Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12]3[N:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:15]=[C:16]([CH3:17])[C:11]=3[C:10](=[O:24])[CH:9]=2)=[CH:4][CH:3]=1.C(OC([N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)=O)(C)(C)C.Cl>>[CH3:17][C:16]1[C:11]2[C:10]([OH:24])=[CH:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:38][CH:35]4[CH2:36][CH2:37][NH:32][CH2:33][CH2:34]4)=[CH:3][CH:4]=3)=[N:13][C:12]=2[N:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1nn(-c2ccccc2)c2[nH]c(-c3ccc(Br)cc3)cc(=O)c12
Agent: Cl
Product: Cc1nn(-c2ccccc2)c2nc(-c3ccc(NC4CCNCC4)cc3)cc(O)c12

Procedure:
The title compound was prepared according to the procedure as described in Example 97 reacting via Suzuki coupling of 6-(4-bromo-phenyl)-3-methyl-1-phenyl-1,7-dihydro-pyrazolo[3,4-b]pyridin-4-one and 4-amino-piperidine-1-carboxylic acid tert-butyl ester, followed by de-protection with HCl.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[CH3:26][C:27]1[S:31][C:30]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:29][C:28]=1[N+:36]([O-])=O>>[CH3:26][C:27]1[S:31][C:30]([S:32](=[O:34])(=[O:33])[NH2:35])=[CH:29][C:28]=1[NH:36][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=3)=[N:6][C:7]=12)=[O:14]
Reactant: Cc1sc(S(N)(=O)=O)cc1[N+](=O)[O-]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1sc(S(N)(=O)=O)cc1NC(=O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 4-amino-5-methyl-thiophene-2-sulfonic acid amide (example B.11) according to general procedure II. Yellow solid. MS (ISP) 530.0 [(M−H)−]; mp 313° C.
Reaction SMILES: Cl.[N:2]12C[CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[OH:12])C1)[CH2:9]2.[O:13]1C2(CCC(=O)CC2)O[CH2:15][CH2:14]1.CC1C=CC(S(C[N+]#[C-])(=O)=O)=CC=1>>[O:12]1[C:5]2([CH2:4][CH2:10][CH:8]([C:9]#[N:2])[CH2:7][CH2:6]2)[O:13][CH2:14][CH2:15]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: OC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Product: N#CC1CCC2(CC1)OCCO2

