Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[CH:5]([NH2:16])[CH2:6][CH2:7][CH2:8][C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11].C(=O)([O-])[O-].[K+].[K+].[C:24](Cl)(=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1.O>[CH3:2][O:3][C:4](=[O:17])[CH:5]([NH:16][C:24]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:33])[CH2:6][CH2:7][CH2:8][C:9]([F:14])([F:15])[C:10]([F:11])([F:12])[F:13]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)C(N)CCCC(F)(F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(CCCC(F)(F)C(F)(F)F)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, 16.9 g (59.2 mmol) of rac-methyl-2-amino-6,6,7,7,7-pentafluoroheptanoate hydrochloride (racemate) from Example 139A were initially charged in 775 ml of THF and 99 ml of water, and 25.37 g (183.6 mmol) of potassium carbonate were added carefully at RT. 11.0 ml (65.1 mmol) of benzyl chlorocarbonate were then added dropwise at 0° C., and the suspension was stirred at RT overnight. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered and concentrated. The crude product was purified by silica gel chromatography (mobile phase: cyclohexane/ethyl acetate gradient: 100/0 to 10/1 to 8/1 to 5/1). The product fraction was then re-purified by preparative RP-HPLC (acetonitrile/water gradient with 0.1% TFA). This gave 13.34 g (56% of theory, purity 94%) of the target compound.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:24]=[CH:23][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH3:22])[CH2:16][C@H:17]3[CH2:21][CH2:20][CH2:19][NH:18]3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH:25]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)=O.C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][N:15]([CH2:16][C@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3[CH2:25][C:27]3[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=3)[CH3:22])=[CH:12][CH:13]=2)=[CH:23][CH:24]=1
Reactant: CN(Cc1ccc(Oc2ccc(Br)cc2)cc1)C[C@H]1CCCN1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc(CN2CCC[C@@H]2CN(C)Cc2ccc(Oc3ccc(Br)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A solution of (R)—N—[[4-(4-bromophenoxy)phenyl]methyl]-N-methyl-2-pyrrolidinemethanamine hydrochloride salt (0.87 g, 2 mmol) and methyl 4-formylbenzoate (346 mg, 2.11 mmol) in dichloroethane (20 mL) was stirred as diisopropylethylamine (0.12 mL, 3 mmol) and sodium triacetoxyborohydride (536 mg, 2.53 mmol) were added sequentially. The reaction was stirred at ambient temperature overnight. The reaction was treated with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (2×). The combined organic extracts were dried and concentrated. Purification by flash chromatography on silica gel gave 0.9 g of methyl 4-[[(R)-2-[[[[4-(4-bromophenoxy)phenyl]methyl]methylamino]methyl]-1-pyrrolidinyl]methyl]benzoate.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][CH:7]=1.C([Li])CCC.[S:16](Cl)([Cl:19])(=[O:18])=[O:17].C(OCC)(=O)C>O1CCCC1.CCCCCC>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[S:16]([Cl:19])(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)Cl
Reactant: c1cc(C2OCCO2)cs1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(Cl)c1sccc1C1OCCO1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 23.4 g of 3-(1,3-dioxolan-2-yl)thiophene (S. Gronowitz, et al., Arkiv. Kemi., 20, 407 (1963)) in 100 ml of anhydrous tetrahydrofuran was added 100 ml of 1.6 molar n-butyllithium in hexane, with ice bath cooling. After stirring at room temperature for 20 minutes the mixture was cooled to -78° and sulfuryl chloride (16.2 g) was then added dropwise. This addition caused the suspended solids to form a tarry mass which broke up when the mixture was allowed to warm to room temperasture. After stirring one and one half hours at room temperature the mixture was cooled to -10° and 10 ml of ethyl acetate was added dropwise. The reaction mixture was then poured into ice water and extracted with ethyl ether. The ether portions were combined, dried over magnesium sulfate, filtered and the ether removed in vacuo-to yield 19.6 g of an oil. Infrared absorption spectra of this product showed peaks at 1330 and 1180 cm-1, consistent for the desired sulfonyl chloride. Mass spectrum analysis: calc. 254, found 253 (Mass-1H) and the presence of a chlorine atom.
