Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:28])[NH:11][CH:12]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:13]([OH:20])[CH2:14][NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1.C([O-])(O)=O.[Na+].[F:34][C:35]1[CH:36]=[C:37]([S:44](Cl)(=[O:46])=[O:45])[CH:38]=[CH:39][C:40]=1[N+:41]([O-:43])=[O:42].CC(O)C>ClCCl>[O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:28])[NH:11][CH:12]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:13]([OH:20])[CH2:14][N:15]([S:44]([C:37]2[CH:38]=[CH:39][C:40]([N+:41]([O-:43])=[O:42])=[C:35]([F:34])[CH:36]=2)(=[O:46])=[O:45])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1
Reactant: CC(C)CNCC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)S(=O)(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 20 °C

Procedure:
(1-Benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid hexahydro-furo[2,3-b]-furan-3-yl ester (6) (9.81 g, 25 mmol, 1 equiv) was dissolved in dichloromethane (100 mL), followed by the addition of saturated NaHCO3 solution (100 mL). A solution of 3-fluoro-4-nitro-benzenesulfonyl chloride (6.11 g, 25.50 mmol, 1.02 equiv) in dichloro-methane (100 mL) was added drop wise to the previous solution. The solution was vigorously stirred at 20° C. After stirring for 4 h, the organic layer was separated and washed with saturated NaHCO3 solution (100 mL), water (100 mL), 5% HCl solution (100 mL) and brine (100 mL). The organic layer was dried on MgSO4, filtered, and evaporated to dryness. The crude product was recrystallized from 2-propanol (550 mL) (9.58 g, 25 mmol, 64.30%). LRMS (ES+): m/z 596 [M+H]+; 1H-NMR (CDCl3) δ0.90 (d, 3H, CH3), 0.92 (d, 3H, CH3), 1.40-1.72 (m, 2H, CH2, H4), 1.80-1.92 (m, 1H, CH (isobutyl)), 2.79 (dd, 1H, CH2—N), 2.87-3.19 (m, 5H, CH2—N (isobutyl), CH, H3, CH2—N and CH of CH2C6H5), 3.19-3.29 (m, 1H, CH of CH2C6H5), 3.29-3.39 (brs, 1H, OH), 3.60-3.78 (m, 2H, CH2, H5 and H2), 3.78-3.90 (m, 3H, CH, H5, CH—OH and CH), 3.95 (dd, 1H, CH2, H2), 4.90 (d, 1H, NH), 4.98-5.10 (m, 1H, CH, H3), 5.66 (d, 1H, CH, H6a), 7.19-7.33 (m, 5H, C6H5), 7.68-7.74 (m, 2H, CH of C6H3FNO2), 8.15-8.20 (m, 1H, CH of C6H3FNO2).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[Si:33]([O:40][CH2:41][C@H:42]([NH2:50])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[I:49])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]>C1COCC1.C(N(CC)CC)C>[Si:33]([O:40][CH2:41][C@H:42]([NH:50][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[I:1])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[I:49])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](N)c1ccccc1I
Reactant: O=C(O)c1ccccc1I
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@H](NC(=O)c1ccccc1I)c1ccccc1I
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-iodobenzoic acid (0.66 g, 2.65 mmol) in THF (90 mL) is added HOBt (0.71 g, 5.3 mmol). After the mixture is stirred at RT for 15 min, EDCl (1.0 g, 5.3 mmol) is added followed by triethylamine (1.1 mL). The mixture is stirred at RT for 20 min then (R)-2-(tert-butyldimethylsilanyloxy)-1-(2-iodophenyl)-ethylamine (Org. Lett. 6, 513 (2004)) (1.0 g, 2.65 mmol) is added and stirring is continued for 18 h. The solvent is removed under reduced pressure and water is added to the residue. The mixture is extracted with EtOAc and the organic phase is washed with brine and dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue purified by flash chromatography using a gradient of 0-60% EtOAc/hexane as eluent to give the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:22][N:21]=[C:20]([CH3:23])[C:19]=3[NH2:24])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH3:2].[Cl:26][C:27]1[CH:28]=[C:29]([CH2:33][CH2:34][C:35](=O)[CH3:36])[CH:30]=[CH:31][CH:32]=1>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:22][N:21]=[C:20]([CH3:23])[C:19]=3[NH:24][CH:35]([CH3:36])[CH2:34][CH2:33][C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([Cl:26])[CH:28]=3)=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: CC(=O)CCc1cccc(Cl)c1
