Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1.CN(C)C=O.[Cl:22]CCl.C(Cl)(=O)C(Cl)=O>>[O:1]=[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][Cl:22])=[O:11])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1
Reactant: ClCCl
Reactant: O=C(O)CCCn1c(=O)[nH]c2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(CCCn1c(=O)[nH]c2ccccc21)OCl

Procedure:
4-(2-Oxo-2,3-dihydrobenzimidazol-1-yl)butyric acid (50 g; 0.227 mol), N,N-dimethylformamide (1.84 g; 0.025 mol; 0.11 eq), and dichloromethane (480 g; 5,652 mol; 24.89 eq) were charged to a stirred-tank reactor. Oxalyl chloride (31.12 g; 0.245 mol; 1.08 eq) was then dosed at 10-20° C. over a 1-hour period while stirring. The resulting mixture was then stirred at 10-20° C. for an additional hour. All the above steps were conducted under a N2 atmosphere.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([I:19](OC(=O)C)OC(=O)C)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>C(OC(=O)C)(=O)C>[F:28][C:29]([F:34])([F:33])[C:30]([O-:32])=[O:31].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([I+:19][C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[CH:15][CH:14]=2)=[CH:11][CH:12]=1
Reactant: CC(=O)OI(OC(C)=O)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: O=C(O)C(F)(F)F
Reactant: c1ccsc1
Solvent: CC(=O)OC(C)=O
Product: Clc1ccc(-c2ccc([I+]c3cccs3)cc2)cc1
Product: O=C([O-])C(F)(F)F
Temperature: -10 °C
Reaction time: 18 h

Procedure:
A mixture of thiophene (8.7 g.) and acetic anhydride (60 ml.) is added to a stirred suspension of 4-(4-chlorophenyl)-(diacetoxyiodo)benzene (21.7 g.) in a mixture of acetic anhydride (50 ml.) and trifluoroacetic acid (15 ml.) below -10° C. during 1 hour. The mixture is stirred at -10° C. for 2 hours, at ambient temperature for 18 hours and is then filtered. The filtrate is concentrated to small volume in vacuo, and ether is added. The solid so formed is filtered off and crystallised from toluene to give 4-(4-chlorophenyl)-phenyl-2-thienyliodonium trifluoroacetate (13.7 g.), m.p. 175°-177° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=2)[CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[CH:12][C:11]([C:17](O)=[O:18])=[CH:10][C:9]2=1)(=[O:3])[NH2:2].C(Cl)CCl.[CH3:33][S:34]([NH2:37])(=[O:36])=[O:35]>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:28][C:22]1[CH:21]=[C:20]([C:6]2[CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:16]3[NH:15][C:14]4[C:9]([C:8]=3[CH:7]=2)=[CH:10][C:11]([C:17]([NH:37][S:34]([CH3:33])(=[O:36])=[O:35])=[O:18])=[CH:12][CH:13]=4)[CH:25]=[CH:24][C:23]=1[O:26][CH3:27]
Reactant: CS(N)(=O)=O
Reactant: COc1ccc(-c2cc(C(N)=O)c3[nH]c4ccc(C(=O)O)cc4c3c2)cc1F
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccc(-c2cc(C(N)=O)c3[nH]c4ccc(C(=O)NS(C)(=O)=O)cc4c3c2)cc1F
Yield: 54.9 %

Procedure:
To a solution of 8-carbamoyl-6-(3-fluoro-4-methoxyphenyl)-9H-carbazole-3-carboxylic acid (53 mg, 0.070 mmol, Example 187) in DMF (1 ml) was added DMAP (63 mg, 0.516 mmol), then EDC (128 mg, 0.668 mmol) and methanesulfonamide (92 mg, 0.967 mmol) and the mixture stirred at room temperature for 18 hours. The reaction mixture was filtered through a 0.45 um Nylon filter and purified by prep HPLC (water/CH3CN/NH4OAc eluent system). Product containing fractions were evaporated to give 17.5 mg 3-(3-fluoro-4-methoxyphenyl)-N6-(methylsulfonyl)-9H-carbazole-1,6-dicarboxamide as an off-white solid. HPLC retention time 11.10 min (HPLC conditions as in Table 9 and Table 10). MS (ESI) m/z [M−H]− 454; [M+H]+ 456. 1H NMR (CD3OD) δ ppm 8.88 (s, 1H), 8.53 (d, 1H, J=1.3), 8.16 (m, 2H), 7.63-7.55 (m, 3H), 7.22 (t, 1H, 8.5), 3.96 (s, 3H), 3.25 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1.[Cl:23]C1C=C(B(O)O)C=CC=1Cl>>[Cl:23][C:7]1[CH:6]=[C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:20])[F:21])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=[O:14])[CH:4]=[CH:3][C:2]=1[Cl:1]
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(Cl)c2)c1

