Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:5]([F:9])=[C:6]([F:8])[CH:7]=1.C(O[B:24]([O:29][CH:30]([CH3:32])[CH3:31])[O:25][CH:26]([CH3:28])[CH3:27])(C)C.C([Li])CCC.OC(C(O)(C)C)(C)C>O1CCCC1.C1(C)C=CC=CC=1>[F:8][C:6]1[CH:7]=[C:2]([B:24]2[O:25][C:26]([CH3:27])([CH3:28])[C:30]([CH3:31])([CH3:32])[O:29]2)[CH:3]=[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:5]=1[F:9]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(COc2cc(Br)cc(F)c2F)cc1
Agent: CC(C)(O)C(C)(C)O
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(COc2cc(B3OC(C)(C)C(C)(C)O3)cc(F)c2F)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-1,2-difluoro-3-(4-methoxy-benzyloxy)-benzene (0.35 g) in tetrahydrofuran (10 ml) under nitrogen was added triisopropylborate (0.29 ml). The mixture was cooled to −78° C. and 2.5M n-butyllithium solution in hexanes was added. The reaction mixture was stirred at −40° C. for 1 hour, then warmed to 20° C. and quenched with 2M hydrochloric acid (aq) (2 ml). The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was adjusted to pH 7 using saturated sodium bicarbonate solution, then partitioned between ethyl acetate and water, dried (MgSO4) and the solvents removed in vacuo to yield a crude residue (0.31 g). A mixture of this crude residue and pinacol (0.25 g) in toluene (10 ml) were stirred under reflux overnight in a Dean-Stark apparatus. The solvents were removed in vacuo, the residue was then partitioned between ethyl acetate and water, the combined organics were washed with water then brine and dried (MgSO4), the solvents were removed in vacuo to yield 2-[3,4-difluoro-5-(4-methoxy-benzyloxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.28 g)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][C:14]([NH:16][CH3:17])=O)[CH:11]=1)[NH:8][CH:7]=[CH:6]2.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CCNC)C=C1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][CH2:14][NH:16][CH3:17])[CH:11]=1)[NH:8][CH:7]=[CH:6]2
Reactant: CNC(=O)CC(c1ccccc1)c1cc(OC)cc2cc[nH]c12
Agent: CNCCC(c1ccccc1)c1cccc2cc[nH]c12
Product: CNCCC(c1ccccc1)c1cc(OC)cc2cc[nH]c12

Procedure:
[3-(5-Methoxy-1H-indol-7-yl)-3-phenyl-propyl]-methyl-amine CLXXXII was prepared from 3-(5-methoxy-1H-indol-7-yl)-N-methyl-3-phenyl-propionamide using the procedure described for preparation of [3-(1H-Indol-7-yl)-3-phenyl-propyl]-methyl-amine XX (Example 4). MS (M+H)=296.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:30])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[C:14]([O:28][CH3:29])[CH:13]=2)[CH2:4][CH2:3]1>[C].[Pd].CO>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9](=[O:30])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[C:14]([O:28][CH3:29])[CH:13]=2)[CH2:6][CH2:7]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCN1CCN(C)CC1
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCN1CCN(C)CC1

Procedure:
Using 1 g of N-(trans-4-methylcyclohexyl)-4-[2-(4-methylpiperazinyl)ethoxy]-3-methoxycinnamamide (Example 145), 0.05 g of 10% palladium-carbon, and 100 ml of methanol, a reaction similar to that conducted in Example 147 was carried out. The product obtained was recrystallized from methylene chloride/ether, yielding 0.64 g of N-(trans-4-methylcyclohexyl)-3-{4-[2-(4-methylpiperazinyl)ethoxy]-3-methoxyphenyl}propionamide (a compound of the present invention) as light-brownish white crystal, which had the following physiochemical properties:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:24][CH2:25][C:26]([CH2:28]Cl)=[CH2:27].C(=O)(O)[O-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:28][C:26]([CH2:25][Cl:24])=[CH2:27])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Reactant: C=C(CCl)CCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(CCl)CC(C(=O)OCC)c1ccc(Br)cc1
Reaction time: 0.5 h

