Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7].Br[CH2:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36].C(N(CC)CC)C>O1CCCC1>[CH2:38]([O:37][C:35]([CH2:34][N:11]1[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=2)[C@H:9]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:10]1)=[O:36])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Reactant: O=C(CBr)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (1.5 g), benzyl 2-bromoacetate (0.79 g), triethylamine (0.55 ml) and tetrahydrofuran (15 ml) was stirred overnight at room temperature. The resulting insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a mixture of dichloromethane and methanol (30:1) to give (2R)-4-(benzyloxycarbonylmethyl)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (1.92 g).
Reaction SMILES: Br[C:2]1[C:3]([NH2:13])=[N:4][C:5]([C:9]([F:12])([F:11])[F:10])=[C:6]([Br:8])[N:7]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[Br:8][C:6]1[N:7]=[C:2]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)[C:3]([NH2:13])=[N:4][C:5]=1[C:9]([F:12])([F:11])[F:10]
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1Br
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1nc(C(F)(F)F)c(Br)nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 66.6 %

Procedure:
To a mixture of 6.08 g 3,5-dibromo-6-trifluoromethyl-pyrazin-2-ylamine, 3.25 g 4-chlorophenylboronic acid and 1.095 g tetrakis(triphenylphosphine)palladium(0) in 60 ml 1,2-dimethoxyethane was added a solution of 4.016 g sodium carbonate in 22.74 ml water and the mixture was heated to reflux for 18 h. The reaction mixture was cooled to room temperature and partitioned between 10% aqueous citric acid and ethyl acetate, the phases were separated and the organic phase was purified by chromatography on silica gel with a gradient of 9:1 heptane: dichloromethane to 1:1 heptane: dichloromethane to yield 4.45 g of the title compound as white solid. MS (M−H) at 352.0 and 350.1.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12]([C:14]3[S:15][C:16]([CH3:20])=[C:17]([NH2:19])[CH:18]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:21]([N:28]=[C:29]=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12]([C:14]3[S:15][C:16]([CH3:20])=[C:17]([NH:19][C:29]([NH:28][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:30])[CH:18]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1sc(C(=O)NCc2ccc3c(c2)OCO3)cc1N
Reactant: O=C=NCc1ccccc1
Solvent: C1COCCO1
Product: Cc1sc(C(=O)NCc2ccc3c(c2)OCO3)cc1NC(=O)NCc1ccccc1
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
A mixture of 5-methyl-4-amino-thiophene-2-carboxylic acid (1,3-benzodioxol-5-ylmethyl)-amide from Step 2 (0.6 g, 2.1 mmol) and benzyl isocyanate (0.28 g, 2.1 mmol) in 1,4-dioxane (100 mL) was stirred under an inert atmosphere and heated to reflux. After 30 minutes, the mixture was allowed to cool, and the solvent was removed under reduced pressure. The residue was triturated in a small amount of acetonitrile, cooled, and filtered to afford 0.33 g of 4-(3-benzyl-ureido)-5-methyl-thiophene-2-carboxylic acid (1,3-benzodioxol-5-ylmethyl)-amide. A sample was recrystallized from methanol to give product with a mp 194-195° C.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH2:8][CH2:9]O)=[C:6]([CH2:11][CH3:12])[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:4]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:39].C(N(CC)CC)C>C(Cl)Cl.C(OCC)C>[Br:39][CH2:9][CH2:8][C:7]1[C:3]([CH2:1][CH3:2])=[N:4][N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:6]=1[CH2:11][CH3:12]
Reactant: BrC(Br)(Br)Br
Reactant: CCc1nn(-c2ccccn2)c(CC)c1CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CCc1nn(-c2ccccn2)c(CC)c1CCBr
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combine 2-(3,5-diethyl-1-pyridin-2-yl-1H-pyrazol-4-yl)-ethanol (0.68 g, 2.78 mmol) and triphenylphosphine (1.09 g, 4.18 mmol) in DCM (20 mL) and cool to 0° C. Add a solution of carbon tetrabromide (1.39 g, 4.18 mmol) and triethylamine (0.77 mL, 5.56 mmol) in DCM (5 mL) dropwise. Warm the reaction mixture to room temperature and stir for 3 hr. Dilute with diethyl ether (20 mL) and filter. Concentrate filtrate and purify using silica gel chromatography, eluting with 90:10 hexanes:ethyl acetate, to give the title preparation as an oil (0.8 g, 93%): 1H-NMR (400 MHz, CDCl3) δ 8.39 (m, 1H), 7.80 (m, 1H), 7.75 (m, 1H), 7.15 (m, 1H), 3.39 (m, 2H), 3.08 (q, 2H), 2.98 (m, 2H), 2.64 (q, 2H), 1.28 (t, 3H), 1.15 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:16][C:17]2[N:27]=[C:26]3[C:20]([N:21]([CH3:34])[C:22](=[O:33])[CH2:23][CH2:24][N:25]3[CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:19][N:18]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[NH2:35][C:36]1[C:48]([Cl:49])=[CH:47][C:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[C:38]([F:50])[C:37]=1Cl>>[Cl:49][C:4]1[C:5]([F:15])=[C:6]([CH:14]=[C:2]([Cl:1])[C:3]=1[NH:16][C:17]1[N:27]=[C:26]2[C:20]([N:21]([CH3:34])[C:22](=[O:33])[CH2:23][CH2:24][N:25]2[CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:19][N:18]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[C:43]([O:42][C:40](=[O:41])[C:39]1[CH:47]=[C:48]([Cl:49])[C:36]([NH2:35])=[CH:37][C:38]=1[F:50])([CH3:46])([CH3:44])[CH3:45]
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)OC(C)(C)C)cc3Cl)ncc21
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(N)c(Cl)c1F
Product: CC(C)(C)OC(=O)c1cc(Cl)c(N)cc1F
Product: CN1C(=O)CCN(C2CCCC2)c2nc(Nc3c(Cl)cc(C(=O)OC(C)(C)C)c(F)c3Cl)ncc21

