Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[CH2:8][CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[CH:17](O)=O>C=O>[ClH:1].[ClH:1].[CH3:17][N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[CH2:8][CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=CO
Reactant: c1cncc(OCC[C@@H]2CCCN2)c1
Agent: C=O
Agent: Cl
Product: CN1CCC[C@H]1CCOc1cccnc1

Procedure:
A 400 mg sample of 3-(2-(2-(S)-pyrrolidinyl)ethoxy)pyridine dihydrochloride, from Example 102 above, was dissolved in 14 mL of 37% HCHO, 14 mL of HCOOH was added, and the reaction mixture was stirred at reflux for 2.5 hours. The solution was washed with ether, adjusted to basic pH with K2CO3 and extracted with methylene chloride. The extract was dried over MgSO4 and concentrated. The residue was purified on a column of-silica gel, eluting with 10% methanol in methylene chloride. The compound was converted to the salt by the HCl in ether according to Example 14c to afford the title compound. MS (DCI/NH3) m/e: 207 (M+H)+. 1H NMR (D2O, 300 MHz) δ: 1.71-1.98 (m, 1H, 2.00-2.23 (m, 3H), 2.37-2.45 (m, 1H, 2.50-2.63 (m, 1H), 2.98 (s, 3H), 3.13-3.25 (m, 1H, 3.53-3.67 (m, 1H), 3.68-3.78 (m, 1H), 4.31-4.48 (m, 2H), 8.00 (dd, J=11.0, 7.0 Hz, 1H), 8.20 (dd, J=10.5, 5.0 Hz, 1H), 8.42 (d, J=6.5 Hz, 1H), 8.50 (d, J=5.0 Hz, 1H). Anal. Calc. for C12H18N2OF.1.9 HCl.1.1 H20. C, 48.49; H, 7.46; N, 9.42; Found C, 48.51; H, 7.69; N, 9.61. [α]25D +36.28° (c=0.5, H2O).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]2[N:10]=[CH:11][N:12]([CH2:13][CH3:14])[C:4]=2[CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[Cl:22].[F-].[Cs+]>COCCOC.CO.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>[CH2:13]([N:12]1[C:4]2[CH:3]=[C:2]([C:19]3[CH:18]=[CH:17][C:16]([Cl:15])=[C:21]([Cl:22])[CH:20]=3)[N:7]=[C:6]([C:8]#[N:9])[C:5]=2[N:10]=[CH:11]1)[CH3:14]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: CCn1cnc2c(C#N)nc(Cl)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Product: CCn1cnc2c(C#N)nc(-c3ccc(Cl)c(Cl)c3)cc21
Temperature: 80 °C
Yield: 46.5 %