Reactant: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3N)cc2)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(C)CCc3cccc(Cl)c3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using [4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-acetic acid ethyl ester and 4-(3-chloro-phenyl)-butan-2-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:21][CH2:22][N:23]3[C@H:28]4[CH2:29][CH2:30][C@@H:24]3[CH2:25][CH:26]([N:31]3[C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=5[N:33]=[C:32]3[CH3:40])[CH2:27]4)[CH2:13][CH2:12][N:11]([C:14](=[O:20])[C@@H:15]3[CH2:19][CH2:18][CH2:17][NH:16]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:41][CH:42]([Cl:46])[C:43](Cl)=[O:44].CCN(C(C)C)C(C)C>>[Cl:41][CH:42]([Cl:46])[C:43]([N:16]1[CH2:17][CH2:18][CH2:19][C@H:15]1[C:14]([N:11]1[CH2:12][CH2:13][C:8]([CH2:21][CH2:22][N:23]2[C@H:28]3[CH2:29][CH2:30][C@@H:24]2[CH2:25][CH:26]([N:31]2[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N:33]=[C:32]2[CH3:40])[CH2:27]3)([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:9][CH2:10]1)=[O:20])=[O:44]
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)[C@@H]2CCCN2)CC1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)[C@@H]2CCCN2C(=O)C(Cl)Cl)CC1
Yield: 49.2 %

Procedure:
1-((1R,5S)-8-{2-[1-[1-(dichloroacetyl)-L-prolyl]-4-(3-fluorophenyl)-4-piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole was obtained from treating 1,1-dimethylethyl (2S)-2-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-1-pyrrolidinecarboxylate (0.645 g, 1.01 mmol) with HCl as outlined in the procedure for Example 890 to form 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)-1-L-prolyl-4-piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole (0.545 g, 99%). 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)-1-L-prolyl-4-piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole (0.050 g, 0.09 mmol), Dichloro-acetyl chloride (0.013 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 1-((1R,5S)-8-{2-[1-[1-(dichloroacetyl)-L-prolyl]-4-(3-fluorophenyl)-4-piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole (0.029 g, 49%) as an oil. ES-LCMS m/z 654 (M+1).
Reaction SMILES: [CH3:1][NH2:2].CO[C:5](=[O:44])[C:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][O:17][N:18]=[C:19]([CH3:43])[C:20](=[N:39][O:40][CH2:41][CH3:42])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][Si:29]([CH3:38])([CH3:37])[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:23][CH:22]=1)=[N:7][O:8][CH3:9]>C(O)C.CO>[CH3:1][NH:2][C:5](=[O:44])[C:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][O:17][N:18]=[C:19]([CH3:43])[C:20](=[N:39][O:40][CH2:41][CH3:42])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][Si:29]([CH3:38])([CH3:37])[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:23][CH:22]=1)=[N:7][O:8][CH3:9]
Reactant: CCON=C(C(C)=NOCc1ccccc1C(=NOC)C(=O)OC)c1ccc(OC[Si](C)(C)c2ccc(F)cc2)cc1
Reactant: CN
Solvent: CO
Solvent: CCO
Product: CCON=C(C(C)=NOCc1ccccc1C(=NOC)C(=O)NC)c1ccc(OC[Si](C)(C)c2ccc(F)cc2)cc1
Reaction time: 48 h

Procedure:
3 ml of a 8M solution of methylamine in ethanol are added to 2.9 g of 2-[[[(1-methyl-2-(4-[{dimethyl-(4-fluorophenyl)-silyl}methoxy]phenyl)-[ethoxyimino]ethylidene) amino]oxy]-methyl]-α-(methoxyimino)-phenylacetic acid methyl ester in 30 ml of methanol and stirring is carried out for 2 days at room temperature. The reaction mixture is concentrated to dryness by evaporation. Recrystallisation of the residue from hexane yields the title compound having a melting point of 88-90° C. (compound 5.23).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:21][CH3:22])[C:18]=2[Cl:20])[NH:13][CH:12]=1>C(O)=O>[CH:1]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:21][CH3:22])[C:18]=2[Cl:20])[NH:13][CH:12]=1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2[nH]cc(CCN)c2c1Cl
Solvent: O=CO
Product: COc1ccc2[nH]cc(CCNC=O)c2c1Cl
Reaction time: 0.17 h

Procedure:
To a mixture of formic acid (90%, 1.25 ml) and acetic anhydride (2.75 ml) was added 3-(2-aminoethyl)-4-chloro-5-methoxyindole (220 mg, 0.98 mmol), and the solution was stirred for 10 minutes. Removal of volatile components in vacuo at 30° C. left a residue which was partitioned between aqueous sodium bicarbonate and chloroform. The organic phase was separated, dried (Na2SO4) and evaporated to dryness. Purification by chromatography (SiO2 ; C6H14 /CHCl3) gave 3-(2-formylaminoethyl)-4-chloro-5-methoxyindole (176 mg) m.p. 120-121° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:34]=[CH:33][C:12]([CH2:13][C:14]23[C:22](=[O:23])[N:21]([C:24]4[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=4)[C:20](=[O:32])[N:19]2[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=1.S(Cl)([Cl:37])=O>C(Cl)Cl>[Cl:37][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:34]=[CH:33][C:12]([CH2:13][C:14]23[C:22](=[O:23])[N:21]([C:24]4[CH:25]=[C:26]([Cl:31])[CH:27]=[C:28]([Cl:30])[CH:29]=4)[C:20](=[O:32])[N:19]2[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(-c4ccccc4CO)cc3)CCCCN12
Solvent: ClCCl
Product: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(-c4ccccc4CCl)cc3)CCCCN12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-[4-[2-(hydroxymethyl)phenyl]benzyl]-8-(3,5-dichlorophenyl)-1,8-diazabicyclo[4.3.0]nonane-7,9-dione (0.318 g) in CH2Cl2 (5 mL) was added thionyl chloride (0.2 mL) and the mixture was stirred for 1 hour at room temperature. The mixture was concentrated and the residue was redissolved in CH2Cl2 (5 mL) and evaporated again. The residue was dried under vacuum to give 6-[4-[2-(chloromethyl)phenyl]benzyl]-8-(3,5-dichlorophenyl)-1,8-diazabicyclo[4.3.0]nonane-7,9-dione. (2) NaH (60% in oil, 0.090 mg) was added to a solution of N,N-dimethylethanolamine (0.58 mg) in DMF (5 mL) and the mixture was stirred for 30 minutes. To the reaction mixture was added a solution of the compound obtained above in DMF (2 mL) and the mixture was stirred overnight at room temperature. The mixture was cooled in ice-water and quenched with EtOAc/water. The organic layer was separated and washed with water and brine. It was dried, filtered, stripped and the residue was purified by chromatography (silica gel: CHCl3/MeOH: 50/1 to 30/1) to yield 84 mg of the titled compound. It was dissolved in MeOH and treated with 1N HCl/Et2O (2 mL). The mixture was evaporated and dried under vacuum to yield 88 mg of the hydrochloride of the titled compound. MS (m/z) 566 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][CH:8]=[N:7][C:6]=12.[OH:17]O>C(O)(=O)C>[N+:13]1([O-:17])[CH:14]=[CH:15][CH:16]=[CH:11][CH:12]=1.[Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][CH:8]=[N:7][C:6]=12
Reactant: OO
Agent: Brc1cnn2c(-c3cccnc3)ccnc12
Solvent: CC(=O)O
Product: [O-][n+]1ccccc1

Procedure:
A mixture of 0.90 g. of 3-bromo-7-(3-pyridyl)pyrazolo[1,5-a]pyrimidine, 25 ml. of glacial acetic acid and 5 ml. of 30% hydrogen peroxide is heated on a steam bath for 4 hours. The mixture is filtered and the solid recrystallized from ethanol to give 0.40 g. of the product of the example, m.p. 280°-284° C.