Procedure:
To a solution of ethyl (4-bromophenyl)acetate (143 g, 588 mmol) in THF (800 mL) was added LHMDS (1.13 eq in THF) at −78° C. After 30 minutes, the reaction mixture was added to a solution of 3-chloro-2-chloromethyl-1-propene (147 g, 1180 mmol) in THF (500 mL) at −78° C. via cannula. The reaction was allowed to slowly warm from −78° C. to rt over 15 hours. The reaction mixture was poured into sodium bicarbonate, extracted with EtOAc, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by column chromatography eluting with 1-20% EtOAc/Hexane. The appropriate fractions were combined and the solvent removed in vacuo to give ethyl 2-(4-bromophenyl)-4-(chloromethyl)pent-4-enoate (1-1) as a clear oil. MS (M+H)+: 332.
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([NH:10][NH2:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[C:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:33]=1>C1(C)C=CC=CC=1>[C:7]([C:8]1[N:33]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:26]2=[N:11][N:10]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNC(=O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC1=NCCCCCC1
Solvent: Cc1ccccc1
Product: c1ccc(C(c2ccccc2)(c2ccccc2)c2nnc3n2CCCCCC3)cc1
Temperature: 25 °C
Yield: 19.8 %

Procedure:
2,2,2-Triphenylacetohydrazide (48.2 mg, 0.159 mmol) was dissolved in anhydrous toluene (3 mL) and stirred at room temperature under nitrogen. 8-Methoxy-2,3,4,5,6,7-hexahydroazocine (24.7 mg, 0.175 mmole) was added and the solution was stirred at 120° C. overnight and 200° C. for two days. After cooling, the toluene was removed by evaporation and crude product was purified by silica gel chromatography (100% ethyl acetate→5% methanol in ethyl acetate→10% methanol in ethyl acetate) to give the product (2-1) as a white solid (12.4 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7]2.[C:12]1([CH2:18][CH2:19][CH:20]=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>CO>[C:12]1([CH2:18][CH2:19][C:20]2[N:10]3[C:11]4[C:6]([CH2:7][CH2:8][CH2:9]3)=[CH:5][CH:4]=[CH:3][C:2]=4[N:1]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CCCc1ccccc1
Reactant: Nc1cccc2c1NCCC2
Agent: Cl
Solvent: CO
Product: c1ccc(CCc2nc3cccc4c3n2CCC4)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thirty-five grams of 8-amino-1,2,3,4-tetrahydroquinoline was dissolved in methanol (700 mL) and, following the addition of 3-phenylpropionaldehyde (37.4 mL) and 1N HCl (7 mL) and subsequent stirring at room temperature for 1 hr, silica gel (75 g) was added to the reaction solution and the solvent was removed under reduced pressure. The residue was heated at 100° C. for 1 hr, purified by silica gel column chromatography (eluent: dichloromethane/ethyl acetate) and recrystallized with ethyl acetate to yield the titled compound as pale yellow crystals (19.3 g).
Reaction SMILES: Cl.Cl.[O:3]1[C@@H:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13][C@H:7]2[NH:6][CH2:5][CH2:4]1.Cl[C:15]1[N:19]([CH3:20])[N:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22].CCN(C(C)C)C(C)C>C(#N)C.O>[CH3:20][N:19]1[C:15]([N:11]2[CH2:12][CH2:13][C@@H:7]3[NH:6][CH2:5][CH2:4][O:3][C@H:8]3[CH2:9][CH2:10]2)=[C:16]([N+:21]([O-:23])=[O:22])[CH:17]=[N:18]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: C1C[C@H]2NCCO[C@@H]2CCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: Cn1ncc([N+](=O)[O-])c1N1CC[C@@H]2NCCO[C@H]2CC1

