Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([C:28]3[S:29][C:30]([CH3:36])=[C:31]([CH2:33][CH2:34]O)[N:32]=3)=[CH:27][C:22]=2[O:21][CH2:20]1.COC(=O)CC(=O)C(Br)C.O1C2C=CC(C(=S)N)=CC=2OC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:34][CH2:33][C:31]2[N:32]=[C:28]([C:26]3[CH:25]=[CH:24][C:23]4[O:19][CH2:20][O:21][C:22]=4[CH:27]=3)[S:29][C:30]=2[CH3:36])=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Reactant: Cc1sc(-c2ccc3c(c2)OCO3)nc1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: COC(=O)CC(=O)C(C)Br
Agent: NC(=S)c1ccc2c(c1)OCO2
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc4c(c3)OCO4)sc2C)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (example 7 a]) was reacted with 2-(2-benzo[1,3]dioxol-5-yl-5-methyl-thiazol-4-yl)-ethanol (prepared from [rac]-4-bromo-3-oxo-pentanoic acid methyl ester [PCT Int. Appl. (2001), WO 01/792023 and benzo[1,3]dioxole-5-carbothioic acid amide in analogy to the procedures described in examples 12 a] and 12 b]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-{4-[2-(2-benzo[1,3]dioxol-5-yl-5-methyl-thiazol-4-yl)-ethoxy]-3-fluoro-phenyl)-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-3-{4-[2-(2-benzo[1,3]dioxol-5-yl-5-methyl-thiazol-4-yl)-ethoxy]-3-fluoro-phenyl}-2-ethoxy-propionic acid as colorless solid.
Reaction SMILES: [OH-].[Na+].C(OC([N:10]([C:29]1[C:34]([O:35][CH3:36])=[N:33][C:32]([CH3:37])=[CH:31][N:30]=1)[S:11]([C:14]1[C:15]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH3:28])=[CH:22][CH:21]=2)=[N:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12])=O)C(C)C>CO>[CH2:26]([C:23]1[CH:24]=[CH:25][C:20]([C:15]2[C:14]([S:11]([NH:10][C:29]3[C:34]([O:35][CH3:36])=[N:33][C:32]([CH3:37])=[CH:31][N:30]=3)(=[O:12])=[O:13])=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:21][CH:22]=1)[CH2:27][CH3:28]
Reactant: CCCc1ccc(-c2ncccc2S(=O)(=O)N(C(=O)OCC(C)C)c2ncc(C)nc2OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1ccc(-c2ncccc2S(=O)(=O)Nc2ncc(C)nc2OC)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 71.5 %

Procedure:
2M Sodium hydroxide solution (1 ml) was added to a solution of N-(isobutoxycarbonyl)-2-(4-propylphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.7 g) in methanol (2 ml) and the reaction mixture stirred for 17 hours at ambient temperature. The methanol was removed by evaporation and water (20 ml) was added. The reaction mixture was extracted with ethyl acetate (4×15 ml), the combined organic extracts were dried (MgSO4) and then the solvent was removed by evaporation. The resultant oil was purified by eluting with 30% ethyl acetate/isohexane through a silica gel Mega Bond Elut column, followed by trituration with isohexane/diethyl ether to give 2-(4-propylphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.4 g) as a solid, m.p. 70°-72° C.; mass spectrum (+ve ESP): 399 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:22])=[C:7]2[C:15](=[CH:16][C:17]=1[CH:18]([CH3:20])[CH3:19])[O:14][C:10]1([CH2:13][CH2:12][CH2:11]1)[CH2:9][C:8]2=O)(=O)C.Cl.[CH3:24][O:25][NH2:26].Cl>CO.C(OCC)(=O)C.O1CCCC1>[CH:18]([C:17]1[CH:16]=[C:15]2[C:7]([CH:8]([NH:26][O:25][CH3:24])[CH2:9][C:10]3([O:14]2)[CH2:13][CH2:12][CH2:11]3)=[C:6]([CH3:22])[C:5]=1[OH:4])([CH3:20])[CH3:19]
Reactant: CON
Reactant: CC(=O)Oc1c(C(C)C)cc2c(c1C)C(=O)CC1(CCC1)O2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CONC1CC2(CCC2)Oc2cc(C(C)C)c(O)c(C)c21
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 59.5 %

