Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH:12]2[C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[C:4]([F:23])[CH:3]=1.[OH-].[Na+:25]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH:12]2[C:17]([C:18]([O-:20])=[O:19])=[CH:16][CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[C:4]([F:23])[CH:3]=1.[Na+:25]
Reactant: CCOC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(Cl)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: O=C([O-])C1=CCCCC1S(=O)(=O)Nc1ccc(Cl)cc1F
Temperature: 55 °C
Reaction time: 12 h

Procedure:
A solution of ethyl 6-[N-(4-chloro-2-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate obtained in Example 1 (Compound 1, 210 mg) in acetonitrile (29 ml) was admixed with a 1N aqueous solution of sodium hydroxide (29 ml) and the mixture was stirred at 55° C. for 12 hours. The mixture was concentrated under reduced pressure and the residue was purified by CHP-20P column chromatography (eluent: water→methanol/water=1/1). The effluent was concentrated under reduced pressure and the residue was dissolved in water (5 ml) and lyophilized to yield sodium 6-[N-(4-chloro-2-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate (43 mg) as a white powder.
Reaction SMILES: C(OC(=O)[N:7]([N:11]1[C:20]([CH2:21][Br:22])=[C:19]([C:23](=[O:37])[NH:24][C@@H:25]([CH:33]2[CH2:36][CH2:35][CH2:34]2)[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[C:18]2[C:13](=[C:14]([F:38])[CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:39])[CH2:8][CH2:9][CH3:10])(C)(C)C>ClCCCl.FC(F)(F)C(O)=O>[CH:33]1([C@H:25]([NH:24][C:23]([C:19]2[C:18]3[C:13](=[C:14]([F:38])[CH:15]=[CH:16][CH:17]=3)[C:12](=[O:39])[N:11]([NH:7][CH2:8][CH2:9][CH3:10])[C:20]=2[CH2:21][Br:22])=[O:37])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[CH2:36][CH2:35][CH2:34]1
Reactant: CCCN(C(=O)OC(C)(C)C)n1c(CBr)c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c2cccc(F)c2c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCCNn1c(CBr)c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c2cccc(F)c2c1=O

Procedure:
0.15 mg (3-Bromomethyl-4-{[(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-8-fluoro-1-oxo-1H-isoquinolin-2-yl)-propyl-carbamic acid tert-butyl ester was stirred at room temperature over night in 2 mL 1,2-dichloroethane and 2 mL trifluoroacetic acid. The reaction mixture was concentrated in vacuo to give the title compound.
Reaction SMILES: [F:1][C:2]([F:14])([C:10]([F:13])([F:12])[F:11])/[CH:3]=[CH:4]/[C:5]([O:7]CC)=[O:6]>[OH-].[Na+]>[F:1][C:2]([F:14])([C:10]([F:11])([F:12])[F:13])/[CH:3]=[CH:4]/[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)/C=C/C(F)(F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)/C=C/C(F)(F)C(F)(F)F
Temperature: 25 °C

Procedure:
Ethyl (E)-4,4,5,5,5-pentafluoropent-2-enoate (5.5 g, 25.2 mmol) was suspended in 10% NaOH (14.5 ml) and heated at reflux until a homogenous solution was obtained (40 min). After cooling to room temperature the mixture was washed with diethylether (2×) and acidified under ice-cooling with concentrated sulfuric acid. The mixture was extracted with diethylether (3×), the combined organic phases were washed with water, dried over magnesium sulfate and the solvent removed under reduced pressure. 2.64 g (13.9 mmol, 55%) were obtained. MS (ES) M/z=189.0 [M−H]−.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:24]([F:27])([F:26])[F:25])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=3)[N:10]=2)[CH:7]=1.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C)C.O>[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:24]([F:26])([F:27])[F:25])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:20])[CH3:21])[CH:16]=3)[N:10]=2)[CH:7]=1
Reactant: CC(C)(C)C(=O)Nc1cc(-c2cn3cc(Br)ccc3n2)ccc1C(F)(F)F
Reactant: OB(O)c1ccccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)C(=O)Nc1cc(-c2cn3cc(-c4ccccc4F)ccc3n2)ccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 16 h
Yield: 27.9 %

