Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][CH2:16]Cl)=[CH:10][CH:9]=1>C(O)C>[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][CH2:16][N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:10][CH:9]=1
Reactant: Fc1ccc(C=CCCl)cc1
Reactant: C1CNCCN1
Solvent: CCO
Product: Fc1ccc(C=CCN2CCNCC2)cc1
Yield: 66.3 %

Procedure:
To a boiling solution of 32.4 g (376 mmoles) of anhydrous piperazine in 45 ml of anhydrous ethanol a solution of 6.3 g (37 mmoles) of 3-(4-fluorophenyl)-2-propenyl chloride in 60 ml of anhydrous ethanol is dropped under stirring and reflux cooling, within 1 hour. The solvent is removed in vacuo, the residue is dissolved in chloroform and washed with water to be free from piperazine. The organic phase is dried, evaporated and the crude product is--if necessary--distilled off in vacuo. Thus 5.4 g (66%) of the desired compound are obtained. B.p.: 148° C./80 Pa.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([OH:24])([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=O.Cl.[NH2:28][OH:29].N1C=CC=CC=1>C(O)C.C(OC)(C)(C)C>[F:1][C:2]([F:26])([F:25])[C:3]([OH:24])([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=[N:28][OH:29]
Reactant: Cc1ccc(C(=O)CC(O)(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: COC(C)(C)C
Solvent: CCO
Product: Cc1ccc(C(CC(O)(c2cccc(C(F)(F)F)c2)C(F)(F)F)=NO)cc1
Yield: 96.2 %

Procedure:
A solution of 4,4,4-trifluoro-3-hydroxy-1-(4-methylphenyl)-3-[3-(trifluoromethyl)phenyl]butan-1-one (1.0 g), hydroxylamine hydrochloride (0.28 g) and pyridine (0.42 g) in ethanol (10 mL) was heated to reflux for 5 hours. After the reaction solution was diluted with t-butylmethylether, the solution was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to yield 4,4,4-trifluoro-3-hydroxy-1-(4-methylphenyl)-3-[3-(trifluoromethyl)phenyl]butan-1-one oxime (1.0 g).
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.Cl[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=1>C(O)C>[CH2:6]([NH:3][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=1)[CH2:7][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCN(CC)CC
Solvent: CCO
Product: CCCCCCNc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
101 g of triethylamine and subsequently 50 g of n-hexylamino are placed into 600 ml of distilled anhydrous ethanol. An amount of 79 g of 2-chloro-5-nitropyridine is added portionwise at room temperature in the course of 15 minutes. The mixture is then heated to reflux temperature, whereby it goes into solution at 60° C. The solution is stirred for 24 hours at the reflux temperature and afterwards cooled to room temperature; the solution is poured into ice/water, and the formed precipitate filtered off. The 2-n-hexylamino-5-nitropyridine obtained after recrystallisation from ethanol/water melts at 56°-57° C.
Reaction SMILES: [CH3:1][C:2]([S:21]([CH3:24])(=[O:23])=[O:22])([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)=[CH:12][CH:11]=1)[C:3]([O:5]CC)=[O:4].O.[OH-].[Li+].O>O1CCCC1.CO.Cl>[CH3:1][C:2]([S:21]([CH3:24])(=[O:22])=[O:23])([CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)=[CH:14][CH:15]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(CCc1ccc(-n2cccn2)cc1)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(CCc1ccc(-n2cccn2)cc1)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-methyl-2-(methylsulfonyl)-4-[4-(1H-pyrazol-1-yl)phenyl]butanoate (316 mg, 0.902 mmol) in tetrahyrofuran/methanol (4:1, 10 mL) was added a solution of lithium hydroxide monohydrate in water (1.8 M, 3.61 mmol). The mixture was stirred at ambient temperature overnight. The mixture was diluted with aqueous 1N HCl and extracted with ether 2×. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to dryness to afford 2-methyl-2-(methylsulfonyl)-4-[4-(1H-pyrazol-1-yl)phenyl]butanoic acid as an oil. 286 mg. LCMS: (M−1) 321.3.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:12]=[C:13]([NH:27][C@H:28]([CH3:31])[CH2:29][OH:30])[C:14]2[S:19][C:18](=[O:20])[N:17](C3CCCCO3)[C:15]=2[N:16]=1.Cl>C(#N)C.O.O1CCCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:12]=[C:13]([NH:27][C@H:28]([CH3:31])[CH2:29][OH:30])[C:14]2[S:19][C:18](=[O:20])[NH:17][C:15]=2[N:16]=1
Reactant: C[C@H](CO)Nc1nc(SCc2cccc(F)c2F)nc2c1sc(=O)n2C1CCCCO1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](CO)Nc1nc(SCc2cccc(F)c2F)nc2[nH]c(=O)sc12
Temperature: 25 °C
Yield: 94.9 %

