Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:32])[CH2:30][CH3:31])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1>>[N:7]1([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:32])[CH2:30][CH3:31])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: CCC(=O)Nc1ccc(C2CCNCC2)cc1
Reactant: ClCCCCCn1ccc2ccccc21
Product: CCC(=O)Nc1ccc(C2CCN(CCCCCn3ccc4ccccc43)CC2)cc1

Procedure:
Prepared by Procedure AH and Scheme P using 1-(5-chloropentyl)-1H-indole and N-[4-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 418.2 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:11])([CH3:10])[CH2:8][OH:9].[C:12]([O-])(=[O:34])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C[O-].C[N+](C)(C)CC1C=CC=CC=1>[C:12]([CH:8]([OH:9])[C:7]([OH:11])([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH3:10])(=[O:34])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]
Reactant: CC(O)(CO)C1CCCCO1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: C[O-]
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)C(O)C(C)(O)C1CCCCO1
Temperature: 70 °C
Yield: 44.1 %

Procedure:
2-tetrahydropyranyl propylene glycol (16.0 grams, 0.1 mole) is inter esterified with 39 grams behenate using 4 ml. of 40% trimethyl benzyl ammonium methoxide as a catalyst. The reactants are stirred in a 250 ml. flask heated at 60-80° C. under a reduced pressure of 200 mm. Hg for 6 hours. The reactants are poured into 600 ml. of hexane and the hexane solution washed with 400 ml. of 1% potassium bicarbonate solution. The washed hexane layer is diluted with 200 ml. ethanol and 75 grams urea are added to the sample. Adduct formation with urea is accomplished by stirring the sample initially at 40° C. and allowing the mixture to cool at 25° C. during a two-hour interval. The urea adduct is removed by filtration and discarded. The adduction with urea is repeated using 60 grams urea. The filtrate from the second urea adduction is water-washed three times and the hexane layer is evaporated to dryness. The residue is dissolved in 300 ml. hexane and the solution is crystallized at -18° C. Filtration at -18° C. yields 21.3 grams of 1-behenoyl-2-tetrahydropyranyl propylene glycol. 1-behenoyl-2-tetrahydropyranyl propylene glycol (8 grams, 0.0165 mole) is cleaved by reaction with 11 ml. of 1.6 molar boric acid in trimethyl borate. The reactants are heated in a boiling water bath with application of vacuum. Heating is continued for 15 minutes with a vacuum of 2-5 mm. Hg pressure during the final 10 minutes. The residue is cooled to room temperature and dissolved in 200 ml. ethyl ether and water-washed three times. The ether phase is dried with sodium sulfate, and evaporated to dryness on an evaporator without warming above 30° C. The residue is dissolved in 100 ml. petroleum ether and crystallized at 70° F. The crystals recovered at 70° F. are recrystallized from 200 ml. petroleum ether at 50° F. to yield ca. 5 grams of 1-propylene glycol monobehenate.
Reaction SMILES: C(N(CC)CC)C.[CH:8]([C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[C:17]2[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=2[O:31][CH3:32])=[CH:12][CH:11]=1)=[O:9].[C:33]1(=[O:39])[O:38][C:36](=[O:37])[CH2:35][CH2:34]1.Cl>[Cl-].[Zn+2].[Cl-].C(OCC)(=O)C.C(Cl)Cl>[C:36]([CH:35]1[CH2:34][C:33](=[O:39])[O:9][CH:8]1[C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[C:17]2[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=2[O:31][CH3:32])=[CH:12][CH:11]=1)([OH:38])=[O:37]
Reactant: COC(=O)c1ccc(Cc2cccc3ccc(C=O)cc23)c(OC)c1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cc2cccc3ccc(C4OC(=O)CC4C(=O)O)cc23)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triethylamine (4.54 g) was added to a mixture of methyl 4-[7-formylnaphth-1-ylmethyl]-3-methoxybenzoate (5.00 g), succinic anhydride (2.99 g), zinc chloride (6.11 g) and methylene chloride (50 ml). During the addition, the reaction was cooled with an ambient temperature bath. The mixture was stirred for 18 h and poured into a vigorously stirred solution of 1:1 ethyl acetate:2N hydrochloric acid (500 ml). The organic layer was washed (water, brine) and dried (MgSO4). After the evaporation of solvent and dissolving the residue in saturated sodium bicarbonate, the solution was washed with ether. The aqueous solution was neutralized with 6N hydrochloric acid, acidified to pH 2 with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed (water, brine), dried (MgSO4) and evaporated to give methyl 4-[7-(3-carboxy-2,3,4,5-tetrahydro-5-oxofuran-2-yl)naphth-1-ylmethyl]-3-methoxybenzoate (6.16 g, 95%, as a mixture of diastereomers) as a pale yellow foam; MS(CI), m/e=434(M+H).
Reaction SMILES: O1CCCC1.[H-].[Na+].[C:8]1(=[O:27])[N:12]([C:13]2[C:14]3[CH:21]=[CH:20][NH:19][C:15]=3[N:16]=[CH:17][N:18]=2)[C:11](=[O:22])[C:10]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:9]12.OP([O-])(O)=O.[K+].[C:34]1([CH3:61])[CH:39]=[CH:38][C:37]([C:40]([O:42][C@@H:43]2[C@@H:47]([CH2:48][O:49][C:50]([C:52]3[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=3)=[O:51])[O:46][C@@H:45]3[O:59][C@:44]23[CH3:60])=[O:41])=[CH:36][CH:35]=1>C(OCC)(=O)C.CN(C)C(=O)C>[C:11]1(=[O:22])[N:12]([C:13]2[C:14]3[CH:21]=[CH:20][N:19]([C@@H:45]4[O:46][C@H:47]([CH2:48][O:49][C:50]([C:52]5[CH:53]=[CH:54][C:55]([CH3:58])=[CH:56][CH:57]=5)=[O:51])[C@@H:43]([O:42][C:40]([C:37]5[CH:38]=[CH:39][C:34]([CH3:61])=[CH:35][CH:36]=5)=[O:41])[C@@:44]4([CH3:60])[OH:59])[C:15]=3[N:16]=[CH:17][N:18]=2)[C:8](=[O:27])[C:9]2=[CH:26][CH:25]=[CH:24][CH:23]=[C:10]12
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@@H]3O[C@]3(C)[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1c1ncnc2[nH]ccc12
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(=O)OC[C@H]2O[C@@H](n3ccc4c(N5C(=O)c6ccccc6C5=O)ncnc43)[C@](C)(O)[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C