Procedure:
U.S. Pat. No. 8,314,119, issued 20 Nov. 2012, shows synthesis of (4s)-1-azaadamantan-4-ol HCl salt from a 7-step process of: (1) Reducing 1,4-dioxaspiro[4.5]decan-8-one with TOSMIC to form 1,4-dioxaspiro[4.5]decane-8-carbonitrile; (2) Reducing resulting product with LAH to form 1,4-dioxaspiro[4.5]decan-8-ylmethanamine; (3) Cyclizing resulting product with a double-Mannich type condensation using paraformaldehyde and sulfuric acid to form azaadamantan-4-one; (4) Reducing the ketone group of azaadamantan-4-one to an alcohol using NaBH4 in presence of borane-THF complex to form a diastereomer mixture of 1-azaadamantan-4-ol N-borane complex; (5) Coupling resulting product with 4-chlorobenzoic acid; (6) Separating (4s) isomer by column chromatography (silica gel, using 3:1 hexanes-EtOAc), followed by removing 4-chlorobenzoic acid moiety with NaOH; and (7) Removing BH3 group with HCl giving (4s)-1-azaadamantan-4-ol HCl salt. Alternatively, the (4s)-isomer from Step (6) can be coupled with 2-chloro-5-phenyl-1,3,4-thiadiazole, giving (4s)-4-(5-Phenyl-1,3,4-thiadiazol-2-yloxy)-1-azatricyclo[3.3.1.13,7]-decane N-borane complex. Removal of borane group affords the free base, which was crystallized as a dihydrogen citrate salt. Resulting ether-linked azaadamantane derivative is useful for treating diminished CNS function associated with traumatic brain injury or treating conditions such as arthritis or osteoarthritic pain.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[NH:12][CH:11]=[CH:10][C:5]2=[N:6][C:7]=1[C:8]#[N:9].[H-].[Na+].[CH3:15][Si:16]([CH2:19][CH2:20][O:21][CH2:22]Cl)([CH3:18])[CH3:17]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[N:12]([CH2:22][O:21][CH2:20][CH2:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:11]=[CH:10][C:5]2=[N:6][C:7]=1[C:8]#[N:9]
Reactant: C[Si](C)(C)CCOCCl
Reactant: N#Cc1nc2cc[nH]c2cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2nc(C#N)c(F)cc21
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
To a solution of 6-fluoro-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile (758 mg, 4.71 mmol) in THF (20 mL) was added NaH (60% in mineral oil, 452 mg, 9.42 mmol). After stirring for 30 min, SEM-Cl (1527 mg, 9.42 mmol) was added, followed by stirring at RT for 16 h. The reaction mixture was quenched by adding sat'd aq.NH4Cl and extracted with EtOAc (100 mL×2). The combined extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by SiO2 chromatography eluting with a petroleum ether:EtOAc gradient (10:1-0:10) to afford 1096 mg (80%) of 6-fluoro-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile. MS (ESI): m/z=292.1[M+1]+.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH2:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]2[CH:21]=[C:22]([CH:24]=O)[CH:23]=[C:13]2[C:12]1=[O:26])[CH3:10].O>C(O)C>[CH2:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]2[CH:21]=[C:22]([CH:24]=[N:2][OH:3])[CH:23]=[C:13]2[C:12]1=[O:26])[CH3:10]
Reactant: NO
Reactant: CCn1c(=O)c2cc(C=O)cn2c2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCn1c(=O)c2cc(C=NO)cn2c2ccccc21
Yield: 80.6 %

Procedure:
A mixture of 1.5 g (21.6 mmole) of hydroxylamine hydrochloride, 2 g (24.4 mmole) of sodium acetate, 3.4 g (14.1 mmole) of the product of Example 25, 20 ml of water and 40 ml of ethanol was warmed on a water bath for one hour and the mixture was evaporated to a volume of 20 ml. The mixture was filtered and the recovered product was rinsed with water and dried over P2O5 under vacuum to obtain 2.9 g of 4,5-dihydro-5-ethyl-4-oxopyrrolo-[1,2-a]-quinoxaline-2-carboxaldehyde oxime in the form of colorless needles melting at 262°-264° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]([OH:17])[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[H-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]([O:17][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:9]=2[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:6][CH:7]=1
Reactant: On1c(-c2ccncc2)c(-c2ccc(F)cc2)c2ncccc21
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2c(-c3ccncc3)n(OCCN3CCOCC3)c3cccnc23)cc1
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a solution of 3-(4-fluorophenyl)-1-hydroxy-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b]-pyridine (0.20 g, 0.65 mmol) and 2-chloroethylmorpholine hydrochloride (0.24 g, 6.56 mmol) in dimethylformamide (5 ml) was added sodium hydride (100 mg, 60% in oil). The reaction mixture was stirred overnight and quenched with 10% HCl (2 ml). The pH was adjusted to pH=8-9 by the addition of saturated sodium bicarbonate solution and the product was extracted into ethyl acetate. The combined extracts were dried over anhydrous MgSO4 and concentrated in vacuo to give an oil. Purified by flash column chromatography (50%-80% ethyl acetate/hexanes, followed by 95/5% methylene chloride/methanol gradient) gave 3-(4-fluorophenyl)-1-[2-(morpholin-4-yl)ethoxy]-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine (180 mg) which recrystallized from hexanes/ethyl acetate to give a white solid.
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH:3][C:2]=1[C:10]1[C:18]2[N:17]3[CH:19]=[CH:20][CH:21]=[C:16]3[C:15](=O)[C:14]=2[CH:13]=[CH:12][CH:11]=1.Cl.[NH2:24][OH:25]>N1C=CC=CC=1>[N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH:3][C:2]=1[C:10]1[C:18]2[N:17]3[CH:19]=[CH:20][CH:21]=[C:16]3[C:15](=[N:24][OH:25])[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: O=C1c2cccc(-c3nc4ccncc4[nH]3)c2-n2cccc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=C1c2cccc(-c3nc4ccncc4[nH]3)c2-n2cccc21
Yield: 81.3 %