Procedure:
To a stirred solution of 5-[[(2,3-difluorophenyl)methyl]thio]-7-[[(1R)-2-hydroxy-1-methylethyl]amino]-3-(tetrahydro-2H-pyran-2-yl)thiazolo[4,5-d]pyrimidin-2-(3H)-one (10.0 g) in acetonitrile (200 ml), water (36 ml) and tetrahydrofuran (30 ml) at 65° C. was added 1M hydrochloric acid (23.25 ml) over 3 hours. The product crystallised during the addition time. The mixture was cooled to 25° C. and the product collected by filtration, washing firstly with water (30 ml) then acetonitrile (30 ml), to afford the title compound as an off-white solid (7.79 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([CH3:9])[CH:8]=1.[C-]#N.[Na+].[C-]#N.C[C:18]#[N:19]>CS(C)=O>[CH3:11][O:10][C:5]1[CH:4]=[C:3]([CH2:2][C:18]#[N:19])[CH:8]=[C:7]([CH3:9])[CH:6]=1
Reactant: COc1cc(C)cc(CBr)c1
Reactant: CC#N
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(C)cc(CC#N)c1
Temperature: 25 °C
Yield: 70 %

Procedure:
To a solution of 3-bromomethyl-5-methylanisole (17 g; 0.008 mol; from step (i) above) in DMSO (25 mL) was added NaCN (8.2 g; 0.16 mol). The mixture, which became very warm upon the addition of the cyanide, was left to cool to room temperature over 1 hour. CH3CN (25 mL) was then added, and the mixture refluxed for 1 hour. The reaction mixture was concentrated, water (200 mL) was added, and the resultant solution was extracted 3 times with ether. The combined organic phase was washed with water, dried (Na2SO4), and concentrated to give 9 g (70%) of the sub-title product as a yellow oil, which was used without further purification in the next step.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH:18]([CH3:32])[C:19]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([Cl:31])[CH:26]=3)([OH:24])[C:20]([F:23])([F:22])[F:21])[CH:12]=2)=[CH:6][C:5]=1[O:33][CH3:34].[Li+].[OH-]>C1COCC1.CO>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:35])=[O:2])=[C:5]([O:33][CH3:34])[CH:6]=2)=[CH:12][C:13]=1[CH:18]([CH3:32])[C:19]([C:25]1[CH:30]=[CH:29][N:28]=[C:27]([Cl:31])[CH:26]=1)([OH:24])[C:20]([F:23])([F:21])[F:22]
Reactant: COC(=O)c1ccc(Oc2ccc(Cl)c(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c2)cc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(Oc2ccc(Cl)c(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-{4-Chloro-3-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-2-methoxy-benzoic acid methyl ester (23 mg, obtained in Example 130, step 8) was dissolved in THF/methanol=5/1 (2.5 mL) followed by the addition of aqueous LiOH solution (1.0M, 0.074 mL). The mixture was stirred overnight at r.t. and then 1 hour at 50° C. The reaction mixture was cooled and evaporated. The residue was poured into water and extracted with ethyl acetate. The aqueous phase was acidified with 2 M aqueous HCl to pH 1 and extracted three times with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4 and the solvent was evaporated. The title compound was obtained as a colorless solid (14 mg, 63%) and was used without further purification. MS (neg. ion, m/e)=514.1 [(M−H)−].
Reaction SMILES: [CH3:1][C:2](=[N:7]O)[C:3](=O)[CH2:4][CH3:5].[C:9]1(=[O:16])[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10]1>>[CH3:1][C:2]1[NH:7][C:11]2[CH2:12][CH2:13][CH2:14][C:9](=[O:16])[C:10]=2[C:3]=1[CH2:4][CH3:5]
Reactant: O=C1CCCC(=O)C1
Reactant: CCC(=O)C(C)=NO
Product: CCc1c(C)[nH]c2c1C(=O)CCC2