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 220, utilising tert-butyl 4-amino-3,5-dichloro-2-fluoro-benzoate (Isolated as a by-product during the preparation of Intermediate 177; 236 mg, 0.45 mmol), as an off-white solid (180 mg, 87%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([CH:12]1[S:17][CH2:16][CH2:15][CH2:14][S:13]1)(O)[CH2:6][CH2:5]2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[C:12]1[S:13][CH2:14][CH2:15][CH2:16][S:17]1)[CH2:6][CH2:5]2
Reactant: OC1(C2SCCCS2)CCc2cc(Br)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: Brc1ccc2c(c1)CCC2=C1SCCCS1
Temperature: 25 °C

Procedure:
A mixture of (rac)-5-bromo-1-[1,3]dithian-2-yl-indan-1-ol (2.15 g, 6.49 mmol) and p-toluenesulfonic acid monohydrate (309 mg, 1.62 mmol) in benzene (30 ml) was heated to reflux for 2 h using a Dean-Stark trap to remove water. The brown solution was allowed to cool to room temperature and was diluted with sat. NaHCO3 solution. The layers were separated and the organic layer was washed with brine, dried with Na2SO4 and evaporated. The title compound was obtained as brown gum (2.024 g, 99%) and was used without purification for the next reaction step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1([F:25])[CH2:22][CH:21]1[CH2:23]Br.O>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:12][CH2:23][CH:21]2[CH2:22][C:20]2([F:25])[F:19])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Reactant: FC1(F)CC1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(OCC2CC2(F)F)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.6 g 2-Chloro-4-fluoro-5-nitrophenol was dissolved in dimethylformamide and treated with potassium carbonate. The mixture was stirred at room temperature for one hour and then 3.3 g 2,2-difluorocyclopropylmethyl bromide added. It was the heated at 80° C. for 2 hours and added to water. The mixture was extracted with methylene chloride and the organic phase washed with saturated brine, dried over magnesium sulphate and concentrated. The residue was chromatographed on silica gel using a mixture of 3 parts hexane and 1 part ethyl acetate. There was obtained 5 g (=93% of theory) of yellow crystals whose nmr spectrum is as follows: δ=1.1-2.4 ppm (m) 3H, δ=4.15 ppm (d 7 Hz,tr 1.5 Hz) 2H, δ=7.35 ppm (d 10 Hz) 1H, δ=7.5 ppm (d 7 Hz) 1H.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[C:15]4[CH:20]=[C:19]([CH2:21]Cl)[CH:18]=[CH:17][N:16]4[C:23]=3[CH3:24])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:25][O-:26].[Na+]>CO>[NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[C:15]4[CH:20]=[C:19]([CH2:21][O:26][CH3:25])[CH:18]=[CH:17][N:16]4[C:23]=3[CH3:24])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: C[O-]
Reactant: Cc1c(CCc2ccc3nc(N)oc3c2)nc2cc(CCl)ccn12
Agent: [Na+]
Solvent: CO
Product: COCc1ccn2c(C)c(CCc3ccc4nc(N)oc4c3)nc2c1
Reaction time: 3 h
Yield: 55.7 %

