Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([Br:28])[C:9]=1[CH2:10][N:11]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[O:26][CH3:27])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=O.CC(C)([O-])C.[K+]>C1COCC1>[CH3:16][O:15][C:13]([CH:12]1[N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[CH2:10][C:9]2[C:8]([Br:28])=[CH:7][S:6][C:5]=2[C:3]1=[O:2])=[O:14]
Reactant: COC(=O)CN(Cc1ccc(OC)cc1OC)Cc1c(Br)csc1C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C1C(=O)c2scc(Br)c2CN1Cc1ccc(OC)cc1OC
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
4-Bromo-3-{[(2,4-dimethoxy-benzyl)-methoxycarbonylmethyl-amino]-methyl}-thiophene-2-carboxylic acid methyl ester (13.3 g, 28.2 mmol), example 31-c, was dissolved in 277 mL of anhydrous THF and cooled to −15° C. in a brine dry ice bath. A solution of 62.0 mL of 1.0 M potassium tert-butoxide in THF was added slowly to cold solution, and the reaction mixture was stirred at −15° C. for 30 min. and then at room temperature for 2 hours. The reaction was quenched with 62.0 mL of 1N HCl, and 500 mL ammonium chloride, and extracted twice with 600 mL of ethyl acetate. The organic fractions were washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-50% ethyl acetate in hexanes to produce 12.4 g of a yellow froth. MS: (+) m/z 461.9, 463.9 (M+Na+, 79Br/81Br).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[Cl:9][C:10]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:11]=1[CH:12]=O.N1CCCCC1.C(O)(=O)C>O1CCCC1>[Cl:9][C:10]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:11]=1[CH:12]=[C:3]([C:1]#[N:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CCOC(=O)CC#N
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: CCOC(=O)C(C#N)=Cc1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
29.7 g (300 millimoles) of ethyl cyanoacetate were added to a solution of 55.7 g (300 millimoles) of 2-chloro-5-nitrobenzaldehyde in 200 ml of tetrahydrofuran, after which 1 ml of piperidine was added as a catalyst at 0° C. The mixture was stirred for 16 hours at room temperature, neutralized with acetic acid and then worked up in a conventional manner to give a product of melting point 83°-85° C. in 71% yield.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH2:15][CH3:16])[CH:7]=1)[CH2:3][CH2:4][OH:5].C[O:18][C:19](=O)[C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:29]Br.C(N(CC)CC)C>CN(C=O)C>[CH2:15]([O:14][C:8]1[CH:7]=[C:6]([C@H:2]([N:1]2[CH2:29][C:21]3[C:20](=[C:25]([N+:26]([O-:28])=[O:27])[CH:24]=[CH:23][CH:22]=3)[C:19]2=[O:18])[CH2:3][CH2:4][OH:5])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13])[CH3:16]
Reactant: CCOc1cc([C@H](N)CCO)ccc1OC
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc([C@@H](CCO)N2Cc3cccc([N+](=O)[O-])c3C2=O)ccc1OC

