Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]3([CH3:30])[CH2:29][CH2:28][C:23]4(OCC[O:24]4)[CH2:22][CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>O1CCCC1.O>[CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]3([CH3:30])[CH2:29][CH2:28][C:23](=[O:24])[CH2:22][CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:2][CH2:3]1
Reactant: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)CCC2(CC1)OCCO2
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.1 %

Procedure:
To a solution of tert-butyl 5-cyclopropyl-2-fluoro-4-((8-methyl-1,4- dioxaspiro[4.5]decan-8-yl)methoxy)benzoate (2.59 g, 6.16 mmol) in tetrahydrofuran (6 mL) and water (4.3 mL) was added trifluoroacetic acid (2.2 mL, 27.72 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. The reaction was quenched with 2 M aqueous sodium hydroxide solution (5 mL) before being diluted with saturated aqueous sodium bicarbonate (20 mL) and ethyl acetate (50 mL). The aqueous layer was separated and extracted with ethyl acetate (3×50 mL). The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography (0% to 15% ethyl acetate in hexanes) afforded the title compound (2.09 g, 90%) as a colorless oil: MS (ES+) m/z 321.2 (M−55).
Reaction SMILES: [NH:1]1[CH:5]=[C:4](CCCCN)[N:3]=[CH:2]1.[Cl:11][C:12]1[CH:13]=[C:14]2[NH:20][C:19](=O)[O:18][C:16](=O)[C:15]2=[CH:22][CH:23]=1>C(O)C>[Cl:11][C:12]1[CH:13]=[C:14]2[C:15]([C:16](=[O:18])[N:20]([CH2:14][CH2:13][CH2:12][CH2:23][N:3]3[CH:4]=[CH:5][N:1]=[CH:2]3)[CH:19]=[N:20]2)=[CH:22][CH:23]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2c(=O)o1
Reactant: NCCCCc1c[nH]cn1
Solvent: CCO
Product: O=c1c2ccc(Cl)cc2ncn1CCCCn1ccnc1
Reaction time: 20 h

Procedure:
A mixture of 1.39 g of imidazole-4-butanamine, 1.98 g of 4-chloroisatoic anhydride and 25 ml of ethanol was left at room temperature for 20 hours and concentrated. The residue and 5 ml of triethyl orthoformate were heated in an oil bath at 100°-125° C. for 3 hours and concentrated. The mixture was treated with ether to obtain the desired product, mp 123°-125° C.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([O:24][C:25](Cl)=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[CH:28]1([N:37]2[CH:44]=[CH:43][C:41]([NH2:42])=[N:40][C:38]2=[O:39])[O:34][C@H:33]([CH2:35][OH:36])[C@@H:31]([OH:32])[C@@H:29]1[OH:30].C(=O)([O-])O.[Na+]>CC(N(C)C)=O>[CH2:8]([O:24][C:25]([NH:42][C:41]1[CH:43]=[CH:44][N:37]([CH:28]2[O:34][C@H:33]([CH2:35][OH:36])[C@@H:31]([OH:32])[C@@H:29]2[OH:30])[C:38](=[O:39])[N:40]=1)=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: Nc1ccn(C2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Reactant: CCCCCCCCCCCCCCCCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCCCCCCCCOC(=O)Nc1ccn(C2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 30.5 %

Procedure:
A toluene solution containing 1.8 g of palmityloxycarbonyl chloride is added to 20 ml of a dimethylacetamide solution containing 1.5 g of arabinofuranosylcytosine and 1.7 g of sodium hydrogen carbonate. The reaction is carried out at room temperature with stirring of the mixture for 3 hours. After the reaction is completed, the reaction mixture is poured into an ice-water and the precipitated solids are collected by filtration, followed by washing successively with acetone and with hot chloroform. The resultant solids are dissolved in a mixture of chloroform-methanol and then subjected once to filtration, followed by removal of the solvent. The residue is subjected to crystallization from n-hexane to give 0.92 g of N4 -palmityloxycarbonylarabinofuranosylcytosine (Yield:30%).
