Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:14]O>>[CH3:14][O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: COC(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of (3,4-dichlorophenyl)acetic acid (16.12 g, 78.5 mmol) in MeOH (500 mL) was bubbled with HCl gas for 5 min. The mixture was stirred at room temperature for 1 h. The solvent was removed by rotary evaporation and the. resulting residue was dissolved in EtOAc (400 mL) and washed with saturated aqueous NaHCO3 (200 mL) and saturated aqueous NaCl (200 mL). The organic extracts were dried over sodium sulfate, filtered and concentrated by rotary evaporation to give (3,4-dichlorophenyl)acetic acid methyl ester (16.22 g, 74.1 mmol, 95%). 1H NMR (300 MHz, CDCl3): δ 7.50 (m, 2H), 7.23 (dd, 1H), 3.81 (s, 3H), 3.69 (s, 2H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:9][S:8][C:7]=2[CH:17]=1.Cl[C:19]1[N:20]([CH3:32])[C:21](=[O:31])[CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][N:26]=2)[N:24]=1.C(N(CC)CC)C>O1CCCC1>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH:11]3[CH2:12][CH2:13][N:14]([C:19]4[N:20]([CH3:32])[C:21](=[O:31])[CH:22]=[C:23]([C:25]5[CH:30]=[CH:29][N:28]=[CH:27][N:26]=5)[N:24]=4)[CH2:15][CH2:16]3)=[CH:9][S:8][C:7]=2[CH:17]=1
Reactant: Fc1ccc2c(C3CCNCC3)csc2c1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCC(c3csc4cc(F)ccc34)CC2)nc(-c2ccncn2)cc1=O
Temperature: 90 °C
Reaction time: 6 h
Yield: 74.6 %

Procedure:
To a solution of 4-(6-fluorobenzo[b]thiophen-3-yl)piperidine hydrochloride (200 mg, 0.74 mmol) and 2-chloro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (160 mg, 0.70 mmol) in tetrahydrofuran (10 mL) was added triethylamine (212 mg, 2.1 mmol). The mixture was stirred at 90° C. for 6 h. The solvent was evaporated off in vacuo and the residue was treated with water and chloroform. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. Recrystallization from ethyl acetate gave 2-[4-(6-fluorobenzo[b]thiophen-3-yl)piperidin-1-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (220 mg, 96%) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O>>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: Nc1c(F)cc(Br)cc1F
Product: Nc1c(F)cc(-c2ccccc2F)cc1F
Yield: 91.8 %

Procedure:
The title compound (0.492 g) was prepared from 4-bromo-2,6-difluoroaniline (0.5 g, 2.4 mmol) and 2-fluorophenylboronic acid (0.436 g, 3.12 mmol) as a yellow liquid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.51 (td, J 1.5, 7.9, 1H), 7.38-7.31 (m, 1H), 7.29-721 (m, 2H), 7.14 (d, J 8.6, 2H), 5.44 (s, 2H).
Reaction SMILES: C(O[C:9]([N:11](C)[N:12]1[C:21]([C:22](O)=[O:23])=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:31])[CH:18]=2)[C:13]1=[O:32])=O)C1C=CC=CC=1.[CH3:34][C:35]1[N:36]=[CH:37][S:38][C:39]=1[CH2:40][CH2:41][OH:42]>>[CH3:34][C:35]1[N:36]=[CH:37][S:38][C:39]=1[CH2:40][CH2:41][O:42][C:22]([C:21]1[N:12]([NH:11][CH3:9])[C:13](=[O:32])[C:14]2[C:19]([C:20]=1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[CH:18][C:17]([Cl:31])=[CH:16][CH:15]=2)=[O:23]
Reactant: CN(C(=O)OCc1ccccc1)n1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: Cc1ncsc1CCO
Product: CNn1c(C(=O)OCCc2scnc2C)c(-c2ccccc2)c2cc(Cl)ccc2c1=O

