Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[OH:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[C:43](=[O:47])[NH:42][CH:41]=[CH:40]2.[N:48]1[CH:53]=[CH:52][CH:51]=[C:50]([CH2:54][CH2:55][N:56]([CH2:61][C:62]2[CH:67]=[CH:66][N:65]=[CH:64][CH:63]=2)[CH2:57][CH2:58][CH2:59]O)[CH:49]=1.C(OC(=O)C)C.[ClH:74]>C(OCC)(=O)C.O1CCCC1>[ClH:74].[ClH:74].[ClH:74].[N:48]1[CH:53]=[CH:52][CH:51]=[C:50]([CH2:54][CH2:55][N:56]([CH2:61][C:62]2[CH:63]=[CH:64][N:65]=[CH:66][CH:67]=2)[CH2:57][CH2:58][CH2:59][O:36][C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[C:43](=[O:47])[NH:42][CH:41]=[CH:40]3)[CH:49]=1
Reactant: O=c1[nH]ccc2cc(O)ccc12
Reactant: OCCCN(CCc1cccnc1)Cc1ccncc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1[nH]ccc2cc(OCCCN(CCc3cccnc3)Cc3ccncc3)ccc12
Reaction time: 8 h

Procedure:
Triphenyl phosphine(51 mg) and di-tert-butyl azodicarboxylate (45 mg) were added to a tetrahydrofuran (THF) solution(1.5 ml) of 6-hydroxy-2H-isoquinolin-1-one(29 mg), and 3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propan-1-ol(40 mg). The mixture was stirred overnight. After the reaction mixture was condensed under reduced pressure, the residue was purified by NH silica gel column chromatography (ethyl acetate: methanol=1:0→4:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution(0.06 ml) was added to an ethyl acetate solution of the residue, which was stirred at room temperature for 30 minutes. The generated insoluble matter was separated by filtration, and was dried to produce the title compound(31.4 mg) as a white powder.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][N:16]=[CH:15]4)[C:9]([CH3:21])=[C:8]([F:22])[CH:7]=2)[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29].O>CN(C=O)C>[CH:1]1([NH:4][C:5]([C:6]2[CH:7]=[C:8]([F:22])[C:9]([CH3:21])=[C:10]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[N:16]=[CH:15]4)[CH:11]=2)=[O:23])[CH2:2][CH2:3]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2[nH]ncc2c1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)cc(F)c3C)ccc21
Reaction time: 0.33 h

Procedure:
A solution of N-cyclopropyl-3-fluoro-5-(1H-indazol-5-yl)-4-methylbenzamide (example 60) (0.35 g) in dry DMF (5 ml) was treated with sodium hydride (60% oil dispersion, 0.08 g) at room temp under nitrogen then stirred for 20 min. A solution of methyl bromoacetate (0.2 ml) in dry DMF (0.5 ml) was added and stirring was continued for 1 h. Water (30 ml) was added and the mixture was extracted with ethyl acetate (×2). The organic extracts were washed with water (×3) and brine, dried (Na2SO4) and concentrated under vacuum. The residue was purified using a Varian Bond-Elut SPE cartridge (silica, 10 g) eluting with cyclohexane:ethyl acetate (4:1 to 1:1) to give the title compound as a yellow foam (0.26 g).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([C:6]1[C:7]([Cl:14])=[N:8][C:9](Cl)=[CH:10][C:11]=1[CH3:12])#[N:5]>O1CCOCC1.C(OCC)(=O)C>[Cl:14][C:7]1[C:6]([C:4]#[N:5])=[C:11]([CH3:12])[CH:10]=[C:9]([N:2]([CH3:3])[CH3:1])[N:8]=1
Reactant: CNC
Reactant: Cc1cc(Cl)nc(Cl)c1C#N
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(N(C)C)nc(Cl)c1C#N
Reaction time: 2 h

Procedure:
Dimethylamine (8 mL) was added to a solution of 3-cyano-2,6-dichloro-4-methylpyridine (11.6 g) in dioxan (100 mL). After stirring for 2 hours the reaction mixture was diluted with ethyl acetate (1 L), washed with water, dried, filtered, and evaporated to a volume of 20 mL. The crystalline material was filtered to give 5.4 g of the title compound, suitable for use in the next reaction.
