Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=2)=[CH:12][C:11]=1[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[BH4-].[Na+].Cl>C(O)C.O.C(OCC)(=O)C>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=2)[OH:28])=[CH:12][C:11]=1[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(C(=O)c2cccc(C(=O)OCC)c2)cc1CC(=O)OCC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCCOc1ccc(C(O)c2cccc(C(=O)OCC)c2)cc1CC(=O)OCC
Reaction time: 3 h
Yield: 86 %

Procedure:
To a solution of 220 mg of 2-(octyloxy)-5-[3-(ethoxycarbonyl)benzoyl]benzeneacetic acid, ethyl ester, in 25 ml of ethanol were added 20 mg of sodium borohydride. After 3 hours of stirring, 5 ml of water and 2 ml of hydrochloric acid were added. After stirring for 15 minutes, additional water was added until the solution turned cloudy. The mixture was poured into ethyl acetate and water. The layers were separated, the organic layer was washed three times with water, and the combined water extracts were back extracted with ethyl acetate. The ethyl acetate extracts were combined, dried over magnesium sulfate, and concentrated to dryness providing 190 mg of the desired title product as a colorless oil. NMR.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[C:26]([Cu])#[N:27]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:26]#[N:27])[N:11]=1)=[O:5])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c(Br)c(Br)n2-c1ccc(F)cc1
Product: CCOC(=O)c1nc(C#N)c2c(c1O)c(Br)c(Br)n2-c1ccc(F)cc1

Procedure:
Prepared in analogy to that of Example 105(a) from 2,3,7-tribromo-4-hydroxy-1-(4-fluoro-phenyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and CuCN. The title compound, ESI MS (m/z): 482 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([C:17]1[CH:30]=[C:29]([CH2:31][CH3:32])[C:28]2[S:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](=[O:33])[C:19]=2[CH:18]=1)[CH3:16].[F:34][C:35]([F:48])([F:47])[S:36]([O:39]S(C(F)(F)F)(=O)=O)(=[O:38])=[O:37]>ClCCl>[F:34][C:35]([F:48])([F:47])[S:36]([O-:39])(=[O:38])=[O:37].[C:9]1([S+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:23]2[CH:24]=[CH:25][C:26]3[S:27][C:28]4[C:19](=[CH:18][C:17]([CH2:15][CH3:16])=[CH:30][C:29]=4[CH2:31][CH3:32])[C:20](=[O:33])[C:21]=3[CH:22]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=S(c1ccccc1)c1ccccc1
Reactant: CCc1cc(CC)c2sc3ccccc3c(=O)c2c1
Solvent: ClCCl
Product: CCc1cc(CC)c2sc3ccc([S+](c4ccccc4)c4ccccc4)cc3c(=O)c2c1
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 64 %