Procedure:
(1R)-2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-hydroxy-propyl]-7-nitro-2,3-dihydro-isoindol-1-one was prepared by the procedure of Example 1 from (3R)-3-amino-3-(3-ethoxy-4-methoxy-phenyl)-propan-1-ol (3.0 g, 13 mmol), 2-bromomethyl-6-nitro-benzoic acid methyl ester (3.6 g, 13 mmol) and triethylamine (2 mL, 14 mmol) in DMF (40 mL) to give a yellow solid (4.1 g, 81% yield): 1H NMR (CDCl3) δ 1.44 (t, J=7 Hz, 3H, CH3), 2.13-2.31 (m, 2H, CH2), 3.54-3.59 (m, 1H, CHH), 3.71-3.77 (m, 1H, NCHH), 3.87 (s, 3H, CH3), 3.94 (d, J=16 Hz, 1H, NCHH), 4.06 (q, J=7 Hz, 2H, CH2), 4.26 (d, J=16 Hz, 1H, NCHH), 5.70 (dd, J=4, 11 Hz, 1H, NCH), 6.85-6.99 (m, 3H, Ar), 7.55-7.77 (m, 3H, Ar); 13C NMR (CDCl3) δ 14.76, 33.92, 45.80, 51.30, 55.98, 58.65, 64.63, 65.84, 111.39, 113.22, 119.75, 122.91, 124.13, 126.74, 130.66, 132.11, 143.84, 146.66, 148.68, 149.33, 164.22.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[CH2:17]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[CH2:18][CH3:19]>>[CH2:17]([C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)=[CH:22][CH:21]=1)[CH2:18][CH3:19]
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Reactant: CCCc1ccc(N)cc1
Product: CCCc1ccc(Nc2ccc3c(=O)[nH]c4ncccc4c3c2)cc1
Yield: 16.2 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (100 mg, 0.43 mmol) and 4-propylaniline (0.10 ml; 0.65 mmol) to provide 243 (23 mg, 15% yield) as a brown solid. LC-MS (M+H (parent)=330, obsd.=330).
Reaction SMILES: [CH3:1][C@H:2]([OH:5])[CH:3]=[CH2:4].N1C=CC=CC=1.[F:12][CH:13]([C:17]([F:20])([F:19])[F:18])[C:14](Cl)=[O:15].O>ClCCl>[F:12][CH:13]([C:17]([F:20])([F:19])[F:18])[C:14]([O:5][CH:2]([CH:3]=[CH2:4])[CH3:1])=[O:15]
Reactant: O=C(Cl)C(F)C(F)(F)F
Reactant: C=C[C@H](C)O
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: C=CC(C)OC(=O)C(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
In 20 ml of dichloromethane were dissolved 0.72 g of (S)-(-)-3-buten-2-ol (98%ee) and 0.95 g of pyridine, and then 1.65 g of 2,3,3,3-tetrafluoropropionyl chloride was dropwise added to the above-obtained solution while the solution was being cooled with ice. The resulting mixture was stirred at room temperature for 30 minutes, subsequently water was added thereto, and then the reaction mixture was subjected to extraction with ether. The resulting extract was washed with 1N hydrochloric acid, a 5% aqueous solution of sodium hydrogencarbonate, and brine, and then dried with magnesium sulfate. Subsequently, the solvent was removed under reduced pressure, and the residual product was distilled, thereby obtaining 1.50 g of 3-buten-2-yl 2,3,3,3-tetrafluoropropionate having the following physical properties.
Reaction SMILES: [N:1](=[C:3]1[CH2:8][S:7][CH2:6][CH2:5][S:4]1)[OH:2].[CH3:9][N:10]([S:14][S:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=1)[C:11](F)=[O:12].C(N(CC)CC)C>O1CCOCC1>[CH3:9][N:10]([S:14][S:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=1)[C:11]([O:2][N:1]=[C:3]1[CH2:8][S:7][CH2:6][CH2:5][S:4]1)=[O:12]
Reactant: CN(SSc1ccc(C(C)(C)C)cc1)C(=O)F
Reactant: ON=C1CSCCS1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(SSc1ccc(C(C)(C)C)cc1)C(=O)ON=C1CSCCS1