Procedure:
A mixture of 2-amino-6-[2-(7-chloromethyl-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (0.4 g), and sodium methoxide (0.13 g) in methanol (10 ml) was stirred for 3 hours at 40°-50° C. and the solvent was evaporated in vacuo. The residue was dissolved in a mixture of ethyl acetate and tetrahydrofuran and the mixture was washed with water and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was purified by silica gel column chromatography eluting with a solution of chloroform and methanol (9:V/V). The fraction containing object compound were concentrated to give 2-amino-6-[2-(7-methoxymethyl-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (0.22 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:29])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]3([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:20](=[O:27])[NH:19][C:18]2=[O:28])=[CH:13][CH:12]=1)[CH3:8].Cl[CH2:31][C:32]([NH:34][C:35]1[C:40]([CH:41]([CH3:43])[CH3:42])=[CH:39][CH:38]=[CH:37][C:36]=1[CH:44]([CH3:46])[CH3:45])=[O:33].O>CN(C)C=O>[CH2:7]([O:9][C:10](=[O:29])[C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:21]3([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:20](=[O:27])[N:19]([CH2:31][C:32](=[O:33])[NH:34][C:35]3[C:36]([CH:44]([CH3:46])[CH3:45])=[CH:37][CH:38]=[CH:39][C:40]=3[CH:41]([CH3:43])[CH3:42])[C:18]2=[O:28])=[CH:15][CH:16]=1)[CH3:8]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CCl
Reactant: CCOC(=O)c1ccc(N2C(=O)NC(=O)C23CCCCC3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N2C(=O)N(CC(=O)Nc3c(C(C)C)cccc3C(C)C)C(=O)C23CCCCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
87 mg (0.63 mmol, 1 eq.) of potassium carbonate are added to a solution of 200 mg (0.63 mmol, 1 eq.) of 4-(2,4-dioxo-1,3-diazaspiro[4.5]dec-1-yl)benzoic acid ethyl ester and 160 mg (0.63 mmol, 1 eq.) of 2-chloro-N-(2,6-diisopropylphenyl)acetamide in 30 ml of dimethylformamide. The reaction medium is stirred at room temperature overnight. It is then poured into water and extracted with ethyl acetate. The organic phases are combined and washed with water. They are dried over sodium sulfate. The solvents are evaporated off. The residue is precipitated from dichloromethane and heptane. The product 4-{3-[(2,6-diisopropyl-phenylcarbamoyl)methyl]-2,4-dioxo-1,3-diaza-spiro[4.5]dec-1-yl}benzoic acid ethyl ester is obtained in the form of a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH:11]1[S:15][C:14](=[O:16])[NH:13][C:12]1=[O:17].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[C:26][CH2:27]Br)=[CH:21][CH:20]=1.FC1C=C(C#CCBr)C=C(F)C=1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1([CH2:27][C:26]#[C:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[S:15][C:14](=[O:16])[NH:13][C:12]1=[O:17]
Reactant: Clc1ccc(C#CCBr)cc1
Reactant: O=C1NC(=O)C(Sc2nc3ccccc3o2)S1
Agent: Fc1cc(F)cc(C#CCBr)c1
Product: O=C1NC(=O)C(CC#Cc2ccc(Cl)cc2)(Sc2nc3ccccc3o2)S1

Procedure:
Prepared from 5-(benzoxazol-2-ylsulfanyl)-thiazolidine-2,4-dione, (III), Example 89 and [3-(4-chlorophenyl)-prop-2-ynyl]-bromide of formula (IX), Example mp 137°-139° C.; Anal. Calc. for C19H11ClN2O3S2 : C, 55.80; H, 2.67; N, 6.75; Found: C, 54.92; H, 2.76; N, 6.82.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH:4]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[CH:14][N:15]4[C:24]5[C:19](=[C:20](Cl)[CH:21]=[CH:22][CH:23]=5)[C:18](=[O:26])[N:17]([CH3:27])[C:16]=34)[N:8]=2)[CH2:6][CH2:5]1>CN(C)C=O>[CH:4]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[CH:14][N:15]4[C:24]5[C:19](=[C:20]([N:2]([CH3:3])[CH3:1])[CH:21]=[CH:22][CH:23]=5)[C:18](=[O:26])[N:17]([CH3:27])[C:16]=34)[N:8]=2)[CH2:6][CH2:5]1
Reactant: CNC
Reactant: Cn1c(=O)c2c(Cl)cccc2n2cnc(-c3noc(C4CC4)n3)c12
Solvent: CN(C)C=O
Product: CN(C)c1cccc2c1c(=O)n(C)c1c(-c3noc(C4CC4)n3)ncn21
Yield: 86 %

