Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[CH3:15][O:16][C:17](=[O:50])[CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][C@H:24]1[C:28](=[O:29])[CH2:27][C@@H:26]([OH:30])[C@@H:25]1[C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[CH:36]([O:40]CC1C=CC(OC)=CC=1)[CH2:35][CH2:34]2.O.C([O-])(O)=O.[Na+]>ClCCl>[CH3:15][O:16][C:17](=[O:50])[CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][C@H:24]1[C:28](=[O:29])[CH2:27][C@@H:26]([OH:30])[C@@H:25]1[C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[CH:36]([OH:40])[CH2:35][CH2:34]2
Reactant: COC(=O)CCC/C=C\C[C@H]1C(=O)C[C@@H](O)[C@@H]1c1ccc2c(c1)CCC2OCc1ccc(OC)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCC/C=C\C[C@H]1C(=O)C[C@@H](O)[C@@H]1c1ccc2c(c1)CCC2O
Reaction time: 0.92 h
Yield: 434.7 %

Procedure:
DDQ (41 mg, 0.18 mmol) was added to a mixture of 15-5 (11 mg, 0.021 mmol) in dichloromethane (3.5 mL)/water (175 μL). After 55 min., saturated NaHCO3 solution was added and the resulting mixture was extracted with dichloromethane (3×50 mL). The combined dichloromethane solution was washed with brine and then was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (50%→60% ethyl acetate/hexanes) gave 15-6 (34 mg, 60%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2[N:17]([CH3:21])[CH:18]=[C:19]([CH3:20])[C:6]1=2)=[O:4].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>O1CCOCC1>[CH3:21][N:17]1[C:7]2[C:8](=[O:16])[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]([C:3](=[O:4])[CH2:2][N:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)[C:6]=2[C:19]([CH3:20])=[CH:18]1
Reactant: CN1CCNCC1
Reactant: Cc1cn(C)c2c1N(C(=O)CCl)c1ccccc1NC2=O
Solvent: C1COCCO1
Product: Cc1cn(C)c2c1N(C(=O)CN1CCN(C)CC1)c1ccccc1NC2=O
Yield: 70.9 %

Procedure:
A solution of 1.75 g of 4-chloroacetyl-1,3-dimethyl-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]benzodiazepin-10-one and 1.15 g of N-methylpiperazine in 50 ml of dry dioxane is warmed at 50° C. for 5 hours with stirring. After the mixture has cooled, the precipitate formed is filtered off. The filtrate is concentrated, 50 ml of saturated sodium bicarbonate solution are added, and the thus-prepared mixture is extracted several times with ethyl acetate. The combined extracts are dried over sodium sulfate and concentrated. 1.5 g of the title compound of m.p. 205° to 207° C. (from ethyl acetate) are obtained. M.p. of the dihydrochloride: 212° C. (D., from water). M.p. of the hemifumarate: 173° C. (from ethanol).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[NH:19][C:18]([C@@H:20]4[CH2:24][CH2:23][CH2:22][N:21]4[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[N:17][CH:16]=3)=[CH:11][CH:10]=2)O1.I[C:34]1[CH:39]=[CH:38][C:37]([C:40]2[NH:44][N:43]=[C:42]([C@@H:45]3[CH2:49][CH2:48][CH2:47][N:46]3[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH:41]=2)=[CH:36][CH:35]=1.C([O-])(O)=O.[Na+]>COCCOC.O.C(OCC)(=O)C.O.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>[C:28]([O:27][C:25]([N:21]1[CH2:22][CH2:23][CH2:24][C@H:20]1[C:18]1[NH:19][C:15]([C:12]2[CH:13]=[CH:14][C:9]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4[NH:44][N:43]=[C:42]([C@@H:45]5[CH2:49][CH2:48][CH2:47][N:46]5[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH:41]=4)=[CH:36][CH:35]=3)=[CH:10][CH:11]=2)=[CH:16][N:17]=1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc(-c2ccc(I)cc2)[nH]n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc(-c2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)[nH]n1
Temperature: 80 °C
Yield: 42.8 %

