Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:15][N:14]([O:16][CH2:17][C:18]([OH:20])=[O:19])[C:13]1=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[CH3:33][C:34]([CH3:41])([CH3:40])[C:35]([O:37][CH2:38]I)=[O:36]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:15][N:14]([O:16][CH2:17][C:18]([O:20][CH2:38][O:37][C:35](=[O:36])[C:34]([CH3:41])([CH3:40])[CH3:33])=[O:19])[C:13]1=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: O=C(O)CON1C[C@H](NC(=O)OCc2ccccc2)C1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCOC(=O)CON1C[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(S)-[[3-[(Benzyloxycarbonyl)amino]-2-oxo-1-azetidinyl]oxy]acetic acid (3 g; see example 79) was dissolved in 200 ml of dimethylformamide and the solution was cooled to 0° C. 1,8-diazabicyclo[5.4.0]-undec-7-ene (0.01 mol) was added followed by 2.7 g of 2,2-dimethylpropionic acid, iodomethyl ester. After 10 minutes, the mixture was diluted with 75ml of ethyl acetate, cooled (ice-water), washed with ice-cold water, ice-cold diluted sodium bicarbonate solution and again with ice-cold water. After drying (MgSO4) the filtrate was evaporated to yield 4g of the title compound, which crystallized on standing; melting point 73°-75° C.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C@@H:7]1[NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])=[O:5])C.[OH-].[Li+].Cl>O1CCCC1>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][C@H:6]([C:4]([OH:5])=[O:3])[C@@H:7]([NH:19][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:8]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1NC(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](C(=O)O)[C@@H](NC(=O)OCc2ccccc2)C1
Reaction time: 60 h
Yield: 101.9 %

Procedure:
In a flask (3R,4S)-3-benzyloxycarbonylamino-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (1.19 g, 2.93 mmol) was dissolved in tetrahydrofuran (48 mL) and lithium hydroxide (12 mL of a 1N aqueous solution, 15 mmol) was added. The mixture was stirred for 60 hours. The reaction mixture was acidified with aqueous hydrochloric acid (3 mL of a 2M solution) and then extracted with ethyl acetate three times (30 mL). The combined organic layers were dried with magnesium sulfate, filtered, and concentrated in vacuo to give a crude white solid (1.13 g) which was used without further purification. 1H NMR (300 MHz, CDCl3), δ: 7.35 (m, 5H), 5.10 (m, 2H), 3.91, (m, 2H), 3.19 (m, 1H), 2.71 (m, 2H), 1.92 (m, 1H), 1.74 (m, 2H), 1.45 (s, 9H). MS (APCI), m+/z: (M+H)+=379.
Reaction SMILES: C1(O)C=CC=CC=1.[Cl:8][C:9]1[C:14]([OH:15])=[C:13]([Cl:16])[C:12](Cl)=[C:11]([Cl:18])[C:10]=1Cl>>[Cl:8][C:9]1[CH:10]=[C:11]([Cl:18])[CH:12]=[C:13]([Cl:16])[C:14]=1[OH:15]
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Solvent: Oc1ccccc1
Product: Oc1c(Cl)cc(Cl)cc1Cl

Procedure:
About 143 g of phenol (an amount that should lead to an equivalent amount of pentachlorophenol product, by moles, obtained when about 300 g of 2,4,6-trichlorophenol is used) were added to a reactor at 60° C. with 0.75 g of AlCl3 (about 0.25 wt. % based on trichlorophenol). The same stirring rate (100-120 RPM) and chlorine flow rate (1.5 mol/hr) as experiments that started with trichlorophenol were used.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][CH:7]=1.Cl[C:19]1[CH:35]=[C:23]2[N:24](C(OC(C)(C)C)=O)[CH2:25][CH2:26][CH2:27][N:22]2[C:21](=[O:36])[N:20]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][O:13][C:19]2[CH:35]=[C:23]3[NH:24][CH2:25][CH2:26][CH2:27][N:22]3[C:21](=[O:36])[N:20]=2)=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2ccc(F)c(F)c2)cc1
Product: O=c1nc(OCc2ccc(Oc3ccc(F)c(F)c3)cc2)cc2n1CCCN2