Procedure:
A mixture of 7-isopropyl-5-methyl-4-oxospiro[chroman-2,1′-cyclobutane]-6-yl acetate (1.0 g) and methoxyamine hydrochloride (1.0 g) in methanol (3 mL) was microwave heated at 60° C. for 3 min., 100° C. for 5 min., and 120° C. for 10 min. Two runs (total 2 g, 6.62 mmol) were combined. The solution was diluted with ethyl acetate and washed with water and brine. The crude product obtained (6.62 mmol) was dissolved in tetrahydrofuran (5 mL) and borane-pyridine complex (4 mL) at 0° C. followed by hydrogen chloride (8 mL, 4.0 M solution in dioxane) were added for 50 minutes. The solution was allowed to warm to room temperature slowly. After 48 hours, ethyl acetate was added. The solution was washed with saturated sodium bicarbonate water solution, water and brine. Evaporation and chromatography (silica gel, hexane-ethyl acetate 1% to 8%) gave 573 mg of 7-isopropyl-4-(methoxyamino)-5-methylspiro[chroman-2,1′-cyclobutan]-6-ol. 1H-NMR (300 MHz, CDCl3) δ=6.63 (s, 1H), 4.54 (s, 1H), 5.35 (s, 1H), 4.30-4.25 (m, 1H), 3.65 (s, 3H), 3.15-3.10 (m, 1H), 2.70-2.60 (m, 2H), 2.40-2.10 (m, 6H), 2.10-1.75 (m, 3H), 1.22 (d, J=6.7 Hz, 6H) ppm. 13C-NMR (75 MHz, CDCl3) δ=148.4, 144.9, 136.1, 123.0, 115.2,112.4, 76.7, 61.9, 52.6, 35.7, 34.4, 32.5, 27.3, 22.7, 22.6, 13.7, 11.5 ppm. MS (m/z)=245 (100, M+H+−18).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=[O:14])[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[N:3]=1.N[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([O:15][CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:14])[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[N:3]=1
Reactant: COc1ccc(COc2ccccc2-c2cc(-c3cccc(C(=O)O)c3)c(C#N)c(N)n2)cc1
Reactant: NCCN1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: COc1ccc(COc2ccccc2-c2cc(-c3cccc(C(=O)OCCN4CCCCC4)c3)c(C#N)c(N)n2)cc1
Temperature: 25 °C
Yield: 58.1 %

Procedure:
To a cold (0° C.) mixture of 3-(2-amino-3-cyano-6-{2-[(4-methoxybenzyl)oxy]phenyl}-4-pyridinyl)benzoic acid (starting compound 5, 1.35 g, 3.00 mmol), N-(2-aminoethyl)piperidine (0.420 g, 3.30 mmol), and 1-hydroxybenzotriazole (0.490 g, 3.60 mmol) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.69 g, 3.60 mmol) with stirring. The mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and partitioned between ethyl acetate and water. The separated organic phase was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The obtained solid was triturated with ethyl ether and dried under reduced pressure to give 2-(1-piperidinyl)ethyl 3-(2-amino-3-cyano-6-{2-[(4-methoxybenzyl)oxy]phenyl}-4-pyridinyl)benzoate (0.98 g, yield 58%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([NH:13][CH2:14][C:15]3[C:16]([OH:23])=[N:17][C:18]([CH3:22])=[CH:19][C:20]=3[CH3:21])=[O:12])=[C:9]([CH3:24])[N:8]([C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[C:6]=2[N:7]=1.[OH-].[NH4+:34]>>[NH2:34][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([NH:13][CH2:14][C:15]3[C:16]([OH:23])=[N:17][C:18]([CH3:22])=[CH:19][C:20]=3[CH3:21])=[O:12])=[C:9]([CH3:24])[N:8]([C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[C:6]=2[N:7]=1
Reactant: [NH4+]
Reactant: Cc1cc(C)c(CNC(=O)c2c(C)n([C@H](C)c3ccccc3)c3nc(Cl)ncc23)c(O)n1
Agent: [OH-]
Product: Cc1cc(C)c(CNC(=O)c2c(C)n([C@H](C)c3ccccc3)c3nc(N)ncc23)c(O)n1
Yield: 38 %

