Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[OH:28][C@H:29]([CH3:33])[C:30](O)=[O:31]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:30](=[O:31])[C@H:29]([OH:28])[CH3:33])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: C[C@@H](O)C(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: C[C@@H](O)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (88.4 mg, 40.3%), MS (ISP) m/z=404.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (200 mg, 544 mmol) and (R)-2-hydroxypropanoic acid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:14]2([C:19]#[N:20])[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:21]([O:25][C:26]([NH:28][C:29]([CH3:39])([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:30][OH:31])=[O:27])([CH3:24])([CH3:23])[CH3:22].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>ClC(Cl)C.FC(F)(F)S([O-])(=O)=O.[Ag+]>[C:21]([O:25][C:26]([NH:28][C:29]([CH3:39])([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:30][O:31][CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:14]2([C:19]#[N:20])[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(CO)(Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cc(CBr)cc(C2(C#N)CCCC2)c1
Agent: [Ag+]
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(C2(C#N)CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-(bromomethyl)-5-(1-cyanocyclopentyl)benzoate (0.15 g, 0.45 mmol) and 2-tert-butoxycarbonylamino-2-methyl-3-phenylpropan-1-ol (0.21 g, 0.79 mmol in 8 mL dichloroethane was added 2,6-di-tert-butylpyridine, polymer bound (0.72 g, 1.3 mmol) and silver trifluoromethanesulfonate (0.20 g, 0.79 mmol). The reaction was stirred at rt overnight and filtered. Concentration and flash chromatography (silica gel, 0-25% EtOAc/hexanes) gave ethyl 3-((2-tert-butoxycarbonylamino-2-methyl-3-phenylpropoxy)methyl)-5-(1-cyanocyclopentyl)benzoate. 1H NMR (400 MHz, CDCl3) δ 8.03 (app d, J=1.5 Hz, 1H), 7.96 (s, 1H), 7.67 (s, 1H), 7.28-7.22 (m, 3H), 7.17 (m, 2H), 4.60 (s, 2H), 4.57 (s, 1H), 4.40 (q, J=7.1 Hz, 2H), 3.55 (d, J=8.9 Hz, 1H), 3.45 (d, J=9.0 Hz, 1H), 3.14 (d, J=13.3 Hz, 1H), 2.95 (d, J=13.2 Hz, 1H), 2.52 (m, 2H), 2.13-1.96 (m, 6H), 1.46 (s, 9H), 1.41 (t, J=7.1 Hz, 3H), 1.28 (s, 3H).
Reaction SMILES: Br[C:2](Br)=[CH:3][CH:4]1[CH2:8][CH:7]([O:9][CH3:10])[O:6][CH:5]1[O:11][CH3:12].C([Li])CCC.[CH2:19]([Sn:23](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22].[NH4+].[Cl-]>CCOCC>[CH3:12][O:11][CH:5]1[CH:4]([C:3]#[C:2][Sn:23]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:8][CH:7]([O:9][CH3:10])[O:6]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: COC1CC(C=C(Br)Br)C(OC)O1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CCCC[Sn](C#CC1CC(OC)OC1OC)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To solution of crude 3-(2,2-dibromoethenyl)-2,5-dimethoxy-tetrahydrofuran (1.78 g, 5.64 mmol) in ether (30 mL) at −78° C. was added n-butyllithium (9.02 mL of 1.25 M in hex). After 1 hour at −78° C., tributyltin chloride (1.68 mL, 6.20 mmol) was added, and the mixture was allowed to warm to ambient temperature. After 16 hours, ether (35 mL) and saturated aqueous NH4Cl (30 mL) were added. The organic layer was separated, washed with saturated aqueous NH4Cl (30 mL), H2O (25 mL), and saturated aqueous NaHCO3 (25 mL), dried over K2CO3, and evaporated to give an orange oil, which was purified via flash column chromatography with 2% MTBE/hex to furnish 1.92 g (77%) of 2,5-dimethoxy-3-(2-tributylstannylethynyl)-tetrahydrofuran as a colorless oil. A mixture of diastereomers was evident in the 1H NMR spectrum, which was used immediately without further purification. IR: 2923, 1456, 1374, 1215, 1105, 1017, 967 cm−1. Anal. Calculated for C20H38O3Sn: C, 53.96; H, 8.60. Found: C, 54.21; H, 8.66.
