Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([CH:20]([CH3:22])[CH3:21])=[N:18][N:19]=2)[N:16]=1.Cl.[NH2:25][N:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31].N1C=CC=CC=1>CC(O)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:25][N:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([CH:20]([CH3:22])[CH3:21])=[N:18][N:19]=2)[N:16]=1
Reactant: CC(C)c1nnc2ccc(CC(=O)c3ccc(F)cc3F)nn12
Reactant: NN1CCCC1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CC(C)c1nnc2ccc(CC(=NN3CCCC3=O)c3ccc(F)cc3F)nn12
Reaction time: 16 h
Yield: 63.7 %

Procedure:
A mixture of 1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.20 g, 0.63 mmol, Preparation #K.1), 1-aminopyrrolidin-2-one hydrochloride (0.13 g, 0.95 mmol, prepared according to WO02/094833 Preparation #38), pyridine (0.15 mL, 1.9 mmol), and HOAc (1.2 mL) was sonicated to give a solution in a sealed vial. After stirring for about 16 h, additional 1-aminopyrrolidin-2-one hydrochloride (0.086 g, 0.632 mmol) was added and the resulting solution was stirred at ambient temperature for about 2 d. The reaction was then concentrated under reduced pressure and purified via silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to give impure 1-(1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethylideneamino)pyrrolidin-2-one (0.16 g) as an oil that was carried on without further purification. A 10 mL round-bottomed flask equipped with reflux condenser and outfitted with a nitrogen inlet adapter was charged with 1-(1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethylideneamino)pyrrolidin-2-one (0.060 g, 0.15 mmol) in toluene (1.5 L) to give a yellow solution. Sodium ethoxide (0.020 g, 0.30 mmol) was added in one portion to give a yellow suspension. The reaction mixture was heated to reflux for about 5 h. The reaction mixture was allowed to cool to ambient temperature and continued stirring for about 2 d. The reaction mixture was diluted with water (5 mL) adjusted to about pH 2 with 6 N HCl. The aqueous layer was extracted with EtOAc. The combined organic extracts were dried with MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM. The product-containing fractions were concentrated under reduced pressure and the resulting material was crystallized from EtOAc/heptane to give the title compound (0.031 g, 54%) as orange needles: LC/MS (Table 1, Method b) Rt=2.44 min; MS m/z: 381.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14].CCN(C(C)C)C(C)C>C(O)CCC>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: COC(=O)c1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COC(=O)c1cccc(Nc2cc(Cl)ncn2)c1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 30.7 %

Procedure:
To a stirred solution of 4,6-dichloropyrimidine (0.5 g, 3.7 mmol) in n-butanol (10 mL) was added methyl 3-aminobenzoate (0.498 g, 3.7 mmol) and DIPEA (0.65 g, 5.0 mmol) and the reaction mixture was heated at 110° C. for 12 h. It was cooled and excess n-butanol was removed under reduced pressure. The residue was extracted with EtOAc (2×30 mL) and the combined EtOAc extract was washed with water (5 mL), brine (2.5 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was stirred with pet ether (30 mL) for 30 min, the pet ether removed by decantation and the solid obtained was dried under high vacuum to give methyl 3-(6-chloropyrimidin-4-ylamino)benzoate (0.3 g, 34%) as light brown solid.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34].Cl>O1CCCC1.C(Cl)(Cl)Cl>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: COC(=O)CN
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)CNC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of Boc-Pro-OH (73.2 g, 340 mmol) and triethylamine (47.6 ml, 340 mmol) in tetrahydrofurane (300 ml), cooled to -10°, was added isobutyl chloroformate (44.5 ml, 340 mmol). After 15 min., a solution of H-Gly-OMe.HCl (42.7 g, 340 mmol) and triethylamine (47.6 ml, 340 mmol) in chloroform (300 ml) was added to the stirring solution. The mixture was stirred at 0° for 1 h and at room temperature for 24 h. The organic solvent was removed under reduced pressure and the residue, dissolved in ethyl acetate, was washed with 10% citric acid solution, 4% sodium bicarbonate solution, water and dried over anhydrous sodium sulfate. The solution was evaporated and the oily residue was crystallized on addition of petroleum ether; yield 71.8 g (84%), m.p. 70°-72° C., Rf1 0.70.
Reaction SMILES: [F:1][C:2]1[C:7](F)=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH2:12][C:13](=[O:15])[CH3:14].[C:16](=O)([O-])[O-:17].[K+].[K+]>CO>[F:1][C:2]1[C:7]([O:17][CH3:16])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH2:12][C:13](=[O:15])[CH3:14]
Reactant: CC(=O)Cc1c([N+](=O)[O-])ccc(F)c1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(CC(C)=O)c1F
Yield: 73.6 %

