Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)C.[Li+].CC([N-]C(C)C)C.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1.[OH-].[Na+].Cl>C1COCC1.C(O)(C)C>[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][C:5]2([C:4]([OH:3])=[O:19])[CH2:6][CH2:7][N:8]([C:11](=[O:18])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:9][CH2:10]2)=[CH:32][CH:31]=1
Reactant: CCOC(=O)C1CCN(C(=O)c2ccccc2)CC1
Reactant: COc1ccc(CCl)cc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COc1ccc(CC2(C(=O)O)CCN(C(=O)c3ccccc3)CC2)cc1
Temperature: 25 °C

Procedure:
A solution of ethyl-N-benzoylisonipecotate (52 g, 0.2 mole) in THF (1 L) at -78° C. is treated with a solution of LDA in THF (110 mL of a 1 M solution). The solution is stirred at -78° for 15 minutes at which time 4-methoxybenzyl chloride (37.5 g, 0.22 moles) is added and the reaction warmed to room temperature over 2 hours. The reaction is concentrated at reduced pressure to @ one quarter volume and then poured into saturated aqueous sodium bicarbonate (1 L) and extracted with ethyl acetate (3×500 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The residue is chromatographed on silica gel with 30% ethyl acetate / hexane as eluent to give 66 g. The material thus obtained is dissolved in isopropyl alcohol (150 mL) and THF (150 mL) and treated with 10 N NaOH (250 mL). The mixture is heated to reflux for 48 hr. The reaction is cooled to room temperature and carefully neutralized by pouring over 1 L of crushed ice and adding 6 N HCl until pH 3. The mixture is then extracted with ethyl acetate (3×500 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure to give the product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[CH2:36][CH2:37][OH:38].C([O-])([O-])=O.[K+].[K+].CC1(C)C(C)(C)O[B:48](B2OC(C)(C)C(C)(C)O2)[O:47]1>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:33]1([C:32]2[C:13]([N:8]([C:5]3[CH:6]=[CH:7][C:2]4[B:48]([OH:47])[O:38][CH2:37][CH2:36][C:3]=4[CH:4]=3)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:14][C:15]3[O:19][C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[C:17]([C:27]([NH:29][CH3:30])=[O:28])[C:16]=3[CH:31]=2)[CH2:34][CH2:35]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)c(CCO)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc4c(c3)CCOB4O)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 70 °C
Yield: 65 %

Procedure:
To a deoxygenated solution of 6-(N-(4-bromo-3-(2-hydroxyethyl)phenyl)methyl-sulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (100 mg, 0.166 mmol) in 1,4-dioxane (4 mL) and water (1.0 mL) was added K2CO3 (92 mg, 0.665 mmol) followed by 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (84 mg, 0.33 mmol) and PdCl2(dppf) (12.16 mg, 0.017 mmol) under nitrogen purging. Then the reaction mixture was heated to 70° C. for 2 h. The mixture was cooled to RT and filtered to remove solids. The filtrate was diluted with water and extracted with EtOAc. The EtOAc solution was washed with water (1×), dried over sodium sulfate, and concentrated to dryness at reduced pressure. The crude product was purified by RP-HPLC (C18, MeCN/water/0.1% formic acid) to afford the title compound in 65% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.89 (dd, J=8.60, 5.28 Hz, 2H) 7.67-7.71 (m, 1H) 7.57-7.62 (m, 1H) 7.45-7.49 (m, 1H) 7.13-7.25 (m, 4H) 5.79 (d, J=3.91 Hz, 1H) 4.31 (s, 1H) 4.19 (t, J=5.96 Hz, 2H) 3.29 (s, 3H) 3.01 (d, J=4.89 Hz, 3H) 2.89 (t, J=5.86 Hz, 2H) 2.02-2.13 (m, 1H) 1.02 (br. s., 1H) 0.83 (br. s., 2H) 0.61 (br. s., 1H). LCMS (m/z, ES+)=549 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:19][C:20]3[CH:21]=[C:22]([CH:26]=[C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[CH:28]=3)[C:23](O)=[O:24])=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.C(Cl)CCl.