Procedure:
A mixture of (S)-tert-butyl 2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (17) (Scheme 9; 0.138 g, 0.314 mmol), (S)-tert-butyl 2-(5-(4-iodophenyl)-1H-pyrazol-3-yl)pyrrolidine-1-carboxylate 8 (0.141 g, 0.321 mmol), NaHCO3 (0.110 g, 1.31 mmol) and Pd(PPh3)4 (0.024 g, 0.0208 mmol) in a mixture of DME (3 mL) and H2O (1 mL) was heated at 80° C. under Ar for 12 hours. The cooled mixture was diluted with ethyl acetate/H2O, the layers separated and the aqueous phase was re-extracted with ethyl acetate (2×). The combined organic layers were washed (H2O, brine) and dried (Na2SO4) and filtered and the solvent was removed in vacuo. The resulting residue was purified by flash chromatography (hexane:ethyl acetate, 2:1 and then ethyl acetate:methanol, 9:1) to give (S)-tert-butyl 2-(5-(4′-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-pyrazol-3-yl)pyrrolidine-1-carboxylate (19) (0.084 g, 43%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 13.01, 12.69, 12.20, 11.91, 11.85 (s, 1H), 7.63-7.85 (m, 8H), 7.50-7.56 (m, 1H), 6.52 (s, 1H), 4.75-4.94 (m, 2H), 3.42-3.58 (m, 2H), 3.30-3.39 (m, 2H, partially obscured by H2O signal), 2.10-2.28 (m, 2H), 1.81-2.01 (m, 6H), 1.40 (s, 7H), 1.20-1.23 (m, 6H), 1.13-1.15 (m, 5H). LCMS: Anal. Calcd. for C36H44N6O4: 624. found: 625 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:24]=[C:11]3[N:12]=[C:13]([CH3:23])[C:14]([CH:17]([OH:22])[C:18]([O:20][CH3:21])=[O:19])=[C:15]([I:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:24]=[C:11]3[N:12]=[C:13]([CH3:23])[C:14]([C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19])=[C:15]([I:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(O)c1c(C)nc2cc(-c3cccc(Br)c3)nn2c1I
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C(=O)c1c(C)nc2cc(-c3cccc(Br)c3)nn2c1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
To a mixture of methyl 2-(2-(3-bromophenyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (2.6 g, 5.18 mmol) in CH2Cl2 (100 mL) was added Dess-Martin Periodinane (2.196 g, 5.18 mmol) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate (500 mL), washed with sat. NaHCO3 solution (100 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel chromatography (5-70% EtOAc/hexane) to afford desired methyl 2-(2-(3-bromophenyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (1.7 g, 3.40 mmol, 65.6% yield) as off-white solid. 1H NMR (500 MHz, CDCl3) δ: 8.21 (t, J=1.7 Hz, 1H), 7.96 (dt, J=7.7, 1.3 Hz, 1H), 7.61-7.58 (m, 1H), 7.39 (t, J=7.9 Hz, 1H), 7.14 (s, 1H), 4.03 (s, 3H), 2.57 (s, 3H). LCMS (M+H)=501.0.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[S:15]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][C:19]1=[O:24])(=[O:17])=[O:16])([O-:4])=[O:3].[N:25]1([CH2:34][C:35](O)=[O:36])[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]1=[O:27]>>[N+:2]([C:5]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:6]=1[S:15]([N:18]1[CH2:23][CH2:22][N:21]([C:35](=[O:36])[CH2:34][N:25]2[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:20][C:19]1=[O:24])(=[O:17])=[O:16])([O-:4])=[O:3]
Reactant: O=C1CNCCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Agent: Cl
Product: Cc1cn(CC(=O)N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3[N+](=O)[O-])C(=O)C2)c(=O)[nH]c1=O
Yield: 94.3 %

