Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].C(O[C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16])C>>[CH3:1][NH:2][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16]
Reactant: CN
Reactant: CCOC(=O)CNC(=O)CN1CCCC1=O
Product: CNC(=O)CNC(=O)CN1CCCC1=O
Reaction time: 8 h
Yield: 92 %

Procedure:
31 g (1 mole) of methylamine are added to 18.24 g (0.08 mole) of N-(2-oxo-1-pyrrolidineacetyl)-glycine ethyl ester and the reaction mixture is kept at -20° C. for 8 hours, while stirring. It is then evaporated and the residue is recrystallized from absolute ethanol, 15.7 g. of N-methyl-2-(2-oxo-1-pyrrolidineacetamido)-acetamide being obtained (yield: 92% of theory); M.P. 139°-140° C.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:17])=O>CN(C)C=O.ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([Cl:17])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CCCCC1CCCCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CCCCC1CCCCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
A solution of 5-cyclohexylpentanoic acid (63.50 g, 345 mmol) in N,N-dimethylformamide (0.5 ml) and dichloromethane (350 ml) was cooled to 5° C. and treated dropwise with oxalyl chloride (31.6 ml, 362 mmol) over 30 minutes. The mixture was stirred at 0° C. for 3 hours then the solvent was removed under reduced pressure to afford 5-cyclohexylpentanoyl chloride as a pale yellow solid (70.0 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH2:11]([O:13][C:14](=[O:22])[CH:15]([C:19](=O)[CH3:20])[C:16](=O)[CH3:17])[CH3:12].N1C=CC=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[C:16]([CH3:17])=[N:10][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=2)[C:19]=1[CH3:20])=[O:22])[CH3:12]
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)nn(-c2cccc(Cl)c2)c1C

Procedure:
Similar to Example 1, equimolar amounts of 3-chlorophenylhydrazine hydrochloride and 2-acetyl-3-oxo-butyric acid ethyl ester were combined in a solution of 50% pyridine in ethanol. Analysis confirmed that the resulting solid was determined to be the named product (m.p. 56° C.–57° C.).
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([CH3:19])=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]=1[C:9]([O:11]C)=O)=[C:2]=[S:3].[CH3:20][C:21]1[N:22]=[CH:23][N:24]([CH2:26][CH2:27][CH2:28][NH2:29])[CH:25]=1>>[CH3:19][C:6]1[S:5][C:4]2[NH:1][C:2](=[S:3])[N:29]([CH2:28][CH2:27][CH2:26][N:24]3[CH:25]=[C:21]([CH3:20])[N:22]=[CH:23]3)[C:9](=[O:11])[C:8]=2[C:7]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1c(N=C=S)sc(C)c1-c1ccccc1
Reactant: Cc1cn(CCCN)cn1
Product: Cc1cn(CCCn2c(=S)[nH]c3sc(C)c(-c4ccccc4)c3c2=O)cn1

Procedure:
The compound was synthesized starting from methyl 2-isothiocyanato-5-methyl-4-phenylthiophene-3-carboxylate (0.100 g. 0.35 mmol) and 3-(4-methyl-1H-imidazol-1-yl)propan-1-amine (9) (0.048 g, 0.35 mmol) as described above.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]([F:25])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>C(OC(=O)C)(=O)C.C(OCC)(OCC)OCC>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17](=[O:24])[C:18](=[CH:22][O:21][CH2:19][CH3:18])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]([F:25])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(C2CCN(C(C)=O)CC2)cc1F
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(OCC)OCC
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(C2CCN(C(C)=O)CC2)cc1F