Reaction SMILES: [CH2:1]([N:9]1[C:18]2[C:13](=[C:14]([CH3:26])[C:15]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:16]([CH3:19])[CH:17]=2)[CH2:12][CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[N+:27]([O-])([OH:29])=[O:28].C(=O)([O-])O.[Na+]>C(OC(=O)C)(=O)C>[CH2:1]([N:9]1[C:18]2[C:13](=[C:14]([CH3:26])[C:15]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:16]([CH3:19])[C:17]=2[N+:27]([O-:29])=[O:28])[CH2:12][CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=[N+]([O-])O
Reactant: CCCCCCCCN1CCCc2c1cc(C)c(CC(=O)OCC)c2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCN1CCCc2c(C)c(CC(=O)OCC)c(C)c([N+](=O)[O-])c21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
1-Octyl-6-ethoxycarbonylmethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinoline (1.0 g) was dissolved in acetic anhydride (5 ml), and a solution of 70% nitric acid (517 mg) in acetic anhydride (3 ml) was dropwise added, which was followed by stirring at the same temperature for 0.5 hr. The reaction mixture was poured into ice water (50 ml), neutralized with saturated aqueous solution of sodium hydrogencarbonate, and extracted with chloroform (50 ml). After washing with water, the chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane-ethyl acetate/n-hexane=1/5) to give 700 mg of oily 1-octyl-6-ethoxycarbonylmethyl-5,7-dimethyl-8-nitro-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH2:19])[C:13]([O:15][CH3:16])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.CCOCC>C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].O.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>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=[CH2:19])[C:13]([O:15][CH3:16])=[O:14])(=[O:10])=[O:9])=[CH:6][CH:7]=2)=[CH:32][CH:31]=1
Reactant: C=CC(OCc1ccccc1)C(NS(=O)(=O)c1ccc(Br)cc1)C(=O)OC
Reactant: COc1ccc(B(O)O)cc1
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: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: C=CC(OCc1ccccc1)C(NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1)C(=O)OC

Procedure:
The methyl 2-[4-bromophenylsulfonyl]amino-3-phenylmethoxy-4-pentenoate 63c (320 mg, 0.683 mmol) is dissolved in benzene (4 mL) and sodium carbonate (148 mg), in water (0.6 mL), is added along with tetrakis(triphenylphosphine)palladium. 4-Methoxyphenylboronic acid (157 mg, 1.03 mmol), in methanol (0.4 mL), is added and the mixture is heat to reflux overnight. Ether is added to the reaction which is washed with water (3 times) and brine, the organic layer is dried over magnesium sulfate and the solvent stripped in vacuo to give the crude product as a yellow solid. The crude material is adsorbed onto silica gel and purified over a silica column eluting with hexane/ethyl acetate (9:1) followed with hexane/ethyl acetate (1/1). Product fractions are combined and dried to give the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][CH:26]1[O:31][C:30](=[O:32])[CH2:29][CH:28]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:27]1>>[CH2:34]([O:33][CH:28]1[CH2:27][CH:26]([CH2:25][CH2:24][N:23]2[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[O:31][C:30](=[O:32])[CH2:29]1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: NCCC1CC(OCc2ccccc2)CC(=O)O1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CCC1CC(OCc2ccccc2)CC(=O)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and 6-(2-aminoethyl)-4-(benzyloxy)tetrahydro-2H-pyran-2-one.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([CH2:15][CH3:16])[C:3]=1[C:17]#[N:18].[Li+].[CH3:20][CH:21]([N-]C(C)C)C.C(Br)C.CCOCC>C1COCC1.O>[CH2:15]([C:4]1[C:3]([C:17]#[N:18])=[C:2]([NH:1][CH2:20][CH3:21])[N:6]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[N:5]=1)[CH3:16]
Reactant: CCc1nn(-c2ccc(OC)cc2)c(N)c1C#N
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCBr
Solvent: O
Solvent: C1CCOC1
Product: CCNc1c(C#N)c(CC)nn1-c1ccc(OC)cc1
Reaction time: 0.08 h
Yield: 23.3 %

Procedure:
To 5-amino-3-ethyl-1-(4-methoxyphenyl)-1H-pyrazole-4-carbonitrile (0.50 g, 2.06 mmol) in THF (10 mL) at −78 C was added LDA (0.6 M in THF, 4.5 mL, 2.7 mmol) and stirred for 5 min, followed by EtBr (500 μL, 6.81 mmol) and the reaction was stirred over night at room temperature. Et2O and water were added, and the organic phase was separated. The water phase was acidified using 1 M HCl which was extracted with EtOAc. After drying using MgSO4, and evaporation of solvent the crude was purified using silica chromatography to give 3-ethyl-5-(ethylamino)-1-(4-methoxyphenyl)-1H-pyrazole-4-carbonitrile (130 mg, 23%).
