Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:13][C@H:12]([OH:14])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:13][C@H:12]([O:14][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@H]1C[C@@H](COCc2ccccc2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@@H](COCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.1 %

Procedure:
To a solution of cis-3-(benzyloxymethyl)cyclobutanol (Albany Molecular, 1.0 g, 5.2 mmol) in CH2Cl2 (20 mL) was added imidazole (0.71 g, 10.4 mmol), DMAP (64 mg, 0.52 mmol) and tert-butyldimethylsilylchloride (TBSCl) (1.6 g, 10.4 mmol). This mixture was stirred at ambient temperature for 16 h, quenched with saturated, aqueous NH4Cl (5 mL) and diluted with EtOAc (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×5 mL). The combined organics were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified via column chromatography (SiO2, 50% hexanes/EtOAc) to give the title compound (1.15 g, 3.8 mmol, 72% yield). MS (DCI/NH3) m/z 307 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([CH3:21])=[CH:4][N:3]=1.[CH3:22][P:23]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([O:33][CH3:34])[CH:27]=1)([CH3:25])=[O:24].Cl>COCCO>[CH3:25][P:23]([C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([CH3:21])=[CH:4][N:3]=2)=[C:28]([O:33][CH3:34])[CH:27]=1)([CH3:22])=[O:24]
Reactant: COc1cc(P(C)(C)=O)ccc1N
Reactant: Cc1cnc(Cl)nc1Nc1ccccc1S(=O)(=O)C(C)C
Agent: Cl
Solvent: COCCO
Product: COc1cc(P(C)(C)=O)ccc1Nc1ncc(C)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 90 °C
Yield: 28.9 %

Procedure:
To a solution of 2-chloro-5-methyl-N-[2-(propan-2-ylsulfonyl)phenyl]-pyrimidin-4-amine (0.035 g, 0.11 mmol) in 1 mL of 2-methoxyethanol in a vial was added 4-(dimethylphosphoryl)-2-methyoxyaniline (0.020 g, 0.085 mmol) as the HCl salt. The vial was sealed and the reaction was heated at 90° C. for 16 h. The reaction was quenched with 1N NaOH solution and the solution extracted ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution, dried with sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (0-10% 7N ammonia in methanol:dichloromethane) to afford the desired compound (12 mg, 29% yield). MS/ES+: m/z=489.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9](OS(C)(=O)=O)[CH2:10][CH:11]=[CH2:12])=[CH:5][C:4]=1[F:18])#[N:2].[CH3:19][C:20]1[NH:21][CH:22]=[CH:23][N:24]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:21]2[CH:22]=[CH:23][N:24]=[C:20]2[CH3:19])[CH2:10][CH:11]=[CH2:12])=[CH:5][C:4]=1[F:18])#[N:2]
Reactant: Cc1ncc[nH]1
Reactant: C=CCC(OS(C)(=O)=O)c1ccc(C#N)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCC(c1ccc(C#N)c(F)c1)n1ccnc1C
Temperature: 100 °C

Procedure:
To a solution of the methanesulfonate from Step I (17.3 mmol) in 20 mL of DMF was added 2-methylimidazole (4.25 g, 51.8 mmol) and potassium carbonate (7.15 g, 51.8 mmol). The reaction was heated to 100° C. for 3 hours, then cooled to room temperature. The solution was poured into EtOAc, washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography (3-6% MeOH/CH2Cl2) provided the titled compound.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C[O-].[Na+]>CO>[C:1]([NH:5][S:6]([C:9]1[CH:17]=[C:16]2[C:12]([C:13]([C:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=3)=[CH:14][NH:15]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCCCC1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc2cc[nH]c2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)NS(=O)(=O)c1ccc2c(C3=CCCCC3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.7 %

Procedure:
To a solution of N-tert-butyl-1H-indole-6-sulfonamide (3.60 g, 14.2 mmol) and cyclohexanone (4.50 ml, 43.4 mmol) in methanol (72 ml) was added 28% sodium methoxide in methanol solution (17 ml), and the mixture was stirred for 12 hr with heating under reflux. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. 2N Hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=3:1-2:1) to give N-tert-butyl-3-(cyclohex-1-enyl)-1H-indole-6-sulfonamide (2.82 g, yield 59.7%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=O.[C:13]([CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:15][CH2:16][CH3:17])=[O:14]>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:18][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1ccc([N+](=O)[O-])c(O)c1

