Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH:25]=[CH:26][C:27](=[O:31])[NH:28]5)=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.C(N(CC)CC)C.[C:39](Cl)(=[O:41])[CH3:40]>C(Cl)Cl>[C:39]([O:31][C:27]1[CH:26]=[CH:25][C:24]2[C:29](=[CH:30][C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][N:13]3[CH2:12][CH2:11][N:10]([C:6]4[C:3]5[CH:4]=[CH:5][S:1][C:2]=5[CH:9]=[CH:8][CH:7]=4)[CH2:15][CH2:14]3)=[CH:22][CH:23]=2)[N:28]=1)(=[O:41])[CH3:40]
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2[nH]1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2n1

Procedure:
To a solution of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one (3.14 g) synthesized in the same manner as in WO2006/112464 (Example 1) in methylene chloride (32 mL) were added with stirring under ice-cooling triethylamine (4.0 mL) and acetyl chloride (1.5 mL), and the mixture was stirred at room temperature for 39 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride:ethyl acetate=7:3→1:9) to give 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]quinolin-2-yl acetate (1.24 g).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][CH2:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:14].C(N(CC)CC)C>C(O)C>[N+:8]([C:7]1[C:2]([NH:11][CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[OH:14])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: NCC(O)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccnc1NCC(O)c1ccccc1
Yield: 5.3 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (20.0 g, 0.13 mole), 2-amino-1-phenylethanol (20.74 g, 0.15 mole), and triethylamine (17.5 ml, 0.13 mole) in 200 ml of absolute ethanol was heated to reflux for 11/2 hours. The reaction mixture was filtered and evaporated to dryness. The residue was partitioned between water and methylene chloride (2×). The methylene chloride layers were combined and extracted with water. The methylene chloride layers were dried, filtered, and evaporated to a solid (30.8 g, 94.5%). A 2.4-g sample was recrystallized from methanol and water to give a yellow solid, which was collected by filtration, washed with water, and dried under high vacuum overnight to give 1.8 g of the compound, mp 101°-103° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[N:14]=[C:15]([CH3:18])[S:16][CH:17]=3)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C]=O>CS(C)=O.CO.CCOC(C)=O.C(Cl)Cl>[CH3:18][C:15]1[S:16][CH:17]=[C:13]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([C:8]([O:9][CH3:10])=[O:12])=[CH:3][CH:4]=3)[O:9][C:8](=[O:12])[CH:7]=2)[N:14]=1
Reactant: Cc1nc(-c2cc(=O)oc3cc(Br)ccc23)cs1
Agent: [C]=O
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(-c3csc(C)n3)cc(=O)oc2c1
Temperature: 25 °C

Procedure:
To a solution of 7-bromo-4-(2-methyl-1,3-thiazol-4-yl)-2H-chromen-2-one (1.17 g, 3.63 mmol) in DMSO (21 ml) and methanol (12 ml) was added triethylamine (1.0 mL, 7.26 mmol) and [Pd(dppf)Cl2]2—CH2Cl2 (0.593 g, 0.73 mmol). The reaction mixture was stirred overnight at 65° C. with a balloon of carbon monoxide. After cooling to rt, the reaction mixture was diluted with EtOAc—CH2Cl2 (9:1) washed with water (3×) and brine. The organic phase was dried over MgSO4 and evaporated to dryness. The residue was purified on silica gel (hexanes-EtOAc, 8:2) to afford the title compound. 1H NMR (400 MHz, acetone-d6): δ 8.45 (m, 1H), 8.12 (s, 1H), 7.92 (m, 2H), 6.80 (s, 1H), 3.97 (s, 3H), 2.85 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[NH:4][N:3]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1[C:25]([F:28])([F:27])[F:26]>>[F:26][C:25]([F:27])([F:28])[C:16]1[CH:17]=[C:18]([C:21]([F:24])([F:22])[F:23])[CH:19]=[CH:20][C:15]=1[CH2:14][N:4]1[C:5]2[C:10](=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=2)[C:2]([Cl:1])=[N:3]1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: O=Cc1ccc2[nH]nc(Cl)c2c1
Product: O=Cc1ccc2c(c1)c(Cl)nn2Cc1ccc(C(F)(F)F)cc1C(F)(F)F