Procedure:
Gaseous dimethylamine was passed through a stirred solution of 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methyl-5-oxo-6-chloro-4,5-dihydro-imidazo(1,5-a)quinazoline (0.4 g, 1.2 mmol) in 25 ml of dry dimethylformamide at 110° C. for 2 h. The reaction mixture was evaporated in vacuo and the residue was triturated with 20 ml of water, filtered off and dried to give 0.35 g (86%) of 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methyl-5-oxo-6-dimethylamino-4,5-dihydro-imidazo(1,5-a)quinazoline, M.p. 170°-171° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][C:9]=2[OH:16])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+].Br[CH:31]([CH3:36])[C:32]([O:34][CH3:35])=[O:33]>C(#N)C>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][C:9]=2[O:16][CH:31]([CH3:36])[C:32]([O:34][CH3:35])=[O:33])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCc1ccc(CN2CCOCC2)c(O)c1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1ccc(CN2CCOCC2)c(OC(C)C(=O)OC)c1
Temperature: 72.5 °C
Yield: 101.3 %

Procedure:
This compound was prepared in the manner of Example 4, using 221.0 grams (0.92 mole--1.0 equiv.) of 92.0% pure 2-(morpholin-4-ylmethyl)-5-ethylphenol, 202.3 grams (2.17 moles--2.36 equiv.) of triethylamine, 276.0 grams (2.17 moles--1.68 equiv.) of potassium carbonate, and 250.0 grams (1.63 moles--1.77 equiv.) of methyl 2-bromopropanoate in about 2000 mL (%Wt/Vol. Phenol to Solvent--11.1 %) of acetonitrile. This preparation differs in that the mixture was heated to 70° C. rather than 78° C. before the methyl 2-bromopropanoate was added and that the methyl 2-bromopropanoate was added during a 15 minute period at a rate to maintain the reaction temperature between 70-75° C. rather than during a ten minute period. A yield of 311 grams of 85.3% pure methyl 2-[2-(morpholin-4-ylmethyl)-5-ethylphenoxy]-propanoate was obtained (93.9% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+].O.Cl>CO>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1ccc(-c2ccnc(C)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(-c2ccc(C(=O)O)cc2)ccn1
Yield: 44.7 %

Procedure:
Ethyl 4-(2-methyl-4-pyridyl)benzoate (185 mg) was dissolved in methanol (7.5 ml) and 1.0M NaOH (3.75 ml) and heated at 60° C. for 3 hours. The resulting mixture was reduced to low volume then water (10 ml) added, the solution neutralised to pH 7 with 10M HCl, the resulting precipitate filtered and dried over P2O5 to give 4-(2-methyl-4-pyridyl)benzoic acid as a light brown solid (73 mg); mp 293-294° C.; 1H NMR (300 MHz, DMSO-d6) δ=2.52 (s,3H), 7.53 (d,1H), 7.62 (s,1H), 7.89 (d,2H), 8.04 (d,2H), 8.52 (d1H) ppm. MS: m/z 214 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]#[C:10][Si](C)(C)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]#[CH:10]
Reactant: C[Si](C)(C)C#Cc1cc(F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Product: C#Cc1cc(F)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ((2-chloro-5-fluorophenyl)ethynyl)trimethylsilane (4.2 g, 18 mmol) in methanol (40 mL) was added potassium carbonate (7.7 g, 56 mmol), and the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was then diluted with diethyl ether (100 mL) and washed with water (300 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 220 g, ISCO, heptane) to afford the title compound as a pale yellow, waxy solid (2.0 g, 70%), which was used in the next step without further purification.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[CH:19]([NH:21][N:22]1[C:26]([SH:27])=[N:25][N:24]=[N:23]1)=[O:20].CS(O)(=O)=O.N>C(#N)C.O>[NH2:13][C@@H:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:27][C:26]3[N:22]([NH:21][CH:19]=[O:20])[N:23]=[N:24][N:25]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=CNn1nnnc1S
Agent: CS(=O)(=O)O
Agent: N
Solvent: O
Solvent: CC#N
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3NC=O)CS[C@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.6 %