Procedure:
The title compound (980 mg, 94%) was synthesized by reaction of 1-(2-nitro-4-trifluoromethyl-benzenesulfonyl)-piperazin-2-one HCl salt (780 mg, 2 mmol) with (thymin-1-yl)-acetic acid (369 mg, 2 mmol) as per the procedure of example 64.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1([CH:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:21](Cl)=[O:22])[CH2:19][CH2:18]1.N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1.O>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:11][O:12][C:21](=[O:22])[CH:20]([C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1)[CH:17]1[CH2:19][CH2:18]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(F)c(Oc2ccccc2)c1
Reactant: O=C(Cl)C(c1ccc(Cl)cc1)C1CC1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(OCc1ccc(F)c(Oc2ccccc2)c1)C(c1ccc(Cl)cc1)C1CC1
Reaction time: 3 h
Yield: 84.3 %

Procedure:
9.4 g (0.043 mol) of 3-phenoxy-4-fluoro-benzyl alcohol and 9.9 g (0.043 mol) of α-cyclopropyl-4-chlorophenyl-acetic acid chloride were dissolved in 100 ml of anhydrous toluene, and 4 g of pyridine, dissolved in 50 ml of anhydrous toluene, were added dropwise at 20°-25° C., while stirring. Stirring was then continued at 25° C. for a further 3 hours. The reaction mixture was poured into 150 ml of water, to which 10 ml of concentrated hydrochloric acid were added, and the organic phase was separated off and washed again with 100 ml of water. The toluene phase was then dried over sodium sulphate and the solvent was distilled off under a waterpump vacuum. Last residues of solvent were removed by brief incipient distillation at a bath temperature of 60° C./1 mm Hg. 14.9 g (84.4% of theory) of α-cyclopropyl-4-chlorophenyl-acetic acid 3-phenoxy-4-fluoro-benzyl ester were obtained as a yellow oil. The structure was confirmed by the H-NMR spectrum.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:20])=[C:4]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[CH2:17]Br)[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[Na+]>C1COCC1.O>[Br:1][C:2]1[C:3]([CH3:20])=[C:4]([N:8]2[CH2:17][C:11]3[C:10](=[CH:15][C:14]([F:16])=[CH:13][CH:12]=3)[C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1NC(=O)c1cc(F)ccc1CBr
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Br)cccc1N1Cc2ccc(F)cc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
Step 3 A mixture of N-(3-bromo-2-methylphenyl)-2-(bromomethyl)-5-fluorobenzamide (2.54 g, 6.33 mmol) and sodium tert-butoxide (0.913 g, 9.50 mmol) in THF (80 mL) was stirred at rt for 30 min. The mixture was diluted with water and extracted with twice with DCM. The combined organic phases were washed with water, dried and concentrated. The residue was purified by column chromatography (eluting with hexane-EtOAc) to provide 2-(3-bromo-2-methylphenyl)-6-fluoroisoindolin-1-one as a white solid (1.18 g, 58%). 1H NMR (400 MHz, chloroform-d) δ 7.59-7.65 (2H, m), 7.45-7.50 (1H, m), 7.33 (1H, td, J=8.6, 2.5 Hz), 7.19-7.24 (1H, m), 7.15 (1H, t, J=7.9 Hz), 4.68 (2H, s), 2.31 (3H, s). Mass spectrum m/z 320, 322 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([CH3:6])[C:3](O)=[O:4].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.FC(F)(F)C(O)=O.[NH2:42][C@@H:43]([CH2:64][C:65]1[CH:70]=[CH:69][C:68]([CH:71]2[S:75](=[O:77])(=[O:76])[NH:74][C:73](=[O:78])[CH2:72]2)=[C:67]([F:79])[CH:66]=1)[C:44]([NH:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][O:52][C:53]1[CH:62]=[CH:61][CH:60]=[C:59]([OH:63])[C:54]=1[C:55]([O:57][CH3:58])=[O:56])=[O:45].C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][C:2]([F:7])([CH3:6])[C:3]([NH:42][C@@H:43]([CH2:64][C:65]1[CH:70]=[CH:69][C:68]([CH:71]2[S:75](=[O:76])(=[O:77])[NH:74][C:73](=[O:78])[CH2:72]2)=[C:67]([F:79])[CH:66]=1)[C:44]([NH:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][O:52][C:53]1[CH:62]=[CH:61][CH:60]=[C:59]([OH:63])[C:54]=1[C:55]([O:57][CH3:58])=[O:56])=[O:45])=[O:4]
Reactant: COC(=O)c1c(O)cccc1OCCCCCNC(=O)[C@@H](N)Cc1ccc(C2CC(=O)NS2(=O)=O)c(F)c1
Reactant: CC(F)(F)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(O)cccc1OCCCCCNC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)c(F)c1)NC(=O)C(C)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.5 %

