Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[OH:16].CCCCCC.C([Li])CCC.[C:28]1([P:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)Cl)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[CH3:42][Si:43](Cl)([CH3:45])[CH3:44]>C(OCC)C>[CH3:42][Si:43]([O:16][C:3]1[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:7][C:2]=1[P:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:45])[CH3:44]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(C)c1cc(Br)c(O)c(C(C)(C)C)c1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C)c1cc(P(c2ccccc2)c2ccccc2)c(O[Si](C)(C)C)c(C(C)(C)C)c1
Temperature: -30 °C
Reaction time: 5 h
Yield: 16.2 %

Procedure:
Next, 5.0 g (17.5 millimole) of 2-bromo-4,6-di-tert-butylphenol described above was dissolved in 45 ml of dehydrated diethyl ether under nitrogen flow, and the solution was cooled down to −30° C. Then, 23.3 ml (37.3 millimole) of a hexane solution having an n-butyllithium concentration of 1.6 mole/liter was added thereto, and then the solution was stirred at a room temperature for 5 hours. The reaction mixture was cooled down to −30° C., and 3.26 ml (17.3 millimole) of diphenylchlorophosphine was added thereto and stirred at a room temperature for 8 hours. In this reaction solution, 2.6 ml (20.5 millimole) of trimethylsilyl chloride was added, and the solution was further stirred for 8 hours. Then, the solvent was distilled off under reduced pressure, and the residue was extracted with hexane. Subsequently, after the solvent was distilled off under reduced pressure, the residue was dissolved in hexane, and the solution was then cooled down to separate a precipitated solid matter, whereby 1.3 g (yield: 16%) of 4,6-di-tert-butyl-2-diphenylphosphinophenyl trimethylsilyl ether was obtained.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][O:9][CH:10]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:24][CH:23]=3)[C:11]3[C:12](=[CH:13][CH:14]=[C:15]4[C:20]=3[CH:19]=[CH:18][C:17]([OH:21])=[CH:16]4)[C:6]=2[CH:5]=[C:4]([F:37])[C:3]=1[Si](C)(C)C.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[ClH:61].CCOCC>C(#N)C>[ClH:61].[F:1][C:2]1[C:7]2[CH2:8][O:9][CH:10]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]4[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]4)=[CH:24][CH:23]=3)[C:11]3[C:12](=[CH:13][CH:14]=[C:15]4[C:20]=3[CH:19]=[CH:18][C:17]([OH:21])=[CH:16]4)[C:6]=2[CH:5]=[C:4]([F:37])[CH:3]=1
Reactant: C[Si](C)(C)c1c(F)cc2c(c1F)COC(c1ccc(OCCN3CCCCC3)cc1)c1c-2ccc2cc(O)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: CC#N
Solvent: CCOCC
Product: Oc1ccc2c3c(ccc2c1)-c1cc(F)cc(F)c1COC3c1ccc(OCCN2CCCCC2)cc1
Temperature: 70 °C
Yield: 92.9 %