Procedure:
1-(2,4-Bis-trifluoromethyl-benzyl)-3-chloro-1H-indazole-5-carbaldehyde was prepared from 3-Chloro-1H-indazole-5-carbaldehyde and 1-Bromomethyl-2,4-bis-trifluoromethyl-benzene following general procedure A.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:12].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.N1CCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:17]/[C:16]3[CH:19]=[CH:20][CH:21]=[C:14]([Cl:13])[CH:15]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:12]
Reactant: O=Cc1cccc(Cl)c1
Reactant: O=C1Cc2cc(F)c(Cl)cc2N1
Solvent: C1CCNC1
Solvent: CO
Product: O=C1Nc2cc(Cl)c(F)cc2/C1=C/c1cccc(Cl)c1

Procedure:
In a manner similar to the method described in example 1a, 6-chloro-5-fluoro-1,3-dihydro-indol-2-one (0.25 g, 1.35 mmol, prepared in procedure described in EP153818) was reacted with 3-chloro-benzaldehyde (0.34 g, 2.44 mmol) and pyrrolidine (0.19 g, 2.68 mmol) in methanol to give a mixture of E- and Z-6-chloro-3-(3-chloro-benzylidene)-5-fluoro-1,3-dihydro-indol-2-one as a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12]C(C(F)(F)F)=[CH:10][C:9]=1[NH:18][C:19](=[O:38])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=2)[CH:24]=1)=O)(C)(C)C.[C:40](O)([C:42]([F:45])([F:44])[F:43])=O>C(Cl)Cl>[CH:35]([C:32]1[N:31]=[CH:30][C:29]([C:25]2[CH:24]=[C:23]([C:21]3[CH2:20][C:19](=[O:38])[NH:18][C:9]4[CH:10]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:28]=[CH:27][CH:26]=2)=[CH:34][CH:33]=1)([CH3:37])[CH3:36]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)c1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: ClCCl
Product: CC(C)c1ccc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (2-{3-[3-(6-isopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M159) (260 mg, 0.506 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (94 mg, 53%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:4]([CH:9]=[O:10])=[CH:5][CH:6]=[CH:7][CH:8]=1.I[CH2:14]Cl.C[Li]>O1CCCC1>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][O:10]1
Reactant: ClCI
Reactant: O=Cc1ccccc1C(F)(F)F
Agent: [Li]C
Solvent: C1CCOC1
Product: FC(F)(F)c1ccccc1C1CO1
Temperature: -78 °C

Procedure:
α,α,α-trifluoro-o-tolualdehyde (3 g) was dissolved in anhydrous tetrahydrofuran and cooled to -78° C., iodochloromethane (1.38 ml) was then added, followed by methyllithium (1.5M complexed with lithium bromide) (12 ml) added over 5 minutes. The reaction was left to warm up to room temperature overnight. The reaction was quenched using saturated ammonium chloride solution and extracted using diethyl ether (2×50 ml). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated to afford a brown oil. Purification on flash silica eluted with 100% hexane up to 5% EtOAC in hexane afforded a colourless oil (1.1 g). 1H NMR (250 MHz, CDCl3) δ2.61-2.71 (1H, dd), 3.14-3.25 (1H, dd), 4.17-4.27 (1H, m), 7.33-7.70 (5H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:44]=[CH:43][C:32]([C:33]([NH:35][CH:36]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:34])=[C:31]([F:45])[CH:30]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:13])[F:15])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH2:28][C:29]1[CH:44]=[CH:43][C:32]([C:33](=[O:34])[NH:35][CH:36]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[C:31]([F:45])[CH:30]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: NCc1ccc(C(=O)NC2CCCCCC2)c(F)c1
Solvent: Cc1ccccc1
Product: O=C(NC1CCCCCC1)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1F
Yield: 53.3 %

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.1 g, 2.5 mmol) with 4-aminomethyl-N-cycloheptyl-2-fluoro-benzamide (1.35 g, 5.1 mmol) in anhydrous toluene (25 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (19:1 to 1:1 gradient) followed by SCX chromatography to obtain 7-chloro-6-[4-cycloheptylcarbamoyl-3-fluoro-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (720 mg, 53%). MS (ES+) m/z: 540.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[C:26]1(=[O:39])[N:30]([CH2:31][CH2:32]Br)[C:29](=[O:34])[C:28]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:27]12>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:32][CH2:31][N:30]2[C:26](=[O:39])[C:27]3=[CH:38][CH:37]=[CH:36][CH:35]=[C:28]3[C:29]2=[O:34])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCCN2C(=O)c3ccccc3C2=O)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
6-Amino-9-benzyl-8-hydroxy-2-mercaptopurine (120 mg, 0.44 mmol) was suspended in dimethylformamide (10 ml). To the suspension were added potassium carbonate (60 mg, 0.43 mmol) and 2-phthalimidoethyl bromide (112 mg, 0.44 mmol) in order. The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo and to the residue was added saturated brine. The mixture was extracted with ethyl acetate, the organic layer was dried on magnesium sulfate, and the solvent was removed in vacuo. Methanol was added to the residue, and the resulting crystals were taken by filtration to give the subject compound (107 mg, yield 54%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1.C(N(CC)CC)C.[NH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCNC(=O)OC(C)(C)C)c1C
Temperature: 60 °C
Yield: 77.4 %