Procedure:
Tetrakis(triphenylphosphine)palladium (15 mg) was added under a nitrogen atmosphere to a mixture of 6-chloro-1-ethyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (42 mg), 3,4-dichloro-phenylboronic acid (152 mg) and cesium fluoride (100 mg) in DME (2mL) and methanol (1 mL). The mixture was heated at 80° C. for 24 hours then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by using preparative LC/MS (eluent: A: NH4HCO3 10 mM/B: CH3CN). to afford the title compound (30 mg) as a white solid. 1H NMR (CDCl3) δ: 8.20-8.15 (m, 2H); 7.94 (d, J=8 Hz, 1H); 7.91 (s, 1H); 7.58 (d, J=8 Hz, 1H); 4.37 (q, J=7 Hz, 2H); 1.65 (t, J=7 Hz, 3H). MS m/z: 317/ 319 (M+1).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([S:39][CH2:40][C:41]5[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][C:42]=5[CH3:49])=[CH:35][CH:34]=4)=[O:31])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:59])C=1>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:34]=[CH:35][C:36]([S:39]([CH2:40][C:41]5[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][C:42]=5[CH3:49])=[O:59])=[CH:37][CH:38]=4)=[O:31])=[CH:20][C:19]=3[CH:50]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4c(C)ncn4CCC)cc2)CCCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4c(C)ncn4CCC)cc2)CCCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[4-methyl-1-propylimidazol-5-yl]methyl]sulfanyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (300 mg) in dichloromethane (10 ml) was added dropwise a 70% solution of 3-chloro-perbenzoic acid (117 mg) in dichloromethane (10 ml) at −78° C. After stirring as such for 1 hour, the dry ice-acetone bath was removed, and an aqueous sodium thiosulfate solution was added with vigorous stirring. The mixture was returned to room temperature and stirred for 30 minutes, after which water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium bicarbonate solution and saturated aqueous brine, and was dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was separated and purified with basic silica gel column chromatography (hexane:ethyl acetate=1:4→ethyl acetate) to give 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[4-methyl-1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (230 mg) as a yellow amorphous material (Compound 37).
Reaction SMILES: [CH2:1]([C@H:5]1[C@H:9]([CH2:10][CH2:11][CH:12]=[O:13])[O:8][C:7](=[O:14])[NH:6]1)[CH:2]([CH3:4])[CH3:3].[CH2:15]([Mg]Br)[CH2:16][CH:17]([CH3:19])[CH3:18].Cl>C1COCC1.CC(C)=O>[CH2:1]([C@H:5]1[C@H:9]([CH2:10][CH2:11][C:12](=[O:13])[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[O:8][C:7](=[O:14])[NH:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C[C@@H]1NC(=O)O[C@H]1CCC=O
Reactant: CC(C)CC[Mg]Br
Agent: Cl
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)CCC(=O)CC[C@@H]1OC(=O)N[C@H]1CC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A 2 g (0.01 mole) portion of the compound from Example 26 was dissolved in THF (50 mL) and treated at 0°-5° C. with 37.5 mL of an 0.8 M solution of isopentyl magnesium bromide in THF. The reaction was stirred for 2 hours at room temperature and then poured into ice water which contained 6.5 mL of 6 N HCl. The mixture was extracted with methylene chloride. Evaporation of the dried methylene chloride solution gave a quantitative yield of the Grignard adduct. This material was dissolved in 300 mL of acetone and treated by dropwise addition with Jones solution until the orange color persisted. The chromium salts were filtered and the filtrate was evaporated. The residue was diluted with ether and the resulting solution was washed successively with aqueous NaHCO3 and brine solution. After drying over MgSO4, the solvent was evaporated to give 1.7 g (66%) of product as an oil. NMR (300 MHz, CDCl3, ppm): 0.86-0.96 (m, 12H), 2.41 (M, 2H), 2.67 (m, 2H), 3.5 (m, 1H), 4.15 (m, 1H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[CH2:16]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([CH2:31][CH3:32])=[CH:24][C:25]([CH3:30])([CH3:29])[O:26]2)=[CH:21][C:20]=1[C:33](=O)[CH3:34])[CH3:17]>>[CH2:16]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([CH2:31][CH3:32])=[CH:24][C:25]([CH3:29])([CH3:30])[O:26]2)=[CH:21][C:20]=1/[C:33](/[CH3:34])=[C:6](/[F:7])\[C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH3:17]
Reactant: CCOc1cc2c(cc1C(C)=O)C(CC)=CC(C)(C)O2
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Product: CCOC(=O)/C(F)=C(/C)c1cc2c(cc1OCC)OC(C)(C)C=C2CC

