Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)(=O)C.CCCCCC>[C:11]1([CH2:10][CH2:9][NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=Cc1ccccc1
Reactant: Nc1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Fc1ccc(NCCc2ccccc2)cc1
Yield: 84 %

Procedure:
According to GWM, 0.011 mol (=1.10 ml) of p-fluoroaniline and 0.011 mol (=1.25 ml) of styrene are reacted with one another. The product is isolated by column chromatography using ethyl acetate/n-hexane (1:1) as eluent, the product N-(2-phenylethyl)-(p-fluoro)aniline being obtained as brown liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH:12]([N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26])[C:13]([OH:15])=[O:14])([O-])=O>CO.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH:12]([N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26])[C:13]([OH:15])=[O:14]
Reactant: O=C(O)C(CCc1ccccc1[N+](=O)[O-])N1C(=O)c2ccccc2C1=O
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1CCC(C(=O)O)N1C(=O)c2ccccc2C1=O
Yield: 84.9 %

Procedure:
In 300 ml of methanol, 13 g of 4-(2-nitrophenyl)-2-phthalimidobutyric acid is catalytically reduced at ambient temperature and under atmospheric pressure with use of 3 g of 5% palladium-carbon as a catalyst. After the calculated amount of hydrogen is absorbed, the insoluble material is separated by filtration, and washed four times with 300 ml of acetone. The acetone washings and the methanol portion are combined and concentrated under reduced pressure. The residue is admixed with 50 ml of ethaniol, and the crystals which separate out are collected by filtration to give 10.1 g of 4-(2-aminophenyl)-2-phthalimidobutyric acid as yellow prisms, m.p. 198°-203° C. (decomp.).
Reaction SMILES: COC1C=C(C[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=2[OH:21])C=C(OC)C=1.[CH3:22][O:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[C:25]=1[CH:26]=O>>[CH3:22][O:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[C:25]=1[CH2:26][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[OH:21]
Reactant: COc1cc(CCCc2ccc(O)cc2O)cc(OC)c1
Reactant: COc1cc(OC)c(C=O)c(OC)c1
Product: COc1cc(OC)c(CCCc2ccc(O)cc2O)c(OC)c1

Procedure:
Compound 31 was synthesized following a similar procedure as described for compound 28 above using as starting materials 2,4-dibenzyloxyacetophenone and 2,4,6-trimethoxybenzaldehyde. 1H-NMR (MeOD, 500 MHz): δ 6.822 (d, 1H, J=8.0 Hz), 6.250 (d, 1H, J=2.5 Hz), 6.197 (dd, 1H, J=2.5 & 8.0 Hz), 6.165 (s, 2H), 3.768 (s, 3H), 3.764 (s, 6H), 2.562 (t, 2H, J=7.5 Hz), 2.461 (t, 2H, J=7.5 Hz), 1.617-1.653 (m, 2H). 13C-NMR (MeOD, 125 MHz): δ 159.273 (C), 158.729 (2C), 155.556 (C), 155.449 (C), 129.655 (2CH), 120.426 (C), 111.382 (C), 105.789 (CH), 101.968 (CH), 90.285 (CH), 54.655 (2CH3), 54.274 (CH3), 29.716 (CH2), 29.064 (CH2), 22.142 (CH2).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[CH:12][C:13](=[O:26])[C:14]=2[C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[C:18]([OH:20])=O)[N:10]=1.C(N(CC)CC)C.C(OC(Cl)=O)C.[CH:45]1([NH2:48])[CH2:47][CH2:46]1>C(Cl)Cl>[CH:45]1([NH:48][C:18](=[O:20])[C:17]2[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:15]([C:14]3[C:13](=[O:26])[CH:12]=[CH:11][N:9]4[C:8]=3[CH:7]=[CH:6][C:5]([O:4][C:3]3[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:2]=3[F:1])=[N:10]4)[CH:16]=2)[CH2:47][CH2:46]1
Reactant: NC1CC1
Reactant: COc1ccc(C(=O)O)cc1-c1c(=O)ccn2nc(Oc3ccc(F)cc3F)ccc12
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)NC2CC2)cc1-c1c(=O)ccn2nc(Oc3ccc(F)cc3F)ccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of Intermediate 1 in CH2Cl2 was added triethyl amine and ethylchloroformate at 0° C. The mixture was warmed to ambient temperature and stirred for 10 min. The reaction was complete by LCMS analysis and concentrated in vacuo to yield crude residue. To the crude residue was added CH2Cl2 and cyclopropyl amine, followed by stirring for ½ hr. LCMS indicated the reaction was complete. The reaction was diluted with CH2Cl2, washed with 0.5 N NaOH, H2O, brine, dried over MgSO4, and concentrated in vacuo. The crude residue was purified via silica gel chromatography (EtOAc/CH2Cl2/MeOH).
Reaction SMILES: Cl.[OH-:2].[NH4+:3].[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([C:19]2[S:20][CH:21]=[C:22]([CH3:25])[C:23]=2[Br:24])=O)[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].Cl>N1C=CC=CC=1>[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([C:19]2[S:20][CH:21]=[C:22]([CH3:25])[C:23]=2[Br:24])=[N:3][OH:2])[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: [NH4+]
Reactant: [OH-]
Reactant: Cc1csc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1csc(C(=NO)C2CCN(C(=O)OC(C)(C)C)CC2)c1Br
Temperature: 70 °C
Reaction time: 4 h
Yield: 23.7 %

