Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:28])/[CH:14]=[C:15](\[C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)/[C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[CH3:29])([CH3:4])([CH3:3])[CH3:2].[C:31]([O:35][C:36](=[O:52])[CH2:37][N:38]=[C:39]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([CH3:34])([CH3:33])[CH3:32].[OH-].[K+].O>C(#N)C>[C:1]([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:28])[CH2:14][C:15]([CH:37]([N:38]=[C:39]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:52])([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)[C:16]([F:17])([F:19])[F:18])=[CH:9][C:8]=1[CH3:29])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Cc1cc(C(=O)CC(c2cc(Cl)cc(Cl)c2)(C(N=C(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Yield: 21.3 %

Procedure:
4-[(E)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid tert-butyl ester (0.100 g, 0.218 mmol) and (benzhydrylidene-amino)-acetic acid tert-butyl ester (0.079 g, 0.261 mmol) were dissolved in acetonitrile (5.0 ml). Potassium hydroxide (0.013 g, 0.239 mmol) and antracen-9-yl-methyl quininium chloride (0.030 g, 0.054 mmol) were added and the resulting mixture was heated at 90 C for 6 days. At this time water was added and the reaction mixture was extracted with dichloromethane (3×). The crude product was purified by flash chromatography (0% to 15% ethyl acetate in cyclohexane) to afford 4-[3-[(Benzhydrylidene-amino)-tert-butoxycarbonyl-methyl]-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-butyryl]-2-methyl-benzoic acid tert-butyl ester (0.035 g, 21%) as a white solid. Chiral HPLC analysis (Chiralpack IA, heptanes:t-buthanol=98:2, 1 ml/min, retention time 8.50 minutes and 9.23 minutes (enantiomers of the minor diasteromer); 13.37 minutes and 14.81 (enantiomers of the major diastereomer) indicated that the reaction products were formed in diastereomeric ratio 2:1.
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1.[Br:16][C:17]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:18]=1[CH2:19]Br>C1COCC1>[Br:16][C:17]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:18]=1[CH2:19][O:3][C@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: Fc1ccc(Br)c(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](OCc2cc(F)ccc2Br)C1
Reaction time: 0.08 h
Yield: 100.6 %

Procedure:
Sodium hydride (60% oil dispersion, 0.24 g) was added to a stirred solution of tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate (0.935 g) in THF (15 mL) and the mixture was stirred for 5 minutes. 2-Bromo-5-fluorobenzyl bromide (1.608 g) was added and stirring was continued for 20 hours. The resultant suspension was filtered and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-15% to give tert-butyl (S)-3-(2-bromo-5-fluorobenzyloxy)-pyrrolidine-1-carboxylate (1.88 g) as a colourless oil.
Reaction SMILES: Cl.Br[C:3]1[C:4]2[N:5]([CH:16]=[CH:17][N:18]=2)[N:6]=[C:7]([Cl:15])[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:19][CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([NH2:28])=[CH:26][CH:27]=1.CC([O-])(C)C.[K+]>>[Cl:15][C:7]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:3]([NH:28][C:25]2[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH3:19])=[CH:27][CH:26]=2)[C:4]2[N:5]([CH:16]=[CH:17][N:18]=2)[N:6]=1
Reactant: CCOc1ccc(N)cc1
Reactant: Clc1nn2ccnc2c(Br)c1-c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: CCOc1ccc(Nc2c(-c3ccccc3)c(Cl)nn3ccnc23)cc1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
To a solution of 8-bromo-6-chloro-7-phenylimidazo[1,2-b]pyridazine HCl salt (0.0431 g, 0.125 mmol) from 1c and 4-ethoxyaniline (0.31 M in THF, 0.40 mL) under nitrogen at 0° C. was added KOtBu (1 N in THF, 0.32 mL, 0.32 mmol). After 1 min, the cold bath was removed, and the reaction mixture was stirred to room temperature for 1 h. After concentrating in vacuo, the residue was taken up in CH2Cl2 and water, and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. Trituration with hexanes provided 6-chloro-N-(4-ethoxyphenyl)-7-phenylimidazo[1,2-b]pyridazin-8-amine (0.0334 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([Br:17])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:18]([O-])([OH:20])=[O:19]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([Br:17])[C:12]([N+:18]([O-:20])=[O:19])=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(Br)cc1OCc1ccccc1
Solvent: CC(=O)O
Product: COc1cc([N+](=O)[O-])c(Br)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
3-Benzyloxy-1-bromo-4-methoxybenzene, 36, (1 g, 3.4 mmol) was dissolved in 50 mL acetic acid in a 100 mL round-bottomed flask and cooled to 0° C. using an ice bath. 2.5 mL nitric acid (70%) in 6 mL acetic acid was added dropwise. The reaction mixture was allowed to slowly rise to room temperature. After 3 h no starting material was detected by thin layer chromatography. Evaporation of acetic acid gave the crude product, which was filtered through a short silica gel column using a 80:20 mixture of hexanes:ethyl acetate to give 3-benzyloxy-4-methoxy-6-nitrobromobenzene (1.15 g) in quantitative yield; mp 134-135° C.; IR (KBr) 2946, 1577, 1518, 1468, 1382, 1329, 1266, 1211 cm−1; UV (MeOH) 246, 212 nm (log ε=3.91, 4.13); 1H NMR (CDCl3) δ3.93 (3H, s), 5.19 (2H. s), 7.17 (1H, s), 7.38-7.45 (5H, m), 7.57 (1H, s); 13C NMR δ56.99, 71.98, 107.69, 109.74, 118.73, 127.98, 129.11, 129.36, 135.50, 142.42, 149.18, 152.44; HRMS (EI) calcd for C14H12NO4Br m/z: 336.9950; found: 336.9941.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][NH:16][C:17](=O)[CH3:18])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:18][C:17]1[N:8]2[C:7]3[C:2]([CH3:1])([O:3][CH2:4][CH2:5][C:6]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:15][N:16]=1
Reactant: CC(=O)NCC1(C)OCCc2c1[nH]c1ccccc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CC1=NCC2(C)OCCc3c2n1c1ccccc31

