Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].S([O:12][CH3:13])(OC)(=O)=O.[C:14]([NH:22][C:23]1[CH:31]=[C:30]([I:32])[CH:29]=[CH:28][C:24]=1[C:25](O)=[O:26])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>C(OCC)(=O)C.CN(C)C=O>[C:14]([NH:22][C:23]1[CH:31]=[C:30]([I:32])[CH:29]=[CH:28][C:24]=1[C:25]([O:12][CH3:13])=[O:26])(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COS(=O)(=O)OC
Reactant: O=C(Nc1cc(I)ccc1C(=O)O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(I)cc1NC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
0.62 g of potassium carbonate and 0.43 ml of dimethyl sulfate were added to 15 mL of N,N-dimethylformamide solution containing 1.5 g of 2-(benzamido)-4-iodobenzoic acid at room temperature and stirred at the same temperature for 1 hour. Ethyl acetate and 1.0 mol/L hydrochloric acid were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residual was purified with silica gel column chromatography [eluent; hexane:ethyl acetate=5:1] to obtain 1.3 g of methyl 2-(benzamido)-4-iodobenzoate as white solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:18])[C@H:10]2[NH:14][C:15]([NH2:17])=[S:16])[C:7]=1[C:19]([O:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2].Br[CH2:36][C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:18])[C@H:10]2[NH:14][C:15]2[S:16][CH:36]=[C:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:17]=2)[C:7]=1[C:19]([O:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])(=[O:3])[CH3:2]
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(N)=S)[C@H]2SC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](Nc3nc(-c4ccccc4)cs3)[C@H]2SC1
Reaction time: 8 h
Yield: 101.9 %

Procedure:
A mixture of 539 mg of (6R-trans)-3-[(acetyloxy)methyl]-7-[(aminothioxomethyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, 240 mg of 2-bromo-1-phenylethanone, 85 mg of potassium carbonate and 7 ml of acetonitrile was stirred overnight, then filtered through hydrous magnesium silicate. The filtrate was evaporated, giving 660 mg of the desired compound [α]D26 =+68°±3° (c, 0.4 chloroform).
Reaction SMILES: Cl.[CH3:2][S:3]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(=[O:5])=[O:4].C(N(C(C)C)CC)(C)C.Cl[C:22]1[N:23]([CH2:44][C:45]([F:48])([F:47])[F:46])[C:24]2[C:29]([N:30]=1)=[C:28]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[N:27]=[C:26]([C:37]1[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=1)[N:25]=2>CN1CCCC1=O>[CH3:2][S:3]([CH:6]1[CH2:11][CH2:10][N:9]([C:22]2[N:23]([CH2:44][C:45]([F:46])([F:48])[F:47])[C:24]3[C:29]([N:30]=2)=[C:28]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[N:27]=[C:26]([C:37]2[CH:42]=[N:41][C:40]([NH2:43])=[N:39][CH:38]=2)[N:25]=3)[CH2:8][CH2:7]1)(=[O:5])=[O:4]
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC(F)(F)F)c3n2)cn1
Reactant: CS(=O)(=O)C1CCNCC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)C1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 31.2 %

Procedure:
4-Methanesulfonylpiperidine hydrochloride (385 mg, 1.93 mmol), diisopropylethylamine (672 μg, 3.9 mmol), and N-methyl-2-pyrrolidone (2 ml) were added to 5-[8-chloro-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (200 mg, 0.48 mmol) and the resulting mixture was stirred at 100° C. for 12 hours. The reaction mixture was partitioned with ethyl acetate and water, the organic layer was dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=20:1) to give the title compound (81 mg, 33%) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1.[CH:14]([NH:16][NH2:17])=O>C(O)CCC>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:3]([CH:14]=[N:16][N:17]=3)[N:4]=2)[CH:9]=1
Reactant: NNC=O
Reactant: Clc1ccc(-c2cccnc2)nn1
Solvent: CCCCO
Product: c1cncc(-c2ccc3nncn3n2)c1