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E111 starting from (4-(3,4-difluorophenoxy)phenyl)methanol and tert-butyl 8-chloro-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido[1,6-a]pyrimidine-1-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][S:14][C:13]([CH3:18])([CH3:17])[C@@H:12]2[C:19]([O:21][CH3:22])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:23](O)[C:24]#[C:25][CH2:26][OH:27]>>[OH:27][CH2:26][C:25]#[C:24][CH2:23][O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][S:14][C:13]([CH3:17])([CH3:18])[C@@H:12]2[C:19]([O:21][CH3:22])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1N(S(=O)(=O)c2ccc(O)cc2)CCSC1(C)C
Reactant: OCC#CCO
Product: COC(=O)[C@@H]1N(S(=O)(=O)c2ccc(OCC#CCO)cc2)CCSC1(C)C
Yield: 65.2 %

Procedure:
According to the procedure of Step 2 of Example 248, Mitsunobu coupling of 0.10 g (0.288 mmoL) of methyl(3S)-4-[(4-hydroxyphenyl)sulfonyl]-2,2-dimethyl-3-thiomorpholinecarboxylate and 0.031 g (0.363 mmol) of 2-butyne-1,4-diol gave 0.078 g of methyl(3S)-4-({4-[(4-hydroxy-2-butynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholine carboxylate as a colorless oil.
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[SH:15])=O)(C)(C)C>C(O)=O>[S:15]1[C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:8]=[CH:6]1
Reactant: CC(C)(C)OC(=O)Nc1cnccc1S
Solvent: O=CO
Product: c1cc2scnc2cn1

Procedure:
3-(tert-Butoxycarbonylamino)-4-mercaptopyridine (Japanese Patent Application Laid-Open No. 321691/1992) (9.20 g) was dissolved in formic acid (60 ml) and heated under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, and a 4N aqueous solution (100 ml) of potassium hydroxide and ether were added to the residue to conduct liquid separation. The resultant organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Ether was added to the residue, and solids deposited were collected by filtration to obtain the title compound (3.97 g) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][C:27]([N:30]4[C@@H:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=5)[CH2:33][O:32][C:31]4=[O:41])=[N:26][C:25]=23)[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]=[CH:11][N:10](COCC[Si](C)(C)C)[N:9]=1.C(O)(C(F)(F)F)=O>CC#N.CO.O>[F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][C:27]([N:30]4[C@@H:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=5)[CH2:33][O:32][C:31]4=[O:41])=[N:26][C:25]=23)[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]=[CH:11][NH:10][N:9]=1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc(-c3cnn4ccc(N5C(=O)OC[C@@H]5c5ccccn5)nc34)cc2F)n1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=C1OC[C@H](c2ccccn2)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)c(F)c3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
To (S)-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-(pyridin-2-yl)oxazolidin-2-one (0.090 g, 0.16 mmol) was added TFA (10 mL) and the reaction was stirred at ambient temperature for 2 hours. The reaction was concentrated in vacuo and the resulting material dissolved in MeOH/CH3CN/water (1:1:1, 30 mL total) and stirred for 20 minutes at ambient temperature. The mixture was basified by adding NaHCO3 (saturated aqueous solution) and the solid that formed was isolated by filtration. The solids were slurried in CH3CN/MeOH/water (1:1:5, 40 mL total) and the material filtered and dried in vacuo to yield (S)-3-(3-(3-fluoro-4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-(pyridin-2-yl)oxazolidin-2-one (0.054 g, 77.1%). LCMS (APCI+) m/z 443 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](/[C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)\O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[N:37]1([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[O:43][C:42]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[N:44][C:9]=2[C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NC(=O)N1CCCC1
Reactant: O=S(=O)(Nc1cccc(/C(O)=C/c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Agent: O=C1CCC(=O)N1Br
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCCC3)oc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F