Procedure:
Following General Procedure K, triethyl-2-fluoro-2-phosphonoacetate (173 mg, 7.15 mmol) and 1-(7-ethoxy-4-ethyl-2,2-dimethyl-2H-chromen-6-yl)-ethanone (Compound 56, 394 mg, 1.43 mmol) were reacted to give the title compound as a yellow oil after purification by flash chromatography (silica gel, 1:9 ethyl acetate/hexane).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[CH3:16][NH:17][C:18]([NH:20][C:21]#[N:22])=[NH:19].Cl>O>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([NH:6][C:21]([NH:20][C:18]([NH:17][CH3:16])=[NH:19])=[NH:22])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: CNC(=N)NC#N
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: O
Product: CNC(=N)NC(=N)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To 22.9 g (0.1 mole) of 3,5-di(trifluoromethyl)aniline and 12.6 g (0.1 mole) of 1-methyl-3-cyanoguanidine is added 10 ml of concentrated hydrochloric acid and 20 ml of water. The solution is heated on a steam bath for 1 hour at which time a solid precipitates out. The reaction mixture is cooled to room temperature, made strongly alkaline with 40% NaOH and extracted with ether. The ether layer is dried over potassium carbonate, and evaporated in vacuo to obtain an oil. The residue is triturated with 500 ml heptane and the solid which forms is recrystallized from methylene chloride to obtain 1-[3,5-di(trifluoromethyl)phenyl]-5-methylbiguanide.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:24][N:25]1[CH:29]=[C:28]([NH2:30])[CH:27]=[N:26]1>CN(C)C=O>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([NH:30][C:28]2[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=2)=[O:11])[CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cc(N)cn1
Reactant: O=C(O)Cc1cccc(Br)n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cn1cc(NC(=O)Cc2cccc(Br)n2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (6-bromopyridin-2-yl)acetic acid (Example 235, Step 2) (30 mg, 0.39 mmol) in dimethylformamide (3 mL) was charged with carbonyldiimidazole (338 mg, 2.08 mmol) and maintained at room temperature for 1 hour. A solution of 1-methyl-1H-pyrazol-4-amine (175 mg, 1.81 mmol) in dimethylformamide (2 mL) was added and the reaction was stirred overnight at room temperature. The reaction was then directly purified by reverse phase HPLC (10-100% acetonitrile/water+0.05% TFA modifier) to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]([NH:10][C:11]([O:13][CH3:14])=[O:12])[C:7]([OH:9])=O)=[O:4].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[NH2:36][C@@H:37]([CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[C@@H:38]([OH:67])[CH2:39][C@@H:40]([NH:54][C:55]([C@@H:57]([NH:62][C:63](=[O:66])[O:64][CH3:65])[C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=2)=[CH:44][CH:43]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:68]([C@H:37]([NH:36][C:7](=[O:9])[CH:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[NH:10][C:11]([O:13][CH3:14])=[O:12])[C@@H:38]([OH:67])[CH2:39][C@@H:40]([NH:54][C:55](=[O:56])[C@H:57]([C:58]([CH3:60])([CH3:61])[CH3:59])[NH:62][C:63]([O:64][CH3:65])=[O:66])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=2)=[CH:44][CH:43]=1)[C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: COC(=O)NC(NC(=O)OC)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)NC(NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.8 %

Procedure:
The product from Example 169A (13.2 mg, 0.06 mmol) was dissolved in N,N-dimethylformamide (0.25 mL) and N-hydroxybenzotriazole (13 mg, 0.10 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (18.4 mg, 0.10 mmol) were added followed by the product from Example 2C (34.2 mg, 0.06 mmol). Triethylamine (9 uL, 0.06 mmol) was added and the mixture was stirred at ambient temperature for 18 hours. The solution was concentrated and the crude residue was purified on a 2 mm preparative silica gel TLC plate (5% CH3OH/CHCl3) to give an amorphous solid (38.4 mg, 83%). 1H NMR (CDCl1) δ 8.65 (d, 1H), 7.86 (d, 2H), 7.78-7.60 (m, 2H), 7.27-7.11 (m, 9H), 6.94-6.70 (br s, 1H), 6.36-6.24 (br s, 1H), 6.24-6.04 (br d, 1H), 6.02-5.84 (br d, 1H), 5.41-5.25 (m, 2H), 4.23-4.10 (m, 1H), 4.10-3.95 (q, 1H), 3.75 (d, 1H), 3.67 (s, 3H), 3.66 (s, 3H), 3.63 (s, 3H), 2.98-2.8 (m, 3H), 2.8-2.65 (m, 1H), 0.91 (s, 9H).
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17]([O:19]CC)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C([Li])CCC>CCCCCC.O1CCCC1>[C:1]1([C:7]2[N:16]=[C:15]([C:17]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCNC1
Reactant: CCOC(=O)c1nc(-c2ccccc2)nc2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(c1nc(-c2ccccc2)nc2ccccc12)N1CCCC1

