Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[C:17]3[C:18]4[CH:24]=[C:23]([CH3:25])[CH:22]=[N:21][C:19]=4[NH:20][C:16]=3[C:15]([C:26]#[N:27])=[N:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[OH-:28].[K+]>C1COCC1.OO>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[C:17]3[C:18]4[CH:24]=[C:23]([CH3:25])[CH:22]=[N:21][C:19]=4[NH:20][C:16]=3[C:15]([C:26]([NH2:27])=[O:28])=[N:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: [OH-]
Reactant: CCS(=O)(=O)c1cccc(-c2cnc(C#N)c3[nH]c4ncc(C)cc4c23)c1
Agent: OO
Agent: [K+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1cccc(-c2cnc(C(N)=O)c3[nH]c4ncc(C)cc4c23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
Compound 48 (10 mg, 0.027 mmol) stirred in THF (1 mL). A solution of KOH (25 mg, 0.44 mmol) in 30% H2O2 (0.5 mL) was added, and the reaction stirred for 3 h at r.t. Purification by prep-HPLC gave 8.2 mg (77%) of the title compound as an off-white solid. 1H NMR (400 MHz, MeOD-d4): δ 8.49 (br s, 1H), 8.41 (s, 1H), 8.26 (s, 1H), 8.15 (d, 1H, J=7.6 Hz), 8.06 (d, 1H, J=7.6 Hz), 7.92 (t, 1H, J=7.6 Hz), 7.85 (s, 1H), 3.32 (q, 2H, J=7.2 Hz), 2.39 (s, 3H), 1.31 (t, 3H, J=7.6 Hz). MS (ES) [m+H] calc'd for C20H18N4O3S, 395; found 395.
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[N:3]=[S:4](Cl)([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:5].C(N(CC)CC)C.[C:23]1([OH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC#N>[C:23]1([O:29][S:4]([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)(=[N:3][Si:2]([CH3:1])([CH3:14])[CH3:15])=[O:5])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[Si](C)(C)N=S(=O)(Cl)c1ccc(F)cc1
Reactant: Oc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)N=S(=O)(Oc1ccccc1)c1ccc(F)cc1
Yield: 15 %

Procedure:
The reactants used in the general procedure were sulfonimidoyl chloride (7c), triethylamine (0.0936 mol, 13.3 ml), phenol (0.0934 mol, 8.79 g). Boiling range of product: 125°-131° C./0.25 mm. Yield: 15%. 1H NMR signals (90 MHz, CH3CN): 0.24 (s, 9H), 6.83-7.57 (m, 7H), and 7.83-8.1 (m, 2H).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][C:6]([NH2:8])=[S:7])[CH3:4].[Cl:9][CH2:10][C:11]([CH2:13]Cl)=[O:12].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[OH:12][C:11]1([CH2:10][Cl:9])[CH2:13][S:7][C:6]([CH2:5][N:3]([CH3:4])[CH3:2])=[N:8]1
Reactant: CN(C)CC(N)=S
Reactant: O=C(CCl)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C)CC1=NC(O)(CCl)CS1
Temperature: 60 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
A mixture of dimethylaminothioacetamide hydrochloride 54.0 g, 350 mmol), 1,3-dichloroacetone (52.0 g, 409 mmol) and sodium bicarbonate (64.0 g, 762 mmol) in 300 ml of toluene was stirred at 60° C. for 2 hours. The hot reaction solution was then cooled and salts which had precipitated during the reaction were removed by filtration. An equal volume of petroleum ether was then added to the filtrate and solids precipitated. These solids were recovered by filtration to afford 55.5 g of titled compound.
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[N:4]1.[CH2:12]([CH:15]([C:18]#[N:19])[C:16]#[N:17])[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:12]([C:15]([CH2:2][N:3]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[N:4]1)([C:18]#[N:19])[C:16]#[N:17])[CH:13]=[CH2:14]
Reactant: FC(F)(F)c1ccn(CCl)n1
Reactant: C=CCC(C#N)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCC(C#N)(C#N)Cn1ccc(C(F)(F)F)n1
Yield: 31.3 %