Procedure:
2-[[O-[N-Methyl-N-(4-tert.butylphenylthiosulfenyl)carbamoyl]oximino]]-1,4-dithiane was prepared according to the procedure described in Example I, by reacting 1.09 g (0.0073 m) of 2-oximino-1,4-dithiane, 2.0 g (0.0073 m) of N-methyl-N-(4-tert.butylphenylthiosulfenyl)carbamoyl fluoride and 0.736 g (0.0073 m) of triethylamine in 25 ml of dioxane. Weight of the residual oil 1.95 g IR (Neat) 5.75μ (C=O). NMR (CDCl3) 1.28δ(s), 9H, t-butyl; 3.10δ(s), 4H, (CH2), 3.20δ(s), 3H, CH3N; 3.52δ(s) 2H, CH2 ; 7.37δ(d), JAB =8.5 Hz 2H and 7.54δ(d) JBA =85 Hz, 2H. Aromatic.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([NH:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]3[N:12]=[C:13]([S:15][CH3:16])[S:14][C:10]=3[CH:9]=2)=[C:4]([N+:21]([O-])=O)[CH:3]=1.C(O)(=O)C.CO>[Zn].C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH2:21])[C:5]([NH:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]3[N:12]=[C:13]([S:15][CH3:16])[S:14][C:10]=3[CH:9]=2)=[CH:19][CH:20]=1
Reactant: CSc1nc2ccc(CNc3ccc(F)cc3[N+](=O)[O-])cc2s1
Agent: [Zn]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CSc1nc2ccc(CNc3ccc(F)cc3N)cc2s1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
To a stirred mixture of 4-fluoro-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline (1.18 g, 3.3 mmol) from the previous step, acetic acid (3 mL), MeOH (3 mL) and DCM (20 mL) at −10° C. was added portionwise zinc dust (1.7 g, 26 mmol). The reaction mixture was stirred at −10° C. for 0.5 h. The mixture was poured into ice-water and extracted with EtOAc (100 mL×3). The combined organic layers were washed sequentially with water, saturated aq NaHCO3 (100 mL×2), and brine (100 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 4-fluoro-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine (0.93 g, yield 87%) as a yellow solid, which was not purified further. 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J=8.4 Hz, 1H), 7.76 (s, 1H), 7.42 (dd, J=8.4, 1.8 Hz, 1H), 6.42-6.56 (m, 3H), 4.35 (s, 2H), 3.60 (br s, 2H), 2.79 (s, 3H); LCMS (ESI) m/z 320 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH:12]=[CH:13][C:14](=[CH2:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]([O:20]CC)=O.[C:23]([NH:36][NH2:37])(=[O:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[C:23]([NH:36][NH:37][C:18]([C:3]1[C:4](=[O:17])[N:5]([CH:12]=[CH:13][C:14](=[CH2:16])[CH3:15])[C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:20])(=[O:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: C=C(C)C=Cn1c(=O)c(C(=O)OCC)c(O)c2ccccc21
Reactant: CCCCCCCCCCCC(=O)NN
Product: C=C(C)C=Cn1c(=O)c(C(=O)NNC(=O)CCCCCCCCCCC)c(O)c2ccccc21

Procedure:
Reagents: Comp 29 (0.66 mmols, 0.2 g); dodecanoyl hydrazine (0.73 mmols, 0.16 g). Yield: 0.125 g (40%), white solid, m.p.=107° C.-108° C.
Reaction SMILES: CN(C)C=O.[C:6]([Cl:11])(=O)[C:7](Cl)=O.[Br:12][C:13]1[C:17]2[N:18]=[CH:19][NH:20]C(=O)C=2[S:15][CH:14]=1.O>ClCCl>[Br:12][C:13]1[C:17]2[N:18]=[CH:19][N:20]=[C:6]([Cl:11])[C:7]=2[S:15][CH:14]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=c1[nH]cnc2c(Br)csc12
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: Clc1ncnc2c(Br)csc12
Yield: 81.5 %

Procedure:
Dimethylformamide (25.8 mL, 0.33 mol) and dichloromethane (150 mL) were added to a reactor. Oxalyl chloride (46.4 mL, 0.53 mol) diluted with dichloromethane (150 mL) at room temperature was added to the reactor for about 30 minutes. 7-bromothieno[3,2-d]pyrimidin-4(3H)-one (35 g, 0.15 mol) was added thereto, and then, the reaction solution was heated to reflux for 3 hours. The temperature of the reaction solution was lowered and water was carefully added thereto. The organic layer was separated, and the aqueous layer was subjected to extraction using dichloromethane. The extracted organic layer was dried over anhydrous sodium sulfate. The dried organic layer was filtered and distilled under reduced pressure, and dried with nitrogen gas to obtain the title compound (30.5 g, 85%).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:16][CH3:17])=[C:13]([F:15])[CH:14]=2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20](=[O:43])[CH2:21][CH:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:18][O:19][C:20](=[O:43])[CH2:21][CH:22]1[CH2:23][CH2:24][CH:25]([C:28]2[CH:29]=[CH:30][C:31]([C:2]3[CH:3]=[CH:4][C:5]([NH:8][C:9]4[CH:10]=[N:11][C:12]([O:16][CH3:17])=[C:13]([F:15])[CH:14]=4)=[CH:6][N:7]=3)=[CH:32][CH:33]=2)[CH2:26][CH2:27]1
Reactant: COc1ncc(Nc2ccc(Br)nc2)cc1F
Reactant: COC(=O)CC1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)CC1CCC(c2ccc(-c3ccc(Nc4cnc(OC)c(F)c4)cn3)cc2)CC1
Temperature: 80 °C