Procedure:
A mixture of 1.5 g. of 3-chloro-6-(3-pyridyl)pyridazine and 0.96 g. of formic acid hydrazide in 50 ml. of n-butyl alcohol is refluxed for 48 hours. The reaction mixture is concentrated, partitioned and crystallized as described in Example 1 to afford 1.0 g. of the product of the Example as a cream colored solid, m.p. 199°-200°.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N+:13]([O-])=[CH:12][C:11]([N+:18]([O-:20])=[O:19])=[C:10]2[C:21]([F:24])([F:23])[F:22]>ClC(Cl)C>[Br:3][C:12]1[C:11]([N+:18]([O-:20])=[O:19])=[C:10]([C:21]([F:24])([F:23])[F:22])[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([Cl:6])[CH:8]=2)[N:13]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=[N+]([O-])c1c[n+]([O-])c2ccc(Cl)cc2c1C(F)(F)F
Solvent: CC(Cl)Cl
Product: O=[N+]([O-])c1c(Br)nc2ccc(Cl)cc2c1C(F)(F)F
Temperature: 25 °C

Procedure:
Alternatively, the above reaction can be run using the following procedure: POBr3 (39.2 g, 137 mmol, 2 equiv) was added to a stirred solution of 3 (20 g, 68 mmol) in dichloroethane (150 mL). The reaction was heated to reflux for 8 h. After cooling to rt, the reaction was quenched by the slow addition of ice. (Here I let it stir over the weekend—but not necessary). The organic layer was separated and the aqueous layer was extracted with CHCl3 (2×100 mL). The combined organic layer was washed with NaHCO3 (1×150 mL), H2O (1×150 mL), NaHSO3 (1×150 mL), H2O (1×150 mL), brine (1×150 mL) and dried over MgSO4. The residue was recrystallized from EtOH to afford the desired product, 16.12 g (67%). An additional 1.87 g was obtained by column chromatography of the concentrated filtrate (SiO2, 5% ethyl acetate-hexane). Total yield 17.99 g (74%).
Reaction SMILES: [F:1][CH:2]([F:32])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[N:13]([N:17]=[C:18]([NH:20][C:21]3[CH:31]=[CH:30][C:24]4[CH2:25][CH2:26][NH:27][CH2:28][CH2:29][C:23]=4[CH:22]=3)[N:19]=2)[CH:14]=[CH:15][CH:16]=1.Cl[CH2:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36]>>[F:32][CH:2]([F:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[N:13]([N:17]=[C:18]([NH:20][C:21]3[CH:31]=[CH:30][C:24]4[CH2:25][CH2:26][N:27]([CH2:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH2:28][CH2:29][C:23]=4[CH:22]=3)[N:19]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: FC(F)COc1ccccc1-c1cccn2nc(Nc3ccc4c(c3)CCNCC4)nc12
Reactant: CN(C)C(=O)CCl
Product: CN(C)C(=O)CN1CCc2ccc(Nc3nc4c(-c5ccccc5OCC(F)F)cccn4n3)cc2CC1

Procedure:
2-(7-{8-[2-(2,2-Difluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-N,N-dimethyl-acetamide was prepared from {8-[2-(2,2-difluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-(2,3,4,5-tetrahydro-1H-3-benzazepin-7yl)-amine (0.100 g, 0.230 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.035 mL, 0.344 mmol) in a manner analogous to Example 313 to give product (0.045 g, 38%). MP=213-215° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.49 (s, 1H), 8.77 (d, 1H), 7.65 (m, 2H), 7.40 (m, 2H), 7.35 (s, 1H), 7.25 (m, 1H), 7.15 (m, 1H), 7.05 (m, 1H), 6.98 (m, 1H), 6.22 (br m, 1H), 4.35 (m, 2H), 3.22 (s, 2H), 3.05 (s, 3H), 2.75 (m, 7H), 2.55 (m, 4H). MS=521 (MH)+.
Reaction SMILES: [CH2:1]=[C:2]([C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1)[C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)=[O:4].O1CCOCC1>[Pd].C(OCC)C>[CH3:25][C:21]1([CH3:26])[CH2:20][CH2:19][C:18]([CH3:27])([CH3:28])[C:17]2[CH:16]=[C:15]([CH:2]([CH3:1])[C:3]([NH:5][C:6]3[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:13][CH:14]=3)=[O:4])[CH:24]=[CH:23][C:22]1=2
Reactant: C=C(C(=O)Nc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Pd]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C(=O)Nc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
650 mg (1.7 mmol) of 4-(α-methylene-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylacetamido)benzoic acid, 100 mg of palladium on charcoal (10%) and 100 ml of dioxane are introduced into a reactor. The mixture is hydrogenated at room temperature and under a pressure of 7 bars for 2 h, the catalyst is filtered off and the filtrate is evaporated. The residue obtained is ground in the minimum amount of ethyl ether, filtered off and dried. 580 mg (89%) of acid, melting point 195°-6° C., is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O>C(Cl)Cl>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[C:22]1[N:12]([CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])[C:3]2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=2[N:1]=1
Reactant: COC(=O)c1cccc(N)c1NCC(OC)OC
Reactant: O=Cc1ccccc1Cl
Solvent: ClCCl
Product: COC(=O)c1cccc2nc(-c3ccccc3Cl)n(CC(OC)OC)c12
Temperature: 55 °C
Yield: 36.7 %