Procedure:
Add ammonium hydroxide hydrochloride (50.68 mmol, 3.52 g, 2.00 equivalents) to a stirred solution of 4-[1-(3-bromo-4-methyl-thiophen-2-yl)-methanoyl]-piperidine-1-carboxylic acid tert-butyl ester (25.54 mol, 9.84 g, 1.00 equivalents) in pyridine (47.5 mL). Stir at room temperature overnight and at 70° C. for 4 hours. Cool the reaction mixture and add hydrochloric acid (3 M solution, 115 mL). Extract the reaction mixture with dichloromethane (115 mL), filter the organic layer, wash with water (100 mL), dry over magnesium sulfate, filter and evaporate. Recrystallize the resulting residue from toluene to yield a white solid (4.84 g).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])(C)(C)C.[N:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1)=C=O.[CH3:27][O:28][CH2:29][CH2:30][NH2:31]>>[CH3:27][O:28][CH2:29][CH2:30][NH:31][C:10]([CH:9]1[CH2:13][C:14](=[CH2:16])[CH2:15][N:8]1[C:6]([NH:17][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1)=[O:7])=[O:12]
Reactant: Cc1cccc(N=C=O)c1
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: COCCN
Product: C=C1CC(C(=O)NCCOC)N(C(=O)Nc2cccc(C)c2)C1

