Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:25](=[O:26])[N:5]2[C:6]([C:22]([O-:24])=[O:23])=[C:7]([CH:10]=[CH:11][CH2:12][N+:13]3[CH:18]=[CH:17][C:16]([C:19](=[O:21])[NH2:20])=[CH:15][CH:14]=3)[CH2:8][S:9][C@H:4]12.Cl.[NH2:28][C:29]1[S:33][N:32]=[C:31]([C:34](=[N:38][O:39][CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[C:35](Cl)=[O:36])[N:30]=1.C([O-])([O-])=O.[Na+].[Na+].Cl>CC(C)=O>[NH2:28][C:29]1[S:33][N:32]=[C:31]([C:34](=[N:38][O:39][CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[C:35]([NH:2][CH:3]2[C:25](=[O:26])[N:5]3[C:6]([C:22]([O-:24])=[O:23])=[C:7]([CH:10]=[CH:11][CH2:12][N+:13]4[CH:14]=[CH:15][C:16]([C:19](=[O:21])[NH2:20])=[CH:17][CH:18]=4)[CH2:8][S:9][C@H:4]23)=[O:36])[N:30]=1
Reactant: Nc1nc(C(=NOC2CCCC2)C(=O)Cl)ns1
Reactant: NC(=O)c1cc[n+](CC=CC2=C(C(=O)[O-])N3C(=O)C(N)[C@H]3SC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: NC(=O)c1cc[n+](CC=CC2=C(C(=O)[O-])N3C(=O)C(NC(=O)C(=NOC4CCCC4)c4nsc(N)n4)[C@H]3SC2)cc1
Temperature: 10 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a stirred solution of 139 mg (0.31 mmole) of 7-amino-3-[3-(4-carbamoylpyridinio)-1-propenyl]-3-cephem-4-carboxylate hydrochloride in 3.5 ml of 50% aqueous acetone in an ice-cooling bath was added portionwise 120 mg (0.44 mmole) of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-cyclopentyloxyiminoacetyl chloride hydrochloride (from Preparation No. 27). The mixture was adjusted to pH 6.5-7.0 with 2N Na2CO3 (0.9 ml) and stirred for 1 hour at 10° C. The reaction mixture was acidified to pH 2 with 1N HCl and evaporated under reduced pressure. The residue was chromatographed on a column of HP-20 resin (20 ml) and was eluted with 300 ml of water and 30% CH3OH-H2O, successively. Fractions containing the product were combined and concentrated in vacuo. The residue was treated with 60 ml of acetone to give 111 mg (83 %) of the title compound I-5H. Mp. 160° C. (dec.). Estimated purity 70%.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[N:12]=[C:11]([CH3:13])[C:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][C:16]=2[F:25])=[C:9]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[N:8]=1.[C:32]([O-])(O)=O.[Na+]>CO.O>[NH2:6][C:7]1[N:12]=[C:11]([CH3:13])[C:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:32])=[O:23])=[CH:17][C:16]=2[F:25])=[C:9]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[N:8]=1
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1F
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)OC)cc1F
Temperature: 70 °C

