Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[C:13]([NH:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=4)[N:14]=[C:15](N4C=NN=C4)[C:16]=3[N:17]=2)=[CH:4][CH:3]=1.[CH3:35][CH2:36][O-:37].[Na+].CCO>C1COCC1.CN(C=O)C>[CH2:36]([O:37][C:15]1[C:16]2[N:17]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:9]=[CH:10][C:11]=2[N:12]=[C:13]([NH:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:29][CH:30]=2)[N:14]=1)[CH3:35]
Reactant: CC[O-]
Reactant: NS(=O)(=O)c1ccc(CNc2nc(-n3cnnc3)c3nc(-c4ccc(F)cc4)ccc3n2)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOc1nc(NCc2ccc(S(N)(=O)=O)cc2)nc2ccc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 4-{[6-(4-fluoro-phenyl)-4-[1,2,4]triazol-4-yl-pyrido[3,2-d]pyrimidin-2-ylamino]-methyl}-benzenesulfonamide (638 mg, 1.34 mmol) in 10 ml THF was added to a solution of 21% (w/w) NaOEt in EtOH (1.50 ml, 4.03 mmol) in 20 ml of dry THF over 5 min. The triazole flask was rinsed once with 5 ml THF and the rinse was added to the reaction flask. The reaction was stirred at room temperature for 15 min. Analysis by reversed phase HPLC/MS indicated the reaction was complete. The pH was adjusted to 7 with 10% acetic acid/EtOAc and then concentrated in vacuo. The residue was partitioned between EtOAc and H2O. The aqueous layer was extracted twice with EtOAc. The combined organics were washed twice with water and once with brine, dried over MgSO4, filtered and concentrated. The solid was absorbed onto SiO2, and purified by eluting onto a 30 g SiO2 column with CH2Cl2/MeOH. The fractions containing the desired compound as determined by LC/MS were combined and concentrated. The solid thus obtained was dissolved in DMF and re-purified by reverse phase HPLC using acetonitrile/H2O in 4 runs. The pure fractions from each run were combined and the acetonitrile was removed in vacuo. The resulting aqueous suspension was neutralized with excess saturated aqueous NaHCO3, and extracted three times with EtOAc. The organics were dried over MgSO4, filtered and concentrated. The material was solidified by addition of MeOH. The solid was dried at high vacuum for 24 hrs, giving 110 mg of 4-{[4-ethoxy-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidin-2-ylamino]-methyl}-benzenesulfonamide (Example 109) as a white powder. MS (m/z) 454 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][C:28]=1[F:39])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[CH2:7][CH:6]1[CH2:22][C:23]([O:25]C)=[O:24].[OH-].[Na+].O1CCOCC1.[ClH:48]>O.CC(C)=O>[ClH:48].[NH2:1][CH:2]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][C:28]=1[F:39])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[CH2:7][CH:6]1[CH2:22][C:23]([OH:25])=[O:24]
Reactant: COC(=O)CC1CN(CCSc2cc(F)ccc2F)CCC1CCC(N)c1c(F)cnc2ccc(OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: COc1ccc2ncc(F)c(C(N)CCC3CCN(CCSc4cc(F)ccc4F)CC3CC(=O)O)c2c1
Temperature: 55 °C
Reaction time: 4 h

Procedure:
A mixture of 0.09 g of methyl (3RS,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetate in 0.36-cm3 of a 1 N aqueous sodium hydroxide solution and 3-cm3 of dioxane was heated at a temperature in the region of 55° C., with stirring and under an inert atmosphere, for 4 hours. After cooling in the vicinity of 20° C., the reaction mixture was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 50° C. The evaporation residue obtained was taken up in 5-cm3 of distilled water and acidified with a 1-N aqueous hydrochloric acid solution and was concentrated. The aqueous phase was washed with 8-cm3 of dichloromethane and then concentrated according to the conditions described above. The residue obtained was taken up in 10-cm3 of acetone and then it was filtered on sintered glass. 0.081 g of (3RS,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetic acid hydrochloride wereobtained in the form of a white solid.
Reaction SMILES: C(OCC)(=O)C=C.FC(F)(F)C1C=CC2N=NN(O)C=2C=1.O=O.[OH:24][CH:25]([CH2:31][C:32]([OH:35])([CH3:34])[CH3:33])[C:26]([O:28]CC)=O>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C(#N)C.CC(O)C>[OH:24][CH:25]1[CH2:31][C:32]([CH3:33])([CH3:34])[O:35][C:26]1=[O:28]
Reactant: CCOC(=O)C(O)CC(C)(C)O
Agent: [Co+2]
Agent: C=CC(=O)OCC
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CC(C)O
Product: CC1(C)CC(O)C(=O)O1