Procedure:
An 8 mL vial is charged with N-[5-(6-bromoimidazo[1,2-a]pyridin-2-yl)-2-(trifluoromethyl)phenyl]-2,2-dimethyl-propanamide (0.044 g, 0.11 mol), (2-fluorophenyl)boronic acid (Combi-Blocks, 28 mg, 0.2 mmol), Na2CO3 (0.032 g, 0.3 mmol), bis(triphenylphosphine)palladium(II) dichloride (7 mg, 0.01 mmol) and isopropanol-water (1 mL, 3:1). The reaction mixture is stirred at 80° C. for 16 hr, then cooled, concentrated, taken into EtOAc and CH2Cl2 (1:1), filtered, concentrated onto celite and purified by silica gel chromatography (0-100% EtOAc in Hexanes) to give the title compound (25.4 mg, 55% yield). LCMS m/z=456.5 [M+H]+, tR=2.69 min. (compound same as Example 83)
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]([CH3:25])[CH:16]([CH:26]=O)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(O)=O.[C:36]([O:40][C:41](=[O:55])[NH:42][S:43]([CH2:46][CH2:47][CH2:48][N:49]([CH3:54])[CH2:50][CH2:51][NH:52][CH3:53])(=[O:45])=[O:44])([CH3:39])([CH3:38])[CH3:37].[BH3-]C#N.[Na+]>CO>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:18]=[CH:24][CH:23]=[CH:22][C:21]=2[N:17]([CH3:25])[CH:16]([CH2:26][N:52]([CH3:53])[CH2:51][CH2:50][N:49]([CH3:54])[CH2:48][CH2:47][CH2:46][S:43](=[O:44])(=[O:45])[NH:42][C:41](=[O:55])[O:40][C:36]([CH3:39])([CH3:37])[CH3:38])[CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C=O)N(C)c1ccccc1-3
Reactant: CNCCN(C)CCCS(=O)(=O)NC(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CN(C)CCN(C)CCCS(=O)(=O)NC(=O)OC(C)(C)C)N(C)c1ccccc1-3
Reaction time: 0.08 h

Procedure:
Methyl 13-cyclohexyl-6-formyl-5-methyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-10-carboxylate was dissolved in MeOH (0.08 M) and HOAc was added. Tert-butyl[(3-{methyl[2(methylamino)ethyl]amino}propyl)sulfonyl]carbamate (1.5 eq. prepared as described in Example 15, Steps 1-3) was added and the mixture was stirred for 5 min. NaCNBH3 (1.5 eq.) was added and the mixture was stirred for 6 h. All volatiles were evaporated and the residual material was dissolved in EtOAc. The solution was extracted with sat. aq. NH4Cl, sat. aq. NaHCO3 and brine. After drying over Na2SO4 all volatiles were evaporated in vacuo. A yellow amorphous solid was obtained which was used without further purification in the next reaction (60%). (ES+) m/z 711 (M+H)+.
Reaction SMILES: BrCCBr.C=C.C[Si](Cl)(C)C.Br[C:13]1[S:14][CH:15]=[CH:16][N:17]=1.[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[CH:25]=[C:26](I)[CH:27]=1)=[O:21]>C1COCC1.[Zn].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)[CH:25]=[C:26]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[CH:27]=1)=[O:21]
Reactant: Brc1nccs1
Reactant: COC(=O)c1cc(I)cc(-c2ccc(C)cc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=C
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COC(=O)c1cc(-c2ccc(C)cc2)cc(-c2nccs2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 9.6 %

