Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C@H:3]([N:28]1[CH2:32][CH2:31][C@H:30]([NH:33]C(=O)OC(C)(C)C)[CH2:29]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:24][CH:25]([CH3:27])[CH3:26])=[C:18]([F:23])[CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1>C(O)(C(F)(F)F)=O>[F:42][C:2]([F:1])([F:41])[C@H:3]([N:28]1[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:24][CH:25]([CH3:27])[CH3:26])=[C:18]([F:23])[CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1
Reactant: CC(C)Oc1cc2nc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)ccc2cc1F
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1cc2nc(-c3nnc4ccc([C@@H](N5CC[C@H](N)C5)C(F)(F)F)cn34)ccc2cc1F
Yield: 64.5 %

Procedure:
tert-Butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-7-isopropoxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (280 mg, 0.476 mmol) was stirred in TFA (3 mL) for 1 hour then concentrated. The residue was dissolved in minimum methanol and added dropwise to a 4N HCl in ether solution. The resulting solid was filtered and dried to yield (S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-7-isopropoxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-amine (150 mg, 64.6% yield) hydrochloride as an off-white solid. LCMS APCI (+) m/z 489 (M+H).
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)#[CH:12]>C(N(CC)CC)C.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>[Cl:19][C:15]1[CH:14]=[C:13]([C:11]#[C:12][C:2]2[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: C#Cc1cccc(Cl)c1
Reactant: Cc1cc(C)c(N)c(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(N)c(C#Cc2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
To a solution of Cul (5.7 mg, 30 μmol) in triethylamine (1.6 ml) were added 2-bromo-4,6-dimethyl-pyridin-3-ylamine (120 mg, 0.60 mmol, described in Example 12), (PPh3)2PdCl2 (21 mg, 30 μmol), and 1-ethynyl-3-chlorobenzene (98 mg, 0.72 mmol). The reaction mixture was stirred for 30 min. at room temperature and for 3 h under reflux. The solvent was evaporated and the crude residue was purified by flash chromatography (cyclohexane/ethyl acetate 4:1) to yield 39 mg (0.15 mmol, 25%) of (2-(3-chloro-phenylethynyl)-4,6-dimethyl-pyridin-3-yl)amine as a brown oil.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][C@@H:13]1[C:17]2([O:21][CH2:20][CH2:19][CH2:18]2)[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1)=[O:11])=[O:7].Cl.O1CCOCC1>>[O:21]1[C:17]2([C@@H:13]([NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:29]=[CH:30][CH:31]=[C:3]([C:2]([F:32])([F:33])[F:1])[CH:4]=3)[CH2:14][NH:15][CH2:16]2)[CH2:18][CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C2(CCCO2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@H]1CNCC12CCCO2
Reaction time: 2 h

Procedure:
The intermediate of step G (0.18 g) was mixed with 5 mL of 4 N HCl/dioxane. The solution was stirred for 2 h and concentrated under vacuum. MS (M+H)+ 372.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].NC1C=CC=CC=1>>[NH:5]([C:6]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])[C:4]1[CH:3]=[CH:2][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(C(=O)O)c(Nc2cccc(F)c2)c1
Solvent: Nc1ccccc1
Product: COc1ccc(C(=O)O)c(Nc2ccccc2)c1

Procedure:
Following the procedure for 2-(3-fluoro-anilino)-4-methoxybenzoic acid, using aniline in place of 3-fluoroaniline, 2-anilino-4-methoxybenzoic acid was obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7](Br)[CH:6]=[C:5]([CH:10]=[O:11])[C:4]=1[OH:12])=[O:2].[CH2:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C([O-])(O)=O.[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH:1]([C:3]1[CH:8]=[C:7]([CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:6]=[C:5]([CH:10]=[O:11])[C:4]=1[OH:12])=[O:2]
Reactant: O=Cc1cc(Br)cc(C=O)c1O
Reactant: C=CCCCCCCCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: CCCCCCCCCCC=Cc1cc(C=O)c(O)c(C=O)c1
Temperature: 82 °C
Reaction time: 40 h
Yield: 50.6 %