Procedure:
A mixture of 3 mmol of ethyl acrylate, 3 ml of 2-propanol, 0.6 mmol of 6-trifluoromethyl-l-hydroxybenzotriazole, 0.003 mmol of cobalt(II) acetate, 0.015 mmol of acetylacetonatocobalt(III), and 1 ml of acetonitrile was stirred at 60° C. in an oxygen atmosphere (1 atm) for 12 hours. A gas chromatographic analysis of products in a reaction mixture found that ethyl 2,4-dihydroxy-4-methylpentanoate and (α-hydroxy-γ,γ-dimethyl-γ-butyrolactone were formed in yields of 2% and 28%, respectively, with a conversion rate from ethyl acrylate of 62%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][C:5]2=[O:12].N1C=CC=CC=1.O1CCOCC1.[Cl:25][C:26]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:26]=1[Cl:25])[CH2:7][CH2:6][C:5]2=[O:12]
Reactant: O=C1CCNc2ccc(Cl)cc21
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1CCN(C(=O)c2ccc(Cl)cc2Cl)c2ccc(Cl)cc21
Yield: 89.6 %

Procedure:
To a mixture of 6-chloro-2,3-dihydro-4(1H)-quinolinone (20 g), pyridine (26 g) and dioxane (200 ml) was added 2,4-dichlorobenzoylchloride (30 g) dropwise under cooling at 0° C. to 5° C. with stirring. The mixture was allowed to react at room temperature for additional 3 hours. The reaction mixture was poured into 500 ml of water, then shaken with dichloromethane (1000 ml). The organic layer was washed once with 1 N HCl (100 ml), twice with water (200 ml each) then once with saturated aqueous NaCl solution (200 ml) and dried over anhydrous sodium sulfate. Dichloromethane was removed in vacuo and the residue was recrystallized with dichloromethane and n-hexane to obtain 6-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4(1H)-quinolinone (yield 35 g) as white crystal.
Reaction SMILES: C(OC([N:7]1[C@H:11]([CH:12]([OH:21])[C:13]2[N:14]3[CH:20]=[N:19][CH:18]=[C:15]3[S:16][CH:17]=2)[CH2:10][C@H:9]([S:22][C:23]2[C@H:24]([CH3:40])[C@@H:25]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:26]3[C:27]=2[C:28]([O:30]CC=C)=[O:29])[CH2:8]1)=O)C=C.CNC1C=CC=CC=1.O>ClCCl.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>[OH:38][C@@H:36]([C@H:35]1[C:34](=[O:39])[N:26]2[C:27]([C:28]([OH:30])=[O:29])=[C:23]([S:22][C@H:9]3[CH2:10][C@@H:11]([CH:12]([OH:21])[C:13]4[N:14]5[CH:20]=[N:19][CH:18]=[C:15]5[S:16][CH:17]=4)[NH:7][CH2:8]3)[C@H:24]([CH3:40])[C@H:25]12)[CH3:37]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(O)c3csc4cncn34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: CNc1ccccc1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(O)c4csc5cncn45)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 20.8 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (13.8 mg) is added to a solution of 70 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-3-yl)methyl]pyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate (stereoisomer A) and 0.077 ml of N-methylaniline in 1.0 ml of dry dichloromethane, and the mixture is stirred in an argon atmosphere at room temperature for 45 min. Distilled water (3 ml) is added thereto, and the mixture is washed three times with 5 ml of ethyl acetate. The water layer is filtered, followed by concentration under reduced pressure and freeze drying to give a colorless flocculent material. The flocculent material is purified by column chromatography (water-methanol) on Cosmosil 40C18-PREP to give 11.5 mg of the title compound as a colorless flocculent material.
Reaction SMILES: [C:1]([O:14][CH2:15][C@@H:16]([O:57][C:58](=[O:70])[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])[CH2:17][S:18][CH2:19][C@H:20]([NH:39]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])=[O:22])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N1CCCCC1>C(#N)C>[C:1]([O:14][CH2:15][C@@H:16]([O:57][C:58](=[O:70])[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])[CH2:17][S:18][CH2:19][C@H:20]([NH2:39])[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:30])=[O:22])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCCCCC(=O)OCc1ccccc1)OC(=O)CCCCCCCCCCC
Solvent: CC#N
Solvent: C1CCNCC1
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCCCCC(=O)OCc1ccccc1)OC(=O)CCCCCCCCCCC
Temperature: 25 °C

