Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH:7]=O.Cl.[C:12]([O:16][C:17]([CH:19]1[CH2:22][NH:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(Cl)Cl>[C:12]([O:16][C:17]([CH:19]1[CH2:20][N:21]([CH2:7][C:6]2[CH:9]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[Cl:10])[CH2:22]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)C1CNC1
Reactant: O=Cc1cc(Br)ccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CN(Cc2cc(Br)ccc2Cl)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-bromo-2-chloro-benzaldehyde (2 g, 9.11 mmol) and azetidine-3-carboxylic acid tert-butyl ester hydrochloride (1.765 g, 9.11 mmol) in dichloroethane (50 mL) was stirred at room temperature for 10 minutes. To this mixture was added sodium triacetoxy-borohydride (3.86 g, 18.23 mmol) in 3 portions over a period of 10 minutes and the cloudy mixture was stirred overnight. The reaction mixture was diluted with CH2Cl2 (100 mL) and washed twice with 10% sodium bicarbonate solution, twice with water then brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude was purified by chromatography on silica gel (cyclohexane/EtOAc).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[CH3:15][O:16][C:17](=[O:24])[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21]>>[CH3:15][O:16][C:17](=[O:24])[CH2:18]/[C:19](/[C:20]([O:22][CH3:23])=[O:21])=[CH:6]\[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=1
Reactant: COC(=O)CCC(=O)OC
Reactant: COc1cc(C=O)cc(OC)c1OC
Product: COC(=O)C/C(=C\c1cc(OC)c(OC)c(OC)c1)C(=O)OC

Procedure:
3,4,5-Trimethoxybenzaldehyde and succinic acid dimethyl ester are treated in the same manner as in Reference Example 1 to give (E)-3-methoxycarbonyl-4-(3,4,5-trimethoxyphenyl)-3-butenoic acid methyl ester as pale yellow syrup.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2Cl.[F:13][C:14]([F:28])([F:27])[C:15]1[CH:16]=[C:17]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[N:24]1[CH2:23][CH2:22][N:21]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:27])([F:28])[F:13])[CH:16]=2)[CH2:26][CH2:25]1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: Clc1ncnc2ccc(Br)cc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(N2CCN(c3ncnc4ccc(Br)cc34)CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.8 %

Procedure:
A mixture of 300 mg 6-bromo-4-chloroquinazoline, 350 mg 1-[3-(trifluoromethyl)phenyl]piperazine, 0.18 mL triethylamine and 5 mL N,N-dimethylformamide was stirred at room temperature for 4 hours. After the solvent was evaporated, the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give a yellow oil. This product was crystallized from diethyl ether to give 360 mg of the title compound as pale yellow crystals.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(OC([N:18]1[C:22]([NH2:23])=[CH:21][C:20]([CH2:24][CH2:25][C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=2)=[N:19]1)=O)(C)(C)C.[NH2:36][CH:37]([CH3:49])[CH2:38][C:39]1[CH:48]=[CH:47][C:42]([C:43](OC)=[O:44])=[CH:41][CH:40]=1>C1COCC1>[NH2:36][CH:37]([CH3:49])[CH2:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([NH:23][C:22]2[CH:21]=[C:20]([CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=3)[NH:19][N:18]=2)=[O:44])=[CH:41][CH:40]=1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Reactant: COC(=O)c1ccc(CC(C)N)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(CC(C)N)cc3)n[nH]2)cc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.2 %

Procedure:
A solution of NaHMDS in THF (1 M, 0.86 ml, 0.86 mmol, 1.5 eq) was added dropwise at ambient temperature to a mixture of tert-butyl-5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate (200 mg, 0.58 mmol, 1 eq) and methyl 4-(2-aminopropyl)benzoate (133 mg, 0.69 mmol, 1.2 eq) in THF (1 ml). The reaction mixture was stirred at ambient temperature for 2 h. It was then concentrated and the crude product was purified by reverse-phase prep. HPLC (basic) using a gradient of acetonitrile in water containing 1% ammonium hydroxide solution. The clean fractions were taken and evaporated to afford the title compound as a pale yellow gum (10 mg, 4% yield); 1H NMR (399.902 MHz, DMSO) δ 0.89 (3H, d), 2.53-2.47 (2H, m), 2.80 (4H, s), 3.01-2.93 (1H, m), 3.65 (6H, s), 6.25-6.24 (1H, m), 6.34 (2H, d), 6.40 (1H, s), 7.21 (2H, d), 7.84 (2H, d), 10.47 (1H, br.s), 12.06 (1H, br.s). MS: m/z 409 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1.[Cl:19][C:20]1[C:21]([F:31])=[CH:22][C:23]([F:30])=[C:24]([S:26](Cl)(=[O:28])=[O:27])[CH:25]=1.N12CCN(CC1)CC2>C(#N)C>[Cl:19][C:20]1[C:21]([F:31])=[CH:22][C:23]([F:30])=[C:24]([S:26]([N:6]([CH2:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]=2[O:2][CH3:1])[C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)(=[O:28])=[O:27])[CH:25]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Reactant: COc1ccc(CNc2ccncn2)c(OC)c1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Yield: 43.9 %

