Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:11])=[C:4]([NH:8][CH2:9][CH3:10])[N:5]=[N:6][CH:7]=1.[CH2:12](OC(OCC)OCC)C>>[Cl:1][C:2]1[C:3]2[N:11]=[CH:12][N:8]([CH2:9][CH3:10])[C:4]=2[N:5]=[N:6][CH:7]=1
Reactant: CCNc1nncc(Cl)c1N
Reactant: CCOC(OCC)OCC
Product: CCn1cnc2c(Cl)cnnc21
Yield: 45 %

Procedure:
A mixture of 5-chloro-N3-ethyl-pyridazine-3,4-diamine (Preparation 7, 10.0 g, 58 mmol) and triethylorthoformate (60 mL) were heated to reflux for 4 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (50 mL) and filtered. The filter cake was washed with EtOAc and then the organic layers were washed with saturated brine solution, dried over Na2SO4 and concentrated in vacuo to afford the title compound as a yellow solid in 45% yield, 4.8 g.
Reaction SMILES: [C:1]12([O:16][CH2:15][CH2:14][O:13]1)[C:10]1[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:4][C@@H:3]([CH:11]=O)[CH2:2]2.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])C=CC=CC=1>C(Cl)Cl>[C:1]12([O:16][CH2:15][CH2:14][O:13]1)[C:10]1[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:4][C@@H:3]([CH:11]=[CH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:2]2
Reactant: O=C[C@@H]1Cc2ccccc2C2(C1)OCCO2
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C=C[C@@H]1Cc2ccccc2C2(C1)OCCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.1 %

Procedure:
To the stirred solution of (R)-3′,4′-dihydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalene]-3′-carbaldehyde (4.1 g, 18.79 mmol) in DCM (10 mL), ethyl 2-(triphenyl phosphoranylidene)acetate (7.85 g, 22.54 mmol) was added and reaction mixture was stirred at RT for 16 h. After completion of reaction, reaction mixture was concentrated under vacuum to get 5.5 g of crude compound. This crude compound was further purified by flash chromatography (Biotage) using eluent hexane/ethyl acetate 80:20 to get the title compound (2.5 g, 46.2% yield); m/z 288.34
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1(C(OCC2C=CC=CC=2)=O)[C:15](=[O:16])[CH2:14][CH2:13][CH2:12]1)[CH3:2].[H][H]>[Pd].C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][C:15]1=[O:16])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CCCCCCC1(C(=O)OCc2ccccc2)CCCC1=O
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCCC1CCCC1=O
Temperature: 130 °C

Procedure:
The crude oil from (ii) above was dissolved in 50 ml. of toluene and reduced over 1 g. of 5% Pd on carbon under 50 psi of hydrogen for 20 hours. The catalyst was removed by filtration and the filtrate refluxed two hours to complete decarboxylation. The toluene was subsequently removed by evaporation and the residual oil distilled on the Kugelrohr apparatus. Heating to 130° C. removed the volatile impurities, and the bulk of the desired product was collected at 175°-180° C. Yield was 11.2 g. (79%).
Reaction SMILES: [CH3:1][CH:2]([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4].[Cl:11]C(Cl)(Cl)Cl>[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:11][C:2]([CH3:1])([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: ClC(Cl)(Cl)Cl
Reactant: COC(=O)C(C)C(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COC(=O)C(C)(Cl)C(=O)OC
Yield: 63.1 %