Procedure:
1.33 g of 1-(chloromethyl)-3-(trifluoromethyl)-1H-pyrazole and 0.76 g of allyl malononitrile were dissolved in 21 ml of N,N-dimethylformamide. 1.99 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain 0.57 g of allyl {[3-(trifluoromethyl)-1H-pyrazole-1-yl]methyl}malononitrile (referred as the compound of the present invention (7), hereinafter) shown by below formula.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][CH2:10]/[C:11](/[CH2:27][O:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][CH:30]=2)=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH:19][O:20]C2CCCCO2)=[O:18])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>CO>[OH:20][NH:19][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]/[CH:12]=[C:11](\[CH2:27][O:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1)/[CH2:10][NH:9][CH2:8][CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: O=C(CCCC/C=C(/CNCCN1CCOCC1)COc1cccc2ccccc12)NOC1CCCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(CCCC/C=C(/CNCCN1CCOCC1)COc1cccc2ccccc12)NO
Yield: 52.8 %

Procedure:
(Z)-8-(2-morpholinoethylamino)-7-((naphthalen-1-yloxy)methyl)-N-(tetrahydro-2H-furan-2-yloxy)oct-6-enamide (63 mg, 0.09 mmol) obtained in Example (3-1-3) was dissolved in methanol (1.5 ml), and trifluoroacetic acid (0.04 ml, 0.45 mmol) was slowly added thereto at room temperature. The resulting mixture was reacted for 8 hours to conduct a deprotection reaction of THP. After the completion of reaction, the reaction solution was concentrated under reduced pressure. The residue thus obtained was purified by a preparative HPLC to obtain 21 mg of the title compound as pale orange oil (yield 53%), which was used in the subsequent analysis.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[F:12].[CH3:13][O-:14].[Na+].CO>C(Cl)Cl>[CH3:13][O:14][C:6]1[CH:7]=[C:2]([Br:1])[C:3]([F:12])=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(Br)c(F)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To 1-bromo-2,5-difluoro-4-nitrobenzene (5.0 g, 21 mmol) was added 0.5 N sodium methoxide (50 mL, 25 mmol). The mixture was stirred at 60° C. for 1 h. The MeOH was rotovaped down. The crude product was dissolved in DCM (100 mL), washed with H2O, dried (Na2SO4), filtered, and rotovaped down to give the title compound of step A (5 g, 20 mmol, 95%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.69 (s, 1H), 7.28 (s, 1H), 3.95 (s, 3H).
Reaction SMILES: O(C)[Na].[NH2:4][OH:5].[Cl:6][C:7]1[CH:12]=[C:11]([N:13]2[C:18](=[O:19])[NH:17][C:16](=[O:20])[CH:15]=[N:14]2)[CH:10]=[CH:9][C:8]=1[CH:21]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:22]#[N:23]>C(O)C>[Cl:6][C:7]1[CH:12]=[C:11]([N:13]2[C:18](=[O:19])[NH:17][C:16](=[O:20])[CH:15]=[N:14]2)[CH:10]=[CH:9][C:8]=1[CH:21]([C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1)[C:22](=[N:4][OH:5])[NH2:23]
Reactant: NO
Reactant: N#CC(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Agent: CO[Na]
Solvent: CCO
Product: NC(=NO)C(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.5 %