Procedure:
Dissolve 1,3-difluoro-11-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-2-trimethylsilanyl-11,13-dihydro-12-oxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-8-ol (2.2 g, 3.8 mmol) in acetonitrile (100 mL) and add tetrabutylammonium fluoride hydrate (2.0 g, 7.6 mmol) and heat to 70° C. for 4 hours. Cool the reaction to room temperature and partition between water and ethyl acetate. Extract the organic layer with water three times. Dry with sodium sulfate, filter and concentrate in vacuo. Dissolve the residue in methylene chloride (8 mL) and add HCl (2M in ether, 3.8 mL, 7.6 mmol). Add the solution slowly to vigorously stirred ether and collect the precipitate. Dry at 50° C. under vacuum over night to yield 1.9 g (93%) of the title compound as a tan solid. 1H NMR (d6-DMSO) δ10.09 (s, 1H), 10.02 (bs, 1H), 8.36 (d, J=9.2 Hz, 1H), 7.92 (d, J=8.6 Hz, 1H), 7.57 (d, J=8.6 Hz, 1H), 7.31 (d, J=2.5 Hz, 1H), 7.22 (dd, J=9.4, 2.7 Hz, 1H), 7.13 (td, J=9.6, 2.3 Hz, 1H), 6.99 (m, 2H), 6.64 (m, 4H), 4.97 (d, J=12.3 Hz, 1H), 4.19 (t, J=5.2 Hz, 2H), 4.07 (d, J=12.3 Hz, 1H), 3.37 (m, 4H), 2.91 (m, 2H), 1.70 (m, 5H), 1.57 (m, 1H). mass spectrum (apci) m/z-502.3 (M−HCl+H). HPLC (5 to 95) Rt (purity at 254 nm)=2.76 min (>99%). Analysis calculated for C31H30ClF2NO3.H2O: C, 66.96; H, 5.80; N, 2.52. Found: C, 67.00; H, 6.20; N, 2.83.
Reaction SMILES: S(O[CH2:12][CH:13]1[O:17][CH2:16][N:15]([C:18]2[CH:27]=[C:26]3[C:21]([C:22](=[O:37])[N:23]4[C:34]5[C:29](=[CH:30][C:31]([F:35])=[CH:32][CH:33]=5)[C:28](=[O:36])[C:24]4=[N:25]3)=[CH:20][CH:19]=2)[CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.[N-:38]=[N+:39]=[N-:40].[Na+].C(Cl)(Cl)Cl>CN(C=O)C>[N:38]([CH2:12][CH:13]1[O:17][CH2:16][N:15]([C:18]2[CH:27]=[C:26]3[C:21]([C:22](=[O:37])[N:23]4[C:34]5[C:29](=[CH:30][C:31]([F:35])=[CH:32][CH:33]=5)[C:28](=[O:36])[C:24]4=[N:25]3)=[CH:20][CH:19]=2)[CH2:14]1)=[N+:39]=[N-:40]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(c3ccc4c(=O)n5c(nc4c3)C(=O)c3cc(F)ccc3-5)CO2)cc1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1CN(c2ccc3c(=O)n4c(nc3c2)C(=O)c2cc(F)ccc2-4)CO1

Procedure:
To a solution of 3-(5-tosyloxymethyloxazolidin-3-yl)-8-fluoroindolo[2,1-b]-quinazoline-6,12-dione (0.2 mmol) in DMF is added sodium azide (0.21 mmol). The reaction mixture is allowed to stir for 18 h at room temperature after which time CHCl3 is added and the organic layer is washed with water, dried (MgSO4) and the solvent is evaporated. Silica gel chromatography (1% MeOH/CHCl3) gives 3-(5-azidomethyloxazolidin-3-yl)-8-fluoroindolo[2,1-b]quinazoline-6,12-dione.
Reaction SMILES: CC(C)([O-])C.[K+].[Si:7]([O:24][CH2:25][C:26]1[C:27](=[O:32])[NH:28][CH:29]=[CH:30][CH:31]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:33][C:34]1[CH:39]=[C:38]([N+:40]([O-:42])=[O:41])[CH:37]=[CH:36][C:35]=1F.O>CN(C=O)C>[Si:7]([O:24][CH2:25][C:26]1[C:27](=[O:32])[N:28]([C:35]2[CH:36]=[CH:37][C:38]([N+:40]([O-:42])=[O:41])=[CH:39][C:34]=2[Cl:33])[CH:29]=[CH:30][CH:31]=1)([C:20]([CH3:23])([CH3:21])[CH3:22])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: CC(C)(C)[Si](OCc1ccc[nH]c1=O)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](OCc1cccn(-c2ccc([N+](=O)[O-])cc2Cl)c1=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 0.500 g (4.46 mmol) of potassium tert-butoxide is added to 1.08 g (2.97 mmol) of the compound from Example 3A in 21 ml of DMF, and the mixture is stirred at room temperature for 30 min. 0.571 g (3.27 mmol) of 2-chloro-1-fluoro-4-nitrobenzene is added, and the mixture is stirred at RT. After 4.5 h, 200 ml of water are added, and the mixture is then extracted three times with ethyl acetate. The combined organic phases are washed with water and then dried over sodium sulphate. After filtration, the solvents are removed under reduced pressure. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 9:1). This gives 872 mg (56% of theory) of the desired compound.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[C:10]([CH:12]=[O:13])[CH:9]=[CH:8][C:7]=1[O:14][CH2:15][CH:16]1[CH2:18][CH2:17]1)(=[O:4])=[O:3].S(=O)(=O)([OH:21])N.Cl([O-])=O.[Na+]>C(O)(=O)C.O>[CH:16]1([CH2:15][O:14][C:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:21])=[O:13])=[CH:11][C:6]=2[O:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:17][CH2:18]1
Reactant: NS(=O)(=O)O
Reactant: CS(=O)(=O)Oc1cc(C=O)ccc1OCC1CC1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)(=O)Oc1cc(C(=O)O)ccc1OCC1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
A mixture of 2-(cyclopropylmethoxy)-5-formylphenyl methanesulfonate (0.565 g, 2.090 mmol) and sulfamic acid (0.223 g, 2.299 mmol) in acetic acid (8 ml) was cooled to 0° C., and a solution of sodium chlorite (0.378 g, 4.18 mmol) in water (3 ml) was added. The resulting yellow mixture was allowed to warm to RT and stirred for 2 hours. Additional sulfamic acid (0.081 g, 0.836 mmol) and sodium chlorite (0.133 g, 1.463 mmol) in water (2 ml) were added over 1 hour. The reaction mixture was diluted with water (15 ml), and the precipitate was collected by filtration, washed with water and dried to obtain 4-(cyclopropylmethoxy)-3-(methylsulfonyloxy)benzoic acid (0.521 g, 1.820 mmol, 87% yield, MS/ESI+ 286.9 [MH]+). This product was employed in the next step without purification.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[NH:14][S:15](=[O:29])(=[O:28])[C:16]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][C:17]=3[C:18]=2[OH:19])=[O:12])[CH:7]=[CH:8][CH:9]=1.[CH3:30]I>CO>[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[N:14]([CH3:30])[S:15](=[O:28])(=[O:29])[C:16]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][C:17]=3[C:18]=2[OH:19])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: O=C(Nc1cccc(Cl)c1)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1C(C(=O)Nc2cccc(Cl)c2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.3 %