Procedure:
In a 10 mL round-bottom flask, a mixture of 1.46 g dimethyl methylmalonate (10 mmol), 1.69 g tetrachloromethane (11 mmol), and 63 mg tetra-n-butylammonium fluoride (0.2 mmol) was mixed by a magnetic stirrer for 15 min at 24° C. Gas chromatographic analysis of the product mixture showed that the solution contained 1.14 g of dimethyl α-chloro-α-methylmalonate (63% yield).
Reaction SMILES: [H-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11].[CH2:14]([CH:16]1[O:18][CH2:17]1)Br>CN(C)C=O.C(OCC)(=O)C>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][N:9]([CH2:14][CH:16]1[CH2:17][O:18]1)[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)NCc1ccco1
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N(Cc1ccco1)CC1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
Sodium hydride (60% mineral oil dispersion, 0.524 g, 13.1 mmol) was added in portions to a 0° C. solution of N-(furan-2-ylmethyl)methanesulfonamide (2.0 g, 11.4 mmol) in 38 ml anhydrous N,N-dimethylformamide (38 mL), and the resultant mixture was allowed to warm to room temperature and stirred for 1 hour. Epibromohydrin (1.2 mL, 14.3 mmol) was added slowly, and the reaction was stirred for 3 hours at room temperature and 16 hours at 70° C. The reaction was cooled, diluted with ethyl acetate, and successively washed twice with water and once with saturated aqueous sodium chloride solutions. The organic layer was dried (anhydrous sodium sulfate), filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (25-60% ethyl acetate in hexanes) to give a pale yellow liquid (2.2 g, 84%). 1H NMR (CDCl3, 300 MHz) δ 7.40-7.39 (m, 1H), 6.37-6.35 (m, 2H), 4.64-4.50 (br dd, 2H, J=25.8, 16.5 Hz), 3.61-3.55 (m, 1H), 3.22-3.12 (m, 2H), 2.82 (s, 3H), 2.82-2.79 (m, 1H), 2.62-2.60 (m, 1H). ESI (m/z): 232.0 (M+H).
Reaction SMILES: [I-].[CH2:2]([O:9][C:10]1[C:36]([F:37])=[CH:35][C:34]([F:38])=[CH:33][C:11]=1[CH2:12][CH2:13][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[C:41]([O:45][C@@H:46]([C:52]1[C:53]([CH3:95])=[N:54][C:55]2[N:56]([N:90]=[C:91]([CH:93]=O)[CH:92]=2)[C:57]=1[N:58]1[CH2:63][CH2:62][C:61]([O:65][CH2:66][CH2:67][CH2:68][CH2:69][C@H:70]([O:72][Si:73]([C:86]([CH3:89])([CH3:88])[CH3:87])([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)[C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)[CH3:71])([CH3:64])[CH2:60][CH2:59]1)[C:47]([O:49][CH2:50][CH3:51])=[O:48])([CH3:44])([CH3:43])[CH3:42]>C1COCC1>[CH2:2]([O:9][C:10]1[C:36]([F:37])=[CH:35][C:34]([F:38])=[CH:33][C:11]=1[CH2:12][CH:13]=[CH:93][C:91]1[CH:92]=[C:55]2[N:54]=[C:53]([CH3:95])[C:52]([C@H:46]([O:45][C:41]([CH3:44])([CH3:43])[CH3:42])[C:47]([O:49][CH2:50][CH3:51])=[O:48])=[C:57]([N:58]3[CH2:63][CH2:62][C:61]([O:65][CH2:66][CH2:67][CH2:68][CH2:69][C@H:70]([O:72][Si:73]([C:86]([CH3:87])([CH3:88])[CH3:89])([C:74]4[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=4)[C:80]4[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=4)[CH3:71])([CH3:64])[CH2:60][CH2:59]3)[N:56]2[N:90]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Fc1cc(F)c(OCc2ccccc2)c(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=O)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=CCc3cc(F)cc(F)c3OCc3ccccc3)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73.4 %