Procedure:
The procedure of Example 24 is followed using ehtyl 2-phenylquinazoline-4-carboxylate (3 g), pyrrolidine (3 ml), a 1.6M solution of butyllithium in hexane (15 ml) and tetrahydrofuran (25 ml) as the starting materials. After recrystallisation from ethanol, 1-[(2-phenylquinazolin-4-yl)-carbonyl]-pyrrolidine (2.1 g), melting at 153° C., is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.Cl.[CH2:16](O)[CH3:17]>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]([O:14][CH2:16][CH3:17])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc2ccc(O)cc2c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc2ccc(O)cc2c1

Procedure:
A solution of 7-hydroxynaphthalene-2-carboxylic acid (56.09 g) in ethanol (200 ml) was saturated with dry hydrogen chloride and then refluxed for 30 minutes. The mixture was evaporated to about half volume, treated with water, and extracted with ethyl acetate, which was washed with water, and sodium bicarbonate solution, dried and evaporated to give a solid. Crystallisation from ethyl acetate afforded ethyl 7-hydroxynaphthalene-2-carboxylate (37.5 g), m.p. 155°-156°.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]([O:7]CC)=O)=[O:2].[CH:10]1([C:13](=[N:15]O)[NH2:14])[CH2:12][CH2:11]1>CCO>[CH:10]1([C:13]2[N:15]=[C:5]([CH2:4][NH:3][CH:1]=[O:2])[O:7][N:14]=2)[CH2:12][CH2:11]1
Reactant: NC(=NO)C1CC1
Reactant: CCOC(=O)CNC=O
Solvent: CCO
Product: O=CNCc1nc(C2CC2)no1
Temperature: 25 °C

Procedure:
A solution of ethyl formylaminomethyl-carboxylate (150 mmol) and cyclopropyl carboxamide oxime (100 mmol) in 100% EtOH (100 ml) was charged with Na (200 mg) and crushed molecular sieve (4Å) (10 g). The mixture thus obtained was stirred and heated to reflux for 8 hours. The mixture was cooled to room temperature, filtered through filter aid and the filtrate was evaporated in vacuo. The oily residue was partitionated into a CHCl3 phase which was dried with Na2SO4 and evaporated.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][N:8]=[C:7]([NH:10][C:11]3[C:12](=[O:19])[N:13]([CH3:18])[CH:14]=[C:15]([Br:17])[CH:16]=3)[CH:6]=2)[CH2:2]1.[CH2:20]=O.[BH4-].[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[Br:17][C:15]1[CH:16]=[C:11]([NH:10][C:7]2[CH:6]=[C:5]([CH:3]3[CH2:4][N:1]([CH3:20])[CH2:2]3)[NH:9][N:8]=2)[C:12](=[O:19])[N:13]([CH3:18])[CH:14]=1
Reactant: C=O
Reactant: Cn1cc(Br)cc(Nc2cc(C3CNC3)[nH]n2)c1=O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CC(c2cc(Nc3cc(Br)cn(C)c3=O)n[nH]2)C1
Yield: 50 %