Procedure:
3.15 ml of 1 N sodium hydroxide (3.15 millimols) were added dropwise to a suspension of 1.2 gm (3 millimols) of N-(3-chloro-phenyl)-4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide in 100 ml of methanol and 1.7 gm (12 millimols) of methyl iodide. The resulting mixture was stirred at room temperature for 72 hours, and was then evaporated to dryness in vacuo. The residue was washedwith a small quantity of water, and the remaining solid matter was recrystallized from ethylene chloride, yielding 0.8 gm (64% of theory) of N-(3-chloro-phenyl)-4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide, m.p. 248°-249° C (decomp.).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1O)[CH:7]=[O:8])[CH3:2].[CH:13]1(Br)[CH2:15][CH2:14]1.C([O-])([O-])=[O:18].[K+].[K+]>CN(C=O)C>[CH:13]1([O:18][C:5]2[C:4]([O:3][CH2:1][CH3:2])=[CH:11][CH:10]=[CH:9][C:6]=2[CH:7]=[O:8])[CH2:15][CH2:14]1
Reactant: BrC1CC1
Reactant: O=C([O-])[O-]
Reactant: CCOc1cc(C=O)ccc1O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cccc(C=O)c1OC1CC1

Procedure:
The title compound was prepared analogously to intermediate 2 (4-methoxy-3-propoxy-benzaldehyde) by reaction of 3-ethoxy-4-hydroxy-benzaldehyde with cyclopropyl bromide in DMF using K2CO3 as base. MS (ISP): 206.9 [M+H]+.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4]1[N:5]([C:16]([O:18]C2C=CC([N+]([O-])=O)=CC=2)=O)[C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([N+:13]([O-:15])=[O:14])=[CH:8][CH:7]=2>C1COCC1.CCOCC>[CH3:1][NH:2][C:16]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([N+:13]([O-:15])=[O:14])=[CH:8][CH:7]=2)[CH:12]=[C:4]1[CH3:3])=[O:18]
Reactant: CN
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2n1C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CNC(=O)n1c(C)cc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
A 2.0 M solution of methylamine in THF (25 ml, 50 mmole) was added to a solution of 2-methyl-5-nitro-1-(4-nitrophenoxycarbonyl)indole 1a (2.11 g, 6.2 mmole) in THF (240 ml). The resultant reaction mixture was stirred at ambient temperature for 4 hours prior to removal of the solvent by concentration, in vacuo. The residue obtained was partitioned between EtOAc (200 ml) and H2O (200 ml). The layers were separated and the aqueous phase was extracted with EtOAc (2×100 ml). The combined organic extracts were washed with sat'd NaHCO3 (150 ml), dried over Na2SO4 and concentrated, in vacuo, to give a yellow solid which was suspended in Et2O (35 ml), filtered and washed with Et2O (2×20 ml) to give 1.17 g (81%) of a pale yellow solid. 1H NMR (DMSO-d6): δ 8.52 (1H, q, J=4.5 Hz), 8.46 (1H, d, J=2.3 Hz), 8.03 (1H, dd, J=2.3, 9.1 Hz), 7.71 (1H, d, J=9.1 Hz), 6.62 (1H, s), 2.89 (3H, d, J=4.5 Hz), 2.51 (3H, s). Anal. Calcd. for C11H13N3O3: C, 56.65; H, 4.75; N, 18.02. Found: C, 56.56; H, 4.78; N, 17.82.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:23][CH2:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:30]([O:32][CH3:33])=[O:31])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.O>C(OCC)(=O)C.O=[Pt]=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]([N:18]3[CH2:19][CH2:20][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:22][CH2:23]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:30]([O:32][CH3:33])=[O:31])[CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CC=C(c4ccccn4)CC3)nc2c1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCC(c4ccccn4)CC3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-(4-(pyridin-2-yl)-5,6-dihydropyridin-1(2H)-yl)quinoxaline-6-carboxylate (150 mg, 0.34 mmol) in ethyl acetate (30 ml) was added PtO2 (38 mg) and the reaction mixture was stirred at room temperature for 2 hours under an atmosphere of H2(g). The reaction mixture was added to water (100 ml), extracted with dichloromethane (3×30 mL), and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the residue, which was purified via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford methyl 2-(4-fluorophenyl)-3-[4-(pyridin-2-yl)piperidin-1-yl]quinoxaline-6-carboxylate as a yellow solid (84 mg, 56%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.Br[CH:10]([CH:12]1[CH2:14][C:13]1([F:16])[F:15])C.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH:12]2[CH2:14][C:13]2([F:16])[F:15])=[CH:4][N:3]=1
Reactant: Oc1ccc(Br)nc1
Reactant: CC(Br)C1CC1(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC1(F)CC1COc1ccc(Br)nc1
Temperature: 70 °C