Procedure:
NaOCH3 (0.189 mol; 30% in CH3OH) was added to a solution of hydroxylamine (0.189 mol) in ethanol (105 ml) The mixture was stirred at RT for 15 minutes and then filtered. The filtrate was added to a mixture of 2-chloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2-(3H)-yl)benzeneacetonitrile (0.054 mol) in ethanol (55 ml). The mixture was stirred at 60° C. for 1 hour, stirred and refluxed for 2 hours and stirred at RT overnight. The solvent was evaporated. The residue was taken up in water and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 20.3 g of (±)-2-chloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-N′-hydroxybenzeneethanimidamide (interm. 66).
Reaction SMILES: C([O:3][C:4](=[O:28])/[CH:5]=[C:6](\[CH3:27])/[CH:7]=[CH:8]/[C:9](/[Br:26])=[C:10](\[C:12]1[CH:21]=[CH:20][C:19]2[C:18]([CH3:23])([CH3:22])[CH2:17][CH2:16][C:15]([CH3:25])([CH3:24])[C:14]=2[CH:13]=1)/[CH3:11])C.[OH-].[Na+]>CCO.C1COCC1>[Br:26]/[C:9](=[C:10](/[C:12]1[CH:21]=[CH:20][C:19]2[C:18]([CH3:23])([CH3:22])[CH2:17][CH2:16][C:15]([CH3:25])([CH3:24])[C:14]=2[CH:13]=1)\[CH3:11])/[CH:8]=[CH:7]/[C:6](/[CH3:27])=[CH:5]/[C:4]([OH:28])=[O:3]
Reactant: CCOC(=O)/C=C(C)/C=C/C(Br)=C(/C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(/C=C/C(Br)=C(/C)c1ccc2c(c1)C(C)(C)CCC2(C)C)=C\C(=O)O
Temperature: 25 °C
Reaction time: 22 h

Procedure:
472 mg of (2E,4E,6E)-6-bromo-3-methyl-7-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-octa-2,4,6-trienoic acid ethyl ester were dissolved in 10 ml of EtOH/THF=1:1 and treated with 2.65 ml of 2N aq. NaOH. The reaction mixture was stirred for 22 hours at ambient temperature in the dark. It was then poured onto crushed ice, extracted with AcOEt, washed with brine and H2O, and dried over Na2SO4. Evaporation of the solvent and twofold crystallization (hexane/AcOEt=8:2) yielded finally 168 mg of (2E,4E,6E)-6-bromo-3-methyl-7-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-octa-2,4,6-trienoic acid as yellow crystals of m.p. 189°-190° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([F:15])[CH:8]=2)[C:4](=[O:16])[CH2:3]1.C([O-])([O-])=O.[K+].[K+].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[F:15][C:9]1[CH:8]=[C:7]([N:5]2[C:4](=[O:16])[CH2:3][CH:2]([NH:1][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:6]2)[CH:12]=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(N2CC(N)CC2=O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc(N2CC(NC(=O)c3ccccc3)CC2=O)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 4-amino-1-(3-fluoro-4-methoxyphenyl)-pyrrolidin-2-one (Step 2, 0.8 g, 3.57 mmol) and K2CO3 (0.99 g, 7.14 mmol) in 20 mL of CH2Cl2 was added benzoyl chloride (0.75 g, 5.35 mmol). The reaction was stirred at RT for 16 h. The solid in the reaction was removed by filtration and the filtrate was diluted with 20 mL of CH2Cl2. The resulted solution was washed with 20 mL of satd. NaHCO3 followed by 20 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (30% to 100% EtOAc/hexane) to provide the title compound as a white solid. MS (ESI pos. ion) m/z: 329.4 (M+H). Calc'd Exact Mass for C18H17FN2O3: 328.34.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]3[N:24]=[CH:25][C:26]([C:27](O)=[O:28])=[C:16]3[N:15]=2)[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2].[S:30]([C:34]1[CH:35]=[C:36]([NH2:40])[CH:37]=[CH:38][CH:39]=1)(=[O:33])(=[O:32])[NH2:31]>>[S:30]([C:34]1[CH:35]=[C:36]([NH:40][C:27]([C:26]2[CH:25]=[N:24][N:17]3[C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:14]([C:6]4[CH:7]=[CH:8][C:9]([C:10]([F:11])([F:13])[F:12])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=4)=[N:15][C:16]=23)=[O:28])[CH:37]=[CH:38][CH:39]=1)(=[O:32])(=[O:33])[NH2:31]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Product: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cccc(S(N)(=O)=O)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.11) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (ISP) 572.1 [(M−H)−]; mp 253° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]([NH2:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.[CH3:14][S:15][C:16]1[N:21]=[C:20]([Sn](CCCC)(CCCC)CCCC)[CH:19]=[CH:18][N:17]=1>C1(C)C=CC=CC=1.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>[CH3:11][C:10]([NH2:13])([CH3:12])[C:9]#[C:8][C:5]1[CH:4]=[CH:3][C:2]([C:18]2[CH:19]=[CH:20][N:21]=[C:16]([S:15][CH3:14])[N:17]=2)=[CH:7][N:6]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Reactant: CC(C)(N)C#Cc1ccc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CSc1nccc(-c2ccc(C#CC(C)(C)N)nc2)n1