Procedure:
A mixture of N-[(1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indol-1-yl)methyl]-acetamide (2.7 g, described in Example 1), phosphorus oxychloride (1.8 ml) and dry benzene (150 ml) is stirred and refluxed for 2 hours, cooled and washed with water (10° C.). The aqueouslayer is separated, basified with 5N sodium hydroxide, and extracted with chloroform. The combined organic extracts are dried over magnesium sulfate, filtered and evaporated to give a residue of the title compound. The residue is dissolved in diethyl ether and hydrogen chloride is added until precipitation is completed. The precipitate is collected and crystallized from ethanol-diethyl ether to obtain the hydrochloride salt of the title compound (1.45 g); mp 226°-227° C.; ir(CHCl3) 2500, 1815, 1623, 1536, 1662 and 1575 cm-1 ; mr (CDCI3) δ 1.66 (s), 2.90 (m), 3.32 (s), 3,48 (d), 4.30 (m) and 7.51 (m).
Reaction SMILES: [CH:1]1([NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([NH:27][S:28](=[O:41])(=[O:40])[NH:29][C:30]([O:32][CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[O:31])=[CH:26][C:20]=4[S:19](=[O:43])(=[O:42])[N:18]=3)[C:7]2=[O:44])[CH2:4][CH2:3][CH2:2]1.[CH3:45][Si](C=[N+]=[N-])(C)C>O1CCCC1.CO>[CH:1]1([NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([NH:27][S:28](=[O:41])(=[O:40])[N:29]([CH3:45])[C:30]([O:32][CH2:33][C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)=[O:31])=[CH:26][C:20]=4[S:19](=[O:43])(=[O:42])[N:18]=3)[C:7]2=[O:44])[CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(NS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NC3CCC3)c1=O)N2)OCc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: CN(C(=O)OCc1ccccc1)S(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NC3CCC3)c1=O)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.5 %