Procedure:
To a solution of 3-(5-(azetidin-3-yl)-1H-pyrazol-3-ylamino)-5-bromo-1-methylpyridin-2(1H)-one 168a (crude, 2.36 mmol) in methanol (30 mL) and acetic acid (5 mL) at 0° C., was added CH2O (30% wt in H2O) (12 g, 120 mmol), followed by the addition of NaBH4 (1.8 g, 47.2 mmol) in small portions over the period of 1 h at 0° C. After the reaction was finished, the mixture was adjusted to pH>7 with 2N aq. NaOH. It was then extracted with methylene chloride (60 mL×3), dried over Na2SO4 and, concentrated to give a yellow solid, which was further purified on flash column eluting with 50:1 methylene chloride/methanol containing 0.5% triethylamine to afford 168b as a yellow solid (50%, two steps).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:18](=[O:48])[C:19]2[C:24]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][C:22]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:21][C:20]=2[O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:55](Br)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1.O>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:10]([C:18]([C:19]2[C:20]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:21][C:22]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:23][C:24]=2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:48])=[C:11]([C:12]([O:14][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[O:13])[CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c(C(=O)c2c(OCc3ccccc3)cccc2C(=O)O)c(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c(C(=O)c2c(OCc3ccccc3)cccc2C(=O)OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 73 %

Procedure:
To a solution of 5.98 g (9.28 mmol) of 3-benzyloxy-2-(2,6-dibenzyloxy-4-(1,1-dimethylethoxycarbonyl)benzoyl)benzoic acid in 75 mL of dry dimethylformamide was added 3.85 g (27.9 mmol) of potassium carbonate and 1.21 mL (1.74 g, 10.2 mmol) of benzyl bromide. The solution was stirred at room temperature under a nitrogen atmosphere for 13 h. The mixture was then poured onto 800 mL of water and extracted with three 400 mL portions of ether. The organic extracts were washed twice with water and then with brine, and dried over magnesium sulfate. Evaporation of the solvent afforded 6.76 g of the crude product, which was chromatographed on silica gel, eluting with 4/1 hexane-ethyl acetate to give 4.98 g (73%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:25]=[CH:24][C:18]([CH:19]=[CH:20][C:21]([OH:23])=O)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.O>CN(C)C(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([CH:19]=[CH:20][C:21]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[O:23])=[CH:24][CH:25]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(C=CC(=O)O)cc2)CC1
Reactant: C1COCCN1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(C=CC(=O)N3CCOCC3)cc2)CC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
The 4-(4-tert-butoxycarbonylaminopiperidin-1-yl)-cinnamic acid (870 mg, 2.5 mmol) obtained in Example 11(1) was dissolved in N,N-dimethylacetamide (hereinafter referred to as DMA) (15 ml), and HOBt (423 mg, 2.8 mmol), WSCD (530 mg, 2.8 mmol), morpholine (241 mg, 2.8 mmol) were added thereto, followed by stirring at 80° C. for 16 hours. After cooling to room temperature, water was added to the mixture, and the precipitate was collected by filtration, thereby obtaining (3-(4-(4-tert-butoxycarbonylaminopiperidin-1-yl)-phenyl)-1-oxo-2-propen-1-yl)-morpholine (836 mg, 80%) as a white solid.
Reaction SMILES: Cl[C:2]1C2OCCCC=2C(C)=C(C2C(C3SC=CC=3)=NN(C)C=2C=O)C=1.[Cl:26][C:27]1[C:36]2[O:35][CH2:34][CH2:33][CH2:32][C:31]=2[C:30]([CH3:37])=[C:29]([C:38]2[C:39]([C:49]3[S:50][CH:51]=[CH:52][CH:53]=3)=[N:40][N:41]([CH3:48])[C:42]=2[CH:43]([OH:47])[C:44]([O-:46])=[O:45])[CH:28]=1>C1CCCCC1.C(OCC)(=O)C>[Cl:26][C:27]1[C:36]2[O:35][CH2:34][CH2:33][CH2:32][C:31]=2[C:30]([CH3:37])=[C:29]([C:38]2[C:39]([C:49]3[S:50][CH:51]=[CH:52][CH:53]=3)=[N:40][N:41]([CH3:48])[C:42]=2[CH:43]([OH:47])[C:44]([O:46][CH3:2])=[O:45])[CH:28]=1
Reactant: Cc1c(-c2c(-c3cccs3)nn(C)c2C=O)cc(Cl)c2c1CCCO2
Reactant: Cc1c(-c2c(-c3cccs3)nn(C)c2C(O)C(=O)[O-])cc(Cl)c2c1CCCO2
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: COC(=O)C(O)c1c(-c2cc(Cl)c3c(c2C)CCCO3)c(-c2cccs2)nn1C