Procedure:
2,6-Diformyl-4-bromophenol (1.00 g, 4.37 mmol), 1-dodecene (4.8 mL, 21.7 mmol), 1.40 g tetrabutylammonium bromide (4.34 mmol), 0.50 g NaHCO3 (5.95 mmol), 1.00 g LiCI (23.6 mmol) and 0.100 g palladium diacetate (Pd(OAc)2) (0.45 mmol) were combined in 30 mL degassed anhydrous dimethylformamide (DMF). The mixture was sparged with argon for 10 min and then sealed in a pressure vial which was warmed to 82° C. and held for 40 h. The crude reaction mixture was partitioned between CH2CI2 and 0.1 M HCI solution. The organic layer was washed with 0.1 M HCI (2×), brine (2×), and saturated aqueous NaHCO3 (2×), dried over MgSO4 and concentrated under reduced pressure. The dark yellow oil was purified by column chromatography on silica gel (25% hexanes in Et2O) to give 0.700 g (51%) of the title compound as primarily the Z isomer.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:29]=[C:28]([CH3:30])[C:7]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:6]([CH3:31])[C:5]=1[CH2:32][CH3:33].[CH2:34]([O:36][C:37](=[O:48])[CH:38]=[C:39]([CH3:47])[CH:40]=[CH:41][CH:42]=[C:43]([CH:45]=O)[CH3:44])[CH3:35]>>[CH2:34]([O:36][C:37](=[O:48])[CH:38]=[C:39]([CH3:47])[CH:40]=[CH:41][CH:42]=[C:43]([CH3:45])[CH:44]=[CH:8][C:7]1[C:28]([CH3:30])=[CH:29][C:4]([O:3][CH3:2])=[C:5]([CH2:32][CH3:33])[C:6]=1[CH3:31])[CH3:35]
Reactant: CCc1c(OC)cc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Agent: [Cl-]
Product: CCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)cc(OC)c(CC)c1C

Procedure:
4-methoxy-2,6-dimethyl-3-ethyl-benzyl-triphenyl-phosphonium chloride is condensed with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl ester to produce 9-(4-methoxy-2,6-dimethyl-3-ethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid ethyl ester which is converted by the procedure of Example 7 to form 9-(4-methoxy-2,6-dimethyl-3-ethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid, m.p.: 197°-198° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C:13]2=[O:18])=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O>C1COCC1.[H][H].[Pd]>[NH2:1][C:4]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C:13]2=[O:18])=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1cc(N2CCOCC2=O)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: N#Cc1cc(N2CCOCC2=O)ccc1N
Yield: 60 %