Procedure:
A solution of the product of Example 465 (0.045 g, 0.07 mmol) in 1:1 tetrahydrofuran/methanol (2 ml) at −10° C. was treated dropwise with trimethylsilyl diazomethane (2.0 M in hexanes, 70 μL, 0.14 mmol), stirred at 25° C. for 16 hours and concentrated under reduced pressure to provide the title compound (0.045 g, 98% yield).
Reaction SMILES: CC1(C)C(=O)C=C([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)CC1.[CH3:21][C:22]1([CH3:30])[CH2:27][C:26](=O)[CH2:25][C:24](=[O:29])[CH2:23]1>>[CH3:30][C:22]1([CH3:21])[CH2:23][C:24](=[O:29])[CH:25]=[C:26]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[CH2:27]1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: CC1(C)CCC(Nc2cccc(C(F)(F)F)c2)=CC1=O
Product: CC1(C)CC(=O)C=C(Nc2cccc(C(F)(F)F)c2)C1

Procedure:
The title compound is prepared in analogy to 6,6-dimethyl-3-(3-(trifluoromethyl)phenyl-amino)cyclohex-2-enone (intermediate 6), using 5,5-dimethylcyclohexane-1,3-dione (1.13 g, 8.04 mmol) as starting material. Yield: 1.73 g, ESI mass spectrum [M+H]+=284, Retention time HPLC: 1.18 min (Z005—001).
Reaction SMILES: [O:1]=[C:2]1[C:10](=[CH:11][C:12]2[NH:16][C:15]([CH3:17])=[C:14]([C:18]([OH:20])=O)[C:13]=2[CH3:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[NH2:22][CH2:23][CH:24]([OH:31])[CH2:25][N:26]1[CH:30]=[CH:29][N:28]=[N:27]1>>[OH:31][CH:24]([CH2:25][N:26]1[CH:30]=[CH:29][N:28]=[N:27]1)[CH2:23][NH:22][C:18]([C:14]1[C:13]([CH3:21])=[C:12](/[CH:11]=[C:10]2\[C:2](=[O:1])[NH:3][C:4]3[C:9]\2=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:16][C:15]=1[CH3:17])=[O:20]
Reactant: NCC(O)Cn1ccnn1
Reactant: Cc1[nH]c(C=C2C(=O)Nc3ccccc32)c(C)c1C(=O)O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccccc32)c(C)c1C(=O)NCC(O)Cn1ccnn1

Procedure:
5-(2-Oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (113 mg, 0.4 mmol) was condensed with 1-amino-3(1,2,3)triazole-1-yl-propan-2-ol (85 mg, 0.48 mmol) to precipitate 2,4-dimethyl-5-[2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-[1,2,3]triazol-1-yl-propyl)-amide (70 mg, 41%). 1H NMR (DMSO-d6) δ 2.45, 2.48 (2×s, 6H, 2×CH3), 3.35 (m, 2H), 4.02 (m, 1H), 4.32 (dd, J=7.6, 14 Hz, 1H), 4.53 (dd, J=3.4, 14 Hz, 1H), 5.43 (d, J=5.6 Hz, 1H, OH), 6.91 (d, J=7.6 Hz, 1H), 7.01 (t, J=7.6 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H), 7.66 (s, 1H), 7.12 (t, J=5.6 Hz, 1H), 7.74 (s, 1H), 7.77 (d, J=7.6 Hz, 1H), 8.11 (s, 1H), 10.93 (s, 1H, CONH), 13.68 (s, 1H, NH). LC-MS (m/z) 405.4 (M−1).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C@H:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1.[C:11]([C:15]1[N:19]([CH3:20])[N:18]([CH2:21][CH2:22][CH3:23])/[C:17](=[N:24]/[C:25](=[O:37])[C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=2F)/[CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>CN(C)C=O>[C:11]([C:15]1[N:19]([CH3:20])[N:18]([CH2:21][CH2:22][CH3:23])/[C:17](=[N:24]/[C:25](=[O:37])[C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:29]=[CH:28][C:27]=2[O:3][CH2:4][C@@H:5]2[CH2:6][CH2:7][C:8](=[O:10])[NH:9]2)/[CH:16]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: O=C1CC[C@@H](CO)N1
Reactant: CCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)cc(C(C)(C)C)n1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2OC[C@@H]2CCC(=O)N2)cc(C(C)(C)C)n1C
Reaction time: 3 h
Yield: 32.3 %

