Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([CH:23]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:16]=2)[N:13]=1.[C:26]([C:28]([C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](O)=[O:35])([CH3:30])[CH3:29])#[N:27].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:26]([C:28]([C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]4[CH2:21][CH2:22]4)=[O:19])[N:16]=3)[N:13]=2)[CH:23]=1)=[O:35])([CH3:30])[CH3:29])#[N:27]
Reactant: COc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 71.2 %

Procedure:
Using N-[6-(5-amino-2-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.44 mmol), 3-(1-cyano-1-methylethyl)benzoic acid (88 mg, 0.46 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (87 mg, 0.46 mmol), 1-hydroxybenzotriazole (62 mg, 0.46 mmol) and N,N-dimethylformamide (10 mL) as starting materials and in the same manner as in Example 318, the title compound (160 mg, 71%) was obtained as a white powder.
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:19]4[CH2:21][CH2:20]4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:22]=1.[CH3:24][C:25]([OH:29])([C:27]#[CH:28])[CH3:26]>>[CH:19]1([C:13]2[N:8]3[CH:9]4[CH2:12][CH:11]([C:5]5[CH:4]=[C:3]([F:23])[C:2]([C:28]#[C:27][C:25]([OH:29])([CH3:26])[CH3:24])=[CH:22][C:6]=5[C:7]3=[N:15][C:14]=2[C:16]([NH2:18])=[O:17])[CH2:10]4)[CH2:21][CH2:20]1
Reactant: NC(=O)c1nc2n(c1C1CC1)C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: C#CC(C)(C)O
Product: CC(C)(O)C#Cc1cc2c(cc1F)C1CC(C1)n1c-2nc(C(N)=O)c1C1CC1

Procedure:
Similar to as described in General Procedure E, 10-bromo-3-cyclopropyl-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with 2-methylbut-3-yn-2-ol to give the titled compound.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:25])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([OH:22])=O)=[C:14]([O:23][CH3:24])[CH:13]=2)[CH2:4][CH2:3]1.P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[N:42]1([CH:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([N:51]3[CH2:52][CH2:53][CH:48]([N:42]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)[CH2:49][CH2:50]3)=[O:22])=[C:14]([O:23][CH3:24])[CH:13]=2)=[O:25])[CH2:6][CH2:7]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCC(=O)O
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCC(=O)N1CCC(N2CCCCC2)CC1

Procedure:
Using 1.9 g of N-(trans-4-methylcyclohexyl)-4-(carboxymethoxy)-3-methoxycinnamamide (Example 172), 1.2 ml of diethyl chlorophosphate, 2.3 ml of triethylamine, 0.92 g of 4-piperidinopiperidine, 0.04 g of 4-dimethylaminopyridine, and 100 ml of methylene chloride, a reaction similar to that conducted in Example 188 was carried out. As a result, 1.51 g of 1-{4-{2-[N-(trans-4-methylcyclohexyl)carbamoyl]vinyl}-2-methoxyphenoxyacetyl}-4-piperidinopiperidine (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH3:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([CH2:21][O:22][NH2:23])=[CH:19][CH:18]=1)([O-:16])=[O:15].N1C=CC=CC=1>CCO>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([CH2:21][O:22]/[N:23]=[C:10](/[C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([OH:1])[CH:3]=2)\[CH3:11])=[CH:24][CH:25]=1)([O-:16])=[O:15]
Reactant: COc1ccc(C(C)=O)cc1O
Reactant: NOCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: COc1ccc(/C(C)=N/OCc2ccc([N+](=O)[O-])cc2)cc1O
Yield: 89.6 %