Procedure:
N-(2,4-Dimethoxybenzyl)pyrimidin-4-amine (Preparation 111, 1.80 g, 7.35 mmol), 5-chloro-2,4-difluorobenzene-1-sulfonyl chloride (1.81 g, 7.35 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.82 g, 7.35 mmol) in acetonitrile (50 mL) were stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between dichloromethane (30 mL) and water (15 mL). The organic layer was separated and dried over anhydrous MgSO4, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 10% dichloromethane in ethyl acetate to give the title compound (1.47 g, 44%) as an orange solid.
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].C([O-])(=O)C.[Na+].[CH2:12]([N:14]([CH2:36][CH3:37])[C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[C:22]([C:24]2[CH:29]=[CH:28][C:27]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[CH:26][CH:25]=2)=O)=[CH:17][CH:16]=1)[CH3:13].O>C(O)(=O)C>[OH:5][C:4]1[N:3]=[N:2][C:21]([C:18]2[CH:19]=[CH:20][C:15]([N:14]([CH2:36][CH3:37])[CH2:12][CH3:13])=[CH:16][CH:17]=2)=[C:22]([C:24]2[CH:25]=[CH:26][C:27]([N:30]([CH2:31][CH3:32])[CH2:33][CH3:34])=[CH:28][CH:29]=2)[N:6]=1
Reactant: CCN(CC)c1ccc(C(=O)C(=O)c2ccc(N(CC)CC)cc2)cc1
Reactant: NNC(N)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCN(CC)c1ccc(-c2nnc(O)nc2-c2ccc(N(CC)CC)cc2)cc1

Procedure:
Semicarbazide hydrochloride (1.57 g, 14.2 mmol) and sodium acetate (1.41 g, 17.3 mmol) are added to a solution of 1,2-bis(4-diethylaminophenyl)-ethane-1,2-dione prepared according to example 2 (5 g, 14.2 mmol) in acetic acid (20 ml). The mixture is heated at reflux for 12 hours. After returning to ambient temperature, the reaction mixture is poured into water. The raw solid is collected by filtration and washed with water. The residue is recrystallized in acetic acid. After filtration and washing with water, 3 g (54%) of a yellow solid are obtained after drying. δH (200 MHz, CDCl3), 1.18 (t; 12H), 3.45 (q; 8H), 6.65 (d; J 7.8; 4H), 7.87 (d; J 7.8; 4H), 10.4 (s; 1H)
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)[CH2:2][CH3:3].[Cl:13][CH:14]=[CH:15][CH2:16]Cl.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[Cl:13]/[CH:14]=[CH:15]/[CH2:16][N:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)[CH2:1][CH2:2][CH3:3]
Reactant: ClC=CCCl
Reactant: CCCNCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCN(C/C=C/Cl)Cc1cccc(O)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
To a solution of 3.30 g (20 mmol) of N-propyl-3-hydroxybenzylamine in 20 ml of dimethyl sulfoxide were added 1.82 g (20 mmol) of 1,3-dichloropropene (E/Z=2/1) and 1.38 g (10 mmol) of ground potassium carbonate under ice cooling. The mixture was stirred for 1.5 hours at room temperature and for 3 hours at 50° C., poured into 70 ml of ethyl acetate, washed with 50 ml×2 of water and 50 ml of saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography (n-hexane→n-hexane/ethyl acetate=9/1). The desired fractions were put together and concentrated under reduced pressure to obtain 2.29 g (yield: 48%) of the above identified compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([NH:12]C(=O)OC(C)(C)C)[CH2:10][OH:11].ClS([N:24]=[C:25]=[O:26])(=O)=O.O.C(=O)([O-])O.[Na+]>C(#N)C>[C:25](=[O:26])([O:11][CH2:10][CH:9]([NH2:12])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1])[NH2:24]
Reactant: CC(C)(C)OC(=O)NC(CO)c1cccc(Cl)c1Cl
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NC(=O)OCC(N)c1cccc(Cl)c1Cl
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Of the compound from Example 182A, 290 mg (about 0.95 mmol) were introduced in 5 ml of acetonitrile under argon. At −15° C., 115 μl (1.33 mmol) of chlorosulphonyl isocyanate were added dropwise. After 30 min, the reaction solution was admixed with 20 ml of water and heated at 60° C. overnight. The reaction mixture was cooled and introduced into saturated aqueous sodium hydrogen carbonate solution. It was extracted with twice 20 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and freed from the solvent on a rotary evaporator. Drying in an HV gave 176 mg (66% of theory) of the title compound in 89% purity.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([S:14][C:15]1[N:16]=[C:17]2[S:22][CH:21]([CH3:23])[C:20](=[O:24])[N:18]2[N:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S(OC)(OC)(=O)=O>CN(C)C=O>[CH2:7]([S:14][C:15]1[N:16]=[C:17]2[S:22][C:21]([CH3:23])=[C:20]([O:24][CH3:1])[N:18]2[N:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC1Sc2nc(SCc3ccccc3)nn2C1=O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COc1c(C)sc2nc(SCc3ccccc3)nn12
Reaction time: 0.17 h