Procedure:
Following a procedure analogous to the procedure described in Intermediate 6 using N-{3-[(Z)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide (2.0 g, 4.72 mmol, NBS (0.924 g, 5.19 mmol) and 1-pyrrolidinecarboxamide (1.077 g, 9.44 mmol) heated to 90° C. for 24 h the title compound of Step A was obtained as an orange solid (0.980 g). MS-ESI m/z 518 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][N:29](C(OC(C)(C)C)=O)[CH:30]=2)O1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>O1CCOCC1.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.O>[NH:28]1[CH:27]=[C:26]([C:2]2[CH:3]=[C:4]([C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[CH:5]=[CH:6][CH:7]=2)[CH:30]=[N:29]1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H](NC(=O)OC(C)(C)C)c1cccc(-c2cn[nH]c2)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
To a degassed solution of Intermediate 11A (3.00 g, 9.99 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (4.410 g, 14.99 mmol) and potassium carbonate (4.14 g, 30.0 mmol) in dioxane (20 mL)/water (8 mL) was added Tetrakis (0.577 g, 0.500 mmol). The vial was purged with argon, sealed and stirred at 90° C. for 16 h. Another 20% of tetrakis and boronic ester were added and the reaction mixture was degassed and heated at 90° C. for 24 h. The reaction was cooled down to rt and NaOH (14.99 mL, 14.99 mmol) was added and the reaction was stirred at 50° C. for 5 h. The mixture was partitioned between EtOAc and water. The organic layer was separated. The aqueous phase was extracted with EtOAc, and the combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography over 120 g of silica gel (15 min gradient, with 0-100% ethyl acetate in hexanes) to afford Intermediate 11B (2.14 g, 7.45 mmol, 74.5% yield) as a white solid. LCMS=1.86 min [M+1]=288.2 (Method B).
Reaction SMILES: Br[C:2]1[C:7]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:6][C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[C:4]([F:27])[CH:3]=1.[H-].[Na+].[C-:30]#[N:31].[Na+]>C(C1C=CC(C)=NC=1)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cl-].[Zn+2].[Cl-]>[C:30]([C:2]1[C:7]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:6][C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[N:16]([CH3:25])[C:15]2=[O:26])=[C:4]([F:27])[CH:3]=1)#[N:31]
Reactant: [C-]#N
Reactant: CCS(=O)(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCc1ccc(C)nc1
Product: CCS(=O)(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1C#N
Reaction time: 0.08 h
Yield: 61 %

Procedure:
0.5 g (1.0 mmol) of 3-(4-bromo-5-ethylsulfonylamino-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)pyrimidinedione was dissolved in 10 ml of 5-ethyl-2-picoline, to which 0.04 g of sodium hydride was added under cooling with ice, and the mixture was stirred for 5 minutes. Next, 0.04 g of palladium acetate and 0.16 g of 1,4-bis(diphenylphosphino)ethane were added to the mixture, which was then stirred at 90° C. under an argon atmosphere for 1 hour. After the mixture was allowed to cool, 0.03 g of zinc chloride and 0.06 g of sodium cyanide were added to the mixture, which was then stirred for further 4 hours. After the reaction was completed, 61% of the title compound was detected as the relative area value in liquid chromatography.
Reaction SMILES: [Br:1]Br.[I:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1>C(O)(=O)C>[Br:1][CH2:11][C:10]([C:7]1[CH:8]=[CH:9][C:4]([I:3])=[CH:5][CH:6]=1)=[O:12]
Reactant: BrBr
Reactant: CC(=O)c1ccc(I)cc1
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc(I)cc1
Reaction time: 10 h
Yield: 90.9 %

Procedure:
A solution of bromine (79.3 g, 508 mmol) in glacial acetic acid (50 mL) was added at room temperature to a solution of 1-(4-Iodo-phenyl)-ethanone (Aldrich, 125 g, 508 mmol) in glacial acetic acid (600 mL). The mixture was stirred for 10 h, then concentrated under reduced pressure and the residue was diluted with ethyl acetate (100 mL), and washed with brine (3×50 mL). The organic layer was concentrated, and the residue was crystallized from ethyl ether to provide the title compound as a yellow solid (150 g, 462 mmol, 91% yield). 1H NMR (300 MHz, CDCl3) δ 4.39 (s, 2H), 7.69 (d, J=8.5 Hz, 2H), 7.87 ppm (d, J=8.5 Hz, 2H); MS (DCl/NH3) m/z 246 (M−Br)+264 (M−Br+NH4)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[Cl:12]N1C(=O)CCC1=O.O>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[C:9]([Cl:12])[CH:10]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(Cl)c1C(=O)O
Temperature: 100 °C

Procedure:
A mixture of 4-bromo-2-methyl-benzoic acid (6.45 g, 30 mmol,), N-chlorosuccinimide (4.67 g, 35 mmol), and palladium (II) acetate (0.675 g, 3 mmol) in dry DMF (35 mL) was heated under a nitrogen atmosphere at 100° C. for 36 h. After this time, the reaction mixture was cooled to ambient temperature and poured into water. The aqueous solution was extracted with ethyl acetate (2×100 mL) and the combined organic extracts washed with aqueous sodium thiosulphate (30 mL) and then brine (30 mL). The remaining organic solution was dried over anhydrous MgSO4, filtered, and concentrated to give 4-bromo-2-chloro-6-methyl-benzoic acid. The product was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5](N)[CH2:4][CH2:3]1.[C:15]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CC.C(OCC)(=O)C>[CH3:1][N:2]1[CH2:9][CH2:8][C:7]2=[C:6]3[C:13](=[CH:12][CH:11]=[CH:10]2)[C:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:15]=2[N:5]3[CH2:4][CH2:3]1
Reactant: O=C1CCCCCC1
Reactant: CN1CCc2ccccc2N(N)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCO
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCc2cccc3c4c(n(c23)CC1)CCCCC4
Temperature: 25 °C
Yield: 47.6 %

