Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.CC1N=C(N)C=C([N:17]2[N:21]=[CH:20][CH:19]=[N:18]2)C=1>>[N:18]1[N:17]([C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=2)[N:21]=[CH:20][CH:19]=1
Reactant: Nc1ccnc(Cl)n1
Reactant: Cc1cc(-n2nccn2)cc(N)n1
Product: Nc1ccnc(-n2nccn2)n1

Procedure:
2-(2H-1,2,3-triazol-2-yl)pyrimidin-4-amine was prepared from 2-chloropyrimidin-4-amine using chemistry analogous to the synthesis of 6-methyl-4-(2H-1,2,3-triazol-2-yl)pyridin-2-amine (PrepEx 2.19 A). MS ESI calc'd. for C6H7N6 [M+H]+ 163. found 163. 1H NMR (500 MHz, DMSO-d6) δ 8.14 (d, J=5.5 Hz, 1H), 8.06 (s, 2H), 7.42 (s, 2H), 6.46 (d, J=5.5 Hz, 1H).
Reaction SMILES: Br[C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:3]1.[N-:33]=[N+]=[N-].[Na+].O>CN(C=O)C.CCO.[Pd]>[NH2:33][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:3]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Br)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [Pd]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](N)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 72 h
Yield: 94.6 %

Procedure:
To a stirred solution of cis-4-bromo-1-tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy) methylpyrrolidine (480 mg, 0.93 mmol) in DMF (5 ml) was added NaN3 (241 mg, 3.70 mmol) at room temperature. The reaction mixture was stirred at 70 for 3 days. Water was added thereto, and extracted with EtOAc. The extract was washed with water, then dried over Na2SO4, and concentrated in vacuo. The crude product was used to the subsequent reaction without further purification. The solution of the crude residue in EtOH (10 ml) was hydrogenated over 10% Pd—C under an atmospheric pressure at room temperature for 4 hr. The catalyst was filtered off, and the filtrate was concentrated in vacuo to give trans-4-amino-1tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy)methylpyrrolidine (400 mg, 95%) as a colorless oil. 1H-NMR (CDCl3) δ 1.06 (s, 9H), 1.32 and 1.45 (each s, total 9H), 2.20–2.35 (m, 1H), 3.05–3.18 (m, 1H), 3.55–4.05 (m, 6H), 7.35–7.41 (m, 6H), 7.61–7.69 (m, 4H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[CH3:38][O:39][C:40](=[O:57])[NH:41][C:42]1[CH:47]=[CH:46][C:45](B2OC(C)(C)C(C)(C)O2)=[CH:44][CH:43]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[C:33]([O:32][C:31]([NH:30][C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:19]3[N:5]4[C:6]5[CH:18]=[CH:17][CH:16]=[N:15][C:7]=5[NH:8][C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=5[C:4]4=[N:3][C:2]=3[C:45]3[CH:44]=[CH:43][C:42]([NH:41][C:40](=[O:57])[O:39][CH3:38])=[CH:47][CH:46]=3)=[CH:21][CH:22]=2)[CH2:29][CH2:28][CH2:27]1)=[O:37])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: COC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Nc1ccc(-c2nc3n(c2-c2ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Yield: 72.5 %