Procedure:
Sulfuric acid (3 ml) was added to a solution of the product from step (viii) (0.54 g) in MeOH (6 mL). The mixture was heated to 70° C. for 2 h and allowed to cool. The mixture was diluted with cold water (10 mL) and the pH adjusted to ˜7 using NaHCO3. The aqueous phase was extracted with EtOAc and the combined organic phase was dried, filtered and evaporated. The crude product was purified by RPHPLC to afford the title compound as a colourless solid 0.08 g.
Reaction SMILES: [OH-].[Na+].C[C:4]([CH:6]1[CH:8]([CH2:9][C:10](Cl)([Cl:12])[Cl:11])[C:7]1([CH3:15])[CH3:14])=[O:5].BrBr.S([O-])([O-])=[O:19].[Na+].[Na+]>O.CO>[CH3:14][C:7]1([CH3:15])[CH:8]([CH:9]=[C:10]([Cl:12])[Cl:11])[CH:6]1[C:4]([OH:5])=[O:19]
Reactant: O=S([O-])[O-]
Reactant: CC(=O)C1C(CC(Cl)(Cl)Cl)C1(C)C
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Temperature: 70 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
To 250 ml of methanol solution containing 24 g of sodium hydroxide were added 17 g of 2,2-dimethyl-3-(2',2',2'-trichloroethyl)-cyclopropyl methyl ketone (purity: 97.9%, cis/trans ratio 91.5/8.5) under cooling with ice, and then 40 g of bromine were added dropwise at -10° C. to -5° C. for 20 minutes and after stirring the mixture at the same temperature for 2 hours, 25.2 g of sodium sulfite (7 hydrate) and 250 ml of water were added thereto, and the mixture was heated up to 70° C. and stirred for 47 hours with heating. Then the methanol was distilled off, water was added to the reaction mixture and neutral part was removed by extraction with ether. The water layer was acidified with conc. hydrochloric acid under cooling with ice. The deposited crystals were filtered, washed with water and dried to obtain 9.85 g of 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropanecarboxylic acid, cis/trans ratio 89.8/10.2, purity 91.8%, yield 72.9%.
Reaction SMILES: [CH2:1]([CH2:3][C:4]([O:6][C:7]1[C:28]([O:29][CH3:30])=[CH:27][C:10]([C:11]([O:13]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:12])=[CH:9][C:8]=1[O:31][CH3:32])=[O:5])[CH3:2]>[Pd].C(O)C.C(OCC)(=O)C.ClCCl>[CH2:1]([CH2:3][C:4]([O:6][C:7]1[C:28]([O:29][CH3:30])=[CH:27][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[O:31][CH3:32])=[O:5])[CH3:2]
Reactant: CCCC(=O)Oc1c(OC)cc(C(=O)OC(c2ccccc2)c2ccccc2)cc1OC
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCC(=O)Oc1c(OC)cc(C(=O)O)cc1OC
Reaction time: 16 h

Procedure:
Combine diphenylmethyl 4-(ethyl acetoxy)-3,5-dimethoxybenzoate (4.3 g, 9.56 mmol), 5% palladium-on-carbon (0.5 g), and ethanol/ethyl acetate/dichloromethane (200 mL/15 mL/15 mL). Hydrogenate at an initial pressure of 55 psi in a Parr apparatus. After 16 hours, filter and concentrate the filtrate to give a residue. Recrystallize the residue from diethyl ether/hexane to give the title compound: Rf=0.35 (silica gel, 6% methanol/dichloromethane).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][C@@H:8]2[CH2:12][O:11][C:10](=[O:13])[NH:9]2)=[CH:5][CH:4]=1.Cl.[N:17]([O-])=O.[Na+].[Sn](Cl)[Cl:22]>O>[ClH:22].[NH:2]([C:3]1[CH:15]=[CH:14][C:6]([CH2:7][C@@H:8]2[CH2:12][O:11][C:10](=[O:13])[NH:9]2)=[CH:5][CH:4]=1)[NH2:17]
Reactant: Cl[Sn]Cl
Reactant: O=N[O-]
Reactant: Nc1ccc(C[C@@H]2COC(=O)N2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(C[C@@H]2COC(=O)N2)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
The product from step (b) (10.3 g) was suspended in water (53 ml) and c.HCl (106 ml) added dropwise. The resulting mixture was cooled to -5° C. and a solution of sodium nitrite (3.2 g) in water (30 ml) added dropwise to the stirred mixture over 15 minutes followed by 30 minutes' stirring at -5° to 0° C. The solution was then added at 0° C. over 15 minutes to a stirred solution of tin (II) chloride (51 g) in c.HCl (91 ml), followed by 3 hours' stirring at room temperature. The solution was evaporated in vacuo and the residue triturated with ether to give the desired product as a pale yellow solid (11 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[CH3:9][CH:10]([OH:13])[C:11]#[CH:12].C(N(CC)CC)C>[Cu]I.CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([C:12]#[C:11][CH:10]([OH:13])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: Fc1cc(I)ccn1
Reactant: C#CC(C)O
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(O)C#Cc1ccnc(F)c1
Yield: 65.2 %