Procedure:
A solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (60 g, 271 mmol) in anhydrous N,N-dimethylfornamide (600 mL) was cooled to 0° C. Triethylamine (44.8 mL, 326 mmol) was added drop wise followed by tert-butyl 2-aminoethylcarbamate (52.2 g, 326 mmol). After 30 minutes the ice bath was removed and the reaction mixture was heated to 60° C. The reaction was heated at 60° C. overnight and then it was concentrated under reduced pressure to provide an orange oil. The oil was dissolved in ethyl acetate (1 L), washed with water (3×500 mL), dried over magnesium sulfate and then concentrated under reduced pressure to provide a yellow oil. The oil was triturated with methanol (˜100 mL). The resulting solid was isolated by filtration and washed with cold methanol to provide 72.3 g of tert-butyl 2-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]ethylcarbamate as a solid.
Reaction SMILES: [NH3:1].[CH2:2]([O:4][C:5]([C@H:7]1[CH2:12][CH2:11][C@@H:10]([N:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[C:15]([I:23])=[CH:14]2)[CH2:9][CH2:8]1)=[O:6])[CH3:3]>CC(O)C>[CH2:2]([O:4][C:5]([C@H:7]1[CH2:12][CH2:11][C@@H:10]([N:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH2:1])[C:16]=3[C:15]([I:23])=[CH:14]2)[CH2:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: N
Reactant: CCOC(=O)[C@H]1CC[C@@H](n2cc(I)c3c(Cl)ncnc32)CC1
Solvent: CC(C)O
Product: CCOC(=O)[C@H]1CC[C@@H](n2cc(I)c3c(N)ncnc32)CC1
Temperature: -78 °C

Procedure:
Gaseous ammonia was bubbled into an iPrOH (1 mL) solution of cis-4-(4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-cyclohexanecarboxylic acid ethyl ester (30 mg, 70% pure by HPLC peak area, 0.048 mmol) in a glass pressure tube, cooled to −78° C. in a dry ice/acetone bath, for 15 min. The tube was equipped with a Teflon washer, sealed and heated to 110° C. for 7 h. After that time, the excess NH3 and the solvent were evaporated. The residue was used for the next reaction without purification. A portion of above crude material were purified by HPLC to give the title compound as pale yellow oil. 1H NMR (CDCl3, 400 MHz): δ=1.31 (t, 3H, J=7.6 Hz), 1.63-1.98 (m, 6H), 2.29-2.35 (m, 2H), 2.73 (m, 1H), 4.22 (q, 2H, J=7.6 Hz), 4.64-4.71 (m, 1H), 5.58 (brs, 2H), 7.11 (s, 1H), 8.26 (s, 1H). MS (ES+): 415.0 [MH+]. tR=2.7 min (polar—5 min).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][N:17]=2)[CH2:15][CH2:14][C:9]2(OCC[O:10]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>>[CH2:1]([O:3][C:4]([C:6]1([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][N:17]=2)[CH2:15][CH2:14][C:9](=[O:10])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(Br)cn2)CCC2(CC1)OCCO2
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(c2ccc(Br)cn2)CCC(=O)CC1
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To 8-(5-bromopyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxylic acid ethyl ester (1.0 g) described in Reference Example 81 (2) was added trifluoroacetic acid (1.1 ml) at room temperature, and stirred at the same temperature for 2 hours. After completion of the reaction, the solvent and trifluoroacetic acid were evaporated. The obtained residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1-(5-bromopyridin-2-yl)-4-oxocyclohexanecarboxylic acid ethyl ester (803 mg) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:26][C:27]1[CH:32]=[C:31](CBr)[CH:30]=[CH:29][C:28]=1[Cl:35]>>[Br:26][C:27]1[CH:32]=[C:31]([CH:30]=[CH:29][C:28]=1[Cl:35])[CH2:21][S:20][C:15]1[C:12]2[CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10][C:11]=2[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: Clc1ccc(CBr)cc1Br
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Cl)c(Br)c3)c2CC1

