Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20](=[O:31])[C@H:21]([C:27]([CH3:30])([CH3:29])[CH3:28])[NH:22][C:23]([O:25][CH3:26])=[O:24])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[CH3:40][O:41][C:42]([NH:44][C@@H:45]([C:49]([CH3:52])([CH3:51])[CH3:50])[C:46](O)=[O:47])=[O:43].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH3:40][O:41][C:42](=[O:43])[NH:44][C@@H:45]([C:49]([CH3:51])([CH3:50])[CH3:52])[C:46](=[O:47])[NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[CH:11][CH:12]=1)[NH:19][C:20](=[O:31])[C@H:21]([C:27]([CH3:30])([CH3:29])[CH3:28])[NH:22][C:23](=[O:24])[O:25][CH3:26]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccncc2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccncc2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 68 h
Yield: 69.7 %

Procedure:
To a solution containing the product from Example 150E (0.22 mmol) in tetrahydrofuran (2.5 mL) were added the product from Example 1F (0.046 g, 0.243 mmol), DEPBT (0.099 g, 0.331 mmol), and N,N-diisopropylethylamine (0.19 mL, 1.09 mmol) and the mixture was stirred at room temperature for 68 hours. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic was washed with additional 10% Na2CO3 solution and then brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed on reverse phase HPLC on a C18 column, eluting with a gradient starting with water and ending with methanol to give the title compound (0.108 g, 70% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.79 (s, 9 H), 0.82 (s, 9 H), 1.42-1.59 (m, 2 H), 2.71-2.79 (m, 3 H), 3.48 (s, 3 H), 3.55 (s, 3 H), 3.61-3.67 (m, 1 H), 3.81 (d, J=9.9 Hz, 1 H), 3.91 (d, J=9.6 Hz, 1 H), 4.03-4.20 (m, 2 H), 4.87 (d, J=5.2 Hz, 1 H), 6.64 (d, J=9.6 Hz, 1 H), 6.80 (d, J=9.6 Hz, 1 H), 7.12-7.23 (m, 8 H), 7.50-7.60 (m, 4 H), 7.65 (d, J=5.9 Hz, 2 H), 7.80 (d, J=8.5 Hz, 1 H), 8.61 (d, J=5.9 Hz, 2 H).
Reaction SMILES: Br.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:24]2[N:25]=[C:26]([NH2:29])[S:27][CH:28]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.Cl>N1C=CC=CC=1>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:24]2[N:25]=[C:26]([NH:29][S:36]([C:33]3[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=3)(=[O:38])=[O:37])[S:27][CH:28]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(-c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cs1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccc(OCc4ccccc4)c(OCc4ccccc4)c3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
A mixture of 0.5 g of 4-(3,4-bis-benzyloxy-phenyl)-thiazol-2-ylamine hydrobromide with 0.23 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored solution was poured into 50 ml of 1N hydrochloric acid and extracted three times with 50 ml of methylene chloride each time. The organic extracts were combined, dried with magnesium sulphate and concentrated. The residue was dissolved in a mixture of 20 ml of ethanol and 15 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated upon neutralization with concentrated hydrochloric acid. Recrystallization from 50 ml of 60% ethanol yielded 0.33 g of N-[4-(3,4-bis-benzyloxy-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17]Cl)[C:12]=2[CH2:19][CH2:20][CH3:21])[CH:3]=1.[CH3:22][NH2:23].[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28]>C(O)C.CO>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:23][CH3:22])[C:12]=2[CH2:19][CH2:20][CH3:21])[CH:3]=1
Reactant: CCCc1c(CCl)cccc1Oc1cc(Cl)ccc1C#N
Reactant: CN
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CO
Product: CCCc1c(CNC)cccc1Oc1cc(Cl)ccc1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.7 %

Procedure:
To a solution of 4-chloro-2-(3-chloromethyl-2-propylphenoxy)-benzonitrile (0.35 g, 1.1 mmol) in ethanol (20 mL) was added methylamine (33% in ethanol, 9.0 mL, 72 mmol), and the reaction mixture stirred 18 h at ambient temperature. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and a solution of fumaric acid (127 mg, 1.1 mmol) in methanol (5 mL) was added. After the solvent was removed in vacuo, the residue was triturated with diethyl ether overnight, collected by filtration, and dried to give 4-chloro-2-(3-methylaminomethyl-2-propyl-phenoxy)-benzonitrile fumarate (354 mg, 75%) as a white solid.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl[CH2:7][C:8]([O:10][CH3:11])=[O:9].[NH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17]>CCOCC>[CH3:11][O:10][C:8](=[O:9])[CH2:7][NH:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:15]([C:16]#[N:17])[CH:14]=1
Reactant: COC(=O)CCl
Reactant: N#Cc1cccc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: COC(=O)CNc1cccc(C#N)c1
Reaction time: 6 h