Procedure:
The present compound was synthesized by a method similar to that in Example 207 and using 2-[(benzyloxycarbonyl)(methyl)amino]-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (150 mg) and 2-(4-methylthiazol-5-yl)ethanol. A colorless powder (41 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[S:5][C:6]=1[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][C:8]=1[Cl:13].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:39])[F:40])[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:16])[S:5][C:6]=1[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][C:8]=1[Cl:13]
Reactant: Cn1ncc(Cl)c1-c1sc(C(=O)O)cc1Cl
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(Cl)c1-c1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1Cl
Reaction time: 1 h
Yield: 81.3 %

Procedure:
To a solution of 4-chloro-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (136.1 mg, 0.49 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (179 mg, 0.51 mmol)[prepared according to Preparation 6], diisopropylethyl amine (260 uL, 1.5 mmol) in DCM (5 mL) was added PyBrop (341 mg, 0.75 mmol) in one portion. After 1 h, the reaction contents were partitioned between H2O/DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, gradient 0-50% ethyl acetate/hexane) affording the title compound (242 mg, 82%) as a white solid: LCMS (ES) m/z=607 (M+H)+.
Reaction SMILES: CN1CCN(C2C=CC(N[CH:15]=[C:16]3[C:24]4[C:19](=[CH:20][C:21]([C:25]([C:27]5[CH:28]=[C:29]([NH:33][C:34]([C:36]6[C:40]([Cl:41])=[CH:39][N:38]([CH2:42][CH3:43])[N:37]=6)=[O:35])[CH:30]=[CH:31][CH:32]=5)=[O:26])=[CH:22][CH:23]=4)[NH:18][C:17]3=[O:44])=CC=2)CC1.C1COCC1.[NH2:50][C:51]1[CH:56]=[CH:55][C:54]([CH2:57][CH2:58][CH2:59][C:60]([OH:62])=[O:61])=[CH:53][CH:52]=1>CCOC(C)=O.CCCCCC>[Cl:41][C:40]1[C:36]([C:34]([NH:33][C:29]2[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=2)[C:25]([C:21]2[CH:20]=[C:19]3[C:24]([C:16](=[CH:15][NH:50][C:51]4[CH:52]=[CH:53][C:54]([CH2:57][CH2:58][CH2:59][C:60]([OH:62])=[O:61])=[CH:55][CH:56]=4)[C:17](=[O:44])[NH:18]3)=[CH:23][CH:22]=2)=[O:26])=[O:35])=[N:37][N:38]([CH2:42][CH3:43])[CH:39]=1
Reactant: Nc1ccc(CCCC(=O)O)cc1
Reactant: CCn1cc(Cl)c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCN(C)CC4)cc3)c2)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCn1cc(Cl)c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CCCC(=O)O)cc3)c2)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 45 %

Procedure:
A small screw cap test tube was charged with 4-Chloro-1-ethyl-1H-pyrazole-3-carboxylic acid [3-(3-{[4-(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 342, 100 mg, 0.229 mmol) and THF (2.5 mL). To the resulting solution was added 4-(4-Amino-phenyl)-butyric acid (41.4 mg, 0.231 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and diluted with EtOAc (˜5 mL) and Hexane (˜40 mL). The solid that precipitated was collected by filtration and washed with 0° C. acetone (˜10 mL) affording the title compound in 45% yield (0.061 g, 0.102 mmol).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[C:28]3[C:27]4[C@@H:26]([CH2:29][CH:30]=[O:31])[CH2:25][CH2:24][C:23]=4[S:22][C:21]=3[N:20]=[CH:19][N:18]=2)[CH2:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Br[Mg][CH2:34][CH3:35]>C1COCC1>[OH:31][C@@H:30]([CH2:34][CH3:35])[CH2:29][C@H:26]1[CH2:25][CH2:24][C:23]2[S:22][C:21]3[N:20]=[CH:19][N:18]=[C:17]([O:16][CH:13]4[CH2:14][CH2:15][CH:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7])[CH2:11][CH2:12]4)[C:28]=3[C:27]1=2.[OH:31][C@H:30]([CH2:34][CH3:35])[CH2:29][C@H:26]1[CH2:25][CH2:24][C:23]2[S:22][C:21]3[N:20]=[CH:19][N:18]=[C:17]([O:16][CH:13]4[CH2:14][CH2:15][CH:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7])[CH2:11][CH2:12]4)[C:28]=3[C:27]1=2
Reactant: CC[Mg]Br
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC=O)CC4)CC1
Solvent: C1CCOC1
Product: CC[C@@H](O)C[C@H]1CCc2sc3ncnc(OC4CCC(N(C)C(=O)OC(C)(C)C)CC4)c3c21
Product: CC[C@H](O)C[C@H]1CCc2sc3ncnc(OC4CCC(N(C)C(=O)OC(C)(C)C)CC4)c3c21
Reaction time: 2 h
Yield: 56 %
Yield: 81 %