Procedure:
To a solution of (6-bromo-pyridin-3-yl)-(5-fluoro-6-methoxy-pyridin-3-yl)-amine (0.17 g, 0.6 mmol, 1.0 equiv) and {4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (0.22 g, 0.6 mmol, 1.0 equiv) in 15 Ml DME was added 1 Ml saturated sodium carbonate solution followed by 10 mg Pd(PPh3)4 catalyst. The reaction was then heated to 80° C. overnight. Removal of volatiles in vacuo followed by silica gel chromatography (20% EtOAc in hexanes) afforded the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93-1.08 (m, 1 H) 1.01 (d, J=2.78 Hz, 1 H) 1.31-1.52 (m, 3. H) 1.62 (s, 2 H) 1.69 (d, J=9.85 Hz, 4 H) 2.02 (d, J=7.07 Hz, 2 H) 3.81 (s, 3 H) 7.28 (d, J=8.34 Hz, 2 H) 7.58 (d, J=13.89 Hz, 1 H) 7.75 (d, J=8.34 Hz, 3 H) 7.70 (d, J=8.59 Hz, 1 H) 7.81 (d, J=2.27 Hz, 1 H) 7.89 (d, J=8.84 Hz, 1 H) 8.15 (s, 1 H) 9.04 (br. S., 1 H); (M+H)+ 450.3.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:14]=[C:13]([O:15][CH2:16][CH:17]=[CH2:18])[CH:12]=[C:6]([C:7]([N:9]([CH3:11])[CH3:10])=[O:8])[CH:5]=1.[OH-].[K+]>C1COCC1.CO>[CH2:16]([O:15][C:13]1[CH:12]=[C:6]([C:7]([N:9]([CH3:11])[CH3:10])=[O:8])[CH:5]=[C:4]([CH:14]=1)[C:3]([OH:19])=[O:2])[CH:17]=[CH2:18]
Reactant: C=CCOc1cc(C(=O)OC)cc(C(=O)N(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=CCOc1cc(C(=O)O)cc(C(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2 g (7.6 mmol) of 5-allyloxy-N,N-dimethyl-isophthalamic acid methyl ester in 16.8 ml of THF/MeOH (1:1) 8.4 ml of 1 M KOH (1.1 eq.) are added at 0° C. The mixture is stirred at rt for 3 h. The organic solvents are removed under reduced pressure, and the aqueous phase is acidified with HCl to pH 2 and extracted with DCM/EtOH (80:20) (2×38 ml). The combined organic layers are washed with 8 ml of water, dried over sodium sulfate and evaporated to give the product in the form of a colorless solid (m.p.: 93-95° C.).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]1[C:33]2[C:28](=[CH:29][C:30]([OH:34])=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH:25]1[C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>O.CO>[CH2:7]([S:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]1[C:33]2[C:28](=[CH:29][C:30]([OH:34])=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH:25]1[C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)=[O:2])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCSCCCCCCCCCC1c2ccc(O)cc2CCC1c1ccc(O)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCCS(=O)CCCCCCCCCC1c2ccc(O)cc2CCC1c1ccc(O)cc1
Reaction time: 16 h

Procedure:
A solution of sodium metaperiodate (0.026 g.) in water (2 ml.) was added to a stirred solution of (1RS, 2RS)-1-(9-n-heptylthiononyl)-2-p-hydroxyphenyl-1,2,3,4-tetrahydronaphth-6-ol (Example 7; 0.052 g.) in methanol (20 ml.) and the mixture was stirred for 16 hours. The methanol was removed by evaporation, the residue was extracted three times with ethyl acetate (10 ml. each time) and the combined extracts were washed with water, dried and evaporated to dryness. The residue was purified by chromatography on a silica gel column using a 2:1 v/v mixture of toluene and ethyl acetate as eluant, and there was thus obtained as an oil (1RS, 2RS)-1-(9-n-heptylsulphinylnonyl)-2-p-hydroxyphenyl-1,2,3,4- tetrahydronaphth-6-ol, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH:12]1([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([F:29])=[C:21]3[C:26]=2[NH:25][CH:24]=[C:23]([I:27])[C:22]3=[O:28])[CH2:14][CH2:13]1.[CH2:30](I)[CH3:31]>O>[CH:12]1([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([F:29])=[C:21]3[C:26]=2[N:25]([CH2:30][CH3:31])[CH:24]=[C:23]([I:27])[C:22]3=[O:28])[CH2:13][CH2:14]1
Reactant: O=c1c(I)c[nH]c2c(OCC3CC3)ccc(F)c12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1cc(I)c(=O)c2c(F)ccc(OCC3CC3)c21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.6 %

