Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][OH:14])[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]=2C)[N:6]=1)(=O)=O.[C-:26]#[N:27].[Na+].C(OCC)(=O)C>CS(C)=O>[C:21]([C:17]1[CH:16]=[C:15]([C:7]2[CH:8]=[C:9]([CH2:11][CH2:12][CH2:13][OH:14])[N:10]=[C:5]([C:26]#[N:27])[N:6]=2)[CH:20]=[CH:19][CH:18]=1)([CH3:22])([CH3:23])[CH3:24]
Reactant: Cc1c(-c2cc(CCCO)nc(S(C)(=O)=O)n2)cccc1C(C)(C)C
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)c1cccc(-c2cc(CCCO)nc(C#N)n2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 106.7 %

Procedure:
To a stirring solution of 2-methylsulphonyl-4-(3-hydroxypropyl)-6-(3-tert-butyl-methyl-phenyl)-pyrimidine (4.6 g) in DMSO (120 ml) at room temperature was added sodium cyanide (647 mg). The resulting suspension was stirred at room temperature for 3 hours. After adding ethyl acetate (200 ml), the mixture was then washed with water (100 ml×3). Organic layer was dried over MgSO4 and concentrated in vacuo, the residue was columned on silica gel using Petrol and EtOAc as eluent to give 4-(3-tert-butyl-phenyl)-6-(3-hydroxy-propyl)-pyrimidine-2-carbonitrile (4.0 g) as an oil.
Reaction SMILES: [C:1]([C:3]1[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)=[CH:7][C:6]([NH:16][C@H:17]([CH:21]2[CH2:23][CH2:22]2)[C:18]([NH2:20])=[O:19])=[C:5]([F:24])[CH:4]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:31]>CCO.CS(C)=O>[NH2:20][C:18](=[O:19])[C@H:17]([NH:16][C:6]1[C:5]([F:24])=[CH:4][C:3]([C:1]([NH2:2])=[O:31])=[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)[CH:7]=1)[CH:21]1[CH2:22][CH2:23]1
Reactant: CC(=O)O
Reactant: Cc1cc(Nc2cc(N[C@@H](C(N)=O)C3CC3)c(F)cc2C#N)sn1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1cc(Nc2cc(N[C@@H](C(N)=O)C3CC3)c(F)cc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (R)-2-(4-cyano-2-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)-2-cyclopropylacetamide (38 mg, 0.110 mmol) in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.5 mL, 0.50 mmol) and aq. H2O2 (50%, 0.5 mL) were added. The mixture was stirred at room temperature for 20 min. HOAc (0.5 mL) was added. The mixture was purified by HPLC to give the titled compound (18 mg). MS 364.2 (M+H); UV 219.3, 280.5, 302.6 nm.
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([C:16](=O)[CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:12][CH:11]=2)[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[CH:2]1.O.[NH2:24][NH2:25]>C(O)C>[N:1]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:17][CH2:18][C:19](=[O:21])[NH:24][N:25]=3)=[CH:12][CH:11]=2)[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[CH:2]1
Reactant: NN
Reactant: O=C(O)CCC(=O)c1ccc(-n2cnc3c2CCCC3)cc1
Solvent: CCO
Solvent: O
Product: O=C1CCC(c2ccc(-n3cnc4c3CCCC4)cc2)=NN1
Yield: 50.7 %