Procedure:
To a solution of tert-butyl N-methyl-N-(4-[[(3R)-3-(2-oxoethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)carbamate (370 mg, 0.83 mmol, 1.00 equiv) in freshly distilled THF (15 mL) was added dropwise bromo(ethyl)magnesium (0.46 mL, 1.25 mmol, 1.50 equiv) at 0° C. under nitrogen. The resulting solution was stirred for 2 h at r.t and quenched by the addition of H2O. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10-1:5) to give 0.11 g (56%) of tert-butyl N-(4-[[(3R)-3-[(2S)-2-hydroxybutyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (195.1) as a light yellow oil and 0.16 g (81%) of tert-butyl N-(4-[[(3R)-3-[(2R)-2-hydroxybutyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (196.1) as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH:9]=[CH2:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C1C(C(OO[C:22]([CH3:25])(C)C)=O)=CC=CC=1.[CH:26]([Cl:29])([Cl:28])[Cl:27]>>[CH2:22]([CH:3]([C:2]([CH3:1])([CH3:11])[CH2:9][CH2:10][C:26]([Cl:29])([Cl:28])[Cl:27])[C:4]([OH:6])=[O:5])[CH3:25].[Cl:27][C:26]([Cl:29])([Cl:28])[CH2:10][CH2:9][C:2]([CH3:1])([CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C=CC(C)(C)CC(=O)OCC
Reactant: CC(C)(C)OOC(=O)c1ccccc1
Reactant: ClC(Cl)Cl
Product: CCC(C(=O)O)C(C)(C)CCC(Cl)(Cl)Cl
Product: CCOC(=O)CC(C)(C)CCC(Cl)(Cl)Cl
Temperature: 120 °C
Yield: 958.5 %

