Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:12]([C:13]1[CH:14]=[CH:15][C:16]([Br:19])=[CH:17][CH:18]=1)[C:48]([CH3:50])([CH3:49])[CH:47]2[OH:51])=[O:20])[CH3:2]
Reactant: CC(C)C=O
Reactant: CCOC(=O)c1ccc(N=Cc2ccc(Br)cc2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1ccc(Br)cc1)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.8 %

Procedure:
To a mixture of 4-{[1-(4-bromo-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (9.8 g, 29.5 mmol) and ytterbium(III) triflate hydrate (1.83 g, 2.95 mmol) in dry tetrahydrofuran (20 mL) at 25° C. was added isobutyraldehyde (2.1 g, 29.5 mmol) and water (0.53 mL, 29.5 mmol) dropwise. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(4-bromo-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (11.9 g, 100%) as a light yellow oil: LC/MS m/e calcd for C20H22BrNO3 M+: 404.3, observed: 404.1, 406.1.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].O.O.O.O.O.O.O.O.O.[S-2:17].[Na+].[Na+].C([O:23][CH2:24][C:25]([CH2:27]Cl)=O)(=O)C.C(N(CC)CC)C>CO.O>[NH2:2][C:1]1[S:17][CH:27]=[C:25]([CH2:24][OH:23])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC(=O)OCC(=O)CCl
Reactant: [S-2]
Reactant: COC(=O)CC#N
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1c(CO)csc1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.3 %

Procedure:
A solution of methyl cyanoacetate (1.18 mL, 13.28 mmol) and sodium sulfide nonahydrate (3.20 g, 13.28 mmol) in methanol (25 mL) at 0° C. was treated with 1-acetoxy-3-chloroacetone (2.0 g, 13.28 mmol). The cold bath was removed and triethylamine (1.86 mL, 13.28 mmol) was added dropwise. The solution was stirred at room temperature for 20 hours then diluted with water and extracted into ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and the solvent removed under vacuum to provide the titled compound (1.25 g, 51%). MS (DCI/NH3) M/Z 188 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 3.68 (s, 3 H) 4.45 (dd, J=5.52, 1.47 Hz, 2 H) 4.88 (t, J=5.70 Hz, 1 H) 6.12 (s, 1 H) 7.28 (s, 2 H)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=3)[CH:14]=2)=[N:2]1.[NH2:24][CH:25]1[CH2:29][CH2:28][N:27]([CH3:30])[C:26]1=[O:31]>C(#N)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:16]=[CH:17][C:18]([C:19]([NH:24][CH:25]4[CH2:29][CH2:28][N:27]([CH3:30])[C:26]4=[O:31])=[O:21])=[CH:22][CH:23]=3)[CH:14]=2)=[N:2]1
Reactant: CN1CCC(N)C1=O
Reactant: O=C(O)c1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Solvent: CC#N
Product: CN1CCC(NC(=O)c2ccc(-n3cc(-c4n[nH]c5ccccc45)nn3)cc2)C1=O

Procedure:
The title compound was obtained following procedure described for example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoic acid (100 mg; 0.33 mmol; 1.0 eq.) and 3-amino-1-methylpyrrolidin-2-one (Chem Bridge Corp., 56 mg, 0.49 mmol, 1.5 eq.). The crude obtained was suspended in acetonitrile, filtered and dried to afford the title compound as a beige powder. 1H NMR (300 Mz, DMSO-d6) δ 13.38 (s, 1H), 9.43 (s, 1H), 8.94 (d, J=8.4 Hz, 1H), 8.36 (d, J=8.1 Hz, 1H), 8.21 (d, J=8.8 Hz, 2H), 8.11 (d, J=8.8 Hz, 2H), 7.61 (d, J=8.4 Hz, 1H), 7.50-7.38 (m, 1H), 7.31-7.15 (m, 1H), 4.74-4.52 (m, 1H), 3.42-3.32 (m, 2H), 2.77 (s, J=7.8 Hz, 3H), 2.44-2.27 (m, 1H), 2.13-1.85 (m, 1H). HPLC (Condition A): Rt 2.69 min (purity 92.2%). MS (ESI+): 402.3, MS (ESI−): 400.3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:13][N:12]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[S:17]([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH2:36][NH2:37])[CH:34]=2)[CH:29]=[CH:28]1)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18].CCN(C(C)C)C(C)C>CCCCO>[CH:14]1([C:11]2[NH:12][N:13]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:37][CH2:36][C:33]4[CH:34]=[C:35]5[C:30]([CH:29]=[CH:28][N:27]5[S:17]([C:20]5[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=5)(=[O:19])=[O:18])=[CH:31][CH:32]=4)[N:7]=3)[CH:10]=2)[CH2:16][CH2:15]1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3ccc(CN)cc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3ccc(CNc4nccc(Nc5cc(C6CC6)[nH]n5)n4)cc32)cc1
Yield: 96.4 %