Procedure:
Following the general method as outlined in Example 22, starting from 1-(tert-butoxycarbonyl)-4-methyleneproline, 1-isocyanato-3-methylbenzene, and 2-methoxyethylamine the title compound was obtained in 85% purity by LC/MS. MS(ESI+): m/z=318.0.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]2)=[C:5]([CH3:14])[O:4][N:3]=1.[CH2:15]([N:22]=[C:23]=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[CH2:15]([NH:22][C:23]([NH:13][C:11]1[CH:10]=[N:9][N:8]([CH2:7][C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:14])[CH:12]=1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C=NCc1ccccc1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Solvent: CC#N
Product: Cc1noc(C)c1Cn1cc(NC(=O)NCc2ccccc2)cn1
Temperature: 25 °C
Yield: 50.7 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine (287 mg, 1.49 mmol) and benzyl isocyanate (199 mg, 1.49 mmol) in acetonitrile (5 mL) were heated at 65° C. for 16 hours. The reaction was cooled down to room temperature and concentrated. The residue was purified by silica column chromotography (100% to 90% dichloromethane in methanol:30 minute gradient) and triturated with ethyl acetate/hexanes (1/9) to afford 1-benzyl-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)urea (246 mg, 51%) as a white solid. LC/MS; [M+H] calculated for C17H19N5O2; expected 326.15. found 326.10.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[CH:38]=[C:39]([CH2:44][CH2:45][OH:46])[CH:40]=[CH:41][C:42]=3[F:43])[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH:47]([C:50]1[S:51][CH:52]=[C:53]([C:55](O)=[O:56])[N:54]=1)([CH3:49])[CH3:48].C(N(CC)CC)C>CN(C=O)C>[F:43][C:42]1[CH:41]=[CH:40][C:39]([CH2:44][CH2:45][OH:46])=[CH:38][C:37]=1[CH2:36][N:33]1[CH2:34][CH2:35][C:30]2([O:25][CH2:26][CH2:27][N:28]([C:55]([C:53]3[N:54]=[C:50]([CH:47]([CH3:49])[CH3:48])[S:51][CH:52]=3)=[O:56])[CH2:29]2)[CH2:31][CH2:32]1
Reactant: CC(C)c1nc(C(=O)O)cs1
Reactant: OCCc1ccc(F)c(CN2CCC3(CC2)CNCCO3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cc(CCO)ccc4F)CC3)C2)cs1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
HATU (1.1 g) was added in one portion to a cooled solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)-4-fluorophenyl)ethanol [Example 44, step c] (0.7 g) and 2-isopropylthiazole-4-carboxylic acid (0.39 g) and triethylamine (0.95 mL) in DMF (15 mL). The reaction mixture was stirred at 20° C. for 1 hour and then partitioned between ethyl acetate and brine. The organic layer was washed with brine (×2), dried, filtered and the solvent removed under reduced pressure. The crude product was purified by flash silica chromatography, using 3% methanol in ethyl acetate containing 1% triethylamine as solvent. Fractions containing the product were evaporated to dryness to afford the subtitled compound. Yield 0.61 g.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].CCN(C(C)C)C(C)C.[C:19](Cl)(Cl)=[O:20].[NH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:33][N:34]([CH2:45][C:46]2[C:51]([CH3:52])=[CH:50][C:49]([CH3:53])=[CH:48][N:47]=2)[CH:35]2[C:44]3[N:43]=[CH:42][CH:41]=[CH:40][C:39]=3[CH2:38][CH2:37][CH2:36]2)=[C:29]([CH2:31][OH:32])[CH:30]=1>C1(C)C=CC=CC=1.CN(C=O)C>[CH3:52][C:51]1[C:46]([CH2:45][N:34]([CH2:33][C:28]2[CH:27]=[CH:26][C:25]([CH2:24][NH:23][C:19](=[O:20])[N:3]([CH2:1][CH3:2])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:30][C:29]=2[CH2:31][OH:32])[CH:35]2[C:44]3[N:43]=[CH:42][CH:41]=[CH:40][C:39]=3[CH2:38][CH2:37][CH2:36]2)=[N:47][CH:48]=[C:49]([CH3:53])[CH:50]=1
Reactant: Cc1cnc(CN(Cc2ccc(CN)cc2CO)C2CCCc3cccnc32)c(C)c1
Reactant: CCNc1ccccc1
Reactant: O=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCN(C(=O)NCc1ccc(CN(Cc2ncc(C)cc2C)C2CCCc3cccnc32)c(CO)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To a solution of N-ethylaniline (23 μL, 0.18 mmol) in toluene (3 mL) was added DIPEA (63 μL, 0.36 mmol) and phosgene (99 μL, 2.2M in toluene, 0.22 mmol). The mixture was stirred for 2 hours at room temperature under N2 and then the solvent was removed under reduced pressure to give a white solid. A solution of (5-aminomethyl-2-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenyl)-methanol (0.075 g, 0.18 mmol) and DIPEA (63 μL, 0.36 mmol) in DMF (4 mL) was added to the white residue and the resulting mixture was stirred for 16 hours. The solvent was removed under reduced pressure and the resulting residue was suspended in CH2Cl2 (30 mL) and quenched with saturated aqueous NaHCO3 (30 mL). The mixture was extracted with CH2Cl2 (3×30 mL) and the combined organic extracts were washed with brine (3×20 mL) and then dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 93:5:2, v/v/v) afforded 3-(4-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-3-hydroxymethyl-benzyl)-1-ethyl-1-phenyl-urea as a white foamy solid (0.080 g, 78%). 1H NMR (CDCl3) δ 1.10 (t, 3H, J=9.0 Hz), 1.60 (m, 1H), 1.99 (m, 1H), 2.19 (m, 2H), 2.20 (s 3H), 2.24 (s, 3H), 2.64 (m, 1H), 2.78 (m, 1H), 3.63 (d, 2H, J=12.0 Hz), 3.70-3.79 (m, 3H), 3.86 (t, 1H, J=7.5 Hz), 4.11 (m, 2H), 4.31 (d+m, 2H), 4.42 (m, 1H), 7.05 (m, 2H), 7.14-7.38 (m, 9H), 8.15 (s, 1H), 8.37 (d, 1H, J=3.0 Hz). HPLC: 99%.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]([CH3:30])([CH3:29])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21]1)=[O:12].O>CN(C)C=O>[CH3:9][C:10]([CH3:30])([CH3:29])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Br:1])[CH:26]=2)[NH:21]1)=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)C(=O)Nc1ccccc1C1Cc2ccccc2N1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccccc1C1Cc2cc(Br)ccc2N1
Reaction time: 1 h
Yield: 94.6 %