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.090 mmol), methyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (49 mg, 0.18 mmol), Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (6 mg, 0.009 mmol), and 2M Na2CO3 aq. (0.090 mL, 0.18 mmol) in DMF (3 mL) was treated with microwave (160° C. for 1 hour). The mixture was diluted with AcOEt, washed with water(×3), brine, dried over Na2SO4, then filtrated through Celite pad. The filtrate was concentrated and the residue was purified by preparative thin-layer chromatography (n-hexane/AcOEt=1:2) to afford the desired product (41 mg, 73%) as a yellow solid. 1HNMR (CDCl3) 400 MHz δ: 8.16 (dd, J=8.0 Hz and 2.3 Hz, 1H), 8.00-7.99 (m, 1H), 7.53 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 7.30 (td, J=8.0 Hz and 2.9 Hz, 2H), 7.16-7.13 (m, 3H), 6.94 (d, J=8.0 Hz, 1H), 6.81-6.77 (m, 1H), 6.59 (dd, J=8.0, 4.6 Hz, 1H), 6.57-6.54 (m, 1H), 6.24-6.22 (m, 1H), 5.18-5.00 (m, 1H), 3.77 (s, 3H), 2.57-2.48 (m, 4H), 2.19-2.10 (m, 1H), 1.93-1.87 (m, 1H), 1.39 (br s, 9H). LCMS: 629 [M+H].
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][CH2:17][CH3:18])(=[O:15])[CH3:14].[C:19]([NH:26][C@H:27]([CH:35]=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].Cl>O1CCCC1.CCCCCCC>[C:22]([O:21][C:19]([NH:26][C@@H:27]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH:35]([OH:36])[CH2:14][C:13]([O:16][CH2:17][CH3:18])=[O:15])=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccccc1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCCC
Product: CCOC(=O)CC(O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
A solution of 92.4 ml (0.706 moles) of diisopropylamine in 600 ml of tetrahydrofuran was cooled to -35° and 271.1 ml (0.706 moles) of a 2.6M solution of n-butyl lithium in heptane was added slowly. The solution was then cooled to -85° in an ethanol/liquid nitrogen bath and 68.9 g (0.706 moles) of ethyl acetate was added slowly keeping the reaction temperature below -80°. After stirring for 15 minutes, a solution of 125.5 g (0.504 moles) of Boc-phenylalaninal [J. A. Fehrentz and B. Castro, Synthesis, 676 (1983).] in 1 L. of tetrahydrofuran, precooled to -78°, was added dropwise, keeping the temperature below -80°. After stirring at -80° for 15 minutes, the solution was allowed to warm to -5° and 400 ml of 12% hydrochloric acid was added. The pH was adjusted to 2.0 and the solution extracted twice with ether. The combined ether solution was washed with 1N hydrochloric acid, water, saturated sodium bicarbonate, and then with saturated sodium chloride solution. After drying over magnesium sulfate the ether was removed under reduced pressure to give 154 g. (90.6% yield) of the crude product as a white solid sufficiently pure for use in the next step.
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH:20]=[O:21])[C:5]([NH:7][C:8]1[S:9][C:10]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:11][N:12]=1)=[O:6])[CH2:2][CH3:3].Cl>O>[CH:13]1([C:10]2[S:9][C:8]([N:7]3[CH:20]([OH:21])[CH2:19][CH2:18][N:4]([CH2:1][CH2:2][CH3:3])[C:5]3=[O:6])=[N:12][N:11]=2)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CCCN(CCC=O)C(=O)Nc1nnc(C2CCCC2)s1
Agent: Cl
Solvent: O
Product: CCCN1CCC(O)N(c2nnc(C3CCCC3)s2)C1=O