Reaction SMILES: [OH-].[Na+].[OH:3][CH:4]([CH2:37][OH:38])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20]CC)=[O:19])=[CH:14][CH:13]=2)=[CH:8][C:7]=1[C:23]1[CH:32]=[CH:31][C:30]2[C:29]([CH3:34])([CH3:33])[CH2:28][CH2:27][C:26]([CH3:36])([CH3:35])[C:25]=2[CH:24]=1.Cl>O1CCCC1.C(O)C>[OH:3][CH:4]([CH2:37][OH:38])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([OH:20])=[O:19])=[CH:16][CH:17]=2)=[CH:8][C:7]=1[C:23]1[CH:32]=[CH:31][C:30]2[C:29]([CH3:34])([CH3:33])[CH2:28][CH2:27][C:26]([CH3:36])([CH3:35])[C:25]=2[CH:24]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(CC(O)CO)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(-c3cc(-c4ccc(C(=O)O)cc4)ccc3CC(O)CO)ccc21
Temperature: 50 °C
Reaction time: 48 h
Yield: 95.7 %

Procedure:
1 ml (1 mmol) of an aqueous solution of sodium hydroxide (1 M) is added to a solution of 200 mg (0.41 mmol) of ethyl 4′-(2,3-dihydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate in 5 ml of tetrahydrofuran and 2 ml of ethanol. The reaction mixture is stirred for 48 h while heating at 50° C. After the reaction mixture has returned to ambient temperature, 2 ml (2 mmol) of a solution of hydrochloric acid (1 N) are added. The medium is extracted with ethyl acetate. The organic phase is washed with water, and then dried over magnesium sulfate. After evaporation of the solvents, the product obtained is purified by crystallization from a heptane/diethyl ether mixture. 180 mg of 4′-(2,3-dihydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylic acid are obtained (beige solid, Mp=145° C., yield=96%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][P:12](=[O:16])([CH3:15])[CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[S:19][C:20]([C:26]2[C:31]([F:32])=[CH:30][C:29]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:28][C:27]=2[F:37])=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24]>>[F:37][C:27]1[CH:28]=[C:29]([C:33]([OH:36])([CH3:35])[CH3:34])[CH:30]=[C:31]([F:32])[C:26]=1[C:20]1[S:19][C:18]([NH:17][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][N:9]3[CH2:14][CH2:13][P:12]([CH3:15])(=[O:16])[CH2:11][CH2:10]3)[N:7]=2)=[C:22]([C:23]([NH2:25])=[O:24])[CH:21]=1
Reactant: CP1(=O)CCN(Cc2cccc(Br)n2)CC1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(CN4CCP(C)(=O)CC4)n3)s2)c(F)c1

Procedure:
The title compound was synthesized from 1-[(6-bromopyridin-2-yl)methyl]-4-methyl-1,4-azaphosphinane 4-oxide (121 mg, 0.40 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (125 mg, 0.40 mmol) according to the general procedure in Example 1.