Procedure:
In analogy to 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (WO 2008/040651) by substituting 4-chlorophenylboronic acid with 3,4-dichlorophenylboronic acid the title compound was obtained as white solid. MS (EI): 365.9 and 364.1 (M−H).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[F:13][C:14]1[N:19]=[CH:18][C:17]([C:20]23[CH2:27][CH2:26][CH2:25][N:24]2[CH2:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=1.[Cl:28]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:28][C:15]1[CH:16]=[C:17]([C:20]23[CH2:27][CH2:26][CH2:25][N:24]2[CH2:23][CH2:22][CH2:21]3)[CH:18]=[N:19][C:14]=1[F:13]
Reactant: Fc1ccc(C23CCCN2CCC3)cn1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Fc1ncc(C23CCCN2CCC3)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.4 %

Procedure:
n-BuLi (2.5M in hexanes, 0.232 mL, 0.58 mmol) was added to di-isopropylamine (0.077 mL, 0.58 mmol) in THF and stirred at room temperature for 15 minutes, then cooled to -78° C. 7a-(6-Fluoro-3-pyridinyl)-hexahydro-1H-pyrrolizine (115 mg, 0.56 mmol, from Example 12d) and hexachloroethane (400 mg, 1.7 mmol) were added. The mixture was slowly warmed to room temperature and stirred overnight. The reaction was quenched with 2N HCl, and the mixture was washed with Et2O. The aqueous layer was basified with 15% NaOH and extracted with methylene chloride. The organic extracts were combined, dried, (MgSO4) and concentrated. The residue was chromatographed (silica gel; CHCl3 /MeOH, 99:1) to afford the title compound as an oil (45 mg, 34%): 1H NMR (CDCl3, 300 MHz) δ1.60-1.72 (m, 2H), 1.80-2.06 (m, 6H), 2.64-2.72 (m, 2H), 3.14-3.27 (m, 2H), 8.00 (dd, J=8.8, 2.0 Hz, 1H), 8.15 (dd, J=2.0, 1.0 Hz, 1H); MS (CI/NH3) m/z: 241 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)=[O:4].[CH3:17][NH2:18]>S(Cl)(Cl)=O.CN(C)C=O.O>[CH3:17][NH:18][C:9]([C:8]1[CH:12]=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]=1[N+:14]([O-:16])=[O:15])=[O:10]
Reactant: CN
Reactant: COC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(C(=O)OC)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
A mixture of 4-methoxycarbonyl-2-nitrobenzoic acid (3.6 g, 0.016 mol) in thionyl chloride (32 mL) was heated to reflux in the presence of two drops of dimethylformamide for 3 h. Thionyl chloride was distilled and the concentrate was left under vacuum for 0.5 h. The residue was dissolved in dichloromethane (10 mL) and added to a solution of aqueous methylamine (40%, 2.0 g, 0.026 mol) in water (5 mL) over a period of 5 min. The mixture was further stirred for 10 min and the white precipitate was collected by filtration. The cake was washed with water, dried, and recrystallized from ethyl acetate-hexane to give 2.1 g (55%) of methyl 4-(methylamino)carbonyl-3-nitrobenzoate as white needles, mp 155° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:50]=[C:51]1[NH:55][C:54]2[CH:56]=[CH:57][C:58]([C:60]3[CH:61]=[C:62]([NH2:66])[CH:63]=[CH:64][CH:65]=3)=[CH:59][C:53]=2[NH:52]1>CN(C=O)C>[O:50]=[C:51]1[NH:55][C:54]2[CH:56]=[CH:57][C:58]([C:60]3[CH:61]=[C:62]([NH:66][C:23]([C:18]4[C:19](=[O:22])[O:20][C:21]5[C:16]([CH:17]=4)=[CH:15][CH:14]=[CH:13][C:12]=5[O:11][CH3:10])=[O:25])[CH:63]=[CH:64][CH:65]=3)=[CH:59][C:53]=2[NH:52]1
Reactant: Nc1cccc(-c2ccc3[nH]c(=O)[nH]c3c2)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc5[nH]c(=O)[nH]c5c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 37.2 %