Procedure:
A solution of 2-fluoro-4-iodopyridine (3.0 g, 13 mmol), 3-butyn-2-ol (2.1 mL, 26 mmol), dichlorobis(triphenylphosphine) palladium (II) (0.9 g, 1.3 mmol), copper (I) iodide (0.5 g, 2.6 mmol), triethylamine (5.4 mL 39 mmol), and anhydrous N,N-dimethylformamide (20 mL) were heated to 75° C. for 4 hours. When judged to be complete, the mixture was partitioned between ethyl acetate and water, the organics were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude mixture was purified using flash chromatography (4:1 hexanes:ethyl acetate) to provide 4-(2-fluoro-4-pyridinyl)-3-butyn-2-ol (1.4 g, 66%) as an orange oil. 1H NMR (DMSO-d6): δ 8.21 (d, 1H), 7.32 (d, 1H), 7.20 (s, 1H), 5.62 (d, 1H), 4.61 (m, 1H), 1.36 (d, 3H).
Reaction SMILES: C([Mg][Cl:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]([CH3:24])[C:12]1([C:22]#N)[CH2:21][CH2:20][C:15]2([O:19][CH2:18][CH2:17][O:16]2)[CH2:14][CH2:13]1.[Cl-].[NH4+].Cl[Si](C)(C)C>C1COCC1.O>[ClH:9].[CH3:10][N:11]([CH3:24])[C:12]1([CH2:22][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:21][CH2:20][C:15]2([O:19][CH2:18][CH2:17][O:16]2)[CH2:14][CH2:13]1
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Reactant: Cl[Mg]Cc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C1(Cc2ccccc2)CCC2(CC1)OCCO2
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
2 M benzylmagnesium chloride solution in THF (3, 285 ml, 570 mmol) was added to a solution of 8-dimethylamino-1,4-dioxa-spiro[4.5]decane-8-carbonitrile (39.8 g, 190 mmol) in THF (300 ml) in the course of 15 min, under argon and while cooling with ice. The mixture was then stirred at RT for 16 h. For working up of the reaction mixture, saturated ammonium chloride solution (200 ml) and water (100 ml) was added, while cooling with ice, and the mixture was extracted with diethyl ether (3×100 ml). The organic phase was extracted by shaking with water (50 ml) and saturated NaCl solution (50 ml) and the extract was then concentrated. A white solid (68.34 g) remained which, apart from the product, still contained the educt. The crude product was dissolved in ethyl methyl ketone (250 ml), and ClSiMe3 (30 ml, 238 mmol) was added, while cooling with ice. After 16 h, dimethyl-(8-benzyl-1,4-dioxa-spiro[4.5]dec-8-yl)amine hydrochloride was isolated in a yield of 52% (40.33 g) as a white solid with a melting point of 276-280° C.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[CH3:5][C:6]1([CH3:12])[CH2:10][CH2:9][C:8](=[O:11])[CH2:7]1>C1COCC1>[CH3:5][C:6]1([CH3:12])[CH2:10][CH2:9][C:8]([CH:1]=[CH2:2])([OH:11])[CH2:7]1
Reactant: C=C[Mg]Br
Reactant: CC1(C)CCC(=O)C1
Solvent: C1CCOC1
Product: C=CC1(O)CCC(C)(C)C1
Temperature: 7.5 °C
Reaction time: 0.5 h
Yield: 76.1 %