Procedure:
A solution of 2.68 g (7.57 mmol) ethyl 4-(1-acetyl-4-piperidinyl)-2,5-difluoro-β-oxobenzenepropionate in 16 ml of acetic anhydride and 1.9 ml of triethyl orthoformate was refluxed 1.25 hours. The title compound was isolated as a syrup after evaporation under vacuum in an oil bath at 80° C.
Reaction SMILES: [S:1]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[O:12]1[CH:16]=[CH:15][C:14]([C:17](=O)[C:18](OCCCC)=[O:19])=[CH:13]1.C([O-])(C)(C)C.[K+].Cl>CO>[CH3:11][O:10][C:8]([C:7]1[S:1][C:2]([C:3]([O:5][CH3:6])=[O:4])=[C:18]([OH:19])[C:17]=1[C:14]1[CH:15]=[CH:16][O:12][CH:13]=1)=[O:9]
Reactant: CCCCOC(=O)C(=O)c1ccoc1
Reactant: COC(=O)CSCC(=O)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: COC(=O)c1sc(C(=O)OC)c(-c2ccoc2)c1O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A mixture of 26 g of dimethyl thiodiacetate and 32 g of butyl 2-(fur-3-yl)-2-oxo-acetate is added dropwise, over 30 minutes at 64°-68° C., to a mixture of 100 ml of methyl alcohol and 39.9 g of potassium tert.-butanolate. The reaction mixture is kept at this temperature for a further 3 hours, and then poured into a mixture of 179 g of ice and 58 g of concentrated hydrochloric acid. The resultant crystals are separated off, washed with ice water until free of chloride, and dried at 60 C./0.1 mbar. Yield: 27.9 g. The product is recrystallized from 250 ml of methyl alcohol, and 22 g of 2,5-bis-(methoxycarbonyl)-3-fur-3-yl-4-hydroxythiophene having a melting point of 102° C. are obtained.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:10][CH2:11][NH:12][C:13]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1)=O)(C)(C)C.[ClH:28]>CO>[ClH:28].[ClH:28].[NH2:8][C@H:9]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:10][CH2:11][NH:12][C:13]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)C1(NCC[C@H](NC(=O)OC(C)(C)C)c2ccccc2)CCCC1
Agent: Cl
Solvent: CO
Product: COC(=O)C1(NCC[C@H](N)c2ccccc2)CCCC1

Procedure:
To a cooled (0° C.) solution of methyl 1-({(3S)-3-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}amino)cyclopentanecarboxylate from Step C (0.920 g, 2.44 mmol) in MeOH (49 mL) was added excess anhydrous hydrogen chloride gas. After 30 min the solution was purged with dry nitrogen for about 40 min. The solvent was then removed in vacuo to provide a solid/oil mix. Additional MeOH (50 mL) was then added and subsequently removed in vacuo to provide the title compound. MS: m/z=277 (M+1).
Reaction SMILES: C([BH3-])#N.[Na+].[Cl:5][C:6]1[CH:7]=[C:8]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:20]([O:22][CH3:23])=[O:21].[C:28]([O:32][CH2:33][CH3:34])(=[O:31])[CH:29]=O.C(O)(=O)C>CO>[Cl:5][C:6]1[CH:7]=[C:8]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][CH2:29][C:28]([O:32][CH2:33][CH3:34])=[O:31])=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1cc2cc(N)ccc2n1Cc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CNc1ccc2c(c1)cc(C(=O)OC)n2Cc1ccc(Cl)c(Cl)c1
Reaction time: 0.08 h
Yield: 67 %

Procedure:
Sodium cyanoborohydride (0.2 g) was added in a single portion to methyl N-(3,4-dichlorobenzyl)-5-aminoindole-2-carboxylate (0.16 g), ethyl glyoxalate (0.2 ml of 50 wt % solution in toluene) and acetic acid (0.1 ml) in methanol (3 ml). The reaction was stirred for 5 mins then partitioned between ethyl acetate and 2M HCl. Combined organic extracts were dried (MgSO4) and concentrated to give an oil which crystallised upon trituration with i-hexane. Filtration yielded the desired end product as an off-white powder (0.136 g, 67%); NMR δ (CD3SOCD3) 1.18 (t, 3H), 3.79 (s, 3H), 3.82 (d, 2H), 4.08 (q, 2H), 5.72 (s, 2H), 6.60-7.50 (in, 7H); M/z (+) 435 (M+), 133.
Reaction SMILES: CC(OC([N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][CH2:13][CH2:12]1)=O)CCCCC.C(O[CH2:26][CH3:27])(=O)C.[ClH:28]>C(OCC)(=O)C>[ClH:28].[CH3:17][CH:16]([CH:13]1[CH2:12][NH:11][CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14]1)[CH2:15][CH2:21][CH2:20][CH2:26][CH3:27]
Reactant: CCCCCC(C)OC(=O)N1CCOc2ccccc2C1
Reactant: CCOC(C)=O
Agent: Cl
Product: CCCCCC(C)C1CNCc2ccccc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.4 %

