Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH2:18][CH3:19])=[CH:4][CH:3]=1.[O:20]([C:22]#[N:23])[Na]>O.C(O)(=O)C>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:22]([NH2:23])=[O:20])=[CH:7][CH:6]=3)=[C:9]([CH2:18][CH3:19])[S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: N#CO[Na]
Reactant: CCc1sc2ncnc(N)c2c1-c1ccc(N)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCc1sc2ncnc(N)c2c1-c1ccc(NC(N)=O)cc1
Yield: 95.7 %

Procedure:
A mixture of Example 78A (0.27 g, 1 mmol) and NaOCN (0.13 g, 2 mmol) in water (1.5 mL) and acetic acid (1.5 mL) was stirred overnight at room temperature and partitioned between water and ethyl acetate. The organic extract was washed with saturated aqueous NaHCO3 and brine, dried (MgSO4), filtered, and concentrated to provide 0.3 g of the desired product. MS (ESI(+)) m/e 314 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 1.15 (t, J=7.46 Hz, 3H); 2.63 (q, J=7.57 Hz, 2H); 5.94 (m, 2H); 7.24 (d, J=8.48 Hz, 2H); 7.56 (d, J=8.48 Hz, 2H); 8.25 (s, 1H); 8.75 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]([S-:13])#[N:12].[K+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]=[C:11]=[S:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: N#C[S-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(N=C=S)c1ccc(Cl)cc1

Procedure:
A solution of 4-chlorobenzoyl chloride (127.1 ml) in 100 ml of dry toluene is added to a vigorously stirred suspension of dried KSCN (106.90 g) in about one liter of dried toluene. The reaction mixture is heated to reflux and after addition is completed the mixture is refluxed overnight. The reaction mixture is allowed to cool, KCl filtered and the filtrate evaporated leaving a reddish residue which solidifies on standing. The residue is vacuum distilled, using a steam filled condenser, yielding 152.4 g of a distillate, b.p. 88°-90° (0.350 torr).
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:19])[CH:14](Cl)[C:15](=O)[CH3:16])[CH3:11]>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[S:8][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[N:9][C:15]=1[CH3:16])=[O:19])[CH3:11]
Reactant: NC(=S)c1cccnc1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1sc(-c2cccnc2)nc1C
Temperature: 25 °C
Yield: 70.2 %

Procedure:
A mixture of thionicotinamide (10 g, 0.07 mol) and 2-chloro-3-oxo-butyric acid ethyl ester (10 mL, 0.07 mol) in ethanol (100 mL) was heated at refluxed for 20 h before it was cooled to room temperature and concentrated in vacuo. It was partitioned between ethyl acetate and saturated sodium bicarbonate, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (12.2 g): MS: (+) m/z 249.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[O:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])[C:19]([Cl:34])=[CH:18][N:17]=1>>[Cl:34][C:19]1[C:20]([NH:22][C:23]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])=[N:21][C:16]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH3:12])[C:10](=[O:13])[O:9][CH2:8][CH2:7][C:6]=3[CH:14]=2)=[N:17][CH:18]=1
Reactant: CNC(=O)c1cccc(C)c1Nc1nc(Cl)ncc1Cl
Reactant: CN1C(=O)OCCc2cc(N)ccc21
Product: CNC(=O)c1cccc(C)c1Nc1nc(Nc2ccc3c(c2)CCOC(=O)N3C)ncc1Cl

Procedure:
Following a procedure analogous to Example 1742a, 2-amino-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3,N-dimethyl-benzamide were converted to 2-[5-chloro-2-(5-methyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-3,N-dimethyl-benzamide. TFA salt: 1H NMR (300 MHz, CDCl3) δ 11.84 (bs, 1H), 9.91 (s, 1H), 7.90 (s, 1H), 7.53-7.33 (m, 5H), 6.91 (d, 1H), 6.52 (bq, 1H), 4.46 (bs, 2H), 3.43 (s, 3H), 3.08 (d, 3H), 2.83 (bt, 2H), 2.32 (s, 3H); MS (m/e) 467 (M+1).
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O)#[N:5].O>N1C=CC=CC=1.C(O)C>[C:4]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[N:2][OH:3])#[N:5]
Reactant: N#Cc1cccc(C=O)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: N#Cc1cccc(C=NO)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 68.8 %