Procedure:
To 320 ml of dichloromethane were dissolved 20.2 g (0.1 mol) of diphenylsulfoxide and 26.8 g (0.1 mol) of 2,4-diethylthioxanthene-9-one, and 28.2 g (0.1 mol) of trifluoromethanesulfonic anhydride was added dropwise thereto at −70 to −60° C., followed by gradually warming to room temperature and reacting with stirring for 4 hours. After completion of the reaction, the obtained reaction solution was washed with water (160 ml×4 times) and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 38.6 g of objective substance as yellow glassy substance (yield: 64%).
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:14]1([CH:17]([NH:25][CH2:26][CH2:27][CH3:28])[C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)[CH2:16][CH2:15]1.O>CC(C)=O>[C:5]([NH:3][C:2](=[S:1])[N:25]([CH:17]([CH:14]1[CH2:15][CH2:16]1)[C:18]1[CH:19]=[CH:20][C:21]([Br:24])=[CH:22][CH:23]=1)[CH2:26][CH2:27][CH3:28])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCNC(c1ccc(Br)cc1)C1CC1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O
Product: CCCN(C(=S)NC(=O)c1ccccc1)C(c1ccc(Br)cc1)C1CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
10.15 g of ammonium thiocyanate are suspended in 60 ml of acetone and the suspension is cooled to 0° C. 14.2 ml of benzoyl chloride dissolved in 15 ml of acetone are slowly added thereto. The mixture is left stirring for 15 minutes, followed by addition of 29 g of N-(α-cyclopropyl-4-bromobenzyl)-N-propylamine (Compound 32). The mixture is allowed to return to room temperature and stirring is continued for 2 hours. 20 ml of water are then added, followed by concentrating to the maximum extent. The residue is taken up in a mixture of water and methylene chloride. The organic phase is dried over anhydrous sodium sulphate and then concentrated and allowed to stand, to give the expected product in the form of yellow crystals.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[C@:14]3([C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH2:23][C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27]([OH:29])=O)[C:15]3=[O:33])[CH2:13]2)=[CH:8][CH:7]=1>>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C@@H:12]2[C@:14]3([C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH2:23][C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:29])[C:15]3=[O:33])[CH2:13]2)=[CH:10][CH:11]=1
Reactant: O=C(O)c1cccc(CN2C(=O)[C@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1
Reactant: CC(C)N
Product: CC(C)NC(=O)c1cccc(CN2C(=O)[C@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 60 starting from isopropyl amine, (3-bromomethyl)-benzoate (commercially available), (1R,2S) and (1S,2R)-3-((2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoic acid prepared as in Scheme 1. LC/MS m/e calcd. for C27H25ClN2O2: 444, observed (M+H)+: 445.2 1H NMR (400 MHz, MeOD-d4) δppm 1.23 (d, J=6.82 Hz, 6 H) 2.21 (d, J=8.59 Hz, 2 H) 3.21-3.28 (m, 1 H) 4.07-4.25 (m, 1 H) 5.10 (s, 2 H) 6.05 (d, J=7.58 Hz, 1 H) 6.69 (t, J=7.58 Hz, 1 H) 6.88 (d, J=7.83 Hz, 1 H) 7.05 (t, J=7.83 Hz, 1 H) 7.16-7.25 (m, 2 H) 7.25-7.34 (m, 2 H) 7.37-7.52 (m, 2 H) 7.69 (d, J=7.58 Hz, 1 H) 7.78 (s, 1 H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9]I)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C-:11]#[C-:12].[Na+].[Na+]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C:11]#[CH:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ICCCC1CCCCC1
Reactant: [C-]#[C-]
Agent: [Na+]
Product: C#CCCCC1CCCCC1

Procedure:
The title compound was synthesized using 3-cyclohexyl-1-iodopropane and sodium acetylide by conducting the reactions similar to those mentioned in Reference example 29.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:5](=[C:7]([S:11](Cl)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[NH3:15]>O1CCCC1>[CH3:1][C:2]1[S:3][C:4]2[C:5](=[C:7]([S:11]([NH2:15])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1
Reactant: N
Reactant: Cc1nc2c(S(=O)(=O)Cl)cccc2s1
Solvent: C1CCOC1
Product: Cc1nc2c(S(N)(=O)=O)cccc2s1
Temperature: 25 °C

Procedure:
A solution of 18 g of the product from Example 1 in 170 mL of tetrahydrofuran was cooled to 0° C. under an atmosphere of nitrogen and treated with 5 mL of anhydrous ammonia. The mixture was stirred at room temperature for about an hour, filtered to remove the ammonium chloride, and the filtrate concentrated in vacuo to give an off-white solid. This crude product was purified by silica gel chromatography; elution with ethyl acetate-hexanes (3:1) gave 1.9 g of 2-methyl-4-benzothiazolesulfonamide as a white powder, m.p. 236°-239° C.; NMR (DMSO-d6 /CDCl3): δ 2.95 (3H, s), 7.0 (2H, br s, SO2NH2), 7.55 (1H, t, J=8 Hz), 8.0 (1H, dd, J=2,8 Hz), 8.2 (1H, dd, J=2,8 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:17][N:18]=[N+]=[N-])[CH2:9][C@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].[H][H]>C1COCC1.[Pd]>[C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:17][NH2:18])[CH2:9][C@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:2])([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: CCCCC[C@@H](C)C[C@H](CN=[N+]=[N-])CC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCC[C@@H](C)C[C@H](CN)CC(=O)OC(C)(C)C
Yield: 71.3 %