Procedure:
A solution of ketone 12 (200 mg, 1.20 mmol) in EtOH (2.0 mL) was treated with compound 19 (0.27 g, 1.32 mmol) and pyridine (0.5 mL) and the resulting mixture heated at reflux for 3 h then cooled and the solvent evaporated under reduced pressure. The ensuing residue was partitioned between CH2Cl2 (10 mL) and H2O (10 mL). The separated aqueous fraction was extracted with CH2Cl2 (1×5.0 ml) and the combined organic fractions were dried (MgSO4) then filtered and concentrated under reduced pressure to give a light-yellow solid. Recrystallisation (isopropanol) of this material afforded the title compound CP30218 (340 mg, 89%) as pale-yellow crystals, m.p. 105.0-105.7° C.
Reaction SMILES: [C:1]([C:4]1([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:7][CH2:6][CH2:5]1)([OH:3])=[O:2].C([N-]C(C)C)(C)C.[Li+].[CH3:26][O:27][CH2:28]Cl.Cl>O1CCCC1.O>[C:14]([O:13][C:11](=[O:12])[CH:10]([CH2:26][O:27][CH3:28])[CH2:9][C:4]1([C:1]([OH:3])=[O:2])[CH2:8][CH2:7][CH2:6][CH2:5]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)CCC1(C(=O)O)CCCC1
Reactant: COCCl
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COCC(CC1(C(=O)O)CCCC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
A solution of t-butyl 3-(1-carboxycyclopentyl)propanoate (1.0 g, 4.13 mmole) in dry tetrahydrofuran was added to a stirred solution of lithium diisopropylamide (9.29 mmole) in dry tetrahydrofuran (50 ml) at -78° C. under nitrogen. After 0.5 hours, chloromethyl methyl ether (0.53 g, 6.58 mmole) was added and the mixture was allowed to warm to room temperature over 16 hours. The solution was poured into water, acidified to pH 3 with 2N hydrochloric acid and extracted with ethyl acetate (3×50 ml). The organic layer was separated, dried over magnesium sulphate and evaporated to give a colourless oil that was chromatographed on silica gel eluting with a mixture of diethyl ether and dichloromethane (1:9-1:4 by volume). Evaporation of the appropriate fractions gave the title compound as a colourless oil (0.78 g, 66%). Found: C,62.75; H,8.94. C15H26O5 requires: C,62.91; H,9.15%.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[C:21][C:22]4[CH:32]=[CH:31][C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][CH:23]=4)[CH:18]=3)[S:13][C:12]([CH3:34])([CH3:33])[CH:11]=2)=[CH:6][CH:5]=1)(C)[CH3:2].[OH-].[Na+].Cl>C1COCC1.CCO>[CH2:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][C:22]4[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:31][CH:32]=4)[CH:18]=3)[S:13][C:12]([CH3:33])([CH3:34])[CH:11]=2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C(C)C)cc2)=CC(C)(C)S3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1ccc(C2=CC(C)(C)Sc3ccc(CCc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of ethyl 4-[[4-(4-isopropylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-benzoate (Compound 228, 89.0 mg, 0.19 mmol) in 3.0 mL THF and 3.0 mL EtOH was added NaOH (80.0 mg, 2.0 mmol, 2.0 mL of a 1M aqueous solution). The resulting solution was heated to 45° C. and stirred overnight. Upon cooling to room temperature the reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before removing the solvent under reduced pressure. The residual solid was recrystallized from CH3CN to give 78.0 mg (93%) of the title compound as a pale-yellow solid. 1H NMR (300 MHz, d6 -acetone) δ: 8.00 (2H, d, J=8.4 Hz), 7.58 (2H, d, J=8.4 Hz), 7.45-7.21 (7H, m), 5.93 (1H, s), 2.95 (1H, hept, J=7.0 Hz), 1.47 (6H, s), 1.25 (6H, d, J=7.0 Hz).
Reaction SMILES: COP([CH2:7][C:8](=[O:25])[CH2:9][N:10]1[C@H:14]([CH3:15])[CH2:13][C@H:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:11]1=[O:24])(=O)OC.C(=O)([O-])[O-].[K+].[K+].[CH3:32][O:33][C:34]1[N:39]=[CH:38][C:37]([CH:40]=O)=[CH:36][CH:35]=1>CN(C)C=O.C(OCC)(=O)C>[C:20]([O:19][C:17](=[O:18])[NH:16][C@H:12]1[CH2:13][C@@H:14]([CH3:15])[N:10]([CH2:9][C:8](=[O:25])[CH:7]=[CH:40][C:37]2[CH:38]=[N:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)[C:11]1=[O:24])([CH3:21])([CH3:22])[CH3:23]
Reactant: COP(=O)(CC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1C)OC
Reactant: COc1ccc(C=O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C=CC(=O)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]2C)cn1
Temperature: 82.5 °C