Reaction SMILES: ClC1C=C[C:5]2[N:6]([C:8]([C:11]([C:13]3C=C4C(=CC=3)N=CC=C4)=O)=CN=2)[N:7]=1.Cl[C:24]1[CH:25]=[CH:26][C:27]2[N:28]([C:30]([C:33]([C:39]3[CH:40]=[C:41]4[C:46](=[CH:47][CH:48]=3)[N:45]=[CH:44][CH:43]=[CH:42]4)([OH:38])[C:34]([F:37])([F:36])[F:35])=[CH:31][N:32]=2)[N:29]=1.CN(C=O)C.FC([Si](C)(C)C)(F)F.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:35][C:34]([F:37])([F:36])[C:33]([C:30]1[N:28]2[N:29]=[C:24]([C:11]3[CH:13]=[N:7][N:6]([CH3:5])[CH:8]=3)[CH:25]=[CH:26][C:27]2=[N:32][CH:31]=1)([C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][CH:48]=1)[N:45]=[CH:44][CH:43]=[CH:42]2)[OH:38]
Reactant: OC(c1ccc2ncccc2c1)(c1cnc2ccc(Cl)nn12)C(F)(F)F
Reactant: O=C(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C(F)(F)F
Agent: [F-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc3ncc(C(O)(c4ccc5ncccc5c4)C(F)(F)F)n3n2)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(rac)-1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-2,2,2-trifluoro-1-quinolin-6-yl-ethanol (6-chloro-imidazo[1,2-b]pyridazin-3-yl)-quinolin-6-yl-methanone (Stage 1.2, 411 mg, 1.331 mmol) was dissolved in THF (1.5 mL) and DMF (1.5 mL) together with (trifluoromethyl)trimethylsilane (0.255 mL, 1.598 mmol) and the mixture was cooled down to 0° C. TBAF solution (1 M, 0.067 mL) was then added slowly. After 5 min, the RM was allowed to warm up to rt. After 24 h of stirring, it was warmed up to 50° C. and stirred for 24 h more. The reaction was then quenched with 1 N HCl. The precipitate formed was filtered off and identified as remaining pure starting material The solution was basified with pellets of NaOH. The second precipitate formed and filtered off was starting material as well. The aqueous layer was extracted twice with EtOAc and then the joined organics were washed with brine and dried over Na2SO4. After removing the solvent, the residue was purified by MPLC with DCM and MeOH to give the title compound as a brown solid (tR 0.8 min (conditions 2), MH+=379).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]2=[N:7][O:8][N:9]=[C:5]2[CH:4]=1)=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:20])C=1>C(Cl)Cl>[O:20]1[CH2:2][CH:1]1[C:3]1[CH:11]=[CH:10][C:6]2=[N:7][O:8][N:9]=[C:5]2[CH:4]=1
Reactant: C=Cc1ccc2nonc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: c1cc2nonc2cc1C1CO1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5-ethenyl-2,1,3-benzoxadiazole (1.80 g, 12.3 mmol) in DCM (20 mL) was slowly added m-CPBA (3.8 g, 22 mmol) at 0° C. The flask was warmed to room temperature; the mixture was then stirred for 12 hours. TLC as well as LC indicated that reaction had gone to completion. The mixture was washed with aqueous Na2S2O3, NaHCO3, and water. The organic layers was washed with brine and then concentrated. The residue was purified over silica gel to afford the title compound.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(O[O:18][C:19]([C:22]1C=CC=CC=1)(C)C)(C1C=CC=CC=1)C.[C]=O.[CH2:30]([OH:32])C>>[C:1]1([CH2:7][C:30]([O:18][CH2:19][CH3:22])=[O:32])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(OOC(C)(C)c1ccccc1)c1ccccc1
Reactant: CCO
Reactant: Cc1ccccc1
Agent: [C]=O
Product: CCOC(=O)Cc1ccccc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 42.7 %

Procedure:
Toluene (1.38 g), ethanol (46 mg), diisopropylbenzene peroxide (135 mg, 1 equivalent), and Pd(Xantphos)Cl2 (3.8 mg, 1 mol %) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 35 mg ethyl phenylacetate was obtained by column chromatography, in a yield of 43%. The ethyl phenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 27 mg product phenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 93%.