Procedure:
A mixture of 1-(2,3-difluoro-6-nitrophenyl)-propan-2-one (183 g) and potassium carbonate (100 g) in methanol (1 L) was heated at reflux for 3 h. The reaction mixture was then cooled and concentrated in vacuo to remove most of the methanol. The residue was diluted with ethyl acetate (1 L), filtered and washed with water. The separated aqueous layer was neutralized with 2N HCl and extracted with ethyl acetate (2×500 mL). The combined organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo to give a brown solid. The solid was triturated with diethyl ether and filtered to provide 1-(2-fluoro-3-methoxy-6-nitrophenyl)-propan-2-one (121 g, 71%) as a yellow solid. LC/MS; (M+H)+=228.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[C:28]([NH:32][S:33]([C:36]1[C:37]([C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[C:44]([F:49])[CH:43]=2)=[CH:38][CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>C(OCC)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:15])[NH:48][C:45]1[CH:46]=[CH:47][C:42]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[S:33](=[O:35])(=[O:34])[NH:32][C:28]([CH3:29])([CH3:30])[CH3:31])=[CH:43][C:44]=1[F:49])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(N)c(F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(NC(=O)C2CCCN2C(=O)OC(C)(C)C)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.6 g, 7.4 mmol) was dissolved in 40 mL dry diethyl ether under Ar. The solution was cooled in an ice water bath as dry pyridine (3 mL, 37.2 mmol) was added, followed by the dropwise addition of oxalyl chloride (1.6 mL, 18.6 mmol). A precipitate formed immediately. The reaction was stirred vigorously at 0° C. for one hour, then at ambient temperature for one hour. 50 mL diethyl ether were added, and the mixture was filtered. The filtered off solids were washed with diethyl ether. The filtrates were combined and concentrated to give an off-white oil. The oil was redissolved in 40 mL dry DCM under Ar, cooled to 0° C., and 3 mL of pyridine were added, followed by 4′-amino-3′-fluoro-biphenyl-2-sulfonic acid tert-butylamide (2 g, 6.2 mmol). The reaction was allowed to warm to ambient temperature, stirred for 3 hours then concentrated. The concentrate was redissolved in 250 mL EtOAc, washed with 10% citric acid (2×100 mL), water (3×100 mL), brine (100 mL), dried with MgSO4, filtered and concentrated. The concentrate was purified on a silica gel column eluted with 30% moving to 50% EtOAc in hexanes. Combined and concentrated pure fractions to yield title compound as a white solid. (1.4 g, 42%) APCI (AP−): 518.2 (M−H)−.
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[NH:24][CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([C@H:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[CH:30][CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:43]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH:44]([C:46]1[S:50][N:49]=[C:48]([CH3:51])[CH:47]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.O>[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:24]([CH2:44][C:46]4[S:50][N:49]=[C:48]([CH3:51])[CH:47]=4)[CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:29]=[CH:30][C:31]([C@H:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[CH:32][CH:33]=4)=[O:26])=[CH:20][C:19]=3[CH:43]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(C=O)sn1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CC(=O)O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3Cc2cc(C)ns2)cc1
Reaction time: 24 h
Yield: 64.6 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (200 mg) and 5-formyl-3-methyl isothiazole (0.44 g) in 1,2-dichloroethane (10 ml) were added sodium triacetoxyborohydride (0.22 g) and acetic acid (1 droplet) at room temperature and the mixture was stirred for 24 hours. To the reaction solution was added sodium triacetoxyborohydride (0.22 g) was added to the mixture, and the mixture was further stirred for 3 days. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:4) and further recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-1-(3-methyl-isothiazol-5-ylmethyl)-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 92) (154.0 mg) as yellow crystals.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCOCC.[F:14][C:15]1[C:20]([S:21]([C:23]2[C:28]([F:29])=[C:27]([F:30])[C:26]([F:31])=[C:25]([F:32])[C:24]=2[F:33])=O)=[C:19]([F:34])[C:18]([F:35])=[C:17]([F:36])[C:16]=1[F:37].[OH:38][S:39]([C:42]([F:45])([F:44])[F:43])(=[O:41])=[O:40]>C1C=CC=CC=1>[O-:41][S:39]([C:42]([F:45])([F:44])[F:43])(=[O:40])=[O:38].[F:14][C:15]1[C:20]([S+:21]([C:23]2[C:28]([F:29])=[C:27]([F:30])[C:26]([F:31])=[C:25]([F:32])[C:24]=2[F:33])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:19]([F:34])[C:18]([F:35])=[C:17]([F:36])[C:16]=1[F:37]
Reactant: O=S(c1c(F)c(F)c(F)c(F)c1F)c1c(F)c(F)c(F)c(F)c1F
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: Br[Mg]c1ccccc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: Fc1c(F)c(F)c([S+](c2ccccc2)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 10 %