Procedure:
To a suspension of (2-(benzyloxy)-3,5-difluorophenethyl)triphenylphosphonium, iodide salt (330 mg, 0.519 mmol) in THF (4 ml) at 0° C. was added NaH (21.27 mg, 0.532 mmol) and the resulting mixture was stirred at rt for 45 min. The mixture was cooled to 0° C. rd (S)-ethyl 2-(tert-butoxy)-2-(7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-2-formyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (200 mg, 0.259 mmol) dissolved in THF (4 ml) was added dropwise and the mixture was stirred at 0° C. for 1 h then warmed to rt and stirred 2 h. The reaction was quenched with water and the product was extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage; 0%-30% EtOAc/hexane) to afford (S)-ethyl 2-(2-(3-(2-(benzyloxy)-3,5-difluorophenyl)prop-1-en-1-yl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (190 mg, 0.190 mmol, 73% yield) as mixture of E and Z isomers. LCMS (M+H)=1002.0.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:32]([OH:34])=O)[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH:35][N:36]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.NO>CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:32]([NH:36][OH:35])=[O:34])[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(S(=O)(=O)c3ccc(OC)cc3)CC2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)NO)CCN(S(=O)(=O)c3ccc(OC)cc3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-[(4-methoxyphenyl)sulfonyl]-4-piperidinecarboxamide was prepared following the procedure Example 64 (step 6). Starting from 4-(4-But-2-ynyloxybenzenesulfonyl)-1-[(4-methoxyphenyl)sulfonyl]-4-piperidinecarboxylic acid (402 mg, 0.79 mmol) in dimethylformamide (8 ml), 1-hydroxybenzotriazole (128 mg, 0.95 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodimide hydrochloride (212 mg, 1.11 mmol), N-methylmorpholine (0.130 ml, 1.19 mmol), and hydroxylamine (0.242 ml, 3.95 mmol), 396 mg (96%) of the product was isolated as a solid. HR-MS: m/z Calculated for C23H26N2O8S2 523.1203; Found 523.1198.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.C([Sn](CCCC)(CCCC)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)CCC>C1(C)C=CC=CC=1.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:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Prepared according to Procedure E using 2,4-dichloro-5,7-difluoro-3-methylquinoline (1.94 g, 7.8 mmol; described herein), 2-(tributylstannyl)pyridine (2.9 mL, 7.8 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.69 g, 0.59 mmol) in toluene. The reaction was stirred at 100° C. for 18 h, then cooled to rt, concentrated, and the resulting residue triturated with hexanes. Column chromatography afforded 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=291.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1.C(O)(C)C>[Fe].O>[NH2:9][C:5]1[CH:6]=[C:7]([Cl:8])[C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Agent: [Fe]
Solvent: O
Solvent: CC(C)O
Product: Nc1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 51.9 %

Procedure:
2,3-Dichloro-5-nitropyridine (3.9 g) and iron powder (3.0 g) were added to isopropyl alcohol (40 ml) and water (8 ml) and the mixture refluxed for 4 hours. The mixture was then cooled to room temperature and filtered (celite). The filtrate was evaporated under reduced pressure and chromatographed [SiO2; hexane:ethyl acetate (80:20) to (50:50)] to give 5-amino-2,3-dichloropyridine (1.71 g).
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH3:14].Cl.C(OCC)(=O)C>C(O)C>[C:2]([C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:14]
Reactant: N
Reactant: ClC(Cl)(Cl)c1nc2ccccc2[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#Cc1nc2ccccc2[nH]1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3.2 Grams of a 2-(trichloromethyl)benzimidazole compound [compound (101)] of the formula (XI) in which X is H and Z is OCF2CFHO was dissolved in 30 ml of ethanol. The resulting solution was added by drops to 4 ml of a 25% aqueous ammonia at 5° C. After stirring for 1 hour at 5° to 15° C., the reaction solution was poured into an ice/conc. hydrochloric acid mixture and extrac.ted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removing the solvent from the dried layer by distillation gave 2.83 g of a 2-cyanobenzimidazole compound [compound (i)] of the formula (II) in which X is H and Z is OCF2CFHO.
Reaction SMILES: [C:1]([CH:5]1[CH2:12][CH2:11][CH2:10][NH:9][C:8](=[O:13])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.[CH3:19][O+](C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([CH:5]1[CH2:6][CH2:7][C:8]([O:13][CH3:19])=[N:9][CH2:10][CH2:11][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[O+](C)C
Reactant: CC(C)(C)C1CCCNC(=O)CC1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC1=NCCCC(C(C)(C)C)CC1
Temperature: 25 °C