Procedure:
A solution of 4.0 g N-bromosuccinimide in 40 ml anhydrous DMF (dimethylformamide) was added dropwise at 5° C. (ice bath) over 20 minutes to a solution of 6.0 g 2,2-dimethyl-N-[2-(2,3-dihydro-1H-indol-2-yl)phenyl]propanamide in 60 ml DMF. After stirring for one hour additionally, the resulting solution was poured into excess water and the precipitated solid was collected, washed, and taken up in Et2O. The extract was washed with water and brine, dried (MgSO4) and concentrated to give 7.2 g solid. Recrystallization from cyclohexane gave 2.2 g needles, m.p. 173°-175° C.
Reaction SMILES: [Zn:1].II.[Br:4]CCCCCCCCC(OCC)=O.[C:18]([O:28][CH2:29][CH3:30])(=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CC(N(C)C)=O>[Br:4][Zn:1][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCCCCCCCC(=O)OCC
Reactant: CCOC(=O)CCCCCCCCBr
Reactant: [Zn]
Agent: II
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCCCCCCC[Zn]Br
Temperature: 80 °C
Reaction time: 4 h

Procedure:
In a dry reaction tube under nitrogen were charged zinc dust (3.70 g, 56.6 mmol), iodine (479 mg, 1.89 mmol) and dry DMA (20 mL). The mixture was stirred at room temperature until the color of iodine disappeared. Ethyl 9-bromononanoate was added, and the mixture was stirred at 80° C. for 4 hours and then at room temperature overnight. (Completion of the zinc insertion reaction was checked by GCMS analysis of the hydrolyzed reaction mixture.) The reaction mixture was used without further treatment in the subsequent step. GCMS m/z 186 [M]+ (ethyl nonanoate).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:20]([CH3:22])[CH3:21])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH:23](=[O:26])[C:24]#[CH:25]>C1COCC1.CC(C)=O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:11]=[C:10]([CH:20]([CH3:22])[CH3:21])[N:9](/[CH:25]=[CH:24]/[CH:23]=[O:26])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)[nH]1
Reactant: C#CC=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/C=O

Procedure:
A solution of 4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazole (200 mg) and propiolaldehyde (75% solution in toluene, 0.15 ml) in dry THF (15 ml) were heated under reflux, under nitrogen for 24 h. The residue was dissolved in acetone and absorbed onto silica gel before purifying by CC eluting with petroleum ether (b.p. 40°-60°)/ethyl acetate (2:1) to give the title compound (84 mg) as a pale yellow solid, δ(CDCl3), 1.49 (d,J=7 Hz, Me2CH), 3.25 (septet, J=7 Hz, Me2CH), 5.67 (dd,J=15 Hz, 7 Hz,CH=CH.CHO), 6.95 and 7.10-7.60 (t,J=9 Hz and m, CH=CH.CHO and aromatic protons), 9.40 (d, J=7 Hz, CH=CH.CHO).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[C:9]([NH2:11])[CH:10]=1.Cl.[N:27]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]2[C:8]([C:12]([S:13]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])=[N:27][NH:11]2)=[CH:7][CH:6]=1
Reactant: O=N[O-]
Reactant: Nc1cc(OCCCl)ccc1CS(=O)(=O)c1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2cc(OCCCl)ccc12
Temperature: 3 °C

Procedure:
A mixture of 5-(2-chloro-ethoxy)-2-(naphthalene-1-sulfonylmethyl)-phenyl amine (0.74 g, 1.99 mmoles) in THF (5 mL), and 4M HCl (10 mL) was stirred in a round bottom flask, under nitrogen, at 3° C. A solution of sodium nitrite (0.14 g, 2.08 mmoles) in H2O (1 mL) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.74 g, 1.93 mmoles).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[CH:9]=2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(C1(C2C=C(OC)C=C(OC)C=2)[S:26][CH2:25][CH2:24][S:23]1)CCC>CCCCCC.C(OCC)(=O)C>[CH:1]1([C:6]2([C:8]3[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[CH:9]=3)[S:26][CH2:25][CH2:24][S:23]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCCC1(c2cc(OC)cc(OC)c2)SCCS1
Reactant: COc1cc(OC)cc(C(=O)C2CCCC2)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(OC)cc(C2(C3CCCC3)SCCS2)c1