Procedure:
Methyl 3-amino-2-(2,2-dimethoxyethylamino)benzoate (498 mg, 2.0 mmol) from Step C of Example 13, 2-chlorobenzaldehyde (303 mg, 2.15 mmol) and 4 {acute over (Å)} molecular sieves were stirred in methylene chloride (6 mL) at room temperature for 1 h. To this mixture was added iodobenzene 1,1-diacetate (1.26 g, 3.92 mmol) and the reaction mixture was heated (external temperature=55° C.) for 10 min. The reaction was quenched with saturated aqueous sodium bicarbonate, 10% aqueous sodium thiosulfate and pH adjusted to 8. The organic phase was extracted with methylene chloride, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 3:1 hexanes/ethyl acetate) to give methyl 2-(2-chlorophenyl)-1-(2,2-dimethoxyethyl)-1H-benzo[d]imidazole-7-carboxylate as a brown oil (275 mg, 38%): 1H NMR (500 MHz, MeOD) δ 7.91 (d, J=8.0 Hz, 1H), 7.82 (d, J=7.5 Hz, 1H), 7.66-7.60 (m, 3H), 7.56 (d, J=7.5 Hz, 1H), 7.40 (t, J=7.5 Hz, 1H), 4.28 (t, J=4.5 Hz, 1H), 4.27-4.08 (m, 2H), 3.98 (s, 3H), 3.12 (s, 3H), 3.09 (s, 3H); MS (ESI+) m/z 375 (M+H).
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[C:17]=1[C:16]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=1.CO.[F:20][B-:21]([F:24])([F:23])[F:22].[CH3:25][O+](C)C>ClCCl>[F:20][B-:21]([F:24])([F:23])[F:22].[CH3:25][N+:1]1[N:2]=[CH:3][N:4]2[C:17]=1[C:16]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=1
Reactant: C[O+](C)C
Reactant: c1ccc2c(c1)c1ccccc1n1cnnc21
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CO
Product: C[n+]1ncn2c3ccccc3c3ccccc3c21
Temperature: 2 °C
Reaction time: 16 h

