Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Cl[C:12]1[C:13]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[C:26]([CH3:31])=[N:27][N:28]([CH3:30])[CH:29]=3)[CH2:20][CH2:19]2)=[N:14][CH:15]=[CH:16][N:17]=1.O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.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>[CH3:30][N:28]1[CH:29]=[C:25]([CH2:24][N:21]2[CH2:20][CH2:19][N:18]([C:13]3[C:12]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[N:17][CH:16]=[CH:15][N:14]=3)[CH2:23][CH2:22]2)[C:26]([CH3:31])=[N:27]1
Reactant: OB(O)c1ccccc1F
Reactant: Cc1nn(C)cc1CN1CCN(c2nccnc2Cl)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: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1nn(C)cc1CN1CCN(c2nccnc2-c2ccccc2F)CC1
Temperature: 110 °C
Reaction time: 16 h
Yield: 54.6 %

Procedure:
Add 2-fluorobenzeneboronic acid (215 mg, 1.5 mmol) to a nitrogen purged solution of 3′-chloro-4-(1,3-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (200 mg, 0.65 mmol) in dry N,N-dimethylacetamide (4 mL), deoxygenated water (2 mL), potassium carbonate (215 mg, 1.72 mmol), tetrakis(triphenylphosphine)palladium(0) (0.004 g, 0.0035 mmol) and stir at 110° C. for 16 hr. Cool to room temperature, add water (10 mL) and extract with DCM (3×20 mL). Concentrate the combined DCM extracts and purify by reverse phase HPLC to give the title compound (0.130 g, 54%). MS (ES): m/z=367 [M+H]+.
Reaction SMILES: [H-].[Na+].Cl.[CH3:4][N:5]([CH3:16])[CH2:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9].Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>CS(C)=O>[CH3:16][N:5]([CH3:4])[CH2:6][CH2:7][CH:8]([O:9][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN(C)CCC(O)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)CCC(Oc1ccc([N+](=O)[O-])cc1)c1ccccc1
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
26 ml of dimethylsulfoxide were added to 2.6 g of a 50% dispersion of sodium hydride in oil and the mixture was stirred at 60°-65° C. for 30 minutes and was then cooled to 22° C. 5.8 g of N,N-dimethyl-3-phenyl-3-hydroxy-propanamine hydrochloride were added to the mixture which was then stirred for 10 minutes at 25° C. Then, 8.95 g of p-chloronitrobenzene were added to the mixture which was stirred at room temperature for 15 minutes. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried, filtered and evaporated to dryness under reduced pressure to obtain 17 g of raw product. The latter was extracted 3 times with 200 ml of N hydrochloric acid and the neutral fraction was eliminated 3 times with 200 ml of ether. The combined aqueous phases were made alkaline with excess concentrated ammonium hydroxide and the precipitate was extracted with methylene chloride. The extract was dried, filtered and evaporated to dryness under reduced pressure to obtain 7.7 g of N,N-dimethyl-γ-(4-nitrophenoxy)benzene-propanamine.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:9][CH2:10][Cl:11])[P:5](Cl)(Cl)=[O:6].CN[C:14]([C:18]1[CH:23]=CC=CC=1)([OH:17])CC.C([N:26](CC)CC)C>C(OCC)(=O)C>[CH2:18]1[CH2:14][O:17][P:5]([N:4]([CH2:9][CH2:10][Cl:11])[CH2:3][CH2:2][Cl:1])(=[O:6])[NH:26][CH2:23]1
Reactant: O=P(Cl)(Cl)N(CCCl)CCCl
Reactant: CCN(CC)CC
Reactant: CCC(O)(NC)c1ccccc1
Solvent: CCOC(C)=O
Product: O=P1(N(CCCl)CCCl)NCCCO1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of bis(2-chloroethyl)phosphoramidic dichloride (10 mmol) in ethyl acetate (100 mL) is added dropwise to a solution of commercial 3 methylamino-1-phenyl-1-propanol (10 mmol) and triethylamine (20 mmol) in ethyl acetate (100 mL) at rt. After stirring at rt for 3 days, the salts are filtered off and the combined filtrates are concentrated under vacuum. The crude product is purified by column chromatography on silica.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:13]=2[C:14](O)=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:13]=2[C:14]([Cl:26])=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cc(NS(=O)(=O)c2ccc(Cl)cc2)c(C(=O)O)cc1OC