Procedure:
A solution of (R)-2-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-methyl-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (70 mg, 0.15 mmol) in ammonium hydroxide (5 mL) was stirred at 150° C. for 30 minutes under microwave (pressure: 17.2 bar, equipment power: 150 W). The mixture was concentrated in vacuo and purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to afford (R)-2-amino-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-methyl-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (25 mg, 38%). LRMS (M+H+) m/z: calcd 430.21. found 430. HPLC purity (214 nm): 93%. 1H NMR (300 MHz, CD3OD): δ 8.57 (s, 1H), 7.34-7.19 (m, 5H), 6.19-6.17 (m, 1H), 6.10 (s, 1H), 4.47 (s, 2H), 2.33 (s, 3H), 2.30 (s, 3H), 2.23 (s, 3H), 1.99 (d, J=7.2 Hz, 3H).
Reaction SMILES: CO[CH:3](OC)[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[C:19]([F:25])[CH:18]=1)S(C1C=CC(C)=CC=1)(=O)=O.FC1C=C2C(=CC=1)C=NC=C2>>[F:25][C:19]1[C:20]([F:24])=[C:21]([F:23])[CH:22]=[C:17]2[C:18]=1[CH:3]=[CH:4][N:5]=[CH:16]2
Reactant: COC(CN(Cc1cc(F)c(F)c(F)c1)S(=O)(=O)c1ccc(C)cc1)OC
Agent: Fc1ccc2cnccc2c1
Product: Fc1cc2cnccc2c(F)c1F

Procedure:
Cyclisation of N-(2,2-dimethoxy-ethyl)-4-methyl-N-(3,4,5-trifluoro-benzyl)-benzene-sulfonamide (100) by the method described for 6-fluoro-isoquinoline (5) gave the desired isoquinoline, which was isolated as trifluoro acetate after final purification by prep. HPLC. Rt=1.15 min (Method #1). Detected mass: 184.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][NH:8]1.Cl[C:39]1[N:44]=[CH:43][C:42]([CH2:45][CH2:46][CH3:47])=[CH:41][N:40]=1.C(N(C(C)C)C(C)C)C>[Cu]I>[CH2:45]([C:42]1[CH:41]=[N:40][C:39]([N:8]2[CH2:9][C@H:10]([S:12][C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:11][C@H:7]2[CH2:6][O:5][CH2:4][C:3]2[CH:32]=[C:33]([F:37])[C:34]([F:36])=[CH:35][C:2]=2[F:1])=[N:44][CH:43]=1)[CH2:46][CH3:47]
Reactant: CCCc1cnc(Cl)nc1
Reactant: Fc1cc(F)c(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2)cc1F
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cnc(N2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2COCc2cc(F)c(F)cc2F)nc1
Yield: 81.2 %