Reaction SMILES: Br[C:2]1(Br)[CH2:10][CH2:9][C:8]2[NH:7][N:6]=[C:5]([CH3:11])[C:4]=2[C:3]1=O.BrC1CCC2NN=C(C)C=2C1=O.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33]([NH2:35])=[S:34]>CCO>[CH3:11][C:5]1[C:4]2[C:3]3[N:35]=[C:33]([NH:32][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=4)[S:34][C:2]=3[CH2:10][CH2:9][C:8]=2[NH:7][N:6]=1
Reactant: Cc1n[nH]c2c1C(=O)C(Br)(Br)CC2
Reactant: NC(=S)Nc1ccccn1
Agent: Cc1n[nH]c2c1C(=O)C(Br)CC2
Solvent: CCO
Product: Cc1n[nH]c2c1-c1nc(Nc3ccccn3)sc1CC2

Procedure:
According to Scheme 4 Step 5: A solution of a mixture of 5,5-dibromo-3-methyl-6,7-dihydro-1H-indazol-4(5H)one, 5-bromo-3-methyl-6,7-dihydro-1H-indazol-4(5H)-one (37.5:62.5, 173 mg) and of 1-(pyridin-2-yl)thiourea (0.67 mmol, 102 mg) in EtOH (2.4 mL) was stirred under reflux for 3 hours. The precipitate formed was filtered, was washed with a saturated solution of NaHCO3, water, EtOH and Et2O and was dried to yield 8-methyl-N-(pyridin-2-yl)-5,6-dihydro-4H-thiazolo[4,5-e]indazol-2-amine (46 μmol, 13 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH:11]2[CH2:13][CH2:12]2)=[CH:9][C:5]([C:6]([NH2:8])=O)=[C:4]([O:14][CH2:15][CH2:16][CH2:17][C:18](=[O:20])[CH3:19])[N:3]=1.O=P(Cl)(Cl)Cl.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(#N)C>[Cl:1][C:2]1[C:10]([CH:11]2[CH2:12][CH2:13]2)=[CH:9][C:5]([C:6]#[N:8])=[C:4]([O:14][CH2:15][CH2:16][CH2:17][C:18](=[O:20])[CH3:19])[N:3]=1
Reactant: CC(=O)CCCOc1nc(Cl)c(C2CC2)cc1C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)CCCOc1nc(Cl)c(C2CC2)cc1C#N
Reaction time: 2 h

Procedure:
To a solution of 6-chloro-5-cyclopropyl-2-(4-oxopentyloxy)nicotinamide (298 mg, 1 mmol) in acetonitrile (20 mL) was added POCl3 (460 mg, 3 mmol) and pyridine (474 mg, 6 mmol). After stirred at r.t for 2 hrs, the mixture was poured into aq. NaHCO3, extracted with EtOAc. The separated organics was dried and concentrated in vacuo to afford 6-chloro-5-cyclopropyl-2-(4-oxopentyloxy)nicotinonitrile. (300 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[CH:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:29])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:44]4[CH2:45][CH2:46][CH:41]([C:34]5[C:35]6[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=6)[NH:32][CH:33]=5)[CH2:42][CH2:43]4)=[O:23])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCC(c2c[nH]c3ccccc23)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-(1H-indol-3-yl)piperidine as in General Procedure 10 to give the title compound. LCMS: m/z=630.02 (M+H+); retention time=0.98 minutes.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([NH:16]C(OC(C)(C)C)=O)[CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C@H:4]1[CH2:5][CH2:6][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)=[N:16]1)=[O:24]
Reactant: COC(=O)[C@@H](CCC(=O)c1cccc(F)c1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H]1CCC(c2cccc(F)c2)=N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (2R)-2-tert-butoxycarbonylamino-5-(3-fluoro-phenyl)-5-oxo-pentanoic acid methyl ester (0.57 g, 1.7 mmol) in 1.7 mL of CH2Cl2 at 0° C. was added dropwise 3.8 mL (49 mmol, 29 eq) of TFA. The mixture was stirred at 0° C. for 2 hr. After concentration under vacuum, the residue was dissolved in CH2Cl2 (30 mL), washed with 10% NaHCO3, water, and brine, dried (Na2SO4) and concentrated under vacuum to give (2R)-5-(3-fluoro-phenyl)-3,4-dihydro-2H-pyrrole-2-carboxylic acid methyl ester as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 7.77–7.70 (2H, m), 7.50 (1H, q), 7.27 (1H, tq), 5.05 (1H, tt), 3.90 (3H, s), 3.30–3.00 (2H, m), 2.55–2.30 (2H, m).