Procedure:
The dimethyl acetal of 3-[1-propyl-3-(5-cyclopentyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde (15 grams), water (400 ml) and hydrochloric acid (4 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. The reaction mixture is then filtered while hot and the filtrate is cooled to form a precipitate. The precipitate is recovered by filtration, is dried and is recrystallized to yield the desired product tetrahydro-1-(5-cyclopentyl-1,3,4-thiadiazol-2-yl)-3-propyl-6-hydroxy-2(1H)-pyrimidinone.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:10].C(N(CC)CC)C.Cl[C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl.O>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:25](=[O:27])[O:10][CH:9]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:3]=2[CH:4]=1
Reactant: Nc1ccc(Br)cc1C(O)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1Nc2ccc(Br)cc2C(c2ccccc2)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-Amino-5-bromo-phenyl)-phenyl-methanol (0.50 g, 1.798 mmol) is dissolved in anhydrous THF (25 mL). Triethylamine (0.55 g, 5.393 mmol) is added followed by triphosgene (0.16 g, 0.539 mmol). The mixture is stirred at room temperature overnight. Water (50 mL) is added and the reaction stirred for 15 minutes then extracted with ethylacetate (3×50 mL). The organic phases is washed with 1N HCl (2×50 mL) and a saturated solution of sodium hydrogencarbonate (50 mL). The organic phase is dried over sodium sulfate and concentrated in vacuo to provide the desired product as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([N:13]1[CH2:20][CH:19]3[CH:15]([CH2:16][NH:17][CH2:18]3)[CH2:14]1)[CH:6]=[N:5]2.[F:21][C:22]1[C:23]([N:31]2[N:35]=[CH:34][CH:33]=[N:32]2)=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=[O:26]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([N:13]1[CH2:14][CH:15]3[CH2:16][N:17]([C:25]([C:24]4[CH:28]=[CH:29][CH:30]=[C:22]([F:21])[C:23]=4[N:31]4[N:35]=[CH:34][CH:33]=[N:32]4)=[O:26])[CH2:18][CH:19]3[CH2:20]1)[CH:6]=[N:5]2
Reactant: Fc1cc2ncc(N3CC4CNCC4C3)nc2cc1F
Reactant: O=C(O)c1cccc(F)c1-n1nccn1
Product: O=C(c1cccc(F)c1-n1nccn1)N1CC2CN(c3cnc4cc(F)c(F)cc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 44 and 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI): mass calculated for C23H18F3N7O, 465.15; m/z found 466.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.28 (s, 1H), 7.75 (d, J=20.8, 2H), 7.65 (dd, J=10.6, 8.4, 1H), 7.50 (tt, J=9.6, 4.8, 1H), 7.43 (dd, J=11.4, 8.0, 1H), 7.39-7.31 (m, 1H), 7.25 (dd, J=12.5, 4.9, 1H), 4.00-3.86 (m, 1H), 3.81 (dd, J=10.0, 5.6, 2H), 3.66-3.49 (m, 4H), 3.32-3.16 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[C:6]=2[C:5]([CH3:14])=[C:4]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:3]=1[CH3:23]>C(OCC)(=O)C.CCCCCC>[Br:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH:7]([OH:13])[C:6]=2[C:5]([CH3:14])=[C:4]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:3]=1[CH3:23]
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)OC(C)(C)C)C(=O)C(C)(C)O2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(Br)c2c(c(C)c1NC(=O)OC(C)(C)C)C(O)C(C)(C)O2
Yield: 98 %

Procedure:
Using tert-butyl (7-bromo-2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Reference Example 66, the title compound was synthesized in the same manner as in Example 234. Yield: 98%. Melting point: 187-188° C. (ethyl acetate-hexane).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[CH:22]1[CH2:27][CH2:26][C:25](=[O:28])[N:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:23]1=[O:36].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:47])(=O)=O)=CC=1.[Cl-].[NH4+]>O1CCCC1.O.C(OCC)(=O)C>[O:21]=[C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12](=[O:11])[N:13]1[C:22]1([F:47])[CH2:27][CH2:26][C:25](=[O:28])[N:24]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[C:23]1=[O:36]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1C(=O)CCC(N2C(=O)c3ccccc3C2=O)C1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C(=O)CCC(F)(N2C(=O)c3ccccc3C2=O)C1=O
Reaction time: 1 h