Procedure:
2-Nitro-5-(3-oxo-morpholin-4-yl)-benzonitrile (1.1 g) was dissolved in THF (80 ml) and hydrogenated with hydrogen (1 atm) over Pd/C 10% (350 mg) for 18 h at 25° C. The reaction mixture was then filtered through decalite and precipitated (AcOEt/heptane) to yield 2-amino-5-(3-oxo-morpholin-4-yl)-benzonitrile as a white solid (580 mg). MH+=218.4
Reaction SMILES: [H-].[Na+].[C:3]([O:6][C@@H:7]1[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:12]([O:18][C:19](=[O:21])[CH3:20])[C@@H:11]([C:22]([O:24][CH3:25])=[O:23])[O:10][CH:8]1[OH:9])(=[O:5])[CH3:4].[Cl:26][C:27]([Cl:31])([Cl:30])[C:28]#[N:29]>ClCCl>[Cl:26][C:27]([Cl:31])([Cl:30])[C:28]([O:9][C@H:8]1[O:10][C@H:11]([C:22]([O:24][CH3:25])=[O:23])[C@@H:12]([O:18][C:19](=[O:21])[CH3:20])[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:7]1[O:6][C:3](=[O:5])[CH3:4])=[NH:29]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: COC(=O)[C@H]1OC(O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
60% Oily sodium hydride (0.366 g) was added to an ice-cooled solution of methyl 2,3,4-tri-O-acetyl-D-glucopyranuronate (3.96 g), trichloroacetonitrile (12 ml) and dichloromethane (100 ml), and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was subjected to short column (70 φ×50 mm) chromatography on silica gel and eluted with ethyl acetate/hexane (1:1). The eluate was concentrated under reduced pressure to obtain the desired compound (4.37 g) as crystals (mp: 108° C.).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[S:16](=[O:18])(=[O:17])[CH2:15][CH2:14][C:13]([C:19]([O:21]C)=[O:20])=[CH:12][C:11]=3[CH:23]=2)=[CH:4][CH:3]=1.Cl>COCCOC>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[S:16](=[O:18])(=[O:17])[CH2:15][CH2:14][C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=3[CH:23]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C1=Cc2cc(-c3ccc(C)s3)ccc2S(=O)(=O)CC1
Agent: Cl
Solvent: COCCOC
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)s1
Temperature: 100 °C
Reaction time: 14 h
Yield: 89.3 %

Procedure:
In 1,2-dimethoxyethane (10.5 ml) was dissolved methyl 7-(5-methyl-2-thienyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (210 mg), and to the solution was added 6N hydrochloric acid (6.3 ml). The mixture was stirred at 100° C. for 14 hours, cooled to room temperature, extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 7-(5-methyl-2-thienyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (180 mg).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:37][CH2:36][C:35]2[NH:34][N:33]=[CH:32][C:31]=2[CH2:30]1.[H-].[Na+].CN(C)C(=O)C.[CH3:46][C:47]1([CH3:50])[CH2:49][O:48]1>O.C(OCC)(=O)C>[OH:48][C:47]([CH3:50])([CH3:49])[CH2:46][N:34]1[C:35]2[CH2:36][CH2:37][CH:29]([N:3]3[C:2](=[O:1])[C:7]([CH2:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]5[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:13][CH:14]=4)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]4[N:26]=[CH:27][N:28]=[C:4]34)[CH2:30][C:31]=2[CH:32]=[N:33]1
Reactant: CC1(C)CO1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCc3[nH]ncc3C2)c2ncnn12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCc3c(cnn3CC(C)(C)O)C2)c2ncnn12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 8 %