Procedure:
5-tert-Butylazocan-2-one (30 mg) was dissolved in 2 mL methylene chloride and stirred at room temperature under nitrogen. 31.3 g Trimethyloxonium tetrafluoroborate was added and the reaction stirred overnight. The mixture was added to saturated aqueous sodium bicarbonate and extracted with methylene chloride (2×). The combined organic layers were washed with brine, dried over magnesium sulfate, and the solvent evaporated to provide crude 5-tert-butyl-8-methoxy-2,3,4,5,6,7-hexahydroazocine.
Reaction SMILES: C(O[N:5]=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:13])[CH2:8][CH2:7]1)(=O)C>C(O)(=O)C.[Pt]=O>[NH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:13])[CH2:8][CH2:7]1
Reactant: CC(=O)ON=C1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: NC1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1

Procedure:
10 Grams of 6-(4-acetyloxyimino-1-piperidylcarbonyl)-3,4-dihydrocarbostyril and 0.5 g of platinum oxide were dispersed in 150 ml of acetic acid, then the mixture was catalytically reduced at room temperature under normal pressure. The catalyst was removed by filtration, then the filtrate was concentrated under reduced pressure by evaporating the solvent, the residue thus obtained was purified by means of a silica gel column chromatography (eluent: dichloromethane:methanol=10:1) to yield 3 g of 6-(4-amino-1-piperidylcarbonyl)-3,4-dihydrocarbostyril.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[N+:7]([O-])([OH:9])=[O:8]>>[N+:7]([CH2:1][CH:2]=[CH:3][CH2:4][CH2:5][CH3:6])([O-:9])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: C=CCCCC
Product: CCCC=CC[N+](=O)[O-]
Temperature: 40 °C
Yield: 20.5 %

Procedure:
1-Hexene (125 mL, 1.0 mole) and concentrated nitric acid (90 mL, 2.0 moles) were mixed at room temperature. With rapid stirring the solution was heated to 40° C. for 41/2 hours. With continued stirring the solution was cooled to room temperature and the organic layer separated. It was washed with a saturated sodium chloride solution then dried over magnesium sulfate. After filtering, vacuum distillation removed unreacted 1-hexene leaving one product, 1-nitro-2-hexene in 20.5% yield. This desired product was confirmed by IR and gas chromatography (GC) analysis.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]([O:11][C:12](=[O:26])[NH:13][CH2:14][C:15]12[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH:18]3O)[CH2:16]1)[CH2:22]2)([CH3:10])([CH3:9])[CH3:8].CC1C=CC(S([CH2:37][N+:38]#[C-])(=O)=O)=CC=1.CCO>COCCOC>[C:7]([O:11][C:12](=[O:26])[NH:13][CH2:14][C:15]12[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH:18]3[C:37]#[N:38])[CH2:16]1)[CH2:22]2)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)NCC12CC3CC(C1)C(O)C(C3)C2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NCC12CC3CC(C1)C(C#N)C(C3)C2
Temperature: 25 °C
Yield: 65.3 %

Procedure:
Solid t-BuOK (240 mg, 2.15 mmol) was added as 6 portions to a solution of ketone 1B (300 mg, 1.07 mmol) and TosMIC (273 mg, 1.40 mmol) in a mixture of DME (5.0 mL) and absolute EtOH (1 mL) while keeping the temperature between 5 and 10° C. The reaction mixture was allowed to warm to rt and was maintained for 30 min. The reaction mixture was then heated at 35-40° C. for 30 min and was then allowed to cool to rt. The precipitate (TosK) was removed by filtration and the filter cake was washed with DME. The combined organic layers were concentrated and the residue was purified by column chromatography (0/100 to 10/90 MeOH/EtOAc) to provide nitrile 17A (203 mg, 70%) as a mixture of equatorial and axial isomers. Data: LC/MS (ESR) m/z=291 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([O:22]C1C=CC=CC=1)=O.[CH2:29]([NH2:32])[CH2:30][NH2:31]>>[NH2:31][CH2:30][CH2:29][NH:32][C:20]([C:11]1[C:12](=[O:19])[N:13]([CH3:18])[C:14](=[O:17])[N:15]([CH3:16])[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:22]
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Reactant: NCCN
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)NCCN)c(=O)n(C)c1=O