Procedure:
A mixture of sodium bicarbonate (35.5 g), methyl chloroacetate (28 ml) and 3-aminobenzonitrile (25 g) were stirred under nitrogen at 80°-100° for 6 h. Heating at 90° was continued overnight, and the mixture was then cooled and poured into ether (400 ml). The solid precipitate was filtered off and the filtrate was retained. The solid was dissolved in dichloromethane (400 ml) and washed with water (200 ml) followed by dilute hydrochloric acid (200 ml). The organic phase was dried and concentrated in vacuo to give the title compound as a solid (13.8 g), m.p. 91.5°-92.5°. The previously obtained filtrate was washed with water (100 ml), dilute hydrochloric acid (200 ml) and water (100 ml), then dried and concentrated in vacuo. The resultant solid was triturated with ether to give a further batch of the title compound (11.7 g).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[N:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.[F:15][C:16]1[C:24]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])=[CH:23][CH:22]=[C:21]([F:32])[C:17]=1[C:18](Cl)=[O:19].O>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[C:8]2[C:9]([C:18]([C:17]3[C:16]([F:15])=[C:24]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=3[F:32])=[O:19])=[CH:10][NH:11][C:12]2=[N:13][CH:14]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Cl)c1F
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To aluminum trichloride (8.89 g, 66.7 mmol) was added methylene chloride (150 mL) under an atmosphere of nitrogen below 5° C. Into this, 5-bromo-7-azaindole (67, 1.64 g, 8.34 mmol) in methylene chloride (20 mL) was added. The reaction was stirred for 60.0 minutes and 2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl chloride (46, 3.50 g, 11.8 mmol) in methylene chloride (20 mL) was added. The reaction was stirred for 6 hours and warmed to room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtrated and concentrated. The desired compound was isolated by silica gel column chromatography (methylene chloride/methanol 5%) to give a white solid (P-0773, 1.2 g, 31.4%). MS (ESI) [M+H+]+=460.0, 462.0.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[N:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]([C:16](O)=[O:17])[C:9]2=[O:19].C([N:22](CC)CC)C.ClC(OCC)=O.CN(C)CCN>CN(C)C=O.O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[N:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]([C:16]([NH2:22])=[O:17])[C:9]2=[O:19]
Reactant: CCN(CC)CC
Reactant: COCCOc1ccc2[nH]cc(C(=O)O)c(=O)c2n1
Agent: CCOC(=O)Cl
Agent: CN(C)CCN
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCOc1ccc2[nH]cc(C(N)=O)c(=O)c2n1
Reaction time: 1.25 h

Procedure:
To a solution of 6-(2-methoxyethoxy)-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid (106 mg, 0.4 mmol) and triethylamine (117 mL, 0.84 mmol) in 4:1 tetrahydrofuran: N,N- dimethylformamide (2 mL) at 0° C. was added ethyl chloroformate (66 mL, 0.82 mmol). After stirring at O C for 1.25 h, 4-[(N-tert-butoxycarbonyl)-methylaminomethyl)benzylamine hydrochloride (120 mg, 0.42 mmol) and triethylamine (59 mL, 0.42 mmol) was added. The reaction mixture was stirred at 0° C. for 0.75 h, then allowed to ambient temperature and stirred for 20 h. N,N-Dimethylethylenediamine (132 mL, 1.2 mmol) was added, the reaction mixture stirred for 1 h, then concentrated in vacuo. The residue was cooled in an ice bath, saturated aqueous ammonium chloride was added and the mixture extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated to give 177 mg of crude N-[4-(N-tert butoxycarbonyl)-methylaminomethyl)benzyl] 6-(2-methoxyethoxy)-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][CH3:12])=[O:10].COCCOC.[H-].[Na+].[CH3:21][S:22][CH2:23]Cl>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:21][S:22][CH3:23])[C:9]([NH:11][CH3:12])=[O:10]
Reactant: CNC(=O)Nc1ccccc1F
Reactant: CSCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CNC(=O)N(CSC)c1ccccc1F
Reaction time: 0.25 h