Procedure:
Tetrahydrofuran (5.4 L), sodium hydride (146 g of 60% dispersion in oil, unwashed), and N,N-dimethylacetamide (4 L) were charged to a 72 L flask and the suspension was cooled to 0° C. 4-Phthalimido-7H-pyrrolo[2,3-d]pyrimidine (3-2) (2.08 kg) was added to the reaction while maintaining the temperature below 25° C. N,N-Dimethylacetamide (1.4 L) was added followed by the solution of the epoxide (2.75 assay kg) in toluene from Step A, and the reaction mixture was heated at 50-90° C. for 9 h. After cooling to ambient temperature, ethyl acetate (19 L) and aqueous KH2PO4 (0.97 kg in 19 L of water) were added. The organic phase was washed with water. The resulting organic solution was solvent-switched to toluene by vacuum distillation (T<40° C.) to give a final volume of 10 L.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[NH:6][C:7](=[O:22])[CH2:8][CH:9]3[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1.Cl>ClCCl>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[NH:6][C:7](=[O:22])[CH2:8][CH:9]3[CH2:14][NH:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN2c3cc(Cl)ccc3NC(=O)CC2C1
Agent: Cl
Solvent: ClCCl
Product: O=C1CC2CNCCN2c2cc(Cl)ccc2N1