Procedure:
To a solution of (R)-3-((R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(6-(benzyloxy)-6-oxohexylamino)-3-oxopropylthio)propane-1,2-diyl didodecanoate (1 eq) was added 20% piperidine (50 eq) in acetonitrile. The resulting mixture was stirred at 25° C. until the deprotection completed. To the mixture was concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 100% EtOAc, then 0-10% MeOH/DCM to give the product.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([NH2:11])[CH2:8][CH2:9][CH2:10][C:3]1=2.C(N(CC)CC)C.[Cl:19][CH2:20][C:21](Cl)=[O:22]>O1CCCC1>[Cl:19][CH2:20][C:21]([NH:11][CH:7]1[C:4]2[CH:5]=[CH:6][S:2][C:3]=2[CH2:10][CH2:9][CH2:8]1)=[O:22]
Reactant: NC1CCCc2sccc21
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCl)NC1CCCc2sccc21
Reaction time: 0.25 h

Procedure:
A mixture of 7.59 g of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride is stirred in 60 ml of dry tetrahydrofuran and 10.1 g of triethylamine in 20 ml of dry tetrahydrofuran is added. After stirring under a nitrogen atmosphere for 15 minutes, 3.5 ml or 5.25 g of chloroacetyl chloride in 30 ml of dry tetrahydrofuran is added dropwise, while the temperature is maintained at 30° C. to 40° C. After an hour of stirring, the mixture is filtered, the filter cake is washed with tetrahydrofuran, and the filtrate is evaporated to dryness. The residue is then triturated with water and the title compound, m.p. 115° C. to 119° C., is collected and washed with water and hexane.
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[Sn](CCCC)(CCCC)CCCC)[CH3:2].Br[C:24]1[S:25][CH:26]=[CH:27][N:28]=1.FC1C=C(C2N(CC3NC4C=NC=CC=4N3CC)C=CN=2)C=CC=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1COCC
Reactant: Brc1nccs1
Agent: CCN1c2ccncc2NC1Cn1ccnc1-c1cccc(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOCn1ccnc1-c1nccs1
Temperature: 25 °C
Yield: 26 %