Procedure:
A mixture of 9 g of 4-(4,5,6,7-tetrahydro-1H-benzimidazol-1-yl)-γ-oxobenzenebutanoic acid and 3.5 g of hydrazine hydrate in 80 ml of ethanol is heated under reflux for six hours. The reaction mixture is allowed to cool and filtered. The crude product is finally crystallized from 2-methoxyethanol to yield 4.5 g of the product 4,5-dihydro-6-[4-(4,5,6,7-tetrahydro-1H-benzimidazol-1-yl)phenyl]-3(2H)-pyridazinone, mp 296°-297° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7](=[O:15])[C:6]=2[CH:16]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1.O.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:12]2[CH:13]=[C:14]3[C:9](=[N:10][CH:11]=2)[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:2][CH:3]=[CH:4][C:5]3=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=c1[nH]c2ncccc2c2ccc(Cl)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2cnc3[nH]c(=O)c4ccccc4c3c2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
8-Chloro-5H-benzo[c][1,8]naphthyridin-6-one (50 mg, 0.22 mmol), 4-methoxyphenylboronic acid (66 mg, 0.43 mmol), palladium(II) acetate (2 mg, 0.01 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (9 mg, 0.02 mmol), and sodium tert-butoxide (63 mg, 0.65 mmol) were dissolved in dioxane/H2O (2.2 mL, 10/1, v/v), and stirred overnight at 100° C. The reaction mixture was diluted with MeOH, filtered through a membrane plug, and purified via prep-LC-MS to provide 14 (10 mg, 15% yield) as a white solid. LC-MS (M+H=303, obsd.=303). 1H NMR (400 MHz, d6-DMSO): δ 12.11 (s, 1H), 8.84 (d, 1H), 8.61 (d, 1H), 8.52 (dd, 1H), 8.18 (dd, 1H), 7.80 (d, 2H), 7.34 (dd, 1H), 7.10 (d, 2H), 6.93 (s, 1H), 3.83 (s, 3H).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[C:20]([C:24]1[CH:25]=[C:26]([NH2:36])[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[N:28]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[C:26]([NH:36][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:15][CH:14]=2)[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[N:28]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1ccccc1-n1nc(C(C)(C)C)cc1N
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Product: Cc1ccccc1-n1nc(C(C)(C)C)cc1NC(=O)Cc1ccc(-n2cnc3cccnc32)cc1

Procedure:
The title compound is prepared as described in Example 28 but using 2-(4-imidazo[4,5-b]pyridine-3-yl-phenyl)-acetic acid and 5-tert-butyl-2-o-tolyl-2H-pyrazol-3-ylamine. Title compound: ES-MS: 465.07 [M+H]+; tR=3.1 min (System 3).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.C(N)(N)=[O:18].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[N+:7]([O-:18])[CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1
Reactant: NC(N)=O
Reactant: O=c1c2cc(Br)ccc2oc2cccnc12
Agent: OO
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=c1c2cc(Br)ccc2oc2ccc[n+]([O-])c12
Reaction time: 2 h

Procedure:
To a solution of 8-bromo-10H-chromeno[3,2-b]pyridin-10-one (60 g, 217 mmol) and urea peroxide (42.9 g, 456 mmol) in 120 mL of DCM at 0° C. was added dropwise trifluoroacetic anhydride (63.9 mL, 456 mmol). The resulting reaction was stirred for 2 h. The reaction was quenched with 10% Na2S2O3, extracted with DCM, dried over Na2SO4 and evaporated to dryness to give crude 8-bromo-10-oxo-10H-chromeno[3,2-b]pyridine 1-oxide as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.C(N(CC)CC)C.Cl.[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([NH:36][NH2:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:36]([C:33]2[CH:34]=[CH:35][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=2)[N:37]=1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Reactant: NNc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1

Procedure:
1.0 g of 2-(2-hydroxyphenyl)benz(e][1,3]oxazin-4-one, 0.5 ml of triethylamine and 0.7 g of 4-nitrophenylhydrazine hydrochloride are boiled under reflux for 1 h in 10 ml of ethanol. On cooling, the product precipitates in crystalline form. It is filtered off and washed with ethanol. After drying, 3,5-bis(2-hydroxyphenyl)-1-(4-nitrophenyl)-1H-[1,2,4]triazole remains as colorless crystals of m.p. 180-183° C.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Cl:5][C:6]1[C:7]([CH:21]=[O:22])=[C:8]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]=[C:11]([O:17][CH3:18])[C:10]([O:19][CH3:20])=[N:9]2.[Cl-].[Na+]>O1CCCC1>[Cl:5][C:6]1[C:7]([CH:21]([OH:22])[CH2:1][CH3:2])=[C:8]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]=[C:11]([O:17][CH3:18])[C:10]([O:19][CH3:20])=[N:9]2
Reactant: COc1nc2cc(Cl)c(Cl)c(C=O)c2nc1OC
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(O)c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Reaction time: 0.5 h
Yield: 43 %