Procedure:
To a stirred suspension of zinc dust (3.06 g, 46.86 mmol) in THF (15 ml) was added 1,2-dibromoethane (0.327 ml, 3.83 mmol). The reaction mixture was heated until the evolution of ethylene was completed. Trimethylsilyl chloride (0.013 ml), THF (5 ml) and 2-bromothiazole (1.39 ml, 15.62 mmol) were added, and the reaction mixture was stirred for 20 minutes at room temperature. 5-Iodo-4′-methyl-biphenyl-3-carboxylic acid methyl ester (5.0 g, 14.2 mmol) and Pd(PPh3)4 (492.3 mg, 0.462 mmol) were added, and the mixture was refluxed for 14 hours. The reaction mixture was cooled in an ice bath and extracted with EtOAc, washed with saturated aqueous NH4Cl, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with hexanes-ethyl acetate (1:6), giving 4′-methyl-5-thiazol-2-yl-biphenyl-3-carboxylic acid methyl ester as a light yellow solid (0.42 g, 80%). MS (M+H)=310.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][SiH:10]([Cl:12])[Cl:11].C1(NS(=O)(=O)[O-])CCCCC1.[Na+]>[Pt].C1(C)C=CC=CC=1>[CH2:1]([CH2:9][SiH:10]([Cl:12])[Cl:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: C[SiH](Cl)Cl
Agent: [Pt]
Agent: O=S(=O)([O-])NC1CCCCC1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cl[SiH](Cl)CCCc1ccccc1
Yield: 70 %

Procedure:
Reaction between styrene and methyldichlorosilane with platinum catalyst in the presence of sodium cyclohexylsulfamate. 427 mg Styrene and 498 mg methyldichlorosilane were introduced into a glass tube, and 38 mg of sodium cyclohexylsulfamate were added. 1 mg Of a toluene solution of a 0-valent platinum complex of divinylsiloxane (0.4 wt % platinum content) was added. The tube was sealed and placed in a 50° C. oil bath where it was heated for 72 hours. After cooling, the tube contents were analyzed by gas chromatography revealing a styrene conversion of 85% and a phenethylmethyldichlorosilane yield of 70%. The ratio between the phenethylmethyldichlorosilane and the (α-methylbenzyl)methyldichlorosilane was 8.7:1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.CN(C)C(=O)C.S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][Cl:19])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCCc1ccc(Cl)cc1
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: ClCCc1ccc(Cl)cc1
Temperature: 67.5 °C
Reaction time: 2 h

Procedure:
Into a 250-mL round-bottom flask equipped with magnetic stirring, a thermocouple, a condenser, and a nitrogen bubbler vented to caustic scrubber, was charged 2-(4-chlorophenyl)ethanol (25.119 g, 160 mmol), toluene (73 mL) and N,N-dimethylacetamide (0.751 ml, 8.02 mmol). The mixture was heated in oil bath to between 65 and 70° C. and thionyl chloride (12.29 ml, 168 mmol) was charged over 1 h with a maximum reaction temperature of 69° C. The reaction was then stirred for 2 h at 65 to 70° C. The resulting dark-brown solution was cooled to 40° C. and washed with water (2×40 mL) by stirring for 2-5 min at 45° C. (bath) and separating the phases at room temperature. The organic phase was further washed with saturated aqueous sodium bicarbonate solution (3×40 mL) by stirring for 2-5 min at 50° C. (bath) and separating the phases at room temperature.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[C:10]([C:12]3[CH:16]=[CH:15][O:14][CH:13]=3)[N:9]=[CH:8][C:7]=2[OH:17])=[CH:2]1.[C:18]([C:20]1[CH:21]=[C:22]([S:27]([NH:30][C:31]2[S:32][CH:33]=[CH:34][N:35]=2)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1F)#[N:19].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:18]([C:20]1[CH:21]=[C:22]([S:27]([NH:30][C:31]2[S:32][CH:33]=[CH:34][N:35]=2)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[O:17][C:7]1[CH:8]=[N:9][C:10]([C:12]2[CH:16]=[CH:15][O:14][CH:13]=2)=[CH:11][C:6]=1[C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)#[N:19]
Reactant: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1F
Reactant: Oc1cnc(-c2ccoc2)cc1-c1ccoc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1Oc1cnc(-c2ccoc2)cc1-c1ccoc1
Reaction time: 2 h
Yield: 23.4 %