Procedure:
To a solution of Example 3C (122 mg, 0.347 mmol) in dichloromethane (5 mL) was added HCl (4 M in dioxane, 0.867 mL, 3.47 mmol). After the reaction was complete by LC/MS analysis, the volatiles were removed in vacuo, and the residue was purified by preparative HPLC to afford the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 7.12-7.20 (m, 2H), 7.01 (d, J=8.24 Hz, 1H), 3.61-3.69 (m, J=8.09 Hz, 1H), 3.27-3.42 (m, 4H), 2.94-3.08 (m, 2H), 2.68 (dd, J=13.73, 7.02 Hz, 1H), 2.08 (d, J=12.51 Hz, 1H); MS (ESI) m/z 251.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:8]=2[C:9]([OH:11])=O)=[C:5]([CH3:17])[O:4][N:3]=1.[CH3:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][NH:21][C@@H:20]1[CH2:25][NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:8]=2[C:9]([N:21]2[CH2:22][CH2:23][CH2:24][C@@H:19]([CH3:18])[C@H:20]2[CH2:25][NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][N:28]=2)=[O:11])=[C:5]([CH3:17])[O:4][N:3]=1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1ccc(C(F)(F)F)cn1
Reactant: Cc1ccc(-c2c(C)noc2C)c(C(=O)O)c1
Product: Cc1ccc(-c2c(C)noc2C)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using 2-(3,5-dimethylisoxazol-4-yl)-5-methylbenzoic acid and N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 487 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:28])[C:7]2[C:12]([CH:13]=1)=[C:11]([Cl:14])[C:10]([O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[C:18]([CH:24]([CH3:26])[CH3:25])[CH:17]=1)=[C:9]([Cl:27])[CH:8]=2)=[O:4].B(Br)(Br)Br>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:28])[C:7]2[C:12]([CH:13]=1)=[C:11]([Cl:14])[C:10]([O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH:24]([CH3:25])[CH3:26])[CH:17]=1)=[C:9]([Cl:27])[CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2c(Cl)c(Oc3ccc(OC)c(C(C)C)c3)c(Cl)cc2n1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1cc2c(Cl)c(Oc3ccc(O)c(C(C)C)c3)c(Cl)cc2n1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.3 %

Procedure:
To a solution of 4,6-dichloro-5-(3-isopropyl-4-methoxy-phenoxy)-1-methyl-1H-indole-2-carboxylic acid methyl ester (46 mg, 0.11 mmol) in dry methylene chloride (1 mL) at room temperature was added boron tribromide (1M in methylene chloride, 0.22 mL, 0.22 mmol). After stirring at room temperature for 1.5 hours, the reaction was quenched with methanol (0.5 mL), stirred for 15 minutes, then diluted with water (10 mL), and stirred for another 15 minutes. The solution was extracted with methylene chloride (3 times 5 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated. The residue was purified by preparative thin layer chromatography (3% methanol in methylene chloride) to afford the title compound (32 mg). 1H NMR (400 MHz, CDCl3) δ7.42 (s, 1H), 7.34 (s, 1H), 6.83 (d, 1H), 6.60 (d, 1H), 6.39-6.36 (dd, 1H), 4.05 (s, 3H), 3.92 (s, 3H), 3.19-3.12 (m, 1H), 1.21 (d, 6H). MS (APCI−) Calc: 407.1, Found: 406.2 (M−1).
Reaction SMILES: Br[C:2]1[C:17]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:16][C:5]2[N:6]([CH3:15])[C:7](=[O:14])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][CH:9]=3.[C:33]([Cu])#[N:34]>CC(N(C)C)=O.C(OCC)(=O)C>[C:33]([C:2]1[C:17]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])[CH2:21][CH:22]([CH3:23])[CH3:24])=[CH:16][C:5]2[N:6]([CH3:15])[C:7](=[O:14])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][CH:9]=3)#[N:34]
Reactant: N#C[Cu]
Reactant: CC(C)C[C@@H](COc1cc2c(cc1Br)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)C[C@@H](COc1cc2c(cc1C#N)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Temperature: 150 °C