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc(NS(=O)(=O)c2ccc(Cl)cc2)c(C(=O)Cl)cc1OC
Temperature: 42.5 °C
Reaction time: 2.5 h
Yield: 92.6 %

Procedure:
33.71 g (0.32 mol) of sodium carbonate were dissolved in 250 ml of water and heated to 60° C. 25.00 g (0.13 mol) of 2-amino-4,5-dimethoxybenzoic acid were introduced into the solution, and 29.55 g (0.14 mol) of 4-chlorobenzenesulfonyl chloride were added in portions to this solution over the course of 15 min. After the mixture had been cooled, the residue was filtered off with suction and taken up in 1% strength sodium bicarbonate solution and, after filtration, the product was precipitated by adding 1 N hydrochloric acid. 25.90 g (55%) of 2-(4-chlorophenylsulfonylamino)-4,5-dimethoxybenzoic acid of melting point 212-214° C. were obtained. 25.90 g (0.07 mol) of 2-(4-chlorophenylsulfonylamino)-4,5-dimethoxybenzoic acid were suspended in 75 ml of toluene and, after addition of 17.30 g (0.08 mol) of phosphorus pentachloride, the mixture was stirred at 40-45° C. for 2.5 h. It was then concentrated to half the volume in vacuo, and the precipitated product was filtered off with suction and washed with a little toluene. 25.30 g (93%) of 2-(4-chlorophenylsulfonylamino)-4,5-dimethoxybenzoyl chloride, of melting point 175-177° C., were obtained.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:5]=[C:4]([CH3:19])[CH:3]=1.[F:20][C:21]([F:27])([F:26])[S:22][CH2:23][CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.CCCCC.C(OCC)(=O)C>[CH3:14][N:13]1[C:9]([O:8][C:6]2[CH:5]=[C:4]([CH3:19])[CH:3]=[C:2]([O:1][CH2:24][CH2:23][S:22][C:21]([F:27])([F:26])[F:20])[N:7]=2)=[CH:10][C:11]([C:15]([F:18])([F:17])[F:16])=[N:12]1
Reactant: OCCSC(F)(F)F
Reactant: Cc1cc(O)nc(Oc2cc(C(F)(F)F)nn2C)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(OCCSC(F)(F)F)nc(Oc2cc(C(F)(F)F)nn2C)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 55.7 %

Procedure:
A mixture of 1A (0.55 g), 2-(trifluoromethylthio)-ethanol (0.35 g, Example A), triphenylphosphine (0.64 g) and diethyl azodicarboxylate (0.42 g) in dry tetrahydrofuran (5 ml) is stirred for 20 hours at ambient temperature. The reaction mixture is diluted with pentane/ethyl acetate (by volume ration 1/1) and filtered through a bed of silica gel. The filtrate is washed with water. The organic layer is dried with anhydrous magnesium sulfate, filtered and evaporated in vacuo. Purification by flash chromatography (silica gel: pentane/ethyl acetate 9/1 v/v) yields 0.45 g of the title compound as an colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:14])[N:3]=1.[CH3:22][C:23]1[NH:27][N:26]=[C:25]([NH2:28])[CH:24]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[O:14])[N:3]=[C:2]2[NH:28][C:25]1[CH:24]=[C:23]([CH3:22])[NH:27][N:26]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: O=C(c1ccc(F)cc1)c1nc(Cl)c2cccc(F)c2n1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3c(F)cccc23)n[nH]1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of (4-chloro-8-fluoroquinazolin-2-yl)(4-fluorophenyl)methanone (0.4 g, 1.32 mmol), 5-methyl-1H-pyrazol-3-amine (0.15 g, 1.58 mmol), DIEA (0.69 mL, 4.0 mmol), and KI (0.24 g, 1.45 mmol) in DMF (8 mL) was stirred at rt for 20 h. The mixture was diluted with H2O (35 mL), and the precipitated solid was collected by filtration, washed with H2O, and triturated with MeOH at 0° C. A portion of the resulting solid was purified by preparative reverse phase HPLC to afford (8-fluoro-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)(4-fluorophenyl)methanone. 1H NMR (300 MHz, DMSO-d6) δ 2.19 (s, 3H), 6.52 (s, 1H), 7.41 (t, 2H), 7.64-7.80 (m, 2H), 8.11 (t, 2H), 8.57 (d, 1H), 10.84 (s, 1H), 12.27 (br s, 1H); LC-MS (ESI) m/z 366 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([OH:14])=[CH:12][C:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:10]1.[CH3:20][O:21][CH2:22][C:23](Cl)=[O:24].Cl>O1CCOCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([OH:14])=[C:12]([C:23](=[O:24])[CH2:22][O:21][CH3:20])[C:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:10]1