Procedure:
The reactor was charged with vinylmagnesium bromide (0.6M in THF, 245 ml, 147 mmol) and the solution was cooled to 5-10° C. 3,3-Dimethylcyclopentanone (2a, 15.0 g, 134 mmol) in THF (50 ml) was added over 10 minutes while keeping the temperature of the reaction mixture between 5-10° C. by means of an ice bath. The mixture was stirred for 30 minutes, then quenched with 10% AcOH (150 ml) and extracted with hexane (2×100 ml). The combined organic phases were washed with water, dried (MgSO4), concentrated and distilled bulb-to-bulb to afford 3a (14.3 g, 76% yield) as a colorless liquid.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[N:13]=[C:12]([O:14][Si](C)(C)C)[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=1.Br[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([F:33])=[C:27]([CH:32]=1)[C:28]([O:30][CH3:31])=[O:29].O1CCOCC1.CO>CN(C=O)C>[F:33][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:12](=[O:14])[NH:13][C:4]2=[O:3])=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)c1cc(CBr)ccc1F
Reactant: C[Si](C)(C)Oc1nc2c(c(O[Si](C)(C)C)n1)CCCC2
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1cc(Cn2c3c(c(=O)[nH]c2=O)CCCC3)ccc1F

Procedure:
Similarly, compounds of this invention can be prepared as illustrated by the exemplary reaction in Scheme 2. Reaction of the intermediate 2,4-di(trimethylsiloxy)-5,6,7,8-tetrahydroquinazoline with methyl 5-(bromomethyl)-2-fluorobenzoate in DMF, followed by treatment with 1,4-dioxane and methanol, produced 1-(4-fluoro-3-methoxycarbonylbenzyl)-5,6,7,8-tetrahydroquinazol ine-2,4(1H,3H)-dione. Treatment of the ester with NaOH in water-methanol produced 1-(4-fluoro-3-carboxybenzyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione. Coupling of the acid with a substituted amine, such as 1-cyclopentylcarbonylpiperazine, in the presence of coupling agents, such as HATU and DIPEA in DMF, produced the targeted compound 1-(4-fluoro-3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][N:13]3[CH2:17][CH2:16][C@H:15]([NH:18][S:19]([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][C:26]([O:32][CH3:33])=[CH:27][CH:28]=5)[CH:23]=4)(=[O:21])=[O:20])[C:14]3=[O:34])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:35](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O.C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][N:13]3[CH2:17][CH2:16][C@H:15]([N:18]([CH3:35])[S:19]([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][C:26]([O:32][CH3:33])=[CH:27][CH:28]=5)[CH:23]=4)(=[O:20])=[O:21])[C:14]3=[O:34])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccc5ccnc(Cl)c5c4)C3=O)cc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: ClCCl
Solvent: CC(C)=O
Product: COc1ccc2ccc(S(=O)(=O)N(C)[C@H]3CCN(Cc4ccc5ccnc(Cl)c5c4)C3=O)cc2c1
Temperature: 25 °C
Yield: 59.2 %

Procedure:
To a solution of 7-methoxynaphthalene-2-sulfonic acid [1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide (0.151 g, 0.304 mmol) in acetone (20 mL) is added potassium carbonate (0.084 g, 0.608 mmol) followed by methyl iodide (0.12 mL, 1.93 mmol). The resulting mixture is heated to reflux overnight, then cooled to room temperature and diluted with methylene chloride. The solution is washed with saturated NaHCO3 solution, water and brine. The organic layer is dried over MgSO4, filtered and concentrated. The residue is purified by column chromatography eluting with 5% MeOH/CH2Cl2 to give the product (0.093 mg, 0.18 mmol) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][NH:9][C:10](=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[C:2]1([CH3:1])[CH:18]=[CH:17][C:5]([C:6]2[O:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)NNC(=O)c1ccc(C)cc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1nnc(-c2ccc(C)cc2)o1
Yield: 93 %