Procedure:
To a solution of 3-hydroxy-4-nitrobenzaldehyde (5 g) in toluene (50 ml) was added carbethoxymethylenetriphenylphosphorane (8.96 g), and the mixture was heated under reflux for 2 h. The mixture was then concentrated and the residue was purified by column chromatography eluting with cyclohexane:ethyl acetate (6:4) to give the title compound. (6.2 g) as a solid, m.p. 95°.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([O:15][CH3:16])[C:13]([C:17]#[N:18])=[C:12]([C:19]#[N:20])[CH:11]=2)=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[Br:1][C:11]1[C:12]([C:19]#[N:20])=[C:13]([C:17]#[N:18])[N:14]([O:15][CH3:16])[C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=1
Reactant: BrBr
Reactant: COn1c(-c2ccc(Cl)cc2)cc(C#N)c1C#N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COn1c(C#N)c(C#N)c(Br)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 62.5 %

Procedure:
Bromine (0.341 g, 0.00213 mol) is added to a stirred mixture of 5-(p-chlorophenyl)-1-methoxypyrrole-2,3-dicarbonitrile (0.5 g, 0.00193 mol) and sodium acetate (0.318 g, 0.00388 mol) in acetic acid. The reaction mixture is heated at 95°-100° C. overnight, cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined ethyl acetate extracts are washed sequentially with water, saturated sodium bicarbonate solution, aqueous sodium metabisulfite solution, water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield a solid that is crystallized from ethyl acetate/hexanes to give the title compound as a yellow solid (0.406 g, 62%), mp 166.5°-167° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:8]([CH2:9][OH:10])[CH:7]2[CH2:11][CH:4]1[CH2:5][CH2:6]2.N1C=CC=CC=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>O>[S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)([OH:1])(=[O:26])=[O:25].[S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)([OH:1])(=[O:26])=[O:25].[OH:1][CH2:2][C@@H:3]1[C@@H:8]([CH2:9][OH:10])[CH:7]2[CH2:11][CH:4]1[CH2:5][CH2:6]2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: OC[C@H]1C2CCC(C2)[C@@H]1CO
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)O)cc1
Reaction time: 3 h

Procedure:
In a 200 ml round bottom flask capped with a CaCl2 drying tube was placed 7.2 g (0.0461 moles) of (2S,3S)-2,3-bis(hydroxymethyl)bicyclo[2.2.1]heptane (m.p. 58° C.) together with 45 ml of pyridine and 18.4 g (0.096 moles) of p-toluenesulfonyl chloride. The mixture was cooled in an ice bath and stirred for 3 hours and then diluted with 10 ml of H2O. The precipitate which formed was filtered and washed to remove pyridine. The solid was recrystallized from ethanol to give 17.2 g (92%) of fine white needles, m.p. 100-101° C., αD =+32.2° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C:17]([CH:19]1[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH:20]1[OH:26])=[O:18])[CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:4].O.[Li+].[OH-]>O1CCOCC1>[OH:26][CH:20]1[CH2:21][CH:22]([CH3:25])[CH2:23][CH2:24][CH:19]1[C:17]([N:10]([CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[C:9]1[CH:8]=[C:7]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2])=[O:18]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1O)C1CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC1CCC(C(=O)N(c2cc(-c3ccccc3)sc2C(=O)O)C2CCOCC2)C(O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.9 %