Reactant: COC(=O)Cc1cc(O)n(-c2ccc(F)cc2Cl)n1
Reactant: COCC(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COCC(=O)c1c(CC(=O)OC)nn(-c2ccc(F)cc2Cl)c1O
Yield: 74 %

Procedure:
The mixture of the above obtained methyl [1-(2-chloro-4-fluorophenyl)-5-hydroxy-1H-pyrazol-3-yl]acetate (Compound of Formula (IV), 0.600 g, 2.11 mmol, 1 eq.), was suspended in dioxane (10 mL) and Ca(OH)2 (0.313 g, 4.22 mmol, 2eq.) and methoxyacetyl chloride (0.229 g, 2.11 mmol, 1 eq.) under nitrogen, was heated at 70° C. for 45-60 minutes. The resulting solution was concentrated in vacuo and the residue was partitioned between dichloromethane (50 ml) and a mixture of brine (10 ml) and 2N hydrochloric acid (1 ml, 2.00 mmol). The dichloromethane phase was collected. The aqueous phase was extracted with more dichloromethane (50 ml) and then ethyl acetate (50 ml). The combined organic phases were dried over Na2SO4 and the solvent evaporated to give methyl [1-(2-chloro-4-fluorophenyl)-5-hydroxy-4-(methoxyacetyl)-1H-pyrazol-3-yl]acetate as a beige solid (550 mg, 1.55 mmol, 74% yield, 92% HPLC) that can be used in the following step without further purification. MS(ESI+): 357.7; MS(ESI−): 355.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[OH:35][CH:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:37]#[N:38].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:24](=[O:26])[O:35][CH:36]([C:37]#[N:38])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: N#CC(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC(C#N)c4ccccc4)cc3)c2cc1OC
Yield: 26 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-hydroxy-2-phenylacetonitrile (35 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (20 mg, yield 24%).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31]#[C:32]/[CH:33]=[CH:34]/[C:35]2[CH:40]=[CH:39][C:38]([C:41](=[O:53])[N:42]([CH:44]([C:49]([NH:51][CH3:52])=[O:50])[C:45]([O:47][CH3:48])=[O:46])[CH3:43])=[CH:37][CH:36]=2)=[CH:27][CH:26]=1)=O>C(Cl)(Cl)Cl.O>[CH:1]1([NH:4][CH2:23][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[C:32]/[CH:33]=[CH:34]/[C:35]3[CH:40]=[CH:39][C:38]([C:41](=[O:53])[N:42]([CH:44]([C:49]([NH:51][CH3:52])=[O:50])[C:45]([O:47][CH3:48])=[O:46])[CH3:43])=[CH:37][CH:36]=3)=[CH:27][CH:26]=2)[CH2:3][CH2:2]1
Reactant: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(/C=C/C#Cc2ccc(C=O)cc2)cc1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(/C=C/C#Cc2ccc(CNC3CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
Cyclopropylamine (99 μL), acetic acid (27 μL) and sodium triacetoxyborohydride (0.10 g) were added to a chloroform (4.0 mL) suspension of 1-formyl-4-[(3E)-4-(4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}phenyl)but-3-en-1-yn-1-yl]benzene (0.20 g) as obtained in Example 22-(3), and the mixture was stirred for 1 hour and 15 minutes at room temperature. Sodium triacetoxyborohydride (0.10 g) was added, and the mixture was stirred for 1.5 hours at room temperature. Water and chloroform were added, and the organic layer was isolated. The extract was dried over anhydrous sodium sulfate, and the desiccant was filtered out. The solvent was distilled off under reduced pressure to obtain 1-[(cyclopropylamino)methyl]-4-[(3E)-4-(4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}phenyl)but-3-en-1-yn-1-yl]benzene (orange oil) (0.20 g, 91%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[N:14]=2)[CH:11]=1)=[CH2:5])[CH3:2].C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=[O:38])=CC=1>C(O)CO>[CH3:5][C:4]1([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([C:15]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:16])[N:14]=3)[CH:11]=2)[O:38][CH2:2][CH2:1][O:3]1