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:7]=[C:8]([C:12]3[CH:16]=[C:15]([O:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=4)[N:14]([CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[N:13]=3)[CH:9]=[CH:10][CH:11]=2)[CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[F:41][C:42]([F:49])([F:48])[CH2:43][S:44](Cl)(=[O:46])=[O:45].O>C(Cl)Cl>[F:27][C:24]([F:25])([F:26])[C:21]1[CH:20]=[CH:19][C:18]([O:17][C:15]2[N:14]([CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[N:13]=[C:12]([C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([C:2]4([NH:1][S:44]([CH2:43][C:42]([F:49])([F:48])[F:41])(=[O:46])=[O:45])[CH2:5][O:4][CH2:3]4)[CH:7]=3)[CH:16]=2)=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: CN(C)C(=O)Cn1nc(-c2cccc(C3(N)COC3)c2)cc1Oc1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Cn1nc(-c2cccc(C3(NS(=O)(=O)CC(F)(F)F)COC3)c2)cc1Oc1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
A stirred solution of 2-{3-[3-(3-aminooxetan-3-yl)phenyl]-5-(4-trifluoromethylphenoxy)-1H-pyrazol-1-yl}-N,N-dimethylacetamide (46 mg, 0.10 mmol) in 1 mL of CH2Cl2 was cooled in an ice bath. Triethylamine (0.021 mL, 0.15 mmol) was added, followed by trifluoroethylsulfonyl chloride (0.013 mL, 0.12 mmol), and the mixture was stirred for 30 min. Water was added and the mixture was extracted with CH2Cl2. The combined organic phases were washed with water and brine, then dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was purified on a C18 reverse phase column using a gradient elution of 20-70% CH3CN:H2O with 0.1% TFA over 20 min at 20 mL/min. Fractions containing pure product were combined and the solvents were removed under reduced pressure to give 2-[5-(4-trifluoromethylphenoxy)-3-(3-{3-[(2,2,2-trifluoroethylsulfonyl)amino]oxetan-3-yl}phenyl)-1H-pyrazol-1-yl]-N,N-dimethylacetamide as a foam. Calcd (M+1)+: 607.1444. Found: 607.1468. 1H NMR (400 MHz, CDCl3) δ 7.75 (m, 2H), 7.64 (d, J=7, 2H), 7.44 (t, J=7, 1H), 7.35 (m, 2H), 7.28 (s, 1H), 6.38 (s, 1H), 6.04 (s, 1H), 5.04 (d, J=7, 2H), 4.98 (d, J=7, 2H), 4.94 (s, 2H), 3.09 (s, 3H), 2.97 (overlapping s and q, 5H).
Reaction SMILES: [Cl:1][C:2]1[C:17]([CH3:18])=[CH:16][C:5]([NH:6][C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])=[C:4]([F:19])[CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[N+:33]([O-])([O-:35])=[O:34].[NH4+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[C:17]([CH3:18])=[C:16]([N+:33]([O-:35])=[O:34])[C:5]([NH:6][C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])=[C:4]([F:19])[CH:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc(NC(=O)Oc2ccccc2)c(F)cc1Cl
Agent: O=C([O-])O
Agent: [NH4+]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1c(Cl)cc(F)c(NC(=O)Oc2ccccc2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 103.1 %

Procedure:
4-Chloro-2-fluoro-5-methyl-N-phenoxycarbonylaniline (7.1 g, 25.4 mmol) was dissolved in chloroform (68 ml) and trifluoroaceticanhydride (13.5 ml) and ammonium nitrate (2.4 g, 30.5 mmol) were slowly added with stirring at ambient temperature. The stirring was continued for 18 hr when a second batch of ammonium nitrate (0.4 g, 5 mmol) was added and stirring continued for 8 hr. Water was added and solution was neutralized by slow addition of sodium bicarbonate solution followed by extraction with chloroform. Organic layer was dried and evaporated under reduced pressure to afford an oily product (8.5 g) which was used for the next step without purification.