Procedure:
In a microwave reaction vial, (4aR,9aR)-2,3,4,4a,5,6,7,8,9,9a-decahydro-[1,4]oxazino[2,3-d]azepine dihydrochloride (509 mg; 2.22 mmol) and 5-chloro-1-methyl-4-nitro-pyrazole (322 mg, 2.00 mmol) were dissolved in acetonitrile (16 mL). DIPEA (3.11 mL, 17.77 mmol) was added and the mixture was irradiated with microwave at 130° C. for 60 min. The reaction mixture was diluted with water, extracted with EA 3×. Combined organic layers were dried over Na2SO4 and concentrated to give trans-7-(2-methyl-4-nitro-pyrazol-3-yl)-3,4,4a,5,6,8,9,9a-octahydro-2H-[1,4]oxazino[2,3-d]azepine. To a solution of this compound in DCM (15 mL) was added di-tert-butyl-dicarbonate (727 mg, 3.33 mmol) and DIPEA (1.16 mL, 6.66 mmol). The mixture was stirred at room temperature for 18 h. The crude reaction mixture was concentrated and the residue was purified via silica gel column chromatography (0-100% EA/heptane) to gave the racemic trans-tert-butyl-7-(2-methyl-4-nitro-pyrazol-3-yl)-2,3,4a,5,6,8,9,9a-octahydro-[1,4]oxazino[2,3-d]azepine-4-carboxylate, which was chirally separated on AD column with 20% methanol w/0.1% NH4OH. The first eluting peak of trans-tert-butyl-7-(2-methyl-4-nitro-pyrazol-3-yl)-2,3,4a,5,6,8,9,9a-octahydro-[1,4]oxazino[2,3-d]azepine-4-carboxylate off the SFC chiral separation was converted to 396 following the procedures of Example 354. 1H NMR (400 MHz, DMSO) δ 8.63 (s, 1H), 7.55 (s, 1H), 7.54-7.43 (m, 3H), 7.26 (t, J=8.7 Hz, 2H), 3.64 (s, 3H), 3.24-3.13 (m, 4H), 3.13-2.95 (m, 3H), 2.65 (d, J=5.6 Hz, 2H), 2.60-2.52 (m, 1H), 1.82-1.68 (m, 3H), 1.64-1.53 (m, 2H). LCMS (ES+) m/z 490 (M+1)
Reaction SMILES: [NH4+:1].[Cl-].[NH4+].[OH-].[CH:5]([CH2:18][C:19]([O-])=[S:20])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO.O>[CH:5]([CH2:18][C:19]([NH2:1])=[S:20])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [NH4+]
Reactant: [O-]C(=S)CC(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC(=S)CC(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 88.6 %

Procedure:
To a solution of NH4Cl (0.29 mol, 2.0 eq) and NH4OH (300 ml) in methanol (200 mL) was added a solution of benzhydrylthioacetate (38.2 g, 0.145 mol) in methanol (50 ml) maintaining the temperature below 20° C. The reaction was stirred for 1 hour and diluted with water (100 ml) resulting in the formation of a precipitate. The precipitate was collected, washed with water and dried to give benzhydrylthioacetamide (31 g) as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:29][C:30]1[O:34][N:33]=[C:32]([CH2:35]OS(C)(=O)=O)[CH:31]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:35][C:32]2[CH:31]=[C:30]([CH3:29])[O:34][N:33]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: Cc1cc(COS(C)(=O)=O)no1
Product: Cc1cc(Cn2cc(C(=O)N3CCC4(CC3)OC(=O)c3cc(F)ccc34)c3ccc(Cl)cc32)no1