Procedure:
A microwave vial was charged with 53 (80 mg, 0.34 mmol), 36 (80 mg, 0.27 mmol), DIPEA (0.2 mL) and n-BuOH (2.0 mL), sealed and irradiated in a microwave reactor at 180° C. for 80 min. The reaction mixture was concentrated and purified with a CombiFlash® to afford 130 mg (95%) of N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-((1-tosyl-1H-indol-6-yl)methyl)pyrimidine-2,4-diamine (38) as yellow solid; MS (ESI) m/z=500.1 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[CH:4](Cl)Cl.S(=O)(=O)(O)[OH:14]>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[CH:4]=[O:14]
Reactant: Fc1cc(C(Cl)Cl)c(Cl)cc1Cl
Reactant: O=S(=O)(O)O
Product: O=Cc1cc(F)c(Cl)cc1Cl

Procedure:
reacting 2,4-dichloro-5-fluorobenzal chloride of the formula ##STR13## with sulphuric acid to obtain 2,4-dichloro-5-fluorobenzaldehyde of the formula ##STR14## then chlorinating to give the compound of formula (I).
Reaction SMILES: [CH3:1][S:2]([CH3:4])=[O:3].C(OC(=O)C)(=O)C.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:18]S(C)=O.[C:22](#[N:24])C>C(Cl)Cl>[CH:17]1([N:12]=[C:22]=[NH:24])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:18]1.[CH3:1][S:2]([CH3:4])=[O:3]
Reactant: c1ccncc1
Reactant: CC#N
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CS(C)=O
Product: N=C=NC1CCCCC1

