Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=4)[CH:24]=[C:23]([C:35]([F:38])([F:37])[F:36])[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:34][C:29]1[CH:28]=[C:27]([C:25]2[CH:24]=[C:23]([C:35]([F:36])([F:38])[F:37])[N:22]=[C:21]([C:19]3[CH:18]=[CH:17][N:16]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=4)[CH:20]=3)[N:26]=2)[CH:32]=[CH:31][C:30]=1[F:33]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)ccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.3 %

Procedure:
To a cooled and stirred solution of 3-{4-[4-(3,4-difluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide (0.25 g) in dichloromethane (4 ml) was added TFA (4 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N NaHCO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.16 g, 48%). MS (ISP) 492.9 [(M+H)+]; mp 233.5° C.
Reaction SMILES: C([O:8][C:9]1[CH:16]2[CH:12]([CH2:13][CH:14]([CH:17]=[O:18])[CH2:15]2)[C:11](=[O:19])[C:10]=1[C:20]1[C:25]([CH2:26][CH3:27])=[CH:24][C:23]([CH3:28])=[CH:22][C:21]=1[CH2:29][CH3:30])C1C=CC=CC=1>[Pd].CO>[CH2:29]([C:21]1[CH:22]=[C:23]([CH3:28])[CH:24]=[C:25]([CH2:26][CH3:27])[C:20]=1[CH:10]1[C:11](=[O:19])[CH:12]2[CH:16]([CH2:15][CH:14]([CH:17]=[O:18])[CH2:13]2)[C:9]1=[O:8])[CH3:30]
Reactant: CCc1cc(C)cc(CC)c1C1=C(OCc2ccccc2)C2CC(C=O)CC2C1=O
Agent: [Pd]
Solvent: CO
Product: CCc1cc(C)cc(CC)c1C1C(=O)C2CC(C=O)CC2C1=O
Yield: 96.5 %

Procedure:
20 mg of palladium on activated carbon (10%) are added to 1.10 g (2.72 mmol) of 6-(benzyloxy)-5-(2,6-diethyl-4-methylphenyl)-4-oxo-1,2,3,3a,4,6a-hexahydropentalene-2-carbaldehyde in 20 ml of methanol, and the mixture is hydrogenated (15 bar, room temperature) for 20 h. The filtration and concentration on a rotary evaporator give 0.82 g (97%) of the title compound (I-a-3, isomer ratio according to 1H-NMR 4:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.[CH2:20](Cl)Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([N:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[C:10](=[O:12])[CH3:20])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccc(Cl)cc1)N1CCCC1
Reactant: ClCCl
Solvent: CO
Product: CC(=O)C(Cc1ccc(Cl)cc1)N1CCCC1

Procedure:
The title compound was prepared according to the procedure of Reference Example 2, Step C except that ethyl 3-(4-chlorophenyl)-2-(1-pyrrolidinyl)-propanoate (from Step A) was the ester used (two steps). TLC Rf=0.7 (95:5 CH2Cl2:MeOH). LC/MS m/e=252 (M+1). 500 MHz 1H NMR (CDCl3) δ 1.86 (br s, 4H), 2.03 (s, 3H), 2.66 (m, 2H), 2.78 (m, 2H), 2.98 (dd, J=2.9, 10.3 Hz, 1H), 3.08 (m, 1H), 3.43 (m, 1H), 7.12 (d, J=8.3 Hz, 2H), 7.26 (d, J=8.3 Hz, 2H)
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:11]([CH3:12])=[C:10]([C:13]([O:15]C(C)(C)C)=[O:14])[S:9][C:4]=2[NH:5][C:6](=[O:8])[N:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][C:2]1[C:3]2[C:11]([CH3:12])=[C:10]([C:13]([OH:15])=[O:14])[S:9][C:4]=2[NH:5][C:6](=[O:8])[N:7]=1
Reactant: Cc1c(C(=O)OC(C)(C)C)sc2[nH]c(=O)nc(N)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(=O)O)sc2[nH]c(=O)nc(N)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To a solution of tert-butyl 4-amino-5-methyl-2-oxo-1,2-dihydrothieno[2,3-d]pyrimidine-6-carboxylate (example 64a) (10.7 g, 38.03 mmol) in CH2Cl2 (25 mL), was added trifluoroacetic acid (25 mL, 324.5 mmol). The reaction mixture was stirred at rt overnight. The precipitated solid was collected by filtration, and washed with CH2Cl2 to yield 4-Amino-5-methyl-2-oxo-1,2-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid (6.98 g, 82%) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ2.78 (s, 3H). MS 226.0 (MH+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]=[O:6].[CH2:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1Br)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[OH:6]
Reactant: O=CCCCCl
Reactant: CCCCCCCCCc1ccccc1Br
Product: CCCCCCCCCc1ccccc1C(O)CCCCl