Procedure:
Potassium t-butoxide (2.6 g) was added to a solution of the product of stage (b) in dimethylformamide (30 ml) with stirring and cooling. After 10 minutes, this solution was treated with dimethyl sulphate (2.8 g) and stirring was continued for 4 hours. Addition to ice/water/ether and filtration gave 2.3 g of desired product, mp 101°-103° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].B(O)(O)[C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH2:1]([O:3][C:4](=[O:31])[C:5]([CH3:7])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:41]4[C:42]5[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH:38]=[CH:39][CH:40]=4)[CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(Br)c3)oc2C)cc1
Reactant: OB(O)c1cccc2ccccc12
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: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(-c4cccc5ccccc45)c3)oc2C)cc1
Temperature: 25 °C

Procedure:
A solution of 2-(4-{2-[2-(3-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (433 mg, 0.907 mmol) (see Ex. 3, part F) and 1-naphthyleneboronic acid (0.998 mmol) in toluene:ethanol (18.2 mL of a 1:1 solution) was treated with Na2CO3(aq) (0.906 mL of a 2M solution). A nitrogen atmosphere was applied, Pd(PPh3)4 (52.5 mg) was added, and the orange mixture was heated at reflux for 2 h. After cooling to room temperature, the mixture was partitioned between ethyl acetate (20 mL) and H2O (30 mL). The layers were separated, and the aqueous phase was back-extracted with ethyl acetate (2×10 mL). Combined organic phases were washed with brine (20 mL), dried over Na2SO4, and concentrated. The product was purified by silica gel chromatography (20 g SiO2, 3:7 ethyl acetate:hexanes). Rf=0.16 in 1:9 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ 8.11-8.05 (m, 2H), 7.90-7.82 (m, 3H), 7.56-7.39 (m, 6H), 6.80-6.72 (m, 4H), 4.22-4.19 (m, 4H), 2.98 (t, 2H), 2.35 (s, 3H) 1.47 (s, 3H), 1.22 (t, 6H); MS (EI) 436.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:9])[C:7]=1[Cl:8].[Mg].[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C:20]1([CH:27]=[O:28])[CH2:24][CH2:25][CH3:26])=[O:18])([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C:20]1([CH:27]([C:4]1[CH:5]=[C:6]([F:9])[C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[OH:28])[CH2:24][CH2:25][CH3:26])=[O:18])([CH3:14])([CH3:15])[CH3:13]
Reactant: CCCC1(C=O)CCCN1C(=O)OC(C)(C)C
Reactant: Fc1cc(Br)cc(Cl)c1Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCC1(C(O)c2cc(F)c(Cl)c(Cl)c2)CCCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
A stirred mixture of 3,4-dichloro-5-fluorophenyl bromide (1.38 g, 5.66 mmol) and magnesium turnings (0.145 g, 5.94 mmol) in THF (8 mL) was heated at reflux under nitrogen for 30 minutes, then cooled to 0° C. To the reaction mixture was added a solution of 2-formyl-2-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.682 g, 2.38 mmol) in THF (2 mL) dropwise over 15 minutes. The cold reaction mixture was stirred for one hour, then quenched by the addition of saturated aqueous NH4Cl (20 mL) and extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to a yellow oil (1.7 g). Purification by chromatography (silica, 0 to 20% EtOAc in hexanes) gave 2-[(3,4-dichloro-5-fluoro-phenyl)-hydroxy-methyl]-2-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.571 g, 1.41 mmol, 50%) as a white solid.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([OH:17])(=[O:16])[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.O1COCO[CH2:19]1.C([O-])(O)=O.[Na+]>O.C(O)(=O)C>[C:11]([C:10]1[CH:14]=[C:15]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:17])[O:16][CH2:19]2)([OH:13])=[O:12]