Procedure:
Ethylmagnesium bromide (9.08 mL, 3M in diethyl ether) was added to a suspension of 6,7dichloro-2,3-dimethoxy-5-formylquinoxaline (3.91 g, 13.62 mmol) (Preparation 2) in dry tetrahydrofuran (200 mL) under nitrogen at room temperature. After 30 minutes, saturated sodium chloride (50 mL) was added, and the product was extracted into ethyl acetate (2×100 mL). The combined extracts were dried (MgSO4) and concentrated under reduced pressure. Purification by flash chromatography (eluting with dichloromethane) gave 6,7-dichloro-2,3-dimethoxy-5-(1-hydroxypropyl)-quinoxaline (1.86 g, 43%), as a pale yellow solid.
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:35])[C@H:24]([CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:25][C@H:24]([C:23]([OH:35])=[O:22])[CH2:26][O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)COCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](COCc2ccccc2)C(=O)O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to O-benzylserine methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17](F)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8].[OH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17]([O:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OCCN1CCOCC1
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(F)c(Cl)c1
Solvent: C1CCOC1
Product: N#Cc1cnc2cnc(OCCN3CCOCC3)cc2c1Nc1ccc(F)c(Cl)c1
Yield: 8 %

Procedure:
Following the procedure described above in Example 36, 4-(3-Chloro-4-fluoro-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile was reacted with a 1 M solution of freshly prepared alkoxide of N-(2-hydroxyethyl)morpholine in THF. The product was collected by filtration to give a yellow solid (0.015 g, 8%). 1H NMR (400 MHz, DMSO-D6) δ ppm 2.5 (m, 2 H) 2.7 (t, J=5.7 Hz, 2 H) 3.6 (m, 6 H) 4.3 (t, J=5.8 Hz, 2 H) 6.7 (ddd, J=8.7, 4.4, 2.5 Hz, 1 H) 6.8 (dd, J=6.8, 2.5 Hz, 1 H) 7.1 (dd, J=9.5, 8.7 Hz, 1 H) 7.4 (d, J=0.8 Hz, 1 H) 7.7 (s, 1 H) 8.4 (d, J=0.8 Hz, 1 H).
Reaction SMILES: P(Br)(Br)([Br:3])=O.[CH2:6]([O:10][C:11]([C:13]1[N:14]=[C:15](O)[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[C:18]([S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:17]=2)=[O:12])[CH2:7][CH2:8][CH3:9].C(=O)(O)[O-].[Na+].O>C(#N)C>[CH2:6]([O:10][C:11]([C:13]1[N:14]=[C:15]([Br:3])[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[C:18]([S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:17]=2)=[O:12])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOC(=O)c1nc(O)c2cc(Sc3ccccc3)ccc2c1O
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCCCOC(=O)c1nc(Br)c2cc(Sc3ccccc3)ccc2c1O
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To a solution of 4.59 g of phosphorous oxybromide (16 mmol) in 25 ml of anhydrous acetonitrile were added 1.11 g of 1,4-dihydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (3 mmol) and the mixture was refluxed gently with stirring for 1 h. Then 5.04 g of sodium bicarbonate (60 mmol) were added, followed by the dropwise addition of 8 ml of water. After stirring at ambient temperature for 90 min the mixture was concentrated in vacuo to about one third of its volume, 40 ml of water were added and the mixture was extracted with 30 ml of ethyl acetate. The mixture was filtered by suction. The organic phase was separated, dried over MgSO4, and filtered through a pad of silica gel. Evaporation in vacuo gave 0.885 g of the title compound; 1H NMR (CDCl3): δ=11.84 (s, 1H), 8.21 (d, 1H), 7.91 (d, 1H), 7.40 to 7.55 (m, 6H), 4.46 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.98 (t, 3H).
Reaction SMILES: C(O[C:4]([N:6]1[CH2:12][CH2:11][N:10]([O:13][CH3:14])[CH2:9][CH2:8][N:7]1[C:15](=[O:25])[CH2:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[CH3:24])=[O:5])C.C[O-].[Na+]>CN(C)C=O>[CH3:24][C:18]1[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=1[CH:16]1[C:4](=[O:5])[N:6]2[CH2:12][CH2:11][N:10]([O:13][CH3:14])[CH2:9][CH2:8][N:7]2[C:15]1=[O:25]
Reactant: CCOC(=O)N1CCN(OC)CCN1C(=O)Cc1cc(C)ccc1C
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON1CCN2C(=O)C(c3cc(C)ccc3C)C(=O)N2CC1
Reaction time: 0.5 h