Procedure:
Hydroxylamine hydrochloride (13.5 g, 194 mmol) was added to a solution of 3-cyanobenzaldehyde (25 g, 191 mmol) in 75 mL of pyridine and 75 mL of ethanol under N2. This was allowed to stir at room temperature for 14 hours. Water (50 mL) was added with vigorous stirring and an off-white solid precipitated. The solid was filtered through a glass frit and washed with another 50 mL of water. Evaporation of residual water under high vacuum gave 19.2 g (69%) of title compound. 1H NMR (CDCl3) δ: 11.61 (s, 1H); 8.21 (s, 1H); 8.00 (s, 1H); 7.96 (d, 1H), 7.85 (d, 1H), 7.61 (t, 1H).
Reaction SMILES: [OH:1][C:2]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH3:20])[C:14]=1[CH2:21][OH:22])([CH2:11][CH3:12])[CH2:3][C:4]([O:6]C(C)(C)C)=O.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH2:11]([C:2]1([OH:1])[C:13]2[C:14](=[C:15]([O:19][CH3:20])[N:16]=[CH:17][CH:18]=2)[CH2:21][O:22][C:4](=[O:6])[CH2:3]1)[CH3:12]
Reactant: CCC(O)(CC(=O)OC(C)(C)C)c1ccnc(OC)c1CO
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCC1(O)CC(=O)OCc2c1ccnc2OC
Yield: 88.8 %

Procedure:
tert-butyl 3-hydroxy-3-[3-(hydroxymethyl)-2-methoxy-4-pyridinyl]pentanoate (8.8 g, 28 mmol) is treated with trifluoroacetic acid (30 ml) for 3 hours at ambient temperature. The volatile components are evaporated off and the residue is purified by column chromatography (SiO2, CH2Cl2/MeOH: 100/0 to 98/2), which produces a limpid oil which, after treatment with toluene, produces 5.9 g of product (L) (89%) in the form of white crystals, m.p. 97-98° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.[N+:7]([C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)([O-:9])=[O:8].F[P-](F)(F)(F)(F)F.ClC1N(C)C=C[N+]=1C.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][CH2:3][C:4]([NH:14][C:13]1[CH:15]=[CH:16][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=1)=[O:6]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: COCC(=O)O
Agent: Cn1cc[n+](C)c1Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)Nc1ccc([N+](=O)[O-])cc1
Yield: 71.4 %

Procedure:
To a mixture solution of 384 μL (5.0 mmol) of methoxyacetic acid and 691 mg (5.0 mmol) of p-nitroaniline in 10 mL of dichloromethane were added 1.53 mg (5.5 mmol) of 2-chloro-1,3-dimethylimidazoliumhexafluorophosphate and 1.53 mL (111.0 mmol) of triethylamine, and the mixture was refluxed for 7 hours. Then, the reaction mixture was extracted with ethyl acetate, the extract was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=2/1) to give 750 mg (71%) of the title compound.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[C:17]2[C:18]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[O:28])[C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:4][CH2:3]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:15])([F:14])[F:16])=[CH:9][C:8]=2[C:17]2[C:18]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:31][CH2:32][N:33]([C:36](=[O:39])[CH2:37][CH3:38])[CH2:34][CH2:35]4)=[O:28])[C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:3][CH2:4]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)(F)F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f31) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][CH:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.O.[OH-].[K+]>C(O)C>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([CH:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:5][C:4]([OH:22])=[O:3])=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: CCOC(=O)CC(c1ccccc1)c1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CC(c1ccccc1)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of 3-(1H-indol-5-yl)-3-phenyl-propionic acid ethyl ester CCLXXIII (0.48 g, 1.6 mmol) in ethanol (30 mL) was added water (ca. 5 mL) followed by potassium hydroxide in pellets (ca. 0.6 g) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure to remove the organic solvent and the residue was diluted with water (50 mL) and diethyl ether (50 mL). The resulting mixture was acidified by addition of an aqueous solution of hydrochloric acid (1 M) and was extracted twice with diethyl ether (50 mL). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to afford 0.42 g (98% yield) of 3-(1H-indol-5-yl)-3-phenyl-propionic acid CCLXXIV as a yellow solid without further purifications.
Reaction SMILES: N1C=CC=C([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:12][CH:11]=2)=[O:9])C=1.ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)(Cl)Cl>[CH:24]([O:23][C:13]1[C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[C:18]=2[C:10]([C:8]([NH2:7]=[O:35])=[O:9])=[CH:11][CH:12]=1)([CH3:26])[CH3:25]
Reactant: CC(C)Oc1ccc(C(=O)Nc2cccnc2)c2c1oc1ccccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(C)Oc1ccc(C(=O)[NH2+][O-])c2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A suspension of N-(pyrid-3-yl)-4isopropyloxy-dibenzo[b,d]furan-1-carboxamide (50 mg, 0.144 mmol) (example 36) and m-chloroperbenzoic acid (50-55%) (125 mg, 0.722 mmol) in chloroform (10 ml) was stirred at room temperature for 12 h. The reaction contents were washed with saturated sodium bicarbonate and water. The organic solvent was distilled off in vacuo and the residue was purified by column chromatography using 40% acetone-chloroform as the eluent to give 30 mg of N-pyrid-3-yl)-4-isopropyloxy-dibenzo[b,d]furan-1-carboxamide-N1-oxide as white solid; mp: 242° C.(dec).
Reaction SMILES: [Si:1]([N:8]1[CH:11]([CH2:12][CH:13]([OH:18])[CH2:14][C:15]([OH:17])=[O:16])[CH2:10][C:9]1=[O:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)([O-:22])=[O:21]>C(N(CC)CC)C>[Si:1]([N:8]1[CH:11]([CH2:12][CH:13]([OH:18])[CH2:14][C:15]([O:17][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=2)=[O:16])[CH2:10][C:9]1=[O:19])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC(O)CC(=O)O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC(O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 48 h