Reaction SMILES: C([Li])CCC.N12CCN(CC1)CC2.[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=1.CN(C)[CH:24]=[O:25]>C(OCC)C.O>[Cl:14][C:15]1[C:16]([CH:24]=[O:25])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=1
Reactant: CN(C)C=O
Reactant: Clc1cncc(Cl)c1
Agent: C1CN2CCN1CC2
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: O=Cc1ncc(Cl)cc1Cl
Temperature: -70 °C
Reaction time: 0.75 h
Yield: 24.1 %

Procedure:
Add a solution of n-butyl lithium (37.5 mL, 0.06 mol, 1.6 M in hexanes) to a mixture of 1,4-diazabicyclo-[2.2.2]octane (6.16 g, 0.055 mol) in diethyl ether (250 mL) at −10 to −20° C. under a nitrogen atmosphere. Stir for 45 min. and then cool to −70° C. Add 3,5-dichloropyridine (7.40 g, 0.05 mol) in small portions and stir for 1.5 h at this temperature. Add N,N-dimethylformamide (7.75 mL, 0.10 mol) dropwise via syringe and stir for 2 h and allow to slowly warm to ˜−20° C. Add water (200 mL) is added and extract with ethyl acetate. Dry over sodium sulfate and concentrate in vacuo. Elute over silica gel with hexanes/ethyl acetate to give the desired aldehyde (2.12 g, 49%) as a light yellowish solid. MS(ES): (M+1)+ 174.8, 175.8 m/z.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:18]3[S:19][CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[N:22]=3)=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:41][CH2:42][C:43]([O:45]CC)=[O:44]>C(O)C.O1CCCC1.[OH-].[Na+].O.Cl>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:18]3[S:19][CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:25][CH:24]=4)[N:22]=3)=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:41][CH2:42][C:43]([OH:45])=[O:44]
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(CN(CCc3ccccc3)c3nc(-c4ccc(C(F)(F)F)cc4)cs3)cc2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1ccc(OCc2ccc(CN(CCc3ccccc3)c3nc(-c4ccc(C(F)(F)F)cc4)cs3)cc2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
The yellow oil obtained in Example 43 was dissolved in a mixed solvent of ethanol (5 mL) and tetrahydrofuran (5 mL), and 2N aqueous sodium hydroxide solution (2 mL) was added. The mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water and neutralized with 1N hydrochloric acid. The precipitated solid was collected by filtration, washed with water and dried to give the title compound (300 mg, yield 47%, 2 steps) as colorless crystals.