Procedure:
Compound 10 was prepared from Compound 6 using the same procedure as described above for Compound 9. Yield 2.92 g (87%) as an oil. Rf=0.52 (hexane:ethyl acetate 92:8); IR (neat) 2955, 1206, 1066, 694 cm−1; 1H NMR δ 6.98 (d, J=2.19 Hz, 2H), 6.34 (t, J=2.25 Hz, 1H), 3.80 (s, 6H), 3.35–3.09 (m, 4H), 2.82–2.71 (m, 1H), 1.80–1.43 (m, 8H). 13C NMR δ 160.03, 149.37, 106.37, 98.35, 79.474, 55.35, 52.14, 38.79, 31.17, 25.73; MS: (ESI, Pos.) m/z 333 ([M+23]+).
Reaction SMILES: C(N(CC)CC)C.[CH:8]([NH:11][C:12]([C@@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)=[O:13])([CH3:10])[CH3:9].Cl[C:20]1[N:28]2[C@@H:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[CH2:30][O:31][C:26]3=[C:27]2[C:22](=[CH:23][CH:24]=[C:25]3[C:38]2[C:39]([CH3:44])=[N:40][O:41][C:42]=2[CH3:43])[N:21]=1>CN1CCCC1=O.CO>[CH3:44][C:39]1[C:38]([C:25]2[C:26]3[O:31][CH2:30][C@H:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[N:28]4[C:20]([N:16]5[CH2:17][CH2:18][C@@H:14]([C:12]([NH:11][CH:8]([CH3:10])[CH3:9])=[O:13])[CH2:15]5)=[N:21][C:22]([C:27]=34)=[CH:23][CH:24]=2)=[C:42]([CH3:43])[O:41][N:40]=1
Reactant: CC(C)NC(=O)[C@@H]1CCNC1
Reactant: Cc1noc(C)c1-c1ccc2nc(Cl)n3c2c1OC[C@@H]3c1ccccn1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CN1CCCC1=O
Product: Cc1noc(C)c1-c1ccc2nc(N3CC[C@@H](C(=O)NC(C)C)C3)n3c2c1OC[C@@H]3c1ccccn1
Temperature: 120 °C
Yield: 10.2 %

Procedure:
Triethylamine (110 μL, 0.79 mmol) and (3R)—N-isopropylpyrrolidine-3-carboxamide (120 mg, 0.74 mmol) were added to a solution of (4S)-2-chloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (66.0 mg, 0.18 mmol) in N-methylpyrrolidinone (1.5 mL), and the resulting mixture was heated in a microwave at 120° C. for 5 min. The mixture was diluted with methanol and purified twice by preparative LCMS using pH 10 buffer to give the title compound, (8.9 mg, 10%). LCMS calc. for C27H31N6O3 (M+H)+: m/z=487.2. found: 487.3. 1H NMR (500 MHz, DMSO) δ 8.54 (dd, J=4.8, 0.8 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.72 (td, J=7.7, 1.8 Hz, 1H), 7.29 (dd, J=6.8, 4.9 Hz, 1H), 6.95 (d, J=8.1 Hz, 1H), 6.80 (d, J=8.1 Hz, 1H), 6.60 (d, J=7.9 Hz, 1H), 6.09 (t, 1H), 4.82 (dd, J=11.4, 1.3 Hz, 1H), 4.53 (dd, J=11.5, 2.8 Hz, 1H), 3.85-3.71 (m, 3H), 3.43 (dd, J=9.6, 7.6 Hz, 1H), 3.39-3.32 (m, 1H), 2.90 (p, J=7.8 Hz, 1H), 2.19 (s, 3H), 2.02 (s, 3H), 2.00-1.89 (m, 2H), 1.01 (dd, J=10.1, 6.6 Hz, 6H).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[F:11].[Li][CH2:13][CH2:14][CH2:15]C.CCCCCC.C1C[O:26]CC1>C(=O)=O.CC(C)=O>[F:11][C:3]1[C:4]([F:10])=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=1[CH2:13][C@H:14]([OH:26])[CH3:15]
Reactant: C1CCOC1
Reactant: [Li]CCCC
Reactant: Fc1cc(F)c(F)c(Br)c1F
Agent: O=C=O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: C[C@@H](O)Cc1c(F)c(F)cc(F)c1F
Reaction time: 0.5 h
Yield: 49 %