Procedure:
The crude carboxylic acid is suspended in anhydrous acetonitrite (150 ml) and treated with p-nitrobenzyl bromide (7.56 g, 35 mμol) and triethylamine (4.9 ml, 35 mμol). The resulting solution is kept at room temperature for 2 days and then in a refrigerator for 3 days. The reddish orange solution is evaporated under vacuum and the residue shaken with ethyl acetate (100 ml, 2×50 ml) and filtered to remove triethylammonium bromide. The ethyl acetate filtrate is washed with water (3×100 ml) and brine, dried with magnesium sulfate, filtered, and evaporated under vacuum to an amber oil (13.62 g). Crystallization from diethyl ether affords N-(t-butyldimethylsilyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-hydroxypropyl]-azetidin-2-one (6.84 g) as an off-white powder. Chromatography of the mother liquors on a silica gel column using 1:1 toluene-ethyl acetate as eluting solvent affords addition product (3.14 g) as an oil which solidifies.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].[CH2:21](Br)[CH:22]=[CH2:23].Cl>C1COCC1.[Zn].C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:23][CH:22]=[CH2:21])([OH:14])[CH:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCBr
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC1(O)CCN(C(=O)OC(C)(C)C)CC1C(=O)OC
Reaction time: 3 h

Procedure:
101.66 g of methyl 1-(tert-butyloxycarbonyl)-4-oxopiperidine-3-carboxylate were added, under an inert atmosphere and at a temperature close to 20° C., to 2.156 liters of a saturated aqueous solution of ammonium chloride and of THF (10/1 by volume) of THF. 34.73-cm3 of allyl bromide were then added, followed by 77.51 g of zinc while maintaining the temperature below 30° C. A solution of 69.47-cm3 of allyl bromide in 50-cm3 of THF was then poured in dropwise. After stirring for 3 hours at a temperature close to 20° C., the reaction was incomplete. 77.51 g of zinc were again added and then 104-cm3 of allyl bromide were poured in dropwise while the temperature was maintained below 30° C. The stirring was maintained at a temperature close to 20° C. for 15 hours, after which the reaction was still incomplete. 35 g of zinc were again added and then 55-cm3 of allyl bromide were poured in dropwise while the temperature was maintained below 30° C. The stirring was maintained at a temperature close to 20° C. for 4 hours, after which the reaction was still incomplete. 10 g of zinc were again added and then 25-cm3 of allyl bromide were poured in dropwise while the temperature was maintained below 30° C. The stirring was maintained at a temperature close to 20° C. for 2 hours. The reaction mixture was taken up in 900-cm3 of a 1 N HCl solution and 2 liters of ethyl ether and filtered on sintered glass. The filtrate was washed with 3 times 500-cm3 of etyl ether. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to dryness under reduced pressure (5 kPa). A yellow oil was obtained, which was purified by chromatography, under a nitrogen pressure of 50 kPa, on a column of silica gel (particle size 20-45μ; diameter 12 cm; height 60 cm), eluting with a mixture of cyclohexane-ethyl acetate (80/20 by volume) and collecting 200-cm3 fractions. Fractions 51 to 75 were combined and then concentrated. 63.5 g of methyl 1-(tert-butyloxycarbonyl)-4-allyl-4-hydroxypiperidine-3-carboxylate were obtained in the form of a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH2:14]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH2:30][C:31]([OH:33])=[O:32])[CH:28]=2)[CH:23]=[CH:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([CH2:30][C:31]([OH:33])=[O:32])[CH:28]=3)[CH:23]=[CH:22]2)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH2:14]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH2:30][C:31]([OH:33])=[O:32])[CH:28]=2)[CH:23]=[CH:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Fc1ccc(CBr)c(C(F)(F)F)c1
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: O=C(O)Cc1ccc2ccn(Cc3ccc(F)cc3C(F)(F)F)c2c1