Procedure:
A 3M solution of phenylmagnesium bromide in ether (17 ml, 0.05 mole) is heated slowly to 80° C. under vacuum to remove the ether. 8 ml benzene and 17 ml heptane were then added and subsequently pentafluorophenyl sulfoxide (3.8 g, 0.01 mole), dissolved in 15 ml benzene, was added dropwise at 80° C. over one hour. After stirring for three hours, the solution is allowed to cool to room temperature, followed by the addition of 33 ml of 25% triflic acid. The organic layer was separated and extracted twice with 10 ml of 5% triflic acid. The aqueous layers were combined and extracted three times with 100 ml diclhoromethane and solvent removed after drying over magnesium sulfate, yielding 600 mg (10%) of di(pentafluorophenyl)phenyl sulfonium triflate. The structure was confirmed by 1H/13C NMR.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[N:11]([C:19](=[O:30])[CH2:20][NH:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]2[CH:31]=[CH:32][CH:33]=[CH:34][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:36]1([CH3:46])C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[OH:48].[Na+]>C(OC(=O)C)(=O)C>[C:36]([N:21]([CH2:20][C:19]([N:11]1[C@@H:12]2[CH2:18][CH2:17][CH2:16][C@@H:13]2[C:14](=[O:15])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]2[CH:34]=[CH:33][CH:32]=[CH:31][C:10]1=2)=[O:30])[C:22](=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:48])[CH3:46]
Reactant: O=C([O-])O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(NCC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21)c1ccccc1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)N(CC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21)C(=O)c1ccccc1
Yield: 58 %

Procedure:
To a solution of (3aR*,10aS*)-9-benzyl-4-(benzamidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (0.18 g, 0.4 mmol) in acetic anhydride (20 mL) was added 10 mg of p-toluenesulfonic acid monohydrate. The mixture was refluxed for two hours. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate, which was subjected to extraction with dichloromethane. The extract was washed with water, which was dried, followed by distilling off the solvent. The residue was purified silica-gel column chromatography (dichloromethane), followed by crystallization from diethylether to give 0.11 g (yield 58%) of the titled compound, m.p. 164-°166° C.
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])/[CH:2]=[CH:3]\[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO[CH2:15][N:16]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:17][Si](C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[C:23]1([CH2:22][N:16]2[CH2:17][CH:3]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:2]([C:1]([O:11][CH3:12])=[O:10])[CH2:15]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: COC(=O)/C=C\c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CN(Cc2ccccc2)CC1c1ccccc1
Reaction time: 1 h
Yield: 72.4 %

Procedure:
A solution of 1.98 g (12.2 mmol) of methyl (Z)-cinnamate and 5.80 g (24.4 mmol) N-(methoxymethyl)-N-(trimethylsilylmethyl)-benzylamine in 30 mL of CH2Cl2 at 0° C. was treated with 20 drops of trifluoroacetic acid and stirred cold for 1 h. The reaction mixture was partitioned between 200 mL of ether and 100 mL of sat'd NaHCO3 and the layers were separated. The organic layer was washed with 100 mL of sat'd NaCl, dried over MgSO4 and concentrated in vacuo. Flash chromatography on 150 g of silica gel using 20:1 v/v CH2Cl2/ether as the eluant afforded 2.61 g (72%) of the title compound as an oil. 1H NMR (500 MHz, CDCl3): δ2.83 (t, J=8.7, 1H), 3.09-3.19 (m, 6H), 3.16 (s, 3H), 3.46-3.51 (m, 1H), 3.73-3.79 (m, 3H), 7.19-7.42 (1OH). Mass Spectrum (NH3 -CI): m/z 296 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:12]2[NH:11][C:10](=[O:13])[CH:9]([CH3:14])[N:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].CN(C)C=O.C12(C)C(C)(C)C(CC1)C[CH2+:31]2[CH:39](C)[C:40]([O:42][CH3:43])=[O:41]>O.C1(C)C=CC=CC=1>[CH3:43][O:42][C:40](=[O:41])[CH:39]([CH3:31])[N:11]1[C:12]2[C:2]([Br:1])=[CH:3][CH:4]=[CH:5][C:6]=2[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[N:8][CH:9]([CH3:14])[C:10]1=[O:13]
Reactant: COC(=O)C(C)[CH2+]1CC2CCC1(C)C2(C)C
Reactant: CC1N=C(c2cccc(F)c2)c2cccc(Br)c2NC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C(C)N1C(=O)C(C)N=C(c2cccc(F)c2)c2cccc(Br)c21
Reaction time: 6 h