Procedure:
A solution of crude 1-ethoxymethyl-2-tributylstannanyl-1H-imidazole (previous experimental), 2-bromothiazole (1.05 mL, 11.6 mmol, 1.0 eq based on integration of 1H NMR of crude 1-ethoxymethyl-2-tributylstannanyl-1H-imidazole), and Pd (PPh3) 4 (0.67 g, 0.58 mmol) in toluene (20 mL) is stirred at 80° C. for 18 h. After cooling to room temperature, the reaction mixture is poured into saturated aqueous NaHCO3 and extracted twice with CH2Cl2. The combined extracts are dried over Na2SO4 and concentrated in vacuo. The residue is purified by flash chromatography on silica gel, eluting with 2:1 hexanes-EtOAc (+0.5% Et3N). Fractions containing product are concentrated and resubjected to flash chromatography on silica gel. Elution with 2:1 hexanes-EtOAc (+0.5% Et3N) affords (26%) of 2-(1-ethoxymethyl-1H-imidazol-2-yl)-thiazole as a bright yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J=3.2 Hz, 1H), 7.33 (d, J=3.2 Hz, 1H), 7.20 (d, J=1.2 Hz, 1H), 7.15 (d, J=1.2 Hz, 1H), 6.03 (s, 2H), 3.56 (q, J=7.2 Hz, 2H), 1.17 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[C:12]3[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]#[CH:29].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:29][C:28]#[CH:27])=[CH:6][C:5]([N:9]2[C:10](=[O:19])[C:11]3[CH2:18][CH2:17][CH2:16][CH2:15][C:12]=3[C:13]2=[O:14])=[C:4]([F:20])[CH:3]=1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)c(Cl)cc1F
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 70.9 %

Procedure:
To a solution of N-(4-chloro-2-fluoro-5-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (1 g) in dimethylformamide (10 ml), there was added anhydrous potassium carbonate (0.34 g) while stirring at room temperature. After stirring for 30 minutes at about 40° C., propargyl bromide (1 g) was added thereto, and the resultant mixture was stirred for 3 hours at 50°-60° C. After being allowed to cool to room temperature, the mixture was poured into water and extracted with ether. The ether layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography to obtain 0.8 g of N-[4-chloro-2-fluoro-5-(2-propynyloxy)phenyl]-3,4,5,6-tetrahydrophthalimide (Compound No. 3). M.P., 136.4° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:8]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[C:14]([CH3:26])[CH:13]=2)(=[O:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.[C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)#[N:28].C(=O)([O-])[O-].[Cs+].[Cs+]>C(COC)OC.O>[C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:2]2[S:3][C:4]([S:8]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[C:14]([CH3:26])[CH:13]=3)(=[O:10])=[O:9])=[C:5]([CH3:7])[N:6]=2)=[CH:31][CH:30]=1)#[N:28]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(NS(=O)(=O)c2sc(Br)nc2C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(NS(=O)(=O)c2sc(-c3ccc(C#N)cc3)nc2C)c1
Temperature: 80 °C
Yield: 33.1 %

Procedure:
A solution of tert-butyl (6-{[(2-bromo-4-methyl-1,3-thiazol-5-yl)sulfonyl]amino}-4-methylpyridin-2-yl)carbamate (0.96 g, 2.08 mmol, 1 equiv), 4-cyanophenylboronic acid (0.336 g, 2.29 mmol, 1.1 equiv), and cesium carbonate (2.03 g, 6.24 mmol, 3 equiv) in 2:1 dimethoxyethane/water (30 mL) was purged with nitrogen for 15 minutes. Dichloro[1,1′-bis(diphenylphosphine)ferrocene] palladium (II) chloride (0.068 g, 0.08 mmol, 0.04 equiv) was then added, and the resulting mixture was purged with nitrogen for another 15 minutes. The reaction was heated to 80° C. for 1 h. After cooling to 24° C., the solution was concentrated in vacuo (˜25 mm Hg). The resulting aqueous mixture was extracted ethyl acetate (60 mL). The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by high performance flash chromatography (0→10% ethyl acetate in hexanes) provided the intermediate (0.334 g, 33%). 1H NMR (400 MHz, CDCl3), δ: 7.97 (d, J=8.3 Hz, 2H), 7.73 (d, J=8.3 Hz, 2H), 7.63 (br s, 1H), 7.43 (s, 1H), 6.90 (s, 1H), 2.65 (s, 3H), 2.32 (s, 3H), 1.50 (s, 9H); LRMS (ESI) m/z: 486.1.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=2)=[CH:6][CH:5]=1)([O-])=O.C(Cl)Cl.C(O)(=O)C.[H][H]>CO.[Pt]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Agent: [Pt]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: Nc1cc(Oc2ccc(N)c3ccccc23)ccn1