Procedure:
DIEA (0.0085 mL, 0.049 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.009 g, 0.044 mmol) and HATU (0.019 g, 0.049 mmol) in 0.3 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-phenylamine (0.009 g, 0.044 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.007 g of product in 39% yield: LCMS (ESI) m/z 428 (MH+).
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])=[C:18]([CH3:23])[C:17]=1[CH3:24].ClC(Cl)(O[C:29](=[O:35])[O:30][C:31](Cl)(Cl)Cl)Cl.[Cl:37][C:38]1[CH:39]=[C:40](CO)[CH:41]=[CH:42][CH:43]=1.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:29](=[O:35])[O:30][CH2:31][C:42]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:37])[CH:43]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCc1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCc4cccc(Cl)c4)c(C)c3C)c2cc1OC
Yield: 96.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (3-chlorophenyl)methanol (67 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 (147 mg, yield 90%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][CH2:8][Si:9]([CH3:19])([CH3:18])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1>C1(C)C(C)=CC=CC=1>[ClH:7].[CH3:8][Si:9]([CH2:19][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:18])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1
Reactant: C[Si](C)(CCl)Cc1ccc(F)cc1
Reactant: C1CCNCC1
Solvent: Cc1ccccc1C
Product: C[Si](C)(Cc1ccc(F)cc1)CN1CCCCC1
Product: Cl

Procedure:
After adding 32.7 g of piperidine to a solution containing 32.5 g of chloromethyl-dimethyl-(4-fluorobenzyl)-silane in 40 ml of xylene, the reaction mixture is refluxed for 6 hours under stirring, then the precipitated piperidine hydrochloride is filtered at 20° C. and washed in 3 portions with a total of 60 ml of benzene. The filtrate is combined with the benzene washings and washed in 3 portions with a total of 150 ml of water and the organic phase is dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is evaporated to solvent-free to give the crude named compound as an oily liquid in the base form in a yield of 40 g. This crude product is purified by distillation under reduced pressure to give the title compound in a yield of 36.8 g (92%) with a boiling point of 97°-98° C./0.5 torr.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:3]([OH:7])[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[C:19]([O:23][C:24](ON=C(C1C=CC=CC=1)C#N)=[O:25])([CH3:22])([CH3:21])[CH3:20]>O.O1CCOCC1>[C:19]([O:23][C:24]([NH:1][C@@H:2]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:3]([OH:7])[C:4]([OH:6])=[O:5])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)C[C@H](N)C(O)C(=O)O
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(O)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.7 %

Procedure:
To a solution of 3.22 g of (2RS, 3S)-3-amino-2-hydroxy-5-methylhexanoic acid and 3.08 ml of triethylamine in 30 ml of water was added a solution of 5.41 g of 2-(tert-butyloxycarbonyloxyimino)-2-phenylacetonitrile in 30 ml of dioxane, and the mixture was stirred ofr 16 hours at room temperature. To the reaction mixture was added 100 ml of water, and the mixture was extracted with ethyl acetate to remove neutral material. The aqueous layer was acidified with an aqueous citric acid solution and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to obtain 5.10 g of (2RS, 3S)-3-tert-butyloxycarbonylamino-2-hydroxy-5-methylhexanoic acid as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[CH:7][CH:8]=2)[C:3]=1[NH:20]C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:20][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([O:12][Si:13]([C:16]([CH3:18])([CH3:17])[CH3:19])([CH3:14])[CH3:15])[CH:5]=2)[CH:10]=[CH:11][C:2]=1[Br:1]
Reactant: CC(C)(C)OC(=O)Nc1c(Br)ccc2ccc(O[Si](C)(C)C(C)(C)C)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](C)(C)Oc1ccc2ccc(Br)c(N)c2c1
Reaction time: 0.75 h

Procedure:
To a solution of 2-bromo-1-(tert-butoxycarbonylamino)-7-(tert-butyldimethylsilyloxy)naphthalene, as described above in Step G, (6.0 g, 13.26 mmol) in CH2Cl2 (100 mL) at 0° C. was added TFA (10 mL). After 45 min, the mixture was poured into saturated aqueous NaHCO3 and extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with a gradient of hexane—5% to 20% CH2Cl2, to yield the above-titled product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(N(C(C)C)CC)(C)C.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>ClCCl>[CH3:24][S:21]([O:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])(=[O:23])=[O:22]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Temperature: 23 °C
Reaction time: 18 h
Yield: 96.7 %