Procedure:
To a solution of 4-methyl-3,4,5,6-tetrahydro-2H-benzo[e][1,4]diazocin-1-ylamine (1.80 g, 9.4 mmol) in 1-propanol (100 mL) was added cycloheptanone (5.28 g, 47.0 mmole), followed by p-toluenesulfonic acid monohydrate (3.2 g, 16.8 mmole), and the resulting reaction mixture was refluxed for 40 hours. The reaction mixture was cooled to room temperature and solvent removed in vacuo to produce a brown residue. The residue was diluted with ethyl acetate (300 mL) and washed with saturated aqueous sodium bicarbonate (150 mL), saturated aqueous sodium chloride (150 mL), dried (sodium sulfate) and concentrated in vacuo. Purification by flash column chromatography (silica gel, ethyl acetate:hexanes 1:1) provided 1.20 g of the title compound as a light yellow solid. 80 mg of this was treated with one equivalent of fumaric acid in ethanol to form a fumarate salt, mp 190-192° C. MS (ESI) m/z 269 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].[NH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: NCCN1CCOCC1
Reactant: COc1cc(C(=O)O)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCCN2CCOCC2)ccc1N
Reaction time: 24 h

Procedure:
4-amino-3-methoxybenzoic acid (Aldrich; 5 g, 29.9 mmol) was stirred and dissolved in DMF (100 mL) at ambient temperature. 4-(2-aminoethyl)morpholine (Aldrich; 4.7 mL, 35.8 mmol) was added followed by DIPEA (15.6 mL, 89.7 mmol) and HATU (13.7 g, 36.0 mmol) causing a slight exotherm. The brown solution was stirred for 24 h and the solvent evaporated to a brown gum.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.C([Li])CCC.CCCCCC.C[Si]([N:27]=[C:28]=S)(C)C.Cl>C1C=CC=CC=1.O>[C:28]([CH:6]1[C:5]2[N:4]=[CH:3][C:2]([CH3:1])=[CH:11][C:10]=2[CH2:9][CH2:8][CH2:7]1)#[N:27]
Reactant: C[Si](C)(C)N=C=S
Reactant: Cc1cnc2c(c1)CCCC2
Agent: Cl
Agent: [Li]CCCC
Solvent: c1ccccc1
Solvent: CCCCCC
Solvent: O
Product: Cc1cnc2c(c1)CCCC2C#N
Yield: 34.8 %

Procedure:
A solution of 3-methyl-5,6,7,8-tetrahydroquinoline (29 g., 0.2 mol) in benzene (200 ml.) was cooled to 0° C and treated dropwise with a 15% w/w solution of n-butyl lithium in hexane (88 ml., 0.2 mol) under nitrogen. After 1 hour at 0° C the reaction mixture was added portionwise to a solution of trimethylsilylisothiocyanate (112 ml., 0.8 mol.) in benzene (200 ml.) at 0° C and under nitrogen. After 21/2 hours at room temperature the reaction mixture was treated with water (100 ml.) and with 2N HCl to pH 2.0. The aqueous layer was separated, washed with ethyl acetate (1 × 50 ml.) and the pH adjusted to 9.0 with sodium carbonate and extracted with chloroform (3 × 100 ml.) The combined chloroform extracts were dried (MgSO4) and the solvent removed in vacuo to give a red oil which was distilled first at 0.25 mmHg to give recovered 3-methyl-5,6,7,8-tetrahydroquinoline (17 g., 59%) b.p. 54°-7° and then at 0.05 mmHg to give the title compound as a pale red oil (12 g. 35%) b.p. 115°-20° RT = 4.1/4 min. (3% SE30, 200° C) identical to authentic material.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.[Br:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23](Br)[C:17]=1[CH2:18][O:19][C:20](=[O:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([N:2]([CH3:14])[CH3:1])[CH:4]=3)[C:9]2=[O:13])[C:17]=1[CH2:18][O:19][C:20](=[O:22])[CH3:21]
Reactant: CN(C)c1ccc2c(c1)CCNC2=O
Reactant: CC(=O)OCc1c(Br)cccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)OCc1c(Br)cccc1N1CCc2cc(N(C)C)ccc2C1=O
Temperature: 150 °C
Yield: 27.9 %