Procedure:
Sodium hydride (50 mg, 60% dispersion in mineral oil, 1.25 mmol) was added to a solution of (S)-5-(hydroxymethyl)pyrrolidin-2-one (72 mg, 0.62 mmol) in dimethylformamide (0.5 mL). After 10 minutes a solution of Example 125A (0.12 g, 0.31 mmol) in dimethylformamide (1.0 mL) was added and the mixture stirred for 3 hours. The reaction mixture was partitioned between EtOAc (15 mL) and saturated NaHCO3 (1 mL). The organic extract was washed with water and brine, dried with MgSO4, filtered and concentrated. The residue was purified by chromatography (hexanes:EtOAc:MeOH:Et3N (4:4:1:0.2) to afford the title compound (50 mg, 0.10 mmol, 33% yield). 1H NMR (500 MHz, Pyridine-d5) δ ppm 0.76 (t, J=7.5 Hz, 3H), 1.16 (s, 9H), 1.57-1.64 (m, 2H), 1.64-1.69 (m, 1H), 1.95-2.03 (m, 1H), 2.27 (ddd, J=16.9, 9.7, 7.3 Hz, 1H), 2.37-2.45 (m, 1H), 3.71 (s, 3H), 3.88 (t, J=9.3 Hz, 1H), 4.05-4.12 (m, 1H), 4.31 (t, J=7.3 Hz, 2H), 4.38 (dd, J=9.6, 3.5 Hz, 1H), 7.17 (d, J=8.5 Hz, 1H), 7.43 (s, 1H), 7.64 (dd, J=8.5, 2.1 Hz, 1H), 8.53 (d, J=2.1 Hz, 1H), 9.25 (s, 1H); MS (ESI+) m/z 481.2 [M+H]+. Anal. calculated for C24H31F3N4O3: C, 59.99; H, 6.50; N, 11.66. Found: C, 59.81; H, 6.45; N, 11.52.
Reaction SMILES: [CH2:1]([O:7][C:8]([C:10]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:14]([C:25]([OH:27])=[O:26])=[C:13]([CH3:28])[NH:12][C:11]=1[CH3:29])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH3:6].[CH2:30](O)[CH:31]=[CH:32][CH:33]=[CH:34][CH3:35].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClC(Cl)C>[N+:22]([C:18]1[CH:17]=[C:16]([CH:15]2[C:10]([C:8]([O:7][CH2:1][CH:2]=[CH:3][CH:4]=[CH:5][CH3:6])=[O:9])=[C:11]([CH3:29])[NH:12][C:13]([CH3:28])=[C:14]2[C:25]([O:27][CH2:30][CH:31]=[CH:32][CH:33]=[CH:34][CH3:35])=[O:26])[CH:21]=[CH:20][CH:19]=1)([O-:24])=[O:23]
Reactant: CC=CC=CCOC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: CC=CC=CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Product: CC=CC=CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC=CC=CC)C1c1cccc([N+](=O)[O-])c1
Yield: 89.5 %

Procedure:
398 mg (1 mM) of 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2,4-hexadienyl)ester, 108 mg (1.1 mM) of 2,4-hexadien-1-ol, 227 mg (1.1 mM) of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-dimethylaminopyridine were dissolved in 20 ml of dichloroethane, and refluxed for 2 hours. Insoluble matters were filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and 428 mg (89.4%) of bis(2,4-hexadienyl) 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate was obtained (yield 89.4%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[CH2:17][CH2:16][O:15][C:14]4[CH:18]=[C:19]([C:22]([O:24]C)=[O:23])[CH:20]=[N:21][C:13]=4[N:12]3[CH:26]=2)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[Li+].[OH-].Cl>CO.O1CCCC1>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[CH2:17][CH2:16][O:15][C:14]4[CH:18]=[C:19]([C:22]([OH:24])=[O:23])[CH:20]=[N:21][C:13]=4[N:12]3[CH:26]=2)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cnc2c(c1)OCCc1nc(-c3ccnn3C(C)C)cn1-2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)n1nccc1-c1cn2c(n1)CCOc1cc(C(=O)O)cnc1-2
Reaction time: 6 h