Procedure:
Potassium carbonate (450 mg, 3.26 mmol) was added to a DMF solution (5 ml) of 8-cyclopropylmethoxy-5-fluoro-3-iodo-1H-quinolin-4-one (910 mg, 2.53 mmol). The mixture was stirred for 15 minutes at room temperature. Ethyl iodide (0.31 ml, 3.87 mmol) was added thereto, and the resulting mixture was stirred at 60° C. for 2 hours. After the reaction mixture was cooled to room temperature, water was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the residue was then purified by silica gel column chromatography (dichloromethane:ethyl acetate=40:1→15:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 750 mg of powdery pale dark brown 8-cyclopropylmethoxy-1-ethyl-5-fluoro-3-iodo-1H-quinolin-4-one (yield: 77%).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:15]([OH:17])=O)=[CH:5][N:4]=1.[CH3:19][NH:20][CH2:21][C@H:22]([OH:30])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=1.Cl.CN1CCOCC1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>O1CCCC1>[OH:30][CH:22]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=1)[CH2:21][N:20]([CH3:19])[C:15]([C:6]1[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:8][C:3]([N:2]([CH3:1])[CH3:18])=[N:4][CH:5]=1)=[O:17]
Reactant: CNC[C@H](O)c1cccc(O)c1
Reactant: CN(C)c1ncc(C(=O)O)c(-c2ccccc2)n1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CN(CC(O)c1cccc(O)c1)C(=O)c1cnc(N(C)C)nc1-c1ccccc1
Reaction time: 0.08 h
Yield: 18.3 %

Procedure:
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid (1.22 g, 5 mmol) is dissolved in tetrahydrofuran (60 ml). After 5 minutes of stirring to the solution are added: L-phenylephrine hydrochloride (1.22 g, 6 mmol) in tetrahydrofuran (50 ml), after another 5 minutes of stirring the N-methylmorpholine (1.21 g, 12 mmol) and after 2 minutes of stirring the 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (1.66 g, 6 mmol). The reaction mixture is stirred for 2 hours at room temperature, then heated at reflux temperature for 2 hours. The solvent is removed in vacuum. To the residue water (50 ml) is added, and the mixture is extracted with chloroform (75 ml), the extract is washed with 10% sodium carbonate solution (35 ml), with water (35 ml), dried over sodium sulphate and evaporated. The residue is chromatographed on silicagel using chloroform-methanol 100/1-100/5 mixture eluent. 0.36 g of the title compound is obtained, m.p.: 79-81° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[I:11]N1C(=O)CCC1=O>CC(O)=O>[NH2:1][C:2]1[C:9]([I:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: N#Cc1ccc(N)cc1Cl
Solvent: CC(=O)O
Product: N#Cc1cc(I)c(N)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
A mixture of 4-amino-2-chlorobenzonitrile (5.0 g, 0.033 mol) and N-iodosuccinimide (8.28 g, 0.036 mol) in HOAc (35 mL) was stirred at RT overnight. A brown solid formed, which was collected by filtration, washed with hexanes, and dried in vacuo to afford 3.6 g (39%) of 4-amino-2-chloro-5-iodobenzonitrile (236) as a pale brown solid: MS (ESI) m/z=278.8 [M+1]+.
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6][CH2:5]1.[CH:37]1([N:40]2[CH:45]=[CH:44][C:43](I)=[CH:42][C:41]2=[O:47])[CH2:39][CH2:38]1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:37]1([N:40]2[CH:45]=[CH:44][C:43]([C:17]3[CH:18]=[CH:19][C:14]([C@@H:12]([N:8]4[CH2:7][CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:36])[CH3:35])([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[O:10][C:9]4=[O:11])[CH3:13])=[CH:15][CH:16]=3)=[CH:42][C:41]2=[O:47])[CH2:39][CH2:38]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CCC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=c1cc(I)ccn1C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: C[C@@H](c1ccc(-c2ccn(C3CC3)c(=O)c2)cc1)N1CCC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 39.9 %