Procedure:
3-(5-Bromo-pyridin-2-yl)-1,1-dimethyl-prop-2-ynylamine (1.05 g, 4.4 mmol), 2-methylthio-4-tri-butylstannylpyrimidine (1.83 g, 4.4 mmol) and PdCl2(PPh3)2 (154 mg, 0.22 mmol) in toluene (22 ml) were refluxed under argon for 2 hours. A second portion of 2-methylthio-4-tri-n-butylstannylpyrimidine (1.83 g, 4.4 mmol) was added and the mixture refluxed for 1 hour. The reaction mixture was filtered, evaporated and purified via chromatography on silicagel (TBME/MeOH/ammonia:97/2.7/0.3 to 95/4.5/0.5) to give the title compound as orange-brown solid, which was recrystallized form ether/hexanes. Yield: 500 mg (40%).
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[N:9]([CH2:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.N1C=CC=CC=1.[CH3:29][CH:30]1[CH2:35][NH:34][CH2:33][CH2:32][NH:31]1>C(O)C>[CH2:19]([N:9]1[C:8]2[N:7]=[C:6]3[CH:21]=[C:2]([N:34]4[CH2:33][CH2:32][NH:31][CH:30]([CH3:29])[CH2:35]4)[C:3]([F:22])=[CH:4][C:5]3=[CH:14][C:13]=2[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]1)[CH3:20]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: CC1CNCCN1
Solvent: c1ccncc1
Solvent: CCO
Product: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(C)C4)cc3nc21

Procedure:
1-Ethyl-7-fluoro-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Example 1 but starting from 2.1 g of 8-chloro-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid, 20 cm3 of pyridine and 2.4 g of 2-methylpiperazine. After taking up in ethanol and concentrating to dryness under reduced pressure (20 kPa at 50° C.), the solid residue is taken up in 20 cm3 of water and 10 cm3 of 2 N potassium hydroxide solution. The aqueous solution obtained is washed with twice 20 cm3 of trichloromethane, 10 cm3 of acetic acid are added and the mixture is again washed with twice 40 cm3 of trichloromethane. 23 cm3 of 4.5 N potassium hydroxide solution are added and the suspension obtained is heated to a temperature close to 90° C. After cooling to a temperature close to 20° C., the precipitate is drained and washed with 3 times 10 cm3 of water and twice 10 cm3 of ethanol. After recrystallizing twice from 120 cm3 of dimethylformamide each time, 1.7 g of 1-ethyl-7-fluoro-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid melting at 310°-312° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH3:11])[C:6]=2[C:5]([C:12]([OH:14])=O)=[CH:4][N:3]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N1CCOCC1)C.Cl.[NH:45]1[CH2:50][CH2:49][S:48](=[O:52])(=[O:51])[CH2:47][CH2:46]1>CN(C)C=O.O>[Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH3:11])[C:6]=2[C:5]([C:12]([N:45]2[CH2:50][CH2:49][S:48](=[O:52])(=[O:51])[CH2:47][CH2:46]2)=[O:14])=[CH:4][N:3]=1
Reactant: Cn1ccc2c(Cl)ncc(C(=O)O)c21
Reactant: O=S1(=O)CCNCC1
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccc2c(Cl)ncc(C(=O)N3CCS(=O)(=O)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
To a solution of 4-chloro-1-methyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (726 mg) in dimethylformamide (12 ml) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (0.73 g), 1-hydroxybenzotriazole (0.52 g), N-ethylmorpholine (0.48 ml) and thiomorpholine 1,1-dioxide hydrochloride (0.66 g). The solution was stirred at room temperature overnight. The reaction was diluted with water and extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed with saturated sodium chloride solution and dried (MgSO4) then evaporated. The residue was triturated with diethyl ether/n-hexane and filtered to afford the title compound as an off-white solid (0.907 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].[H-].[Na+].Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(OCc3ccccc3)cc(C)c21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.2 g, 0.8 mmol) in anhydrous DMF (3 mL) was added sodium hydride (0.08 g, 1.6 mmol). After stirring for 15 minutes bromomethyl-benzene (0.274 g, 1.6 mmol) was added and the resulting mixture stirred at room temperature for 4 hours then quenched with crushed ice. The pH was adjusted to 4 with 6M HCl and the mixture extracted with EtOAc. The organic extracts were washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Biotage (5-60% EtOAc in hexane) to give 6-benzyloxy-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.2 g, 73%). 1H NMR 400 MHz (DMSO-d6) δ 9.15 (s, 1H), 7.45-7.31 (m, 5H), 7.11 (d, J=2.0 Hz, 1H), 6.94 (d, =2.0 Hz, 1H), 5.44 (dd, J=9.2, 2.4 Hz, 1H), 5.10 (s, 2H), 4.05 (q, J=7.2 Hz, 2H), 3.08 (dd, J=15.2, 2.4 Hz, 1H), 2.26 (s, 3H), 2.21 (m, 1H), 1.08 (t, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16]([NH:18][C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[O:28])[O:26]C(C)(C)[O:24][C:23]=4[CH:31]=3)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1>[C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:27]([OH:28])=[O:26])=[C:23]([OH:24])[CH:31]=3)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Nc3ccc4c(c3)OC(C)(C)OC4=O)n2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Nc3ccc(C(=O)O)c(O)c3)n2)s1
Temperature: 25 °C
Reaction time: 240 h
Yield: 39.1 %