Procedure:
A mixture of 21 mg (0.06 mmol) of methyl 9-(1-isopropyl-1H-pyrazol-5-yl)-6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepine-3-carboxylate and 1.0 ml of 1 N aq LiOH in 4 ml of methanol and 4 ml of tetrahydrofuran was stirred for 6 hours. The mixture was acidified to pH 3 by addition of 1 N HCl and concentrated in vacuum. The residue was partitioned between ethyl acetate and water, the organic layer was washed with brine, dried over Na2SO4 and concentrated. Yield 17 mg. MS (ESI+): 340.1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1OC[C@H]1CO1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:28])=[CH:22]2.C(N)(C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:28])=[CH:22]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC[C@H]1CO1
Solvent: CC(C)N
Solvent: C1CCOC1
Product: COc1ccc2ncnc(Oc3ccc4[nH]c(C)cc4c3)c2c1
Temperature: 75 °C
Reaction time: 18 h
Yield: 120.6 %

Procedure:
A mixture of (2R)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (250 mg, 0.66 mmol), (prepared as described for the starting material in Example 269), and isopropylamine (1.5 ml) in THF (10 ml) was stirred at 75° C. for 18 hours under an atmosphere of nitrogen and then allowed to cool to ambient temperature. The mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by silica gel chromatography using gradient elution with dichloromethane/methanolic ammonia (7M) (100/0 to 90/10) to give (2R)-7-(2-hydroxy-3-isopropylamino)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (243 mg, 84%).
Reaction SMILES: [CH3:1][CH:2]([N:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1)[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.[CH3:41][N:42]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[N:43]1>C(Cl)Cl>[CH3:1][CH:2]([N:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([S:47]([C:44]2[CH:45]=[CH:46][N:42]([CH3:41])[N:43]=2)(=[O:49])=[O:48])[CH2:6][CH2:5]1
Reactant: Cn1ccc(S(=O)(=O)Cl)n1
Reactant: CC(CN1CCNCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(CN1CCN(S(=O)(=O)c2ccn(C)n2)CC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-[1-(1-methyl-2-piperazin-1-ylethyl)-1H-pyrazol-4-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (0.21 g, 0.48 mmol) and DIPEA (0.26 mL, 0.0015 mol) in DCM (5 mL) was added 1-methyl-1H-pyrazole-3-sulfonyl chloride (0.14 g, 0.78 mmol) in portions at 0° C. The reaction mixture was stirred at RT overnight, quenched with water, and extracted with DCM. The organic layers were dried over MgSO4, concentrated and purified on silica gel (eluting with 0-5% MeOH in DCM) to give the desired product. LCMS calculated for C26H40N9O3SSi(M+H)+: m/z=586.3; Found: 586.4.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15](F)[CH:14]=3)[CH:11]=2)[NH:6][C:5](=[O:20])[CH:4]=1.[CH3:23]C1C=CC=CC=1B(O)O>>[F:1][C:2]([F:22])([F:21])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:23])[CH:11]=2)[NH:6][C:5](=[O:20])[CH:4]=1
Reactant: O=c1cc(C(F)(F)F)c2cc(-c3cccc(F)c3)ccc2[nH]1
Reactant: Cc1ccccc1B(O)O
Product: Cc1ccccc1-c1ccc2[nH]c(=O)cc(C(F)(F)F)c2c1

Procedure:
This compound was made according to General Procedure XXIV in Example 406 from Compound 308 (Structure 16c of Scheme XXX, where R=H, R1=trilfuoromethyl) and commercially available 2-methylbenzeneboronic acid. Compound 742 was isolated as a white solid: 1H NMR (400 MHz, DMSO-d6) 12.42 (s, 1H), 7.68 (dd, J=9.6, 1.4, 1H), 7.53 (m, 2H), 7.33-7.23 (m, 4H), 7.04 (s, 1H), 2.51 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F:11][C:12]([Si](C)(C)C)([F:14])[F:13].Cl>C1COCC1.C(Cl)(Cl)Cl.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[C:12]([F:14])([F:13])[F:11]
Reactant: O=Cc1ccc(F)cc1Br
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: OC(c1ccc(F)cc1Br)C(F)(F)F
Temperature: 0 °C
Yield: 90 %