Procedure:
2,2-Difluoropropanoic acid (2.31 mg, 0.0210 mmol) in DMF (1.00 mL) was treated with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (9.97 mg, 0.0225 mmol). The solution was stirred at ambient temperature for 5 minutes. Methyl 2-[5-((2S)-2-amino-3-[4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)-3-fluorophenyl]-propanoylamino)pentyl]oxy-6-hydroxybenzoate trifluoroacetate (10.0 mg, 0.0150 mmol) in DMF (1.00 mL) was added followed by N,N-diisopropylethylamine (13.1 μL, 0.0751 mmol). The solution stirred at rt for 2 h. The product was directly purified by preparative LCMS to afford product as a white solid (7.1 mg, 73%). LCMS found for C28H33F3N3O9S (M+H)+: m/z=644.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:10](=[O:12])[C:9]3[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:8]=3[S:7][C:6]=2[CH:20]=1.[BH4-].[Na+].[OH-].[Na+]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10]([OH:12])[C:9]3[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:8]=3[S:7][C:6]=2[CH:20]=1
Reactant: O=C1Cc2ccc(F)cc2Sc2ccc([N+](=O)[O-])cc21
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)C(O)Cc1ccc(F)cc1S2
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
A solution of 6.9 g of the foregoing ketone in 90 ml of dioxane was treated dropwise with a solution of 9.8 g of sodium borohydride in 3 ml of water containing 1 drop of a 20% sodium hydroxide solution. The mixture was stirred for 2 hours at room temperature and after standing overnight, dioxane evaporated. The residue was diluted with water, acidified with hydrochloric acid and the product extracted with chloroform. Processing of the extract and crystallization of the crude product from benzene yielded 4.1 g pure 3-fluoro-8-nitro-10,11-dihydrodibenzo(b,f)thiepin-10-ol, m.p. 133°-135° C.
Reaction SMILES: Br[C:2]1[C:3]([CH:9]=[N:10][C:11]([CH3:14])([CH3:13])C)=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:15]([Si:19]([CH3:25])([CH3:24])[O:20]CC#C)([CH3:18])([CH3:17])[CH3:16]>C(#N)C.C(Cl)Cl.[Zn]>[Si:19]([O:20][CH2:14][C:11]1[N:10]=[CH:9][C:3]2[C:2]([CH:13]=1)=[CH:7][N:6]=[C:5]([Cl:8])[CH:4]=2)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:25])[CH3:24]
Reactant: CC(C)(C)N=Cc1cc(Cl)ncc1Br
Reactant: C#CCO[Si](C)(C)C(C)(C)C
Agent: [Zn]
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCc1cc2cnc(Cl)cc2cn1
Temperature: 70 °C