Reactant: C1OCOCO1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc2c(c1)COC2=O
Temperature: 131.5 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To 892 g of fuming sulfuric acid, containing 25-27% of SO3, 100 g (0.6 m) of terephthalic acid are added at 20-23° C., under stirring, then 46 g (0.5 m) of 1,3,5-trioxane are added portionwise thereto at about 15° C. At the end of the addition, the mixture is heated 2 hours at 130-133° C. whereby a dark, clear solution is obtained. When the reaction is complete, as shown by a HPLC control, the mixture is cooled to 20-22° C. and 210 g of glacial acetic acid are slowly added thereto, without exceeding the temperature of 23-25° C. The mass is cooled to −5-0° C. and 1800 ml of cold deionized water are added thereto. During this operation the temperature rises to 43-45° C. At the end of the addition, the mixture is kept 1 hour under stirring at 23-25° C., then it is filtered, the solid is washed with deionized water abundantly and suspended, still wet, in 1200 ml of deionized water at room temperature. To the suspension thus obtained, about 1550 g of a 7% solution of NaHCO3 are added to a constant pH of 7,6-7,8. The mixture is filtered on Celite®, washing with deionized water. The pH of the filtrate is brought to about 1 by slow addition of about 120 ml of 35% hydrochloric acid at 22-25° C. The suspension is kept 1 hour under stirring at 22-25° C., then it is filtered and washed with deionized water abundantly. The product is dried in vacuo at about 50° C. to give 81 g of 5-carboxyphthalide with a titer (HPLC)>94% and purity (HPLC)>95%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C@H:10]2[O:19][C@H:13]3[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@H:12]3[C@H:11]2[CH2:20][CH2:21][N:22]2[C:27](=[O:28])[C:26]3[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=3[N:24]=[N:23]2)=[CH:4][CH:3]=1.O1CCCC1>[Pd].CO>[CH3:17][C:15]1([CH3:18])[O:14][C@@H:13]2[O:19][C@H:10]([CH2:9][CH2:8][C:5]3[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=3)[C@H:11]([CH2:20][CH2:21][N:22]3[C:27](=[O:28])[C:26]4[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=4[N:24]=[N:23]3)[C@@H:12]2[O:16]1
Reactant: CC1(C)O[C@@H]2O[C@H](/C=C/c3ccc(Br)cc3)[C@H](CCn3nnc4ccccc4c3=O)[C@@H]2O1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)O[C@@H]2O[C@H](CCc3ccccc3)[C@H](CCn3nnc4ccccc4c3=O)[C@@H]2O1
Reaction time: 4 h
Yield: 118.2 %

Procedure:
To the solution of the compound obtained from step j of Example 1 (0.3 g) in a solvent mixture of tetrahydrofuran:methanol (10 mL:10 mL) palladium/carbon (0.2 g, 10%) was added at room temperature, and the reaction mixture was hydrogenated at 35 psi for 4 hours in a Paar apparatus. The reaction mixture was filtered through a celite pad and the residue was washed with methanol. The filtrate was concentrated to afford the title compound (0.3 g).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=O)=[C:4]([OH:11])[CH:3]=1.Br[CH:13](C(OCC)=O)[C:14]([O:16]CC)=[O:15].C(=O)([O-])[O-].[K+].[K+].[OH-].[K+]>C(O)C.CC(CC)=O>[F:10][C:9]1[C:2]([F:1])=[CH:3][C:4]2[O:11][C:13]([C:14]([OH:16])=[O:15])=[CH:6][C:5]=2[CH:8]=1
Reactant: O=Cc1cc(F)c(F)cc1O
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCC(C)=O
Product: O=C(O)c1cc2cc(F)c(F)cc2o1
Yield: 60.8 %