Reaction SMILES: C[O:2][C@@H:3]([C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:27]=[C:15]3[C:16]4[C:21]([CH2:22][CH2:23][N:14]3[C:13](=[O:28])[CH2:12][N:11]=2)=[C:20]([C:24]([CH3:26])=[CH2:25])[CH:19]=[CH:18][CH:17]=4)[CH:9]=1)[CH3:4].[CH:29]1([Mg]Br)C[CH2:30]1.[NH4+].[Cl-]>C1COCC1>[CH:24]1([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:21]=2[CH2:22][CH2:23][N:14]2[C:13](=[O:28])[CH2:12][N:11]=[C:10]([N:8]4[CH:9]=[C:5]([CH:3]([CH:4]5[CH2:30][CH2:29]5)[OH:2])[N:6]=[CH:7]4)[CH:27]=[C:15]23)[CH2:26][CH2:25]1
Reactant: Br[Mg]C1CC1
Reactant: C=C(C)c1cccc2c1CCN1C(=O)CN=C(n3cnc([C@@H](C)OC)c3)C=C21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C1CN=C(n2cnc(C(O)C3CC3)c2)C=C2c3cccc(C4CC4)c3CCN12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1-(9-cyclopropyl-5-oxo-4,5,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinolin-2-yl)-1H-imidazole-4-carbaldehyde (230 mg, 0.66 mmol, it can be obtained by analogy to example 118) in THF (35 mL) was cooled to 0° C. and then treated with a solution of cPrMgBr in THF (1.39 mL, 0.70 mmol) dropwise. The mixture was stirred at 0° C. for 1 h, and an aq. solution of saturated NH4Cl was then added. The mixture was extracted with AcOEt, and the combined org. layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, AcOEt:MeOH 100:0 to 90:10) and crystallization in AcOEt gave the tile compound (66 mg). UPLC-MS: MS 389.2 (M+H+); UPLC rt 0.92 min. 1H NMR (600 MHz, DMSO-d6): δ ppm 0.21-0.46 (m, 4H); 0.58-0.70 (m, 2H); 0.91-1.00 (m, 2H); 1.08-1.25 (m, 1H); 1.91-2.04 (m, 1H); 3.01-3.17 (m, 2H); 3.88 (br s, 2H); 3.93-4.03 (m, 1H); 4.24 (br s, 2H); 4.96 (d, J=5.27 Hz, 1H); 7.12-7.25 (m, 2H); 7.25-7.35 (m, 1H); 7.49 (s, 1H); 7.91 (d, J=8.03 Hz, 1H); 8.17 (s, 1H).
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[NH2:11][C:12]1[N:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]2)=[CH:14][CH:13]=1>>[Br:8][C:6]1[CH:7]=[C:2]([NH:11][C:12]2[N:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:14][CH:13]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: C[C@H]1CN(c2ccc(N)nc2)CCN1C(=O)OC(C)(C)C
Reactant: Cn1cc(Br)cc(Br)c1=O
Product: C[C@H]1CN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CCN1C(=O)OC(C)(C)C
Yield: 81.5 %

Procedure:
Following the procedures as described for compound 108c, reaction of 3,5-dibromo-1-methylpyridin-2(1H)-one (83 mg) and 107b (90 mg), gave 107c as a yellow solid (120 mg, 81%). MS: [M+H]+ 480
Reaction SMILES: [C:1]1([CH:7]2[O:12][C:11]3[CH:13]=[CH:14][C:15]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N+]([O-])=O)=[CH:20][N:19]=4)=[CH:16][C:10]=3[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2OC3C=CC(O)=CC=3OC2)C=CC=CC=1.ClC1C=CC([C:51]([F:54])([F:53])[F:52])=CN=1>>[C:1]1([CH:7]2[O:12][C:11]3[CH:13]=[CH:14][C:15]([O:17][C:18]4[CH:23]=[CH:22][C:21]([C:51]([F:54])([F:53])[F:52])=[CH:20][N:19]=4)=[CH:16][C:10]=3[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)OCC(c2ccccc2)O3)nc1
Agent: Oc1ccc2c(c1)OCC(c1ccccc1)O2
Product: FC(F)(F)c1ccc(Oc2ccc3c(c2)OCC(c2ccccc2)O3)nc1

Procedure:
2-(2,3-Dihydro-2-phenyl-benzo[1,4]dioxin-6-yloxy)5-trifluoromethylpyridine was prepared in the same way as 2-(2,3-dihydro-2-phenyl-benzo[1,4]dioxin-6-yloxy)-5-nitropyridine above from 2,3-dihydro-2-phenyl-benzo[1,4]dioxin-6-ol (80 mg) and 2-chloro-5-(trifluoromethyl)pyridine (64 mg). Yield is 50 mg and mp 104-110° C. 1H NMR (DMSO-d6) δ=4.15 (dd, J=8.3, 11.4Hz, 1H), 4.46 (dd, J=2.3, 11.4 Hz, 1H), 5.27 (dd, J=2.3, 8.3 Hz, 1H), 6.72 (dd, J=2.8, 8.8 Hz, 1H), 6.84 (d, J=2.8 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 7.39-7.52 (m, 5H), 8.20 (dd, J=8.8, 2.6 Hz, 1H), 8.58 (d, J=2.6 Hz, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[NH:51][C:52]2[CH:58]=[CH:57][CH:56]=[CH:55][C:53]=2[N:54]=1.N1C=CC=CC=1>C(Cl)Cl.O>[NH:51]1[C:52]2[CH:58]=[CH:57][CH:56]=[CH:55][C:53]=2[N:54]=[C:50]1[NH:49][C:40](=[O:42])[C@@H:39]([C:31]1[CH:32]=[CH:33][C:34]([S:35]([CH3:38])(=[O:36])=[O:37])=[C:29]([Cl:28])[CH:30]=1)[CH2:43][CH:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1nc2ccccc2[nH]1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2nc3ccccc3[nH]2)cc1Cl