Procedure:
6A (8.1 g, 32.4 mmol) was dissolved in toluene (200 ml) and pyridine (2.6 mL, 32.4 mmol). Thionyl chloride (9.6 g, 81 mmol) was added and the reaction was refluxed for 8 h. The solvent was evaporated and the residue was partitioned between DCM and aqueous NaHCO3 (sat.). The organic phase was further washed with 0.1 M HCl and aqueous NaHCO3 (sat.), filtered through a phase separator and the solvent was removed by evaporation. There was obtained 7.0 g (93%) of 6B as an off white solid. 1H NMR (400 MHz, CDCl3): δ 1.48 (t, 3H), 2.44 (s, 3H), 4.54 (q, 2H), 7.34 (d, 2H), 8.04 (d, 2H).
Reaction SMILES: [Li+].[OH-].[N:3]1([S:9]([C:12]2[CH:13]=[CH:14][C:15]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:16]([CH:21]=2)[C:17]([O:19]C)=[O:18])(=[O:11])=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.Cl>O1CCCC1.O.C(OCC)(=O)C>[N:3]1([S:9]([C:12]2[CH:13]=[CH:14][C:15]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[C:16]([CH:21]=2)[C:17]([OH:19])=[O:18])(=[O:11])=[O:10])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: COC(=O)c1cc(S(=O)(=O)N2CCOCC2)ccc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(S(=O)(=O)N2CCOCC2)ccc1OCc1ccccc1
Temperature: 50 °C

Procedure:
LiOH (23.25 mg, 0.97 mmol) was added to a stirred solution of methyl 5-(4-morpholinylsulfonyl)-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 65; 380 mg, 0.97 mmol) in a mixture of tetrahydrofuran and water (3:1, 40 ml). The mixture was heated at 50° C. for 6 h, and then diluted with ethyl acetate (50 m). 10% Aqueous HCl was added to the mixture to adjust pH to 2. The organic phase was isolated, washed with brine, dried over MgSO4, and concentrated to yield the title compound as a white solid. 250 mg.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:15].[C:16](Cl)(=[O:18])[CH3:17].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:12][O:11][C:10]1[C:2]([NH:1][C:16](=[O:18])[CH3:17])=[C:3]2[C:7](=[CH:8][C:9]=1[O:13][CH3:14])[C:6](=[O:15])[CH2:5][CH2:4]2
Reactant: COc1cc2c(c(N)c1OC)CCC2=O
Reactant: CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(c(NC(C)=O)c1OC)CCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
4-Amino-5,6-dimethoxy-indan-1-one (Intermediate U) (0.214 g, 1.0 mmol) was taken up into 5 mL of DMF and acetyl chloride (0.071 mL, 1.0 mmol) and DIEA (0.18 mL, 1.0 mmol) were added. The reaction stirred overnight at room temperature. The reaction was quenched with sat. sodium bicarbonate and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and removed in vacuo. 0.25 g of the crude material was produced (Intermediate V); MS m/z 250.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@H:7]2[CH2:11][NH:10][CH2:9][C@H:8]2[OH:12])=[CH:4][C:3]=1[F:15].C=O.[BH3-][C:19]#N.[Na+]>CO>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@H:7]2[CH2:11][N:10]([CH3:19])[CH2:9][C@H:8]2[OH:12])=[CH:4][C:3]=1[F:15]
Reactant: [BH3-]C#N
Reactant: O[C@@H]1CNC[C@@H]1Oc1ccc(Cl)c(F)c1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1C[C@@H](O)[C@@H](Oc2ccc(Cl)c(F)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 222.3 %