Procedure:
To a solution of 2-[2-(2,5-dimethyl-phenyl)-acetyl]-5-methoxy-[1,2,5]triazepane-1-carboxylic acid ethyl ester (800 mg, 2.29 mmol) in absolute dimethylformamide (10 ml) at 10° C. was added sodium methoxide (371 mg, 6.87 mmol) in one portion and stirring continued at 10° C. for 30 minutes, then at room temperature for two hours. The solvent was evaporated in vacuo, the residue diluted in cold water (10 ml), acidified to pH 5 with 2N HCl and thoroughly extracted with ethyl acetate. The combined organic layers were washed with brine (3×15 ml), dried over sodium sulfate and concentrated. The residue was triturated with diethyl ether, filtered, washed with cold ether and dried in vacuo. Yield: 450 mg of 8-(2,5-dimethyl-phenyl)-3-methoxy-tetrahydro-pyrazolo[1,2-a][1,2,5]triazepine-7,9-dione (title compound P2.4) as an off-white solid, mp 167-169° C.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2([CH2:11][O:12][C:13]([NH:15][C@@H:16]([CH2:21][CH2:22][CH2:23][CH3:24])[C:17]([O:19]C)=O)=[O:14])[CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl.[C:31]1([P:37](=[CH:50][C:51]#[N:52])([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.O.ClCCl>[C:51]([C:50](=[P:37]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:17]([C@@H:16]([NH:15][C:13](=[O:14])[O:12][CH2:11][C:7]1([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:26][CH:25]=2)[CH2:10][CH2:9][CH2:8]1)[CH2:21][CH2:22][CH2:23][CH3:24])=[O:19])#[N:52]
Reactant: CCCC[C@H](NC(=O)OCC1(Cc2ccc(F)cc2)CCC1)C(=O)OC
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CCCC[C@H](NC(=O)OCC1(Cc2ccc(F)cc2)CCC1)C(=O)C(C#N)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
To a solution of 760 mg (2.1 mmol) of methyl(2S)-2-[({[1-(4-fluorobenzyl)cyclobutyl]methoxy}carbonyl)amino]hexanoate in 5 mL of tetrahydrofuran was added a solution of 105 mg (2.5 mmol) of lithium hydroxide monohydrate in 5 mL of water. The reaction was heated briefly to promote homogeneity and then let stir at room temperature for 18 h. The reaction was diluted with water, acidified with iced 1M hydrochloric acid, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting carboxylic acid was dissolved in 50 mL of dichloromethane before 630 mg (2.1 mmol) of (triphenylphosphoranylidene) acetonitrile was added. The mixture was cooled to 0° C. before a catalytic amount of N,N-dimethylaminopyridine was added followed by 400 mg (2.1 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The reaction was allowed to warm to room temperature and stirred for 18 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 1:9 ethyl acetate:dichloromethane to afford 400 mg (300%) of [1-(4-fluorobenzyl)cyclobutyl]methyl(1S)-1-[cyano(triphenylphosphoranylidene)acetyl]pentylcarbamate. 1H NMR (300 MHz, DMSO-d6) δ 7.75 (m, 3H), 7.50-7.68 (m, 12H), 7.22 (m, 3H), 7.01 (t, J=9 Hz, 2H), 4.56 (m, 1H), 3.81 (dd, J=11 Hz, J=39 Hz, 2H), 2.77 (s, 2H), 1.70-1.95 (m, 7H), 1.61 (m, 1H), 1.38 (m, 4H), 0.92 (t, J=7 Hz, 3H). ES-LCMS m/z 635 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:28].I[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1.C(=O)([O-])[O-].[K+].[K+].BrC1C=CC=CN=1.C(N(CC)CC)C>CN(C=O)C.O>[CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:31][CH2:32][N:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[CH2:34][CH2:35]1)=[O:28]
Reactant: Ic1ccccn1
Reactant: COc1c(C(=O)NC2CCNCC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Agent: Brc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1c(C(=O)NC2CCN(c3ccccn3)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Reaction time: 1 h
Yield: 11.5 %