Procedure:
In a 25 mL sealed tube, (S)-tert-butyl (1-((9-bromo-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (150 mg, 0.297 mmol) (as prepared in Ex. 3, Part A) was taken up in DMA (4 mL). To this mixture was added CuCN (53.3 mg, 0.595 mmol) and the mixture heated at 150° C. for 24 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (20 mL) and filtered through diatomaceous earth (Celite®). The ethyl acetate solution was washed with brine (10 mL) and water (10 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford the crude product as gummy solid which was carried forward without further purification. LC/MS (ESI) m/e 451.2 [(M+H)+, calcd for C25H31N4O4, 451.5]; LC/MS retention time (method B): tR=2.02 min.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[CH:8][CH:7]=[N:6]3)[N:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:25]=[C:26]([C:39]3[N:44]=[C:43]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[N:42]=[C:41]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[N:40]=3)[CH:27]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:29]=2)O1.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C.C1(C)C=CC=CC=1>[N:3]1[C:4]2[C:13](=[CH:12][CH:11]=[C:10]3[C:5]=2[N:6]=[CH:7][CH:8]=[CH:9]3)[CH:14]=[CH:15][C:2]=1[C:28]1[CH:27]=[C:26]([C:39]2[N:40]=[C:41]([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[N:42]=[C:43]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:44]=2)[CH:25]=[C:24]([C:7]2[CH:8]=[CH:9][C:10]3[C:5](=[C:4]4[C:13](=[CH:12][CH:11]=3)[CH:14]=[CH:15][CH:2]=[N:3]4)[N:6]=2)[CH:29]=1
Reactant: Clc1ccc2ccc3cccnc3c2n1
Reactant: CC1(C)OB(c2cc(B3OC(C)(C)C(C)(C)O3)cc(-c3nc(-c4ccccc4)nc(-c4ccccc4)n3)c2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1ccc(-c2nc(-c3ccccc3)nc(-c3cc(-c4ccc5ccc6cccnc6c5n4)cc(-c4ccc5ccc6cccnc6c5n4)c3)n2)cc1
Temperature: 100 °C
Reaction time: 94 h

Procedure:
In a stream of argon, 4.26 g of 2-chloro-1,10-phenanthroline, 4.67 g 2-[3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4,6-diphenyl-1,3,5-triazine, 1.06 g of lithium chloride and 767 mg of tetrakis(triphenylphosphine) palladium were suspended in a toluene (200 mL)/ethanol (50 mL) mixed solvent. 33.2 mL of a 2.0 M aqueous sodium carbonate solution was added in the suspension, and the mixture was stirred at 100° C. for 94 hours. Then the reaction mixture was left to be cooled to room temperature and distilled under a reduced pressure to remove low-boiling point ingredients. The obtained residue was purified by alumina column chromatography using a hexane/chloroform (1:2 to 0:1) mixed solvent as a developing solvent, and then recrystallized from a dichloromethane/methanol mixed solvent to give 4.76 g of target 2-[3,5-bis(1,10-phenanthrolin-2-yl)phenyl]-4,6-diphenyl-1,3,5-triazine as a white powder (yield, 86%).
Reaction SMILES: [C:1](=[CH:3][C@@:4]12[C@@H:20]([C:21](=[O:23])[CH3:22])[CH2:19][CH2:18][C@H:17]1[C@H:16]1[C@@H:7]([C@:8]3([CH3:25])[C:13]([CH2:14][CH2:15]1)=[CH:12][C:11](=O)[CH2:10][CH2:9]3)[CH2:6][CH2:5]2)=[CH2:2].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>CO>[N:26]1([C:11]2[CH2:10][CH2:9][C@@:8]3([CH3:25])[C:13](=[CH:14][CH2:15][C@@H:16]4[C@@H:7]3[CH2:6][CH2:5][C@@:4]3([CH:3]=[C:1]=[CH2:2])[C@H:17]4[CH2:18][CH2:19][C@@H:20]3[C:21](=[O:23])[CH3:22])[CH:12]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C1CCNC1
Reactant: C=C=C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(C)=O
Solvent: CO
Product: C=C=C[C@]12CC[C@H]3[C@@H](CC=C4C=C(N5CCCC5)CC[C@@]43C)[C@@H]1CC[C@@H]2C(C)=O