Procedure:
A stirred suspension of 4-3 (190 mg, 0.50 mmol), potassium carbonate (104 mg, 0.75 mmol), and 6-methoxy-pyridine-3-carboxaldehyde (for preparation, see U.S. Pat. No. 6,048,861, which is incorporated by reference herein in its entirety) (69 mg, 0.50 mmol) in N,N-dimethylformamide (2 mL) was heated at 80-85° C. for 3 hours and then cooled to ambient temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium chloride, dried over magnesium sulfate, and filtered. Following evaporative removal of the solvent, the residue was purified by flash column chromatography (silica gel, 95:5% ethyl acetate/methanol) to give 4-4 as a colorless oil.
Reaction SMILES: [C:1]([O:6][CH2:7][O:8][C:9]([C:11]1[N:15]2[C:16](=[O:28])[C@H:17]([C@H:18]([O:20][Si](C(C)(C)C)(C)C)[CH3:19])[C@H:14]2[C@@H:13]([CH3:29])[C:12]=1[S:30][C@H:31]1[CH2:35][NH:34][C:33](=[S:36])[CH2:32]1)=[O:10])(=[O:5])[CH:2]([CH3:4])[CH3:3].CN(C)C=O.F.[NH4+].P([O-])([O-])([O-])=O>CN1CCCC1=O>[C:1]([O:6][CH2:7][O:8][C:9]([C:11]1[N:15]2[C:16](=[O:28])[C@H:17]([C@H:18]([OH:20])[CH3:19])[C@H:14]2[C@@H:13]([CH3:29])[C:12]=1[S:30][C@H:31]1[CH2:35][NH:34][C:33](=[S:36])[CH2:32]1)=[O:10])(=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)C(=O)OCOC(=O)C1=C(S[C@H]2CNC(=S)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Agent: F
Agent: O=P([O-])([O-])[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: CC(C)C(=O)OCOC(=O)C1=C(S[C@H]2CNC(=S)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 20 °C
Reaction time: 72 h
Yield: 91 %

Procedure:
A mixture of (1R,5S,6S)-2-[(4R)-pyrrolidine-2-thion-4-ylthio]-6-[(1R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid isobutyryloxymethyl ester (3 g), dimethylformamide (20 ml), N-methylpyrrolidone (7 ml) and ammonium hydrogenfluoride (1.21 g) is stirred at 20° C. for three days. The reaction mixture is poured into a phosphate buffer (pH 7.0), and the mixture is extracted with ethyl acetate. The aqueous layer is extracted with ethyl acetate, and the organic layers are combined, washed with water, dried, and concentrated under reduced pressure. The resulting residue is crystallized from a mixture of ethyl acetate and diisopropyl ether. To the resultant is added diisopropyl ether, and the precipitate is collected by filtration, and washed to give (1R,5S,6S)-2-[(4R)-pyrrolidine-2-thion-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid isobutyryloxymethyl ester (2.17 g) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:16])([CH3:15])[CH2:4][CH2:5][CH2:6][C:7]([CH3:14])=[CH:8][CH2:9][CH2:10][C:11](=[O:13])[CH3:12].[C:17](=O)([O-:20])[O:18][CH3:19].[H-].[Na+].Cl>CN(C)C=O>[CH3:1][O:2][C:3]([CH3:16])([CH3:15])[CH2:4][CH2:5][CH2:6][C:7]([CH3:14])=[CH:8][CH2:9][CH2:10][C:11](=[O:13])[CH2:12][C:17]([O:18][CH3:19])=[O:20]
Reactant: COC(C)(C)CCCC(C)=CCCC(C)=O
Reactant: COC(=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CC(=O)CCC=C(C)CCCC(C)(C)OC
Temperature: 40 °C
Reaction time: 6 h