Procedure:
To a solution of 420 (0.35 g, 1.52 mmol) and MeOH (5 mL) was added HCHO (37% in water, 0.42 mL, 15.2 mmol). The mixture was stirred at RT for 2 h and then NaCNBH3 (1.43 g, 22.8 mmol) was added. The reaction was stirred at RT for 3 h. The reaction was quenched with aqueous NH4OH (50 mL) and the mixture was extracted with EtOAc (3×10 mL). The combined organic phases were washed with water (3×50 mL), dried (Na2SO4) and concentrated in vacuo to afford 0.830 g of cis-(±)-4-(4-chloro-3-fluorophenoxy)-1-methylpyrrolidin-3-ol as a brown oil (422) which used for next step without further purification: LC-MS (ESI) m/z 246 (M+H).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:5])C.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.Br[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH:37]([CH3:39])[CH3:38])=[CH:32][CH:31]=1>>[CH:37]([O:36][C:33]1[CH:34]=[CH:35][C:30]([N:7]2[C:8]3[C:13](=[CH:12][C:11]([C:21]4[CH:22]=[CH:23][C:18]([C:17]([F:28])([F:27])[F:16])=[CH:19][CH:20]=4)=[CH:10][CH:9]=3)[CH:14]=[C:6]2[C:4]([OH:3])=[O:5])=[CH:31][CH:32]=1)([CH3:39])[CH3:38]
Reactant: CC(C)Oc1ccc(Br)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Product: CC(C)Oc1ccc(-n2c(C(=O)O)cc3cc(-c4ccc(C(F)(F)F)cc4)ccc32)cc1

Procedure:
The title compound was prepared in accordance with Example 1, using 5-bromoindole-2-carboxylic acid ethyl ester, 4-(trifluoromethyl)phenyl-boronic acid and 4-bromo-1-isopropoxybenzene.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=3)[N:10]=2)[CH:5]=[CH:6][N:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.[NH2:48][C:49]1[CH:50]=[CH:51][C:52]2[O:57][C:56]([F:59])([F:58])[C:55](=[O:60])[NH:54][C:53]=2[CH:61]=1>O1CCOCC1.O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:19][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:10]=[C:3]3[C:2]([NH:48][C:49]4[CH:50]=[CH:51][C:52]5[O:57][C:56]([F:59])([F:58])[C:55](=[O:60])[NH:54][C:53]=5[CH:61]=4)=[N:7][CH:6]=[CH:5][N:4]3[N:8]=2)[CH:17]=[C:16]([CH3:18])[CH:15]=1
Reactant: Nc1ccc2c(c1)NC(=O)C(F)(F)O2
Reactant: Cc1cc(C)cc(Nc2nc3c(Cl)nccn3n2)c1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Cc1cc(C)cc(Nc2nc3c(Nc4ccc5c(c4)NC(=O)C(F)(F)O5)nccn3n2)c1

Procedure:
8-Chloro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl-(3,5-dimethyl-phenyl)-amine (0.075 g, 0.2 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.01 g, 0.01 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.01 g, 0.02 mmol) and 6-amino-2,2-difluoro-2H-1,4-benzoxazin-3(4H)-one (0.049 g, 0.2 mmol) are taken in dry 1,4 dioxane (2 mL). Sodiumhexamethyldiisilylamide (1 M in tetrahydrofuran) (0.27 mL, 0.2 mmol) is added and the reaction irradiated in the microwave at 150° C. for 30 minutes. The reaction mixture is quenched with dry methanol (1 mL) and passed through a celite pad. The filtrate is concentrated and purified by flash column chromatography using Silica gel (230-400) mesh to get the titled product as an off white solid (10 mg, 10.4%). TLC: pet ether/ethylacetate (6/4) Rf-0.4. LCMS (method A): mass found (M+H+, 438), Rt (min): 5.11 area % 93.7 (max), 94.4 (254 nm); 1H NMR (400 MHz, DMSO-d6): δ [ppm] 11.99 (s, 1H), 9.63 (s, 1H), 9.39 (s, 1H), 8.27 (d, J=4.48 Hz, 1H), 7.93 (d, J=2.44 Hz, 1H), 7.63 (m, 1H), 7.57 (d, J=4.48 Hz, 1H), 7.35 (s, 2H), 7.27 (d, J=8.92 Hz, 1H), 6.55 (s, 1H), 2.25 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]=[C:13]=[O:14])=[C:4]([F:15])[CH:3]=1.[NH2:16][C:17]([CH2:25][CH3:26])=[C:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(OCC)C>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[CH:6][C:5]([NH:12][C:13](=[O:14])[NH:16][C:17]([CH2:25][CH3:26])=[C:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:4]([F:15])[CH:3]=1
Reactant: CCOC(=O)C(C)=C(N)CC
Reactant: CC(C)Oc1cc(N=C=O)c(F)cc1Cl
Solvent: CCOCC
Product: CCOC(=O)C(C)=C(CC)NC(=O)Nc1cc(OC(C)C)c(Cl)cc1F