Procedure:
In a manner analogous to that described in Example 17a, but starting from 4-chlorobutyraldehyde, 2-nonylbromobenzene yields the title compound in the form of a colourless oil; IR (CH2Cl2): 3600, 2960, 2930, 2860, 1470, 1055 cm-1.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([OH:16])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.CO>CC(C)=O>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCCC(COCc2ccccc2)C1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CC(C)=O
Product: O=C1CCCC(COCc2ccccc2)C1
Temperature: 0 °C

Procedure:
To a solution of the compound (10) (4.9 g; 22.2 mmol) in acetone (90 ml), Jones reagent (chromic anhydride acid-sulfuric acid) (0.07 mol) is dropwise added, and the resultant mixture is stirred at a temperature of 0° to 10° C. for 2 hours. Methanol is dropwise added to the reaction mixture, which is poured into ice-water and extracted with chloroform. The extract is washed with water, dried and concentrated under reduced pressure. The residue is chromatographed on a silica gel column to give 3-benzyloxymethylcyclohexanone (11).
Reaction SMILES: [CH3:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]([C:21]([N+:24]([O-])=O)=[CH:22][CH:23]=2)[CH:15]=[CH:16][C:17](OC)=[O:18])[CH2:8][CH2:7]1)=[O:4].[H][H]>C(O)C.[C].[Pd]>[CH3:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:21](=[CH:22][CH:23]=2)[NH:24][C:17](=[O:18])[CH2:16][CH2:15]3)[CH2:8][CH2:7]1)=[O:4]
Reactant: [H][H]
Reactant: CCC(=O)NC1CCN(c2ccc([N+](=O)[O-])c(C=CC(=O)OC)c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCC(=O)NC1CCN(c2ccc3c(c2)CCC(=O)N3)CC1

Procedure:
1.25 Grams of methyl 3-[4-(N-methylacetylamino)1-piperidyl]-6-nitrocinnamate was dissolved in 50 ml of ethanol, then 0.4 g of 10%-palladium carbon was added thereto, the reaction mixture was stirred until the absorption of hydrogen gas was stopped under conditions of at room temperature and normal pressure. The catalyst was removed by filtration, the filtrate was concentrated by evaporating the solvent, the residue thus obtained was purified by means of a silica gel column chrmatography (eluent: dichloromethane:methanol=50:1), then recrystallized from methanol-diethyl ether to yield 0.82 g of 6-[4-(N-methylacetylamino)-1-piperidyl]-3,4-dihydrocarbostyril. Light yellow needle-like crystals. Melting point: 195°-197° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][CH:6]=[C:5]([C:8]([O:10]C)=O)[CH:4]=1.C[O-].[Na+].[CH3:15][NH:16][CH3:17]>CO>[OH:1][CH2:2][C:3]1[S:7][CH:6]=[C:5]([C:8]([N:16]([CH3:17])[CH3:15])=[O:10])[CH:4]=1
Reactant: COC(=O)c1csc(CO)c1
Reactant: CNC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN(C)C(=O)c1csc(CO)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of methyl 5-(hydroxymethyl)-3-thiophenecarboxylate (3 g), sodium methoxide (0.2 g) and excess anhydrous dimethylamine in dry methanol (20 ml) was stirred for 24 h at ambient temperature. The solvent was removed in vacuo, water was added and the product was extracted with ethyl acetate. The organic extract was evaporated to leave an oily residue which was chromatographed on silica with ethyl acetate-light petroleum 40°-60°; (1:1) to give the title compound (1.3 g).
Reaction SMILES: Cl.[CH:2]([NH:5][NH2:6])([CH3:4])[CH3:3].[C:7]([C:10](=[C:16]=CN(C)C)[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=O)[CH3:8]>>[CH:2]([N:5]1[C:7]([CH3:8])=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:16]=[N:6]1)([CH3:4])[CH3:3]
Reactant: CCOC(=O)C(=C=CN(C)C)C(C)=O
Reactant: CC(C)NN
Agent: Cl
Product: CCOC(=O)c1cnn(C(C)C)c1C