Temperature: 0 °C
Yield: 55.1 %

Procedure:
A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (183 mg, 1.0103 mmol). The reaction mixture was stirred at 0° C. until it became homogeneous. The resulting light purple reaction mixture was then treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 19, 200 mg, 0.61 mmol). The reaction mixture was stirred at 0° C. for 20 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminobenzimidazole (121 mg, 0.91 mmol) and pyridine (0.15 mL, 1.82 mmol), and the resulting reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then diluted with water (15 mL) and extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 60/40 hexanes/ethyl acetate) afforded the N-(1H-benzoimidazol-2-yl)-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (150 mg, 56%) as a light brown solid: mp>215° C.; [α]23589=−21.9° (c=0.041, chloroform); EL-HRMS m/e calcd for C22H24ClN3O3S (M+) 445.1227, found 445.1235.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[Se:19][C:18]=1[C:26]([NH2:28])=[O:27].[OH-].[Na+].[K+].[Br-]>CN(C=O)C.O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[NH:16][C:17]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:23])[CH3:24])[Se:19][C:18]=1[C:26]([NH2:28])=[O:27]
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(Nc3cc(C(C)(C)C)[se]c3C(N)=O)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-chloro-6,7-dimethoxyquinazoline (500 mg, 2.23 mmol) in DMF (20 mL) was added sequentially 3-amino-5-tert-butylselenophene-2-carboxamide (820 mg, 3.34 mmol), powdered NaOH (270 mg, 6.69 mmol) and catalytic amount of KI at rt and the mixture was stirred at rt for 16 h. The mixture was poured into ice cooled water and stirred for 10 min. The solid separated was filtered, washed with water and dried (730 mg, 76%). The crude product was further chromatographed and recrystallized from chloroform-methanol to give the product as a pale yellow color solid, mp 248-252° C. IR (KBr) vmax 3470, 3134, 2960, 1626, 1577, 1469, 1385, 1238, 1211, 1133, 1010, 856, 750 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 12.65 (1H, s, exchangeable with D2O), 8.74 (1H, s), 8.62 (1H, s), 7.64 (2H, br s, exchangeable with D2O), 7.36 (1H, s), 7.25 (1H, s), 3.96 (3H, s), 3.95 (3H, s), 1.42 (9H, s); 13C NMR (100 MHz, DMSO-d6): δ 168.3, 167.5, 154.5, 153.8, 152.9, 149.4, 146.9, 146.1, 120.7, 111.8, 108.7, 107.5, 99.8, 55.9, 55.5, 36.5, 32.2; LC-MS (positive ion mode): m/z 433, 435 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:31]([O:30][CH2:29][CH2:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:26][CH:25]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(C=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
A mixture of methyl 7-bromo-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.25 g), 4-(2-butoxyethoxy)phenyl borate (0.23 g), 1M potassium carbonate solution (2.5 ml), ethanol (2.5 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.04 g), and the mixture was refluxed overnight under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-2.3-dihydro-1H-1-benzazepine-4-carboxylate (0.23 g) as colorless oil.