Procedure:
A mixture of 0.1 mole of 9-bromo-1,3-dihydro-5-(m-fluorophenyl)-3-methyl-2H-1,4-benzodiazepin-2-one and 0.11 mole of sodium methoxide in about 200 ml. of dimethylformamide is heated at about 95° C. for about 20 minutes. To the mixture is added a solution of 0.11 mole of methyl 2-bormopropionate in about 200 ml. of toluene over a period of about 1 hour at about 95° C., and heating is continued for an additional period of about 6 hours. The reaction mixture is then evaporated in vacuo and the residue thus obtained is stirred with about 500 ml. of water. The resulting suspension is filtered and the solids thus obtained are crystallized from a suitable organic solvent such as ether, methanol, methylene chloride, methylene chloride-methanol and the like to obtain 9-bromo-2,3-dihydro-2-oxo-5-(m-fluorophenyl)-3,α-dimethyl-1H-1,4-benzodiazepin-1-acetic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[C:25]3[C:20](=[C:21]([CH2:26][S:27][CH3:28])[CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH3:9])=[CH:4][CH:3]=1.ClC1C=CC(C(C2C=CC(Cl)=CC=2)C2C3C(=C(CS(C)=[O:48])C=CC=3)NC=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:17]2[C:25]3[C:20](=[C:21]([CH2:26][S:27]([CH3:28])=[O:48])[CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[CH3:9])=[CH:6][CH:7]=1
Reactant: CSCc1cccc2c(C(C)(c3ccc(F)cc3)c3ccc(Cl)cc3)c[nH]c12
Reactant: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c[nH]c12
Product: CS(=O)Cc1cccc2c(C(C)(c3ccc(F)cc3)c3ccc(Cl)cc3)c[nH]c12