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20]C([C@H](O)[C@@H](NC(C2C=CC=CC=2)=O)C2C=CC=CC=2)=O)[CH2:18][C@:14]2([OH:41])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([O:59]C(C)=O)[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6].CC1[C@@H](OC([C@H](O)[C@@H](NC(C2C=CC=CC=2)=O)C2C=CC=CC=2)=O)C[C@]2(O)C(C)(C)C=1[C@@H](O)C([C@@]1(C)[C@H]([C@@H]2OC(C2C=CC=CC=2)=O)[C@]2(OC(C)=O)CO[C@@H]2C[C@@H]1O)=O>ClCCl>[CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([OH:59])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6]
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Agent: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Solvent: ClCCl
Product: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](O)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C

Procedure:
In contrast, the same procedure as described in Example II was run on 10 grams of starting material having the same taxol and 10-deacetyltaxol percentages. The reaction solvent used was dichloromethane (as was used in the Magris, et al. procedure). The 10-deacetylbaccatin III yield was only 24%, 90 mg (a lower yield resulted from larger amounts of material) as analyzed by TLC. there as 69 mg of 10-deacetyltaxol remaining; 47% of the 10-deacetyltaxol was converted. Based on TLC analysis, the reaction in dichloromethane was run for one hundred twenty hours versus seventy-two hours.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]([N:17]3[CH2:20][CH:19]([NH:21][C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=4)=[O:23])[CH2:18]3)=[O:16])[N:14]=2)[CH2:7]1)(=O)=O.[C:35]([O-:38])(=[S:37])[CH3:36].[K+]>CN(C)C=O>[C:35]([S:37][CH:6]1[CH2:7][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]([N:17]3[CH2:18][CH:19]([NH:21][C:22]([O:24][CH2:25][C:26]4[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=4)=[O:23])[CH2:20]3)=[O:16])[N:14]=2)[CH2:9]1)(=[O:38])[CH3:36]
Reactant: CS(=O)(=O)OC1CN(c2nc(C(=O)N3CC(NC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)cs2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N3CC(NC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)cs2)C1
Temperature: 80 °C
Reaction time: 9 h
Yield: 55.7 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-{4-[3-(p-nitrobenzyloxycarbonylamino)-azetidine-1-carbonyl]-1,3-thiazol-2-yl}azetidine (760 mg, 1.45 mmol) (obtained as described in Reference Example 57(6)) in dimethylformamide (38 ml) was added potassium thioacetate (993 mg, 8.70 mmol) at room temperature. The mixture was stirred in an oil bath (80° C.) for 9 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 3acetylthio-1-{4-[3-(p-nitrobenzyloxycarbonylamino)-azetidine-1-carbonyl]-1,3-thiazol-2-yl}azetidine (397 mg, yield 56%) as a pale brown solid.
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C@@H:11]1[CH2:20][CH2:19][CH2:18][C@H:17]2[N:12]1[C:13](=[O:29])[CH:14](P(=O)(OCC)OCC)[CH2:15][CH2:16]2.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[N:40]1[CH:44]=[C:43]([CH3:45])[N:42]=[CH:41]1)[CH:35]=O.C(OCC)(=O)C>O1CCCC1.C(O)C>[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]1[CH2:20][CH2:19][CH2:18][CH:17]2[N:12]1[C:13](=[O:29])[C:14](=[CH:35][C:34]1[CH:37]=[CH:38][C:39]([N:40]3[CH:44]=[C:43]([CH3:45])[N:42]=[CH:41]3)=[C:32]([O:31][CH3:30])[CH:33]=1)[CH2:15][CH2:16]2
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CCOP(=O)(OCC)C1CC[C@H]2CCC[C@@H](c3ccccc3F)N2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C=C2CCC3CCCC(c4ccccc4F)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
Lithium hydroxide monohydrate (169 mg) was added to a mixed solution of diethyl [(6S*,9aR*)-6-(2-fluorophenyl)-4-oxooctahydroquinolizin-3-yl]phosphonate (501 mg) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (290 mg) in tetrahydrofuran (12 mL) and ethanol (4 mL) at room temperature, and the reaction solution was stirred at room temperature for two hours. Ethyl acetate was added to the reaction solution, which was then sequentially washed with saturated sodium bicarbonate water and brine. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 483 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:16]=[C:15]([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:14]=[CH:13][N:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:26]I.O>CCCCCC.CN(C)C=O>[C:3]([O:7][C:8]([N:10]([C:11]1[CH:16]=[C:15]([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:21])[CH:14]=[CH:13][N:12]=1)[CH3:26])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CI