Procedure:
A mixture of N-((5-bromo-2-chloropyridin-4-yl)methylene)-2-methylpropan-2-amine (530 mg, 1.9 mmol), tert-butyldimethyl(2-propynyloxy)silane (0.59 mL, 2.9 mmol), NiCl2(DPPP) (52 mg, 0.1 mmol), and zinc (252 mg, 3.9 mmol) in acetonitrile (5 mL) was heated at 70° C. under an atmosphere of nitrogen. The cooled reaction mixture was diluted with methylene chloride (50 mL), filtered over Celite, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 12 g, ISCO, 0-40% ethyl acetate in heptane) to afford the title compound as an orange waxy solid (340 mg, 57%), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([O:13]CC)=[O:12])[N:8]([CH2:16][C:17](=[O:26])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=2)[N:7]=1)=[O:5])[CH3:2].Cl>C1COCC1.O.[OH-].[Na+]>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[N:8]([CH2:16][C:17](=[O:26])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C(=O)OCC)n(CC(=O)Nc2ccc(Cl)cn2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(C(=O)O)n(CC(=O)Nc2ccc(Cl)cn2)n1
Reaction time: 16 h

Procedure:
To a solution of 8 g 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-1H-pyrazole-3,5-dicarboxylic acid diethyl ester in 200 ml THF and 50 ml H2O 17.2 ml IN NaOH is added. After standing for 16 h, the solution was acidified using 1 N HCl. THF was removed in vacuo and water was removed by lyophilization. The residue was purified by chromatography on silica gel using ethyl acetate followed by CH2Cl2/MeOH/HOAC/H2O=9/1/0.1/0.1. The fractions containing the product were evaporated and lyophilized to give a white solid. Yield: 4.42 g.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][Cl:11])=[CH:8][CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)(Cl)Cl>[CH:1]([C:4]1[C:9]([CH2:10][Cl:11])=[CH:8][CH:7]=[CH:6][N+:5]=1[O-:20])([CH3:3])[CH3:2]
Reactant: CC(C)c1ncccc1CCl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(C)c1c(CCl)ccc[n+]1[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The 2-isopropyl-3-hydroxymethylpyridine (240 mg, 1.59 mmol) was dissolved in CH2Cl2 (15 mL) and cooled under nitrogen to 0° C. and thionyl chloride (1.0 mL) was slowly added and the reaction was stirred for 3 hours. The solvent was removed under reduced pressure and the residue was partitioned between CH2Cl2 and saturated sodium bicarbonate. The organic layer was dried with MgSO4, filtered and the solvent removed under reduced pressure to give the desired 2-isopropyl-3-chloromethylpyridine. The 2-isopropyl-3-chloromethylpyridine (65 mg, 0.383 mmol) was dissolved in CHCl3 (10 mL) and cooled under nitrogen to 0° C. and m-chloroperbenzoic acid (55%, 150 mg) was added in small portions. The reaction was stirred for 2 hours. The solution was extracted with saturated aqueous sodium bicarbonate (2×5 mL). The organic phase was dried with MgSO4, filtered, and the solvent removed under reduced pressure. The residue was chromatographed on silica gel packed in 99:1 CH2Cl2 :MeOH and eluted with same. The appropriate fractions were combined and the solvent removed under reduced pressure to give the desired 2-isopropyl-3-chloromethylpyridine-N-oxide.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[CH2:15]([N:22]1[CH2:27][C@@H:26]([CH3:28])[NH:25][CH2:24][C@@H:23]1[CH3:29])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:15]([N:22]1[C@@H:23]([CH3:29])[CH2:24][N:25]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=3)[N:7]=2)[C@H:26]([CH3:28])[CH2:27]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](C)CN1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](C)CN1c1ccc2nnc(C(F)(F)F)n2n1
Yield: 78.9 %