[NH3:39].O1CCOCC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:19][C:20]3[CH:21]=[C:22]([CH:26]=[C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[CH:28]=3)[C:23]([NH2:39])=[O:24])=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(C(=O)O)cc(N2CCOCC2)c1
Reactant: N
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(C(N)=O)cc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure U by stirring 3-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-5-morpholinobenzoic acid (0.014 g, 0.031 mmol), DMAP (7.46 mg, 0.061 mmol), EDC (0.023 g, 0.122 mmol), 0.5M ammonia in dioxane (0.092 mL, 0.046 mmol), and DCM (0.3 mL) at 23° C. for 48 h. Reverse-phase HPLC afforded 3-((7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)amino)-5-(4-morpholinyl)benzamide as a yellow amorphous solid. 1H NMR (400 MHz, Methanol) δ ppm 8.72 (1H, br. s.), 7.98-8.27 (2H, m), 7.82 (1H, d, J=7.2 Hz), 7.67 (1H, d, J=9.6 Hz), 7.59 (1H, d, J=3.9 Hz), 7.39 (1H, m), 7.08 (1H, br. s.), 6.77 (1H, br. s.), 6.66 (1H, br. s.), 3.70-3.94 (4H, m), 3.03-3.25 (5H, m), 2.01-2.24 (3H, m). Mass Spectrum (ESI) m/e=457.2 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=[CH:8][C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH2:27]([NH:29][CH2:30][CH2:31][OH:32])[CH3:28]>>[CH2:27]([N:29]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=[CH:8][C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:30][CH2:31][OH:32])[CH3:28]
Reactant: CCNCCO
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2ccccc2)c(OCCCCl)c1
Product: CCN(CCO)CCCOc1cc(CNC(=O)OC(C)(C)C)ccc1-c1ccccc1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 139 using tert-butyl N-[2-(3-chloropropoxy)biphenyl-4-ylmethyl]carbamate instead of 3-(3-chloropropoxy)-4-phenylbenzonitrile and 2-ethylaminoethanol instead of pyrrolidine.
Reaction SMILES: [CH:1]([N:4]1[C:9]2=[N:10][C:11](S(C)=O)=[N:12][CH:13]=[C:8]2[CH2:7][NH:6][C:5]1=[O:17])([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1.FC(F)(F)C(O)=O>C(#N)C>[CH:1]([N:4]1[C:9]2=[N:10][C:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)=[CH:23][CH:24]=3)=[N:12][CH:13]=[C:8]2[CH2:7][NH:6][C:5]1=[O:17])([CH3:3])[CH3:2]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CC(C)N1C(=O)NCc2cnc(S(C)=O)nc21
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1C(=O)NCc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Temperature: 85 °C
Yield: 78.5 %

Procedure:
Prepared from 400 mg (1.57 mmol) of 1-isopropyl-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one, 600 mg (3.14 mmol) of 1-(4-aminophenyl)-4-methylpiperazine and 605 μL (7.85 mmol) of trifluoroacetic acid in 6.4 mL of acetonitrile. The reaction mixture is heated at 85° C. for 48 hours. After the workup, the crude residue is triturated in ethyl acetate/dichloromethane and filtered. The solids are redissolved in dichloromethane, and the solvent is evaporated under a flow of nitrogen while ethyl acetate is added to maintain a volume of 5 mL. The suspension is filtered, and the solids are washed with ethyl acetate/dichloromethane, and dried to give 470 mg (78%) of the title compound:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:47]1[CH2:52][CH2:51][O:50][CH2:49][CH:48]1[C:53]1[C:61]2[S:60][C:59]([NH2:62])=[N:58][C:57]=2[C:56]([O:63][CH3:64])=[CH:55][CH:54]=1>C1COCC1.C(Cl)(Cl)Cl>[O:47]1[CH2:52][CH2:51][O:50][CH2:49][CH:48]1[C:53]1[C:61]2[S:60][C:59]([NH:62][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:58][C:57]=2[C:56]([O:63][CH3:64])=[CH:55][CH:54]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: COc1ccc(C(=O)O)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)cc1OC

Procedure:
From 3,4-dimethoxybenzoic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+33.4° (c=0.53, CHCl3), ES-MS m/e (%): 431 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:6]2[CH:7]=[CH:8][C:9]3=[N:10][NH:11][C:12]4[C:13](=[CH:14][N:15]([CH3:29])[CH2:16][C:17]=4[C:18]4[CH2:19][CH2:20][N:21]([CH2:25][C:26](O)=[O:27])[CH2:22][CH2:23][CH:24]=4)[C:4](=[C:5]23)[CH:3]=1.[NH:31]1[CH2:34][CH:33]([OH:35])[CH2:32]1.Cl.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[F:1][C:2]1[CH:30]=[C:6]2[CH:7]=[CH:8][C:9]3=[N:10][NH:11][C:12]4[C:13](=[CH:14][N:15]([CH3:29])[CH2:16][C:17]=4[C:18]4[CH2:19][CH2:20][N:21]([CH2:25][C:26]([N:31]5[CH2:34][CH:33]([OH:35])[CH2:32]5)=[O:27])[CH2:22][CH2:23][CH:24]=4)[C:4](=[C:5]23)[CH:3]=1
Reactant: CN1C=C2C(=C(C3=CCCN(CC(=O)O)CC3)C1)NN=C1C=Cc3cc(F)cc2c31
Reactant: OC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1C=C2C(=C(C3=CCCN(CC(=O)N4CC(O)C4)CC3)C1)NN=C1C=Cc3cc(F)cc2c31

Procedure:
A mixture of Example 90B (60 mg, 0.125 mmol), azetidin-3-ol, hydrochloric acid (20.57 mg, 0.188 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (57.1 mg, 0.150 mmol) and triethylamine (87 μL, 0.626 mmol) in 2 mL N,N-dimethylformamide was stirred at room temperature overnight. The mixture was extracted with dichloromethane and purified by flash chromatography on silica using an Analogix system (0-10% methanol/dichloromethane) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 2.46-2.90 (m, 10H), 3.17 (d, J=5.1 Hz, 2H), 3.62 (dd, J=10.3, 4.4 Hz, 1H), 3.89-4.14 (m, 5H), 4.33-4.61 (m, 2H), 5.72 (d, J=5.9 Hz, 1H), 5.92 (t, J=6.3 Hz, 1H), 7.18-7.35 (m, 3H), 7.69 (dd, J=10.4, 3.0 Hz, 1H), 8.22 (d, J=5.2 Hz, 1H), 11.51 (s, 1H). MS (ESI+) m/z 462 (M+H)+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].C([O:8][C:9]1[C:14]2[CH:15]([C:21]#[N:22])[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:13]=2[CH:12]=[C:11]([C:23]([CH3:31])([CH3:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:10]=1)(=O)C.C(O)C.Cl.CN1CCCCC1>CN1CCCCC1>[OH:8][C:9]1[C:14]2[CH:15]([C:21]3[NH:22][N:3]=[N:2][N:1]=3)[CH2:16][C:17]([CH3:19])([CH3:20])[O:18][C:13]=2[CH:12]=[C:11]([C:23]([CH3:30])([CH3:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:10]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCC(C)(C)c1cc(OC(C)=O)c2c(c1)OC(C)(C)CC2C#N
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCCC1
Solvent: CCO
Product: CCCCCCC(C)(C)c1cc(O)c2c(c1)OC(C)(C)CC2c1nnn[nH]1
Reaction time: 1 h

Procedure:
Finely ground sodium azide (325 mg, 5 mmole) is added to a solution of 5-acetoxy-4-cyano-2,2-dimethyl-7-(1,1-dimethylheptyl)-3,4-dihydro-2H-benzopyran (1.855 g, 5 mmole) in 10 ml ethanol-free chloroform containing 271 mg (2 mmole) N-methylpiperidine hydrochloride and 5 drops of N-methylpiperidine. The mixture is heated at reflux for one hour, another 2 mmoles of N-methylpiperidine hydrochloride is added, refluxing is continued for one hour and the mixture is allowed to stand overnight at room temperature. The mixture is partitioned between chloroform and aqueous sodium carbonate solution, the aqueous phase is adjusted to pH 5 and extracted again with chloroform. The combined organic layers are washed with water, dried (MgSO4) and the solvent evaporated in vacuo to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:23])[N:6]([CH2:8][CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)[CH:7]=1.CNCCNC.[NH:30]1[CH2:34][CH2:33][CH2:32][C:31]1=[O:35].C(=O)([O-])[O-].[Cs+].[Cs+].[NH4+].[OH-]>[Cu]I.C1(C)C=CC=CC=1>[CH3:22][O:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][CH2:9][CH2:8][N:6]3[CH:7]=[C:2]([N:30]4[CH2:34][CH2:33][CH2:32][C:31]4=[O:35])[CH:3]=[CH:4][C:5]3=[O:23])=[CH:12][CH:13]=[N:14]2)=[CH:19][CH:18]=1
Reactant: O=C1CCCN1
Reactant: COc1ccc2c(OCCn3cc(Br)ccc3=O)ccnc2c1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccc2c(OCCn3cc(N4CCCC4=O)ccc3=O)ccnc2c1
Temperature: 120 °C

Procedure:
A dry 5 mL, 1-neck round bottom flask was charged with 5-bromo-1-(2-(7-methoxyquinolin-4-yloxy)ethyl)pyridin-2(1H)-one (0.0476 g, 0.13 mmol), copper(I)iodide (0.0033 mL, 0.098 mmol), 1 mL toluene, N,N′-dimethylethylenediamine (0.017 g, 0.20 mmol), 2-pyrrolidone (0.048 mL, 0.63 mmol), cesium carbonate (0.12 g, 0.38 mmol), a stirbar and a reflux condenser. The solution was placed in a 120° C. bath for 6 h. The solution was cooled and retreated with the same amounts of CuI and diamine. The solution was heated to 120° C. for 16 h, and cooled. The solution was treated with 2 mL 50% concentrated NH4OH, and stirred/sonicated for 2 min. The biphasic solution was loaded onto an unbuffered Varian Chem elute (10 mL, PN 12198007). The column was extracted with CH2Cl2 (5×10 mL), and the extracts were concentrated in vacuo. The residue was taken up in 0.5 mL 20% THF in DCE, and filtered. The solid was washed with 20% THF in DCE (2×0.5 mL). The solid was heated into 2 mL EtOH and filtered hot. The solvent was removed in vacuo to afford 1-(2-(7-methoxyquinolin-4-yloxy)ethyl)-5-(2-oxopyrrolidin-1-yl)pyridin-2(1H)-one. 1H NMR (400 MHz, CDCl3) δ ppm 2.11-2.20 (m, 2H) 2.58 (t, J=8.12 Hz, 2H) 3.66 (t, J=6.94 Hz, 2H) 3.93 (s, 3H) 4.47-4.55 (m, 4H) 6.60 (dd, J=9.78, 0.59 Hz, 1H) 6.62 (d, J=5.38 Hz, 1H) 7.13 (dd, J=9.15, 2.59 Hz, 1H) 7.35 (d, J=2.54 Hz, 1H) 7.47 (dd, J=9.78, 2.93 Hz, 1H) 8.10 (d, J=9.10 Hz, 1H) 8.19 (dd, J=2.93, 0.59 Hz, 1H) 8.64 (d, J=5.28 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ ppm 17.91 (s, 1 C) 31.78 (s, 1 C) 48.39 (s, 1 C) 49.78 (s, 1 C) 55.46 (s, 1 C) 65.70 (s, 1 C) 99.42 (s, 1 C) 107.20 (s, 1 C) 115.69 (s, 1 C) 118.46 (s, 1C) 120.67 (s, 2 C) 123.03 (s, 1 C) 131.19 (s, 1 C) 134.70 (s, 1 C) 151.21 (s, 1 C) 151.76 (s, 1 C) 160.57 (s, 1 C) 160.79 (s, 1 C) 160.99 (s, 1 C) 173.95 (s, 1 C). MS (ESI pos. ion) m/z (MH+): 380.2, calcd for C21H21N3O4+H+=380.2.