Procedure:
A mixture of tert-butyl 9-bicyclo[2.2.1]hepta-2-yl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (100 mg, 0.292 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (2 ml) was stirred at room temperature for 0.5 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (24.0 mg, 29.4%) as a solid.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:28]=[CH:27][C:10]3[C:11]4[N:15]([CH2:16][CH2:17][O:18][C:9]=3[CH:8]=2)[CH:14]=[C:13]([C:19]2[N:20]([CH:24]([CH3:26])[CH3:25])[N:21]=[CH:22][N:23]=2)[N:12]=4)[CH2:3][CH2:2]1>[OH-].[OH-].[Pd+2].C(OCC)(=O)C>[CH:24]([N:20]1[C:19]([C:13]2[N:12]=[C:11]3[C:10]4[CH:27]=[CH:28][C:7]([CH:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)=[CH:8][C:9]=4[O:18][CH2:17][CH2:16][N:15]3[CH:14]=2)=[N:23][CH:22]=[N:21]1)([CH3:26])[CH3:25]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3=CCOCC3)cc1OCC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCOCC3)cc1OCC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.7 %

Procedure:
A mixture of 8-(3,6-dihydro-2H-pyran-4-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (73 mg, 0.19 mmol), 20% palladium hydroxide on carbon (50 mg) and ethyl acetate (10 mL) was degassed then stirred at RT for 72 h under an atmosphere of hydrogen. The reaction mixture was filtered, the filtrate concentrated in vacuo and the residue triturated in cyclohexane to give 294 as a white solid (51 mg, 71%). LCMS: RT=4.30 min, [M+H]+=380 1H NMR 400 MHz (DMSO-d) δ: 8.34 (1H, d, J=8.29 Hz), 7.91 (2H, d, J=1.36 Hz), 7.08 (1H, dd, J=8.34, 1.79 Hz), 6.92 (1H, d, J=1.73 Hz), 5.90-5.89 (1H, m), 4.50 (4H, q, J=5.58 Hz), 3.96-3.95 (2H, m), 3.44 (2H, td, J=11.21, 3.01 Hz), 2.77-2.76 (1H, m), 1.73-1.66 (4H, m), 1.49 (6H, d, J=6.60 Hz)
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][CH:6]([O:8][C:9](=[O:13])[CH:10]([CH3:12])[OH:11])[CH2:5][C:4]([CH3:15])([CH3:14])[NH:3]1.CC1(C)[O:23][C:22](=O)[CH:21]=[C:20]([CH3:25])[O:19]1>C1(C)C=CC=CC=1>[CH3:16][C:2]1([CH3:1])[CH2:7][CH:6]([O:8][C:9](=[O:13])[CH:10]([O:11][C:22](=[O:23])[CH2:21][C:20]([CH3:25])=[O:19])[CH3:12])[CH2:5][C:4]([CH3:15])([CH3:14])[NH:3]1
Reactant: CC(O)C(=O)OC1CC(C)(C)NC(C)(C)C1
Reactant: CC1=CC(=O)OC(C)(C)O1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OC(C)C(=O)OC1CC(C)(C)NC(C)(C)C1