Procedure:
In words relative to the above diagram for the preparation of 1, the 4-(2-acetoxyvinyl)azetidine-2-one (3) is prepared by reacting chloro sulphonyl isocyanate and an acyloxybutadiene such as 1-acetoxybutadiene in a solvent such as anhydrous dimethyl ether at a temperature of from about -30° C. to 0° C. under a nitrogen atmosphere. The reaction intermediate 2 is converted to 3 by hydrolysis. The reduction of 3 to provide the 4-(2-acetoxyethyl)-2-azetidinone (4) is conducted by any convenient means such as hydrogenation in the presence of a catalyst such as platinum, palladium or oxides thereof under a hydrogen pressure of from 1 to 20 atmospheres in a solvent such as ethanol, ethylacetate, or the like at a temperature of from 0° to 25° C., for from 5 minutes to 1 hour. The 4-(2-hydroxyethyl)-2-azetidinone species, 5, is obtained from 4 by hydrolysis. The 8-oxo- 2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octane species, 6, is obtained on treatment of 5 with 2,2-dimethoxypropane in the presence of a catalyst such as boron trifluoride etherate in a solvent such as methylene chloride at a temperature of from 0° to 40° C. for from 1 to 40 minutes. Alternatively, 5 can be treated with borontrifluoride etherate and trimethylorthoformate to give 8-oxo-2-methoxy-3-oxa-1-azabicyclo[4.2.0]octane which can be mono- or dialkylated following the procedures for 6→7 or 8. Alkylation of 6 provides 7. Typically, 6 is treated with a strong base such as lithium diisopropyl amide, sodium hydride, phenyl lithium or butyl lithium and the like in a solvent such as tetrahydrofuran (THF), ether, dimethoxyethane and the like at a temperature of from -80° C. to 0° C., whereupon the alkylating agent of choice, R1X, is added (R1 is as described above and X is chloro or bromo; alternatively the alkylating agent may be R1 -tosylate, R1 -mesylate or an aldehyde or ketone such as acetaldehyde and the like) to provide mono- alkylated species 7. When desired dialkylated species 8 may be obtained from 7 by repeating the alkylating procedure, 6→7. Species 9 is obtained from 7 or 8 by acid hydrolysis. Oxidation of 9 with an oxidizing agent such as DMSO-acetic anhydride, pyridine.CrO3, cyclohexylcarbodiimide/DMSO, and the like in a solvent such as DMSO, pyridine, acetonitrile, methylene chloride, and the like at a temperature of from about 0° to 25° C. for from 0.5 to 12 hours provides 10 which upon treatment with the Grignard reagent R3MgX (R3 is as defined above and X is halogen) provides 11. Typically, the alkylation reaction 10→11 is conducted in a solvent such as ether, THF, benzene and the like at a temperature of from -78° to about 25° C. at from 0.5 to about 24 hours.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][CH2:10][O:11][C:12]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])=[O:13])[N:8]=1)([CH3:3])[CH3:2].[NH2:22][C@H:23]([C@@H:31]([OH:51])[CH2:32][C@@H:33]([NH:41][C:42]([O:44][CH2:45][C:46]1[S:50][CH:49]=[N:48][CH:47]=1)=[O:43])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][CH2:10][O:11][C:12]([NH:14][C@H:15]([C:19]([NH:22][C@H:23]([C@@H:31]([OH:51])[CH2:32][C@@H:33]([NH:41][C:42]([O:44][CH2:45][C:46]2[S:50][CH:49]=[N:48][CH:47]=2)=[O:43])[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:21])[CH:16]([CH3:17])[CH3:18])=[O:13])[N:8]=1)([CH3:2])[CH3:3]
Reactant: N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Reactant: CC(C)c1nc(CCOC(=O)N[C@H](C(=O)O)C(C)C)cs1
Product: CC(C)c1nc(CCOC(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1

Procedure:
Using the procedure of Example 1U, but replacing N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine with N-((2-(2-isopropyl-4-thiazolyl)ethoxy)carbonyl)valine and replacing (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane with (2S,3S,5S)-2-amino-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane provided, after purification by silica gel chromatography using 99:1 CHCl3 :CH3OH, 50 mg (30%) of the desired compound (Rf 0.3, 95:5 CHCl3 :CH3OH) as a solid, mp 159-160° C. Mass spectrum: (M+H)+ =722 HRMS. Exact mass calcd for C37H47N5O6S2 : 722.3046. Found: 722.3036.
Reaction SMILES: [C:1]1([C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH2:10]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14]C1C=CC(C(=O)C)=CC=1>CCOC(C)=O>[CH3:14][C:4]1[CH:3]=[CH:2][C:1]([C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH3:10])=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccc(C)cc1
Reactant: CCC(=O)CC(=O)c1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)c1ccc(C)cc1