Procedure:
A solution of 4-(4-nitronaphthalen-1-yloxy)pyridin-2-amine (2.00 g, 7.11 mmol) in a mixture of methanol (70 mL), DCM (70 mL) and acetic acid (5 mL) was subjected to hydrogenation by passage through a Thales H-cube (1.0 mL min−1, RT, 55 mm 10% Pt/C Cat-Cart, full hydrogen mode) and was then evaporated in vacuo. The residue was taken up into DCM (100 mL), and was washed with sat. NaHCO3 (100 mL) and brine (100 mL) and then dried (MgSO4) and evaporated in vacuo. The crude product was purified by flash column chromatography (SiO2, 80 g, EtOAc in isohexane, 20 to 80%, gradient elution) to afford the title compound, Intermediate E as a brown solid (1.70 g, 85%); Rt 1.04 min (Method 2); m/z 252 (M+H)+ (ES+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][NH:13][C:12](=[O:15])[C@H:11]([NH:16]C(=O)OCC3C=CC=CC=3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1>[Pd].C1(C)C=CC=CC=1.CO>[NH2:16][C@@H:11]1[CH2:10][CH2:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[CH2:14][NH:13][C:12]1=[O:15]
Reactant: O=C(N[C@@H]1CC=C(c2ccc(O)cc2)CNC1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: Cc1ccccc1
Product: N[C@@H]1CCC(c2ccc(O)cc2)CNC1=O
Reaction time: 18 h

Procedure:
10% Palladium on carbon (10 mg) was added to a solution of benzyl (3R)-6-(4-hydroxyphenyl)-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate (15 mg, 0.043 mmol) in toluene (5 mL) and methanol (1 mL). The reation vessel is evacuated and back-filled with nitrogen (3×), then back-filled with hydrogen (1 atm). After 18 h, the mixture was filtered and concentrated. MS 221 (M+1).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([C:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]=1[NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1)[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[Br:19].[C:37](N1C=CN=C1)(N1C=CN=C1)=[O:38].O>C(#N)C>[Br:19][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:11]=1[CH:10]1[NH:9][C:37](=[O:38])[N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=2)[C:21]2[CH2:22][CH2:23][C:24](=[O:25])[C:20]1=2)[C:15]#[N:16]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N#Cc1ccc(C(N)C2=C(Nc3cccc(C(F)(F)F)c3)CCC2=O)c(Br)c1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)c(Br)c1
Temperature: 25 °C

Procedure:
Triethylamine (0.43 mL, 3.0 mmol) is added to a mixture of 4-(amino(5-oxo-2-(3-(tri-fluoromethyl)phenylamino)cyclopent-1-enyl)methyl)-3-bromobenzonitrile hydrochloride (intermediate 20, 5.90 g, 12.1 mmol) and 1,1′-carbonyldiimidazole (2.46 g, 15.2 mmol) in acetonitrile (60 mL), and the mixture is stirred at room temperature over night. Water (700 mL) is added and the precipitate is filtered, washed with water and dried. Yield: 5.45 g. ESI a) mass spectrum: [(79Br)-M+H]+=476, [(81Br)-M+H]+=478; Retention time HPLC: 1.10 min (X011_S01).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[C:13]([CH2:26][CH2:27][CH3:28])=[N:14][C:15]([O:18][C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[OH:29].[C:30]([O:35]C)(=[O:34])[C@@H:31]([CH3:33])O>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[C:13]([CH2:26][CH2:27][CH3:28])=[N:14][C:15]([O:18][C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[O:29][C@@H:31]([CH3:33])[C:30]([OH:35])=[O:34]
Reactant: CCCc1nc(Oc2ccc(Cl)cc2)ccc1-c1nn(C)c2cc(Cl)c(O)cc12
Reactant: COC(=O)[C@@H](C)O
Product: CCCc1nc(Oc2ccc(Cl)cc2)ccc1-c1nn(C)c2cc(Cl)c(O[C@@H](C)C(=O)O)cc12