Reaction SMILES: Br[CH2:2][CH:3]([F:5])[F:4].[Cl:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([F:14])[C:8]=1[C:15]1[C:24](=[O:25])[NH:23][C:18]2=[N:19][CH:20]=[CH:21][N:22]=[C:17]2[C:16]=1[O:26]C(=O)C(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O.C(OCC)(=O)C>[Cl:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([F:14])[C:8]=1[C:15]1[C:24](=[O:25])[N:23]([CH2:2][CH:3]([F:5])[F:4])[C:18]2=[N:19][CH:20]=[CH:21][N:22]=[C:17]2[C:16]=1[OH:26]
Reactant: FC(F)CBr
Reactant: CC(C)(C)C(=O)Oc1c(-c2c(F)ccc(F)c2Cl)c(=O)[nH]c2nccnc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1c(-c2c(F)ccc(F)c2Cl)c(O)c2nccnc2n1CC(F)F
Temperature: 120 °C

Procedure:
1-Bromo-2,2-difluoroethane (0.754 g) was added to a mixture of 2,2-dimethyl-propionic acid 7-(2-chloro-3,6-difluoro-phenyl)-6-oxo-5,6-dihydro-pyrido[2,3-1)]pyrazin-8-yl ester (Example 1.3) (1.00 g), potassium carbonate (1.76 g) and potassium iodide (catalytic amount) in anhydrous N,N-dimethylformamide (15 ml). The reaction mixture was heated in a microwave for 20 minutes at 120° C. The reaction mixture was allowed to cool to ambient temperature before diluting with water and ethyl acetate. The phases were separated. The organic phase was washed with water, dried over magnesium sulfate, and concentrated. The residue was dissolved in diethyl ether, and the solution was washed with water. The phases were separated and the organic phase was concentrated to give Compound No. B2 of Table B as an orange viscous oil (0.553 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][N:8]3[CH:19]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[N:21]=[C:7]3[C:6]=2[CH:26]=1.[CH3:27][C:28]1[O:32][N:31]=[C:30]([C@:33]([OH:37])([C:35]#[CH:36])[CH3:34])[CH:29]=1>>[OH:37][C@:33]([C:30]1[CH:29]=[C:28]([CH3:27])[O:32][N:31]=1)([CH3:34])[C:35]#[C:36][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][N:8]3[CH:19]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[N:21]=[C:7]3[C:6]=2[CH:26]=1
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)ccc1OC(CN1CCOCC1)C2
Product: COC(=O)c1cn2c(n1)-c1cc(C#C[C@@](C)(O)c3cc(C)on3)ccc1OC(CN1CCOCC1)C2

Procedure:
Similar to as described in General Procedure G, racemic methyl 10-bromo-6-(morpholinomethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate was reacted with (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol to produce methyl 10-((R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl)-6-(morpholinomethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate as a diasteromeric mixture. A suspension of methyl 10-((R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl)-6-(morpholinomethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate (220 mg, 0.45 mmol, 1.00 equiv) in aqueous ammonia (40 mL) was stirred overnight at 60° C. The resulting mixture was concentrated under vacuum and the residue was purified on a silica gel column with dichloromethane/methanol (20:1). This resulted in 43 mg (20%) of 10-((R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl)-6-(morpholinomethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide as a colorless solid. The two diasteromers were separated by Chiral-Prep-HPLC with the following conditions: Column, CHIRALPAK IC-3; mobile phase, Hex (0.1% TEA):EtOH=50/50; Detector, 254 nm. This resulted in 12.2 mg (30%) of Compound 1 and 15.3 mg (38%) Compound 2.