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with methanesulfonic acid 5-methyl-isoxazol-3-ylmethyl ester (described in WO 2004092172) gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:19]=[O:20])=[C:6]([NH:8][C:9](=[O:18])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1.[F:21][C:22]([SiH3])([F:24])[F:23].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>CCOCC.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:19]([OH:20])[C:22]([F:24])([F:23])[F:21])=[C:6]([NH:8][C:9](=[O:18])[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=1
Reactant: FC(F)(F)[SiH3]
Reactant: O=Cc1ccc(F)cc1NC(=O)CCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(CCc1ccccc1)Nc1cc(F)ccc1C(O)C(F)(F)F
Temperature: 23 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
To a mixture of aldehyde from Step 3 (252 mg, 0.929 mmol) and THF (8 mL) under argon at 0° C., was added trifluoromethylsilane (132 mg, 0.929 mmol), followed by tetrabutylammonium fluoride (1M solution in THF, 50 mL). The reaction was warmed to 23° C. After 2 h at 23° C., the reaction was treated with 3N HCl (125 mL). After 4 h, the reaction was diluted with ether (75 mL), washed with brine (2×100 mL), and dried (MgSO4). Concentration in vacuo afforded a brown oil (214 mg, 67.4%) which was taken on to the next step without further purification: 1H NMR (CDCl3) δ2.63 (t, J=7 Hz), 2.97 (t, J=7 Hz), 4.68 (br s), 4.88 (q, J=6 Hz), 6.73-6.82 (m), 7.11-7.35 (m), 7.83-7.92 (m), 8.85 (br s). IR (neat) 3450-3050, 1667 cm−1. MS (EI) 341 (M+), 323, 209, 140. Anal. Calc'd. for C17H15NO2F4: C, 59.82; H, 4.43; N, 4.10. Found: C, 59.81; H, 4.57; N, 4.08.
Reaction SMILES: O[Li].O.[CH3:4][CH:5]([C:7]1[CH:8]=[CH:9][C:10]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:11]([CH:22]=1)[C:12]([O:14]CC1C=CC=CC=1)=[O:13])[CH3:6].C1COCC1.Cl>C(OCC)(=O)C.O>[CH3:6][CH:5]([C:7]1[CH:8]=[CH:9][C:10]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[C:11]([CH:22]=1)[C:12]([OH:14])=[O:13])[CH3:4]
Reactant: CC(C)c1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)c1ccc(OCc2ccccc2)c(C(=O)O)c1

Procedure:
LiOH.H2O (0.70 g, 16.65 mmol) was added to a stirred solution of phenylmethyl 5-(1-methylethyl)-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 2; 1.5 g, 4.16 mmol) in a 3:1 mixture of THF:H2O (40 ml). The mixture was heated to reflux for 12 h and then diluted with ethyl acetate (50 ml). 10% aqueous HCl was added to the mixture to adjust the pH to 2. The organic phase was isolated, washed with brine, dried over MgSO4, and concentrated to give a yellow oil. 700 mg.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9](B3OC(C)(C)C(C)(C)O3)[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:26])[O:4][N:3]=1.Cl[C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[N:30][C:29]=1[C:38]([O:40]C)=[O:39].C(Cl)Cl.N1(C2CCCCCCCCCC2)CCCN=CCCCCC1>CS(C)=O.O>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=[N:30][C:29]=3[C:38]([OH:40])=[O:39])[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: COC(=O)c1nnc2ccccc2c1Cl
Reactant: Cc1noc(C)c1-c1cc(B2OC(C)(C)C(C)(C)O2)c2[nH]c(=O)[nH]c2c1
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1noc(C)c1-c1cc(-c2c(C(=O)O)nnc3ccccc23)c2[nH]c(=O)[nH]c2c1
Temperature: 110 °C

Procedure:
A mixture of 6-(3,5-dimethylisoxazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one (100.0 mg, 0.282 mmol) and methyl 4-chlorocinnoline-3-carboxylate (94.0 mg, 0.422 mmol) was treated with PdCl2dppf.CH2Cl2 (20.6 mg, 0.028 mmol) in the presence of 1,8-Diazabicycloundec-7-ene (DBU, 300.0 mg, 1.971 mmol, 7.0 equiv) in DMSO (1 mL) and water (1 mL). The reaction mixture was heated at 110° C. for 12 min in oil bath. The reaction mixture was purified by HPLC to give 4-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)cinnoline-3-carboxylic acid.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[NH2:1][CH2:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1
Reactant: [N-]=[N+]=NCc1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.2 %