Reaction SMILES: [C@H:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:9]([CH3:21])[C:10](=[O:20])[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][N:15]=2)[N:13]=1.[H-].[Na+].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)C=O>[C:24]([N:5]1[CH2:6][C@@H:1]2[CH2:7][CH:4]1[CH2:3][N:2]2[C:8]1[N:9]([CH3:21])[C:10](=[O:20])[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][N:15]=2)[N:13]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cn1c(N2CC3C[C@H]2CN3)nc(-c2ccncn2)cc1=O
Reactant: O=C(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(N2CC3C[C@H]2CN3C(=O)c2ccccc2)nc(-c2ccncn2)cc1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 50.4 %

Procedure:
To a solution of 0.13 g (0.46 mmol) of (1S)-2-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one in 3 ml of anhydrous dimethylformamide was added 24 mg (0.6 mmol) of sodium hydride and the resulting mixture was stirred at 0° C. for 15 min. There is added 0.07 ml (0.6 mmol) of benzoyl chloride and the resulting solution was stirred at 0° C. for 2h. Water was added to the mixture and the resulting solution extracted with ethyl acetate. The combined extracts were washed with saturated aqueous ammonium chloride and evaporated. The crude product was purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol in the proportions 100/0 to 97/3 to give 90 mg (50%) of pure compound as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=O.C[O-].[Na+].Br[CH2:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19]>CN(C=O)C.C(O)C>[CH3:10][C:7]1[CH:8]=[CH:9][C:2]2[O:1][C:15]([C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]#[N:19])=[CH:4][C:3]=2[CH:6]=1
Reactant: Cc1ccc(O)c(C=O)c1
Reactant: N#Cc1ccccc1CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1ccc2oc(-c3ccccc3C#N)cc2c1
Temperature: 75 °C
Reaction time: 0.33 h
Yield: 68.9 %

Procedure:
A solution of the product of step (a) (130 g) in dry DMF (400 ml) was added dropwise to a solution of sodium methoxide (56.2 g) in ethanol (400 ml) mechanically stirred under nitrogen. After a further 20 mins, a solution of 2-(bromomethyl)benzonitrile (182.2 g) in dry DMF (400 ml) was added dropwise. The mixture was then heated to 75° C. for 30 min. The solution was allowed to cool for 1 h. A slurry of sodium methoxide (56.2 g) in dry DMF (100 ml) was added and the mixture heated at reflux for 1.5 h. The mixture was concentrated in vacuo and then poured into iced water. The solid was collected, and then triturated with methanol to give the title compound (Intermediate 7) as a beige solid (149.4 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O)[C:6]([O:8][CH3:9])=[O:7])#[N:2].Br[Zn][CH2:23][CH:24]([CH3:26])[CH3:25]>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:23][CH:24]([CH3:26])[CH3:25])[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c1
Reactant: CC(C)C[Zn]Br
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC(C)C)c(C#N)c1
Yield: 22.1 %

Procedure:
To methyl 3-cyano-4-{[(trifluoromethyl)sulfonyl]oxy}benzoate (D25) (1.5 g, 4.85 mmol) was added bromo(2-methylpropyl)zinc (48.5 ml, 24.25 mmol) in tetrahydrofuran (50 ml) under argon. To the solution was then added 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (0.355 g, 0.485 mmol) and the reaction heated to reflux for 6 h. The mixture was quenched with water (2 mL) and then filtered through celite, washing with ethyl acetate. The solvent was removed in vacuo. The residue was partitioned between ethyl acetate (50 mL) and water (50 mL) and the organic phase dried (phase separator) and the solvent removed in vacuo. The residue was purified by silica chromatography, eluting 0-15% EtOAc in iso-hexane over 40 min. Two batches were collected, one of which was the title compound as a colourless oil (233 mg, 1.072 mmol). δH (CDCl3, 400 MHz): 8.28 (1H, d), 8.15 (1H, dd), 7.38 (1H, d), 3.94, 3H, s), 2.78 (2H, d), 2.02 (1H, m), 0.96 (6H, d).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[CH2:13]([O:20][C:21]([N:2]([CH3:1])[CH2:3][CH2:4][OH:5])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CNCCO