Procedure:
A pressure-resistant tubular reactor was charged with a mixture of 20.0 g of ethyl 3,3-dimethyl-4-pentenate, 200 g of chloroform and 1.0 g of t-butyl perbenzoate and, after the tube was sealed, the contents were heated at 120° C. for 20 hours. Then, the reaction mixture was distilled to remove the low-boiling fraction and further subjected to distillation under reduced pressure. By the above procedure there were obtained 27.2 g of ethyl β-(3,3,3-trichloropropyl)isovalerate(ethyl 6,6,6-trichloro-3,3-dimethylhexanoate) (yield: 77%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2N=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][CH:3]=1.[NH:19]1[CH:23]=[C:22]([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH:21]=[N:20]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:39]S(C)=O>>[F:18][C:15]([F:16])([F:17])[C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:6]2[N:7]=[C:2]([N:20]3[CH:21]=[C:22]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH:23]=[N:19]3)[CH:3]=[CH:4][CH:5]=2)[CH:39]=1
Reactant: CCOC(=O)CCc1cn[nH]c1
Reactant: CS(C)=O
Reactant: FC(F)(F)c1ccnc(Nc2cccc(Br)n2)n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: O=C(O)CCc1cnn(-c2cccc(Nc3cc(C(F)(F)F)ccn3)n2)c1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
N-(6-Bromopyridin-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine (0.015 g, 0.047 mmol), ethyl 3-(1H-pyrazol-4-yl)propanoate (0.008 g, 0.047 mmol), potassium phosphate tribasic (0.030 g, 0.14 mmol), and DMSO (0.48 mL) were added to a microwave vial. The reaction tube was sealed and heated to 130° C. for 12 hours. The completed reaction was diluted DMSO (0.5 mL) and passed through a syringe filtered where the eluent was collected and concentrated under reduced pressure. The residue was taken up in dichloromethane (1.0 mL), MeOH (0.5 mL), and NaOH (0.5 mL, 1.0 M) and was allowed to stir at ambient temperature for 4 hours. The reaction was concentrated under reduced pressure. The residue was taken up in DMSO (1.0 mL), passed through a syringe filter and purified by reverse phase preparative HPLC (0 to 95% ACN/H2O with 0.1% ammonium hydroxide modifier) to afford 3-(1-(6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)-1H-pyrazol-4-yl)propanoic acid. MS ESI calc. for C12H15F3N5O2 [M+H]+ 378. found 378. 1H NMR (600 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.48 (d, J=5.2, 1H), 8.19 (s, 1H), 8.18 (s, 1H), 7.80 (t, J=8.0, 1H), 7.60 (s, 1H), 7.49 (d, J=8.2, 1H), 7.34 (d, J=7.8, 1H), 7.20 (d, J=5.3, 1H), 2.62 (t, J=7.6, 2H), 2.23 (t, 2H).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OOC(C)(C)C)(C)(C)C.[CH:18]([O:20][CH2:21][CH3:22])=[CH2:19]>>[CH2:18]([O:20][CH2:21][CH2:22][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C:1]1=[O:7])[CH3:19]
Reactant: C=COCC
Reactant: O=C1CCCCC1
Agent: CC(C)(C)OOC(C)(C)C
Product: CCOCCC1CCCCC1=O
Yield: 95 %