Procedure:
A solution of 16.8 g. (0.1 mol) of N-(2-fluorophenyl)-N'-methyl urea in 250 ml. of 1,2-dimethoxyethane was cooled to 0°C. Then 4.8 g. (0.1 mol) of a 50% dispersion of sodium hydride in mineral oil was added slowly. After addition was complete, the solution was stirred for 15 minutes. This solution was added slowly to a stirred solution of 9.7 g. (0.1 mol) of chloromethyl methyl sulfide in 100 ml. of 1,2-dimethoxyethane. The resulting mixture was stirred at room temperature for 65 hours. At the end of this time, the precipitate was removed by filtration and the resulting filtrate was evaporated to give an oil which solidified upon adding water. The solid was isolated by filtration, washed with hexane and dried. Recrystallization from a hexene-benzene mixture gave 12 g. crystalline solid, melting point 102.5°-103°C. An infrared spectrum showed sharp, strong adsorptions at 3.0, 6.1, 13.05 and 13.2μ .
Reaction SMILES: [CH:1]1([P:7]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:19]([CH:20]([CH3:22])[CH3:21])=[CH:18][C:17](C(C)C)=[CH:16][C:15]=2[CH:26]([CH3:28])[CH3:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.[OH:38][S:39](O)(=[O:41])=[O:40].[OH-].[Na+:44]>CO>[CH:1]1([P:7]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:19]([CH:20]([CH3:22])[CH3:21])=[CH:18][C:17]([S:39]([O-:41])(=[O:40])=[O:38])=[CH:16][C:15]=2[CH:26]([CH3:28])[CH3:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+:44]
Reactant: O=S(=O)(O)O
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)c1cc(S(=O)(=O)[O-])cc(C(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Temperature: 0 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
To an oven-dried 25 mL round bottom flask equipped with a Teflon-coated magnetic stir bar and rubber septum was added dicyclohexyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane (476 mg, 1.00 mmol) and CH2Cl2 (1.0 mL). The solution was cooled to 0° C. using an ice/water bath and then concentrated H2SO4 (1.00 mL) and fuming sulfuric acid (3.0 mL, 20% SO3) were added dropwise. The solution was allowed to warm to room temperature and stir for 24 h. At this time it was cooled to 0° C. using an ice/water bath and crushed ice (˜10 g) was added. The solution turned cloudy and white in color. An aqueous solution of NaOH (6.0 M, ˜20.0 mL) was then added dropwise to the cooled solution until it became neutral (pH ˜7.0 as judged by pH paper). The aqueous solution was extracted with CH2Cl2 (3×50 mL) and concentrated under reduced pressure to give a beige solid. The crude material was then dissolved in a minimum amount of cold methanol (˜20 mL), filtered and concentrated (this cycle was repeated) to give sodium 2′-(dicyclohexyl-phosphanyl)-2,6-diisopropyl-biphenyl-4-sulfonate (4) as a beige solid (503 mg, 94%). Mp=>250° C. 1H NMR (400 MHz, CD3OD) δ: 7.52 (s, 2H), 7.46 (m, 1H), 7.22 (m, 2H), 6.90 (m, 1H), 2.24 (m, 1H), 0.71-1.83 (34H). 13C NMR (125 MHz, CD3OD) δ: 148.4, 147.9, 147.8, 147.5, 145.6, 142.8, 137.4, 137.2, 133.92, 133.91, 132.43, 132.42, 129.3, 128.1, 121.3, 121.0, 40.1, 39.9, 39.7, 39.5, 39.3, 38.8, 35.8, 35.7, 32.5, 32.3, 31.9, 30.8, 30.6, 28.7, 28.6, 28.4, 28.3, 27.7, 26.0, 25.9, 23.3, 23.1. 31P NMR (162 MHz, CD3OD) δ: −10.7. IR (neat, cm−1): 3459, 2927, 2851, 1634, 1463, 1447, 1184, 1078, 1040. Anal. Calcd for C30H42NaO3PS: C, 67.14; H, 7.89. Found: C, 66.93; H, 7.77.
Reaction SMILES: [C:1]1([CH3:37])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:13][CH:12]([NH:28]C(OC(C)(C)C)=O)[C:11]2=[O:36])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1>Cl.O1CCOCC1>[C:1]1([CH3:37])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)[CH2:13][CH:12]([NH2:28])[C:11]2=[O:36])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)OC(C)(C)C)CN2C1CCCCC1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(N)CN2C1CCCCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
1-(2-Toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (0.28 g) was dissolved in 4N HCl-dioxane (5 ml), the solution was stirred for one hour at 60° C. The reaction mixture was concentrated under reduced pressure, the residue was neutralized with saturated aqueous sodium bicarbonate, and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, to thereby obtain 0.22 g of the titled compound (Yield: 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7]([OH:10])=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl[C:13]([F:19])([F:18])C(OC)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:18][CH:13]([F:19])[O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[OH:11]
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OC(F)F)c(O)c1
Yield: 27 %