Procedure:
The mixture of 0.30 g (1.7 mmol) of 2-bromo-5-hydroxypyridine, 0.59 g (3.5 mmol) of 1-bromoethyl-2,2-difluorocyclopropane and 0.60 g (4.3 mmol) of K2CO3 in 10 ml ACN is stirred at 70° C. over night. The reaction mixture is filtered over alumina/activated carbon. The solvent is removed in vacuo.
Reaction SMILES: C1(C2C(OCC3(C(F)(F)F)CCCCC3)=CC(F)=C(C=2)C(O)=O)CC1.[CH:26]1([CH2:32][O:33][C:34]2[C:42]([CH:43]3[CH2:45][CH2:44]3)=[CH:41][C:37]([C:38]([OH:40])=O)=[C:36]([F:46])[CH:35]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.CS(N)(=O)=O.[N:52]1([S:56]([NH2:59])(=[O:58])=[O:57])[CH2:55][CH2:54][CH2:53]1>>[N:52]1([S:56]([NH:59][C:38](=[O:40])[C:37]2[CH:41]=[C:42]([CH:43]3[CH2:45][CH2:44]3)[C:34]([O:33][CH2:32][CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)=[CH:35][C:36]=2[F:46])(=[O:58])=[O:57])[CH2:55][CH2:54][CH2:53]1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CCCCC2)cc1F
Reactant: NS(=O)(=O)N1CCC1
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC2CCCCC2)cc1F

Procedure:
Following the procedure as described in preparation of Example 158 step 5, and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoic acid with 4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained (0.13 g, 47%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.71-8.61 (m, 1H), 7.62-7.55 (m, 1H), 6.62-6.51 (m, 1H), 4.30-4.18 (m, 4H), 3.86-3.76 (m, 2H), 2.34-2.20 (m, 2H), 2.13-2.00 (m, 1H), 1.96-1.67 (m, 6H), 1.41-1.02 (m, 5H), 0.99-0.87 (m, 2H), 0.72-0.61 (m, 2H); MS (ES−) m/z 409.3 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].[H-].[Na+].[Cl:12][C:13]1[CH:18]=[C:17]([N+]([O-])=O)[CH:16]=[CH:15][N:14]=1>>[Cl:12][C:13]1[CH:18]=[C:17]([O:9][C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])[CH:16]=[CH:15][N:14]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: Oc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Product: Fc1cccc(F)c1Oc1ccnc(Cl)c1
Yield: 94.4 %