Procedure:
A mixture of 900 mg of the product from Step B, 1 ml of methyl carbonate and 15 ml of dimethylformamide was heated to 40° C. and 360 mg of sodium hydride in a 50% oil suspension were added thereto portion wise and the mixture was stirred for 6 hours at room temperature. The mixture was poured into an aqueous hydrochloric acid solution and was extracted with petroleum ether (b.p.= 40°-75° C.). The extracts were washed with water, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed over silica and was eluted with a 7-3 petroleum ether-ethyl ether mixture to obtain 374 mg of methyl 11-methoxy-7,11-dimethyl-3-oxo-6-dodecenoate in the form of a colorless oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][OH:8])=[CH:2]1.[Br:9]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:9][C:2]1[S:1][CH:5]=[CH:4][C:3]=1[CH2:6][CH2:7][OH:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCc1ccsc1
Solvent: ClC(Cl)(Cl)Cl
Product: OCCc1ccsc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a stirred solution of 2-(3-thienyl)ethanol (25.0 g, 0.195 mol) in carbon tetrachloride (250 ml) was added N-bromosuccinimide (34.7 g, 0.195 mol) in several portions over a 15 minute period. The mixture was stirred at room temperature for one hour. The succinimide was removed by filtration and the filtrate was concentrated in vacuo at room temperature to give the product as a viscous amber oil (40.2 g) (99%). TLC indicated that the product was pure and mass spectral analysis showed a molecular ion at M/Z 206. NMR supported the structure.
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].C([O-])([O-])=O.[Na+].[Na+].[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([F:24])=[C:19]([CH:23]=1)[C:20]([OH:22])=[O:21]>O>[F:24][C:18]1[CH:17]=[CH:16][C:15]([NH:14][S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])=[CH:23][C:19]=1[C:20]([OH:22])=[O:21]
Reactant: Nc1ccc(F)c(C(=O)O)c1
Reactant: CCCS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1
Temperature: 60 °C

Procedure:
Propane-1-sulfonyl chloride (0.0871 mL, 0.774 mmol) was dissolved in 10% Na2CO3 (1.65 mL, 1.55 mmol) at room temperature. 5-Amino-2-fluorobenzoic acid (0.100 g, 0.645 mmol) was added and heated to 60° C. overnight. Propane-1-sulfonyl chloride (0.0871 mL, 0.774 mmol) was added again, and the reaction mixture was heated at 60° C. for another hour. The reaction mixture was cooled to room temperature, diluted with water, taken to a pH of 10 with 10% Na2CO3 and extracted with DCM (2×). The reaction mixture was then taken to a pH of 2 with 1N HCl, extracted with DCM (3×) and concentrated to a solid, 2-fluoro-5-(propylsulfonamido)benzoic acid (29%).
Reaction SMILES: [OH:1][C@H:2]([C@@H:18]([NH:26][C:27](=[O:47])[C@@H:28]([N:33]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[N:40]=2)[C:34]1=[O:46])[C@@H:29]([CH3:32])[CH2:30][CH3:31])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][NH:4][NH:5][C:6]([C@@H:8]([NH:13][C:14](=[O:17])[O:15][CH3:16])[C@@H:9]([CH3:12])[CH2:10][CH3:11])=[O:7].[CH:48](=O)[C:49]1[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[OH:1][C@H:2]([C@@H:18]([NH:26][C:27](=[O:47])[C@@H:28]([N:33]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[N:40]=2)[C:34]1=[O:46])[C@@H:29]([CH3:32])[CH2:30][CH3:31])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][N:4]([CH2:48][C:49]1[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=1)[NH:5][C:6]([C@@H:8]([NH:13][C:14](=[O:17])[O:15][CH3:16])[C@@H:9]([CH3:12])[CH2:10][CH3:11])=[O:7]
Reactant: COc1ccc(C=O)cc1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NNC[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H]([C@@H](C)CC)N1CCN(Cc2cccc(C)n2)C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NN(Cc1ccc(OC)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H]([C@@H](C)CC)N1CCN(Cc2cccc(C)n2)C1=O
Yield: 58.3 %