Procedure:
A mixture of (S)-7-(2-hydroxy-2-methylpropyl)-7-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazepan-2-one (20 mg, 0.04 mmol), 1-cyclopropyl-4-iodopyridin-2(1H)-one (10 mg, 0.04 mmol), Pd(PPh3)4 (5 mg), and Na2CO3 (43 mg, 0.36 mmol) in toluene/EtOH/H2O (3 mL/2 mL/2 mL) was stirred under N2 at 100° C. for 2 h. The reaction mixture was diluted with water (5 mL), and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude product, which was purified by preparative-HPLC to give (S)-3-((S)-1-(4-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-7-(2-hydroxy-2-methylpropyl)-7-phenyl-1,3-oxazepan-2-one (8 mg, yield 40%) LC-MS Method 4 tR=1.166 min, m/z=443.1; 1H NMR (CDCl3) d 0.85 (m, 5H), 1.10 (m, 6H), 1.43 (m, 1H), 1.52 (d, 3H), 2.18 (m, 2H), 2.20 (d, 1H), 2.36 (d, 1H), 2.79 (m, 1H), 3.12-3.35 (m, 2H), 4.00 (s, 1H), 5.59 (m, 1H), 6.30 (d, 1H), 6.70 (d, 1H), 7.18-7.32 (m, 6H), 7.45 (m, 4H)
Reaction SMILES: ClC([O:4][CH2:5][CH:6]([CH3:8])C)=O.[CH3:9]N1CCOCC1.[NH2:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][C:21]([C:27]#[N:28])=[C:20]2[NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1.O>C1COCC1.CN(C=O)C>[C:27]([C:21]1[CH:22]=[N:23][C:24]2[C:19]([C:20]=1[NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1)=[CH:18][C:17]([NH:16][C:5](=[O:4])[C:6]#[C:8][CH3:9])=[CH:26][CH:25]=2)#[N:28]
Reactant: CN1CCOCC1
Reactant: CC(C)COC(=O)Cl
Reactant: COc1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(OC)c3)c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 44 %

Procedure:
Dissolved 362 mg (4.31 mmol) acid in 20 ml THF under N2 and chilled to 0° C. Added 560 μl (4.30 mmol) isobutyl chloroformate and 475 μl (4.31 mmol) N-methylmorpholine and stirred for 10 minutes. Dissolved 500 mg (1.72 mmol) 6-amino-4-[(3-methoxyphenyl)amino]-3-quinolinecarbonitrile in 2 ml hot DMF and added 10 ml THF. Added this to the mixed anhydride dropwise, stirred for 15 minutes at 0° C. and at 25° C. overnight. Stripped solvent, slurried residue with water, collected solids, and air dried. Recrystallized from ethyl acetate and dried in vacuo, giving 270 mg of yellow solid: mass spectrum (electrospray m/e): M+H=357.1.
Reaction SMILES: [Cl:1][C:2]1[C:20]([NH:21][C:22](=[O:35])[CH2:23][N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])=[CH:19][CH:18]=[C:17]([Cl:36])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.[CH3:37]N(C)C=O.[H-].[Na+].CI>O>[Cl:1][C:2]1[C:20]([N:21]([C:22](=[O:35])[CH2:23][N:24]2[C:25](=[O:34])[C:26]3=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]3[C:28]2=[O:29])[CH3:37])=[CH:19][CH:18]=[C:17]([Cl:36])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(NC(=O)CN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Reaction time: 0.5 h

Procedure:
To a mixture of 8-[2,6-dichloro-3-(phthalimidoacetylamino)benzyloxy]-2-methylquinoline (4.44 g) and N,N-dimethylformamide (44 ml) was added sodium hydride (60% in oil, 375 mg) in an ice-water bath. After stirring for 30 minutes in an ice-water bath, methyl iodide (0.6 ml) was added thereto and the mixture was stirred at ambient temperature for 1 hour. To this mixture was added water (88 ml) in an ice-water bath and the mixture was stirred at the same temperature for 1.5 hours. The precipitate was collected by vacuum filtration and washed with water and methanol to give 8-[2,6-dichloro-3-[N-(phthalimidoacetyl)-N-methylamino]benzyloxy]-2-methylquinoline (3.99 g) as a yellow powder.