Reactant: C=C(OCC)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCCO
Solvent: Cc1ccccc1
Product: CC1(c2ccc3nc(C(=O)Nc4ccccc4)cn3c2)OCCO1
Yield: 20.2 %

Procedure:
A mixture of 80 mg of 6-(1-ethoxyvinyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide, 2.5 mL of toluene, 280 μL of ethylene glycol and 170 mg of para-toluenesulfonic acid is placed over molecular sieves. The mixture is refluxed for 2 hours and then cooled, filtered and diluted with 20 mL of dichloromethane and 20 mL of water, and neutralized with 2N sodium hydroxide solution. The aqueous phase is washed with dichloromethane and the combined organic phases are dried and concentrated to dryness. The residue is chromatographed on a silica cartridge, eluting with a gradient of dichloromethane and ethyl acetate of from 0/30 to 70/30 to give 17 mg of 6-(2-methyl-1,3-dioxolan-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][C:14](=[O:16])[CH3:15])=[C:7]([CH3:17])[C:6]=1[CH2:18][CH2:19][C:20](=[O:22])[CH3:21])(=[O:3])[CH3:2].C[N:24]([CH3:27])C=O.[C-]#N.[K+].OS(O)(=O)=O>O>[C:27]([C:20]([OH:22])([CH2:19][CH2:18][C:6]1[C:7]([CH3:17])=[C:8]([O:13][C:14](=[O:16])[CH3:15])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=1[O:4][C:1](=[O:3])[CH3:2])[CH3:21])#[N:24]
Reactant: CC(=O)CCc1c(C)c(OC(C)=O)c(C)c(C)c1OC(C)=O
Reactant: CN(C)C=O
Agent: O=S(=O)(O)O
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: CC(=O)Oc1c(C)c(C)c(OC(C)=O)c(CCC(C)(O)C#N)c1C
Reaction time: 0.17 h

Procedure:
A solution of the crude 4-(2,5-diacetoxy-3,4,6-trimethylphenyl)butan-2-one prepared in Example 56 in 963 ml. of dimethylformamide was cooled under N2 in an ice bath. A solution of 69.4 g. of potassium cyanide in 150 ml. of H2O was added over 20 minutes. The mixture was stirred another 10 minutes and then 161 ml. of 6N H2SO4 was added dropwise over 20 minutes while an internal temperature of +10° to +13° was maintained. The viscous suspension (pH 8) was stirred another 30 minutes, brought to pH 4 by the addition of 16.5 ml. of 6N H2SO4, poured into ice-H2O, and extracted with ether. The ether solutions were washed with brine, dried over Na2SO4, and stripped of solvent to give (±)-2-cyano-4-(2,5-diacetoxy-3,4,6-trimethylphenyl)butan-2-ol as an orange-brown foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:26])/[CH:16]=[CH:17]/[C:18]3[CH:19]=[CH:20][C:21]([CH2:24][OH:25])=[CH:22][CH:23]=3)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(/C=C/C(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: O=C(/C=C/c1ccc(CO)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4.4 g (12.16 mmol) of (E)-N-(4′-chlorobiphenyl-4-yl)-3-(4-formylphenyl)acrylamide in 200 mL of THF is adjusted with glacial acetic acid to a pH of three, combined with 8.14 g (36.48 mmol) of sodium triacetoxyborohydride, and stirred for 18 hours at ambient temperature. Then the reaction mixture is poured into water and the precipitate is filtered off. The filtrate is extracted with ethyl acetate, washed with water, and dried over sodium sulfate. The solvent is removed and the residue is combined with the solid which has been filtered off. The purification is carried out by column chromatography on silica gel (eluant: dichloromethane/ethanol/ammonia (30:1:0.1)). Yield: 3.2 g (72.4% of theory); C22H18ClNO2 (M=363.84); calc.: molecular ion peak (M+H)+: 364/366; found: molecular ion peak (M+H)+: 364/366; Rf value: 0.2 (silica gel, dichloromethane/ethanol (20:1)).