Reaction SMILES: [Na].[CH3:2][C:3]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[CH2:5][C:4]2=[N:12][OH:13].[CH2:14](Br)[C:15]#[CH:16]>CO>[CH2:16]([O:13][N:12]=[C:4]1[CH2:5][CH:6]2[C:9]([CH3:10])([CH3:11])[C:3]1([CH3:2])[CH2:8][CH2:7]2)[C:15]#[CH:14]
Reactant: C#CCBr
Reactant: CC12CCC(CC1=NO)C2(C)C
Agent: [Na]
Solvent: CO
Product: C#CCON=C1CC2CCC1(C)C2(C)C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
4.6 g (0.2 mole) of metallic sodium are dissolved in 200 ml of methanol, and 33.4 g (0.2 mole) of (±)-1,7,7-trimethyl-bicyclo[2,2,1]heptane-2-one-oxime are added to the solution. After one hour of boiling 23.8 g (0.2 mole) of propargyl bromide are introduced, and the reaction is continued for a further hour. The mixture is cooled, the separated sodium bromide is filtered off, the filtrate is concentrated, and the concentrate is subjected to fractional distillation in vacuo. 33.2 g (81%) of (±)-2-(propargyloxyimino)-1,7,7-trimethyl-bicyclo[2,2,1]heptane are obtained as a light yellow oil; b.p.: 94° C./1.5 mm Hg, nD20 =1.4955.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][C@H:13]([CH2:18]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-:30].[Li+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][C@H:13]([CH2:18][I:30])[CH2:12]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: [I-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2Cc3ccc(NC(=O)OC(C)(C)C)cc3C2)cc1
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)C[C@@H](CI)C2
Yield: 78.2 %

Procedure:
Toluene-4-sulfonic acid (S)-5-tert-butoxycarbonylamino-indan-2-ylmethyl ester (2.93 g, 7.02 mmol) was dissolved in DMF (60 mL) and heated and stirred at 70° C. with lithium iodide (4.7 g, 35.1 mmol) for 18 hours. Volatiles were removed under reduced pressure and the resulting residue was stirred with 100 mL of CH2Cl2 and solids removed by filtration. The filtrate was again evaporated, the residue was purified by flash column chromatography (10% of ethyl ether in hexanes) to yield a white solid as (S)-2-iodomethyl-indan-5-yl-carbamic acid tert-butyl ester (2.05 g, 78.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([CH3:31])([CH3:30])[CH2:10][C:11]([OH:29])([C:25]([F:28])([F:27])[F:26])[C:12]([NH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:20](=[O:21])[O:19][CH2:18]2)=[O:13].N1C=CC=CC=1.[S:38](Cl)([CH3:41])(=[O:40])=[O:39]>C(OCC)(=O)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:38]([CH3:41])(=[O:40])=[O:39])=[C:3]([C:9]([CH3:31])([CH3:30])[CH2:10][C:11]([OH:29])([C:25]([F:28])([F:27])[F:26])[C:12]([NH:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:20](=[O:21])[O:19][CH2:18]3)=[O:13])[CH:4]=1
Reactant: CC(C)(CC(O)(C(=O)Nc1ccc2c(c1)COC2=O)C(F)(F)F)c1cc(F)ccc1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(CC(O)(C(=O)Nc1ccc2c(c1)COC2=O)C(F)(F)F)c1cc(F)ccc1NS(C)(=O)=O

Procedure:
17.7 mg of 5-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalide, 0.4 ml of pyridine and 0.078 ml of mesyl chloride are stirred for 17 hours at room temperature, mixed with ethyl acetate, and washed three times with 1N hydrochloric acid. The ethyl acetate solution is dried and concentrated by evaporation. After chromatography on silica gel with ethyl acetate/hexane (1:1), 11 mg of 5-[4-(5-fluoro-2-mesylaminophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-phthalide is obtained, flash point 218° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[O:22]1[C:26]2([CH2:30][CH2:29][NH:28][CH2:27]2)[CH2:25][CH:24]([OH:31])[CH2:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:28]3[CH2:29][CH2:30][C:26]4([O:22][CH2:23][CH:24]([OH:31])[CH2:25]4)[CH2:27]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: OC1COC2(CCNC2)C1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CCC2(CC(O)CO2)C1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 1-oxa-7-azaspiro[4.4]nonan-3-ol hydrochloride in the presence of TBTU and DIEA to obtain the title compound as yellow oil; MS (EI): m/e=410.5 [MH+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.CCOCC.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[N:23][CH:24]=1.CCN(CC)CC>[Cl-].[Cl-].[Zn+2].ClCCCl.CC(O)(C)C>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)=[N:23][CH:24]=2)[N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cn2)CC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cn2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2,4-Dichloro-5-(trifluoromethyl)pyrimidine (411 mg, 1.89 mmol) was stirred in 1:1 t-BuOH:DCE (100 mL) at room temperature. A 1.0 M ZnCl2 solution in Et2O (2.16 mL, 2.16 mmol) was added cautiously and after addition the mixture was stirred at room temperature for 20 minutes. tert-Butyl 4-(5-aminopyridin-2-yl)piperidine-1-carboxylate I9 (500 mg, 1.80 mmol) was added followed by NEt3 (0.30 mL, 2.16 mmol) and the mixture was stirred at room temperature for 44 hours. The organic solvents were evaporated to dryness and the crude tan solid was suspended in water (250 mL) and sonicated for 10 minutes. The solid was isolated by filtration, washed with water (2×100 mL) and air-dried to give a cream solid. The solid was adsorbed onto silica and purified by silica gel column chromatography (40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A70 as an off white solid (346 mg, 42%). LCMS-A: rt 5.949 min; m/z 458 [M+H]+.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:21]1[S:25][N:24]=[CH:23][N:22]=1)[S:7]([C:10]1[CH:19]=[C:18]2[C:13]([C:14](=O)[NH:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C1CCN2C(=NCCC2)CC1.[NH:70]1[CH2:74][CH2:73][CH2:72][CH:71]1[C:75]1[CH:80]=[CH:79][N:78]=[CH:77][CH:76]=1.C(O)(C(F)(F)F)=O>C(#N)C.C(OCC)(=O)C>[N:78]1[CH:79]=[CH:80][C:75]([CH:71]2[CH2:72][CH2:73][CH2:74][N:70]2[C:14]2[C:13]3[C:18](=[CH:19][C:10]([S:7]([NH:6][C:21]4[S:25][N:24]=[CH:23][N:22]=4)(=[O:9])=[O:8])=[CH:11][CH:12]=3)[N:17]=[CH:16][N:15]=2)=[CH:76][CH:77]=1
Reactant: c1cc(C2CCCN2)ccn1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(=O)[nH]cnc3c2)c(OC)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ncns1)c1ccc2c(N3CCCC3c3ccncc3)ncnc2c1
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-(2,4-dimethoxybenzyl)-4-oxo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydroquinazoline-7-sulfonamide (0.611 g, 1.330 mmol) and BOP (0.765 g, 1.729 mmol) in acetonitrile (6.65 ml) was added DBU (0.301 ml, 1.995 mmol). The reaction was stirred for 10 minutes at 40° C. 4-(pyrrolidin-2-yl)pyridine (0.272 ml, 1.995 mmol) was added and the reaction was stirred for 8 hours at 40° C. 4-(pyrrolidin-2-yl)pyridine (0.272 ml, 1.995 mmol) was added and the reaction was stirred for four hours at 40° C. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 40 g, gradient elution 0-10% MeOH:DCM). The material was dissolved in DCM and TFA (0.2 ml, 2.60 mmol) was added. The reaction was stirred for one hour at room temperature. The reaction was concentrated and purified via column chromatography (RediSep Gold 12 g, gradient elution 0-10% MeOH:DCM) to afford 4-(2-(pyridin-4-yl)pyrrolidin-1-yl)-N-(1,2,4-thiadiazol-5-yl)quinazoline-7-sulfonamide as a light yellow solid. (ESI) 440.2 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:11]=[CH:10][C:8](O)=[CH:7][C:6]=1[OH:12])=O.[C:13]1([CH:20]=[CH:19][CH:18]=[C:16](O)[CH:15]=1)O>CS(O)(=O)=O>[Cl:1][CH2:2][CH:3]1[C:20]2[CH:19]=[CH:18][CH:16]=[CH:15][C:13]=2[O:12][C:6]2[C:5]1=[CH:11][CH:10]=[CH:8][CH:7]=2