Procedure:
In a similar fashion, lithium bis(trimethylsilyl)amide (24 mL, 24 mmol, 1.0 M) is added to a stirred solution of 1,3-dioxo-2-(1-tert-butoxycarbonyl-2,6-dioxopiperidin-3-yl)isoindoline(7.16 g, 20 mmol) in tetrahydrofuran (250 mL) at -40° C. After 1 hour, N-fluorobenzenesulfonimide (7.6 g, 24 mmol) is added to the mixture. The mixture is allowed to reach room temperature and kept overnight. The solution is stirred with ethyl acetate (200 mL), aqueous ammonium chloride (100 ml, sat), and water (100 mL). The aqueous layer is separated and extracted with ethyl acetate (200 mL). The combined organic layers are washed with water (100 mL), brine (100 mL), and dried over sodium sulfate. The solvent is removed in vacuo. The residue is purified by chromatography (silica gel) to give the intermediate 1,3-dioxo-2-(1-tert-butoxycarbonyl-2,6-dioxo-3-fluoropiperidin-3-yl)isoindoline.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][C:7]=1[CH3:8].ClC1N=NC(C2C=CC=CC=2)=C(C)C=1C.[CH3:29][N:30](C)[C:31]1N=NC(C2C=CSC=2)=CC=1C>>[CH3:29][N:30]([CH3:31])[C:2]1[N:3]=[N:4][C:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(-c2cccs2)nnc1Cl
Reactant: Cc1cc(-c2ccsc2)nnc1N(C)C
Agent: Cc1c(Cl)nnc(-c2ccccc2)c1C
Product: Cc1cc(-c2cccs2)nnc1N(C)C

Procedure:
The above-named compound is prepared in the same manner as described for the aminopyridazines of Example 38, excepting that 3-chloro-4-methyl-6-(2-thienyl)pyridazine is substituted for 3-chloro-4,5-dimethyl-6-phenylpyridazine. The product obtained has a melting point of 50°-52° C. 3-(Dimethylamino)-4-methyl-6-(3-thienyl)pyridazine, a red oil, (Example 51a) is made in the same manner as described above for the 2-thienyl derivative.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.C[OH:25].[H-].[Na+].O>CS(C)=O.C(O)(=O)C>[O:13]=[C:12]1[C:6]2[CH:5]=[N:4][C:3](=[O:25])[NH:8][C:7]=2[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH2:22][CH3:23])[NH:11]1
Reactant: CO
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCCOc1ccccc1-c1nc2[nH]c(=O)ncc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
7-Methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.66 g) and methanol (0.26 g) were added to a stirring suspension of sodium hydride (0.38 g, 50% suspension in oil) in dry dimethylsulphoxide (15 ml). The mixture was stirred at ambient temperature for 1.5 hours and at 70°-80° C. for 18 hours. The cooled reaction mixture was poured into water (500 ml), then glacial acetic acid (0.46 ml) was added and the mixture was extracted with chloroform (20o ml and then 2×100 ml). The combined extracts were washed with water, dried (magnesium sulphate) and evaporated under reduced pressure to yield a solid which was washed successively with ether and 40°-60° petroleum ether and recrystallised from dimethylformamide: water to yield a crude product (0.18 g). This together with another sample (0.24 g) similarly prepared was eluted from a silica column with chloroform and 10% methanol in chloroform. The combined fractions containing product were evaporated under reduced pressure and the residue recrystallised from dimethylformamide dilute hydrochloric acid and then from dimethylformamide to yield the title compound, 0.15 g, m.p. 271°-3° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1C=C[C:5]([NH:16][C:17](=O)C)=[N:6][C:7]=1[CH:8]=[N:9][S@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11].BrC1C(C=O)=N[C:24]([S:27]C)=NC=1>>[Br:1][C:2]1[C:7]([CH:8]=[N:9][S@:10]([C:12]([CH3:13])([CH3:14])[CH3:15])=[O:11])=[N:6][C:5]([S:27][CH3:24])=[N:16][CH:17]=1
Reactant: CSc1ncc(Br)c(C=O)n1
Reactant: CC(=O)Nc1ccc(Br)c(C=N[S@@](=O)C(C)(C)C)n1
Product: CSc1ncc(Br)c(C=N[S@@](=O)C(C)(C)C)n1

Procedure:
The title compound (11C) was prepared according to the method presented for the synthesis of compound 1D of Example 1 utilizing 11B. MS (m/z) 337.7 [M+H]+.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7][CH2:6]2)[NH2:2].[CH:14]1([C:19](=O)[CH2:20][C:21]#[N:22])[CH2:18][CH2:17][CH2:16][CH2:15]1>CCO>[NH2:22][C:21]1[N:1]([C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[NH:9][C:8](=[O:13])[CH2:7][CH2:6]3)[N:2]=[C:19]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:20]=1
Reactant: N#CCC(=O)C1CCCC1
Reactant: NNc1ccc2c(c1)CCC(=O)N2
Solvent: CCO
Product: Nc1cc(C2CCCC2)nn1-c1ccc2c(c1)CCC(=O)N2
Temperature: 80 °C
Yield: 86.5 %