Reaction SMILES: CN1CCOCC1.Cl[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10].Cl.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH:25]([NH:27][C:28](=[O:34])[C@H:29]([CH:31]([CH3:33])[CH3:32])[NH2:30])[CH3:26])=[N:21][CH:22]=1.O>C(Cl)Cl>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH:25]([NH:27][C:28](=[O:34])[C@H:29]([CH:31]([CH3:33])[CH3:32])[NH:30][C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH3:26])=[N:21][CH:22]=1
Reactant: CC(COc1ccc(Cl)cn1)NC(=O)[C@@H](N)C(C)C
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: CC(COc1ccc(Cl)cn1)NC(=O)[C@@H](NC(=O)OC(C)C)C(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 39.5 %

Procedure:
0.8 g of N-methylmorpholine, and subsequently 0.5 g of isopropyl chloroformate were added to a suspension containing 1.4 g of N1 -[2-(5-chloro-2-pyridyloxy)-1-methylethyl]-L-valinamide hydrochloride suspended in 50 ml of methylene chloride at -15° C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.6 g of the desired product in the form of colorless grains (yield: 38%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[N:18][C:19]=1[CH:20]([O:23][CH3:24])[O:21][CH3:22])[N:16]([C:25](OC1C=CC=CC=1)=[O:26])[CH2:15][CH2:14][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:34][C:35]1[CH:42]=[C:41]([O:43][CH:44]([CH3:46])[CH3:45])[C:38]([C:39]#[N:40])=[CH:37][N:36]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[N:18][C:19]=1[CH:20]([O:21][CH3:22])[O:23][CH3:24])[N:16]([C:25]([NH:34][C:35]1[CH:42]=[C:41]([O:43][CH:44]([CH3:46])[CH3:45])[C:38]([C:39]#[N:40])=[CH:37][N:36]=1)=[O:26])[CH2:15][CH2:14][CH2:13]2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Oc1ccccc1
Reactant: CC(C)Oc1cc(N)ncc1C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Nc1cc(OC(C)C)c(C#N)cn1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of phenyl 6-(((tert-butyldimethylsilyl)oxy)methyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (intermediate 38, 1 g, 2.116 mmol) and 6-amino-4-isopropoxynicotinonitrile (intermediate 97, 380 mg, 2.144 mmol) in THF (8 ml) at −78° C. was added LHMDS 1M in THF (4.3 ml, 4.30 mmol) and the reaction mixture was stirred at −78° C. for 2 h and 10 min. The reaction mixture was quenched by the addition of saturated aqueous NaH4CI and partitioned between ethyl acetate/hepatane (1:1) and water. The organic layer was washed with water, the water layer was back extracted with ethyl acetate/hepatane (1:1) and the combined organic layers were dried using Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with a gradient of ethyl acetate (0-20%) in heptane to yield the title compound as a white solid. (UPLC-MS 3) tR 1.69 min; ESI-MS 556.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 14.00 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.75 (s, 1H), 5.44 (d, 1H), 4.89-4.79 (m, 3H), 4.08-4.00 (m, 2H), 3.45 (s, 6H), 2.87 (t, 2H), 2.06-1.95 (m, 2H), 1.44 (d, 6H), 0.95 (s, 9H), 0.12 (d, 6H).