Procedure:
A mixture of 4′-{[5-oxo-7-propyl-4-(4,5,6,7-tetrahydro-1H-indazol-5-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.36 g), sodium hydride (0.044 g) and N,N-dimethylacetamide (3 mL) was stirred at 0° C. for 5 min and then at room temperature for 20 min. 2,2-Dimethyloxirane (0.65 mL) was added, and the mixture was stirred at 120° C. for 1.5 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.035 g, 8%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C(=O)(O)[O-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]([Cl:20])([Cl:19])[Cl:18])=[O:14]>C1C=CC=CC=1>[Cl:18][C:17]([Cl:20])([Cl:19])[CH2:16][O:15][C:13]([N:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1)=[O:14]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: C1=CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(OCC(Cl)(Cl)Cl)N1CC=CCC1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
124.5 g (1.5 mol) of 1,2,5,6-tetrahyropyridine are dissolved in 1,200 ml of benzene. 124 g of sodium bicarbonate are introduced into this solution and the mixture is then cooled to 0° under a nitrogen atmosphere and, at this temperature, is treated slowly dropwise in the course of 31/2 hours with a solution of 316 g (1.5 mol) of 2,2,2-trichloroethyl chloroformate in 250 ml of benzene. The resulting white suspension is subsequently stirred for a further 15 hours at 0° and then poured into 2,000 ml of ice-water. The benzene phase is separated off and the aqueous phase is extracted by shaking with twice 1,000 ml of methylene chloride; the combined organic phases are washed with 1 N hydrochloric acid and then with a saturated solution of sodium chloride, dried over sodium sulphate and evaporated under a water pump vacuum, whereupon 1-(β,β,β-trichloroethoxycarbonyl)-1,2,5,6-tetrahydropyridine is obtained as a slightly reddish oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]1([N:13]2[C:22]3[N:21]=[C:20]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][C:24]=4[NH:29]C(=O)OC(C)(C)C)[N:19]=[CH:18][C:17]=3[N:16]([CH3:37])[C:15](=[O:38])[C@H:14]2[CH2:39][CH3:40])[CH2:12][CH2:11][CH2:10][CH2:9]1>C(Cl)Cl>[NH2:29][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:23]=1[C:20]1[N:19]=[CH:18][C:17]2[N:16]([CH3:37])[C:15](=[O:38])[C@@H:14]([CH2:39][CH3:40])[N:13]([CH:8]3[CH2:12][CH2:11][CH2:10][CH2:9]3)[C:22]=2[N:21]=1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3NC(=O)OC(C)(C)C)nc2N1C1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3N)nc2N1C1CCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Three mL of TFA was added to a solution of (R)-tert-butyl 4-(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)pyridin-3-ylcarbamate (Example 92, 760 mg) in 3 mL of DCM. The mixture was stirred for 4 h at rt, and the solvent was removed under reduced pressure. Aqueous Na2CO3 was added and extracted with EtOAc. The organic layer was dried with Na2SO4, concentrated and the residue was purified by silica column to give the title compound. LCMS (0.05% TFA): 353.0 m/z (M+H)+; 1H-NMR (CDCl3, 500 MHz): δ: 8.17 (s, 1H), 8.08 (d, 1H, J=5 Hz), 7.99 (d, 1H, J=5 Hz), 7.94 (s, 1H), 6.23 (s, 2H), 4.48 (m, 1H), 4.32 (m, 1H), 3.39 (s, 3H), 2.0-1.69 (m, 10H), 0.88 (t, 3H, J=7.5 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-])=O.[NH2:15][C@@H:16]([C:20]([NH2:22])=[O:21])[CH:17]([CH3:19])[CH3:18].Cl.CO.C(N(CC)CC)C>>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:15]([C@H:16]([CH:17]([CH3:19])[CH3:18])[C:20]([NH2:22])=[O:21])[C:9]2=[O:14]
Reactant: CC(C)[C@@H](N)C(N)=O
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)[C@H](C(N)=O)n1ccc2c(N)cccc2c1=O

Procedure:
5-Nitro-isochromen-1-one (2 g, 0.01 mol) and H-D-Val-NH2HCl (1.9 g, 0.012 mol) were refluxed in methanol (40 mL, 1 mol) with triethylamine (5 g, 0.05 mol) for 2 hours. The volatiles were removed via rotovapor, and the residue was purified via flash column chromatography (40 g of silica gel, 0-30% EtOAc/Hexane) to give a yellow solid. MS m/z 290.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:13]([C:14](Cl)=[O:15])=[CH:12][S:11][N:10]=2)[CH:4]=1.[CH3:19][OH:20]>>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:13]([C:14]([O:20][CH3:19])=[O:15])=[CH:12][S:11][N:10]=2)[CH:4]=1
Reactant: O=C(Cl)c1csnc1-c1cccc(C(F)(F)F)c1
Reactant: CO
Product: COC(=O)c1csnc1-c1cccc(C(F)(F)F)c1