Procedure:
The titled compound (36 mg) as a reddish brown solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 4-fluoro-2-(trifluoromethyl)benzyl bromide according to the method of the process (7) of Example 4.
Reaction SMILES: C([O-])(=[O:3])C.[NH4+].Cl[C:7]1[C:16]([C:17]#[N:18])=[C:15]([Cl:19])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:20])[CH:13]=2)[N:8]=1>C(O)(=O)C>[Cl:19][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:20])[CH:13]=2)[NH:8][C:7](=[O:3])[C:16]=1[C:17]#[N:18]
Reactant: Cc1ccc2nc(Cl)c(C#N)c(Cl)c2c1
Reactant: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: Cc1ccc2[nH]c(=O)c(C#N)c(Cl)c2c1
Temperature: 140 °C
Yield: 69 %

Procedure:
Ammonium acetate was added to a suspension of Compound 105 (7.1 g, 29.95 mmol) in glacial acetic acid and heated at 140° C. for 4 h. The solution was cooled and poured into ice water. The solids formed were filtered, washed by water, and dried under vacuum to yield 4.5 g (69%) of white solids. M.P. 264° C. 1H NMR (DMSO-d6): δ 2.32 (s, 3H), 7.34 (d, Jo 8.4 Hz, 1H), 7.63 (dd, J=1.5, 8.4 Hz, 1H), 7.75 (s, 1H). EIMS m/z 219 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([NH2:12])=[CH:5][CH:4]=1.[C:13]([OH:22])(=[O:21])[C:14]1C(=CC=[CH:19][CH:20]=1)N>>[C:8]([C:7]1[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[NH:12][CH:14]1[CH2:20][CH2:19][O:22][C:13]1=[O:21])([OH:10])=[O:9]
Reactant: COc1ccc(N)c(C(=O)O)c1
Reactant: Nc1ccccc1C(=O)O
Product: COc1ccc(NC2CCOC2=O)c(C(=O)O)c1

Procedure:
In the method of the Reference Example 1, 5-methoxyanthranilic acid was reacted in the place of anthranilic acid to obtain α-[(2-carboxy-4-methoxyphenyl)-amino]-γ-butyrolactone, melting point: 206.5°-208° C(decomp.).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH3:18])[C:15](O)=[O:16])=[CH:9][CH:8]=1.[NH3:19]>C(Cl)Cl>[N:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH3:18])[C:15]([NH2:19])=[O:16])=[CH:9][CH:8]=1
Reactant: CC(Cc1ccncc1)C(=O)O
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(Cc1ccncc1)C(N)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
Oxalyl chloride (154 mg, 1.21 mmol) was added to a stirred solution of 2-((pyridin-4-yl)methyl)propanoic acid (100 mg, 0.61 mmol) in DCM (5 ml) at 0° C. under an atmosphere of nitrogen and stirred for 1.5 h at room temperature. The reaction mixture was concentrated under reduced pressure to give the crude acid chloride. Aqueous ammonia (5 ml) was added to the above acid chloride solution at 0° C. and stirred for 30 min. The reaction mixture was extracted with ethyl acetate. The combined ethyl acetate layer was washed with water followed by brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to afford 92.0 mg (92.9%) of 2-((pyridin-4-yl)methyl)propanamide as a pale brown solid.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH:2]=[CH2:3].[N:7](=[C:9]1[CH:13]([CH3:14])[O:12][CH2:11][S:10]1)[OH:8]>CCOCC.C(N(CC)CC)C>[CH2:1]([NH:4][C:5]([O:8][N:7]=[C:9]1[CH:13]([CH3:14])[O:12][CH2:11][S:10]1)=[O:6])[CH:2]=[CH2:3]
Reactant: CC1OCSC1=NO
Reactant: C=CCN=C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CCNC(=O)ON=C1SCOC1C