Procedure:
Lactic acid 2,2,6,6-tetramethyl-4-piperidyl ester (5 g, 21.8 mmol) was dissolved in 100 ml of toluene. At reflux temperature, 3.1 g (21.8 mmol) of 2,2,6-trimethyl-4H-1,3-dioxine-4-one was added dropwise. After 3 hours at reflux, the solvent was distilled of in vacuo. A viscous residue was left. Yield 4.8 g (70%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[I:11].BrC1C=C(C=CC=1F)C([Cl:18])=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:18])=[O:7])=[CH:4][C:3]=1[I:11]
Reactant: O=C(Cl)c1ccc(F)c(Br)c1
Reactant: O=C(O)c1ccc(Cl)c(I)c1
Product: O=C(Cl)c1ccc(Cl)c(I)c1

Procedure:
4-Chloro-3-iodobenzoylchloride was prepared from 4-chloro-3-iodobenzoic acid according to the procedure described in Example 183 for the synthesis of 3-bromo-4-fluorobenzoyl chloride.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.Cl[C:10]1[N:15]=[C:14]([Cl:16])[N:13]=[C:12]2[N:17]([CH3:20])[N:18]=[CH:19][C:11]=12>>[Cl:16][C:14]1[N:13]=[C:12]2[N:17]([CH3:20])[N:18]=[CH:19][C:11]2=[C:10]([NH:1][CH2:2][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[N:15]=1
Reactant: NCc1cccnc1
Reactant: Cn1ncc2c(Cl)nc(Cl)nc21
Product: Cn1ncc2c(NCc3cccnc3)nc(Cl)nc21

Procedure:
Reaction of 3-aminomethylpyridine with 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 5 by General Procedure B gave (6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-pyridin-3-ylmethyl-amine.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([S:18]([N:8]2[CH2:9][CH2:10][CH2:11][CH:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(C2CCCN2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=S(=O)(c1ccccc1)N1CCCC1c1ccccc1

Procedure:
The title compound, light pink solid, m.p. 116° C. and MS: m/e=287 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-phenyl-pyrrolidine and benzenesulfonyl chloride.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.I[CH3:30]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])=[C:19]5[CH3:30])=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CI
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Solvent: CN(C)C=O
Product: Cc1c(C(C)(C)C)[nH]c2ccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc12

Procedure:
A solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5-yl)cyclopropanecarboxamide (75 mg, 0.20 mmol) and iodomethane (125 μL, 2.0 mmol) in N,N-dimethylformamide (1 mL) was heated at 120° C. in a sealed tube for 24 h, The reaction was filtered and purified by reverse phase HPLC. ESI-MS m/z calc. 390.5, found 391.3 (M+1)+; retention time 2.04 minutes. 1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.39 (s, 1H), 7.51 (m, 1H), 7.13-7.11 (m, 1H), 7.03-6.90 (m, 4H), 6.03 (s, 2H), 2.25 (s, 3H), 1.40-1.38 (m, 11H), 1.03-1.01 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:7][C:6]=1[NH2:8])([O-:11])=[O:10]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 4 h
Yield: 21.8 %

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (5 g, 29 mmol), piperidine (2.9 mL, 29 mmol), and K2CO3 (4.0 g, 29 mmol) in DMF (20 mL) was stirred at 120° C. for 4 h. The reaction mixture was cooled to room temperature and poured into ice cold water (100 mL). The crude solid product was collected by filtration, air dried, and purified by flash chromatography (silica gel, 4×15 cm, eluted with CHCl3) to yield the product as orange crystals (1.4 g, 22%). See, Aust. J. Chem., 47:247-262 (1994).
Reaction SMILES: C([NH:4][C:5]1[N:6]=[C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[CH:16][C:17]([CH3:30])=[C:18]([NH:20][C:21]([C:23]4[N:27]([CH3:28])[N:26]=[C:25]([CH3:29])[CH:24]=4)=[O:22])[CH:19]=3)=[N:9][N:8]2[CH:31]=1)(=O)C.[ClH:32].C(OCC)(=O)C>CO>[ClH:32].[NH2:4][C:5]1[N:6]=[C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[CH:16][C:17]([CH3:30])=[C:18]([NH:20][C:21]([C:23]4[N:27]([CH3:28])[N:26]=[C:25]([CH3:29])[CH:24]=4)=[O:22])[CH:19]=3)=[N:9][N:8]2[CH:31]=1
Reactant: CC(=O)Nc1cn2nc(Oc3ccc(C)c(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2C)n(C)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.4 %