Procedure:
A mixture of 2 g (3.85 mmol)(2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine, 1.2 g (7.7 mmol) 2-chloro5-n-propylpyrimidine, 1.98 ml (11.55 mmol) N-ethyldiisopropylamine and a catalytic amount of copper(I) iodide was heated for 10 h at 80° C. The reaction was cooled and partitioned between H2O/Et2O (3×300). The organic phases were washed with aqueous saturated NaHCO3, aqueous 10% NaCl, dried (NaSO4) and evaporated. Flash chromatography on silica gel (toluene/Et2O 99:1) gave 2 g (81%) (2S,4R)-5-Propyl-2-[2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidin-1-yl]-pyrimidine, MS: 640 (MH+).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[Cl:16][CH2:17][C:18]1[C:19](=[O:41])[N:20]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([OH:37])=O)=[CH:31][C:30]=2[N+:38]([O-:40])=[O:39])[O:21][C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH2:42]([O:54][CH2:55][CH2:56][CH2:57][NH2:58])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]>C(Cl)(Cl)Cl>[Cl:16][CH2:17][C:18]1[C:19](=[O:41])[N:20]([C:29]2[CH:34]=[CH:33][C:32]([C:35](=[O:37])[NH:58][CH2:57][CH2:56][CH2:55][O:54][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])=[CH:31][C:30]=2[N+:38]([O-:40])=[O:39])[O:21][C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccc(-n2oc(-c3ccccc3)c(CCl)c2=O)c([N+](=O)[O-])c1
Reactant: CCCCCCCCCCCCOCCCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCOCCCNC(=O)c1ccc(-n2oc(-c3ccccc3)c(CCl)c2=O)c([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 32.5 %