Procedure:
A stirred solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (4.45 g, 20 mmol), (2S,5R)-1-benzyl-2,5-dimethylpiperazine (4.90 g, 24.00 mmol) and DIPEA (5.14 mL, 30.00 mmol) in DMF (40 mL) was heated at 125° C. for 2 hours. The reaction mixture was evaporated to dryness, redissolved in DCM and washed sequentially with 1M aqueous K2CO3, water and saturated brine. The organic layer was dried over MgSO4, filtered and evaporated. The crude product was purified by MPLC silica chromatography, eluting with 75% EtOAc/isohexane. Pure fractions were evaporated to dryness to afford 6-[(2R,5S)-4-benzyl-2,5-dimethylpiperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (6.16 g, 79%) as a tan gum.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(=O)[NH2:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[C:1]([C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])#[N:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(N)=O
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C#N
Temperature: -20 °C
Yield: 72.8 %

Procedure:
(2S,4R)-tert-Butyl 2-carbamoyl-4-hydroxypyrrolidine-1-carboxylate 13c (74 g, 0.3217 mol) was dissolved in 740 mL of pyridine with stirring under argon atmosphere. The mixture was cooled to −20° C. followed by dropwise addition of trifluoroacetic anhydride (169 g, 0.804 mol). Upon completion of the addition, the reaction mixture was warmed up to room temperature. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was quenched with water and diluted with 0.8 L of ethyl acetate. The separated organic phase was washed with 500 mL of saturated brine and neutralized with 400 mL of concentrated hydrochloric acid to slight acidity. The resulting mixture was washed with 300 mL of aqueous sodium hydroxide solution (2 M) and 500 mL saturated brine successively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (2S,4R)-tert-butyl 2-cyano-4-hydroxypyrrolidine-1-carboxylate 13d (49.7 g, yield 73%) as a brown oil.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10](S(C)=O)[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:16])[CH3:2].[F:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>>[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[C:18]([F:17])[CH:19]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:16])[CH3:2]
Reactant: Nc1cccc(F)c1
Reactant: CCn1c(=O)ccc2cnc(S(C)=O)nc21
Product: CCn1c(=O)ccc2cnc(Nc3cccc(F)c3)nc21
Temperature: 175 °C
Yield: 25 %

Procedure:
A mixture of 8-ethyl-2-methylsulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (112 mg, 0.47 mmol) and 500 μL of 3-fluoroaniline was heated at 175° C. for 10 minutes. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate. Recrystallization from chloroform and hexane provided 33 mg (25%) of 8-ethyl-2-(3-fluorophenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, mp 210-212° C.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]([OH:28])([CH2:15][C:16]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[O:26][CH3:27])([CH3:18])[CH3:17])[C:11]([F:14])([F:13])[F:12])[CH2:3]1.N1C=CC=CC=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>C(Cl)Cl>[F:25][C:23]1[CH:22]=[CH:21][C:20]([O:26][CH3:27])=[C:19]([C:16]([CH3:18])([CH3:17])[CH2:15][C:10]([OH:28])([C:11]([F:12])([F:13])[F:14])[CH2:9][N:4]2[CH2:3][CH:2]([CH3:1])[N:7]([C:35](=[O:37])[CH3:36])[CH:6]([CH3:8])[CH2:5]2)[CH:24]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CC(C)NC(C)C1)C(F)(F)F
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CC(C)N(C(C)=O)C(C)C1)C(F)(F)F
Reaction time: 8 h

Procedure:
To a solution of 2-(3,5-dimethylpiperazin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol (18 mg) in methylene chloride (1 mL) was added pyridine (55.8 μL) followed by acetic anhydride (43.4 μL). The resulting mixture was stirred overnight, quenched with saturated aqueous sodium bicarbonate solution and extracted twice with methylene chloride. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 50% ethyl acetate-hexanes) to give the title compound as a clear oil (20 mg).
Reaction SMILES: [N:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH2:59])=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1>C1COCC1.C(Cl)(Cl)Cl>[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH:59][C:8](=[O:10])[CH2:7][N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: O=C(O)CN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)CN3CCOCC3)nc12

Procedure:
From morpholin-4-yl-acetic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+18.8° (c=1.04, CHCl3), ES-MS m/e (%): 394 (M+H+, 100).