Procedure:
A solution is prepared from 3.3 g of 18-vinylidenepregn-4-ene-3,20-dione in the minimum amount of hot methanol and 700 mg of pyrrolidine is added to the hot solution. When the product begins to crystallize, the mixture is chilled rapidly in ice water. The mixture is diluted with methanol and the solid is separated by filtration and dried under high vacuum to give 3-(1-pyrrolidinyl)-18-vinylidenepregna-3,5-dien-20-one which is used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:13]([F:12])[CH:14]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: Clc1ccc2[nH]ncc2c1Br
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Fc1cc(-n2ncc3c(Br)c(Cl)ccc32)ccc1OCc1ccccc1
Reaction time: 120 h

Procedure:
A mixture of 4-bromo-5-chloro-1H-indazole (D22) (0.361 g, 1.56 mmol), {3-fluoro-4-[(phenylmethyl)oxy]phenyl}boronic acid (0.57 g, 2.32 mmol), copper (II) acetate (0.42 g, 2.31 mmol) and pyridine (0.25 mL, 3.10 mmol) in dichloromethane (50 mL) were stirred together vigorously under an air atmosphere with powdered 4A molecular sieves (1.5 g). After 5 days, the mixture was filtered through celite and the solvent evaporated. The concentrate was chromatographed (silica, dichloromethane/hexane) to give the title compound (D23) as an off white solid (0.32 g)
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH2:13])=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:24]=2[O:23][CH3:22])=[N:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccccc2)cc1
Product: COc1ccc(-c2nc(NC(=O)c3ccc(OC)cc3OC)sc2Cc2ccccc2)cc1
Yield: 71 %

Procedure:
A procedure similar to that in Example 4 was used. 5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 1 and 2,4-dimethoxy-benzoyl chloride prepared in the step 1 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (100:0-10:1) to obtain a product as a white solid in a yield of 71.0%, mp: 196-197 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.85 (3H, s, OCH3), 3.88 (3H, s, OCH3), 4.08 (3H, s, OCH3), 4.20 (2H, s, CH2), 6.54 (1H, d, J=2.24 Hz, ArH), 6.65 (1H, dd, J=8.96 Hz, 2.24 Hz, ArH), 6.97 (2H, d, J=8.96 Hz, ArH), 7.22˜7.34 (5H, m, ArH), 7.56 (2H, d, J=8.96 Hz, ArH), 8.22 (1H, d, J=8.68 Hz, ArH), 11.01 (1H, br, CONH); EI-MS m/e (%): 460.1 (M+, 58), 165.0 (100); HREI-MS Calcd. for C26H24N2O4S: 460.1457. found: 460.1454. Anal. Calcd. for C26H24N2O4S: C, 67.81; H, 5.25; N, 6.08. found: C, 68.04; H, 5.16; N, 6.19.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC#N.[OH2:24]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=2)[C@@H:12]([OH:24])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(Br)c2)CC1
Reactant: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@H](c2cccc(Br)c2)[C@@H](O)C1

Procedure:
The title compound is prepared analogously as described for the title B compound in Example 1 from the title A compound, 4-(3-bromo-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester: MS 356.2/358.1 [M+H]+; retention time 6.59 min (HPLC, Nucleosil C18; 5→100% CH3CN in H2O within 8 min).
Reaction SMILES: Cl.C(OC(=O)[NH:8][C:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([NH:33][C:34](=[O:36])[CH3:35])[C:22]3[NH:23][CH:24]=[C:25]([CH2:27][C:28]([CH3:32])([CH3:31])[CH2:29][CH3:30])[N:26]=3)=[CH:16][CH:15]=2)=[CH:12][N:11]([CH3:37])[N:10]=1)(C)(C)C>CO>[NH2:8][C:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH:21]([NH:33][C:34](=[O:36])[CH3:35])[C:22]3[NH:23][CH:24]=[C:25]([CH2:27][C:28]([CH3:32])([CH3:31])[CH2:29][CH3:30])[N:26]=3)=[CH:18][CH:19]=2)=[CH:12][N:11]([CH3:37])[N:10]=1
Reactant: CCC(C)(C)Cc1c[nH]c(C(Cc2ccc(-c3cn(C)nc3NC(=O)OC(C)(C)C)cc2)NC(C)=O)n1
Agent: Cl
Solvent: CO
Product: CCC(C)(C)Cc1c[nH]c(C(Cc2ccc(-c3cn(C)nc3N)cc2)NC(C)=O)n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane) (1 mL, 4 mmol) was added to an ambient temperature solution of tert-butyl[4-(4-{2-(acetylamino)-2-[4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]ethyl}phenyl)-1-methyl-1H-pyrazol-3-yl]carbamate (Example 51) (4.2 mg, 0.01 mmol) in methanol (2 mL). After stirring at 70° C. for 1 h, volatiles were removed in vacuo. The residue was partitioned between methanol/ethyl acetate and 10% aqueous sodium hydroxide. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to afford the title compound. (M+H) found: 409.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)=O)(C)(C)C.Cl[C:19]1[C:20]([C:28]#[N:29])=[N:21][CH:22]=[C:23]([C:25]([CH3:27])=[CH2:26])[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CO>[CH2:26]=[C:25]([C:23]1[CH:22]=[N:21][C:20]2[C:19]([CH:24]=1)=[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]1=[N:8][C:28]=2[NH2:29])[CH3:27]
Reactant: C=C(C)c1cnc(C#N)c(Cl)c1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCO
Product: C=C(C)c1cnc2c(N)nc3ccccc3c2c1
Temperature: 25 °C