Procedure:
A solution of 4-nitrobenzene-1,2-diol (4.18 g, 27.1 mmol), methyl chlorodifluoroacetate (3.0 mL, 28.5 mmol) and cesium carbonate (11.05 g, 33.9 mmol) in DMF (75 mL) was heated at 90° C. for 24 h. The reaction was cooled, evaporated and diluted with ethyl acetate. Product was extracted twice into 1N NaOH, the combined aqueous phase was acidified, extracted with ethyl acetate (twice) and the organic layers were washed with water (twice) and brine, dried (sodium sulfate) and evaporated. Purification by flash chromatography (SiO2) eluted with 2:8 ethyl acetate:hexanes provided 2-difluoromethoxy-5-nitro-phenol (1.50 g, 27% yield) as a bright yellow solid. 1H-NMR (DMSO-d6, 500 MHz) 10.9 (s, 1H), 7.76 (d, 1H), 7.73 (dd, 1H), 7.36 (d, 1H), 7.28 (t, 1H) ppm; MS (FIA) 204.1 (M−H); HPLC (Method A) 3.307 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1.[NH:29]1[CH2:32][CH2:31][C:30]1=[O:33].[O-]P([O-])([O-])=O.[K+].[K+].[K+].N[C@@H]1CCCC[C@H]1N>O1CCOCC1.C([O-])(O)=O.[Na+].[Cu]I>[F:1][C:2]1[CH:7]=[C:6]([N:29]2[CH2:32][CH2:31][C:30]2=[O:33])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1
Reactant: O=C1CCN1
Reactant: COc1cn(-c2ccc(I)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: COc1cn(-c2ccc(N3CCC3=O)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 110 °C
Yield: 44 %

Procedure:
A mixture of 1-(2-fluoro-4-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (244 mg, 0.5 mmol), azetidin-2-one (42.6 mg, 0.6 mmol), K3PO4 (212 mg, 1.0 mmol), trans-1,2-diaminocyclohexane (0.012 mL, 0.1 mmol) and CuI (9.5 mg, 0.05 mmol) in 1,4-dioxane (2 mL) was heated to 110° C. for 18 h under Ar. To the mixture was added azetidin-2-one (42.6 mg, 0.6 mmol). The mixture was heated to 110° C. for 24 h under Ar. The mixture was diluted with NaHCO3 aqueous solution, extracted with AcOEt, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100) and recrystallized with EtOH/hexane to yield the title compound (95 mg, 44% yield) as a pale yellow solid: mp 189-194° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.15 (2H, t, J=4.5 Hz), 3.68 (2H, t, J=4.5 Hz), 3.77 (3H, s), 6.96 (1H, d, J=1.9 Hz), 7.06 (1H, t, J=8.7 Hz), 7.18 (1H, dd, J=8.7, 1.5 Hz), 7.29-7.48 (6H, m), 7.78 (1H, d, J=1.9 Hz), 8.45 (1H, d, J=1.9 Hz). Anal. Calcd for C23H18FN5O3: C, 64.03; H, 4.21; N, 16.23. Found: C, 63.75; H, 4.16; N, 16.22.
Reaction SMILES: [C:1]1(=[N:6][NH:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([S:18](=[O:21])(=[O:20])[NH2:19])[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:25]=1.N12CCCN=C1CCCCC2.Cl>O.C(#N)C>[C:1]1(=[N:6][NH:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([S:18]([NH:19][C:33]([NH:32][C:26]3[N:25]=[C:24]([O:23][CH3:22])[CH:29]=[C:28]([O:30][CH3:31])[N:27]=3)=[O:34])(=[O:20])=[O:21])[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NN=C2CCCC2)cc1S(N)(=O)=O
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(NN=C2CCCC2)cc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Reaction time: 2 h
Yield: 65.6 %