Procedure:
In a specific embodiment, the invention provides a method of manufacturing molindone through a 3-step process, wherein in the 1st step 2,3-pentadione is reacted with hydroxylamine hydrochloride to produce 2,3-pentanedione-2-oxime (SUMO-1); in the 2nd step 2,3-pentanedione-2-oxime and 1,3-cyclohexanedione are reacted to produce 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (SUMO-2); and in the 3rd step 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole reacts with bismorpholinomethane to produce molindone (SUMO-3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C@@:10]3([C@@H:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH2:14][C:13](=[O:29])[NH:12][C@H:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:51][S:52]([NH2:55])(=[O:54])=[O:53].[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C@@:10]3([C@@H:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:28])([CH3:27])[C:25]([NH:55][S:52]([CH3:51])(=[O:54])=[O:53])=[O:26])[CH2:14][C:13](=[O:29])[NH:12][C@H:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc(F)cc1[C@@H]1NC(=O)C[C@H](c2cc(Cl)ccc2OC(C)(C)CO)[C@@]12C(=O)Nc1cc(Cl)ccc12
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1[C@@H]1NC(=O)C[C@H](c2cc(Cl)ccc2OC(C)(C)C(=O)NS(C)(=O)=O)[C@@]12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30.8 %

Procedure:
A solution of chiral (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxy-1,1-dimethyl-ethoxy)-phenyl]-2′-[5-fluoro-2-methylphenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (20 mg, 0.035 mmol) and CDI (11 mg, 0.068 mmol) in DMF (0.2 mL) was heated at 60° C. for 30 min, and then cooled to root temperature. To this solution was added a mixture of methanesulfonamide (19 mg, 0.2 mmol) and NaH (8 mg, 60%, 0.2 mmol) in DMF (0.2 mL). The resulting mixture was stirred at room temperature for 10 min, purified by prep-HPLC to give the title compound as a white solid (7 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:17]=[CH:16][C:10]([O:11][CH2:12][CH:13]2[O:15][CH2:14]2)=[CH:9][CH:8]=1.[NH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[CH:30][C:31](=[O:34])[NH:32][N:33]=2)=[CH:24][C:23]=1[CH3:35]>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:17]=[CH:16][C:10]([O:11][CH2:12][CH:13]([OH:15])[CH2:14][NH:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:29]=[CH:30][C:31](=[O:34])[NH:32][N:33]=3)=[CH:24][C:23]=2[CH3:35])=[CH:9][CH:8]=1
Reactant: COCCOCc1ccc(OCC2CO2)cc1
Reactant: Cc1cc(-c2ccc(=O)[nH]n2)ccc1OCCN
Product: COCCOCc1ccc(OCC(O)CNCCOc2ccc(-c3ccc(=O)[nH]n3)cc2C)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-methoxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-methyl-phenyl]-3(2H)-pyridazinone.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:19][C:20]([Br:23])=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:31]=[CH:32][CH:33]=[CH:34][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:24]([OH:26])=[O:25])=[CH:19][C:20]([Br:23])=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:31]=[CH:32][CH:33]=[CH:34][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccc(Br)cc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccc(Br)cc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-benzimidazol-1-yl)-methyl]-4-bromo-biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=O)[CH2:15][CH2:16][C:17]2([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][C:17]2([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCC1(c2ccc(F)cc2)CCCCC1)N1CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(C2(CCCN3CCN(Cc4ccccc4)CC3)CCCCC2)cc1
Yield: 78.6 %

Procedure:
1-Benzyl-4-[3-[1-(4-fluorophenyl)cyclohexyl]-1-oxopropyl]piperazine (5.90 g) was dissolved in tetrahydrofuran (100 ml), and 80% lithium aluminum hydride, (1.03 g) was added thereto under ice-cooling. After heating under reflux for 1.5 hours, the mixture was cooled as it was to room temperature. Under ice-cooling, water, a 1N aqueous sodium hydroxide and further water were added thereto, and the insoluble matters were filtered off. The filtrate was evaporated, and the resulting residue was recrystallized from ethanol, to give 4.48 g (79%) of the title compound as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:17]([C:18]#[N:19])=[CH:16][O:15][CH:14]3[C:20]4[C:24](=[CH:25][CH:26]=[C:13]23)[N:23]=[CH:22][CH:21]=4)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].IC.[C:29](=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:17]([C:18]#[N:19])=[CH:16][O:15][C:14]3[C:20]4[CH:21]=[CH:22][N:23]([CH3:29])[C:24]=4[CH:25]=[CH:26][C:13]2=3)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C2C(C#N)=COC3C4=CC=NC4=CC=C32)cc(Br)c1OC
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(C2C(C#N)=COc3c2ccc2c3ccn2C)cc(Br)c1OC
Temperature: 25 °C
Yield: 96.7 %