Procedure:
The phenol from Step 2 (0.43 g, 1.0 mmol) and methyl (R)-lactate (0.16 g, 1.5 mmol) were reacted according the general procedure described in Step 11 of Example 1 to give the title compound as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[OH:17])=[CH:3][N:2]=1.[C:18]([C:20]1[CH:21]=[C:22]([S:27]([N:30]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][C:38]=2[O:45][CH3:46])[C:31]2[S:35][N:34]=[CH:33][N:32]=2)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1F)#[N:19].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:18]([C:20]1[CH:21]=[C:22]([S:27]([N:30]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][C:38]=2[O:45][CH3:46])[C:31]2[S:35][N:34]=[CH:33][N:32]=2)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[O:17][C:8]1[CH:9]=[CH:10][C:11]([C:13]([F:15])([F:16])[F:14])=[CH:12][C:7]=1[C:4]1[CH:5]=[CH:6][N:1]=[N:2][CH:3]=1)#[N:19]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Reactant: Oc1ccc(C(F)(F)F)cc1-c1ccnnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3-c3ccnnc3)c(C#N)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
To a solution of 2-pyridazin-4-yl-4-(trifluoromethyl)phenol (Preparation 712, 60.6 mg, 0.25 mmol) in dimethylsulfoxide (2.5 mL) was added 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 68, 109.2 mg, 0.25 mmol) followed by potassium carbonate (101.7 mg, 0.74 mmol). The resulting mixture was stirred overnight at room temperature under nitrogen. The reaction mixture was poured into water (125 mL), and extracted with ethyl acetate (3×25 mL). The combined organic extract was washed successively with aqueous sodium hydroxide solution (1M, 15 mL) and saturated aqueous sodium chloride solution (4×25 mL), dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo. The resulting residue was purified by column chromatography using a gradient of 25-40% v/v ethyl acetate in heptane to give the title compound as a white foam (59.7 mg, 36%).
Reaction SMILES: Cl[CH:2]([CH2:6][CH2:7][Cl:8])[C:3](=[O:5])[CH3:4].[C:9]([S-:11])#[N:10].[Na+]>C(O)C>[S:11]([CH:2]([CH2:6][CH2:7][Cl:8])[C:3](=[O:5])[CH3:4])[C:9]#[N:10]
Reactant: CC(=O)C(Cl)CCCl
Reactant: N#C[S-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)C(CCCl)SC#N
Yield: 86.7 %

Procedure:
A solution of 7.8 g (0.05 moles) of 3,5-dichloro-2-pentanone with 4.15 g (0.051 moles) of sodium rhodanide in 50 cm3 of ethanol is boiled for 2 hours under stirring. Then the procedure described in Example 1 is followed. 7.7 g (87%) of 3-thiocyanato-5-chloro-2-pentanone are obtained, which is identical in all respect with the product of Example 1 after distillation.
Reaction SMILES: [C:1]1([N:7]2[C:11]([B:12]([OH:14])[OH:13])=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:16]([C:19](O)([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C1(C)C=CC=CC=1.ClCCl>[C:1]1([N:7]2[C:11]([B:12]3[O:13][C:19]([CH3:21])([CH3:20])[C:16]([CH3:18])([CH3:17])[O:14]3)=[CH:10][CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(O)C(C)(C)O
Reactant: OB(O)c1ccnn1-c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC1(C)OB(c2ccnn2-c2ccccc2)OC1(C)C
Temperature: 40 °C
Reaction time: 48 h
Yield: 55.1 %

Procedure:
(1-Phenyl-1H-pyrazol-5-yl)boronic acid (25.0 g) was dissolved in toluene (700 mL), pinacol (18.0 g) was added at room temperature, and the mixture was stirred at 40° C. for 2 days. The reaction mixture was diluted with dichloromethane, washed successively with water and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The resulting solid was collected by filtration, and washed with hexane to give the title compound (19.8 g).