Procedure:
Use a method similar to the Preparation 177, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylsulfanyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 2-bromo-4-bromomethyl-1-chloro-benzene, to give the title compound.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[C:18](I)[N:17]=2)=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH2:30](B1OC(C)(C)C(C)(C)O1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>COC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[C:18]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:17]=2)=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(Cc2ccccc2)OC1(C)C
Reactant: Cc1nc(-c2cncc(I)n2)sc1C(=O)NCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: COC
Solvent: O
Product: Cc1nc(-c2cncc(Cc3ccccc3)n2)sc1C(=O)NCc1ccccc1
Reaction time: 4 h
Yield: 64 %

Procedure:
Part C. To a solution of 2-(6-iodo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid benzylamide (70 mg, 0.16 mmol, 1.0 equiv) in dimethyl ether (1 mL) was added Na2CO3 (34 mg, 0.32 mmol, 2.0 equiv), benzyl boronic acid pinacol ester (87 μL, 0.40 mmol, 2.5 equiv), PdCl2(dppf) (11 mg, 0.02 mmol, 0.1 equiv) and water (0.1 mL) in a sealed tube. The reaction was immersed in an oil bath preheated to 100° C. After stirring for 4 hr, the reaction was cooled and the solvent was removed in vacuo. The crude product was purified by column chromatography [SiO2, methanol/dichloromethane, 0:100 to 10:90, v/v] and recrystallization (methanol/pentane) to give 2-(6-benzyl-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid benzylamide (41 mg, 65%). 1H NMR (400 MHz, CD2Cl2) δ 9.17 (s, 1H), 8.47 (s, 1H), 7.22-7.37 (m, 10H), 6.23 (bs, 1H), 4.59 (d, J=8.0 Hz, 2H), 4.19 (s, 2H), 2.72 (s, 3H); HRMS (M+H)+=401.14.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[C@@H:7]([N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:13][C:12]1=[O:20])[CH2:8][CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[I-].C[N+](C)(C)[CH2:31][C:32]1[C:33]2[C:40]([CH3:41])=[CH:39][CH:38]=[CH:37][C:34]=2[S:35][CH:36]=1>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:21])[C@@H:7]([N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([CH2:31][C:32]2[C:33]3[C:40]([CH3:41])=[CH:39][CH:38]=[CH:37][C:34]=3[S:35][CH:36]=2)[C:12]1=[O:20])[CH2:8][CH2:9][CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cccc2scc(C[N+](C)(C)C)c12
Reactant: CCC[C@@H](C(=O)OC(C)(C)C)n1c(=O)[nH]c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC[C@@H](C(=O)OC(C)(C)C)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Temperature: 80 °C
Yield: 71.8 %

Procedure:
To a solution of (S)-2-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-pentanoic acid tert-butyl ester (0.1 g, 0.34 mmol) in DMF (2 mL) were added K2CO3 (0.1 g, 0.69 mmol) and trimethyl-(4-methyl-benzo[b]thiophen-3-ylmethyl)-ammonium iodide (0.24 g, 0.69 mmol). The reaction mixture was heated to 80° C. for 5 h. The reaction mixture was then diluted with ethyl acetate and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 98:2 CH2Cl2:MeOH as an eluent to afford 0.11 g (71%) of the desired product as an oily residue. LCMS (ESMS): m/z 451.33 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:20])[C:6](=[O:19])[NH:7]2.Cl[Sn]Cl>CCO>[NH2:12][C:11]1[C:2]([Cl:1])=[C:3]2[C:8](=[CH:9][C:10]=1[C:15]([F:17])([F:18])[F:16])[NH:7][C:6](=[O:19])[C:5](=[O:20])[NH:4]2
Reactant: O=c1[nH]c2cc(C(F)(F)F)c([N+](=O)[O-])c(Cl)c2[nH]c1=O
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1c(C(F)(F)F)cc2[nH]c(=O)c(=O)[nH]c2c1Cl
Yield: 73.6 %

Procedure:
A mixture of 5-chloro-6-nitro-7-trifluoromethyl-1,4-dihydroquinoxaline-2,3-dione (230 mg, 0.743 mmol), SnCl2 ·2H2O (1.90 g, 7.43 mmol) and EtOH (300 mL) was refluxed for 24 h, then rota-evaporated to dryness. The residual solid was washed on a Bursch funnel with water (6×15 mL), and dried to give 153 mg (74%) of the title compound as a yellow powder. Mp>360° C. (1H NMR (DMSO-d6) 11.777 (s, 1H), 11.360 (s, 1H), 7.140 (s, 1H), 5.499 (s, 2H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1.C1(B(O)O)C=CC=CC=1.[Cl:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>>[Cl:30][C:31]1[CH:36]=[C:35]([C:2]2[C:3]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[CH:11][C:4]=3[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: CN1C(=O)CN=C(Cl)c2cc(-c3ccccc3)ccc21
Reactant: OB(O)c1cccc(Cl)c1
Agent: OB(O)c1ccccc1
Product: CN1C(=O)CN=C(c2cccc(Cl)c2)c2cc(-c3ccccc3)ccc21
Yield: 37 %