Procedure:
A mixture of 4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-indolo[4,5-b]pyran (51 mg, 0.124 mmol), iodomethane (23 μL, 0.370 mmol) and cesium carbonate (120 mg, 0.368 mmol) in acetone (2 mL) was stirred at room temperature in a sealed tube. After stirring at room temperature for 2.5 days, the reaction was diluted with EtOAc (20 mL). The insoluble material was filtered, and washed with EtOAc (30 mL). The EtOAc solution were combined, washed with brine (2×5 mL), dried over MgSO4, and evaporated to yield an off-white solid. The crude product was purified by column chromatography (silica gel, EtOAc:hexanes, 1:1) to yield 51 mg (97%) of an off-white solid. 1H NMR (CDCl3): 7.43 (d, J=0.6 Hz, 1H), 7.07 (d, J=3.3 Hz, 1H), 7.05 (dd, J=0.6, 8.4 Hz, 1H), 6.95 (d, J=2.1 Hz, 1H), 6.76 (d, J=2.4 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 6.58 (dd, J=0.6, 3.3 Hz, 1H), 4.81 (s, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.78 (s, 3H).
Reaction SMILES: [N-]=[C:2]=[O:3].[F:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:6]=1[C:7]([NH2:9])=[O:8].C(Cl)(=O)C(Cl)=O.Cl>ClCCCl>[F:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:6]=1[C:7]([N:9]=[C:2]=[O:3])=[O:8]
Reactant: NC(=O)c1c(F)cccc1F
Reactant: [N-]=C=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1c(F)cccc1F

Procedure:
In order to synthesize the isocyanate, 1.57 g (10 mmol) of 2,6-difluorobenzamide and 15 ml of dry 1,2-dichloroethane were introduced into a 100 ml flask and then 0.92 g (10.5 mmol) of oxalyl chloride was slowly added thereto at normal temperature by means of a syringe, during which an exothermic reaction occurred that generated hydrochloride gas. The resulting reaction mixture was refluxed for 5 hours and cooled to normal temperature. The reaction solvent and the excess oxalyl chloride were removed therefrom under vacuo to obtain 2,6-difluorobenzoyl isocyanate in an oily state. Thus obtained 2,6-difluorobenzoyl isocyanate was then dissolved in 20 ml of dry 1,2-dichloroethane. Then, 2.63 g of 2-chloro-3,5-bis(trifluoromethyl)aniline was added thereto, reacted for 3 hours, and filtered to obtain 4.15 g (Yield from benzamide, 93%) of the title compound as a solid.
Reaction SMILES: [ClH:1].[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].Cl.[C:12]([CH2:15][CH2:16][C:17]([NH:19][CH2:20][C:21]1[O:25][C:24]([C:26]([O:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:39](=[NH:41])[NH2:40])[CH:35]=3)[CH:30]=2)=[O:27])=[CH:23][CH:22]=1)=[O:18])(O)=[O:13].CN(C=O)C.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[ClH:1].[C:2]([O:6][C:7]([CH2:8][NH:9][C:12]([CH2:15][CH2:16][C:17]([NH:19][CH2:20][C:21]1[O:25][C:24]([C:26]([O:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:39](=[NH:40])[NH2:41])[CH:35]=3)[CH:30]=2)=[O:27])=[CH:23][CH:22]=1)=[O:18])=[O:13])=[O:10])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN
Reactant: N=C(N)c1ccc2cc(OC(=O)c3ccc(CNC(=O)CCC(=O)O)o3)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNC(=O)CCC(=O)NCc1ccc(C(=O)Oc2ccc3cc(C(=N)N)ccc3c2)o1
Reaction time: 0.17 h
Yield: 74.4 %

Procedure:
To 0.75 g of glycine t-butyl ester hydrochloride, 0.15 g of DMAP and 1.5 g of 6-amidino-2-naphthyl 5-(3-carboxypropionylaminomethyl)furan-2-carboxylate hydrochloride were added 20 ml of DMF and 1 ml of pyridine, and the mixture was stirred while cooling with ice. After 10 minutes, 0.9 g of DCC was added thereto, and the mixture was stirred for 3 hours while cooling with ice and then for 24 hours at room temperature. The precipitate was filtered off, the filtrate was added in small portions to 300 ml of ether, and the mixture was stirred at room temperature for 3 hours. The supernatant was decanted, then 200 ml of ether was added to the residue and stirred at room temperature for 19 hours. The precipitate was collected by filtration, then dissolved in 15 ml of methanol, 0.4 g of active carbon was added thereto and the mixture was stirred for 15 minutes while cooling with ice. The insoluble was filtered off, the filtrate was added to 200 ml of ether and the mixture was stirred for 5 hours while cooling with ice. The precipitate was collected by filtration to obtain 1.4 g of the intended product.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18](NC1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH2:38]([SH:48])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>>[CH2:38]([S:48][C:18](=[O:19])[CH2:17][S:14](=[O:15])(=[O:16])[NH:13][C:5]1[C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:10]([CH3:12])[CH3:11])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CCCCCCCCCCS
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Product: CCCCCCCCCCSC(=O)CS(=O)(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with decanthiol, mp 57°-59° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:31])=[C:4]([C:8]2[N:9]=[C:10]([C:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=1[S:40](Cl)(=[O:42])=[O:41]>N1C=CC=CC=1>[Cl:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:22])[CH3:21])=[N:9][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:40]([C:34]3[C:35]([F:39])=[CH:36][CH:37]=[CH:38][C:33]=3[F:32])(=[O:42])=[O:41])[C:3]=2[F:31])[CH:18]=[CH:17][N:16]=1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.8 %