Procedure:
A solution of compound 160 (1.86 g, 6.25 mmol) in THF (50 mL) was shaken over 5% Pd/C under hydrogen and pressure for 8 hours with three purges of hydrogen. The catalyst was filtered off and the filtrate evaportated. The crude material was chromatographed on silica eluting with methanol to give 161 as an oil (1.21 g, 71%). 1H NMR (400 MHz, CDCl3) δ2.70 (dd, J=12.9, 4.40 Hz, 1H), 2.54 (dd, J=12.7, 6.59 Hz, 1H), 2.26 (dd, J=14.5, 6.96, 1H), 2.12 (dd, J=14.5, 6.47 Hz, 1H), 1.91 (m, 1H), 1.91 (m, 1H), 1.43 (s, 12H), 1.39-1.25 (m, 4H), 1.14-1.07 (m, 1H), 1.03-0.97 (m, 1H), 0.86-0.82 (m, 6H).
Reaction SMILES: C([S:4][C@@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[CH:7]([C:8](=[CH2:25])[CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1)(=O)C>CO.[OH-].[Na+]>[SH:4][C@@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[CH:7]([C:8](=[CH2:25])[CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CC[C@@H](SC(C)=O)CC12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CC[C@@H](S)CC12
Yield: 99.7 %

Procedure:
To a solution of 3α-acetylthio-6-methyleneandrostan-17-one (210 mg) in MeOH (3 mL), 1N NaOH (0.6 mL) was added. After 1 h at room temperature 5% NaH2PO4 aqueous solution was added and the mixture extracted with Et2O (2×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated to dryness to give the title compound (185 mg, 100%).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.[C:15]([OH:18])(=[O:17])[CH3:16]>C(OCC)C>[C:15]([O:18][CH:14]1[CH:13]([Br:8])[CH2:12][CH2:11][CH2:10][O:9]1)(=[O:17])[CH3:16]
Reactant: CC(=O)O
Reactant: O=C1CCC(=O)N1Br
Reactant: C1=COCCC1
Solvent: CCOCC
Product: CC(=O)OC1OCCCC1Br
Yield: 73 %

Procedure:
To the solution of N-bromosuccimide (4.5 g ) in acetic acid (14.5 ml), was added dropwise 2.3 ml of 3,4-dihydro-2H-pyran at 10° C. The reaction mixture was diluted with 50 ml of diethyl ether and washed with 50 ml of water three times. The organic layer was washed with 1N NaHCO3 solution, dried, and then concentrated under a reduced pressure to give 4.1 g of 2-acetoxy-3-bromo-tetrahydropyran as a colorless oil (yield: 73%).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][C:10](Cl)=[O:11].[NH2:14][N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]1[C:26]([F:29])([F:28])[F:27]>>[CH3:1][C:2]1([CH3:13])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][C:10]([NH:14][N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]1[C:26]([F:28])([F:27])[F:29])=[O:11]
Reactant: Nn1c(C(F)(F)F)nc2ccccc2c1=O
Reactant: CC1(C)[C@H]2CC[C@@H](CC(=O)Cl)[C@@H]1C2
Product: CC1(C)[C@H]2CC[C@@H](CC(=O)Nn3c(C(F)(F)F)nc4ccccc4c3=O)[C@@H]1C2