Procedure:
3-[(2-Hydroxy-4-methyl-cyclohexanecarbonyl)-(tetrahydro-pyran-4-yl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (31 mg, 0.062 mmol) was dissolved in a 4:1 mixture of dioxane:H2O (0.6 ml) and then LiOH 1N (310 ul, 0.310 mmol) was added. After 4 hours of stirring at room temperature, solvents were removed and then partitioned between 5 ml of H2O acidified to pH 4 and 5 ml of EtOAc. The organic layer was separated and the aqueous phase was washed twice with ethyl acetate (2×5 mL). The combined ethyl acetate layer was dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC to obtain 14 mg (52%) of 3-[(2-Hydroxy-4-methyl-cyclohexanecarbonyl)-(tetrahydro-pyran-4-yl)-amino]-5-phenyl-thiophene-2-carboxylic acid (Compound 31).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:9]2)=[CH:4][C:3]=1[CH2:47][C:48]([OH:50])=O.Cl.[NH2:52][CH2:53][C:54]([C:56]1[CH:60]=[CH:59][S:58][CH:57]=1)=[O:55].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:38]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@@H:10]([CH2:11][O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:9]2)=[CH:4][C:3]=1[CH2:47][C:48]([NH:52][CH2:53][C:54](=[O:55])[C:56]1[CH:60]=[CH:59][S:58][CH:57]=1)=[O:50]
Reactant: NCC(=O)c1ccsc1
Reactant: O=C(O)Cc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Cc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl)NCC(=O)c1ccsc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 43.3 %

Procedure:
To a mixture of the carboxylic acid 55 (1.04 g, 1.5 mmol), 2-amino-1-(thiophen-3yl)ethanone hydrochloride (533 mg, 3.0 mmol), EDCI (575 mg, 3.0 mmol), and HOBt (507 mg, 3.75 mmol) in DMF (10 mL) was added NMM (0.83 mL, 7.5 mmol). The resulting mixture was stirred at room temperature for 15 h. The reaction mixture was poured into a HCl solution (1.0 M, 50 mL), and extracted with EtOAc. The organic phase was dried over anhydrous MgSO4, filtered and evaporated under vacuum. The residue was further purified by silica column chromatography to provide the titled amide compound (529 mg, 0.65 mmol, 43%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:4][CH:3]=1.[Cl:23][CH2:24][CH2:25][N:26]=[C:27]=[O:28]>C1COCC1>[Cl:23][CH2:24][CH2:25][NH:26][C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:6][CH:7]=1)=[O:28]
Reactant: CCn1c(-c2ccc(N)cc2)c(C#N)c2ccc(OC)cc21
Reactant: O=C=NCCCl
Solvent: C1CCOC1
Product: CCn1c(-c2ccc(NC(=O)NCCCl)cc2)c(C#N)c2ccc(OC)cc21
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (50 mg, 0.172 mmole) in THF (2 mL) was added 2-chloroethyl isocyanate (22 uL, 0.258 mmole) at room temperature. After stirring overnight at reflux, the reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate. The resulting semi-solid was triturated with hexane and the precipitate collected was collected by filtration and washed well with 50% ethyl acetate in hexane and dried in vacuo to afford (62 mg, 91%) of 1-(2-chloroethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-urea.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[S:7][CH2:6][CH2:5][NH:4][C@H:3]1[C:8]([O:10][CH3:11])=[O:9].CN1CCOCC1.[CH2:20]([O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH:21]=[C:22]=[CH2:23]>C(Cl)Cl>[CH2:20]([O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:4]2[CH2:5][CH2:6][S:7][C:2]([CH3:12])([CH3:1])[C@@H:3]2[C:8]([O:10][CH3:11])=[O:9])(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH:21]=[C:22]=[CH2:23]
Reactant: COC(=O)[C@@H]1NCCSC1(C)C
Reactant: C=C=CCOc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C=C=CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 52.2 %

Procedure:
To a solution of product from Example 23 (155 mg, 0.82 mmol) in methylene chloride (5 ml) was added N-methylmorpholine (0.180 ml, 1.64 mmol) followed by the product from Example 5 (200 mg, 0.82 mmol). The resulting mixture was stirred for 15 hours at room temperature. The solvent was removed in vacuo and the residue dissolved in ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated sodium bicarbonate, saturated sodium chloride and dried over anhydrous sodium sulfate. The crude residue was purified by flash chromatography to give 170 mg (52%) of the product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]2)[N:3]=1.C(N(CC)CC)C.[Cl:35][CH2:36][CH2:37][CH2:38][S:39](Cl)(=[O:41])=[O:40]>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH:27][S:39]([CH2:38][CH2:37][CH2:36][Cl:35])(=[O:41])=[O:40])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](N)CC2)nc1N
Reactant: O=S(=O)(Cl)CCCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](NS(=O)(=O)CCCCl)CC2)nc1N
Reaction time: 0.17 h