Procedure:
To a solution of 1,1-dimethylethyl {1-[4-(3-amino-2-fluorophenyl)-5-(2-chloro-4-pyrimidinyl)-1,3-thiazol-2-yl]-1-methylethyl}carbamate (400 mg, 0.862 mmol) in pyridine (50 mL) was added dropwise 2,6-difluorobenzenesulfonyl chloride (238 mg, 1.121 mmol). After 4 h, 2,6-difluorobenzenesulfonyl chloride (0.20 g) was added to the reaction mixture and stirred at rt overnight. The reaction mixture was concentrated. The residue was purified via chromatography on silica gel to obtain the title compound (330 mg 59% yield). MS (ESI): 639.9 [M+H]+
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:33])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@H:24]([CH2:27][CH2:28][C:29](=[O:31])[CH3:30])[CH2:25][CH3:26])[C:5]1=[O:32])[CH:2]=[CH2:3].[CH3:34][Mg]Br>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([C@@:4]1([CH3:33])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@H:24]([CH2:27][CH2:28][C:29]([OH:31])([CH3:34])[CH3:30])[CH2:25][CH3:26])[C:5]1=[O:32])[CH:2]=[CH2:3]
Reactant: C[Mg]Br
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CCC(C)=O)C1=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CCC(C)(C)O)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-6-oxoheptan-3-yl)piperidin-2-one prepared above in Step C (78 mg, 0.16 mmol) in THF (1.6 mL) was added 1.4 M methylmagnesium bromide in toluene and THF (75:25) (344 μL, 0.481 mmol) at 0° C. Then the reaction was allowed to warm to rt and stirred for 2 h. The reaction was quenched (sat NH4Cl solution), extracted (2×EtOAc), and washed (sat. aq. NaCl solution). The combined organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (12 g SiO2, 33% and 43% EtOAc/Hex) provided the title compound as a colorless foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:12]=[C:13]3[C:19]([C:20]([NH:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25])=[O:21])=[CH:18][N:17](COCC[Si](C)(C)C)[C:14]3=[N:15][CH:16]=1)[N:6]=[CH:5]2.FC(F)(F)C(O)=O>ClCCl>[OH:25][CH2:24][C:23]([NH:22][C:20]([C:19]1[C:13]2[C:14](=[N:15][CH:16]=[C:11]([N:7]3[C:8]4[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=4)[CH:5]=[N:6]3)[N:12]=2)[NH:17][CH:18]=1)=[O:21])([CH3:27])[CH3:26]
Reactant: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4cc(Cl)ccc43)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CO)NC(=O)c1c[nH]c2ncc(-n3ncc4cc(Cl)ccc43)nc12
Yield: 62.2 %

Procedure:
2-(5-Chloro-1H-indazol-1-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (124 mg, 241 μmol) was dissolved in dichloromethane (3 mL) then trifluoroacetic acid (1 mL) added. After 15 h the mixture was concentrated in vacuo and Jan. 10, 1960 ammonium hydroxide/methanol/dichloromethane solution (25 mL) added. After 1 h the mixture was concentrated in vacuo and purified by chromatography (silica, 24 g Analogix column, 0-4% of methanol containing 10% ammonium hydroxide in dichloromethane) to give 2-(5-chloro-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)amide (57.7 mg, 62%) as a solid. MS (M+H)+=385; 1H NMR (DMSO-d6) δ: 9.04 (s, 1H), 8.70 (d, J=9.0 Hz, 1H), 8.53 (s, 1H), 8.43 (s, 1H), 8.07 (d, J=1.5 Hz, 1H), 7.63 (s, 1H), 7.60 (d, J=2.1 Hz, 1H), 3.59 (d, J=5.7 Hz, 2H), 1.44 (s, 6H).