Procedure:
A solution of 1,2,4-triazolo[4,3-f]phenanthridine (A. G. Mikhailovskii, V. S. Shklyaev, Chem. Heterocycl. Comp. 1992, 445) (5.9 g, 27 mmol) in dichloromethane (200 ml) and methanol (20 ml) is admixed under argon at 2° C. with trimethyloxonium tetrafluoroborate (4.3 g, 29 mmol) and stirred at 2° C. for 1 h and at room temperature for 16 h. The resulting precipitate is filtered off and washed with dichloromethane, methanol and petroleum ether. Yield: 5.9 g (69%).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.CCN(CC)CC.[N:20]1[N:21]([C:29]2[N:50]=[CH:49][CH:48]=[CH:47][C:30]=2[C:31]([NH:33][CH:34]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:35]([OH:39])[C:36](O)=[O:37])=[O:32])[CH:22]=[C:23]2[C:28]=1[CH:27]=[CH:26][CH:25]=[CH:24]2.Cl.[CH3:52][O:53][NH2:54]>CN(C=O)C>[OH:39][CH:35]([C:36]([NH:54][O:53][CH3:52])=[O:37])[CH:34]([NH:33][C:31](=[O:32])[C:30]1[CH:47]=[CH:48][CH:49]=[N:50][C:29]=1[N:21]1[CH:22]=[C:23]2[C:28]([CH:27]=[CH:26][CH:25]=[CH:24]2)=[N:20]1)[CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CON
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1cc2ccccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CONC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc2ccccc2n1
Reaction time: 0.08 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (663 mg, 3.46 mmol) and Et3N (0.900 ml, 6.46 mmol) were successively added to a solution of 3-[2-(2H-indazol-2-yl)nicotinamido]-2-hydroxy-4-phenylbutanoic acid (1200 mg, 2.88 mmol) and O-methylhydroxylamine hydrochloride (0.350 ml, 4.61 mmol) in DMF (35 ml) at 5° C., and the mixture was stirred for 5 minutes. A pH of 10 was adjusted by adding Et3N (0.643 ml, 4.61 mmol), stirring was continued for 1 hour at 5° C. and then overnight at room temperature. The reaction mixture was then concentrated under reduced pressure. To the obtained residue were added water (150 ml) and a saturated aqueous solution of NaHCO3 (20 ml) with stirring. Following stirring for about 20 minutes the precipitate formed was filtered off with suction and treated with methyl-tert.-butylether (40 ml) to give, after filtration and drying in vacuo, 1.07 g of the title compound as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=2)=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:26][C:27]1[C:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:30][NH:29][N:28]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:13])[O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N:29]3[CH:30]=[C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:27]([CH3:26])=[N:28]3)=[CH:19][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1n[nH]cc1-c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(B(O)O)cc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(-n3cc(-c4ccccc4)c(C)n3)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.4 %

Procedure:
A mixture of 4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)oxy]ethyl}phenylboronic acid (200 mg, 0.55 mmol), 3-methyl-4-phenylpyrazole (87 mg, 0.55 mmol), Copper(II) acetate (120 mg, 0.66 mmol), triethylamine (0.23 mL, 1.65 mmol), molecular sieves 4A (200 mg), and dichloromethane (8 mL) was stirred at room temperature for 3 days. After filtration through a bed of celite, the filtrate was diluted with dichloromethane, and washed with water. The organic fraction was dried over MgSO4. After concentration under reduced pressure, the residue was purified by TLC with dichloromethane/ethylacetate (10:1) to afford 56 mg (21%) of the title compound as white solids: MS (ESI) m/z 476 [M+H]+, 474 [M−H]−, 1H-NMR (CDCl3) δ 7.88 (2H, d, J=8.5 Hz), 7.61-7.19 (11H, m), 4.31 (2H, t, J=6.6 Hz), 2.92 (2H, t, J=6.6 Hz), 2.49 (3H, s), 2.42 (3H, s).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[CH:22]([NH:25][CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23]>ClCCl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:25]([CH:26]([CH3:28])[CH3:27])[CH:22]([CH3:24])[CH3:23])=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CC(C)NC(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)c1ccc(O)cc1)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 4-hydroxybenzoic acid (5 g, 36.2 mmol) in 50 mL of dichloromethane is treated at 0° C. with oxalyl chloride (6.3 mL, 72.4 mmol) and N,N-dimethylformamide (5.6 mL, 72.4 mmol). This solution is stirred at room temperature for 2 hours and treated with diisopropylamine (40 mL, 286 mmol) at 0° C. After stirring at room temperature for overnight, the reaction is partitioned between ethyl acetate and 1N hydrochloride solution. The organic phase is washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford 4-hydroxy-N,N-bis(1-methylethyl)benzamide.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[Cl:11])[NH:4][N:3]=1.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[C:14]1([S:20]([N:4]2[C:5]3=[N:6][CH:7]=[N:8][C:9]([Cl:11])=[C:10]3[C:2]([Br:1])=[N:3]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Clc1ncnc2[nH]nc(Br)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1nc(Br)c2c(Cl)ncnc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 87.6 %