Reactant: O=C(CCl)c1ccc(O)cc1O
Reactant: Oc1cccc(O)c1
Agent: CS(=O)(=O)O
Product: ClCC1c2ccccc2Oc2ccccc21
Temperature: 85 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
A mixture of 4.91 g (51.84 mmol) of chloroacetic acid, 4 mL (54.84 mmol) of thionyl chloride and one drop of DMF was stirred at 90° C. for 3 hours. The resulting solution was cooled and evaporated to remove excess thionyl chloride, hydrogen chloride and sulfur dioxide to yield crude chloroacetyl chloride as a colorless oil, pure enough to use in the next step without further purification. To a stirred suspension of 8.01 g (60.07 mmol) of anhydrous aluminum chloride in 10 mL of nitrobenzene were added 2 mL of chloroacetyl chloride and 2.37 g (21.52 mmol) of resorcinol at 0° C. The mixture was stirred at 0° C. for 10 minutes and at room temperature for 16 hours, poured into ice (ca. 20 mL), hydrolyzed by conc. HCl (10 mL), diluted with water (20 mL) and chloroform (50 mL) and separated. The organic layer was dried over MgSO4, evaporated and purified by column chromatography (75 g of SiO2, 20% ethyl acetate-hexane) to yield 2.57 g (13.77 mmol, 64.0% yield) of 4-(2-chloroacetyl)resorcinol. A mixture of 167.2 mg (0.896 mmol) of 4-(2-chloroacetyl)resorcinol and 109.0 mg (0.990 mmol) of resorcinol in methanesulfonic acid (0.5 mL) was stirred at 85° C. for 1 hour. To the resulting deep red solution, ice (ca. 10 mL) was added to precipitate a product as a black gummy material which eventually became reddish brown fine powder after scratching with a spatula. The precipitate was collected by filtration, washed with water and dried over P2O5 under vacuum to yield 196.6 mg (0.754 mmol, 84% yield) of 9-chloromethylxanthene as a reddish brown solid. 1H NMR (D2O+K2CO3) δ 7.66 (1H, d, J=9 Hz). 6.60 (1H, dd, J=9 & 2 Hz), 6.30 (1H, d, J=2 Hz), 4.82 (2H, s); MS (ES, positive) 261.4, 263.4; UV (KMOPS, pH 7.2) λmax (ε) 515 nm (41,200 M−1cm−1).
Reaction SMILES: [C:1]([CH:3]1[NH:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)#[N:2].[OH:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]=O.C(O)=O.C([BH3-])#N.[Na+]>ClCCl.O>[C:1]([CH:3]1[N:8]([CH2:21][CH2:20][O:19][CH2:18][CH2:17][OH:16])[CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCNC(C#N)C1
Reactant: O=CCOCCO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=CO
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CCOCCO)C(C#N)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 3-cyanopiperazine-1-carboxylate, prepared as described in the previous step, (10 g, 0.047 mol) and 2-(2-hydroxyethoxy)acetaldehyde (14.8 g) (see: Bodin, A., Contact Dermatitis, 2001, 44:207) in dichloromethane was treated with formic acid (12.7 g), and the reaction mixture was stirred at room temperature overnight. Sodium cyanoborohydride (7.2 g, 0.118 mol) was added in portions. The reaction mixture was stirred at room temperature for 3 hours followed by the addition of water and extraction with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to provide the product.