Procedure:
A quantity of 3 ml of allyl isocyanate was caused to react with 3 grams of 4-oximino-5-methyl-1,3-oxathiolane dissolved in 50 ml of ether containing 2 drops of triethylamine over a period of 20 hours at room temperature. Conventional workup and recrystallization from isopropyl ether afforded 3 grams of product, mp 66.0°-67.5°, structure confirmed by spectral analysis.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:34])=[C:6]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:12][CH:11]=2)[CH:7]=1.[N:35]1[N:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH3:34][C:5]1[CH:4]=[CH:3][C:2]([C:37]2[NH:36][N:35]=[CH:39][CH:38]=2)=[CH:7][C:6]=1[NH:8][C:9](=[O:33])[C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[N:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:14][CH:15]=1
Reactant: Cc1ccc(Br)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Reactant: OB(O)n1cccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccn[nH]2)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Temperature: 110 °C
Yield: 68.9 %

Procedure:
A mixture of N-(5-bromo-2-methylphenyl)-4-[(4-phenylquinazolin-2-yl)amino]benzamide (116 mg, 0.228 mmol), pyrazole-2-boronic acid (218 mg, 1.9 mmol), potassium carbonate (1.4 mmol) and tetrakis(triphenylphosphine)palladium (27 mg, 0.023 mmol) in dioxane (2 mL) was heated to 110° C. overnight. The reaction was cooled, concentrated on a rotary evaporator and purified by preparative reverse phase HPLC to give N-[2-methyl-5-(1H-pyrazol-5-yl)phenyl]-4-[(4-phenylquinazolin-2-yl)amino]benzamide (78 mg, 69%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.33 (s, 1H), 9.79 (s, 1H), 8.18 (d, 2H), 8.02 (d, 2H), 7.86 (m, 3H), 7.80 (m, 3H), 7.70 (s, 1H), 7.64 (m, 3H), 7.60 (dd, 1H), 7.42 (dt, 1H), 7.31 (d, 1H), 6.69 (d, 1H), 2.50 (s, 3H). MS (EI) for C31H24N6O: 497.1 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.C(O)(=O)C.O=[Pt]=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][NH:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccccn1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC1CCCCN1
Yield: 80.6 %

Procedure:
A solution of 108 g (0.518 mol) of 2-[N-(tert-butoxycarbonyl)aminomethyl]pyridine in 500 mL of ethanol and 50 mL of glacial acetic acid was hydrogenated over 5 grams of PtO2 at 55 psi for 36 hours employing a Parr apparatus. The mixture was cautiously filtered through Celite® and solvent was removed at reduced pressure. The crude material was dissolved in ethyl acetate, washed with 2N aqueous NaOH, water, brine, and dried over MgSO4. Solvent was removed at reduced pressure and the resulting solid was recrystallized from ethyl acetate/hexane to provide 89.5 grams (80%) of 2-[N-(tert-butoxycarbonyl)aminomethyl]piperidine as a white solid. Mp. 93° C.
Reaction SMILES: CO[CH2:3][CH2:4][C:5]([NH2:7])=[O:6].[CH:8]1(N)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.N.[OH-].[Na+]>>[CH:8]1([NH:7][C:5](=[O:6])[CH:4]=[CH2:3])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: NC1CCCCC1
Reactant: COCCC(N)=O
Agent: N
Agent: [Na+]
Agent: [OH-]
Product: C=CC(=O)NC1CCCCC1

Procedure:
103.1 g (1.0 mole) of 3-methoxypropionamide are heated with 104.1 g (1.05 mole) of cyclohexylamine for 8 hours in a temperature range of 130°-170° C. until the evolution of ammonia is complete. The mixture is allowed to cool, 1.5 g of sodium hydroxide is added and the mixture is heated in a high vacuum at 90°-110° C. The methanol is split off within about 30 minutes, vigorous foaming occurring. The temperature is increased and 93.5 g (0.61 mole=61% of the theoretical yield) of N-cyclohexylacrylamide having a Bp0.1 of 124°-128° C., which solidifies into crystalline form in the receiver, are distilled off.