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(CCO)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
75 g of 2-methylaminoethanol and 101 g of triethyl amine are mixed with 1000 ml of absolute chloroform. 171 g of chloroformic acid benzyl ester are added dropwise to this solution at about 20° C. The mixture is stirred for 1 hour at room temperature, washed with water, diluted hydrochloric acid and again with water and dried over sodium sulphate. After evaporation of the solvent in vacuo 173 g of oil remain.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[N:9]([CH3:25])[C:10]3[C:15]([C:16]=2[CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:14][CH:13]=[C:12]([C:22](O)=[O:23])[CH:11]=3)=[N:6][CH:7]=1.S(Cl)(Cl)=O.C(NCC)C.C(N(CC)C(C)C)(C)C.[NH2:44][C:45]1([C:49]2[N:53]([CH3:54])[C:52]3[CH:55]=[C:56](/[CH:59]=[CH:60]/[C:61]([O:63][CH2:64][CH2:65][CH2:66][CH3:67])=[O:62])[CH:57]=[CH:58][C:51]=3[N:50]=2)[CH2:48][CH2:47][CH2:46]1>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[N:9]([CH3:25])[C:10]3[C:15]([C:16]=2[CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:14][CH:13]=[C:12]([C:22]([NH:44][C:45]2([C:49]4[N:53]([CH3:54])[C:52]5[CH:55]=[C:56](/[CH:59]=[CH:60]/[C:61]([O:63][CH2:64][CH2:65][CH2:66][CH3:67])=[O:62])[CH:57]=[CH:58][C:51]=5[N:50]=4)[CH2:46][CH2:47][CH2:48]2)=[O:23])[CH:11]=3)=[N:6][CH:7]=1
Reactant: CCCCOC(=O)/C=C/c1ccc2nc(C3(N)CCC3)n(C)c2c1
Reactant: Cn1c(-c2ncc(Br)cn2)c(C2CCCC2)c2ccc(C(=O)O)cc21
Solvent: O=S(Cl)Cl
Solvent: CCNCC
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOC(=O)/C=C/c1ccc2nc(C3(NC(=O)c4ccc5c(C6CCCC6)c(-c6ncc(Br)cn6)n(C)c5c4)CCC3)n(C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
To the suspension of 2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxylic acid II (see Step 4) (33.36 g, 90.0 wt %, containing ˜0.2 equiv of NMP from previous step, 75.00 mmol) in THF (133.4 g) was added thionyl chloride (10.71 g). The mixture was stirred at 25±5° C. for at least 1 h. After the conversion was completed as determined by HPLC (as derivative of diethylamine), the mixture was cooled to 10±5° C. and N,N-diisopropylethylamine (378.77 g, 300 mmol) below 25° C. A solution of (E)-butyl 3-(2-(1-aminocyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylate VI (25.86 g, 97.8 Wt %, 77.25 mmol) dissolved in THF (106.7 g) was added at a rate to maintain the temperature of the content ≦25° C. The mixture was stirred at 25±5° C. for at least 30 min for completion of the amide formation. The mixture was distilled at normal pressure to remove ca. 197 mL (171.5 g) of volatiles (Note: the distillation can also be done under reduced pressure). The batch was adjusted to 40±5° C., and MeOH (118.6 g) was added. Water (15.0 g) was added and the mixture was stirred at 40±5° C. until crystallization occurred (typically in 30 min), and held for another 1 h. Water (90 g) was charged at 40±5° C. over 1 h, and the batch was cooled to 25±5° C. in 0.5 h, and held for at least 1 h. The solid was filtered, rinsed with a mixture of MeOH (39.5 g), water (100 g), and dried in vacuo (≦200 Torr) at 50±5° C. to give (E)-butyl 3-(2-(1-(2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxamido)cyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylate VII (51.82 g, 96.6% yield) with a HPLC purity of 98.0 A % (240 nm) and 99.0 Wt %.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:42])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:40])(=[O:39])[N:26]([CH:36]([CH3:38])[CH3:37])[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:41])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[F:41][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:42])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25](=[O:39])(=[O:40])[N:26]([CH:36]([CH3:38])[CH3:37])[CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)N(Cc3ccc(OC)cc3)C(C)C)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(CN(C(C)C)S(=O)(=O)c2ccc(-c3c(C)c(CC(=O)O)cc4ccc(F)cc34)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