Procedure:
To a suspension of N-(5-{[2-(acetylamino)imidazo[1,2-b]pyridazin-6-yl]oxy}-2-methylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (310 mg, 0.73 mmol) in methanol (10 mL) was added 4N hydrochloric acid/ethyl acetate (10 mL, 40 mmol), and the mixture was stirred at room temperature for 16 hr. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate/tetrahydrofuran, and then with diethyl ether to give the title compound (240 mg, 78%) as a pale-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:22]([Cl:37])=[CH:21][N:20]=1.Cl.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>O1CCOCC1>[Cl:37][C:22]1[C:23]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[N:24][C:19]([NH:1][C:2]2[C:15]([O:16][CH3:17])=[CH:14][C:5]3[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCCc2cc(N)c(OC)cc21
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCN1C(=O)CCCc2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)c(OC)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Combined 7-Amino-1-ethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (124.8 mg, 0.0005327 mol), N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (180 mg, 0.00053 mol), 4 M of Hydrogen chloride in 1,4-Dioxane (200 uL) and heat in a Radley tube for 4.5 h at 110° C. Cool to RT and then treated with xs solid MP-carbonate resin and stirred for 30 min. Filtration, followed by concentration afforded a gummy solid that was put on high-vac overnight. The mixture was purified by ISCO chromoatography (40 g SiO2, 30% EA/hexane to 100% EA) afforded N-{(1R,2R)-2-[5-Chloro-2-(1-ethyl-8-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as an off-white foam that was dried under high vac and broken into a powder (112.41 mg, 39%). MP: 120-128° C. 1H-NMR (DMSO, 400 MHz) δ 8.10 (s, 1H), 7.96 (d, J=1.1 Hz, 1H), 7.69 (s, 1H), 7.18 (d, J=8.3 Hz, 1H), 7.00 (s, 1H), 6.85 (d, J=7.9 Hz, 1H), 3.88-3.83 (m, 1H), 3.35-3.31 (m, 1H), 2.90 (s, 3H), 2.60 (broad s, 2H), 2.11-2.00 (m, 8H), 1.70-1.67 (m, 2H), 1.40-1.15 (m, 5H), 1.00 (t, J=6.9 Hz, 3H); LC/MS: 537.34 (M+H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=1)=[O:8].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1>>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:11]=[N:12][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(SC(F)(F)F)nc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cncnc1
Product: O=C(Nc1ccc(SC(F)(F)F)nc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 169 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(6-((trifluoromethyl)thio)pyridin-3-yl)nicotinamide (Stage 279.1) and pyrimidin-5-ylboronic acid to afford a white resinous powder. HPLC (Condition 4) tR=4.41 min, UPLC-MS (Condition 3) tR=0.83 min, m/z=463.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.93 (m, 2H) 2.91 (d, J=11.34 Hz, 1H) 3.20-3.44 (m, 3H) 4.22 (br. s, 1H) 4.90 (d, J=3.52 Hz, 1H) 7.81 (d, J=8.60 Hz, 1H) 8.07-8.16 (m, 1H) 8.29-8.38 (m, 1H) 8.80-8.85 (m, 1H) 8.90 (s, 2H) 8.95-9.03 (m, 1H) 9.17-9.24 (m, 1H) 10.44 (s, 1H).
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[N:24]1[CH:29]=[CH:28][CH:27]=[N:26][C:25]=1[NH:30][CH2:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1>>[N:24]1[CH:29]=[CH:28][CH:27]=[N:26][C:25]=1[NH:30][CH2:31][C:32]1[CH:38]=[CH:37][C:35]([NH:36]/[C:4](=[C:11]2\[C:12](=[O:23])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:34][CH:33]=1
Reactant: Nc1ccc(CNc2ncccn2)cc1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(CNc2ncccn2)cc1)c1ccccc1