Reaction SMILES: Cl.[C:2]([NH:21][C:22]1[S:23][CH:24]=[C:25](/[C:27](=[N:31]/[O:32][CH3:33])/[C:28](O)=[O:29])[N:26]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[NH2:48][C@@H:49]1[C:80](=[O:81])[N:51]2[C:52]([C:64]([O:66][CH:67]([C:74]3[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=3)[C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)=[O:65])=[C:53]([CH2:56][S:57][C:58]3[CH2:62][O:61][C:60](=[O:63])[CH:59]=3)[CH2:54][S:55][C@H:50]12>CN(C)C=O.N1C=CC=CC=1>[O:63]=[C:60]1[CH:59]=[C:58]([S:57][CH2:56][C:53]2[CH2:54][S:55][C@@H:50]3[C@H:49]([NH:48][C:28](=[O:29])/[C:27](/[C:25]4[N:26]=[C:22]([NH:21][C:2]([C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=5)([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=5)[C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[S:23][CH:24]=4)=[N:31]\[O:32][CH3:33])[C:80](=[O:81])[N:51]3[C:52]=2[C:64]([O:66][CH:67]([C:74]2[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=2)[C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)=[O:65])[CH2:62][O:61]1
Reactant: CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSC3=CC(=O)OC3)CS[C@H]12
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSC3=CC(=O)OC3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
A stirred solution of 2-(2-tritylaminothiazol-4-yl)-2-(Z)-methoxyiminoacetic acid hydrochloride (528 mg) and N,N-diisopropylethylamine (0.383 ml) in dry dimethylformamide (4 ml) was cooled to -55° to -60° C. and methanesulphonyl chloride (0.085 ml) was added. The mixture was stirred at the same temperature for 30 mins, and then diphenylmethyl 7β-amino-3-(2,5-dihydro-2-oxofuran-4-ylthiomethyl)ceph-3-em-4-carboxylate (494 mg), dimethylformamide (2 ml) and pyridine (0.08 ml) were added. The mixture was then stirred at 0° for 90 mins. The mixture was partitioned between ethyl acetate and citric acid solution, and the ethyl acetate phase was washed twice with water, then with saturated sodium bicarbonate solution, then water and finally with brine. The solution was dried over magnesium sulphate and evaporated. The title compound (703 mg) was isolated by column chromatography of the residue using gradient elution (Kieselgel 5:2 going to 3:7 hexane:ethyl acetate). υmax (CHCl3), 3400, 1785, 1745, and 1685cm-1. δH (CDCl3) 3.42 (1H, d, J 18.3Hz), 3.61 (1H, d, J 18.4Hz), 3.89 (1H, d, J 12.6Hz), 4.04 (1H, d, J 12.6Hz), 4.08 (3H, s), 4.71 (2H, s), 5.08 (1H, d, J 5.0Hz), 5.65 (1H, s), 5.97 (1H, dd, J 4.9 and 8.8Hz), 6.73 (1H, s), 6.84 (1H, d, J 8.7Hz), 6.96 (1H, s), 7.03 (1H, s), 7.2-7.45 (25H, m). [mass spectrum: +ve ion (3 NOBA, Na+) M Na+ 942].
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C@@H:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@@H:9]([CH2:20][NH:21][CH3:22])[CH2:8][CH2:7]2.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.[CH3:34][O:35][C:36](=[O:40])[CH:37](Br)[CH3:38]>O>[CH3:34][O:35][C:36](=[O:40])[CH:37]([N:21]([CH3:22])[CH2:20][C@H:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][CH:13]=[C:4]([O:3][CH3:2])[CH:5]=2)[C@H:10]1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:38]
Reactant: CNC[C@H]1CCc2cc(OC)ccc2[C@H]1c1ccccc1
Reactant: COC(=O)C(C)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)N(C)C[C@H]1CCc2cc(OC)ccc2[C@H]1c1ccccc1
Temperature: 25 °C

Procedure:
To a mixture of cis-6-methoxy-2-methylaminomethyl-1-phenyl-1,2,3,4-tetrahydronaphthalene hydrochloride (1.00 g; prepared according to the procedures in Process 1), cesium carbonate (5.13 g) and N,N-dimethylformamide (20 cm3) was added methyl-2-bromopropionate (0.35 cm3) and the resultant mixture was stirred at 75° C. for 5 h. The reaction was then allowed to cool to room temperature and water (100 cm3) was added. The resulting mixture was extracted with diethyl ether (2×100 cm3) and the combined organic extracts were washed with water (100 cm3), dried (Na2SO4) and the solvent was removed under reduced pressure. The crude product (1.11 g) was purified by column chromatography [basic alumina, eluting with toluene-hexane (1:1)] to afford the title compound as a gum (284 mg); positive ion ESI (M+H)+ 368.4.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Cl)[CH2:2][CH3:3].[C-:13]#[N:14].[Na+].O.CCOCC>CS(C)=O>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][C:13]#[N:14])[CH2:2][CH3:3]
Reactant: [C-]#N
Reactant: CCCOc1ccccc1CCl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: CCCOc1ccccc1CC#N
Temperature: 50 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
A 2 liter flask was charged with 367 grams (1.90 moles, 1.0 ec.) of crude 2-propoxybenzyl chloride in 700 ml of DMSO. The reaction is cooled by a water bath and 102 grams of sodium cyanide (2.09 moles, 1.1 eq.) was added and allowed to warm to 50° C. After the exotherm was complete, the reaction was stirred at room temperature overnight then worked up with water, dilute acid and ether. Removal of the solvent was followed by distillation (120°-150° C. at 1 mm) and gave 180 grams (54% Yield) of a light yellow oil.