Procedure:
In a 250 ml round-bottomed flask under argon, a mixture of 444 mg of 5-(3H-imidazo[4,5-c]pyridin-2-yl)pyrrolo[1,2-a]indol-9-one obtained according to the preceding stage and 323 mg of hydroxylamine hydrochloride in 60 ml of pyridine is refluxed for 3 hours. The reaction medium is evaporated to dryness under vacuum, the residue is taken up in a saturated solution of sodium bicarbonate and the precipitate is filtered off and washed with water. The solid is dissolved in methanol and the solvent is evaporated to dryness under vacuum. The residue is taken up in toluene and then re-evaporated to dryness under vacuum. 380 mg of 5-(3H-imidazo[4,5-c]pyridin-2-yl)pyrrolo[1,2-a]indol-9-one oxime are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N+:20]([O-])=O)[C:14]=3[Cl:23])[C:5]2=[N:4][C:3]=1[CH3:24].[ClH:25]>[Fe].CO>[ClH:19].[ClH:25].[NH2:20][C:15]1[C:14]([Cl:23])=[C:13]([C:18]([Cl:19])=[CH:17][CH:16]=1)[CH2:12][O:11][C:10]1[C:5]2[N:6]([C:2]([Br:1])=[C:3]([CH3:24])[N:4]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1nc2c(OCc3c(Cl)ccc([N+](=O)[O-])c3Cl)cccn2c1Br
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: Cc1nc2c(OCc3c(Cl)ccc(N)c3Cl)cccn2c1Br
Temperature: 0 °C

Procedure:
A suspension of 3-bromo-8-(2,6-dichloro-3-nitrobenzyloxy)-2-methylimidazo[1,2-a]pyridine (215 mg) and iron (powder, 84 mg) in a mixture of conc. hydrochloric acid (1 ml) and methanol (1 ml) was refluxed for half an hour. The cooled mixture was poured into an ice water (15 ml). The precipitates were collected and washed with water to give 8-(3-amino-2,6-dichlorobenzyloxy)-3-bromo-2-methylimidazo[1,2-a]pyridine dihydrochloride (140 mg) as an off-white solid.
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([CH3:12])[N:9]=[C:10]([CH3:11])[N:6]2[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.Cl.Cl.[NH2:21][CH2:22][CH2:23][NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:12][C:8]1[N:9]=[C:10]([CH3:11])[N:6]2[C:7]=1[C:2]([NH:21][CH2:22][CH2:23][NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=1)=[N:3][C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[N:5]2
Reactant: N#Cc1ccc(NCCN)nc1
Reactant: Cc1nc(C)n2nc(-c3ccccc3)nc(Cl)c12
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C)n2nc(-c3ccccc3)nc(NCCNc3ccc(C#N)cn3)c12
Temperature: 150 °C

Procedure:
183 mg (0.71 mmol) of the 4-chloro-5,7-dimethyl-2-phenylimidazo[5,1-f][1,2,4]triazine (Example 16A) were initially charged in 4 ml of DMSO, and 200 mg (0.85 mmol) of 6-[(2-aminoethyl)amino]nicotinonitrile (Example 2A) and 1.23 ml (7 mmol) of N,N-diisopropylethylamine were added and the mixture was heated at 150° C. for 12 h. Purification by chromatography on silica gel (mobile phase: dichloromethane/methanol 100:1) gave 10 mg (4% of theory) of the product.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11](=[O:46])[C@H:12]([CH2:32][CH2:33][CH2:34][NH:35]C(OCC1C=CC=CC=1)=O)[NH:13][C:14](=[O:31])[C@@H:15]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH:16]C(OC(C)(C)C)=O.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].C([SiH](CC)CC)C>>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11](=[O:46])[C@H:12]([CH2:32][CH2:33][CH2:34][NH2:35])[NH:13][C:14](=[O:31])[C@@H:15]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[NH2:16]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)Sc1nc2ccccc2s1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: NCCC[C@H](NC(=O)[C@H](N)Cc1ccccc1)C(=O)Sc1nc2ccccc2s1