Procedure:
Charge 2-bromo-4-fluoro-benzaldehyde (6.1 g, 30.1 mmol) and trifluoromethyl trimethylsilane (5.4 g, 36.1 mmol) in THF (50 mL) in a 100-mL round bottom flask. Cool the solution to 0° C. under N2. Add Bu4NF (0.3 g, 1.20 mmol). Stir the mixture at 0° C. for another hour. Add hydrogen chloride (40 mL, 1 M, 40 mmol) to the mixture. Stir the mixture at RT overnight. Dilute the reaction mixture with chloroform. Wash the organic layer with water/aqueous saturated sodium chloride, dry over sodium sulfate, and concentrate in vacuo to give the crude product. Purify by FCC (hexanes/ethyl acetate, 4/1) to give the title compound as a yellow oil (7.40 g, 90%). MS (ES) m/z 273/275 [M+1]+.
Reaction SMILES: Cl[C:2](Cl)=[CH:3][C:4]([C:6]1[C:7]([Cl:14])=[N:8][C:9]([Cl:13])=[C:10]([F:12])[CH:11]=1)=[O:5].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCOCC1>[NH:16]([C:2]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:3][C:4]([C:6]1[C:7]([Cl:14])=[N:8][C:9]([Cl:13])=[C:10]([F:12])[CH:11]=1)=[O:5])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(C=C(Cl)Cl)c1cc(F)c(Cl)nc1Cl
Reactant: Nc1ccccc1
Solvent: C1COCCO1
Product: O=C(C=C(Nc1ccccc1)Nc1ccccc1)c1cc(F)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a 0° C. solution of 3,3-dichloro-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-1-one (6.70 g, 23.2 mmol) in dioxane (50 mL) was added TEA (9.7 mL, 69.6) followed by aniline (6.3 mL, 69.6 mmol). After 1 h the reaction was allowed to warm to room temperature and was stirred overnight. The mixture was concentrated in vacuo until most of the solvent was removed and then the residue was diluted with water and extracted with CH2Cl2 (2×). The combined organic extracts were washed with water, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by silica gel Biotage chromatography provided 3,3-dianilino-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-1-one as yellow solid (4.2 g, 49%): LCMS RT: 3.47 min; MH+: 402.6.
Reaction SMILES: [C:1]([O:4][CH:5]([C:9](=O)[CH:10]([CH3:12])[CH3:11])[C:6](=O)[CH3:7])(=[O:3])[CH3:2].C(O)(=O)C.[NH2:18][C:19]([NH2:21])=[NH:20]>CN(C)C=O>[C:1]([O:4][C:5]1[C:9]([CH:10]([CH3:12])[CH3:11])=[N:18][C:19]([NH2:21])=[N:20][C:6]=1[CH3:7])(=[O:3])[CH3:2]
Reactant: N=C(N)N
Reactant: CC(=O)OC(C(C)=O)C(=O)C(C)C
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(=O)Oc1c(C)nc(N)nc1C(C)C
Temperature: 100 °C
Yield: 30.1 %

Procedure:
A mixture of 3-acetoxy-5-methyl-2,4-hexanedione (5 g, 27 mmol) and guanidine acetate (6.4 g, 54 mmol) in 100 ml dimethylformamide (DMF) was heated at 100° C. for 3 hours. After cooling, the concentrated reaction was filtered through a pad of silica gel using an eluent consisting of equal volume parts of hexane and ethylacetate. The filtrate was concentrated and the residue was treated with excess acetic anhydride in the presence of triethylamine. The reaction mixture was concentrated and the residue was crystallized from boiling hexane to yield 1.7 g (31%) 5-acetoxy-2-amino4-isopropyl-6-methylpyrimidine, m.p. 141°-142° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([Cl:14])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1cnc(Cl)cn1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)c1cnc(Cl)cn1
Yield: 104 %

Procedure:
5-Chloropyrazine-2-carboxylic acid (3.15 mmol, 500 mg) was dissolved in DCM (55 ml). Oxalyl dichloride (6.62 mmol, 841 mg) was added slowly and the resulting mixture was refluxed for 2 h. After, the reaction had stopped the mixture was concentrated. 580 mg of the title compound was obtained. 1H-NMR (400 MHz, CDCl3) δ 8.78 (d, 1H), 9.09 (d, 1H).