Procedure:
A solution of 4-(4-azidomethylbenzyl)-nitrobenzene (5.835 g) in tetrahydrofuran (175 mL) was treated with water (0.43 mL) and triphenylphosphine (6.45 g, 1.1 eg). The mixture was stirred at room temperature for 18 hours, and the solvent was evaporated. The residue was suspended in water, and suspension made acidic by the dropwise addition of hydrochloric acid to about pH 1, then extracted with diethyl ether (3×). The aqueous phase was made alkaline with 50% aqueous sodium hydroxide, extracted with dichloromethane (3×) to afford a crude brown oil (5.66 g). Chromatography on silica gel, eluting with dichloromethane/methanol/ammonium hydroxide, gave 4-(4-aminomethylbenzyl)-nitrobezene (3.91 g, 79%) as a yellow solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:24]([F:25])=[C:23]([NH2:26])[C:9]2[C:10](=[O:22])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:21])[CH:15]=3)[O:13][C:8]=2[C:7]=1[F:27])(=[O:3])[CH3:2].Cl.[CH3:29][N:30]([CH3:37])[CH2:31][CH2:32][CH2:33][C:34](O)=[O:35].Cl.CN(C)CCCN=C=NCC.O>CN(C)C=O>[C:1]([O:4][CH2:5][C:6]1[C:24]([F:25])=[C:23]([NH2:26])[C:9]2[C:10](=[O:22])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:34](=[O:35])[CH2:33][CH2:32][CH2:31][N:30]([CH3:37])[CH3:29])=[C:16]([F:21])[CH:15]=3)[O:13][C:8]=2[C:7]=1[F:27])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3ccc(N)c(F)c3)oc2c1F
Reactant: CN(C)CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3ccc(NC(=O)CCCN(C)C)c(F)c3)oc2c1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 59.5 %

Procedure:
To a solution of 7-(acetoxymethyl)-5-amino-2-[4-amino-3-fluorophenyl]-6,8-difluoro-4H-1-benzopyran-4-one (500 mg, 1.32 mmol) in dimethylformamide (15 mL) were added 4-dimethylaminobutyric acid hydrochloride (3.06 g, 16.9 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.23 g, 16.9 mmol), and the mixture was stirred at room temperature for 2.5 hours. Water was added thereto, and the mixture was extracted with ethyl acetate. Purification by silica gel column chromatography (9:1 chloroform/methanol) gave 1j (386 mg, 60%).
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2]2.Br[C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:23][C:22]1[C:17]([N:8]2[CH:5]3[CH2:6][CH2:7][CH:1]2[CH2:2][N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]3)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CC2CCC(C1)N2
Reactant: Clc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC2CCC(C1)N2c1ncccc1Cl
Temperature: 120 °C
Reaction time: 48 h