Procedure:
1.5 g (4.8 mmol) of methyl 4-cyclopentylidenehydrazino-2-sulfamoylbenzoate and 1.6 g (5.8 mmol) of phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate are initially introduced into 20 ml of acetonitrile. 1.6 g (10.6 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) are added dropwise at 0° C. and the mixture is stirred at this temperature for 2 hours. It is poured into water and the pH is brought to 2-3 with 2 N hydrochloric acid. The aqueous phase is extracted three times with CH2Cl2. After the methylene chloride phase has been washed with 2 N hydrochloric acid and water, it is dried and evaporated. The residue is triturated with diisopropyl ether. After filtering off with suction and drying, 1.55 g (65% of theory) of methyl 4-cyclopentylidenehydrazino-2-[3-(4,6-dimethoxypyrimidin-2-yl)-ureidosulfonyl]benzoate of melting point 168-170° C. (decomposition) are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:20]=[CH:19][N:18]([C:21]5[CH:31]=[CH:30][C:24]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:23][N:22]=5)[C:17]=4[CH:32]=3)=[CH:11][N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)=[CH:4][CH:3]=1>O1CCCC1.CO.Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:20]=[CH:19][N:18]([C:21]5[CH:31]=[CH:30][C:24]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:23][N:22]=5)[C:17]=4[CH:32]=3)=[CH:11][NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)c1ccc(-n2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc32)nc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(-n2cnc3ccc(-c4c[nH]nc4-c4ccc(F)cc4)cc32)nc1
Reaction time: 3 h
Yield: 87.5 %

Procedure:
43 mg 6-{6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-1H-benzo[d]imidazol-1-yl}-N,N-dimethyl-nicotinamide (compound in Example 716) was dissolved in 8.0 mL solvent mixture of tetrahydrofuran and methanol (1:1), 3.0 mL of 5 N hydrochloric acid was added thereto, and the mixture was left at room temperature for 3 hours. The reaction solution was neutralized and then extracted with ethyl acetate. The extract was purified by silica gel column chromatography (ethyl acetate/methanol) and recrystallized from methanol/diethyl ether, to give 24 mg of the title compound as colorless crystals.
Reaction SMILES: CC(CC)[O-].[CH3:6][Si:7]([CH3:39])([CH3:38])[CH2:8][CH2:9][O:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]([Cl:19])=[C:15]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=2)[C:14]([O:33][CH:34](CC)C)=[N:13]1.C[Si](C)(C)CCOCN1C(=O)C(Cl)=C(NCC2C=CC(OC)=C(OC)C=2)C(OC(CC)C)=N1>>[CH3:39][Si:7]([CH3:6])([CH3:38])[CH2:8][CH2:9][O:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]([Cl:19])=[C:15]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=2)[C:14]([O:33][CH3:34])=[N:13]1
Reactant: CCOc1cc(CNc2c(OC(C)CC)nn(COCC[Si](C)(C)C)c(=O)c2Cl)ccc1OC
Agent: CCC(C)Oc1nn(COCC[Si](C)(C)C)c(=O)c(Cl)c1NCc1ccc(OC)c(OC)c1
Agent: CCC(C)[O-]
Product: CCOc1cc(CNc2c(OC)nn(COCC[Si](C)(C)C)c(=O)c2Cl)ccc1OC

Procedure:
In the same manner as above, by using sec-butoxide instead of sodium methoxide, 2-(2-trimethylsilylethoxymethy)-4-chloro-5-(3-ethoxy-4-methoxybenzylamino)-6-sec-butoxy-3(2H)pyridazinone (oily substance) and 2-(2-trimethylsilylethoxymethyl)-4-chloro-5-(3,4-dimethoxybenzylamino)-6-sec-butoxy-3(2H)pyridazinone (oily substance), were prepared from the corresponding 2-(2-trimethylsilylethoxymethyl)-4-chloro-5-(3-alkoxy-4-methoxybenzylamino)-6-nitro-3(2H)pyridazinones.
Reaction SMILES: [CH2:1]([O:3][C:4](=[S:17])[NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])[CH3:2].C[C:19](C)([O-:21])C.[Li+]>CN(C)C=O>[CH3:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][N:5]1[CH2:2][C@@H:1]([CH2:19][OH:21])[O:3][C:4]1=[S:17]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=S)NCCOc1ccccc1OC
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1ccccc1OCCN1C[C@@H](CO)OC1=S

Procedure:
Using N,N-dimethylformamide solution of ethyl-2-(2-methoxyphenoxy)ethylthiocarbamate 25.5 g (0.1 mol) [J. Chem. Soc., 1952, 2076; J. Chem. Soc., 1952, 2079; Tetrahedron Lett., 1969, 3631], lithium-t-butoxide 1.6 g (0.02 mol) and (S)-2-oxyranylmethoxy-tetrahydropyran 17.38 g (0.11 mol), the procedures as described in Example 1 were carried out to obtain the targeted product.