Procedure:
To a solution of 3-Bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (1.3 g, 5.5 mmol) in DMF (42 mL) at 0° C. was added NaH (180 mg, 7.7 mmol) in portions. The reaction mixture was stirred at 0° C. for 5 minutes, then stirred at room temperature for 1.5 hours, after which it was cooled back to 0° C. Neat PhSO2Cl (0.7 mL, 5.6 mmol) was added and the reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with saturated aqueous NH4Cl and diluted further with H2O. The resulting precipitate was isolated by vacuum filtration to give 1-Benzenesulfonyl-3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (1.8 g, 88%.) 1H NMR (DMSO-d6, 400 MHz) δ 9.11 (1H, s), 8.11 (2H, d, J 8.1 Hz), 7.84 (1H, t, J 7.5 Hz), 7.70 (2H, t, J 8.0 Hz.)
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-])=O)=[N:5][N:6]=1.[H][H]>CO.C(OCC)(=O)C.[Ni]>[CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:13])=[N:5][N:6]=1
Reactant: [H][H]
Reactant: Cc1nnc(-c2ccccc2[N+](=O)[O-])o1
Agent: [Ni]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nnc(-c2ccccc2N)o1
Yield: 99.5 %

Procedure:
A mixture of 2-methyl-5-(2-nitro-phenyl)-[1,3,4]oxadiazole (0.73 g) and 50% Raney Ni (1 mL) in methanol (5 mL) and ethyl acetate (25 mL) was shaken under 50 psi of hydrogen for 3 hours. Filtration through celite and concentration of the filtrate provided 0.62 g of 2-methyl-5-(2-amino-phenyl)-[1,3,4]oxadiazole: 1H NMR (400 MHz, CDCl3) δ 7.71 (dd, 1H), 7.26 (dd, 1H), 6.76 (m, 2H), 5.81 (bs, 2H), 2.61 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:14]=[C:13]([CH2:23]O)[CH:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:56]I>C1C=CC=CC=1.CCOCC>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:10]([C:11]3[CH:12]=[C:13]([CH2:23][I:56])[N:14]=[C:15]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:16]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)nc(NC2CCCC2)n1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: Fc1ccc(-c2nn3c(Cl)cccc3c2-c2cc(CI)nc(NC3CCCC3)n2)cc1
Yield: 59.6 %

Procedure:
[6-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-(cyclopentylamino)-4-pyrimidinyl]methanol (215 mg, 0.49 mmol) was dissolved in a mixture of benzene (4 mL) and ether (8 mL). Imidazole (134 mg, 2.0 mmol) and triphenylphosphine (191 mg, 0.73 mmol) were added sequentially. A solution of iodine (179 mg, 0.71 mmol) in ether (5 mL) was added dropwise to the reaction mixture over 10 minutes. The resultant solution was stirred for an additional 20 minutes then diluted with 10 mL of ether. The mixture was filtered to remove solids. Concentration followed by flash chromatography (4:1 hexanes:ethyl acetate) provided 4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-6-(iodomethyl)-2-pyrimidinamine (160 mg, 60%) as a solid. Rf 0.47 (4:1 hexanes:ethyl acetate); 1H NMR (CDCl3) δ 8.38 (d, 1H), 7.67 (m, 2H), 7.28 (m, 1H), 7.18 (t, 2H), 7.03 (d, 1H), 6.38 (s, 1H), 5.19 (d, 1H), 4.35 (m, 1H), 4.02 (s, 2H), 2.10 (m, 2H), 2.67 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][C:5]([O:10][CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8].[F:18][C:19]1[C:20]([OH:29])=[CH:21][C:22]2[CH2:26][O:25][B:24]([OH:27])[C:23]=2[CH:28]=1>>[Cl:1][C:2]1[C:3]([O:29][C:20]2[C:19]([F:18])=[CH:28][C:23]3[B:24]([OH:27])[O:25][CH2:26][C:22]=3[CH:21]=2)=[N:4][C:5]([O:10][CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CC(=O)CCCOc1nc(Cl)c(Cl)cc1C#N
Reactant: OB1OCc2cc(O)c(F)cc21
Product: CC(=O)CCCOc1nc(Oc2cc3c(cc2F)B(O)OC3)c(Cl)cc1C#N