Procedure:
After adding 90.8 g of dicyclohexylcarbodiimide to a mixture of 150 g (0.400) of 4-chloromethyl-5-phenyl-2-(4-carboxy-2-nitrophenyl)-4-isoxazolin-3-one prepared in the above step and 600 ml of chloroform, the reaction was performed for 30 minutes at room temperature. Then, 97.4 g of 3-dodecyloxypropylamine was added dropwise to the reaction mixture and thereafter, the reaction was further performed for 5 hours. The reaction product was purified by a short column of silica gel and the product was recrystallized from acetonitrile to provide 78.0 g of the desired product with a yield of 33.4%. The melting point thereof was 110° C. to 111° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][CH:7]=1.[C:11]([OH:14])(=[O:13])[CH3:12].C(ON1C(=O)N(OC(=O)C)C(=O)N(OC(=O)C)C1=O)(=O)C.O=O>[Ti].C([O-])(=O)C.[Co+2].C([O-])(=O)C.O>[C:8]([OH:10])(=[O:9])[C:5]1[CH:6]=[CH:7][C:12]([C:11]([OH:14])=[O:13])=[CH:3][CH:4]=1.[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC(=O)O
Agent: [Co+2]
Agent: [Ti]
Agent: CC(=O)On1c(=O)n(OC(C)=O)c(=O)n(OC(C)=O)c1=O
Solvent: O
Product: O=C(O)c1ccc(C(=O)O)cc1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
In a 500-ml titanium autoclave equipped with a stirrer and a pressure gauge, 15.36 g of p-toluicacid, 104.0 g of acetic acid, 0.114 g of 1,3,5-triacetoxy-hexahydro-1,3,5-triazine-2,4,6-trione (1,3,5-triacetoxyisocyanuric acid) (0.33% by mole relative to p-toluic acid), 0.112 g of cobalt (II) acetate 4 H2O and 0.277 g of manganese(II) acetate 4 H2O were placed. The autoclave was charged with 2 MPa of oxygen gas and 2 MPa of nitrogen gas and placed in a heated oil bath. The mixture was stirred at 150° C. for 1 hour. After the completion of the reaction, the autoclave was placed on cold water to cool down the reaction mixture quickly. The resulting mixture was analyzed by high performance liquid chromatography and was found to yield terephthalic acid in 90% yield at 93% conversion of p-toluic acid.
Reaction SMILES: I.[CH3:2][S:3][C:4]1[NH:5][CH2:6][CH2:7][N:8]=1.C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22]>C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:21]([N:8]2[CH2:7][CH2:6][N:5]=[C:4]2[S:3][CH3:2])=[O:22])[CH:24]=[CH:25][CH:26]=1
Reactant: CSC1=NCCN1
Reactant: COc1cccc(C(=O)Cl)c1
Agent: I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)N2CCN=C2SC)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-methylsulfanyl-4,5-dihydro-1H-imidazole hydroiodide (1.22 g, 1.0 equiv) in CH2Cl2 (25 mL) under an atmosphere of argon at 0° C. was added triethylamine (1.5 mL, 2.2 equiv) and then 3-methoxybenzoyl chloride (0.78 mL, 1.1 equiv) dropwise. Thereaction mixture was allowed to warm to room temperature and stir for 24 hr. After concentration, the resulting residue was diluted with EtOAc (50 mL) and hexane (50 mL). The mixture was filtered and then the filtrate concentrated and dried under vacuum to give a quantitative yield of (3-methoxyphenyl)-(2-methylsulfanyl-4,5-dihydroimidazol-1-yl)-methanone which was used directly in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH:16]([CH3:18])[CH3:17])=[CH:9][C:10]([CH3:15])([CH3:14])[O:11]2)=[CH:6][C:5]=1/[C:19](/[CH3:27])=[C:20](/[F:26])\[C:21](OCC)=O)[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH:16]([CH3:18])[CH3:17])=[CH:9][C:10]([CH3:15])([CH3:14])[O:11]2)=[CH:6][C:5]=1/[C:19](/[CH3:27])=[C:20](/[F:26])\[CH3:21])[CH3:2]
Reactant: CCOC(=O)/C(F)=C(/C)c1cc2c(cc1OCC)OC(C)(C)C=C2C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CCOc1cc2c(cc1/C(C)=C(\C)F)C(C(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure L, ethyl (2E)-3-(7-ethoxy-4-isopropyl-2,2-dimethyl-2H-chromen-6-yl)-2-fluoro-but-2-enoate (Compound 72, 163,mg, 0.44 mmol) and diisobutylaluminum hydride (1M in hexanes, 1.74 mL, 1.74 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 1:9 to 1:4 ethyl acetate/hexane).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:18]#[N:19])=[C:4]2[N:9]([C:10]=1[C:11]1[C:12]([F:17])=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:8][CH2:7][CH2:6][CH2:5]2.S(=O)(=O)(O)[OH:21]>>[Cl:1][C:2]1[C:3]([C:18]([NH2:19])=[O:21])=[C:4]2[N:9]([C:10]=1[C:11]1[C:12]([F:17])=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:8][CH2:7][CH2:6][CH2:5]2
Reactant: N#Cc1c(Cl)c(-c2cccnc2F)n2c1CCCC2
Reactant: O=S(=O)(O)O
Product: NC(=O)c1c(Cl)c(-c2cccnc2F)n2c1CCCC2

Procedure:
2-Chloro-3-(2-fluoro-3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide is prepared according to the method described in Example 10, from 1.8 g of 2-chloro-3-(2-fluoro-3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carbonitrile and 30 cm3 of 60% sulphuric acid. 1.3 g of 2-chloro-3-(2-fluoro-3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide is thus obtained in the form of a white powder melting at 191° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9](Cl)[C:8]([CH3:12])=[C:7]([Cl:13])[N:6]=1)(=O)[CH3:2].[OH2:14]>O1CCCC1.C(N(CC)CC)C.CN1CCNCC1>[C:7]([NH:6][CH:1]1[CH2:2][N:4]([CH3:5])[CH2:1][CH2:2][N:4]1[C:5]1[N:10]=[CH:9][C:8]([CH3:12])=[C:7]([Cl:13])[N:6]=1)(=[O:14])[CH3:8]
Reactant: O
Reactant: CC(=O)Nc1nc(Cl)c(C)c(Cl)n1
Agent: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NC1CN(C)CCN1c1ncc(C)c(Cl)n1
Reaction time: 6 h