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:28])[C:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][N:9]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])=[CH:4][C:3]=1F.[NH:30]1[CH2:36][CH2:35][CH2:34][C@H:31]1[CH2:32][OH:33].C(N(C(C)C)CC)(C)C.O>C(#N)C>[CH3:22][O:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=1[CH2:12][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([N:30]3[CH2:36][CH2:35][CH2:34][C@H:31]3[CH2:32][OH:33])[N:11]=2)[C:6](=[O:28])[C:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8]1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(Cl)c(F)cc2c1=O
Reactant: OC[C@@H]1CCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(N3CCC[C@H]3CO)ccc2c1=O

Procedure:
A mixture of EXAMPLE 1B (2.96 g), (S)-prolinol (850 μL), and diisopropylethylamine (4 mL) in acetonitrile (70 mL) at 25° C. was stirred for 3 days, treated with water, and extracted with dichloromethane. The extract was washed with 1M hydrochloric acid, water, saturated NaHCO3, and water, and concentrated.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([Br:21])[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].[CH:23](=[O:27])[CH:24]([CH3:26])[CH3:25].O>O1CCCC1.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>[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:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([Br:21])[CH:14]=1)[C:24]([CH3:26])([CH3:25])[CH:23]2[OH:27])=[O:22])[CH3:2]
Reactant: CCOC(=O)c1ccc(N=Cc2cc(Br)cc(OC)c2)cc1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(Br)cc(OC)c1)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.3 %

Procedure:
To a mixture of 4-{[1-(3-bromo-5-methoxy-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (4.5 g, 12.4 mmol) and ytterbium(III) triflate hydrate (0.77 g, 1.24 mmol) in dry tetrahydrofuran (20 mL) at 25° C. was added isobutyraldehyde (0.89 g, 12.4 mmol) and water (0.22 mL, 12.4 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-(3-bromo-5-methoxy-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (5.4 g, 100%) as a light yellow oil: LC/MS m/e calcd for C21H24BrNO4 M+: 434.3, observed: 418.1.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=2)[NH:11][CH:10]=1)(=O)=O.[CH3:20][O:21][C:22]1[C:23]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:24][CH:25]=[N:26][CH:27]=1.C(N(CC)C(C)C)(C)C>C(#N)C.C(Cl)(Cl)Cl>[C:18]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:8][CH2:7][CH2:6][N:31]1[CH2:32][CH2:33][N:28]([C:23]2[C:22]([O:21][CH3:20])=[CH:27][N:26]=[CH:25][N:24]=2)[CH2:29][CH2:30]1)#[N:19]
Reactant: CS(=O)(=O)OCCCc1c[nH]c2ccc(C#N)cc12
Reactant: COc1cncnc1N1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(C#N)cc23)CC1
Yield: 42.4 %

Procedure:
To a solution of 3-(5-cyano-1H-indol-3-yl)propyl methanesulfonate (2.35 mmol, 1.0 equiv.) in 25 mL of anhydrous acetonitrile was added 0.874 g (4.5 mmol, 1.5 equiv.) of (5-methoxy-4-pyrimidinyl)piperazine and 1.0 mL of N,N-diisopropylethylamine. The mixture was heated to reflux for thirteen hours. The solution was cooled, diluted with 100 mL of chloroform and washed once with 20 mL of 10% aqueous sodium carbonate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on silica gel using 5% methanol in methylene chloride containing 0.5% concentrated aqueous ammonium hydroxide to yield 0.375 g (42%, two steps) of 1-[3-(5-cyano-1H-indol-3-yl)propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine pure by 1H NMR analysis.