Procedure:
2.45 g of 7β-aminocephalosporanic acid and 1.31 g of 1-formamido-5-mercapto-1H-tetrazole were dissolved in 13 ml of acetonitrile, and 4.32 g of methanesulfonic acid were added dropwise thereto at room temperature under stirring. The mixture was stirred at room temperature for 30 minutes and then at 50° C. for 4 hours. 15 ml of water were added to the reaction mixture, and said mixture was adjusted to pH 5 with 28% ammonia. The resultant precipitates were collected by filtration, washed with water and acetone, and then dried. 2.43 g of 7β-amino-3-[(1-formamido-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid were obtained as pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=1[NH2:8].[F:11][C:12]([F:17])([F:16])[C:13](O)=O.[OH-].[Na+]>>[CH3:9][C:6]1[C:7]2[NH:8][C:13]([C:12]([F:17])([F:16])[F:11])=[N:1][C:2]=2[CH:3]=[C:4]([OH:10])[CH:5]=1
Reactant: Cc1cc(O)cc(N)c1N
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(O)cc2nc(C(F)(F)F)[nH]c12

Procedure:
0.20 g (1.45 mmol) 3,4-diamino-5-methylphenol were stirred together with 1 mL (13.07 mmol) trifluoroacetic acid for 1 h at 100° C. The reaction mixture was cooled and purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with an aqueous 1M NaOH solution and extracted with ethyl acetate. The organic phase was evaporated down i.vac.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[CH:4][C:3]=1[OH:25].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[CH:4][C:3]=1[O:25][CH2:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38]
Reactant: COC(=O)c1ccc(-c2ccccc2C)c(-c2ccc(Cl)c(O)c2)n1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccccc2C)c(-c2ccc(Cl)c(OCCCN(C)C)c2)n1
Yield: 89.6 %

Procedure:
According to the method described in example 1.6, starting from 5.4 g (15.26 mmol) of methyl 6-(4-chloro-3-hydroxyphenyl)-5-(2-methylphenyl)pyridine-2-carboxylate, 9.95 g (30.53 mmol) of caesium carbonate and 2.9 g (18.3 mmol) of 3-chloro-N,N-dimethylpropan-1-amine hydrochloride in 60 mL of DMF, we obtain 6 g of methyl 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridine-2-carboxylate in the form of oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][OH:6].CO[C:18](OC)([CH3:20])[CH3:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][O:6][C:18]([CH3:20])([CH3:19])[N:7]1[C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])=[O:15]
Reactant: COC(=O)C(CO)NC(=O)OC(C)(C)C
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (34) in CH2Cl2, stirring under nitrogen at 0° C., was added 2,2-dimethoxypropane (29.5 mL, 237.9 mmol) and p-toluene sulfonic acid monohydrate (9.050 g, 47.58 mmol). The mixture was removed from the ice bath after 15 minutes and stirred at room temperature for 1.5 hours. The reaction mixture was poured into 50 mL of saturated NaHCO3 (aq) and extracted with diethyl ether (3×50). The organic layer was extracted with NaHCO3 and brine, then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on SiO2 (1:1 EtOAc/Hexanes) to yield 7.659 g (62%, 3 steps) of a clear liquid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([OH:9])[C:5]([F:8])([F:7])[F:6].[F:10][C:11]([F:24])([O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O)[CH:12]([F:14])[F:13].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[F:10][C:11]([F:24])([O:15][C:16]1[CH:17]=[C:18]([CH2:19][NH:1][CH2:2][CH2:3][CH:4]([OH:9])[C:5]([F:8])([F:7])[F:6])[CH:21]=[CH:22][CH:23]=1)[CH:12]([F:13])[F:14]
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: NCCC(O)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: OC(CCNCc1cccc(OC(F)(F)C(F)F)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.8 %

Procedure:
The 4-amino-2-hydroxy-1,1,1-trifluorobutane (1.0 g, 7.0 mmol) from EX-611A and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (1.5 g, 7.0 mmol) were dissolved in 20 mL of dichloroethane and acetic acid (0.40 mL, 7.7 mmol), then solid NaBH(OAc)3 (1.8 g, 8.4 mmol) was added. The mixture was stirred at room temperature for 3 d, then quenched with water and extracted with ether. The ether layer was washed with water and brine, then dried over MgSO4, and evaporated to give 1.6 g of crude product, which was purified by reverse phase HPLC to give 0.90 g (37%) of the desired 4-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-butanol product as a yellow oil. HRMS calcd. for C13H14F7NO2: 350.0991 [M+H]+, found: 350.0971.