Procedure:
A solution of tert-butyl 2-hydroxyethylcarbamate (25 mL, 161.6 mmol) in dichloromethane (60 mL) was cooled to 0° C. and stirred while first diisopropylethylamine (33.8 mL, 193.9 mmol) was added and then mesyl chloride (13.7 mL, 177.8 mmol) then was added dropwise. The mixture was allowed to warm to 23° C., stirred for 18 hours, poured into dichloromethane (200 mL) and washed with aqueous hydrochloric acid (3M, 3×25 mL) and saturated aqueous sodium hydrogencarbonate (2×25 mL). The organic layer was separated, dried (MgSO4) and concentrated in vacuo to provide tert-butyl 2-methylsulfonyloxyethylcarbamate (37.39 g, 97% yield) as a brown oil; MS (PB-PCI) C8H17NO5S m/e calc 239.08; found 240 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]2[CH:12]=[N:11][N:10]=[N:9]2)=[CH:5][CH:4]=1.CN(C)CCN(C)C.C([Li])CCC.[C:28]1([CH3:36])[C:29]([CH:34]=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([CH:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH3:36])[OH:35])=[N:11][N:10]=[N:9]2)=[CH:13][CH:14]=1
Reactant: Cc1ccccc1C=O
Reactant: COc1ccc(Cn2cnnn2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(Cn2nnnc2C(O)c2ccccc2C)cc1
Temperature: -85 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
A stirred solution of 1-(4-methoxybenzyl)tetrazole (7.04 g, Tetrahedron Letters, 1995, p1759-1762) in a mixture of dry tetrahydrofuran (120 ml) and N,N,N',N',-tetramethylethylenediamine (12 ml) under a nitrogen atmosphere at -85° C. was treated dropwise with n-butyl lithium (18 ml, 2.5 M solution in hexanes) over 10 minutes. After stirring at -85° C. for an additional 5 minutes a solution of o-tolualdehyde (4.45 g) in dry tetrahydrofuran (20 ml) was added dropwise over 10 minutes. The reaction mixture was stirred at -85° C. for 30 minutes, allowed to warm to room temperature, then quenched with saturated ammonium chloride solution (50 ml). The organic phase was separated and the aqueous phase extracted three times with ethyl acetate (100 ml). The combined organic phases were dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography on silica eluting initially with a mixture of ethyl acetate and pentane (1:1, v/v) then with a mixture of ethyl acetate and pentane (66:34, v/v). Fractions homogenous in the required product were combined and evaporated affording the title compound (9.8 g) as a whlite solid, m.p. 90-92° C. [Elemental analysis:-C,65.91, H,5.9, N,18.1%. Calculated:-C,65.79, H,5.85, N,18.05%].
Reaction SMILES: [OH:1][CH:2]1[CH2:5][CH:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1.CCN(CC)CC.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:1][CH:2]1[CH2:5][CH:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1)(=[O:26])=[O:25]
Reactant: O=C(OCc1ccccc1)C1CC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CC(C(=O)OCc2ccccc2)C1
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a solution of benzyl 3-hydroxycyclobutanecarboxylate (Intermediate 32; 0.90 g; 4.4 mmol), Et3N (1.20 mL; 8.6 mmol) in DCM (50 mL) was added MsCl (0.40 mL; 5.2 mmol) under nitrogen. The reaction mixture was stirred for 1 hour, quenched with water (20 mL), and extracted with DCM (50 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to afford 1.24 g (100%) of the title compound as a yellow oil, which was used directly without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[C:4]([CH3:13])([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:5][CH2:6][CH:7]=1.[CH3:15][Mg]Cl>C1COCC1.C1(C)C=CC=CC=1>[CH3:15][C:3]1([OH:14])[C:4]([CH3:13])([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:5][CH2:6][CH:7]=[C:2]1[CH3:1]
Reactant: C[Mg]Cl
Reactant: CC(C)=CCC1(C)CCC=C(C)C1=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)=CCC1(C)CCC=C(C)C1(C)O
Temperature: 15 °C
Reaction time: 0.75 h
Yield: 78 %