Reaction SMILES: [N:1]1([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:5][CH2:4][CH:3]([C:6]([O:8]C(C)(C)C)=[O:7])[N:2]1C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.O>ClCCl>[C:24]1([CH2:23][O:22][C:20]([N:1]2[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=[O:7])[NH:2]2)=[O:21])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)C1CCN(C(=O)OCc2ccccc2)N1C(=O)OC(C)(C)C
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)N1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
1-Benzyl 2,3-di-tert-butyl pyrazolidine-1,2,3-tricarboxylate (14.15 g, 34.8 mmol) was dissolved in dichloromethane (68.6 ml) under N2 at room temperature. TFA (80 ml, 1045 mmol) and water (9.41 ml, 522 mmol) were then added in one portion. The reaction was stirred at 25° C. for 2 days. The solvent was then removed under reduced pressure to give 1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (8.72 g, 34.8 mmol, 100% yield).
Reaction SMILES: [CH:1]1([N:4]([CH:30]2[CH2:32][CH2:31]2)[C:5]([C:7]2[N:27]([CH2:28][CH3:29])[C:10]3=[N:11][C:12]([NH:19]/[C:20](/SC)=[CH:21]/[C:22](=O)[CH3:23])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH2:33]([N:35](C(OC(C)(C)C)=O)[NH2:36])[CH3:34].C(O)=O>C(O)(=O)C>[CH:1]1([N:4]([CH:30]2[CH2:32][CH2:31]2)[C:5]([C:7]2[N:27]([CH2:28][CH3:29])[C:10]3=[N:11][C:12]([NH:19][C:20]4[CH:21]=[C:22]([CH3:23])[N:35]([CH2:33][CH3:34])[N:36]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCN(N)C(=O)OC(C)(C)C
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N/C(=C/C(C)=O)SC)nc21
Solvent: O=CO
Solvent: CC(=O)O
Product: CCn1nc(Nc2nc3c(cc(C(=O)N(C4CC4)C4CC4)n3CC)c3c2ncn3C)cc1C
Temperature: 35 °C
Reaction time: 4 h
Yield: 54.9 %

Procedure:
A mixture of (Z)-N,N-dicyclopropyl-6-ethyl-1-methyl-4-(1-(methylthio)-3-oxobut-1-enylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 74B, 70 mg, 0.155 mmol) and tert-butyl 1-ethylhydrazinecarboxylate (49.6 mg, 0.309 mmol) in acetic acid (1 mL) wan stirred at 35° C. for 4 h (monitored by LC/MS until no starting material left). Formic acid (1 mL) was added and the reaction mixture stirred at 60° C. for 6 h. The solvent was evaporated and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (12 g column, eluting with 2-10% methanol/dichloromethane). The material was further purified by preparative HPLC to afford N,N-dicyclopropyl-6-ethyl-4-(1-ethyl-5-methyl-1H-pyrazol-3-ylamino)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (38 mg, 53.4% yield) as an off-white solid.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[C:9]#[N:10])=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[Cl:19]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:19][C:2]1[O:1][C:5]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[C:9]#[N:10])=[CH:4][N:3]=1
Reactant: N#Cc1cccc(-c2cnco2)c1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2cnc(Cl)o2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
To a round bottom flask was added 3-(oxazol-5-yl)benzonitrile (1.93 gm, 11.34 mmol) and THF (45 mL). The reaction was cooled to −78° C. and 2.5 M nBuLi (4.99 mL, 12.48 mmol) was added dropwise. The reaction turned deep red color. After 30 min, a solution of hexachloroethane (4.03 gm, 17.01 mmol) in THF (10 mL) was slowly added. The reaction was slowly warmed to rt over 30 min. After 1 h at rt the reaction was quenched by slow addition of sat. NH4Cl (20 mL). The mixture was concentrated to remove most of the THF. The mixture was then partitioned between EtOAc (40 mL) and water (20 mL). The organic phase was isolated, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography eluting with a gradient of 0-100% EtOAc/Hexanes to give the product, 3-(2-chlorooxazol-5-yl)benzonitrile, (1.01 gm, 4.94 mmol, 44% yield) as a white solid. Anal. Calcd. for C10H5ClN2O m/z 204.0, found: 205.0 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1[OH:22])([CH3:14])([CH3:13])[CH3:12].C=O.[CH2:25](NCCCC)CCC>>[C:11]([C:15]1[CH:20]=[C:19]([CH:18]=[C:17]([CH3:21])[C:16]=1[OH:22])[CH2:25][C:7]1[C:5]2[NH:6][C:2](=[S:1])[O:3][C:4]=2[CH:10]=[CH:9][CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CCCCNCCCC
Reactant: Cc1cccc(C(C)(C)C)c1O
Reactant: Sc1nc2ccccc2o1
Agent: C=O
Product: Cc1cc(Cc2cccc3oc(=S)[nH]c23)cc(C(C)(C)C)c1O
Reaction time: 2 h

Procedure:
2-Mercaptobenzoxazole (10.96 g, 0.073 mol), 2-tertbutyl-6-methylphenol (11.9 g, 0.073 mol), paraformaldehyde (2.18 g, 0.073 mol) and di-n-butylamine (0.5 ml) are heated to 120° C. After two hours, the reaction mixture solidifies. The solid mass is crystallised from ethanol to yield a white solid (19.8 g, 84% of theory) of m.p. 155°-157° C. (Found N=4.17; C19H21NO2S requires N=4.28%).