Procedure:
Using the method of Example 3, Step A, 2,6-difluorophenol (821 mg, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol), and 2-chloro-4-nitropyridine (1.00 g, 6.31 mmol) were reacted to provide 2-chloro-4-(2,6-difluorophenoxy)pyridine (1.44 g, 94% yield) as an oil. 1H NMR (CDCl3) δ 8.27 (d, 1H), 7.26 (m, 1H), 7.04-7.10 (m, 2H), 6.80-6.86 (m, 2H).
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:5]1[C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[OH:4][CH:3]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[CH2:11][OH:12])[CH2:2][CH3:1]
Reactant: CCC(=O)c1ccccc1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCC(O)c1ccccc1CO

Procedure:
This compound was prepared in an analogous manner to Example XI from 10 g (56 mM) of propiophenone-2-carboxylic acid and lithium aluminium hydride to yield the title compound as an oil.
Reaction SMILES: Cl.[F:2][CH2:3][C:4]([C:8]1[O:12][N:11]=[C:10]([NH:13][C:14](=[O:38])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[CH:26][N:25]=3)=[CH:18][CH:17]=2)[CH:9]=1)([CH3:7])[CH2:5][F:6].CCN(C(C)C)C(C)C.FC(F)(F)S(O[CH2:54][C:55]([F:58])([F:57])[F:56])(=O)=O>CC#N>[F:2][CH2:3][C:4]([C:8]1[O:12][N:11]=[C:10]([NH:13][C:14](=[O:38])[NH:15][C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:32][CH2:33][N:34]([CH2:54][C:55]([F:58])([F:57])[F:56])[CH2:35][CH2:36]4)=[CH:26][N:25]=3)=[CH:20][CH:21]=2)[CH:9]=1)([CH3:7])[CH2:5][F:6]
Reactant: CC(CF)(CF)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNCC4)cn3)cc2)no1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(CF)(CF)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCN(CC(F)(F)F)CC4)cn3)cc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a stirred solution of N-(4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(piperidin-4-yloxy)picolinamide hydrochloride (50 mg, 0.091 mmol) from Step 4 of Example 17 in 3 mL of CH3CN was added DIEA (32 mL, 0.18 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (21 mg, 0.18 mmol). The resulting mixture was then stirred at rt for 1 h, heated at 85° C. for 1 h. CH3CN was then evaporated under reduced pressure and the residue was taken up in 2 mL of DMF. To the reaction mixture was then added DIEA (32 μL, 0.18 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (21 mg, 0.18 mmol), and heated at 85° C. for 2 h. LC-MS indicated that the reaction was complete. Purification by reverse phase HPLC yielded N-(4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(1-(2,2,2-trifluoroethyl)piperidin-4-yloxy)picolinamide (40 mg, 74%) as a white solid. LC-MS (ESI) m/z 597 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.59 (s, 1H), 8.77 (s, 1H), 8.36 (d, J=2.83 Hz, 1H), 8.08 (d, J=8.85 Hz, 1H), 7.81 (d, J=8.85 Hz, 2H), 7.67 (dd, J=2.83, 8.85 Hz, 1H), 7.42 (d, J=8.85 Hz, 2H), 6.79 (s, 1H), 4.73 (s, 2H), 4.65 (td, J=3.93, 8.15 Hz, 1H), 4.57 (s, 2H), 3.23 (q, J=10.24 Hz, 2H), 2.80-2.96 (m, 2H), 2.62 (t, J=9.42 Hz, 2H), 1.97 (br. s., 2H), 1.60-1.76 (m, 2H), 1.34 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([F:23])[CH:17]=3)=[C:13]([C:24](O)=[O:25])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].Cl.[F:28][C:29]1[CH:34]=[CH:33][C:32]2[C:35]3([CH2:41][O:42][C:31]=2[CH:30]=1)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([F:23])[CH:17]=3)=[C:13]([C:24]([N:38]3[CH2:37][CH2:36][C:35]4([C:32]5[CH:33]=[CH:34][C:29]([F:28])=[CH:30][C:31]=5[O:42][CH2:41]4)[CH2:40][CH2:39]3)=[O:25])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn2c(Nc3ccc(C)c(F)c3)c(C(=O)O)cnc12
Reactant: Fc1ccc2c(c1)OCC21CCNCC1
Agent: Cl
Product: CCOC(=O)c1cnn2c(Nc3ccc(C)c(F)c3)c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc12
Yield: 96.1 %