Procedure:
A solution of 1-bromo-2,3,5,6-tetrafluorobenzene (4.71 g, 20.57 mmol) in anhydrous THF (100 mL) was stirred in a −78° C. in dry ice/acetone bath under argon gas. After 30 min, 2.5 M n-BuLi in hexane (9.05 mmol, 22.63 mmol) was added dropwise at that temperature for 20 min. After adding, the mixture was stirred at −78° C. in the dry ice/acetone bath for 30 min, and stirred more for 10 min without the bath. And then, the solution was cooled again in the dry ice/acetone to −78° C. and a solution of R-(+)-propylene (1.44 mL, 20.57 mmol) in 10 mL anhydrous THF was added dropwise at the temperature for 10 min and stirred at ambient temperature for overnight. And then, the solution was quenched slowly by sat. NH4Cl, and stirred more for 2 h. Water (20 mL) was added and extracted with EtOAc, dried over anhydrous MgSO4, evaporated and purified by column chromatography (DCM/hexane 9/1) to give pale yellow oil (yield 49%˜59%). 1H NMR (CDCl3, 500 MHz) δ 6.97 (m, 1H), 4.12 (m, 1H), 2.89 (m, 2H), 1.45 (bs, 1H), 1.29 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)=O.[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19].C1C=CC=CC=1>O>[CH2:16]([N:20]=[C:1]=[C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH2:4]1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCN
Reactant: CCOC(=O)COc1ccc(C=O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCN=C=C1C=CC(OCC(=O)OCC)=CC1
Reaction time: 1 h
Yield: 82.5 %

Procedure:
Ethyl (4-formylphenoxy)acetate (104.1 g, 0.5 mole), butylamine (36.6 g, 0.5 mole) and benzene (400 ml) were united and refluxed in a flask equipped with a Dean-Stark water separator. After one hour, water ceased to separate. The heating was terminated after 6 hours and the mixture distilled. There was obtained 108.6 g of product boiling at 178°-181° C. at 0.5 mm Hg pressure.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C(N(CC)C(C)C)(C)C.[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][CH2:24][CH2:25]Br)([CH3:19])([CH3:18])[CH3:17].[C:28]([C:30]1[CH:60]=[CH:59][C:33]([O:34][C:35]2[N:49]=[C:48]([O:50][C:51]3[CH:56]=[CH:55][C:54]([C:57]#[N:58])=[CH:53][CH:52]=3)[CH:47]=[CH:46][C:36]=2[C:37]([NH:39][CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[O:38])=[CH:32][CH:31]=1)#[N:29]>CN(C=O)C>[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][CH2:24][CH2:25][N:43]1[CH2:44][CH2:45][CH:40]([NH:39][C:37]([C:36]2[C:35]([O:34][C:33]3[CH:32]=[CH:31][C:30]([C:28]#[N:29])=[CH:60][CH:59]=3)=[N:49][C:48]([O:50][C:51]3[CH:56]=[CH:55][C:54]([C:57]#[N:58])=[CH:53][CH:52]=3)=[CH:47][CH:46]=2)=[O:38])[CH2:41][CH2:42]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: N#Cc1ccc(Oc2ccc(C(=O)NC3CCNCC3)c(Oc3ccc(C#N)cc3)n2)cc1
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCCN1CCC(NC(=O)c2ccc(Oc3ccc(C#N)cc3)nc2Oc2ccc(C#N)cc2)CC1
Temperature: 45 °C
Yield: 88.7 %

Procedure:
0.117 g (0.85 mmol) of K2CO3 and N,N-diisopropylethylamine 0.072 g (0.56 mmol) followed by 0.201 g (0.85 mmol) of (3-bromo-propyl)-carbamic acid tert-butyl ester, dissolved in 5 ml of DMF, were added to a stirred solution of 0.373 g (0.85 mmol) of 2,6-bis-(4-cyano phenoxy)-N-piperidine-4-yl nicotinamide, dissolved in 5 ml of DMF over a period of 15 min at 20° C. Reaction mixture was allowed to attain RT and heated to 45° C. for 2 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was partitioned between water (150 ml) and ethyl acetate (150 ml). The organic phase was washed with 1 M Na2CO3 and saturated brine solution, and dried over sodium sulphate. The solution was concentrated and the oily residue was purified by column chromatography using hexane-ethyl acetate (10:2) to afford 0.45 g of the required product. Percentage purity (LCMS): 72.5%, (M+1)=596.2+1.