Procedure:
2′-(acetylamino)-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-7-yl)-4′-methyl-4,5′-bi-1,3-thiazole-2-carboxamide (150 mg; 0.33 mmol; 1 eq.) is dissolved in THF (6 ml). Sodium hydroxide (0.82 ml; 5 M; 4.09 mmol; 12.50 eq.) is added and the mixture is stirred at rt for 10 days. Hydrogen chloride (0.82 ml; 5 M; 4.09 mmol; 12.50 eq.) is added and the solvents are evaporated. The resulting crude product is purified by preparative HPLC. To remove the TFA, the compound is dissolved in THF and an excess of POL-Trisamine (Argonault) is added. The solution is filtrated and evaporated, affording Compound (31)(54 mg; 39%). Potassium salt of 4-({[2′-(acetylamino)-4′-methyl-4,5′-bi-1,3-thiazol-2-yl]carbonyl}amino)-2-hydroxybenzoic acid, Compound (31), is prepared by dissolving the parent compound (54 mg, 0.129 mmol) in THF (2 ml) and water (2 ml). Potassium hydroxide 0.5N solution (258 μl, 1 eq) is added. The mixture is stirred 10 min at rt, filtered through cotton and is lyophilized. Potassium salt of compound (31) is isolated as a yellow solid (21.6 mg; 36%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][CH2:8][NH2:9])[S:5][CH:6]=1.[CH3:10][CH:11](C)[CH:12]=O.[BH4-].[Na+].CCOC(C)=O>C(Cl)Cl.CO.C(O)(=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][CH2:8][NH:9][CH:11]([CH3:12])[CH3:10])[S:5][CH:6]=1
Reactant: NCCc1cc(Br)cs1
Reactant: CC(C)C=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)NCCc1cc(Br)cs1
Yield: 67.2 %