Procedure:
Prepared analogously to Example 89 by reacting 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone with 4-(pyrimidin-2-ylaminomethyl)-aniline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]2[C:19](=O)[C:18](=[CH:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)[CH2:17][O:16][CH2:15]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH2:34][C:35]1[S:36][CH2:37][CH2:38][N:39]=1.CCO>C(Cl)(Cl)Cl>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([CH:13]2[N:39]3[CH2:38][CH2:37][S:36][C:35]3=[N:34][C:19]3[C:18](=[CH:21][C:22]4[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=4)[CH2:17][O:16][CH2:15][C:14]2=3)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C=C2COCC(=Cc3cc(OC)c(OC)c(OC)c3)C2=O)cc(OC)c1OC
Reactant: NC1=NCCS1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1cc(C=C2COCC3=C2N=C2SCCN2C3c2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC

Procedure:
A stirred solution of tetrahydro-3,5-bis[(3,4,5-trimethoxyphenyl)methylene]-4H-pyran-4-one (3.0 g, 6.5 mmole) and 2-amino-2-thiazoline (0.8 g, 7.8 mmole) in 75 ml of CHCl3 is heated at reflux for 44 hours. After cooling, the solution is filtered to remove a small amount of insoluble material. The solvent is evaporated to give an oily residue which solidifies when treated with a small amount of EtOH. The yield is 2.2 g, m.p. 166°-168°. Crystallization from 10 ml of MeCN gives 1.5 g (42%) of light yellow solid, m.p. 153°-155°. The m.p. of a sample of this material does not change when recrystallized from MeCN.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH2:21][CH2:22][C:23]([N:25]1[C@@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:28][O:27][C:26]1=[O:36])=[O:24])=[CH:15]2.[CH2:37](I)[CH:38]=[CH2:39]>C1COCC1>[CH3:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH2:21][C@H:22]([CH2:39][CH:38]=[CH2:37])[C:23]([N:25]1[C@@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:28][O:27][C:26]1=[O:36])=[O:24])=[CH:15]2
Reactant: C=CCI
Reactant: Cc1ccc2[nH]c(CCC(=O)N3C(=O)OC[C@@H]3c3ccccc3)cc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@@H](Cc1cc2cc(C)ccc2[nH]1)C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
To a stirred solution of NaHMDS 1 M in THF (36.40 mL, 36.40 mmol) was added dropwise a solution of 8 (11.51 g, 33.04 mmol) in THF (180 mL) at −78° C. under argon. The solution was stirred at −78° C. (2 h), then allyl iodide (6.66 g, 39.65 mmol) in THF (70 mL) was added and the mixture was stirred for an additional 2 h at −78° C. The reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched by the addition of ice-cold saturated NH4Cl solution (200 mL), extracted with EtOAc, washed with brine and dried (Na2SO4). Evaporation provided a residue, which was purified by silica gel flash chromatography to provide 9 as colorless oil. (7.82 g, 61% yield). H NMR (d6-DMSO) δ 7.37-7.21 (m, 8H), 6.97 (dd, 1H, J=1.5 Hz & 8.5 Hz), 6.31 (dd, 1H, J=0.8 Hz & 3.1 Hz), 5.56 (m, 1H), 5.34 (dd, 1H, J=3.8 Hz & 8.5 Hz), 4.94-4.90 (m, 2H), 4.50 (t, 1H, J=8.7), 4.46-4.38 (m, 2H), 4.17 (m, 1H), 4.11 (dd, 1H, J=3.5 Hz & 8.8 Hz), 2.37 (s, 3H), 2.32 (m, 1H), 2.17 (m, 1H). FABMS (+Ve) m/z 388 [M+], 389 [MH+]. Anal. Calcd for C24H24N2O3 C, 74.21; H, 6.23; N, 7.21. Found C, 74.29; H, 6.22; N, 7.20.