Reactant: CC(C)(C)OC(=O)Nc1cc(CO[Si](C)(C)C(C)(C)C)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: CN(C(=O)OC(C)(C)C)c1cc(CO[Si](C)(C)C(C)(C)C)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60% Sodium hydride (310 mg, 7.6 mmol) was washed with hexane (5.0 mL), and the residue was suspended in N,N-dimethylformamide (20 mL). 2-tert-Butoxycarbonylamino-4-(tert-butyldimethylsilyloxymethyl)pyridine (Reference compound No. 5-1, 1.3 g, 3.7 mmol) was added dropwise to the suspension for 15 minutes under ice-cooling, and methyl iodide (2.4 mL, 39 mmol) was added thereto, and then the mixture was stirred overnight at room temperature. Water (70 mL) was added to the reaction suspension, and the whole was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (50 mL) and brine (100 mL), and dried over anhydrous magnesium sulfate. The organic layer was evaporated under reduced pressure to give 1.4 g of the mixture including the title reference compound as an orange-red oil.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[NH:25]([C:27]1[N:34]=[C:33]([CH3:35])[CH:32]=[C:31]([CH3:36])[C:28]=1[C:29]#[N:30])N>>[CH3:23][S:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:25]([C:27]4[N:34]=[C:33]([CH3:35])[CH:32]=[C:31]([CH3:36])[C:28]=4[C:29]#[N:30])[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)(=[O:22])=[O:21]
Reactant: Cc1cc(C)c(C#N)c(NN)n1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Product: Cc1cc(C)c(C#N)c(-n2nccc2-c2nn(-c3cccc(S(C)(=O)=O)c3)ccc2=O)n1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and 2-hydrazino-4,6-dimethyl-nicotinonitrile according to example 43 gave the desired product. MS: M=447.0 (M+H)+
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8][C:7]=1[CH2:17][C:18]12[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2)=[O:5])C.[OH-].[Na+]>C(O)C>[C:18]12([CH2:17][C:7]3[NH:8][C:9]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)=[CH:10][C:6]=3[C:4]([OH:5])=[O:3])[CH2:25][CH:24]3[CH2:23][CH:22]([CH2:21][CH:20]([CH2:26]3)[CH2:19]1)[CH2:27]2
Reactant: CCOC(=O)c1cc(-c2ccccc2)[nH]c1CC12CC3CC(CC(C3)C1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(-c2ccccc2)[nH]c1CC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 95.5 %

Procedure:
To a solution of the product of step b (750 mg, 2.06 mmol) in ethanol (45 ml) was added sodium hydroxide (5 ml of 6.0M solution). The mixture was heated at reflux for 48 h, it was allowed to cool to room temperature and concentrated to small volume under reduced pressure. The concentrated solution was diluted with 2M hydrochloric acid (40 ml), the precipitated solid was filtered, washed with water and dried to afford the acid (660 mg, 94%). 1H NMR (300 MHz, CDCl3) 11.5 (1H, br s), 8.26 (1H, br s), 7.48 (2H, m), 7.40 (2H, m), 7.26 (1H, m), 6.94 (1H, d), 2.87 92H, s), 1.97 (3H, br s), 1.63 (12H, m).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[C:4]([O:6]C)=[O:5]>[OH-].[Na+].O>[F:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]([C:13]2[N:14]=[CH:15][CH:16]=[CH:17][N:18]=2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1c(-c2ncccn2)ccc(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1c(-c2ncccn2)ccc(F)c1F
Temperature: 25 °C

Procedure:
A solution of methyl 2,3-difluoro-6-(pyrimidin-2-yl)benzoate in 2 N NaOH and water was heated at reflux for 4 h. After this time, the reaction mixture was cooled to rt and concentrated to half volume under reduced pressure. The resulting mixture was acidified to pH 4 with 1 N HCl and extracted with EtOAc. The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was dried under high vacuum to give the title compound. ESI MS (M+H) 237.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[C:13]2[C:20]([CH3:21])=[CH:19][NH:18][C:14]=2[N:15]=[CH:16][CH:17]=1.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[NH:18][CH:19]=[C:20]([CH3:21])[C:13]=12
Reactant: Cc1c[nH]c2nccc(Nc3ccc([N+](=O)[O-])cc3F)c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1c[nH]c2nccc(Nc3ccc(N)cc3F)c12

Procedure:
23 mg (80 μmol) of N-(2-fluoro-4-nitrophenyl)-3-methyl-1H-pyrrolo[2,3-b]pyridine-4-amine are dissolved in 12 ml of ethanol. 19 mg (19 μmol) of 10% palladium-on-carbon are added and the mixture is hydrogenated in a hydrogen atmosphere at atmospheric pressure overnight. The mixture is filtered through Celite and the solvent is removed under reduced pressure.