Procedure:
The product from Example 1C and 3-amino-2-(trifluoromethyl)quinazolin-4(3H)-one (Bionet) were processed using method analogous to that described in Example 1D to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.00 (d, J=9.8 Hz, 1H) 1.08 (s, 3H) 1.23 (d, J=5.1 Hz, 3H) 1.85-2.05 (m, 5H) 2.06-2.24 (m, 1H) 2.31-2.45 (m, 2H) 2.53-2.61 (m, 2H) 2.62-2.76 (m, 1H) 7.58 (s, 1H) 7.60-7.68 (m, 1H) 7.88 (d, J=3.7 Hz, 1H) 8.31 (d, J=7.8 Hz, 1H); MS (ESI+) m/z 394 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH2:5][C@@H:6]1[C@H:8](/[CH:9]=[CH:10]/[C:11](/[CH3:18])=[CH:12]/[C:13]([O:15]CC)=[O:14])[C@@:7]1([CH3:33])[C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:32])([CH3:31])[C:21]=2[CH:20]=1.Cl>C1COCC1.CO.C(OCC)(=O)C>[CH3:3][O:4][CH2:5][C@@H:6]1[C@H:8](/[CH:9]=[CH:10]/[C:11](/[CH3:18])=[CH:12]/[C:13]([OH:15])=[O:14])[C@@:7]1([CH3:33])[C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:32])([CH3:31])[C:21]=2[CH:20]=1
Reactant: CCOC(=O)/C=C(C)/C=C/[C@H]1[C@@H](COC)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: COC[C@@H]1[C@H](/C=C/C(C)=C/C(=O)O)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 50 °C
Reaction time: 16 h
Yield: 83.4 %

Procedure:
Sodium hydroxide solution (1N, 1 mL) was added to a solution of Compound 16a (59 mg, 0.13 mmol) in 4 mL of THF/MeOH (1:1) at 50° C. After stirring at 50° C. for 16 h, the mixture was diluted with ethyl acetate (10 mL) ad acidified with 1 mL of 1 HCl at 0° C. The organic layer was then washed with brine (1×5 mL), dried (Na2SO4) and concentrated. The residue was purified by flash chromatography using 30% EtOAc in hexane to give the title compound (43 mg, 79% yield) as a white solid:
Reaction SMILES: [Cl:1][C:2]1=[C:3]([CH:28]=[CH:29][C:30]2[C:38]([CH3:40])([CH3:39])[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([S:41]([O-:44])(=[O:43])=[O:42])[CH:36]=3)[N+:31]=2CCCS([O-])(=O)=O)[CH2:4][CH2:5][CH2:6]/[C:7]/1=C\C=C1/C(C)(C)C2C(=N/1)N(CCCS([O-])(=O)=O)C=CC=2.[Na+:52].[Na+].CC1C(C)(C)C2[C:57](=[CH:58][CH:59]=[C:60]([S:66]([O-:69])(=[O:68])=[O:67])C=2)[N+]=1CCC(S([O-])(=O)=O)C.[Na+].[Cl:79][C:80]1[CH:81]=[C:82]2[C:96]([CH3:98])([CH3:97])[C:95]([CH3:99])=[N:94][C:83]2=[N+:84]([CH2:86][CH2:87][CH2:88][CH2:89][S:90]([O-:93])(=[O:92])=[O:91])[CH:85]=1>>[Cl:1][C:2]1=[C:3]([CH:28]=[CH:29][C:30]2[C:38]([CH3:39])([CH3:40])[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([S:41]([O-:44])(=[O:42])=[O:43])[CH:36]=3)[N+:31]=2[CH2:57][CH2:58][CH2:59][CH2:60][S:66]([O-:69])(=[O:68])=[O:67])[CH2:4][CH2:5]/[C:6]/1=[CH:7]\[CH:99]=[C:95]1/[C:96]([CH3:98])([CH3:97])[C:82]2[C:83](=[N:94]/1)[N:84]([CH2:86][CH2:87][CH2:88][CH2:89][S:90]([O-:93])(=[O:92])=[O:91])[CH:85]=[C:80]([Cl:79])[CH:81]=2.[Na+:52].[Na+:52]
Reactant: CC1=Nc2c(cc(Cl)c[n+]2CCCCS(=O)(=O)[O-])C1(C)C
Reactant: CC1=[N+](CCC(C)S(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc2C1(C)C
Reactant: CC1(C)C2=CC=CN(CCCS(=O)(=O)[O-])C2=N/C1=C/C=C1\CCCC(C=CC2=[N+](CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)=C1Cl
Agent: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C1\CCC(/C=C/C2=[N+](CCCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)=C1Cl
Agent: CC1(C)C2=CC=CN(CCCS(=O)(=O)[O-])C2=N/C1=C/C=C1\CCCC(/C=C/C2=[N+](CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)=C1Cl
Agent: [Na+]
Product: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C1\CCC(C=CC2=[N+](CCCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)=C1Cl