Reaction SMILES: Br.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.[N:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[Cl-].[NH4+]>C1COCC1>[N:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([N:23]2[CH2:24][CH2:25][CH:20]([C:17]3[S:18][CH:19]=[C:15]([C:7]4[CH:6]=[CH:5][C:4]5[C:3]([CH3:26])([CH3:2])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]=5[CH:8]=4)[N:16]=3)[CH2:21][CH2:22]2)=[O:35])=[CH:29][CH:28]=1
Reactant: O=C(O)Cc1ccncc1
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCNCC4)n3)ccc21
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCN(C(=O)Cc5ccncc5)CC4)n3)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
200 mg (0.46 mmol) of 4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidine hydrobromide, 81 mg (0.46 mmol) of pyridin-4-ylacetic acid, 202 μl (1.84 mmol) of 4-methylmorpholine, 361 mg (1.84 mmol) of EDCl and 135 mg (0.73 mmol) of HOBt are dissolved in 10 ml of THF and stirred at room temperature for 24 h. The reaction mixture is added to saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase is separated off, dried over sodium sulfate and evaporated to dryness. The crude mixture is purified by column chromatography on silica gel.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]([CH3:27])[CH3:26])=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.CO.C(Cl)Cl>[NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([O:12][C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([N:25]([CH3:27])[CH3:26])=[N:23][N:24]=3)[CH:21]=2)[CH2:4][CH2:3]1
Reactant: CN(C)c1nnc2ccc(F)cn12
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CN(C)c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of Intermediate A (75 mg, 0.458 mmol) in DMF (2 mL) was added NaH (60% in oil, 50 mg, 1.25 mmol) and the mixture stirred at RT for 20 min, before Intermediate 59b (75 mg, 0.416 mmol) was added. This mixture was stirred at 60° C. for 1 h. The reaction mixture was applied to an SCX-2 cartridge (10 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM gave the title compound as a yellow gum (82 mg, 61%). LCMS (Method 4): Rt 1.49 min, m/z 324 [MH+].
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:13](Br)[C:14]#[CH:15].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CCOCC>[CH2:15]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[C:14]#[CH:13]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: C#CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: CCOCC
Product: C#CCOc1ccc(C(=O)O)cc1
Reaction time: 8 h
Yield: 43.6 %

Procedure:
Into a reaction flask fitted with a stirrer, a thermometer, a nitrogen gas inlet tube and a reflux condenser, were placed 19.276 parts of p-hydroxybenzoic acid, 50.242 parts of deionized water, 12.633 parts of NaOH and 0.011 part of tetrabutylammoniumbromide and to this mixture, 17.848 parts of propargyl bromide was added dropwise and reacted at 80° C. for 6 hours. After completion of the reaction, the content was treated with 1N-HCl and then with a mixture of ether and deionized water and the ether layer was separated, added with magnesium sulfate and kept standing overnight. After filtering off magnesium sulfate, the ether solvent was removed by an evaporator and the residue was subjected to a column chromatography (silica gel 200 mesh) to obtain a purified 1propargyloxybenzene-4-carboxylic acid. Yield 43.6%
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[C:11]([Br:13])[CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH3:14]I>CN(C=O)C>[CH3:14][N:9]1[C:10]2[C:6](=[CH:5][C:4]([F:3])=[CH:12][C:11]=2[Br:13])[CH:7]=[CH:8]1
Reactant: CI
Reactant: Fc1cc(Br)c2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2cc(F)cc(Br)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (60%, 1.75 g, 43.8 mmol) in DMF (134 mL) was added a solution of 5-fluoro-7-bromoindole (7.8 g, 36.4 mmol) in DMF (10 mL). After 1 h at room temperature, the mixture was treated with methyl iodide (3.4 mL, 54.6 mmol) with cooling in an ice-water bath. The reaction mixture was allowed to warm up room temperature and stirred overnight. The reaction was quenched with water, extracted with ethyl acetate, and the organic layer was washed with water and brine, dried (sodium sulfate) and concentrated to give a crude product, which was used without further purification. 1H NMR (400 MHz, CDCl3) 4.06 (s, 3H), 6.34 (d, J=3.13 Hz, 1H), 6.96 (d, J=3.13 Hz, 1H), 7.07 (dd, J1=2.34 Hz, J2=8.60 Hz, 1H), 7.12 (dd, J1=2.34 Hz, J2=9.0 Hz, 1H).