Procedure:
2940 g (30 mol) of cyclohexanone were heated to reflux while stirring and, at this temperature, a solution of 87.6 g (0.6 mol) of di-tert-butyl peroxide in 216 g (3 mol) of ethyl vinyl ether was added over the course of 5 hours (h). The mixture was subsequently refluxed for a further 1 h. After the mixture had cooled, the low boilers (tert-butanol, remaining vinyl ether and peroxide) and the excess cyclohexanone were removed by distillation under reduced pressure (25-40 mbar; diaphragm pump). The residue (about 500 g) was distilled under reduced pressure (0.5 to 2 mbar; oil pump). A total of 350 g of a 95% pure 2-(2-ethoxyethyl)cyclohexanone of boiling point 60°-65° C. (0.5 mbar) was obtained, corresponding to a yield of 69% of theory.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=[O:5])C.[NH2:28][C:29]1[N:34]=[CH:33][C:32]([CH2:35][N:36]([CH3:41])[CH2:37][C:38]([NH2:40])=[O:39])=[CH:31][CH:30]=1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[C:38]([CH2:37][N:36]([CH2:35][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=3[F:22])=[CH:14][CH:15]=2)=[O:5])=[N:34][CH:33]=1)[CH3:41])(=[O:39])[NH2:40]
Reactant: CN(CC(N)=O)Cc1ccc(N)nc1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN(C)CC(N)=O)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 22 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), 2-[(6-amino-pyridin-3-ylmethyl)-methyl-amino]-acetamide (Step 118.1), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 22 h at 80° C. and pouring it onto a saturated aqueous solution of NaHCO3 and DCM. The title compound: ESI-MS: 523.1 [M+H]+; tR=3.53 min (System 1); TLC: Rf=0.16 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12](=[O:21])[CH2:13][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:6][CH:5]=1>C(Cl)(Cl)Cl>[Br:1][C:13]1[C:12](=[O:21])[CH:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=2)[O:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: BrBr
Reactant: CCOC(=O)C(=O)CC(=O)C=Cc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1oc(-c2ccc(Cl)cc2)cc(=O)c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of bromine (7.06 ml) in chloroform (70 ml) was added dropwise to a stirred solution of ethyl 6-(4-chlorophenyl)-2,4-dioxo-hex-5-enoate (19.2 g) in chloroform (300 ml) at 5° to 10° C. The solution was stirred for 30 minutes at room temperature then evaporated to a yellow oil. This crude tribromide was dissolved in dimethylsulphoxide (150 ml), and 1,5-diazabicyclo[4.3.0]non-5-ene (16.9 g) was added at 20° to 25° C. The mixture was stirred for 30 minutes at room temperature then diluted with ice-water (300 ml) to precipitate a sticky brown solid. A solution of this crude product in chloroform was passed down a short column of silica-gel (100 g) and then evaporated. The residual solid was washed with ethyl acetate-petroleum ether 60°-80° C., then recrystallised from ethyl acetate-petroleum ether 60°-80° C. to give the title product as yellow needles (mp 146°-149° C.).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14]([NH2:16])=[O:15])[CH:5]=[CH:4][CH:3]=1.[I:17]N1C(=O)CCC1=O>CN(C)C=O.ClCCl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[I:17][C:11]1[S:10][C:9]([NH:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)=[C:13]([C:14]([NH2:16])=[O:15])[CH:12]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cccc(Nc2sccc2C(N)=O)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cccc(Nc2sc(I)cc2C(N)=O)n1

Procedure:
To a solution of 2-[(6-methylpyridin-2-yl)amino]thiophene-3-carboxamide (2.8 g, 12.0 mmol) in dimethylformamide (40 mL) and dichloromethane (80 mL) was added slowly N-iodosuccinimide (1.060 g, 4.71 mmol). After twenty minutes, the reaction mixture was diluted with ethyl acetate (400 mL), hexanes (40 mL), and saturated aqueous sodium bicarbonate (100 mL) and filtered through a Buchner funnel. The layers of the filtrate were separated, and the organic layer was washed with water (3×100 mL, filtering before separated layers as above) and a 5:1 mixture of brine:saturated aqueous sodium thiosulfate (120 mL). The resulting organic layer was dried over sodium sulfate, filtered through a pad of Celite, and concentrated. The resulting solid was triturated with a mixture of dichloromethane, ethyl acetate, methanol, and dichloromethane to afford the title compound as a purple powder.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[NH:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.[NH4+].[Cl-].C(Cl)CCl.CC[N:30](CC)CC>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:7])[NH2:30])=[CH:4][C:3]=1[NH:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: CCN(CC)CC
Reactant: COc1ccc(C(=O)Nc2cc(C(=O)O)ccc2N)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccc(C(=O)Nc2cc(C(N)=O)ccc2N)cc1
Yield: 30 %

Procedure:
A solution of 108 (200 mg, 0.70 mmol), NH4Cl (74 mg, 1.40 mmol), HOBT-hydrate (104 mg, 0.77 mmol), EDC (119 mg, 0.77 mmol) and Et3N (0.29 ml, 2.1 mmol) in DMF (3 ml) was stirred for 16 h at room temperature. The solvent was evaporated, ethyl acetate was added and the organic layer was washed successively with saturated solutions of NH4Cl, NaHCO3 and NaCl, dried over MgSO4, filtered and concentrated. The crude product was triturated in ethyl acetate and filtered to give the title compound 109 (60 mg, 30%). 1H NMR: (DMSO) δ (ppm): 9.57 (s, 1H), 7.96 (d, J=8.8 Hz, 2H), 7.67 (d, J=2.2 Hz, 1H), 7.59 (sb, 1H), 7.52 (dd, J=8.2, 2.0 Hz, 1H), 7.02 (d, J=8.8 Hz, 2H), 6.90 (sb, 1H), 6.72 (d, J=8.4 Hz, 1H), 5.41 (s, 2H), 3.83 (s, 3H). MS: (calc.) 285.1; (obt.) 286.1 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][C:14]([OH:16])=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].S(Cl)([Cl:19])=O>ClC(Cl)Cl>[Cl:19][C:14](=[O:16])[CH2:13][CH2:12][CH:9]1[CH2:10][CH2:11][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]1
Reactant: CCOC(=O)N1CCC(CCC(=O)O)CC1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC(CCC(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47 %