Procedure:
Boc-D-phenylalanyl-Nδ-CBz-ornithinyl 2-benzothiazolyl thioether (A) was stirred at 25° C. with trifluoroacetic acid-triethylsilane (3:1-10 ml) for 2 hrs and concentrated in vacuo. The crude residue was purified by HPLC.(method C, retention time=49.57 min); 1H NMR (400 MHz, D2O) δ1.46 (m, 3H), 1.74 (m, 1H), 2.98 (m, 2H), 3.22 (m, 2H), 3.40 (dd, J=13.6; 8.0 Hz, 1H), 3.66 (d, J=14.0 Hz, 1H), 4.17 (m, 2H), 7.30 (m, 2H), 7.44 (m, 3H), 7.52 (t, J=8.0 Hz, 1H), 7.62 (t, J=7.2 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), and 8.02 (d, J=8.4 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:14]([O:21][CH2:22][C:23](Cl)=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:23](=[O:24])[CH2:22][O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN)cc1OC
Reactant: O=C(Cl)COCc1ccccc1
Product: COc1ccc(CCNC(=O)COCc2ccccc2)cc1OC

Procedure:
prepared by reaction of 3,4-dimethoxyphenylethylamine with benzyloxy acetyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[CH:31]=[CH:30][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=O)=[O:20])=[CH:17][CH:16]=1.Cl.C(N=C=NCCCN(C)C)C.O[C:45]1[C:53]2[N:52]=N[NH:50][C:49]=2[CH:48]=[CH:47][CH:46]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([NH:50][C:49]2[CH:48]=[CH:47][CH:46]=[CH:45][C:53]=2[NH2:52])=[O:29])=[O:20])=[CH:30][CH:31]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)CCCCCNC(=O)c1ccc(C=NN=C2C(=O)Nc3ccc(F)cc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ccccc1NC(=O)CCCCCNC(=O)c1ccc(C=NN=C2C(=O)Nc3ccc(F)cc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.9 %

Procedure:
6-(4-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)benzamido)hexanoic acid (424 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxybenzo-triazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and o-phenylenediamine (432 mg, 4 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (375 mg, 73% yield) as a brown solid. LC-MS (m/z) 515 (M+1).
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.Cl.[CH3:34][C:35]1([OH:40])[CH2:39][CH2:38][NH:37][CH2:36]1.CCN(C(C)C)C(C)C.Cl.C([O-])(O)=O.[Na+]>CO.CC(O)C>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([N:37]3[CH2:38][CH2:39][C:35]([OH:40])([CH3:34])[CH2:36]3)=[N:3][CH:4]=2)=[CH:14][CH:13]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Reactant: CC1(O)CCNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC1(O)CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2ccn[nH]2)C1
Reaction time: 1 h