Procedure:
20.0 mg of 4,6-di(furan-3-yl)pyridin-3-ol and 24.9 mg of 3-cyano-4-fluoro-N-(thiazol-2-yl)benzenesulfonamide were dissolved in DMF, and 86.0 mg (3.0 eq) of Cs2CO3(86.0 mg, 3.0 eq) was added thereto. After reacting at room temperature for 2 hours, the resulting mixture was reacted at 60° C. for 16 hours. The solvent was removed by concentrating under reduced pressure. AS work-up with EA/H2O, the ethyl acetate layer was treated with magnesium sulfate, and concentrated under reduced pressure. The residue was separated by PLC (developing solvent, EA:n-Hex=1:4) to obtain 10.1 mg (24% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[OH-:13].[Na+]>C(OC(=O)C)(=O)C>[OH:13][CH:6]1[C:5]2[N:4]=[CH:3][C:2]([CH3:1])=[CH:11][C:10]=2[CH2:9][CH2:8][CH2:7]1
Reactant: Cc1cc2c([n+]([O-])c1)CCCC2
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1cnc2c(c1)CCCC2O

Procedure:
The N-oxide (60 g.) was dissolved in acetic anhydride (120 ml.) and added to boiling acetic anhydride (120 ml.) and the mixture heated at reflux for 30 minutes. The solvent was removed in vacuo and the residual oil was treated with 10% hydrochloric acid (700 ml.) and the solution heated on a steam bath for 2 hours. The cooled reaction mixture was adjusted to pH 9.0 with sodium hydroxide and extracted with ether (3 × 100 ml). The combined ethereal extracts were washed with saturated brine, dried (MgSO4) and the solvent removed in vacuo. The resultant oil as distilled at 0.15 mmHg to give a colourless oil (22 g.) b.p. 70°-78° C which crystallised from n-hexane to give 8-hydroxy-3-methyl-5,6,7,8-tetrahydroquinoline as colourless needles m.p. 58° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:23][C:9]2=[N:10][CH:11]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:13]=[C:8]2[CH:7]=1)=[O:5])C.[OH-].[Li+:25]>O.CO.O1CCCC1>[N:18]1([CH2:17][CH2:16][CH2:15][O:14][C:12]2[CH:13]=[C:8]3[CH:7]=[C:6]([C:4]([O-:5])=[O:3])[NH:23][C:9]3=[N:10][CH:11]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1.[Li+:25]
Reactant: CCOC(=O)c1cc2cc(OCCCN3CCCC3)cnc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])c1cc2cc(OCCCN3CCCC3)cnc2[nH]1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To the suspension of 0.19 g (0.6 mmol) 5-(3-pyrrolidin-1-yl-propoxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester in 0.4 ml water, 0.4 ml methanol and 0.4 ml tetrahydrofuran was cooled to 0° C. and treated with 0.63 ml (0.63 mmol) of a 1M aqueous lithium hydroxide solution. After stirring for 5 hours at room temperature the volatile components were evaporated at a rotary evaporator and the residue dried under high vacuum over phosphorus pentoxide to give 0.18 g (100%) of the compound as a light yellow solid (100%).
Reaction SMILES: Br[CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:21]([O:23][CH3:24])=[O:22].C(Cl)Cl.C(N(CC)C(C)C)(C)C.[NH2:37][C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][N:39]=1>O>[CH3:24][O:23][C:21]([C:4]1[N:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:37][C:38]1[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=[CH:40][N:39]=1)=[CH:10][CH:9]=[C:8]([Cl:14])[CH:7]=2)=[O:22]
Reactant: Nc1nccc2ccccc12
Reactant: COC(=O)c1c(CBr)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(CNc2nccc3ccccc23)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
In a 10 mL round-bottomed flask, methyl 3-(bromomethyl)-7-chloro-4-oxo-1-phenyl-1,4-dihydroquinoline-2-carboxylate (50 mg, 0.123 mmol) was combined with methylene chloride (5 mL) to give a colorless solution. To this solution, N,N-diisopropylethylamine and 1-aminoisoquinoline were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 25 mL H2O and extracted with ethyl acetate (1×25 mL). The organic layer was washed with 1 M HCl (1×10 mL), saturated aqueous NaHCO3 (1×10 mL), and H2O (1×10 mL). The organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4 g, 5% to 40% ethyl acetate in hexanes), giving 7-chloro-3-(isoquinolin-1-ylaminomethyl)-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (4 mg, 7%). MS calcd. for C27H20ClN3O3 [(M+H)+] 470.1, obsd. 470.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[S:7][C:8]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16](O)=[O:17])[C:9]=3[CH2:10][CH2:11][C:5]=2[CH:4]=1.S(Cl)([Cl:23])=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[S:7][C:8]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([Cl:23])=[O:17])[C:9]=3[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCc1c(cccc1C(=O)O)S2
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc2c(c1)CCc1c(cccc1C(=O)Cl)S2