Procedure:
A mixture of 6.5 g (41.1 mmol) of 4,5-difluoro-2-hydroxybenzaldehyde, 10.4 ml (61.7 mmol) of diethyl bromo-malonate, 11.3 g (82.2 mmol) of potassium carbonate and 50 ml of ethyl methyl ketone was boiled at reflux for 3 hours while stirring, filtered and concentrated in a vacuum. The brown oil obtained was dissolved in 65 ml of ethanol, treated with 6.5 g of potassium hydroxide pellets and heated at reflux for one hour while stirring. The mixture was concentrated in a vacuum and the residue was treated with 65 ml of water and 65 ml of 3N sulfuric acid and heated at reflux over 30 minutes. Subsequently, the mixture was filtered and the residue was washed with water and triturated in 50 ml of hexane over 30 minutes. The solid was filtered off and dried. There were obtained 4.95 g (60%) of 5,6-difluorobenzofuran-2-carboxylic acid as a light yellow solid with m.p. 270°.
Reaction SMILES: [P:1]([CH2:5][C:6]([OH:8])=[O:7])([OH:4])([OH:3])=[O:2].[CH3:9]O>>[P:1]([CH2:5][C:6]([O:8][CH3:9])=[O:7])([OH:4])([OH:3])=[O:2]
Reactant: CO
Reactant: O=C(O)CP(=O)(O)O
Product: COC(=O)CP(=O)(O)O

Procedure:
Phosphonoacetic acid, 5 g., was dissolved in 25 ml. methyl alcohol. Dry hydrogen chloride was bubbled through the solution for 30 minutes at O° C. The solution was refluxed for 4 hours. Evaporation of the solvent left an oil which was dried in vacuo over P2O5 and NaOH.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[F:39])[CH2:5][N:6]1[C:15](=[O:16])[C:14]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][C:20]=3[S:19](=[O:33])(=[O:32])[N:18]=2)=[C:13]([OH:34])[C@H:12]2[C@@H:7]1[C@H:8]1[CH2:35][C@@H:11]2[CH2:10][CH2:9]1.[C:40](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[F:39])[CH2:5][N:6]1[C:15](=[O:16])[C:14]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][C:25]([N:27]([CH3:40])[S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][C:20]=3[S:19](=[O:33])(=[O:32])[N:18]=2)=[C:13]([OH:34])[C@H:12]2[C@@H:7]1[C@H:8]1[CH2:35][C@@H:11]2[CH2:10][CH2:9]1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)c(F)c3)C1=O)N2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(c1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)c(F)c3)C1=O)N2)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
N-{3-[(1R,2S,7R,8S)-3-(3,4-Difluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (prepared as described in Example 16, 114 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (7 mL). Potassium carbonate (55 mg, 0.40 mmol) and iodomethane (0.014 mL, 0.22 mmol) were added sequentially. The reaction was stirred at 25° C. for 18 h. The reaction was quenched via the addition of 1.0M aqueous hydrochloric acid solution (20 mL). The mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with saturated aqueous brine solution (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a golden oil. Purification by flash column chromatography (Teledyne Isco RediSep column; 0 to 20% ethyl acetate in dichloromethane) afforded the desired product, N-{3-[(1R,2S,7R,8S)-3-(3,4-difluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-N-methyl-methanesulfonamide (94 mg, 0.06 mmol, 77%) as a white powder. 1H NMR (400 MHz, CDCl3) δ: 1.42-1.76 (6H, m), 2.51-2.54 (1H, m), 2.84-2.88 (2H, m), 3.07 (3H, s), 3.38 (3H, s), 3.47-3.49 (1H, m), 5.07-5.10 (2H, m), 6.96-7.16 (3H, m), 7.72-8.01 (3H, m). LC-MS (ESI) calcd for C26H26F2N4O6S2 592.63, found 593.4 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.C(Cl)Cl.[Cl:15][C:16]1[CH:17]=[C:18]([C:22]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)=[CH:23][C:24]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])[CH:19]=[CH:20][CH:21]=1>C(N(CC)CC)C>[Cl:38][C:34]1[CH:33]=[C:32]([C:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=2)=[CH:23][C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:7](=[O:8])[C:6]3[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:28][CH2:27]2)=[O:25])[CH:37]=[CH:36][CH:35]=1
Reactant: O=C(C=C(c1cccc(Cl)c1)c1cccc(Cl)c1)N1CCNCC1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCN(C(=O)C=C(c3cccc(Cl)c3)c3cccc(Cl)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
0.25 g of p-methoxybenzoyl chloride were added to 10 ml of a methylene chloride solution containing 0.529 g of 1-[3,3-bis(3-chlorophenyl)acryloyl]piperazine (prepared as described in Preparation 111) and 0.41 ml of triethylamine, whilst ice-cooling, and the mixture was stirred at room temperature for 1 hour. The mixture was then worked up and purified as described in Example 68 to give 0.682 g of the title compound as a powder.