Procedure:
The title compound was prepared (as described above for Intermediate 16) from 2.0 g of 4′-methylacetophenone and 2.9 mL of EtOAc to yield 1.68 grams of Intermediate 27: TLC analysis: Rf=0.61 (5/1, hexanes/EtOAc), 1H NMR (400 MHz, CDCl3, enol form) δ7.72 (d, 2H, J=8.2), 7.24 (d, 2H, J=7.4), 6.15 (s, 1H), 2.4 (s, 3H), 2.2 (s, 3H).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]4[CH2:28][CH2:27][CH2:26][C:12]=4[N:13]=[C:14]([N:16]4[CH2:20][C@H:19]([O:21][CH3:22])[CH2:18][CH:17]4[C:23]([OH:25])=[O:24])[N:15]=3)[CH:5]=2)[CH2:3][CH2:2]1.[CH:29]1C=CC2N(O)N=NC=2C=1.O.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>CO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]4[CH2:28][CH2:27][CH2:26][C:12]=4[N:13]=[C:14]([N:16]4[CH2:20][C@H:19]([O:21][CH3:22])[CH2:18][CH:17]4[C:23]([O:25][CH3:29])=[O:24])[N:15]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CO[C@@H]1CC(C(=O)O)N(c2nc3c(c(Nc4cc(C5CC5)[nH]n4)n2)CCC3)C1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Solvent: CN1CCOCC1
Solvent: O
Product: COC(=O)C1C[C@@H](OC)CN1c1nc2c(c(Nc3cc(C4CC4)[nH]n3)n1)CCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (4R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxypyrrolidine-2-carboxylic acid (3.5 g, 9.11 mmol) in MeOH (20 mL) was added HOBt.H2O (2.27 g, 4.56 mmol), N-methylmorpholine (2 mL, 18.22 mmol) and EDCI.HCl (2.44 g, 12.75 mmol). The reaction mixture was allowed to stir at RT for 1 h. MeOH was removed under reduced pressure and the residue was dissolved in EtOAc (200 mL). The solution was washed with water (10×100 mL) followed by brine (100 mL) and dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure afforded (4R)-methyl 1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxypyrrolidine-2-carboxylate (3 g).
Reaction SMILES: [CH:1]1([CH2:6][N:7]([C:20]2[CH:25]=[CH:24][C:23](S(C)(=O)=O)=[CH:22][CH:21]=2)[C:8](=[O:19])[NH:9][C:10]2[S:11][CH:12]=[C:13](CC(O)=O)[N:14]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(CNC2C=CC=[C:39]([C:43](=[O:45])C)C=2)CCCC1.C([O:48][C:49](=[O:58])[CH2:50][S:51]C1SC(N)=NC=1)C>>[C:43]([C:24]1[CH:25]=[C:20]([N:7]([CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8](=[O:19])[NH:9][C:10]2[S:11][C:12]([S:51][CH2:50][C:49]([OH:48])=[O:58])=[CH:13][N:14]=2)[CH:21]=[CH:22][CH:23]=1)(=[O:45])[CH3:39]
Reactant: CC(=O)c1cccc(NCC2CCCC2)c1
Reactant: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Reactant: CCOC(=O)CSc1cnc(N)s1
Product: CC(=O)c1cccc(N(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)c1

Procedure:
The title compound was prepared via {2-[3-(3-acetyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl esterin a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(3-acetyl-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1O.C(N1C=CN=C1)(N1C=CN=C1)=O>C1COCC1>[O:12]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:10]1[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][OH:1])=[CH:8][CH:7]=1
Reactant: Nc1ccccc1O
Reactant: O=C(O)Cc1ccc(CO)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: OCc1ccc(Cc2nc3ccccc3o2)cc1
Temperature: 180 °C
Reaction time: 72 h
Yield: 20.8 %

Procedure:
A mixture of (4-hydroxymethyl-phenyl)-acetic acid (5.0 g, 30.1 mmol) and 2-amino-phenol (6.6 g, 60.2 mmol) was heated at 180° C. for 3 h. The crude residue was cooled and then dissolved in THF (50 mL). The resulting solution was treated with carbonyldiimidazole (3.7 g, 22.5 mmol) and stirred at 80° C. for 72 h. The reaction mixture was then partitioned between EtOAc (200 mL) and water (200 mL). The organic layer was dried (MgSO4), filtered and concentrated. Purification by silica gel flash chromatography (0% to 80% EtOAc in hexanes) followed by a second silica gel flash chromatography (0% to 10% CH3OH in CH2Cl2) afforded a colorless oil. The crude oil was then partitioned between EtOAc (200 mL) and 1 N NaOH (200 mL). The organic layer was dried (MgSO4), filtered and concentrated to afford the title compound as a colorless oil (1.5 g, 20%). MS (ESI): mass calcd. for C15H13NO2, 239.09; m/z found, 240.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.70-7.68 (m, 1H), 7.49-7.46 (m, 1H), 7.40-7.35 (m, 4H), 7.33-7.29 (m, 2H), 4.69 (br d, J=4.5 Hz, 2H), 4.28 (s, 2H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([S:16][C:17]1[S:18][C:19]([C:23]#[N:24])=[C:20]([NH2:22])[N:21]=1)[CH2:13][CH2:14][CH3:15].C(=O)(O)[O-].[Na+].[OH2:30]>C(Cl)Cl>[CH2:12]([S:16]([C:17]1[S:18][C:19]([C:23]#[N:24])=[C:20]([NH2:22])[N:21]=1)(=[O:9])=[O:30])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCSc1nc(N)c(C#N)s1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCS(=O)(=O)c1nc(N)c(C#N)s1
Temperature: 25 °C