Procedure:
This compound was prepared from 5,6-dichloro-2-(4-oxopentyloxy)nicotinonitrile and 6-fluorobenzo[c][1,2]oxaborole-1,5(3H)-diol in a similar manner to that of D230. 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 1.63-1.67 (m, 2H), 2.02 (s, 3H), 2.3 (t, J=5.25 Hz, 2H), 3.94 (t, J=4.95 Hz, 2H), 5.0 (s, 2H), 7.51 (d, J=4.8 Hz, 1H), 7.63 (d, J=9.0 Hz, 1H), 8.62 (s, 1H), 9.4 (s, 1H).
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([OH:26])=O)[CH2:19]3)[N:15]3[N:27]=[CH:28][CH:29]=[C:14]3[N:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[CH:32]([NH2:35])([CH3:34])[CH3:33].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[OH:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:35][CH:32]([CH3:34])[CH3:33])=[O:26])[CH2:19]3)[N:15]3[N:27]=[CH:28][CH:29]=[C:14]3[N:13]=2)=[O:10])=[CH:30][CH:31]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC[C@@H](C(=O)O)C3)n3nccc3n2)cc1
Reactant: CC(C)N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)NC(=O)[C@@H]1CCCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)C1
Yield: 39.2 %

Procedure:
A solution of (R)-1-(5-(4-(2-hydroxypropan-2-yl)benzamido)pyrazolo[1,5-a]pyrimidin-7-yl)piperidine-3-carboxylic acid (Compound 84, 100 mg, 0.236 mmol), isopropylamine (14 mg, 0.236 mmol), EDCI (90 mg, 0.472 mmol), and HOBT (16 mg, 0.118 mmol) in DMF (4 mL) were stirred for 12 hours at room temperature. The reaction was complete as determined by LCMS analysis. The reaction mixture was then partitioned between ethyl acetate and water and the separated organic layer was dried over Mg2SO4, filtered, and concentrated under reduced pressure. Purification by preparatory HPLC, 25-35% (MeCN/H2O gradient+0.01% TFA) provided the titled compound as a white solid (43 mg, 39%). 1H NMR (DMSO-d6) δ: 10.92 (s, 1H), 8.10 (d, J=2.3 Hz, 1H), 7.97-8.04 (m, 2H), 7.92 (d, J=7.6 Hz, 1H), 7.55-7.66 (m, 2H), 7.39 (s, 1H), 6.37 (d, J=2.3 Hz, 1H), 4.26 (t, J=12.4 Hz, 2H), 3.84 (dq, J=13.8, 6.7 Hz, 1H), 3.36 (dd, J=12.4, 10.4 Hz, 1H), 2.98-3.14 (m, 1H), 2.53-2.58 (m, 1H), 1.67-2.01 (m, 4H), 1.39-1.51 (m, 6H), 1.05 (t, J=6.2 Hz, 6H). ESI-MS: m/z 465.0 (M+H)+.
Reaction SMILES: C(C1C=CC=CC=1C1[S:10]C=C(C2C=CC=CC=2)N=1)=O.[CH3:20][O:21][CH:22]([O:31][CH3:32])[C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]#[N:26].S>>[CH3:20][O:21][CH:22]([O:31][CH3:32])[C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]([NH2:26])=[S:10]
Reactant: O=Cc1ccccc1-c1nc(-c2ccccc2)cs1
Reactant: COC(OC)c1ccccc1C#N
Agent: S
Product: COC(OC)c1ccccc1C(N)=S

Procedure:
A solution of 2.65 g of 2-(o-formylphenyl)-4-phenylthiazole [M.P. 99°-100°; obtainable by reacting o-dimethoxymethylbenzonitrile with H2S to give o-dimethoxymethylthiobenzamide (M.P. 100°-102°), reacting the latter with α-bromoacetophenone to give o-dimethoxymethylthiobenzoic acid imide S-phenacyl ester (oil), and cyclizing the latter to give 2-(o-dimethoxymethylphenyl)-4-phenylthiazole by boiling with methanol and subsequent hydrolysis with aqueous hydrochloric acid], 1.06 ml of 33% aqueous ammonia, 2.32 g of methyl acetoacetate and 120 ml of methanol is boiled for 18 hours and evaporated. Treating the residue with ether gives 2,6-dimethyl-3,5-dimethoxycarbonyl-4-o-(4-phenyl-2-thiazolyl)-phenyl-1,4-dihydropyridine, M.P. 145°-148° (decomposition).