Procedure:
6-Hydrazinyl-3,4-dihydroquinolin-2(1H)-one (1.00 g, 4.68 mmol, available from Example A35) was dissolved in EtOH (10 mL) and 3-cyclopentyl-3-oxopropanenitrile (0.706 g, 5.15 mmol) was added. The reaction mixture was heated at 80° C. for 22 h. The reaction mixture was concentrated and the residue was suspended in EtOAc (30 mL) and treated slowly with satd. Na2CO3 (30 mL). The solution was extracted with EtOAc (3×), and the combined organics were washed H2O and dried (Na2SO4), filtered, concentrated and dried to yield 6-(5-amino-3-cyclopentyl-1H-pyrazol-1-yl)-3,4-dihydroquinolin-2(1H)-one (1.2 g, 87% yield) which was used without further purification. LC-MS (EI) m/z: 297.2 (M+H+).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH:10][NH2:11].C(O[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18])C.C(N(CC)CC)C.C(OCC)C>C(O)C>[NH2:20][C:19]1[N:10]([C:4]2[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:3]=2[CH3:2])[N:11]=[CH:15][C:16]=1[C:17]#[N:18]
Reactant: CCOC=C(C#N)C#N
Reactant: Cc1cccc(C)c1NN
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1-n1ncc(C#N)c1N
Temperature: 25 °C

Procedure:
3.0 g (17.3 mmol) of 2,6-dimethylphenylhydrazine hydrochloride are suspended with 2.1 g (17.3 mmol) of ethoxymethylenemalononitrile in 40 ml of ethanol, and 7.3 ml (52.1 mmol) of triethylamine are added. The reaction mixture is heated to reflux for 3 h, during which a clear solution forms. After cooling to room temperature, diethyl ether is added to this. The triethyl-ammonium chloride which precipitates is filtered off. The solvent is removed in vacuo, and the residue is purified by preparative HPLC (YMC gel ODS-AQ S 5/15 μm; eluent A: water, eluent B: acetonitrile; gradient: 0 min 30% B, 5 min 30% B, 50 min 95% B). 2.3 g (62% of theory) of the product are obtained as yellow crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:5][CH:6]=[C:7]([CH2:9][OH:10])[N:8]=1.[N+]([O-])(O)=O.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:1][O:2][CH2:3][C:4]1[NH:5][CH:6]=[C:7]([CH:9]=[O:10])[N:8]=1
Reactant: COCc1nc(CO)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Product: COCc1nc(C=O)c[nH]1

Procedure:
A 145.9 gm. portion of 2-methoxymethyl-4-imidazolemethanol and 137 ml. of concentrated HNO3 are reacted as described in Example 15. After adjusting the pH to 7.0 with concentrated aqueous Na2CO3, the solution is concentrated under vacuum. Extraction of the residue three times with hot ethanol gives, after combining and concentrating the extracts, a yellow gum. This gum is chromatographed on silica gel. Fractions 7-15 are combined and recrystallized from 120 ml. of 2-propanol, treated with charcoal and the desired product is recovered, m.p. 100°-103° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14]3[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=3)[CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:7][C:6]2=[O:23])[CH2:3][CH2:2]1.[S]>ClC1C=CC=CC=1Cl>[CH:1]1([CH2:4][N:5]2[C:14]3[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=3)[C:8]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[N:7][C:6]2=[O:23])[CH2:3][CH2:2]1
Reactant: COc1ccc2c(c1)C(c1ccccc1)NC(=O)N2CC1CC1
Agent: [S]
Solvent: Clc1ccccc1Cl
Product: COc1ccc2c(c1)c(-c1ccccc1)nc(=O)n2CC1CC1
Yield: 88.2 %