Procedure:
To a stirred solution of trans-[4-amino-2-(4-amino-cyclohexylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (565 mg, 1.5 mmol, Example 120) and triethylamine (167 mg, 0.25 mL, 1.69 mmol) in tetrahydrofuran (20 mL) at 0° C., 3-chloropropane sulfonyl chloride (0.20 mL, 1.65 mmol, Aldrich) was added. The mixture was stirred for 10 minutes and the reaction was quenched with water. The mixture was extracted with ethyl acetate and the extracts were combined and dried with sodium sulfate. The solvent was removed and the residue was chromatographed (4% methanol/dichloromethane) to give 600 mg of yellow solid. Yield, 77%. MS (ES) MH+=518.
Reaction SMILES: [O:1]1CCCC1.O1CCOCC1.CC(C)=[CH:14][CH:15]1[CH:17]([C:18]([O:20][CH2:21][C:22]2[C:27]([F:28])=[C:26]([F:29])[C:25]([CH2:30][O:31][CH3:32])=[C:24]([F:33])[C:23]=2[F:34])=[O:19])[C:16]1([CH3:36])[CH3:35].I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O>[CH:14]([CH:15]1[CH:17]([C:18]([O:20][CH2:21][C:22]2[C:23]([F:34])=[C:24]([F:33])[C:25]([CH2:30][O:31][CH3:32])=[C:26]([F:29])[C:27]=2[F:28])=[O:19])[C:16]1([CH3:36])[CH3:35])=[O:1]
Reactant: COCc1c(F)c(F)c(COC(=O)C2C(C=C(C)C)C2(C)C)c(F)c1F
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COCc1c(F)c(F)c(COC(=O)C2C(C=O)C2(C)C)c(F)c1F

Procedure:
To a mixture of 25 ml of tetrahydrofuran and 150 ml of 1,4-dioxane, 15.4 g of 4-methoxymethy-2,3,5,6-tetrafluorobenzyl 3-(2-methyl-1-propenyl)-2,2-dimethylcyclopropanecarboxylate (prepared by the method described above) were dissolved and 1.0 g of osmium tetraoxide was added thereto at room temperature. Further, 50 ml of water containing 24.0 g of sodium metaperiodate were added thereto and refluxed for 2 hours under heating. After that, the reaction mixture was poured into about 200 ml of water and extracted with 200 ml of ethyl acetate twice. The combined organic layer was washed with 1% aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogencarbonate solution and saturated brine, subsequently, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give 10.4 g of 4-methoxymethy-2,3,5,6-tetrafluorobenzyl 3-formyl-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [Br: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][CH:3]=1.Cl[CH2:15][CH2:16][NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)NCCCl
Reactant: Brc1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NCCN1CCN(c2ccc(Br)cc2)CC1
Temperature: 130 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
A mixture of 1-(4-bromophenyl)piperazine (0.018 mol) and ethyl (2-chloroethyl)-carbamate (0.036 mol) was stirred for 2 hours at 130° C. Triethylamine (3 ml) was added and the mixture was stirred for 15 minutes at 130° C. The reaction mixture was cooled to room temperature, CH2Cl2 was added and the resulting mixture was washed with water. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 95/5). The pure fractions were collected and the solvent was evaporated, yielding 4.3 g (67.2%) of ethyl [2-[4-(4-bromophenyl)-1-piperazinyl]-ethyl]carbamate (interm. 1).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([N:11]2[C:15]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)=[CH:14][C:13]([C:21]([F:24])([F:23])[F:22])=[N:12]2)[CH:6]=1)=[N+]=[N-].O.O.[Sn](Cl)Cl>CO>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:15]1[N:11]([C:7]2[CH:6]=[C:5]([CH2:4][NH2:1])[CH:10]=[CH:9][N:8]=2)[N:12]=[C:13]([C:21]([F:22])([F:23])[F:24])[CH:14]=1
Reactant: [N-]=[N+]=NCc1ccnc(-n2nc(C(F)(F)F)cc2-c2ccco2)c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: NCc1ccnc(-n2nc(C(F)(F)F)cc2-c2ccco2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
To a stirred solution of 39 (205 mg, 0.613 mmol) in MeOH (3.1 mL) at room temperature was added tin(II) chloride dihydrate (415 mg, 1.840 mmol) drop wise. The resulting solution was allowed to stir for 2 h at room temperature. The solvent was evaporated. The mixture was quenched with a saturated sodium carbonate solution and extracted with ethyl acetate, washed with brine, dried (MgSO4) filtered and concentrated. Compound 40 (175 mg, 93%) was isolated and used as is for the next step. LRMS (ESI): calc. 308.1; found 309.1 (MH)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:36]=[CH:35][C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][N:18]3[C:26]([O:27]C)=[N:25][C:24]4[C:19]3=[N:20][C:21]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[N:22][C:23]=4[NH2:29])[CH2:12][CH2:11]2)=[CH:7][CH:6]=1)[CH3:3].CO.Cl.N>O1CCOCC1>[NH2:29][C:23]1[N:22]=[C:21]([O:30][CH2:31][CH2:32][O:33][CH3:34])[N:20]=[C:19]2[C:24]=1[NH:25][C:26](=[O:27])[N:18]2[CH2:17][CH2:16][CH:13]1[CH2:14][CH2:15][N:10]([CH2:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:36][CH:35]=2)[CH2:11][CH2:12]1
Reactant: COCCOc1nc(N)c2nc(OC)n(CCC3CCN(Cc4ccc(CN(C)C)cc4)CC3)c2n1
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: CO
Product: COCCOc1nc(N)c2[nH]c(=O)n(CCC3CCN(Cc4ccc(CN(C)C)cc4)CC3)c2n1
Temperature: 0 °C
Yield: 33.3 %