Procedure:
8.8 parts of 2-acetylamino-4,6-dichloro-5-methylpyrimidine are dissolved in 100 parts by volume of tetrahydrofuran in the presence of 4 parts of triethylamine and 4 parts of N-methylpiperazine. The mixture is held for 6 hours at the reflux temperature. The reaction mixture is poured into water and the insoluble material is filtered off which is recrystallised from ethanol. M.p. 202° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)[CH3:2].Br[C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[O:31][CH3:32].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH:11][C:24]2[CH:25]=[C:26]([N+:28]([O-:30])=[O:29])[CH:27]=[CH:22][C:23]=2[O:31][CH3:32])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)[CH3:2]
Reactant: CCOC(Cn1nc(-c2cccnc2)cc1N)OCC
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CCOC(Cn1nc(-c2cccnc2)cc1Nc1cc([N+](=O)[O-])ccc1OC)OCC
Temperature: 150 °C

Procedure:
200 mg (0.72 mmol) of the compound of Example 4A together with 201 mg (0.87 mmol) of 2-bromo-4-nitroanisole were dissolved in 3.6 ml of dioxane, the mixture was degassed with argon and 16 mg (0.07 mmol) of palladium(II) acetate, 63 mg (0.11 mmol) of xantphos [4,5-bis(diphenylphosphino)-9,9-dimethylxanthene] and 589 mg (1.81 mmol) of caesium carbonate were added. The mixture was heated in a microwave oven (Biotage Initiator, with Dynamic Field Tuning) at 150° C. for 30 min. The reaction was then filtered through kieselguhr, the filtrate was concentrated under reduced pressure and the residue was separated by preparative HPLC (Method 12) into its components. The product-containing fractions were combined and, under reduced pressure, concentrated almost completely. The residue was made alkaline with a little saturated aqueous sodium bicarbonate solution. The precipitate formed was filtered off, washed with water and dried. This gave 210 mg (92% pure, 62% of theory) of the title compound.
Reaction SMILES: C(O[C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]([CH2:21][CH2:22][CH2:23][CH3:24])[N:18]=[C:17]([C:25]([OH:27])=[O:26])[CH:16]=2)[CH2:11][CH2:10]1)=[O:7])(C)(C)C.Cl.O1CCOCC1.Cl.NC1CCN(C2C=C(C=C(Cl)N=2)C(N)=O)CC1.Cl.NC1CCN(C2N=C(CCCC)N=C(C(O)=O)C=2)CC1.[Cl:74][C:75]1[C:79]([Cl:80])=[C:78](C)[NH:77][C:76]=1[C:82](NC1CCN(C2C=C(C#N)N=C(Cl)N=2)CC1)=O>>[CH2:21]([C:19]1[N:18]=[C:17]([C:25]([OH:27])=[O:26])[CH:16]=[C:15]([N:12]2[CH2:11][CH2:10][CH:9]([NH:8][C:6]([C:78]3[NH:77][C:76]([CH3:82])=[C:75]([Cl:74])[C:79]=3[Cl:80])=[O:7])[CH2:14][CH2:13]2)[N:20]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCc1nc(C(=O)O)cc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C#N)nc(Cl)n3)CC2)c(Cl)c1Cl
Agent: CCCCc1nc(C(=O)O)cc(N2CCC(N)CC2)n1
Agent: Cl
Agent: NC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Solvent: C1COCCO1
Product: CCCCc1nc(C(=O)O)cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1