Procedure:
The title compound was prepared starting from 300 mg (0.73 mmol) of the compound from Example 289 in analogy to the synthesis of the compound from Example 296. 193 mg (62% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]=[CH2:14])[C:5]([O:7][CH3:8])=[O:6].[Zn](CC)[CH2:16]C.ClCI.[NH4+].[Cl-]>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]1[CH2:16][CH2:14]1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: C=COc1ccc(C(=O)OC)cc1Br
Reactant: CC[Zn]CC
Agent: ClCI
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(OC2CC2)c(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
To a solution of methyl 3-bromo-4-vinyloxy-benzoate (1.00 g, 3.89 mmol, 1.00 eq) in DCM (15.00 mL) was added ZnEt2 (960.91 mg, 7.78 mmol, 2.00 eq) at 0° C. under N2 protection. Then the mixture was stirred at 0° C. for 30 min, and ClCH2I (1.72 g, 9.73 mmol, 2.50 eq) was added. The formed mixture was stirred at 25° C. for 16 hrs. The mixture was poured into NH4Cl solution, and extracted with EA, the combined organic layer was dried over Na2SO4, concentrated, the residue was diluted in THF (5.00 mL) and H2O (5.00 mL), NaIO4 (832.00 mg, 3.89 mmol, 1.00 eq) and K2OsO4 (74.01 mg, 389.00 umol, 0.10 eq) was added, the mixture was stirred at 25° C. for 30 min, then the reaction was quenched by saturated Na2SO3, extracted with EA, the combined organic layer was dried over Na2SO4, concentrated, the residue was purified by silica gel chromatography (PE:EA=10:1) to afford product methyl 3-bromo-4-(cyclopropoxy)benzoate (530.00 mg, 1.95 mmol, 50.26% yield) as colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J=2.01 Hz, 1H), 8.00 (dd, J=8.78, 2.01 Hz, 1H), 7.28-7.33 (m, 1H), 3.92 (s, 3H), 3.88 (t, J=4.39 Hz, 1H), 0.76-0.99 (m, 4H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:29]=[CH:28][C:9]2[S:10][C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][NH:24][C:23]4=[O:27])[N:14]=3)=[CH:12][C:8]=2[CH:7]=1.C(N(CC)CC)C.O>ClCCl>[O:27]=[C:23]1[NH:24][CH2:25][CH2:26][N:22]1[CH2:21][CH2:20][NH:19][C:15]1[N:14]=[C:13]([C:11]2[S:10][C:9]3[CH:28]=[CH:29][C:6]([NH:5][C:1](=[O:3])[CH3:2])=[CH:7][C:8]=3[CH:12]=2)[CH:18]=[CH:17][N:16]=1
Reactant: Nc1ccc2sc(-c3ccnc(NCCN4CCNC4=O)n3)cc2c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2sc(-c3ccnc(NCCN4CCNC4=O)n3)cc2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Acetyl chloride (61 mg, 0.78 mmol) was added to a mixture of 1-(2-(4-(5-aminobenzo[b]-thiophen-2-yl)pyrimidin-2-ylamino)ethyl)imidazolidin-2-one (230 mg, 0.65 mmol) and triethylamine (131 mg, 1.30 mmol) in dichloromethane (10 mL) at 0° C. and stirred at rt for 6 h. Water (50 mL) was added and the mixture was extracted with dichloromethane (3×50 mL). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate and filtered. After removing the solvent in vacuo the product was purified by column chromatography eluting with methanol/dichloromethane (1:20) to give the title compound as a slightly yellow solid (39 mg, 15%). MS (M+H)+ 397.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@:10]1([CH2:34][O:35]S(C)(=O)=O)[O:11][C@H:12]2[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH:25][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:40]([O-])(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[Na+]>CN(C=O)C>[CH2:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@:10]1([CH2:34][O:35][C:40](=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[O:11][C@H:12]2[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH:25][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OC[C@]12CO[C@@H]([C@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)O1)[C@@H]2OCc1ccccc1
Reactant: O=C([O-])c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@]2(COC(=O)c3ccccc3)CO[C@@H]1[C@@H]2OCc1ccccc1)c1ccccc1
Temperature: 90 °C
Yield: 88 %

Procedure:
(1S, 3R, 4R, 7S)-7-Benzyloxy-1-methanesulfonyloxymethyl-3-(6-N-benzoyl-adenine-9-yl)-2,5-dioxabicyclo-[2.2.1]heptane (5D) (11.5 g.; 20.8 mmol) was dissolved in anh. DMF (450 mL). Sodium benzoate (5.40 g.; 37.4 mmol) was added and the mixture was heated to 90° C. for 7 h. The solution was cooled to rt., filtered, evaporated and coevaporated with AcCN. The residue was redissolved in dichloromethane (150 mL) and a saturated aqueous solution of NaHCO3 (150 mL) was added. The phases were separated and the organic phase was washed with a saturated aqueous solution of NaHCO3 (2×100 mL) and brine (100 mL), dried (Na2SO4) and evaporated to give 12.5 g. of a yellowish solid. Recrystallization from EtOH:H2O (1250 mL; 1:1 v/v) gave 28 in 88% yield (10.63 g.). δH (DMSO-d6): 11.2 (1H, br s), 8.72 (1H, s), 8.48 (1H, s), 8.06 (2H, m), 7.94 (2H, m), 7.66 (2H, m), 7.54 (4H, m), 7.36-7.26 (5H, m), 6.11 (1H, s), 4.97 (1H, s), 4.82 (2H, s), 4.77 (1H, s), 4.75 (1H, d, J=12.4 Hz), 4.69 (1H, d, J=11.9 Hz), 4.19 (1H, d, J=8.0 Hz), 4.07 (1H, d, J=7.9 Hz). δC (DMSO-d6): 165.3, 150.5, 141.9, 137.7, 133.7, 132.5, 129.3, 129.1, 128.9, 128.6, 128.5, 128.3, 127.7, 127.6, 125.7, 85.9, 85.3, 77.9, 77.1, 72.0, 71.3, 60.6.