Procedure:
Prepared from 5-chloro-1-methyl-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one using the same method described for Example 9 and instead of using benzene boronic acid, we used 3-chlorophenyl boronic acid. The title compound was obtained as a pale yellow solid, (yield=37%).
Reaction SMILES: Cl[CH:2]([CH3:6])[C:3]([OH:5])=[O:4].[OH-].[Na+].[Cl:9][C:10]1[CH:23]=[CH:22][C:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1>O.C1(C)C(C)=CC=CC=1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:2]([CH3:6])[C:3]([OH:5])=[O:4])=[CH:17][CH:16]=2)=[CH:22][CH:23]=1
Reactant: CC(Cl)C(=O)O
Reactant: Oc1ccc(Cc2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(Oc1ccc(Cc2ccc(Cl)cc2)cc1)C(=O)O
Reaction time: 0.25 h

Procedure:
129.8 Parts of 2-chloropropionic acid, 194 parts of 50% sodium hydroxide solution and 80 parts of water are mixed as described in Example 1. The clear, viscous liquid so obtained is added portionwise to a solution of 218.5 parts of 4-(4'-chlorobenzyl)-phenol in 1,000 parts of xylene; the reaction temperature being maintained at 110°-115° C. by azeotropic distillation of water in a water trap. The addition being complete, stirring is continued for 15 minutes at 110° C. Work-up is as described in Example 2. 290.5 Parts of 2-[4'-(4"-chlorobenzyl)-phenoxy]-propionic acid are obtained. The content of pure final product is 99.8%, corresponding to a yield of 99.8% of theory. The residual content of 4-(4'-chlorobenzyl)--phenol is 0.1%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:26]=[CH:25][CH:24]=[CH:23][C:11]=3[C:12]=2[C:13](=[O:22])[C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:33]([N:35]([CH2:39][CH3:40])[CH2:36][CH2:37]Cl)[CH3:34]>CC(C)=O>[CH2:33]([N:35]([CH2:39][CH3:40])[CH2:36][CH2:37][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:26]=[CH:25][CH:24]=[CH:23][C:11]=3[C:12]=2[C:13](=[O:22])[C:14]2[CH:15]=[C:16]([CH3:21])[CH:17]=[C:18]([CH3:20])[CH:19]=2)=[CH:6][CH:7]=1)[CH3:34]
Reactant: CCN(CC)CCCl
Reactant: Cc1cc(C)cc(C(=O)c2c(-c3ccc(O)cc3)oc3ccccc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)CCOc1ccc(-c2oc3ccccc3c2C(=O)c2cc(C)cc(C)c2)cc1

Procedure:
2-p-Hydroxyphenyl-3-(3',5'-dimethylbenzoyl)benzofuran (5.25 g., 15.3 mmol.) was dissolved in 200 ml. of dry acetone and 10.5 g. (0.076 mol.) of potassium carbonate and 2.10 g. (15.3 mmol.) of 2-diethylaminoethyl chloride were added. The reaction mixture was refluxed for three hours, then it was cooled and filtered. The filtrate was concentrated at reduced pressure to give the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:14][C:13]=1[F:26])[N:5]=2.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1.C(N(CC)CC)C.O>CN(C)C(=O)C>[CH:27]1([C:30]([NH:1][C:2]2[S:3][C:4]3[C:9]([N:10]=2)=[CH:8][CH:7]=[C:6]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:14][C:13]=2[F:26])[N:5]=3)=[O:31])[CH2:29][CH2:28]1
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc3nc(N)sc3n2)c(F)c1
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.7 %

Procedure:
To a solution of tert-butyl {4-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-3-fluorophenyl}carbamate (2.02 g, 5.37 mmol) in N,N-dimethylacetamide (20.2 mL) were added cyclopropanecarbonyl chloride (0.97 mL, 10.7 mmol) and triethylamine (2.24 mL, 16.1 mmol), and the mixture was stirred at room temperature for 24 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, methanol (20 mL) and 5% aqueous sodium carbonate solution (10 mL) were added to the residue, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with hexane/ethyl acetate (=1/1) and collected by filtration to give the title compound (1.33 g, 56%).