Lithium hydroxide monohydrate (0.051 g, 1.23 mmol) was added to a solution of (6-fluoro-4-{4-[isopropyl-(4-methoxy-benzyl)-sulfamoyl]-phenyl}-3-methyl-naphthalen-2-yl)-acetic acid methyl ester (0.17 g, 0.30 mmol) in a 3:1 mixture of THF—H2O mixture (15 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove the THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane gave (6-fluoro-4-{4-[isopropyl-(4-methoxy-benzyl)-sulfamoyl]-phenyl}-3-methyl-naphthalen-2-yl)-acetic acid (0.138 g, 82%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.49 (br. s, 1 H), 7.98-8.04 (m, 3 H), 7.90-7.92 (m, 1 H), 7.47 (d, J=7.80 Hz, 1 H), 7.39 (td, J=8.60, 2.40 Hz, 1 H), 7.33 (d, J=8.00 Hz, 2 H), 6.91 (d, J=8.20 Hz, 2 H), 6.67 (dd, J=11.00, 2.60 Hz, 1 H), 4.41-4.44 (m, 2 H), 4.13 (spt, J=6.80 Hz, 1 H), 3.86 (s, 2H), 3.74 (s, 3H), 2.08 (s, 3H), 0.93 (d, J=6.85 Hz, 6 H). MS calcd. for C30H29FNO5S [(M−H)−] 534, obsd. 534.3.
Reaction SMILES: [H-].[Na+].C1COCC1.[C:8]([O:12][C:13](=[O:21])/[CH:14]=[CH:15]/[C:16]1[CH:20]=[CH:19][NH:18][CH:17]=1)([CH3:11])([CH3:10])[CH3:9].[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>O>[C:8]([O:12][C:13](=[O:21])/[CH:14]=[CH:15]/[C:16]1[CH:20]=[CH:19][N:18]([S:29]([C:26]2[CH:27]=[CH:28][C:23]([Br:22])=[CH:24][CH:25]=2)(=[O:31])=[O:30])[CH:17]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)/C=C/c1cc[nH]c1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)cc2)c1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.85 g NaH with 70.0 ml THF is cooled to −30° C. and 5.0 g (E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester are added. During the addition there is liberated a gas. The solution is stirred at ambient temperature for 0.5 h. Then 7.9 g 4-bromobenzenesulfonylchloride is added by -30° C. The suspension is stirred at ambient temperature for 3 h. The mixture is treated with water and then it is extracted with ethyl acetate. The title compound is isolated by flash chromatography. By this method 7.0 g of a colorless solid are obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:9]([OH:14])[C:10]([O:12][CH3:13])=[O:11])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].CS([C:37]1[N:42]=[C:41]([O:43][CH3:44])[CH:40]=[C:39]([CH3:45])[N:38]=1)(=O)=O>CN(C=O)C.O>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:9]([O:14][C:37]1[N:42]=[C:41]([O:43][CH3:44])[CH:40]=[C:39]([CH3:45])[N:38]=1)[C:10]([O:12][CH3:13])=[O:11])(=[O:3])[CH3:2]
Reactant: COC(=O)C(O)C(OCCOC(C)=O)(c1ccccc1)c1ccccc1
Reactant: COc1cc(C)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Oc1nc(C)cc(OC)n1)C(OCCOC(C)=O)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
4 g (11.1 mmol) of methyl 3-(2-acetoxyethoxy)-2-hydroxy-3,3-di-phenylpropionate were dissolved in 20 ml of DMF under N2, 770 mg (5.6 mmol) of K2CO3 and 2.24 g (11.1 mmol) of 2-methanesulfonyl-4-methoxy-6-methylpyrimidine were added, and the mixture was stirred at 80° C. for 2 h. It was subsequently diluted with 20 ml of H2O and extracted twice with 30 ml of diethyl ether, the organic phase was dried over MgSO4 and concentrated, and the residue was purified by chromatography on silica gel with ethyl acetate/cyclohexane mixtures. 4.8 g (90%) of a colorless oil were obtained.