Procedure:
A mixture of 1.54 g of 1-cyclopropylmethyl-4-phenyl-6-methoxy-3,4-dihydro-2(1H)-quinazolinone, 0.48 g of sulfur and 10 ml of o-dichlorobenzene was stirred under reflux for 5 hours. The solvent was then removed under reduced pressure, and the residue was treated with hot acetone. The insoluble sulfur was filtered off and the filtrate was concentrated to dryness. The residue was recrystallized from toluene to give 1.35 g of 1-cyclopropylmethyl-4-phenyl-6-methoxy-2(1H)-quinazolinone, m.p. 114°-115° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C(Cl)(=O)C([Cl:15])=O>ClCCl>[Cl:1][C:2]1[C:7]([C:8]([Cl:15])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Solvent: ClCCl
Product: O=C(Cl)c1ccc(Cl)nc1Cl
Reaction time: 2 h

Procedure:
To 2,6-dichloropyridine-3-carboxylic acid (75, 1.00 g, 0.00521 mol) in dichloromethane (75 mL) was added 2 M Oxalyl chloride (2.61 mL, 0.727 g, 0.00573 mol). The solution began to show vigorous gas evolution, which slowed but continued for about 2 hours. The reaction was allowed to continue at room temperature for an additional 3 hours. The reaction was concentrated to give the compound as a brown oil that crystallized on standing (76, 1.09 g, 99%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH:7]1[CH2:10][NH:9][CH2:8]1.[C:16]1([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[C:16]1([CH:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:9]2[CH2:10][CH:7]([O:6][C:5]3[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=3)[CH2:8]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Reactant: c1ccc(Cc2ccccc2)cc1
Solvent: CO
Product: FC(F)(F)c1cccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c1

Procedure:
A 30 gallon glass-lined reactor was charged with a solution containing equal parts of 3-(3-trifluoromethylphenoxy)azetidine and diphenylmethane in methanol as obtained from the catalytic hydrogenolysis of 78.32 moles of 1-diphenylmethyl-3-(3-trifluoromethylphenoxy)azetidine. The methanol was distilled off at a pressure of 150 mm Hg until the reactor temperature reached 65° C. The reactor was flushed with nitrogen and charged with 117.4 moles of urea. Heating was continued to approximately 135° C. and held at 135° C. until thin layer chromatographic analysis showed the azetidine derivative to be consumed. When the reaction was complete the mixture was cooled to approximately 80° C. A 30 gallon receiver equipped with an agitator was charged with 80 L of petroleum ether (80°-110° C. boiling range) and the contents of the reactor drained into the receiver with the agitator at high speed. The mixture was slowly cooled to 50° C. and held at that temperature for 5-6 hours. The resulting slurry was then pumped onto a vacuum filter and the filter cake compressed under a rubber dam for 4-5 hours to remove as much solvent as possible.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[NH:16][C:17]2[C:18]3[C:25]([CH3:26])=[C:24]([C:27]([OH:29])=O)[S:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:4][CH2:3]1.[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][NH2:36]>>[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][NH:36][C:27]([C:24]1[S:23][C:19]2[N:20]=[CH:21][N:22]=[C:17]([NH:16][C:10]3[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=3[O:8][CH:5]3[CH2:6][CH2:7][C:2]([CH3:30])([CH3:1])[CH2:3][CH2:4]3)[C:18]=2[C:25]=1[CH3:26])=[O:29]
Reactant: CN(C)CCCN
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC3CCC(C)(C)CC3)c12
Product: Cc1c(C(=O)NCCCN(C)C)sc2ncnc(Nc3ccc(F)cc3OC3CCC(C)(C)CC3)c12

Procedure:
Prepared analogously to 29.3 from 0.150 g 4-[2-(4,4-dimethyl-cyclohexyloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (cpd. 31.2) and 0.044 ml N,N-dimethyl-propane-1,3-diamine.