Procedure:
9.0 g of 85% m-chloroperbenzoic acid are added in portions to a solution of 4.26 g of 2-n-butylthio-4-amino-5-cyanothiazole in 200 ml of methylene chloride, while stirring and at room temperature. After stirring overnight at room temperature an excess of sodium bicarbonate in water is added and the solution is stirred for one hour. The organic layer is separated, washed with water, dried, filtered and diluted with isopropanol. After distilling off a part of the methylene chloride the desired product crystallises: yield 4.34 g; melting-point 150°-152° C.; TLC: Rf (CH2Cl2) 0.05.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:26])=[C:8]([C:16]([C:18]2[CH:19]=[N:20][N:21]([CH2:24][CH3:25])[C:22]=2[OH:23])=[O:17])[CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13].C(N(CC)CC)C.[CH3:34][CH2:35][S:36][C:37](Cl)=[O:38].C(OCC)(=O)C>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:26])=[C:8]([C:16]([C:18]2[CH:19]=[N:20][N:21]([CH2:24][CH3:25])[C:22]=2[O:23][C:37]([S:36][CH2:35][CH3:34])=[O:38])=[O:17])[CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(OCCOC)c2C)c1O
Reactant: CCSC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCSC(=O)Oc1c(C(=O)c2ccc(S(C)(=O)=O)c(OCCOC)c2C)cnn1CC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude 5-hydroxy-1-ethylpyrazol-4-yl 3-(2-methoxyethoxy)-2-methyl-4-(methylsulfonyl)phenyl ketone obtained in the above step (1) was dissolved in anhydrous THF (10 mL), and triethylamine (139 mg) and 96% S-ethyl chlorothiolformate (111 mg) were added, followed by stirring for 1 hour at room temperature. Ethyl acetate (200 mL) was added to the obtained reaction mixture, and the mixture was washed twice with a saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the desired product (170 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:25])[N:7]2[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([O:23][CH3:24])=[O:22])[CH:15]=1.FC1C=CC(F)=CC=1B(O)O.ClC1C=CC=C(Cl)C=1N1C2C(=C([C:57]3[CH:62]=[CH:61][C:60]([F:63])=[CH:59][C:58]=3[F:64])C=C(OC)C=2)CCC1=O>>[F:63][C:60]1[CH:59]=[C:58]([F:64])[CH:57]=[CH:62][C:61]=1[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:25])[N:7]2[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([O:23][CH3:24])=[O:22])[CH:15]=1
Reactant: COc1cc(-c2ccc(F)cc2F)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Reactant: COC(=O)c1ccc(C)c(N2C(=O)CCc3c(Br)cc(OC)cc32)c1
Agent: OB(O)c1cc(F)ccc1F
Product: COC(=O)c1ccc(C)c(N2C(=O)CCc3c(-c4ccc(F)cc4F)cc(OC)cc32)c1