Procedure:
Example 42 was synthesized following a similar procedure described in the synthesis of Example 5 by reaction of compound 2A and ethane-1,2-diamine. 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J=8.0 Hz, 1H) 7.62 (d, J=8.0 Hz, 1H) 7.01 (t, J=8.0 Hz, 1H) 3.63 (t, J=4.0 Hz, 2H) 3.27 (s, 3H) 3.15 (t, J=4.0 Hz, 2H) 3.11 (s, 3H). [M+H] calc'd for C15H17FIN5O3, 462; found, 462.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].[C:25]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH2:1]([C:4]1[C:13]([O:14][CH3:25])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)c(OC)cc2ncnc(Nc3cccc(Br)c3)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: C=CCc1c(OC)c(OC)cc2ncnc(Nc3cccc(Br)c3)c12
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of 5-allyl-4-(3-bromo-phenylamino)-7-methoxy-quinazolin-6-ol (0.27 g, 0.7 mmol) (from Example 17, Step D, supra) in acetone (30 mL) was added K2CO3 (0.48 g, 3.5 mmol) and methyl iodide (0.4 g, 2.8 mmol) (Aldrich). The reaction mixture was heated with stirring at 90° C. for 4 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:3:0.01) as eluent to give the desired (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-(3-bromo-phenyl)-amine as a yellow solid. (Yield 0.14 g, 50%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][N:9]3[C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=[C:8]3[CH:7]=2)=[N:2]1.[NH2:18][C:19]1[CH:20]=[C:21]([C:26]2[N:30]=[C:29]([CH:31]3[CH2:34][N:33]([C:35]([O:37][CH3:38])=[O:36])[CH2:32]3)[O:28][N:27]=2)[CH:22]=[CH:23][C:24]=1[CH3:25].CCCP(=O)=O>C(OCC)(=O)C>[NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][N:9]3[C:12]([C:15]([NH:18][C:19]4[CH:20]=[C:21]([C:26]5[N:30]=[C:29]([CH:31]6[CH2:34][N:33]([C:35]([O:37][CH3:38])=[O:36])[CH2:32]6)[O:28][N:27]=5)[CH:22]=[CH:23][C:24]=4[CH3:25])=[O:17])=[CH:13][N:14]=[C:8]3[CH:7]=2)=[N:2]1
Reactant: COC(=O)N1CC(c2nc(-c3ccc(C)c(N)c3)no2)C1
Reactant: O=C(O)c1cnc2cc(-c3cc[nH]n3)ccn12
Agent: CCCP(=O)=O
Solvent: CCOC(C)=O
Product: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5cc(-c6cc[nH]n6)ccn45)c3)no2)C1
Temperature: 80 °C

Procedure:
To a stirring solution of 7-(1H-pyrazol-3-yl)imidazo[1,2-a]pyridine-3-carboxylic acid (63) (31.7 mg, 0.14 mmol), and methyl (3-(3-amino-4-methylphenyl)-1,2,4-oxadiazol-5-yl)methylcarbamate (31) (52 mg, 0.18 mmol) in ethyl acetate (0.1 mL) was added propylphosphonic anhydride (50 wt % in ethyl acetate 0.41 mL). The reaction was heated at 80° C. for 12 hours. The resulting mixture was diluted in ethyl acetate and washed with 1N Na2CO3. After aqueous workup, the residue was purified by reverse phase HPLC to afford methyl 3-(3-(3-(7-(1H-pyrazol-3-yl)imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F68). MS (m/z) 499.1 (M+1)+.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[C:7]([NH:19][CH2:20][CH2:21][CH2:22][CH:23]2[C:32]3[N:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)=[N:8][CH:9]=[C:10]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:11]=1.[OH-].[Na+]>O.S(=O)(=O)(O)O>[N:31]1[C:32]2[CH:23]([CH2:22][CH2:21][CH2:20][N:19]3[C:7]4=[N:8][CH:9]=[C:10]([CH2:12][C:13]5[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=5)[CH:11]=[C:6]4[N:5]=[N:1]3)[CH2:24][CH2:25][CH2:26][C:27]=2[CH:28]=[CH:29][CH:30]=1
Reactant: O=N[O-]
Reactant: Nc1cc(Cc2cccnc2)cnc1NCCCC1CCCc2cccnc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1cncc(Cc2cnc3c(c2)nnn3CCCC2CCCc3cccnc32)c1
Temperature: 4 °C
Yield: 106.7 %