Procedure:
An amount of 572 mg of 2-methoxy-9-carboxy-10,11-dihydrodibenzo[b,f]thiepin was dissolved in 10 ml of anhydrous benzene and to the mixture was added 1 ml of thionyl chloride. The resulting mixture was refluxed for 3 hours and freed of solvent under reduced pressure to obtain 614 mg of 2-methoxy-10,11-dihydrodibenzo[b,f]thiepin-9-carbonyl chloride.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH3:10][O:11][C:12]([NH:14][C@@H:15]([CH:27]([CH3:29])[CH3:28])[C:16]([N:18]1[C@@H:22]([CH3:23])[CH2:21][CH2:20][C@H:19]1[C:24](O)=O)=[O:17])=[O:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC(C)=CC=1C>CN(C=O)C.O.C(O)(=O)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:23]([C@@H:22]3[CH2:21][CH2:20][C@H:19]([CH3:24])[N:18]3[C:16]([C@@H:15]([NH:14][C:12](=[O:13])[O:11][CH3:10])[CH:27]([CH3:28])[CH3:29])=[O:17])=[N:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(I)cc1N
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1c1nc2cc(I)ccc2[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
To a cold (0-4° C.) stirred solution of 4-iodobenzene-1,2-diamine (1.3 g, 5.3 mmol) and (2S,5S)-1-[(2S)-2-(methoxycarbonylamino)-3-methyl-butanoyl]-5-methyl-pyrrolidine-2-carboxylic acid (1.52 g, 4.99 mmol) in DMF (23.8 ml) is sequentially added HATU (2.321 g, 6.103 mmol) and 2,4,6-collidine (1.052 ml, 7.964 mmol). The reaction mixture is stirred at rt overnight, diluted with water, extracted with ethyl acetate. Combined extracts are washed with water, saturated bicarbonate solution, brine, dried (Na2SO4), concentrated and dried under high vacuum to afford crude amide. The resulting residue dissolved in acetic acid (28 ml) is heated at 60° C. for 8 hours. Acetic acid is removed, the residue neutralized with sat. NaHCO3 solution, and diluted with ethyl acetate (20 ml). The aqueous solution is extracted with ethyl acetate, combined organic extracts are washed with aq. NaHCO3 solution, brine, dried (Na2SO4), and concentrated. The concentrate is purified by flash column chromatography on silica gel using ethyl acetate-hexanes (1:1 to 7:3) as eluent afforded methyl N-[(1S)-1-[(2S,5S)-2-(5-iodo-1H-benzimidazol-2-yl)-5-methyl-pyrrolidine-1-carbonyl]-2-methyl-propyl]carbamate (2.3 g, 2.28 mmol, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH:18][C:19]4[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=4)[O:22][CH2:23][C:24]([NH2:26])=O)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:5][CH:4]=1.N1C(Cl)=NC(Cl)=NC=1Cl.O.C(OCC)(=O)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:16]([NH:18][C:19]4[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=4)[O:22][CH2:23][C:24]#[N:26])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Nc4cccc(OCC(N)=O)c4)c23)cc1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Nc4cccc(OCC#N)c4)c23)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Dissolve 800 mg (1.72 mmol) of 2-(3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenoxy)acetamide in 5 ml of DMF, cool to 0° C. and add 316 mg (1.72 mmol) of cyanuric chloride. Stir the mixture at 0° C. for 2 h. Then add water and ethyl acetate. After phase separation, extract the aqueous phase twice with ethyl acetate. Wash the combined organic phases three times with buffer solution (pH 7), dry them over magnesium sulphate and concentrate them under reduced pressure. The crude product is purified by chromatography on silica gel (eluent: dichloromethane/ethyl acetate 20:1). 179 mg (22.3% of theory) of the target product are obtained as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([C:15]2[CH:19]=[CH:18][O:17][C:16]=2[CH2:20][OH:21])=[CH:13][CH:12]=[C:11]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[H][H]>O1CCOCC1.C(O)(=O)C.[OH-].[OH-].[Pd+2]>[C:1]([NH:4][C:5]1[C:14]([C@H:15]2[CH2:19][CH2:18][O:17][C@H:16]2[CH2:20][OH:21])=[CH:13][CH:12]=[C:11]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc(-c2ccoc2CO)c1NC(C)=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc([C@H]2CCO[C@H]2CO)c1NC(C)=O
Reaction time: 8 h
Yield: 69.3 %

