:16]2)[CH:22]=[C:23]([CH3:25])[CH:24]=1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reactant: Cc1cc(C)cc(B(O)O)c1
Product: Cc1cc(C)cc(-n2cnc3ccc(O)nc32)c1

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 3,5-dimethylphenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=239.9 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][O:6][C:7]1[N:12]=[C:11](S(C)(=O)=O)[C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])[N:8]=1.[CH3:36][NH:37][CH3:38]>>[F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][O:6][C:7]1[N:12]=[C:11]([N:37]([CH3:38])[CH3:36])[C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])[N:8]=1
Reactant: CNC
Reactant: CS(=O)(=O)c1nc(OCc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Product: CN(C)c1nc(OCc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
2-(3,4-Difluorobenzyloxy)-4-(methylsulfonyl)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-pyrimidine (Reference Example 7) (29 mg, 0.05 mmol) was reacted with 2 equivalents of dimethylamine by the same general procedure described in Example 103 to afford the title compound: HPLC/MS: m/e=520 (M++1); Rt=3.68 min. 1H-NMR 400 MHz (CDCl3): δ 2.80 (s, 6H), 5.28-5.42 (m, 2H), 6.90 (d, J=9 Hz, 1H), 7.01-7.21 (m, 8H), 7.35-7.40 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:5]([OH:7])=O.O=[O+][O-].O=O.S(Cl)(Cl)=O.Cl.[CH3:23]NOC.C[Mg]Br>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[CH3:23])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: CNOC
Reactant: COc1cc(Cl)cc(C(=O)O)c1
Agent: C[Mg]Br
Agent: Cl
Agent: O=O
Solvent: O=S(Cl)Cl
Product: COc1cc(Cl)cc(C(C)=O)c1

Procedure:
3-Chloro-5-methoxybenzoic acid (3 g) was reacted analogously to O3.043/O2.043 with thionyl chloride (23.3 ml) and N,O-dimethylhydroxylamine hydrochloride (1.57 g) and methylmagnesium bromide (8.91 ml). 2.42 g were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].Br[CH2:39][CH:40]([F:42])[F:41]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][CH2:39][CH:40]([F:42])[F:41])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Reactant: FC(F)CBr
Product: COc1ccc(CC2c3cc(OCC(F)F)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with 1-bromo-2,2-difluoro-ethane
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].FC(F)(F)S(O[CH2:32][C:33]([F:36])([F:35])[F:34])(=O)=O.[H-].[Na+]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][N:22]([CH2:32][C:33]([F:36])([F:35])[F:34])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CN(CC(F)(F)F)C2=O)CC1
Yield: 28 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), 2,2,2-trifluoroethyl trifluoromethanesulfonate and sodium hydride, to give the desired product as a colorless oil (28%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])=[CH:18][N:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10](Br)[CH:11]=2)[CH:6]=1.[CH3:29]B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])=[CH:18][N:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:29])[CH:11]=2)[CH:6]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)OC)cc3ccc(Br)cc23)nc1
Reactant: CB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)OC)cc3ccc(C)cc23)nc1
Reaction time: 8 h
Yield: 71.5 %

Procedure:
A mixture of [6-bromo-4-(5-ethanesulfonyl-pyridin-2-yloxy)-naphthalen-2-yl]-acetic acid methyl ester (30 mg, 0.07 mmol, methyl ester of example 12-1), methylboronic acid (7 mg, 0.11 mmol), tetrakis(triphenylphosphine)palladium(0) (8 mg, 0.007 mmol), potassium phosphate (45 mg, 0.21 mmol) and toluene (0.5 mL) was stirred at 115 overnight under an argon atmosphere. The resulting mixture was diluted with water (5 mL), and then extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (20% ethyl acetate in petroleum ether) to give [4-(5-ethanesulfonyl-pyridin-2-yloxy)-6-methyl-naphthalen-2-yl]-acetic acid methyl ester (20 mg) as a colorless oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C@H:12]1[C@H:16]([C:17](OCC)=[O:18])[O:15][CH2:14][O:13]1)=O)C.O.[OH-].[Na+]>O1CCCC1>[OH:9][CH2:10][C@H:12]1[C@H:16]([CH2:17][OH:18])[O:15][CH2:14][O:13]1
Reactant: CCOC(=O)[C@@H]1OCO[C@H]1C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OC[C@@H]1OCO[C@H]1CO

Procedure:
300 ml of tetrahydrofuran was added dropwise to 43.61 g of lithium aluminum hydride while cooling with ice. To this was added dropwise a solution of 125.3 g of (4R,5R)-4,5-bis(ethoxycarbonyl)-1,3-dioxolane prepared in Example 13 in 200 ml of tetrahydrofuran and reacted while vigorously stirring under cooling with ice. After the addition, the mixture was reacted for one hour while refluxing. Then, water was added drop by drop to hydrolyze lithium aluminum hydride under cooling with ice. After the addition of 0.5 ml of 4 mol/l sodium hydroxide dropwise, the mixture was stirred for 30 minutes and filtered with suction. 700 ml of ethanol was added to the precipitate, and the mixture was heated at 60°-70° C., stirred, and filtered with suction. This procedure was repeated three times. All filtrates were combined and concentrated by evaporator to obtain a crude title compound.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([S:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:18][CH2:17]3)=[N:6][C:5]=2[S:4][C:3]=1C(O)=O.C([N:33](CC)CC)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>C(O)(C)(C)C>[NH2:33][C:3]1[S:4][C:5]2[N:6]=[C:7]([S:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:17][CH2:18][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:20][CH2:21]3)[NH:8][C:9](=[O:11])[C:10]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C(=O)O)sc2nc(SCCCN3CCN(c4ccccn4)CC3)[nH]c(=O)c12
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Product: Cc1c(N)sc2nc(SCCCN3CCN(c4ccccn4)CC3)[nH]c(=O)c12
Reaction time: 9 h
Yield: 18 %

Procedure:
In 20 ml of tert-butanol, 470 Milligrams of 5-methyl-4-oxo-2-[3-(4-pyridin-2-ylpiperazin-1-yl)propylthio]-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid as synthesized in Example 2-17 was dissolved to which 107 mg of triethylamine and 305 mg of DPPA were added by the order stated, followed by 9 hours' heating under reflux. Distilling the solvent off under reduced pressure, the residue was purified on silica gel column chromatography (chloroform:methanol=50:1). The purified product was added to 6 ml of 4N-hydrochloric acid-dioxane solution, stirred for an overnight and from which the solvent was distilled off under reduced pressure. To the residue chloroform was added, followed by washing with saturated aqueous sodium hydrogencarbonate solution, drying over anhydrous magnesium sulfate and removal of the solvent by distillation under reduced pressure. The residue was purified on silica gel column chromatography (chloroform:methanol=25:1) to provide 78 mg (18%) of 6-amino-5-methyl-2-[3-(4-pyridin-2-ylpiperazin-1-yl)propylthio]-3H-thieno[2,3-d]pyrimidin-4-one.