Procedure:
Sodium nitrite (1.3 g) in water (60 ml) was added over 25 minutes to a solution of 3-amino-2-[3-(5,6,7,8-tetrahydroquinol-8-yl)propylamino]-5-(pyrid-3-ylmethyl)pyridine (5.5 g) in molar sulphuric acid (250 ml) stirred at 4° C. The reaction mixture was stirred at 4° C. for 50 minutes, then allowed to warm to room temperature, basified with 10 molar sodium hydroxide solution to pH 13 and extracted with chloroform (3×150 ml). The chloroform extracts were combined, dried over magnesium sulphate, and the solvent removed to give a brown oil (6.04 g). The oil was chromatographed on silica in 5% MeOH/chloroform to give the title compound as an oil (3.61 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[H-].[Na+].Cl[C:12]1[C:13]([CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:14][C:15]2[N:16]([C:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)=[N:19][N:20]=2)[N:17]=1>CN(C)C=O>[CH:26]1([C:13]2[C:12]([O:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)=[N:17][N:16]3[C:18]([C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)=[N:19][N:20]=[C:15]3[CH:14]=2)[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: Clc1nn2c(-c3cccs3)nnc2cc1C1CCCC1
Reactant: OCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COc2nn3c(-c4cccs4)nnc3cc2C2CCCC2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
b 2-Hydroxymethylpyridine (56 mg) was dissolved in dimethylformamide (2 ml) under N2. Sodium hydride (60% w/w in oil, 21 mg) was added followed after 5-10 minutes by 6-chloro-7-cyclopentyl-3-(thiophen-2-yl)-1,2,4-triazolo[4,3-b]pyridazine (100 mg). Reaction was stirred at room temperature for 18 hours, partitioned between ethyl acetate and water, organic phase separated dried (MgSO4) and evaporated to dryness. Recrystallized in ethyl acetate in ether or methanol to give pure product. 1H NMR (250 MHz, CDCl3) δ1.73 (6 H, m), 2.16 (2 H, m) 3.38 (1 H, m), 5.68 (2 H, s), 7.21 (1 H, m), 7.28 (1 H, m), 7.51 (2 H, m), 7.77 (1 H, m), 7.88 (1 H, d, J=1.1 Hz), 8.15 (1 H, m), 8.65 (1 H, m); MS (ES+) m/e 377 [MH]+.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]2=[O:21])C=CC=CC=1.N>C1COCC1>[C:15]1([CH2:14][CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][C:9]2=[O:21])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1C(Cc2ccccc2)CCCN1Cc1ccccc1
Agent: N
Solvent: C1CCOC1
Product: O=C1NCCCC1Cc1ccccc1
Reaction time: 0.25 h
Yield: 146.9 %

Procedure:
A solution of 1,3-diphenylmethyl-2-piperidinone (2.79 g, 10 mmol) in dry THF (25 mL) was added at -78° C. to a well stirred solution of Li metal (0.70 g, 100 mmol) in liquid NH3 (200 mL). After 15 min, the cooling bath was removed, and the NH3 was allowed to escape (ca. 2 h). The resulting colorless residue was treated with saturated NH4Cl (50 mL), and extracted with EtOAc (3×50 mL). The combined organic extract was washed with brine (25 mL), dried over MgSO4, and concentrated in vacuo to give 2.78 g of brown viscous residue. Flash chromatography over silica gel (1% MeOH in CHCl3 -EtOAc, 1:1) afforded the lactam (See: Rodriquez m, Heitz A, Martinez J (1992) supra) (0.87 g, 46% ) as a colorless solid: mp 120°-122° C. (CH2Cl2 -hexanes).