Procedure:
A mixture of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2, 500 mg, 1.035 mmol), 3-methylpyrrolidin-3-ol hydrochloride (244 mg, 1.77 mmol), DIPEA (0.723 mL, 4.14 mmol) and iPrOH (1.4 mL) in a MW vial was subjected to MW irradiation at 140° C. for 1.5 h. The cooled mixture was treated with aqueous HCl (37%) and MeOH (2 mL) and stirred for 1 h. The mixture was basified with sat. aq. NaHCO3, extracted with EtOAc and the combined extracts were washed with water and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was crystallized from toluene/EtOAc to afford the title product as a white solid. UPLC-MS (Condition 3) tR=0.95 min, m/z=464.1 [M+H]+, m/z=508.1 [M+formic acid-H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (s, 3H) 1.60-1.85 (m, 2H) 2.93-3.12 (m, 2H) 3.25-3.31 (m, 1H) 3.42-3.54 (m, 1H) 4.61-4.76 (m, 1H) 6.31-6.42 (m, 1H) 7.33 (d, J=8.80 Hz, 2H) 7.51-7.84 (m, 1H) 7.87 (d, J=9.05 Hz, 2H) 8.03 (d, J=2.32 Hz, 1H) 8.73 (m, J=2.32 Hz, 1H) 10.19 (s, 1H) 12.86-13.15 (m, 1H).
Reaction SMILES: C(OC(=O)C(N([S:22][S:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[C:31](=[O:45])[NH:32][CH:33]([C:38]([O:40]C(C)(C)C)=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36])C(=O)C1C=C(F)C=CC=1)CC(C)C)(C)(C)C.F[C:48](F)(F)[C:49]([OH:51])=[O:50]>ClCCl.C1(OC)C=CC=CC=1>[C:49]([CH:48]([NH:32][C:31]([C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[S:22][S:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[C:31]([NH:32][CH:33]([CH2:34][CH:35]([CH3:36])[CH3:37])[C:38]([OH:40])=[O:39])=[O:45])=[O:45])[CH2:37][CH:35]([CH3:34])[CH3:36])([OH:51])=[O:50]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)CC(NC(=O)c1cc(F)ccc1SSN(C(=O)c1cccc(F)c1)C(CC(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CC(C)CC(NC(=O)c1cc(F)ccc1SSc1ccc(F)cc1C(=O)NC(CC(C)C)C(=O)O)C(=O)O

Procedure:
The general method of Preparation 20 was followed using [S-(R*,R*)]-2-[2-[[2-(1-tert-butoxycarbonyl-3-methyl-butylcarbamoyl)-4-fluorophenyldisulfanyl]-5-fluorobenzoylamino]-4-methyl pentanoic acid tert-butyl ester (1.8 g, 2.6 mmol) in 20 mL dichloromethane, anisole (2 mL), and 20 mL trifluoroacetic acid. The crude product was recrystallized from methanol/water to afford 0.9 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]#[CH:14])[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O>[OH-].[NH4+].O1CCCC1.[Zn]>[C:13]([C:6]1[CH:7]=[CH:8][C:9]([NH2:10])=[C:4]([NH2:1])[CH:5]=1)#[CH:14]
Reactant: C#Cc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: C1CCOC1
Product: C#Cc1ccc(N)c(N)c1
Temperature: 25 °C
Yield: 60.1 %

Procedure:
To a rapidly stirred suspension of 4.1 g of powdered zinc in 10 ml of concentrated ammonium hydroxide was added a solution containing 1.2 g (6.3 mmoles) of 3,4-dinitroethynyl benzene dissolved in 10 ml of tetrahydrofuran. The mixture was stirred at room temperature for one-half hour at which time it was filtered by suction and the residue was washed with ether. The filtrate was extracted with ether, and the combined extracts evaporated to dryness. The residual oil was chromatographed on a 1/2 × 4 inch dry quartz column of silica gel. Elution with methylene chloride removed a first band of impurity, while further elution with ethylacetate produced the product. Evaporation of the eluate to dryness yielded 0.5 g (62% yield) of 4-ethynyl-o-phenylenediamine.
Reaction SMILES: [C:1]([CH2:3][C@@H:4]([O:16][Si](C(C)(C)C)(C)C)[CH2:5][C:6](=[O:15])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])#[N:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)C>O1CCCC1>[C:1]([CH2:3][C@@H:4]([OH:16])[CH2:5][C:6](=[O:15])[CH2:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])#[N:2]
Reactant: CC(C)(C)OC(=O)CC(=O)C[C@@H](CC#N)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CC(=O)C[C@H](O)CC#N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of crude (R)-1,1-dimethylethyl 6-cyano-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-oxohexanoate, 43 g (0.126 mol) in 350 mL of tetrahydrofuran is treated with 213 mL of tetrabutylammonium fluoride solution (1.0M in hexane). The resulting mixture is stirred for five hours, at 25° C. The mixture is treated with 500 mL of water, 300 mL of diethyl ether is added, and the layers separated. The organic layer is dried (magnesium sulfate) and then filtered through a plug of silica gel with the aid of anhydrous diethyl ether. The solvent is removed under a vacuum to obtain 21 g of crude (R)-1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate with acceptable NMR, MS and IR spectra.
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[Cl:10][C:11]1[N:16]=[CH:15][C:14]([CH2:17][NH2:18])=[CH:13][CH:12]=1>CCO>[Cl:10][C:11]1[N:16]=[CH:15][C:14]([CH2:17][NH:18][C:3]([S:2][CH3:1])=[CH:4][N+:5]([O-:7])=[O:6])=[CH:13][CH:12]=1
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCc1ccc(Cl)nc1
Solvent: CCO
Product: CSC(=C[N+](=O)[O-])NCc1ccc(Cl)nc1
Yield: 47.1 %