Procedure:
In a procedure analogous to Example B6, isopropylhydrazine hydrochloride (896 mg, 8.10 mmol) and ethyl 2-acetyl-3-(dimethylaminomethylene)acrylate (1.50 g, 8.10 mmol) were combined and purified by chromatography (ethyl acetate/hexane) to afford ethyl 1-isopropyl-5-methyl-1H-pyrazole-4-carboxylate (faster elution, 537 mg), 1H NMR (300 MHz, DMSO-d6): δ 1.30 (t, 3 H), 1.39 (d, 6 H), 4.23 (q, 2 H), 4.61 (hp, 1 H), 7.82 (s, 1 H); MS (ESI) m/z: 197.0 (M+H+) and ethyl 1-isopropyl-3-methyl-1H-pyrazole-4-carboxylate (slower elution, 91 mg), 1H NMR (300 MHz, DMSO-d6), δ 1.29 (t, 3 H), 1.42 (d, 6 H), 2.36 (s, 3 H), 4.21 (q, 2 H), 4.49 (hp, 1 H), 8.24 (s, 1 H); MS (ESI) m/z: 197.0 (M+H+).
Reaction SMILES: [CH3:1][S:2][CH:3]([S:8][CH3:9])[CH2:4][CH2:5][S:6][CH3:7].C([Li])CCC.[C:15](=[O:17])=[O:16].[OH-].[K+]>CCCCCC.C1COCC1>[CH3:1][S:2][C:3]([S:8][CH3:9])([CH2:4][CH2:5][S:6][CH3:7])[C:15]([OH:17])=[O:16]
Reactant: O=C=O
Reactant: CSCCC(SC)SC
Agent: [K+]
Agent: [Li]CCCC
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSCCC(SC)(SC)C(=O)O
Reaction time: 2 h