Procedure:
using 4-chloro-2-fluoro-5-isopropoxyphenyl isocyanate in diethyl ether with ethyl 3-amino-2-methyl-2-pentenoate there is obtained ethyl 3-[3-(4-chloro-2-fluoro-5-isopropoxyphenyl)ureido]-2-methyl-2-pentenoate, m.p. 104°-106° C., and from this intermediate with sodium hydride in dimethylformamide there is obtained 6-ethyl-3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5 -methyl-2,4(1H,3H)-pyrimidinedione, m.p. 196°-198° C.:
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=O)[NH:8][C:4]=2[CH:3]=1.O=P(Cl)(Cl)[Cl:14]>[Cl-].C[N+](C)(C)C>[Cl:14][C:7]1[NH:6][C:5]2[CH:10]=[CH:11][C:2]([I:1])=[CH:3][C:4]=2[N:8]=1
Reactant: O=c1[nH]c2ccc(I)cc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: C[N+](C)(C)C
Agent: [Cl-]
Product: Clc1nc2cc(I)ccc2[nH]1
Reaction time: 0.5 h

Procedure:
Heat a solution of 5-iodo-1,3-dihydro-benzimidazol-2-one (6.50 g, 25.0 mmol; Feitelson et al. (1952) J. Chem. Soc. 2389) and tetramethylammonium chloride (1.37 g, 12.5 mmol) to 100° C. in POCl3 (10 mL) for 18 hours. After cooling, remove the excess POCl3 in vacuo, and triturate the residue in ice-water (200 mL). After stirring for 30 minutes, filter the precipitate to obtain 2-chloro-5-iodo-1H-benzimidazole as a gray solid. B. 1′-(5-iodo-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([NH2:17])=O)=[C:10]3[C@@H:9]3[CH2:18][CH2:19][N:8]3[C:7](=[O:20])[C:6]=2[CH:21]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]#[N:17])=[C:10]3[C@@H:9]3[CH2:18][CH2:19][N:8]3[C:7](=[O:20])[C:6]=2[CH:21]=1
Reactant: NC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1cc(Cl)ccc1-2
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1ncn2c1[C@@H]1CCN1C(=O)c1cc(Cl)ccc1-2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 78.3 %

Procedure:
2.38 g (7.85 mmol) of (S)-7-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamide were suspended in 15 ml of dioxan and 1.4 ml of pyridine and treated dropwise at a temperature of about 10° with 1.2 ml (8.25 mmol) of trifluoroacetic anhydride. The mixture was stirred at room temperature for 45 min. and a further 0.26 ml of pyridine and 0.11 ml of trifluoroacetic anhydride were added. The reaction mixture was stirred for 30 min. Thereupon, the solvent was removed in a vacuum and the residue was triturated with 30 ml of water. The crude material was chromatographed on 50 g of silica gel (methylene chloride/acetone 9:1). The product was recrystallized from acetonitrile. There were obtained 1.75 g (80%) of (S)-7-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carbonitrile of m.p. 258°-261°.