Procedure:
A solution of Example 283A (50 mg, 0.45 mmol) in 1,2-dichloroethane (1 mL) and treated with p-anisaldehyde (16 mg, 1.5 equivalents), acetic acid (5 μL, 2 equivalents), and sodium triacetoxy borohydride (32 mg, 2 equivalents) at 25° C. for 16 hrs. The mixture was quenched with 10% NaHCO3 (2 mL) and CHCl3. The organic layer was separated, dried over sodium sulfate, filtered and the solvents were evaporated. The residue was purified using 5% methanol/CHCl3 to give 53 mg (90%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH:16]([CH3:18])[CH3:17])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[CH:6]=[C:7]([S:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[O:8]2.C(OC([N:35](C(OC(C)(C)C)=O)[CH2:36][C:37](O)=[O:38])=O)(C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1.[ClH:62]>ClCCl.C(OCC)(=O)C>[ClH:62].[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH:16]([CH3:18])[CH3:17])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[CH:6]=[C:7]([S:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][C:37](=[O:38])[CH2:36][NH2:35])=[CH:24][CH:25]=1)[O:8]2
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)C(=O)OC(C)(C)C
Reactant: COc1c(OC(C)C)cc2oc(Sc3ccc(O)cc3)cc(=O)c2c1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1c(OC(C)C)cc2oc(Sc3ccc(OC(=O)CN)cc3)cc(=O)c2c1OC
Reaction time: 1 h

Procedure:
300 ml in dichloromethane of 9.11 g of 5,6-dimethoxy-2-(4-hydroxyphenylthio)-7-isopropoxychromone obtained in Example 22, 4.52 g of N-t-butoxycarbonyl(Boc)glycine, and 5.32 g of dicyclohexylcarbodiimide (DCC) was stirred over 3.5 hours at room temperature. The solution thus reacted was gravitationally filtered. The solvent was distilled out from the filtrate, so that 10.95 g of N-t-butoxycarbonyl(Boc)glycine ester was obtained. 5.27 g of N-t-butoxycarbonyl(Boc)glycine ester thus prepared was dissolved in 100 ml of ethyl acetate. Then, hydrochloric acid gas was introduced and bubbled in the solution for 10 min., followed by stirring for 1 hour. Subsequently, 200 ml ether was added and the resulting crystals were collected by filtration and then dried, whereby 3.53 g of 5,6-dimethoxy-2-(4-glycyloxyphenylthio)-7-isopropoxychromone hydrochloride with the following physicochemical properties was obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[N:13]1([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:21]2[CH2:22][CH2:23][CH:18]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:19][CH2:20]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: C1CCN(C2CCNCC2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1cc(N2CCC(N3CCCC3)CC2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 17 h

Procedure:
200 mg (1.170 mmol) 4-fluoro-2-methoxy-1-nitro-benzene are dissolvedjin 1 ml NMP, combined with 198 mg (1.284 mmol) 4-pyrrolidin-1-yl-piperidine and 300 μl diisopropylethylamine and stirred for 17 h at 80° C. Then the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier material used is C18-RP gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and 5% water and 95% acetonitrile at the finishing point.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C1COCC1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: C1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(F)cc1)N1CCCCC1