Procedure:
6-Dimethylamino-3,4-dihydro-2H-isoquinolin-1-one (150 mg, 0.789 mmol), Acetic acid 2,6-dibromo-benzyl ester (487 mg, 1.58 mmol), cuprous iodide (30 mg, 0.16 mmol) and potassium carbonate (109 mg, 0.789 mmol) were deposited in a sealed vessel. 3 mL DMSO was added. Argon was bubbled through the mixture for 2 minutes and the lid was tightly closed. This was heated at 150° C. for 24 hours. Cuprous iodide (30 mg, 0.l6 mmol) was added and the mixture was heated at 150° C. for an additional 24 hours. This was diluted with dichoromethane and filtered through a pad of celite. The filtrate was partitioned between dichloromethane and 5% aq. ammonium hydroxide. The dichloromethane layer was dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 25 to 50% ethyl acetate/hexanes) to yield Acetic acid 2-bromo-6-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-benzyl ester (93 mg, 0.22 mmol). MS (ESI) 417.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[C:21](=[O:23])=[O:22].[OH-].[Na+]>CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.C(OCC)C.O.O1CCCC1>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:21]([OH:23])=[O:22])=[CH:11][CH:10]=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccnc1-n1cccn1
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: O=C(O)c1ccnn1-c1ncccc1Cl
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 2.0 g of 3-chloro-2-(1H-pyrazol-1-yl)pyridine and 100 ml of tetrahydrofuran was added dropwise 6.7 ml of a 2.0 mol/L lithium diisopropylamide solution in heptane/tetrahydrofuran/ethylbenzene at −78° C. The mixture was stirred at −78° C. for 10 minutes, poured into a mixture of dry ice and 50 ml of tetrahydrofuran, and stirred for 0.5 hour with allowing it to rise to around room temperature. After water and diethyl ether were added to the reaction mixture, the aqueous layer was adjusted to pH 10-12 by an addition of a 2N aqueous sodium hydroxide solution and layers were separated. After the aqueous layer was washed with diethyl ether two times, the aqueous layer was adjusted to around pH 3 by an addition of 2N hydrochloric acid, and the mixture was extracted with methyl tert-butyl ether three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 1.22 g of 1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid of the formula:
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=2)[N:4]=[C:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH:17]=1>CO.O1CCCC1>[CH3:1][C:2]1([CH3:30])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)N3CCCC3)c1)=N2
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)N3CCCC3)c1)N2
Yield: 78.9 %

Procedure:
A mixture of methyl 3,3-dimethyl-2-(3-(pyrrolidin-1-ylsulfonyl)phenyl)-3,4-dihydroquinoline-6-carboxylate (140 mg, 0.328 mmol) in methanol/tetrahydrofuran (6 mL/6 mL) was treated with H2 at room temperature overnight. C-MS showed the reaction was complete. The mixture was separated by filtration and the filtrate was concentrate in vacuo to give 110.9 mg of methyl 3,3-dimethyl-2-(3-(pyrrolidin-1-ylsulfonyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate, yield: 78.9%.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([N:30]3[CH2:33][CH2:32][CH2:31]3)=[O:29])[CH:23]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.N1(C(C2C=CC=C(NCC3CCCC3)C=2)=O)CCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[N:30]1([C:28]([C:24]2[CH:23]=[C:22]([N:15]([CH2:16][CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:13](=[O:14])[NH:12][C:10]3[S:11][C:7]([S:6][CH2:5][C:4]([OH:34])=[O:3])=[CH:8][N:9]=3)[CH:27]=[CH:26][CH:25]=2)=[O:29])[CH2:31][CH2:32][CH2:33]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(C(=O)N3CCC3)c2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: O=C(c1cccc(NCC2CCCC2)c1)N1CCC1
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(C(=O)N3CCC3)c2)s1

Procedure:
The title compound was prepared via (2-{3-[3-(azetidine-1-carbonyl)-phenyl]-3-cyclopentylmethyl-ureido}-thiazol-5-ylsulfanyl)-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using azetidin-1-yl-[3-(cyclopentylmethyl-amino)-phenyl]methanone and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.