Procedure:
Using the procedure described in example 1, step 5, 4-(8-chloro-5-methyl-3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-3-(thiophen-2-yl)-1H-pyrazole-5-carbaldehyde (35a) (180 mg, 0.48 mmol) is converted, after purification by preparative TLC (dichloromethane/ethyl acetate 70/30) into 2-[4-(8-chloro-5-methyl-3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-3-(thiophen-2-yl)-1H-pyrazol-5-yl]-2-hydroxyacetate (35b) (69 mg, 0.16 mmol, 33%).
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=O.[F:9][C:10]1[CH:20]=[CH:19][C:13]([O:14][CH:15](C)[CH2:16]Cl)=[CH:12][CH:11]=1.[I-].[Na+].C(N(CC)CC)C>CN(C)C=O>[F:9][C:10]1[CH:20]=[CH:19][C:13]([O:14][CH:15]([CH3:16])[CH2:1][N:3]2[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]2)=[CH:12][CH:11]=1
Reactant: O=CN1CCNCC1
Reactant: CC(CCl)Oc1ccc(F)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(CN1CCNCC1)Oc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1-Formyl piperazine (2.8 g) and 2-(4-fluorophenoxy)propyl chloride (4.7 g) were dissolved in dimethylformamide (60 ml), and sodium iodide (3.2 g) and triethylamine (4.4 ml) were added thereto, and the mixture was stirred overnight at 50 to 70° C. The organic layer was partitioned by adding water and ethyl acetate, washed with brine, dried over sodium sulfate anhydrous, and evaporated. The residue was purified by Cromatorex NH silica gel column chromatography (ethyl acetate). The resulting yellow oil (12.3 g) was dissolved in methanol (20 ml), and 5N aqueous sodium hydroxide (10 ml) was added thereto and then stirred for 1 hour under reflux. The reaction mixture was evaporated, then the organic layer was partitioned by adding water and ethyl acetate, washed with brine, and dried over sodium sulfate anhydrous. The residue obtained by evaporation was purified by Cromatorex NH silica gel column chromatography (ethyl acetate/methanol system), whereby the title compound (2.2 g, 38%) was obtained as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12]C)=O)[CH:3]=1.[OH-].[NH4+:15]>CO>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([NH2:15])=[O:12])[CH:3]=1
Reactant: COC(=O)c1cc(Cl)c(Cl)c(Cl)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1cc(Cl)c(Cl)c(Cl)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methyl 4,5,6-trichloropyridine-2-carboxylate (15 g, 62.4 mmol) was suspended in concentrated aqueous ammonium hydroxide (80 mL) and methanol (150 mL). After stirring for 4 hours at 25° C., the methanol was removed and the aqueous suspension was filtered. The filter cake was washed with water and dried to provide 4,5,6-trichloropyridine-2-carboxamide (13 g, 56.9 mmol), mp 169-170° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([NH:8][CH2:9][CH3:10])=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1.[C:16]([C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1)#[N:17].O>O1CCCC1>[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([N:8]([CH2:9][CH3:10])[S:24]([C:21]2[CH:20]=[CH:19][C:18]([C:16]#[N:17])=[CH:23][CH:22]=2)(=[O:26])=[O:25])=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1
Reactant: CCNc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCN(c1ccc(Cl)cc1[N+](=O)[O-])S(=O)(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Yield: 64.6 %

Procedure:
To a suspension of sodium hydride (60%, 0.10 g (2.50 mmol)) in tetrahydrofuran (THF)(3.0 ml), 4-chloro-N-ethyl-2-nitroaniline (0.40 g (1.99 mmol)) was added with stirring at room temperature. To the mixture, after stirring for 30 minutes at room temperature, 4-cyanobenzenesulfonyl chloride (0.50 g (2.48 mmol)) was added and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:2) as eluent, to give 0.47 g (64%) of the title compound as pale yellow crystals.