Procedure:
A solution of methyl 2-acetylamino-6-(2,2-dimethylpropionylamino)-3-(2-hydroxymethylfuran-3-yl)benzoate (Intermediate 38, 0.2 g) in dioxane (4 mL) and acetic acid (1 mL) was treated under an atmosphere of nitrogen with palladium hydroxide on carbon (10%, 0.03 g). The nitrogen was replaced by hydrogen and the mixture was stirred under an atmosphere of hydrogen overnight. The mixture was filtered through Celite and the pad was washed thoroughly with ethyl acetate. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of methanol and ethyl acetate with a gradient of 0-10% to give methyl 2-acetylamino-6-(2,2-dimethylpropionylamino)-3-[cis-(2RS,3RS)-2-(hydroxymethyl)tetrahydrofuran-3-yl]benzoate (0.14 g) as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([OH:11])=[C:9]([OH:12])[N:8]=[C:7]([CH2:13][C:14]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:18][CH2:17][CH2:16][CH2:15]2)[N:6]=1)=O.[CH3:25][NH2:26]>C1COCC1>[CH3:25][NH:26][C:3]([C:5]1[N:6]=[C:7]([CH2:13][C:14]2([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:18][CH2:17][CH2:16][CH2:15]2)[NH:8][C:9](=[O:12])[C:10]=1[OH:11])=[O:2]
Reactant: COC(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1O
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1nc(CC2(c3ccccc3)CCCC2)[nH]c(=O)c1O
Temperature: 110 °C
Yield: 36 %

Procedure:
To a solution of 5,6-dihydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid methyl ester (55 mg, 0.167 mmol) in THF (2 ml) was added 2M solution of methyl amine in THF (0.419 mL, 0.838 mmol) under nitrogen atmosphere in a microwave vessel. The reaction mixture was heated in a microwave oven at 110° C. for 10 min, then cooled and evaporated to dryness. The residue was washed with water and 30% ethyl acetate in hexane to get the title compound as an off-white solid (0.020 g, 36%). LCMS: m/z=327.8 (MH+).