Procedure:
A solution of 2.92 g (0.010 mol) of 3-(α,α,α-trifluoro-m-tolyl)-4-isothiazolecarbonyl chloride prepared as in Example 29 and 10 ml of methanol was held at reflux for 0.5 hours and was concentrated under vacuum to 80° (0.3 torr) to 2.72 g of oil, nD23.4° =1.5404.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21](O)=[O:22])[N:9]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Br.Br.[S:35]1[C:44]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39][C:38]=2[N:37]=[C:36]1[NH2:45].C(=O)([O-])O.[Na+]>CN(C=O)C.C(Cl)Cl>[NH2:45][C:36]1[S:35][C:44]2[CH2:43][CH2:42][N:41]([C:21](=[O:22])[CH2:20][N:10]3[C:11]([C:13]4[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=4)=[N:12][C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:9]3)[CH2:40][CH2:39][C:38]=2[N:37]=1
Reactant: O=C(O)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Reactant: Nc1nc2c(s1)CCNCC2
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1nc2c(s1)CCN(C(=O)Cn1nc(-c3ccc(F)cc3)nc1-c1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 53.7 %

Procedure:
350 mg (3,5-bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetic acid and 0.2 mL DIPEA were dissolved in 4.5 mL DMF. 570 mg PFTU was added to this solution and the mixture was stirred for 7 min at RT. Then, 333 mg 5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepin-2-ylamine dihydrobromide and 0.4 mL DIPEA were added and the reaction was stirred over night at RT. Then, sodium hydrogencarbonate solution (10%) and CH2Cl2 were added, the organic phase was separated and the solvent was removed. The residue was purified by HPLC to yield 252 mg of the desired compound.
Reaction SMILES: [NH:1]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17]C)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].O.[OH-].[Li+]>CO.O>[NH:1]([C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 3.5 h
Yield: 90.5 %

Procedure:
To a stirred solution of N-Cbz-L-Leu-L-Leu-OCH3 (6.0 g, 14.6 mmol) in MeOH/H2O (3:1) (60 mL) at R. T. was added lithium hydroxide monohydrate (LiOH.H2O) (1.0 g, 43.9 mmol) and hydrogen peroxide H2O2 (30% weight in H2O) (4.5 mL, 43.9 mmol). The reaction mixture was stirred for 3.5 h and then quenched with 10% HCl. The resulting mixture was extracted with EA (3×20 mL). The combined organic extracts were washed with sat. NaCl (2×10 mL), dried (MgSO4) and concentrated in vacuo to afford N-Cbz-L-Leu-L-Leu-OH as a white solid (5.0 g, 90.5%): 1H NMR (CDCl3, 300 MHz) δ0.89-0.92 (t, 12 H, J=3.0 Hz), 1.48-1.71 (m, 6 H), 4.11-4.13 (m, 1 H), 4.55-4.62 (m, 1 H), 5.09 (s, 2 H), 5.64 (d, 1 H, J=9.0 Hz), 6.83 (d, 1 H, J=9.0 Hz), 7.33-7.40 (m, 5 H) ppm.
Reaction SMILES: [CH:1]1([CH2:6]O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CS(Cl)(=O)=O.O.[NH2:21][NH2:22].[P:23](=[O:27])([OH:26])([OH:25])[OH:24]>O1CCCC1.C(O)C.C1(C)C=CC=CC=1.O>[P:23]([OH:27])([OH:26])([OH:25])=[O:24].[CH:1]1([CH2:6][NH:21][NH2:22])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: OCC1CCCC1
Agent: CS(=O)(=O)Cl
Agent: O=P(O)(O)O
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: NNCC1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cyclopentyl methanol (22.3 g, 0.22 mol) and triethylamine (33.8 g, 0.33 mol) in tetrahydrofuran was added dropwise methanesulfonyl chloride (29.3 g, 0.26 mol) with keeping the temperature below 15° C. over 50 minutes, and the reaction mixture was stirred at the same condition for 1 hour. To the mixture was added dropwise water (134 g) with keeping the internal temperature below 15° C. over 10 minutes. To the resultant was further added toluene (232 g), and the mixture was extracted. The organic layer was washed with water (134 g), and the solvent was evaporated under reduced pressure to give a crude product of Compound (Ie) (40.0 g), which was used in the next step without further purification. The resulting Compound (Ie) and hydrazine monohydrate (66.9 g, 1.34 mol) were dissolved in ethanol (178 g), and the reaction mixture was stirred at 60° C. to 65° C. (internal temperature) for 7 hours. The mixture was cooled to room temperature, and partitioned between chloroform (674 g) and water (71.5 g). The chloroform layer was washed with water (71.5 mL, ×2) to give a solution of a free base of Compound (IIff) in chloroform (808 g). To the solution (202 g, equivalent to 55 mmol) were added at room temperature 85% phosphoric acid (6.42 g, 60 mmol) and then 2-propanol (30 g), and the solvent was evaporated under reduced pressure. To the concentrated residue was added 2-propanol (36.7 g), and the solvent was evaporated under reduced pressure (×4). To the concentrated residue (24 g) was added 2-propanol to adjust the total weight to 45 g, and the mixture was stirred at 40° C. for 1 hour. The mixture was cooled to 5° C. over 1.5 hours, and then stirred at 5° C. for 1 hour. The precipitate was collected by filtration, washed with a mixed solution of 2-propanol (1.98 g) and n-hexane (3.47 g), and dried under reduced pressure to give Compound (IIff) (9.33 g, 80%) as a white crystalline solid.
Reaction SMILES: [NH2:1][S:2]([N:5]1[CH2:8][CH:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6]1)(=[O:4])=[O:3].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:58]1[CH:63]=[C:62]([O:64][CH3:65])[N:61]=[C:60]([S:66][CH2:67][C:68]2[CH:73]=[CH:72][CH:71]=[C:70]([F:74])[C:69]=2[F:75])[N:59]=1.[Cl-].[NH4+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:75][C:69]1[C:70]([F:74])=[CH:71][CH:72]=[CH:73][C:68]=1[CH2:67][S:66][C:60]1[N:59]=[C:58]([NH:1][S:2]([N:5]2[CH2:8][CH:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:6]2)(=[O:4])=[O:3])[CH:63]=[C:62]([O:64][CH3:65])[N:61]=1
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: CC(C)(C)OC(=O)NC1CN(S(N)(=O)=O)C1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1cc(NS(=O)(=O)N2CC(NC(=O)OC(C)(C)C)C2)nc(SCc2cccc(F)c2F)n1
Temperature: 100 °C