Procedure:
A solution of 2-(tert-butoxycarbonylamino)phenylboronic acid (1.0 eq.) and 3-chloro-5-(prop-1-en-2-yl)picolinonitrile (from step 1) (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (2.0 eq.) in toluene/ethanol (2:1, 0.03 M) was stirred at 100° C. overnight. After cooling to ambient temperature, the reaction content was diluted with methanol. The insoluble solids were filtered off, and the filtrate was concentrated en vacuo to obtain a crude residue. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 2-(prop-1-en-2-yl)benzo[f][1,7]naphthyridin-5-amine as a white solid. 1H NMR (dmso-d6): δ 9.03 (d, 1H), 8.96 (d, 1H), 8.55 (d, 1H), 7.47-7.53 (m, 2H), 7.25 (m, 1H), 7.07 (bs, 2H) 5.80 (s, 1H), 5.36 (s, 1H), 2.27 (s, 3H). LRMS [M+H]=236.2.
Reaction SMILES: [CH3:1][C:2]1([CH2:14][OH:15])[O:7][C:6]2=[N:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][N:5]2[CH2:4][CH2:3]1.[I:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.[H-].[Na+]>>[I:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:15][CH2:14][C:2]2([CH3:1])[O:7][C:6]3=[N:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][N:5]3[CH2:4][CH2:3]2)=[CH:19][CH:18]=1
Reactant: BrCc1ccc(I)cc1
Reactant: CC1(CO)CCn2cc([N+](=O)[O-])nc2O1
Agent: [H-]
Agent: [Na+]
Product: CC1(COCc2ccc(I)cc2)CCn2cc([N+](=O)[O-])nc2O1
Yield: 54 %

Procedure:
Alkylation of oxazine alcohol 149 (see Example 2OO) with 4-iodobenzyl bromide (1.7 equiv.) and NaH (1.9 equiv.) as in Example 2UU above for 3 h, followed by chromatography of the product on silica gel, eluting with CH2Cl2 (foreruns) and then with 1% EtOAc/CH2Cl2, gave 7-{[(4-iodobenzyl)oxy]methyl}-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (156) (54%) as a cream solid: mp (CH2Cl2/pentane) 130-132° C.; 1H NMR (CDCl3) δ 7.67 (dt, J=8.3, 2.0 Hz, 2H), 7.39 (s, 1H), 6.99 (br d, J=8.3 Hz, 2H), 4.49 (s, 2H), 4.09 (ddd, J=12.5, 7.0, 5.9 Hz, 1H), 4.01 (ddd, J=12.5, 7.1, 5.9 Hz, 1H), 3.62 (d, J=10.2 Hz, 1H), 3.58 (d, J=10.2 Hz, 1H), 2.37 (ddd, J=14.4, 7.0, 6.0 Hz, 1H), 2.10 (ddd, J=14.4, 6.9, 6.0 Hz, 1H), 1.46 (s, 3H). Anal. (C15H16IN3O4) C, H, N.