Procedure:
To 100 ml of EtOH were added 2.4 g (1.5×10-2 mole) of 1,1-bis(methylthio)-2-nitroethylene and 1.4 g (9.8×10-3 mole) of 6-chloro-3-pyridylmethylamine and the mixture was refluxed for 2 hours. The EtOH was distilled off and the residue was subjected to silica gel column chromatography using CH2Cl2 as an eluent. The procedure gave 1.2 g of the title compound as a pale yellow solid.
Reaction SMILES: [O-2].[Al+3].[O-2].[O-2].[Al+3].C(OCC)C.[CH2:11]([N:18]1[CH2:25][CH2:24][C:21]2([CH2:23][O:22]2)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:26]([O:30][C:31]1[CH:38]=[CH:37][C:34]([NH:35][CH3:36])=[CH:33][CH:32]=1)[CH2:27][CH2:28][CH3:29]>CO>[CH2:11]([N:18]1[CH2:25][CH2:24][C:21]([CH2:23][N:35]([C:34]2[CH:37]=[CH:38][C:31]([O:30][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:32][CH:33]=2)[CH3:36])([OH:22])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCCOc1ccc(NC)cc1
Reactant: c1ccc(CN2CCC3(CC2)CO3)cc1
Agent: [Al+3]
Agent: [O-2]
Solvent: CCOCC
Solvent: CO
Product: CCCCOc1ccc(N(C)CC2(O)CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
Activated neutral aluminum oxide 90 (activity I, made by Merck Co.) (5 g) was added to a diethyl ether solution (10 mL) of 1-benzylpiperidin-4-spiro-2′-oxirane (0.50 g) and 4-butoxy-N-methylaniline (0.53 g) and stirred at room temperature overnight. Methanol (20 mL) was added to the reaction solution and stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (elution solvent; ethyl acetate) to obtain the titled compound (0.71 g).
Reaction SMILES: Br.[C@@H:2]1([NH:13][C:14]2[S:15][CH:16]=[C:17]([C:19]([O:21]CC)=O)[N:18]=2)[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[NH3:24]>CO>[C@@H:2]1([NH:13][C:14]2[S:15][CH:16]=[C:17]([C:19]([NH2:24])=[O:21])[N:18]=2)[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: N
Reactant: CCOC(=O)c1csc(N[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n1
Agent: Br
Solvent: CO
Product: NC(=O)c1csc(N[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Ethyl 2-(N-β-D-glucopyranosyl)aminothiazole-4-carboxylate hydrobromide (4.15 g., 0.01 mole) was added to a solution of methanol (50 ml.) saturated with ammonia at 0° in a pressure bottle. The reaction mixture was magnetically stirred at room temperature for 48 hours with the stopper well closed. The mixture was evaporated to dryness in vacuo. The residue was mixed with a small amount of ethyl acetate and chromatographed on a column of silica gel (2.54×20 cm) using acetone as the first solvent (300 ml.) and methanol as the second solvent (300 ml.). The methanol effluent was concentrated to ca. 75 ml., and ethyl acetate (500 ml.) was added to give a precipitate. The creamy yellow precipitate was filtered and dried at room temperature in vacuo, yielding 2.77 g. (76.2%); m.p. over 96° (dec.).