Procedure:
A solution of piperidine (5.64 g, 66 mmol), diisopropylethyl amine (1 3.64 mL, 78 mmol), and p-fluorobenzenesulfonyl chloride (13.64 mL, 78 mmol) in THF at 0° C. was stirred for 2 hours at ambient temperature. The solvent was removed in vacuo and the crude reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with aqueous HCl, and brine. It was dried over sodium sulfate, and filtered. Removal of the solvent gave near quantitative yield of the title compound.
Reaction SMILES: CC1(C)CCC(C)(C)C2C=C(O)C(C(O)=O)=CC1=2.[CH3:19][C:20]1([CH3:37])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:26]2[C:25]([Br:32])=[C:24]([OH:33])[C:23]([C:34]([OH:36])=[O:35])=[CH:22][C:21]1=2.[CH3:38][O:39][CH2:40]Cl>>[CH3:19][C:20]1([CH3:37])[CH2:29][CH2:28][C:27]([CH3:30])([CH3:31])[C:26]2[C:25]([Br:32])=[C:24]([O:33][CH2:38][O:39][CH3:40])[C:23]([C:34]([OH:36])=[O:35])=[CH:22][C:21]1=2
Reactant: COCCl
Reactant: CC1(C)CCC(C)(C)c2c1cc(C(=O)O)c(O)c2Br
Agent: CC1(C)CCC(C)(C)c2cc(C(=O)O)c(O)cc21
Product: COCOc1c(C(=O)O)cc2c(c1Br)C(C)(C)CCC2(C)C

Procedure:
5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-hydroxynaphthalene (Compound H, available in accordance with the publication Krause Synthesis 1972 140), is the starting material in the example shown in Reaction Scheme 2. Compound H is brominated to provide the corresponding 3-bromo compound (Compound I) which is thereafter protected in the hydroxyl function by treatment with methoxymethyl chloride (MOMCl) to yield 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methoxymethoxy-2-bromonaphthalene (Compound J). Compound J is reacted with t-butyllithium and carbon dioxide to provide the corresponding carboxylic acid (Compound K) from which the methoxymethyl protecting group is removed by acid to give 5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2-hydroxynaphthalene-3-carboxylic acid (Compound L). Compound L is brominated to yield 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-1-bromo-2-hydroxynaphthalene-3-carboxylic acid (Compound M). Compound L and Compound M serve as reagents in accordance with Formula 6. The hydroxy group of Compound M is protected for further transformations with methoxymethyl chloride (MOMCl) in the presence of base, yielding 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-1-bromo-2-methoxymethoxynaphthalene-3-carboxylic acid (Compound N).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH:20]([CH3:22])[CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].C(N(C(C)C)CC)(C)C.Br[C:33]1[S:34][C:35]2[C:41]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1>>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:33]3[S:34][C:35]4[C:41]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:40][CH:39]=[CH:38][C:36]=4[N:37]=3)[CH2:15][C@H:14]2[O:19][CH:20]([CH3:21])[CH3:22])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCNC[C@H]2OC(C)C)nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](OC(C)C)C3)sc12
Yield: 63 %

Procedure:
The same operation as in Example (1h) was performed using cis(±)-4-chloro-N-(3-isopropoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (148a) (0.150 g, 0.427 mmol), diisopropylethylamine (0.186 mL, 1.07 mmol) and ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained in Example (1f) (0.147 g, 0.514 mmol), to obtain 0.140 g of the title compound as a yellow foamy solid (63%).
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]2[CH2:7][CH2:8][C:9]3[C:10]([C:16](=[O:17])[C:5]=2[CH:4]=1)=[N+:11]([O-])[CH:12]=[CH:13][CH:14]=3)#[N:2].S(Cl)(C1C=CC(C)=CC=1)(=O)=[O:21].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[C:1]([C:3]1[CH:19]=[CH:18][C:6]2[CH2:7][CH2:8][C:9]3[CH:14]=[CH:13][C:12](=[O:21])[NH:11][C:10]=3[C:16](=[O:17])[C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)C(=O)c1c(ccc[n+]1[O-])CC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: N#Cc1ccc2c(c1)C(=O)c1[nH]c(=O)ccc1CC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 0.85 gram (0.0034 mole) of the N-oxide thus obtained and 0.77 gram (0.0043 mole) of tosyl chloride in 37.5 milliliters of chloroform was added a solution of 0.58 gram (0.0042 mole) of potassium carbonate in 5.8 milliliters of water and the resulting mixture was stirred vigorously at room temperature for two days and the reaction mixture washed with alkali to obtain an 11-oxo-5,6-dihydrobenzo[5,6]-cyclohepta[1,2-b]pyrid-2(1H)one product which is recovered and purified by conventional procedures.