Procedure:
In a three-neck flask under a protective gas atmosphere, 1,1,3-tris(methylthio)propane (2) (3.65 g, 20 mmol) was dissolved in 50 ml of abs. THF. Subsequently, at −20° C., a butyllithium solution in n-hexane (14 ml, 1.6 M) was slowly added dropwise with stirring. In the course of this, the solution turned bright yellow. After stirring had been continued at this temperature for 2 h, gaseous dry CO2 was passed through via a frit at −70° C. over a period of 30 minutes. The reaction solution was thawed slowly until a temperature of 20° C. was attained, at which a 10% aqueous KOH solution (80 ml) was added. After phase separation, the organic phase was washed with 10% aqueous KOH solution (2×50 ml). The combined KOH phases were washed with diethyl ether (3×30 ml) and then adjusted cautiously to pH 1 with conc. HCl while cooling. The product was extracted with diethyl ether (3×50 ml). The combined ether phases were subsequently dried over Na2SO4 and, after filtration, concentrated on a rotary evaporator. 2,2,4-tris(methylthio)butanoic acid (4) was obtained as a yellowish oil (4.1 g, yield=90%), which crystallized slowly when left to stand. The NMR characterization gave the same data as in Example 3.
Reaction SMILES: CC([N:5]([CH2:9][C@H:10]1[C@H:14]([C:15]([NH2:17])=[O:16])[CH2:13][N:12]([CH2:18][CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[N:28]=3)[N:23]=[CH:22][C:21]=2[F:32])[CH2:11]1)C(=O)[O-])(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:5][CH2:9][C@@H:10]1[CH2:11][N:12]([CH2:18][CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[N:28]=3)[N:23]=[CH:22][C:21]=2[F:32])[CH2:13][C@@H:14]1[C:15]([NH2:17])=[O:16]
Reactant: COc1ccc2ncc(F)c(CCN3C[C@@H](CN(C(=O)[O-])C(C)(C)C)[C@H](C(N)=O)C3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2ncc(F)c(CCN3C[C@@H](CN)[C@@H](C(N)=O)C3)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1-dimethylethyl[((3S,4S)-4-(aminocarbonyl)-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]carbamate (0.51 g, 1.14 mmol) was dissolved in methylene chloride (5 mL). HCl in dioxane (2.87 mL, 11.14 mmol) was added and the solution stirred at ambient temperature for 2 hours. The solvent was removed under reduced pressure. (0.534 g, quant.) LCMS: m/z 348.4 (MH+).
Reaction SMILES: C(NCC)C.[CH2:6]([O:13][NH:14][C@H:15]1[CH2:20][N:19](C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH:18]([C:38](=[O:40])[NH2:39])[C:17]([CH2:41][O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])=[CH:16]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[CH2:6]([O:13][NH:14][C@H:15]1[CH2:20][NH:19][CH:18]([C:38]([NH2:39])=[O:40])[C:17]([CH2:41][O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:44])[CH3:45])=[CH:16]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)[Si](C)(C)OCC1=C[C@@H](NOCc2ccccc2)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1C(N)=O
Solvent: CCNCC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1=C[C@@H](NOCc2ccccc2)CNC1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
Diethylamine (0.824 mL, 7.89 mmol) was added to a solution of (5R)-(9H-fluoren-9-yl)methyl 5-((benzyloxy)amino)-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-carbamoyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 162, 0.968 g, 1.58 mmol) in DCM (20 mL) and the resulting solution was allowed to stir at room temperature overnight. The volatiles were removed by evaporation and the residue was purified on silica gel (0-12%, MeOH/DCM, UV 220 nm) to afford the title compound (0.564 g, 91%) as a yellow film.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:31][O:32][CH2:33][CH2:34][OH:35]>>[CH3:31][O:32][CH2:33][CH2:34][O:35][CH2:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Product: COCCOCc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
4-Chloromethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide (200 mg, 0.48 mmol) and sodium hydride (42 mg 55% dispersion in mineral oil, 0.96 mmol) were dissolved in 2-methoxy-ethanol (3.8 ml, 48 mmol) and stirred at ambient temperature for 18 h. Workup and, purification as described in the general procedure C afforded the title compound as white solid (70%), MS: m/e=458 (M+H+).
Reaction SMILES: [CH:1]([NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=2)[C:9]([NH:20][CH2:21][C:22](=[O:28])[NH:23][CH:24]2[CH2:27][NH:26][CH2:25]2)=[N:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:29][O:30][C:31]1[N:36]=[CH:35][C:34]([CH:37]2[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]2)=[CH:33][CH:32]=1>>[CH:1]([NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:18])([F:19])[F:17])=[CH:13][CH:14]=2)[C:9]([NH:20][CH2:21][C:22](=[O:28])[NH:23][CH:24]2[CH2:25][N:26]([CH:40]3[CH2:41][CH2:42][CH:37]([C:34]4[CH:35]=[N:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=4)[CH2:38][CH2:39]3)[CH2:27]2)=[N:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: COc1ccc(C2CCC(=O)CC2)cn1
Reactant: CC(C)NC(=O)n1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Product: COc1ccc(C2CCC(N3CC(NC(=O)CNc4nn(C(=O)NC(C)C)c5ccc(C(F)(F)F)cc45)C3)CC2)cn1