Procedure:
In the same manner as in Example 21, step 5 and using 3-ethoxycarbonyl-7-(3-fluoro-4-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.130 g, 0.363 mmol) obtained in step 2 and 6-fluoro-2H-spiro[benzofuran-3,4′-piperidine]hydrochloride (0.082 g, 0.399 mmol), the title compound (0.191 g, 96%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:5]([N+:17]([O-])=O)=[CH:4][CH:3]=1>[Ni].CO.ClCCl>[NH2:17][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: N#Cc1cccc(Nc2nc(Cl)ccc2[N+](=O)[O-])c1
Agent: [Ni]
Solvent: ClCCl
Solvent: CO
Product: N#Cc1cccc(Nc2nc(Cl)ccc2N)c1

Procedure:
In step 1-2, Raney nickel was added to a suspension of 3-(6-chloro-3-nitropyridin-2-ylamino)benzonitrile in methanol/dichloromethane (1:1) and the resulting suspension was set up in Parr shaker under a hydrogen atmosphere (40 psi) for 18 hours. The remaining catalyst was removed through a Celite pad, and the reaction mixture was concentrated to afford the crude product 3-(3-amino-6-chloropyridin-2-ylamino)benzonitrile (1-2) which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:11]([NH2:12])=[CH:10][C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6]C)=O.O=[C:15]1CC(=O)CN(C(OCC2C=CC=CC=2)=O)C1.[CH3:32][N:33]1[CH2:45][C:44]2NC3C=CC=C4C(=O)[NH:47][N:48]=[C:35]([C:36]=2C=34)[CH2:34]1>>[CH2:32]([N:33]1[CH2:45][C:44]2[NH:12][C:11]3[CH:10]=[C:9]([F:13])[CH:8]=[C:3]4[C:4](=[O:6])[NH:47][N:48]=[C:35]([C:36]=2[C:2]=34)[CH2:34]1)[CH3:15]
Reactant: CN1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1
Reactant: O=C1CC(=O)CN(C(=O)OCc2ccccc2)C1
Reactant: COC(=O)c1cc(F)cc(N)c1Br
Product: CCN1CC2=NNC(=O)c3cc(F)cc4[nH]c(c2c34)C1

Procedure:
Compound 58 was prepared from methyl 2-bromo-5-fluoro-3-aminobenzoate and benzyl 3,5-dioxopiperidine-1-carboxylate according to the procedures similar to those for Compound 44. 1H NMR (DMSO-d6). δ 11.8 (s, 1H), 10.1 (s, 1H), 7.35 (dd, 1H, J=2.4, 9.6 Hz), 7.19 (dd, 1H, J=2.4, 10.2 Hz), 3.80 (s, 2H), 3.30 (s, 2H), 2.60-2.64 (m, 2H), and 1.09 (t, 3H, J=7.2 Hz). MS (ESI) m/e [M+1]+ 273.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[CH:13])=[CH:9][CH:10]=2)[N:5]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH2:4][CH2:3]1.[F:22][C:23]1[CH:33]=[C:32](I)[CH:31]=[CH:30][C:24]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(N(CC)CC)C.C(Cl)Cl>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][C:32]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:23]([F:22])[CH:33]=3)=[CH:9][CH:10]=2)[N:5]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(I)cc1F
Reactant: C#Cc1ccc2c(c1)N(c1ccc(C)cc1)CCC2(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)N(c2ccc(C)cc2)CCC3(C)C)cc1F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 0.20 g (0.72 mmol) of 4,4-dimethyl-1,2,3,4-tetrahydro-N-(4-methylphenyl)-7-ethynylquinoline (Compound 3) and 0.39 g (1.5 mmol) of ethyl 2-fluoro-4-iodobenzoate were added 2.9 g (4.0 mL, 29 mmol) of triethylamine, 0.029 g (0.15 mmol) of copper(I) iodide, and 0.113 g (0.16 mmol) of bis(triphenylphosphine)palladium(II) chloride, consecutively. The resulting mixture was stirred at room temperature for 20 hours. Methylene chloride was added and the reaction was adsorbed onto silica gel. The product was obtained by flash chromatography (5% ethyl acetate in hexanes) followed by recrystallization in ethanol to give the title compound as orange crystals. PNMR (300 MHz, CDCl3) d 1.37 (6 H, s), 1.40 (3 H, t, J=7.1 Hz), 1.86 (2 H, t, J=6.0 Hz), 2.38 (3 H, s), 3.61 (2 H, t, J=6.0 Hz), 4.39 (2 H, q, J=7.1 Hz), 6.77 (1 H, d, J=1.7 Hz), 6.87 (1 H, dd, J=7.9, 1.7 Hz), 7.23-7.28 (7 H, m), 7.86 (1 H, t, J=7.8 Hz).