Procedure:
tert-Butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (454 mg, 2.36 mmol) and 2-bromo-3-chloropyridine (418 mg, 1.97 mmol) were combined in dry N,N-dimethylformamide (10 mL) and treated with potassium carbonate (408 mg, 2.95 mmol). After stirring at 120° C. for 48 hours, the mixture was allowed to cool to room temperature, diluted with ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (4:1, hexanes:ethyl acetate) to provide the title compound.
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([Cl:11])[CH:9]=[CH:10][N:6]2[N:5]=[C:4]([CH:12]2[CH2:14][CH:13]2[C:15]#[N:16])[N:3]=1.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:11][C:8]1[CH:9]=[CH:10][N:6]2[C:7]=1[C:2]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[N:3][C:4]([CH:12]1[CH2:14][CH:13]1[C:15]#[N:16])=[N:5]2
Reactant: NCc1ccccn1
Reactant: N#CC1CC1c1nc(Cl)c2c(Cl)ccn2n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1CC1c1nc(NCc2ccccn2)c2c(Cl)ccn2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of (±)-2-(4,5-dichloropyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopropanecarbonitrile (60.0 mg, 0.237 mmol) in THF (1 mL) was added 2-(aminomethyl)pyridine (0.0290 mL, 0.284 mmol) followed by DIPEA (0.124 mL, 0.711 mmol). The reaction mixture was stirred at RT for 1 hour. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts was washed with brine (25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by CombiFlash (REDISEP®, silica gel, 4 g, 10% EtOAc/petroleum ether) to afford (±)-2-(5-chloro-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopropanecarbonitrile (50.0 mg, 59.1%) as off-white solid. LCMS Condition B-41: retention time 0.67 min, [M+1]=325.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30-1.34 (m, 1H), 1.48-1.51 (m, 1H), 1.92-1.96 (m, 1H), 2.45-2.49 (m, 1H), 4.76 (t, J=4.8 Hz, 2H), 6.72 (d, J=2.8 Hz, 1H), 7.29 (q, J=4.8 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.68 (d, J=2.8 Hz, 1H), 7.77 (q, J=2.0 Hz, 1H), 8.14 (s, 1H), 8.53 (dd, J=1.2 Hz, J=3.2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](N(C)C)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16].C(N(C(C)C)CC)(C)C>C1COCC1>[C:15]([NH:19][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([Cl:1])[N:11]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)N
Reactant: CN(C)c1nc(Cl)nc2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)Nc1nc(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
To a solution of 2,4-dichloro-quinazoline obtained in step B of example 1 (4 g, 20 mmol) in THF (50 mL) were added tert-butyl amine (2.15 mL, 20.5 mmol) and diisopropylethylamine (3.5 mL, 21 mmol). The mixture was stirred at ambient temperature for 2 hr. The mixture was concentrated and the residue was dissolved in EtOAc. The organic layer was washed with water, dried over Na2SO4, and filtered. The mixture was concentrated to give tert-butyl-(2-chloro-quinazolin-4-yl)-amine as a white solid (3 g, 64%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([CH3:11])[C:7]=2[CH:12]=1>Br.C(O)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([CH3:11])[C:7]=2[CH:12]=1
Reactant: COc1ccc2onc(C)c2c1
Agent: Br
Solvent: CC(=O)O
Product: Cc1noc2ccc(O)cc12
Yield: 138.6 %

Procedure:
A mixture of 5-Methoxy-3-methyl-benzo(d)isoxazole (4.9 g, 0.03 mol.) in 48% hydrobromic acid (20 mL) and acetic acid (20 mL) was refluxed for 4 hrs. The mixture was concentrated to give 6.2 g solid. MS (m/e): 149 (M+).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][N:11]=[CH:12][C:13]1[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1.[N+](C1OC(C=O)=CC=1)([O-])=O.N(C1SC2C=C([O:42][C:43]([F:46])([F:45])[F:44])C=CC=2N=1)N>>[F:44][C:43]([F:46])([F:45])[O:42][C:7]1[CH:8]=[CH:9][C:4]2[N:3]=[C:2]([NH:10][N:11]=[CH:12][C:13]3[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[S:1][C:5]=2[CH:6]=1
Reactant: NNc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: O=[N+]([O-])c1ccc(C=NNc2nc3ccccc3s2)o1
Agent: O=Cc1ccc([N+](=O)[O-])o1
Product: O=[N+]([O-])c1ccc(C=NNc2nc3ccc(OC(F)(F)F)cc3s2)o1

Procedure:
The compound 3i was prepared according procedure described for 3a by employing 5-nitrofuran aldehyde (141 mg, 1 mmol) and 2-hydrazino-6-trifluoromethoxy-benzothiazole (249 mg, 1 mmol) at 70° C. for 2 h (yield 298 mg, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.CO.S(=O)(=O)(O)O.[C:19]([O-])(O)=O.[Na+]>ClCCCl>[CH3:19][O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: COC(=O)Cc1ccc(Cl)cc1
Yield: 94 %

Procedure:
4-Chlorophenylacetic acid (100 g, 0.59 mol) was dissolved in 1,2-dichloroethane (165 ml) and methanol (96 ml, 2.4 moles) and to the solution was added concentrated sulfuric acid (2.75 ml), followed by refluxing for 6 hours. The mixture was cooled and aqueous NaHCO3 was added, followed by stirring. The resulting organic layer was separated, dried over anhydrous sodium sulfate, collected by filtration and concentrated to dryness to obtain methyl-(4-chlorophenyl)-acetate (102 g, yield 94%).