Procedure:
The title compound was prepared as a white solid from reaction of 3-[(azetidin-3-ylcarbamoylmethyl)-amino]-5-trifluoromethyl-indazole-1-carboxylic acid isopropylamide (as prepared in Example 90, Step A) and 4-(6-methoxy-pyridin-3-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][CH2:12][CH:13]([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:8][C:7]([CH3:22])=[CH:6][N:5]2[C:23]=1[C:24](O)=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:58][C:59]([NH2:66])([CH2:62][CH:63]([CH3:65])[CH3:64])[CH2:60][NH2:61]>CN(C=O)C>[NH2:66][C:59]([CH3:58])([CH2:62][CH:63]([CH3:65])[CH3:64])[CH2:60][NH:61][C:24]([C:23]1[N:5]2[CH:6]=[C:7]([CH3:22])[CH:8]=[C:9]([O:10][CH2:11][CH2:12][CH:13]([C:14]([F:16])([F:15])[F:17])[C:18]([F:19])([F:20])[F:21])[C:4]2=[N:3][C:2]=1[CH3:1])=[O:25]
Reactant: CC(C)CC(C)(N)CN
Reactant: Cc1cc(OCCC(C(F)(F)F)C(F)(F)F)c2nc(C)c(C(=O)O)n2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(OCCC(C(F)(F)F)C(F)(F)F)c2nc(C)c(C(=O)NCC(C)(N)CC(C)C)n2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
31 mg (0.08 mmol) of 2,6-dimethyl-8-[4,4,4-trifluoro-3-(trifluoromethyl)butoxy]imidazo[1,2-a]-pyridine-3-carboxylic acid Example 259A, dissolved in 0.3 ml of DMF, 40 mg (0.104 mmol) of HATU, dissolved in 0.3 ml of DMF, and then 16 mg (0.16 mmol) of 4-methylmorpholine were added to 10 mg (0.08 mmol) of rac-2,4-dimethylpentane-1,2-diamine. The mixture was shaken at RT overnight. The target compound was concentrated by preparative HPLC (Method 12). This gave 10 mg (25% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:13]=[CH:14][C:15]([CH3:19])=[C:16]([CH:18]=1)[NH2:17].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:13]=[CH:14][C:15]([CH3:19])=[C:16]([CH:18]=2)[NH2:17])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Br)cc1N
Reactant: OB(O)c1ccc(Cl)cc1
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: COCCOC
Solvent: O
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1N
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 96.5 %

Procedure:
4-Chlorophenylboronic acid (20.2 g, 0.13 mol) and tetrakis(triphenylphosphine)palladium (0) (3.7 g, 0.003 mol) are added to a solution of 5-bromo-2-methylaniline (20 g, 0.1 mol) in 1,2-dimethoxyethane (200 ml). After stirring the reaction mixture for 15 minutes at 20° C., a solution of 20% aqueous sodium carbonate (300 ml) is added to the mixture, and the resulting mixture is refluxed for 24 hours. The reaction mixture is cooled to room temperature, diluted with water (600 ml) and extracted using ethyl acetate. The combined organic extracts are dried over anhydrous sodium sulfate, filtered and the filtrate evaporated in vacuo. The residue is further purified by column chromatography on silica gel, eluting with 7% ethyl acetate in hexane to give 5-(4-chlorophenyl)-2-methylaniline (21.0 g).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[NH:10][C:9](=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5]1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1.O>[CH2:12]([N:10]1[CH:4]([CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: CC1CCCCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1CCCCC(=O)N1Cc1ccccc1
Temperature: 23 °C
Reaction time: 20 h

Procedure:
Sodium hydride (95%, 1.74 g, 68.7 mmol, 1.15 equiv) was added to a solution of 7-methylazepan-2-one (2-2, 7.60 g, 59.8 mmol, 1 equiv) in THF (150 mL) at 0° C. and the resulting mixture was warmed to 23° C. and stirred for 20 h. Benzyl bromide (7.82 mL, 65.7 mmol, 1.10 equiv) was added followed by 2 drops of water, and the resulting mixture was stirred at 23° C. for 20 h. Excess sodium hydride was quenched carefully with water and the mixture was concentrated. The residue was partitioned between water and dichloromethane. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (100% hexanes initially, grading to 100% EtOAc) to give 1-benzyl-7-methylazepan-2-one (2-3) as a colorless oil. LRMS m/z (M+H) 218.2 found, 218.2 required.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[B:12]1[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]1.C([O-])([O-])=O.[K+].[K+].N#N.[CH2:29](Br)[CH:30]=[CH2:31]>CN(C=O)C.O>[CH2:31]([N:10]1[CH2:9][CH2:8][O:7][C:6]2[CH:5]=[CH:4][C:3]([B:12]3[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]3)=[C:2]([Cl:1])[C:11]1=2)[CH:30]=[CH2:29]
Reactant: CC1(C)OB(c2ccc3c(c2Cl)NCCO3)OC1(C)C
Reactant: C=CCBr
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN1CCOc2ccc(B3OC(C)(C)C(C)(C)O3)c(Cl)c21
Temperature: 70 °C
Yield: 84.2 %