Procedure:
(6-{4-[(tert-Butoxycarbonyl)amino]piperidin-1-yl}-2-butylpyrimidine-4-carboxylic acid) (Intermediate 100) was treated with 4 N HCl/dioxane for as described for Intermediate 70. The resulting hydrochloride salt, 6-(4-aminopiperidin-1-yl)-2-butylpyrimidine-4-carboxylic acid hydrochloride salt was coupled to 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3) in a manner analogous to Example 29 to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[Cl:11].C([Li])CCC.CN(C)[CH:20]=[O:21]>O1CCCC1>[Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[CH:9]=[C:8]([CH:20]=[O:21])[S:7][C:6]=2[C:10]=1[Cl:11]
Reactant: CN(C)C=O
Reactant: Oc1cc2ccsc2c(Cl)c1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc2cc(O)c(Cl)c(Cl)c2s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 8.7 g of 6,7-dichloro-5-hydroxybenzo[b]thiophene in 50 ml of anhydrous tetrahydrofuran is placed in a 250 ml 3-necked flask and cooled to -25°. To the solution under nitrogen, is added dropwise 42 ml of a solution of 2.5M n-butyllithium at a rate such that the temperature did not rise above -10°. After total addition, the mixture is stirred at 0°-5° for 3 hrs. To the mixture is added 14 ml of anhydrous dimethylformamide over a period of 20 mins. The reaction mixture is allowed to warm to room temperature and stirred for 1 hr. Quenching with 400 ml of 2N hydrochloric acid, followed by extraction with ethyl acetate, gives a precipitate. Recrystallization from acetone-hexane affords 6.5 g of 6,7-dichloro-2-formyl-5-hydroxy-benzo[b]thiophene, mp 197°-198°.
Reaction SMILES: Br[CH:2]([CH2:8][C:9]([OH:11])=[O:10])[C:3](=[O:7])[C:4]([OH:6])=[O:5].[CH2:12]([SH:14])[CH3:13].C(N(CC)CC)C>ClCCl>[CH2:12]([S:14][CH:2]([CH2:8][C:9]([OH:11])=[O:10])[C:3](=[O:7])[C:4]([OH:6])=[O:5])[CH3:13]
Reactant: CCS
Reactant: O=C(O)CC(Br)C(=O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCSC(CC(=O)O)C(=O)C(=O)O

Procedure:
To a suspension of 1.00 g of 3-bromo-2-oxoglutaric acid in 20 ml of dichloromethane was added 0.33 ml of ethane thiol while stirring under ice-cooling, followed by addition of 1.83 ml of triehtylamine. The reaction mixture was stirred at room temperature for 3 hours, then the solvent was distilled off. The residue was distributed to ethyl acetate and 1N-HCl. The ethyl acetate layer was separated, washed with water and dried (Na2SO4), followed by distilling off the solvent to give 0.82 g of 3-ethylthio-2-oxoglutaric acid as a pale yellow oily substance.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6][CH:7]=[C:8]([CH3:9])[C:4]=2[CH:3]=1.C1C(=O)N([Br:19])C(=O)C1>C(#N)C.O>[Br:19][C:7]1[S:6][C:5]2[CH:10]=[CH:11][C:2]([F:1])=[CH:3][C:4]=2[C:8]=1[CH3:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc2ccc(F)cc12
Solvent: O
Solvent: CC#N
Product: Cc1c(Br)sc2ccc(F)cc12
Temperature: 40 °C
Reaction time: 0.58 h

Procedure:
A mechanically-stirred solution of 5-fluoro-3-methylbenzo[b]thiophene (50.32 g, 0.303 mol, 1.0 equiv) in acetonitrile (350 mL) is treated with NBS (56.32 g, 0.318 mol, 1.05 equiv). An initial endotherm reduces the reaction temperature to 17° C. A subsequent exotherm then increases the reaction temperature to 40° C. over a 10 min. period, at which time the reaction is cooled to 18-20° C. by application of an ice water bath. The reaction is stirred at RT for an additional 35 min. and the resultant slurry is slowly diluted with water (350 mL). The slurry is stirred for 10 min and the product is filtered, washed with 50:50 acetonitrile:water (100 mL) and dried to a colorless crystalline solid (65.56 g, 88%).