Procedure:
To the compound (0.28 g, 0.57 mmol) obtained in Step (iii) were added methanol (3 ml) and a 4N hydrochloric acid in dioxane (3 ml), and the mixture was stirred at room temperature for one hour. The mixture was cooled to 0° C., and neutralized with 4% aqueous ammonia. The precipitated solid was collected by filtration, and washed with water to give the title compound (0.18 g, 0.19 mmol) as a white solid. Yield: 65%.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]([F:21])([F:20])[C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])(=O)=O.[I-:22].[Na+].O>CC(C)=O>[I:22][CH2:6][CH2:7][CH2:8][C:9]([F:21])([F:20])[C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13]
Reactant: [I-]
Reactant: CS(=O)(=O)OCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCI
Yield: 86.8 %

Procedure:
1-Methanesulfonyloxy-4,4,5,5,6,6,7,7,7-nonafluoro-heptane (6.7 g, 18.8 mmol) and sodium iodide (8.5 g, 56.4 mmol) were stirred in acetone (400 ml) for 12 hours under heating. After the reaction was completed, water was added to the reaction mixture, which was then extracted with ether. The organic layer was washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off to give 1-iodo-4,4,5,5,6,6,7,7,7-nonafluoroheptane (6.33 g, Yield 87%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].CCN=C=NCCCN(C)C.Cl.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38].Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:8]
Reactant: O=C(O)c1cc(Cl)c(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1F
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
To a stirred solution of 5-chloro-4-(4-chloro-3-(trifluoromethyl)phenoxy)-2-fluorobenzoic acid (Preparation 32, 219 mg, 0.58 mmol) in DCM (3 mL) were added EDCl (167 mg, 0.87 mmol) and DMAP (106 mg, 0.87 mmol) and the reaction stirred at room temperature for 30 minutes. Methanesulfonamide (83 mg, 0.87 mmol) was added and the stirring continued at room temperature for 16 hours. DCM (25 mL) and 2M aq. HCl (5 mL) were added and the two layers separated. The organic extract was washed with 2M aq. HCl (5 mL) and brine (10 mL), dried (MgSO4), filtered and the solvent removed in vacuo. The crude material was purified by silica gel column chromatography eluting with EtOAc:heptane:AcOH (50:50:0.5), followed by recrystallisation from hot IPA to yield the title compound (89 mg, 34%) as a white solid.