Procedure:
A solution of 5-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.504 g, 1.426 mmol, Ref. WO20100130034) and K2CO3 (0.504 g, 3.65 mmol) in dry DMF (5 mL) was sparged with N2 for 5 min, then treated with allyl bromide (0.8 mL, 9.17 mmol). The reaction tube was sealed and then heated (70° C.) for 22 h, then cooled and diluted with water (50 mL) and extracted into EtOAc (50 mL). The organic layer was washed with water, brine, then dried (Na2SO4), filtered, concentrated, and purified by biotage chromatography (4 g SiO2, 0% (3 CV), 0-40% (15 CV), 40% (2 CV); EtOAc in hexanes) to afford the desired product (0.403 g, 1.201 mmol, 84% yield) as a clear viscous oil. 1H NMR (500 MHz, CDCl3) δ 7.30 (d, J=8.2 Hz, 1H), 6.79 (d, J=8.2 Hz, 1H), 6.15-6.02 (m, 1H), 5.31 (dd, J=17.2, 1.4 Hz, 1H), 5.28-5.21 (m, 1H), 4.18-4.13 (m, 2H), 3.59 (d, J=6.0 Hz, 2H), 3.14-3.07 (m, 2H), 1.36 (s, 12H). LCMS (M+H)=336.9.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.Br[C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].O>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]=[CH:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:18]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(N=Cc2ccc(O)cc2)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(C=Nc2ccc(OC)cc2)cc1
Reaction time: 2 h
Yield: 66.6 %

Procedure:
(a) 2.38 g of 50% sodium hydride is suspended in 75 ml of anhydrous dimethylformamide, and 7.5 g of 4-[N-(4-methoxyphenyl)formimidoyl]phenol is added in four portions to the suspension at room temperature with stirring. Subsequently, 9.65 g of ethyl 2-bromo-2-methylpropionate is added dropwise to the resulting mixture at 20° to 25° C. over a period of about 40 minutes. The mixture is stirred at room temperature for 1 hour and then at 50° to 55° C. for 2 hours. The reaction mixture is poured into cold water, extracted with ether, and the extract is washed with 5% aqueous solution of sodium hydroxide until disappearance of the color of the aqueous layer, then washed with water and dried. After drying, the ether is distilled off to give 7.5 g of ethyl 2-[4-{N-(4-methoxyphenyl)formimidoyl}phenoxy]-2-methylpropionate in the form of an oil.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[CH:17][C:18]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([NH:25][NH2:26])=[O:24])=[CH:21][CH:20]=3)=[C:12]2[N:11]=1)([CH3:3])[CH3:2].N1([C:34](N2C=CN=C2)=[O:35])C=CN=C1>CN(C=O)C.CCOC(C)=O>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[CH:17][C:18]([C:19]3[CH:28]=[CH:27][C:22]([C:23]4[O:24][C:34](=[O:35])[NH:26][N:25]=4)=[CH:21][CH:20]=3)=[C:12]2[N:11]=1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(C(=O)NN)cc3)c2n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4n[nH]c(=O)o4)cc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.1 %

Procedure:
To a solution of (S)-4-(5-(4-isopropyl-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)benzohydrazide (Example 9, Step 2; 91 mg, 0.239 mmol) in DMF (2 mL) was added di(1H-imidazol-1-yl)methanone (40.7 mg, 0.251 mmol). The reaction mixture was allowed to stir for 1 hour at ambient temperature, then dissolved in EtOAc, washed with water and brine, and concentrated. The resulting solid was suspended in dichloromethane, filtered, washed with dichloromethane, then concentrated to give crude product. The residue was purified by silica gel chromatography (0-5% MeOH in dichloromethane) to afford 42.8 mg (44%) of (S)-5-(4-(5-(4-isopropyl-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenyl)-1,3,4-oxadiazol-2(3H)-one. LCMS (APCI+) m/z 407.5 [M+H]+.