Procedure:
A solution of the compound of Example 77 (284 mg, 0.60 mmol), 2-iodopyridine (0.13 mL, 1.2 mmol) and potassium carbonate (208 mg, 1.5 mmol) in DMF (3.0 mL) was stirred at 90° C. for 5.5 hr. 2-Bromopyridine (0.23 mL, 2.5 mmol) and triethylamine (0.49 mL, 3.5 mmol) were added to the reaction mixture, and the mixture was stirred under microwave irradiation at 165° for 1 hr. The reaction mixture was diluted with water, and extracted twice with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate/hexane=30/70-100/0) and recrystallized from THF-diethyl ether to give the title compound (38 mg, 12%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:6]1[CH:27]=[CH:26][C:9]([C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][CH:19]=[C:18]3[C:24]#[N:25])=[O:11])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].C[Si]([N:32]=[C:33]=[O:34])(C)C>O1CCOCC1>[C:24]([C:18]1[C:17]2[C:21](=[CH:22][CH:23]=[C:15]([CH2:14][CH2:13][NH:12][C:10](=[O:11])[C:9]3[CH:8]=[CH:7][C:6]([C:3]([CH3:5])([CH3:4])[CH2:2][NH:1][C:33]([NH2:32])=[O:34])=[CH:27][CH:26]=3)[CH:16]=2)[NH:20][CH:19]=1)#[N:25]
Reactant: CC(C)(CN)c1ccc(C(=O)NCCc2ccc3[nH]cc(C#N)c3c2)cc1
Reactant: C[Si](C)(C)N=C=O
Solvent: C1COCCO1
Product: CC(C)(CNC(N)=O)c1ccc(C(=O)NCCc2ccc3[nH]cc(C#N)c3c2)cc1
Reaction time: 16 h
Yield: 98.1 %

Procedure:
To a solution of 4-[2-amino-1,1-dimethyl-ethyl]-N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-benzamide (90 mg, 0.25 mmol) (reference example 105) in 1,4-dioxane (1 ml) was added trimethylsilyl isocyanate (68 μL, 0.50 mmol). The resulting mixture is stirred for 16 h. The precipitated solids are collected by vacuum filtration, washed with a small volume of CH2Cl2 and dried under high vacuum to give 99 mg of product. MS (ion spray) m/z 404 (M+H)+.
Reaction SMILES: [F:1][C:2]1[S:6][C:5]2[CH2:7][S:8][CH2:9][C:4]=2[C:3]=1[F:10].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[F:1][C:2]1[S:6][C:5]2=[CH:7][S:8][CH:9]=[C:4]2[C:3]=1[F:10]
Reactant: Fc1sc2c(c1F)CSC2
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Fc1sc2cscc2c1F
Temperature: 25 °C
Yield: 35.9 %