Reaction SMILES: CO[CH:3]1[CH2:8][NH:7][CH2:6][CH2:5][N:4]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:15](=[O:18])([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][Cl:24]>CN(C=O)C>[CH3:15][O:18][C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:4]1[CH2:3][CH2:8][N:7]([CH2:22][CH2:23][Cl:24])[CH2:6][CH2:5]1
Reactant: O=C([O-])[O-]
Reactant: COC1CNCCN1c1ccccc1
Reactant: ClCCBr
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCCl)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At room temperature, a solution of 19.2 g (0.1 mol) of o-methoxyphenylpiperazine and 13.8 g (0.1 mol) of potassium carbonate in 200 ml of DMF was initially charged and, after 30 min, 30 ml (0.36 mol) of 1-bromo-2-chloroethane were added. The mixture was stirred at room temperature for 2 h. The mixture was poured into ice-water then extracted with methyl tert-butyl ether, and the organic phases were washed with water, dried with sodium sulfate and subsequently concentrated. The residue was dissolved in ethyl acetate and the hydrochloride was precipitated out by addition of 30% strength isopropanol/HCI solution, filtered off with suction and dried at 40° C. in a vacuum drying oven. This gave 17 g (67%) of substance. Melting point 200° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:14]1([C:19]2([CH3:39])[CH2:27][C:26]3[C:21](=[C:22]([Cl:37])[C:23]([Cl:36])=[C:24](OS(C(F)(F)F)(=O)=O)[CH:25]=3)[C:20]2=[O:38])[CH2:18][CH2:17][CH2:16][CH2:15]1.Cl>CN(C)C=O.C(Cl)Cl>[CH:14]1([C:19]2([CH3:39])[CH2:27][C:26]3[C:21](=[C:22]([Cl:37])[C:23]([Cl:36])=[C:24]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH:25]=3)[C:20]2=[O:38])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC1(C2CCCC2)Cc2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c(Cl)c2C1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)OCC)c1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of sodium hydride (2.88 g., 120 mmole) in dry dimethylformamide (20 ml), under dry nitrogen and cooled in an ice-bath is added dropwise, a solution of diethyl malonate (19.2 g., 120 mmole) in dimethylformamide (30 ml). The mixture is stirred for one hour in the ice-bath and another hour at room temperature, then is cooled in the ice-bath again and 2-cyclopentyl-6,7-dichloro-2-methyl-5-trifluoromethylsulfonyloxy-1-indanone (12.93 g., 30 mmole) in dimethylformamide (25 ml) is added dropwise over 1-1/2 hours. The mixture is stirred at room temperature overnight and then poured into a mixture of ice-water (750 ml), methylene chloride (200 ml) and 6 N hydrochloric acid (20 ml). The methylene chloride layer is separated and the aqueous layer extracted with methylene chloride (50 ml). The combined extract is washed with water (500 ml), dried (MgSO4) and evaporated under vacuum, finally at 70°/0.05 Torr, to give an oil (18.28 g.). This is purified by chromatography on Merck silica gel (1.04 Kg) using 1,1,1-trichloroethane as the solvent. The product is accompanied by some diethyl malonate which is removed at 125°/0.05 Torr to give a viscous oil, 10.25 g. (77%),