Procedure:
To a stirred mixture of 200 parts of 1-(ethoxycarbonyl)-4-piperidinepropanoic acid and 750 parts of trichloromethane were added 320 parts of thionyl chloride. The whole was stirred for 18 hours at room temperature. The reaction mixture was evaporated with methylbenzene. The residue was distilled, yielding 102.6 parts (47%) of ethyl 4-(3-chloro-3-oxopropyl)-1-piperidinecarboxylate; bp. 165-170 at 399 Pa (int. 45).
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[Na+].[Na+].Br[C:8]1[CH:18]=[CH:17][C:11]([C:12](OCC)=[O:13])=[CH:10][CH:9]=1.[OH-].[Na+].Cl.[C:22]1([CH3:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O.C(OCC)(=O)C.C(O)C>[O:13]1[C:12]([C:11]2[CH:17]=[CH:18][C:8]([C:1]([OH:2])=[O:4])=[CH:9][CH:10]=2)=[CH:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]1=2
Reactant: Cc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(-c2cc3ccccc3o2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Benzofuranyl-2-boric acid (2.1 g), palladium tetratriphenylphosphine (200 mg) and 2M aqueous sodium carbonate solution were added to toluene (40 ml)-ethanol (10 ml) solution of ethyl 4-bromobenzoate (2.3 g), which was refluxed at 80° C. for 5 hours under an argon atmosphere. The reaction mixture was diluted with water, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The resulting residue was purified using silica gel chromatography (development solvent; ethyl acetate:hexane=1:4), and concentrated, which was dissolved in methanol (10 ml)-THF (10 ml). 8 mol of aqueous sodium hydroxide solution (8 ml) was added to the resulting solution at room temperature, which was stirred for 2 hours. After 1 mol of hydrochloric acid was added to the reaction mixture to make the mixture acidic, extraction was conducted using ethyl acetate-THF (1:1). The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The resulting residue was washed with hexane to give the titled compound (2.272 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][CH2:6][CH:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([CH3:18])[N:13]=[C:14](O)[C:15]=3[N:16]=2)[CH2:4][CH2:3]1.C1(C)C=CC=CC=1.P(Cl)(Cl)([Cl:29])=O>CN(C=O)C>[Cl:29][C:14]1[C:15]2[N:16]=[C:8]([CH:5]3[CH2:6][CH2:7][C:2]([CH3:19])([CH3:1])[CH2:3][CH2:4]3)[S:9][C:10]=2[N:11]=[C:12]([CH3:18])[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(O)c2nc(C3CCC(C)(C)CC3)sc2n1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1nc(Cl)c2nc(C3CCC(C)(C)CC3)sc2n1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-(4,4-dimethylcyclohexyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidin-7-ol (16.2 g) and toluene (160 mL) were added DMF (10 mL) and phosphorous oxychloride (11 mL), followed by stirring at 95° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure. To the residue was added chloroform, and the mixture was neutralized with a 1 M aqueous NaOH solution in an ice bath and extracted with chloroform. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by silica gel column (hexane/EtOAc) to obtain 7-chloro-2-(4,4-dimethylcyclohexyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidine (13.2 g).