Procedure:
An oven-dried 250 ml flask equipped with a magnetic stir bar was charged with 560 mg of 2,3-difluoro-4,6-dihydrothieno[3,4-b]thiophene (3.15 mmol) and 50 ml methylene chloride. The solution was cooled to 0° C. m-CPBA (0.71 g, 77%, 3.15 mmol) was added to one portion and the reaction mixture was allowed to warm up to room temperature overnight. The solvent was removed by a roto-vap and the residue was redissolved in 15 ml acetic anhydride and heated for 2 hours. The acetic anhydride was then removed by roto-vap and the product was purified by column chromatography to produce 199.5 mg of product. (GC-MS found m/q: 176 (Calculated for C6H2F2S2 176.21)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][C:4]=1[O:16]C)#[N:2].[C-]#N.[Na+].CC(O)=O>CS(C)=O.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][C:4]=1[OH:16])#[N:2]
Reactant: CCOC(=O)CCc1ccc(C#N)c(OC)c1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCOC(=O)CCc1ccc(C#N)c(O)c1
Temperature: 160 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 3-(4-cyano-3-methoxyphenyl)propionate (3.17 g, 13.6 mmol, 1 equiv) and sodium cyanide (2.00 g, 40.8 mmol, 3.00 equiv) in DMSO (60 mL) was stirred at 140-180° C. for 2 h. After 2.5 hours the reaction mixture was taken up in H2O (300 mL), adjusted to pH 7 with AcOH (2.1 mL), and extracted with Et2O (1×150 mL). The organic layer was washed with H2O (2×50 mL), dried (anh. Na2SO4), and concentrated (75° C.). This yielded 2.05 g (68.8%) of ethyl 4-(4-cyano-3-hydroxyphenyl)propionate as a light yellow crystalline solid: 1H-NMR (CDCl3) 7.42 (1H, d), 7.40 (1H, br s), 6.92 (1H, d), 6.81 (1H, dd), 4.15 (2H, q), 2.94 (2H, dd), 2.64 (2H, dd), 1.25 (3H, t).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.C([O:22][C:23]([C:25]1[N:30]2[C:31]([C:34](=[O:39])C(Cl)(Cl)Cl)=[CH:32][N:33]=[C:29]2[CH:28]=[CH:27][CH:26]=1)=O)C>C(#N)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:23](=[O:22])[C:25]3[N:30]4[C:31](=[CH:32][N:33]=[C:29]4[CH:28]=[CH:27][CH:26]=3)[C:34]2=[O:39])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc2ncc(C(=O)C(Cl)(Cl)Cl)n12
Reactant: NCCc1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Nc1ccc(CCn2c(=O)c3cccc4ncc(c2=O)n43)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.6 %

Procedure:
To a solution of 1.63 g (12.0 mmol) of 2-[4-(amino)phenyl]ethylamine and 1.68 g (13 mmol) of N,N-diisopropylethylamine in 40 ml of acetonitrile was added a solution of 3.50 g (10.0 mmol) of 5-ethoxycarbonyl-3-trichloroacetylimidazo[1,2-a]pyridine in 10 ml of acetonitrile. The mixture was stirred for one hour at room temperature. The resulting crystalline precipitates were collected by filtration, washed with acetonitrile and dried to afford 1.03 g of the desired compound (33.6%, a yellow crystals). The filtrate was concentrated. The residne was crystallized from acetonitrile-methylene chloride. Crystalline precipitatse were collected by filtration, washed with acetonitrile to afford 1.60 g of the desired compound (52.1%, a yellow crystals).