Reaction SMILES: S(O)(=O)(=O)C.[NH2:6][C:7]1[C:8]2[N:9]([C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=2)[CH:10]=[C:11]([C:13]([NH2:15])=[O:14])[CH:12]=1.[CH2:21]([O:28][CH2:29][CH2:30][C:31]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:32]=1[CH:33]=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([BH3-])#N.[Na+].C(N(CC)CC)C>CO.[Cl-].[Zn+2].[Cl-]>[CH2:21]([O:28][CH2:29][CH2:30][C:31]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:32]=1[CH2:33][NH:6][C:7]1[C:8]2[N:9]([C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=2)[CH:10]=[C:11]([C:13]([NH2:15])=[O:14])[CH:12]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1cccc(CCOCc2ccccc2)c1C=O
Reactant: Cc1nc2c(N)cc(C(N)=O)cn2c1C
Agent: CS(=O)(=O)O
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cccc(CCOCc2ccccc2)c1CNc1cc(C(N)=O)cn2c(C)c(C)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.7 %

Procedure:
To a solution of 8-Amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide mesylate 1.4 g (0.0038 mol) in methanol (20 ml) in a nitrogen atmosphere was added zinc chloride (1.0 g, 0.0039 mol) solved in methanol(10 ml) and the mixture was stirred for 30 min. To the mixture were added 2-[2-(benzyloxy)ethyl]-6-methylbenzaldehyde (1.0 g, 0.0039 mol) and sodium cyano borohydride (0.48 g, 0.0076 mol) and the mixture was refluxed overnight. The reation mixture was cooled to room temperature, triethylamine (4 ml) was added, the mixture was stirred for 30 min, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride:methanol (9:1) as eluent. The residue was solved in diethyl ether, treated with diethyl ether/HCl and the precipitated product as HCl salt was filtered off . The salt was soloved in methylene chloride and washed with saturated sodium carbonate. The organic layer was separated, washed with water, dried and evaporated under reduced pressure to give 0.13 g (7.7 g) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:10]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([OH:23])=O)[CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11].[Cl:24]CCl>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:10]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([Cl:24])=[O:23])[CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11]
Reactant: ClCCl
Reactant: COc1ccccc1NS(=O)(=O)c1cccc(C=CC(=O)O)c1
Solvent: CN(C)C=O
Product: COc1ccccc1NS(=O)(=O)c1cccc(C=CC(=O)Cl)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
To a suspension of 3-[3-(2-methoxy-phenylsulfamoyl)-phenyl]-acrylic acid (15c) (0.36 g, 1.04 mmol) in dichloromethane (4 ml) oxalyl chloride (0.27 ml, 3.12 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.37 g, 97%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[NH:13][C:12]4[N:20]=[CH:21][CH:22]=[CH:23][C:11]=4[N:10]3[C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([C:31]3([NH:35]C(=O)OC(C)(C)C)[CH2:34][CH2:33][CH2:32]3)=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:43]>ClCCl.O1CCOCC1.CCOCC>[ClH:43].[C:1]1([C:7]2[N:8]=[C:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[NH:13][C:12]4[N:20]=[CH:21][CH:22]=[CH:23][C:11]=4[N:10]3[C:24]=2[C:25]2[CH:26]=[CH:27][C:28]([C:31]3([NH2:35])[CH2:34][CH2:33][CH2:32]3)=[CH:29][CH:30]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC1(c2ccc(-c3c(-c4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of tert-butyl (1-(4-(2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutyl)carbamate (0.55 g) in dichloromethane (50 mL) was added 4.0 M HCl in dioxane (5 mL). The reaction was stirred at room temperature for 6 hours and then diluted with ether (50 mL). The product was removed by filtration under reduced pressure and dried to give 1-(4-(2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutanamine hydrochloride as a pale yellow solid (0.52 g, 88% based on tris HCl salt). 1H NMR (DMSO-d6) 400 MHz δ 8.80 (bs, 3H), 8.68 (s, 1H), 8.12 (dd, JA=4.8 Hz, JB=1.6 Hz, 1H), 7.98-7.95 (m, 1H), 7.57-7.48 (m, 4H), 7.43-7.27 (m, 7H), 7.15 (t, J=7.2 Hz, 1H), 6.91-6.88 (m, 1H), 6.79-6.74 (m, 1H), 2.56 (t, J=8 Hz, 4H), 2.24-2.16 (m, 1H), 1.85-1.77 (m, 1H); LCMS: 456 [M+H]. Calc. for C30H25N5.3.07HCl.0.14 dioxane.0.28 diethylether: C, 63.36; H, 5.37; N, 11.66. Found C, 63.36; H, 5.50; N, 11.67.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:22]I>CN(C=O)C.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:22])[N:15]=[CH:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CI
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3[nH]ncc3c2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc2cc(Oc3ccc([N+](=O)[O-])cn3)ccc21
Reaction time: 3.5 h

Procedure:
To a solution of 5-(5-Nitro-pyridin-2-yloxy)-1H-indazole (1.0 g, 3.9 mmol) in 15 mL of DMF is added sodium hydride (3.9 mmol) and methyl iodide (20 mmol). The resulting mixture is stirred at room temperature to 50° C. for 1-6 hours. The mixture is diluted with water, extracted 3× with ethyl acetate, and the combined organic layers are dried over sodium sulfate, filtered and concentrated in vacuo. Purification by column chromatography eluting with ethyl acetate-hexanes, affords 5-(5-Nitro-pyridin-2-yloxy)-1-methyl-1H-indazole.