Procedure:
To a solution of [2-(4-bromo-2-thienyl)ethyl]amine (100 mg, 0.48 mmol) in DCM (2.0 mL) and MeOH (1.0 mL) was added acetic acid (3 drops) and 2-methylpropanal (105 mg, 1.44 mmol). The reaction was stirred overnight at room temperature before addition of Sodium borohydride (53.3 mg, 1.44 mmol). Reaction run for 1 h and then treated with EtOAc and brine. Organic layers were then dried and concentrated to give 80 mg of [2-(4-bromo-2-thienyl)ethyl](1-methylethyl)amine (64%).
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl.O(CCCNC(C)(C)CC1C=CC(OC)=CC=1)[C:29]1C=CC=C[CH:30]=1.Cl.OC(COC1C=CC(OC)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.OC(COC1C=CC(C(C)(C)C)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:26].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:29][CH3:30])[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: COc1ccc(CC(C)(C)NCCCOc2ccccc2)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)cc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)cc2)cc1
Agent: Cl
Product: CCc1ccccc1OCC(O)CNC(C)(C)Cc1ccc(OC)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 342 (M−15,1), 237 (16), 236 (100), 163 (5), 121 (17), 114 (7), 91 (6), 77 (7).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].[H-].[Na+].[Cl:9][C:10]1[C:11]([N:16]2[CH2:25][CH2:24][C:23]3[C:22]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)=[N:21][C:20](S(C)(=O)=O)=[N:19][C:18]=3[CH2:17]2)=[N:12][CH:13]=[CH:14][CH:15]=1>CN(C=O)C>[F:36][C:33]([F:34])([F:35])[C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:22]2[C:23]3[CH2:24][CH2:25][N:16]([C:11]4[C:10]([Cl:9])=[CH:15][CH:14]=[CH:13][N:12]=4)[CH2:17][C:18]=3[N:19]=[C:20]([O:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[N:21]=2)=[CH:28][CH:29]=1
Reactant: CS(=O)(=O)c1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1Cl)C2
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1Cl)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.3 %

Procedure:
Methyl glycolate (31 mg, 0.33 mmol) was dissolved in DMF (dry), NaH (8 mg, 0.31 mmol) was added and stirred at room temperature under an atmosphere of Nitrogen for 30 min. 7-(3-Chloropyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-4-amine (120.0 mg, 0.22 mol) (in 4 mL DMF, dry) was added to the above mixture. The reaction was heated via microwave at 180° C. for 15 minutes. Solvent was removed and the residue was purified by flash chromatography over silica gel to obtain the product as a white solid (25 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[C:9]([C:24]2[N:28]([CH3:29])[N:27]=[N:26][N:25]=2)/[CH:10]=[CH:11]\[C@H:12]2[O:17]C(C)(C)[O:15][C@@H:14]([CH2:20][C:21](O)=[O:22])[CH2:13]2)=[CH:4][CH:3]=1>C1COCC1.Cl>[F:36][C:33]1[CH:34]=[CH:35][C:30]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:9]([C:24]2[N:28]([CH3:29])[N:27]=[N:26][N:25]=2)/[CH:10]=[CH:11]/[C@H:12]2[O:17][C:21](=[O:22])[CH2:20][C@H:14]([OH:15])[CH2:13]2)=[CH:31][CH:32]=1
Reactant: Cn1nnnc1C(/C=C\[C@@H]1C[C@H](CC(=O)O)OC(C)(C)O1)=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Solvent: C1CCOC1
Product: Cn1nnnc1C(/C=C/[C@@H]1C[C@@H](O)CC(=O)O1)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 16 h
Yield: 40.7 %

Procedure:
Cis-(4R,6S)-6-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H tetrazol-5-yl)-1,3-butadienyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid (3.7 g, 7.45 mmol) was dissolved in a solution of THF (90 mL) and 0.2N HCl (60 mL) and allowed to stand for 16 hours. The solution was partitioned between ethyl acetate and water. The organic layer was washed with brine (2x), dried (Na2SO4), and concentrated under reduced pressure. The residue was dissolved in dry methylene chloride (60 mL )and stirred for 4 hours in the presence of 1-cyclohexyl-3-(2-morpholinomethyl) carbodiimide metho-p-toluenesulfonate (6.6 g, 15.6 mmoL). The solution was concentrated under reduced pressure and the residue was partitoned between ethyl acetate and water. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (1:1/ethyl acetate:diethyl ether). After recrystallization from ethyl acetate-hexane, 1.33 g (40.1%) of the title compound was obtained as a white solid; m.p.=172°-173° C. [α]D25 =+237.8° (c=2.17, CHCl3).