Procedure:
5-(2,4-Difluorophenyl)-3,4-dihydro-7-methoxy-1-(3-methoxycarbonyl-6-methylphenyl)-2(1H)-quinolinone was prepared from 5-bromo-3,4-dihydro-7-methoxy-1-(3-methoxycarbonyl-6-methylphenyl)-2(1H)-quinolinone (INTERMEDIATE 14) and 2,5-difluorophenylboronic acid by a procedure analogous to that described in INTERMEDIATE 2. Mass spectrum (ESI) 438.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.06 (d, J=5.0 Hz, 1H); 7.89 (s, 1H); 7.42 (d, J=5.0 Hz, 2H); 7.01 (m, 2H); 6.49 (s, 1H); 5.86 (s, 1H); 3.95 (s, 3H); 3.68 (s, 3H); 2.81 (m, 4H); 2.21 (s, 3H).
Reaction SMILES: [CH2:1]([CH2:11]/[C:12](/[CH3:24])=[CH:13]/[CH2:14][CH2:15]/[C:16](/[CH3:23])=[CH:17]/[CH2:18][CH2:19]C(=O)C)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].ClCC([O:29][CH2:30][CH3:31])=O.[O-][CH2:33]C.[Na+].[OH-].[K+]>CO.O>[CH3:33][CH:31]([CH2:19][CH2:18][CH:17]=[C:16]([CH3:23])[CH2:15][CH2:14][CH:13]=[C:12]([CH3:24])[CH2:11][CH2:1][CH:2]=[C:3]([CH3:4])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH:30]=[O:29]
Reactant: CC(=O)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CCC=C(C)C
Reactant: CCOC(=O)CCl
Reactant: CC[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)C=O
Temperature: 150 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
To a mixture of geranylgeranylacetone (32.2 g) and ethyl monochloroacetate (17.2 g), sodium ethoxide (8.85 g) is portionwise added at -10°C in nitrogen stream. The resultant mixture is stirred for 7 hours, a solution of potassium hydroxide (99 g) in methanol (560 ml) is added thereto, stirring is continued for 3 hours and then the resulting mixture is allowed to stand overnight. Then, the reaction mixture is poured into water, washed with petroleum ether, neutralized with acetic acid and extracted with ether. The ether extract is washed with water, dried and evaporated. The residue is heated at 150°C for 30 minutes for decarboxylation. The resulting crude produce (31 g) is purified by chromatography on silica gel (300 g) using benzene to give 2,6,10,14,18-pentamethyl-5,9,13,17-nonadecatetraenal (23.8 g). IR: 2680, 1720 cm-1 (CHO).
Reaction SMILES: [C:1]12([O:14]CCO1)[C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:10])[C:4]=1[CH2:3][CH2:2]2.[C:15](Cl)(=[O:17])[CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>N1C=CC=CC=1>[O:14]=[C:1]1[C:9]2[C:4](=[C:5]([NH:10][C:15](=[O:17])[CH3:16])[CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)Cl
Reactant: Nc1cccc2c1CCC21OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1cccc2c1CCC2=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a vigorously stirred solution of Example 25 (3.9 g, 20.6 mmol) in pyridine (40 mL) was slowly added acetyl chloride (1.6 mL, 22.6 mmol). The reaction was stirred at room temperature for about 15 minutes and then the solvent was removed under vacuum. The residue was dissolved in acetone (38 mL) and water (12 mL) and p-toluenesulfonic acid (3.9 g, 20.6 mmol) was added. The mixture was heated to reflux for about 1 hour, cooled, and concentrated under vacuum. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with saturated aqueous sodium bicarbonate, dried (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel using hexane/ethyl acetate (1:1) as the mobile phase to provide the desired product. MS (ESI): m/z 188 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][CH2:22][C:23]1[N:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:16])([F:17])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:26]3[CH:25]=[N:24][C:23]([CH2:22][F:21])=[CH:28][N:27]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reactant: O=C(O)c1cnc(CF)cn1
Product: C[C@@]1(c2cc(NC(=O)c3cnc(CF)cn3)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1

Procedure:
The coupling of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1) and 5-(fluoromethyl)pyrazine-2-carboxylic acid [J. M. Ellard et al. WO2011009898 (2011)] following General Procedure F yielded the title compound as a colorless amorphous solid. MS: m/z=430.5 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.C([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)(OC(C)(C)C)=O.C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: COc1cccc(CCl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(CN2CCNCC2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.1 %

Procedure:
A mixture of 2.0 g 3-methoxy benzylchloride, 2.9 g 1-Boc piperazine, 5 mL triethylamine, and 20 mL tetrahydrofuran was stirred at room temperature for 20 minutes. The mixture was concentrated, and the residue was added to 20 mL trifluoroacetic acid and stirred at room temperature for 20 minutes. The trifluoroacetic acid was evaporated, and the residue was suspended in methanol and neutralized with an aqueous saturated sodium bicarbonate solution. The solvent was evaporated, and the residue was suspended in dichloromethane and purified by NH silica gel chromatography to give 2.4 g of the title compound as a white solid.