Procedure:
2,6-Dimethyl-6-(3-methyl-but-2-enyl)-cyclohexenone (245 g, 1.28 mol) was added dropwise to a solution of methyl magnesium chloride (105 g, 1.41 mol) in THF (400 ml) and toluene (1.5 L) at room temperature. The temperature rose to 50° C. The mixture was stirred for additional 45 min, was then cooled to 15° C. and poured on ice. The organic phase was separated and washed with water (0.5 L) and brine (0.5 L), dried (MgSO4) and concentrated in vacuo. The residue was distilled over a 70 cm silverplated column (bp. 83-85° C./0.1 Torr) to yield 208 g (78%) product as a mixture of two diastereomers. 1H-NMR (400 MHz, CDCl3): 5.39 (bs, 1H, 3-H), 5.29-5.24 (m, 1H, 2′-H), 2.26-2.05 (m, 2H, 2′-H), 1.98-1.88 (m, 2H, 4-H), 1.75-1.71 (m, 6H, 2-CH3, 3′-CH3), 1.63 (s, 3H, 4′-H), 1.60 (bs, 1H, O—H), 1.50-1.46 (m, 2H, 5-H), 1.24/1.23 (2s, 3H, 1a,b-CH3), 0.96/0.90 (2s, 3H, 6a,b-CH3) ppm. GC/MS (EI), Isomer a: 208 (M+, 1), 190 (20), 175 (17), 147 (56), 121 (100), 105 (46), 98 (52), 83 (45), 43 (82). Isomer b: 208 (M+, 2), 190 (8), 175 (6), 147 (58), 121 (75), 105 (46), 98 (100), 83 (52), 43 (78). IR (ATR): 3476s, 2967vs, 2922vs, 1450s, 1376s, 1073vs, 921m, 902 m cm−1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[S:39](Cl)(=[O:41])=[O:40]>>[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[S:39]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:23])=[O:24])(=[O:41])=[O:40]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Product: O=S(=O)(Nc1cc(N2CCNCC2)ccc1NS(=O)(=O)c1ccc(F)cc1F)c1ccccc1

Procedure:
2,4-Difluoro-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl] benzenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and 2,4-difluorobenzenesulfonylchloride (94 mg, 0.455 mmol) according to general method 3 to give before Boc-deprotection 160 mg of a purple solid. MS (posES-FIA) m/z=Found: 509.1; Calcd 509.11; 1H-NMR δ 77.71–7.46 (m, 6H), 7.25–7.17 (m, 1H), 7.03–6.96 (m, 2H), 6.72 (dd, 1H), 6.44 (d, 1H), 3.20–3.16 (m, 8H).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:24])[CH:3]=1.[C:25]([N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33])(=[O:27])[CH3:26]>>[C:25]([N:28]1[CH2:32][CH2:31][N:30]([C:2]2[CH:3]=[C:4]([CH3:24])[C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:6][N:7]=2)[C:29]1=[O:33])(=[O:27])[CH3:26]
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3cnc(Br)cc3C)CC2)c(C)c1
Product: CC(=O)N1CCN(c2cc(C)c(C(=O)N3CCN(c4ncc(C)cc4C)CC3)cn2)C1=O
Yield: 53.4 %

Procedure:
Using (6-bromo-4-methylpyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (389 mg) described in Preparation Example 228 and 1-acetylimidazolidin-2-one (128 mg) and by the reaction and treatment in the same manner as in Example 511, the title compound (233 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:12][N:13]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:9][CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].O.NN>CCO.C(Cl)Cl>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:12][NH2:13])[CH2:9][CH2:10][CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC[C@@H](CN1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Agent: NN
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CCC[C@@H](CN)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of [(S)-1-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-butyl]-carbamic acid tert-butyl ester (2.80 g, 8.42 mmol) and hydrazine monohydrate (3.0 mL, 60.0 mmol) in EtOH (50 mL) and DCM (75 mL) is stirred at RT for 48 h. The precipitated solid is collected by filtration and washed with DCM to afford the crude product as a white solid that is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl.[C:31](OCC)(=[O:33])C>O1CCCC1.C(OCC)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:10](=[O:19])[CH2:11][CH2:12][CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:31]1[OH:33]
Reactant: CCOC(=O)CCCC(=O)Nc1c(Cl)cccc1Cl
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC=O
Product: CCOC(=O)C1CCC(=O)N(c2c(Cl)cccc2Cl)C1O
Reaction time: 2 h

Procedure:
Under an atmosphere of nitrogen, to a solution of ethyl 5-[(2,6-dichlorophenyl)amino]-5-oxopentanoate (9.22 g, the compound described in Reference Example 1 of WO03/043988) in tetrahydrofuran (150 mL) were added a solution of lithium bis(trimethylsilyl)amide (1.6 mol/L) in tetrahydrofuran (56.8 mL) and ethyl formate (4.90 mL) at −78° C. and the mixture was stirred on ice bath for 2 hours and then at room temperature for 4 days. The reaction mixture was added by hydrochloric acid (1 mol/L) and ethyl acetate on ice bath, then the water layer was extracted with ethyl acetate. The obtained extract was dried with anhydrous sodium sulfate, filtrated and concentrated to give the title compound. The obtained compound was used in the following reaction without further purification.