Procedure:
A mixture of tert-butyl [1-(aminosulfonyl)azetidin-3-yl]carbamate (0.50 g), tris(dibenzylideneacetone)-dipalladium (0) (0.12 g), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (63 mg), cesium carbonate (0.65 g) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product of example 35 step i, 0.400 g) in anhydrous dioxane (17 ml) was heated to reflux in a microwave at 100° C., 300 W, open vessel with cooling for 15 min. Saturated aqueous ammonium chloride was added and the resulting mixture extracted with EtOAc. The combined organic extracts were washed with saturated aqueous sodium chloride, dried with sodium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica using a 1:19 to 3:7 mixture of EtOAc and iso-hexane as eluent to give the subtitle compound as a yellow oil. Yield: 0.48 g
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][N:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:10][CH2:9]1)(C)(C)C.[ClH:19]>O1CCOCC1>[ClH:19].[N:15]1[C:16]2[CH2:17][N:8]([CH2:7][C:6]([OH:18])=[O:5])[CH2:9][CH2:10][C:11]=2[CH:12]=[CH:13][CH:14]=1.[ClH:19]
Reactant: CC(C)(C)OC(=O)CN1CCc2cccnc2C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CN1CCc2cccnc2C1

Procedure:
(5,8-Dihydro-6H-[1,7]naphthyridin-7-yl)-acetic acid tert-butyl ester (Preparation 234, 1.25 g, 5.03 mmol) was treated with 4N HCl in dioxane (25 ml) at room temperature for 2 hours. The mixture was evaporated to dryness in vacuo and the solid residue was triturated with diethyl ether to afford the title compound as white solid in 78% yield (calculated as HCl salt), 900 mg.