Procedure:
Compound 39 is prepared analogously to compound 16, except with compound 38, compound 26, and the cyclopentyl chloro dye precursor as starting materials.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[C@@H:16]([CH3:17])[CH2:15][CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[C:23]3[C:28]([CH:29]=[CH:30][C:20]=2[N:19]=1)=[CH:27][C:26]1[C:31]2[C:36]([CH2:37][O:38][C:25]=1[CH:24]=3)=[CH:35][C:34]([C:39]1[NH:43][C:42]([C@@H:44]3[CH2:48][C@H:47]([CH3:49])[CH2:46][N:45]3C(OC(C)(C)C)=O)=[N:41][CH:40]=1)=[CH:33][CH:32]=2)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].[CH3:57][O:58][C@H:59]([CH3:69])[C@H:60]([NH:64][C:65]([O:67][CH3:68])=[O:66])[C:61]([OH:63])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>Cl.CCO.CN(C=O)C>[CH3:57][O:58][C@@H:59]([CH3:69])[C@H:60]([NH:64][C:65]([O:67][CH3:68])=[O:66])[C:61]([N:45]1[CH2:46][C@@H:47]([CH3:49])[CH2:48][C@H:44]1[C:42]1[NH:43][C:39]([C:34]2[CH:35]=[C:36]3[CH2:37][O:38][C:25]4[CH:24]=[C:23]5[C:28]([CH:29]=[CH:30][C:20]6[N:19]=[C:18]([C@@H:13]7[CH2:14][CH2:15][C@H:16]([CH3:17])[N:12]7[C:10](=[O:11])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:7]([CH3:9])[CH3:8])[NH:22][C:21]=65)=[CH:27][C:26]=4[C:31]3=[CH:32][CH:33]=2)=[CH:40][N:41]=1)=[O:63]
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1c1nc2ccc3cc4c(cc3c2[nH]1)OCc1cc(-c2cnc([C@@H]3C[C@H](C)CN3C(=O)OC(C)(C)C)[nH]2)ccc1-4)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCO
Product: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1c1nc2ccc3cc4c(cc3c2[nH]1)OCc1cc(-c2cnc([C@@H]3C[C@H](C)CN3C(=O)[C@@H](NC(=O)OC)[C@H](C)OC)[nH]2)ccc1-4)C(C)C
Reaction time: 3 h
Yield: 22.5 %

Procedure:
tert-butyl (2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate (20 mg, 0.079 mmol) in 1.25 N HCl in EtOH (2 mL) was heated to 50° C. for 3 h and then concentrated under reduced pressure. The crude residue was treated with (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (8 mg, 0.04 mmol), HATU (12 mg, 0.03 mmol) and DMF (0.5 mL), then N-methylmorpholine (0.009 mL, 0.078 mmol) was added dropwise. After 3 h, the mixture was quenched with 1N HCl (0.100 mL) and then purified by HPLC to afford methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2S,3S)-3-methoxy-2-[(methoxycarbonyl)amino]butanoyl}-4-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (7.5 mg, 35%).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH:9]([NH2:13])[CH2:8][O:7]2)([O-:3])=[O:2].CCN(CC)CC.[F:21][C:22]([F:43])([F:42])[O:23][C:24]1[CH:41]=[CH:40][C:27]([O:28][CH:29]2[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][C:37](Cl)=[O:38])[CH2:31][CH2:30]2)=[CH:26][CH:25]=1.ClCCl>CN(C=O)C>[N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][C@H:9]([NH:13][C:37](=[O:38])[CH2:36][CH2:35][N:32]1[CH2:31][CH2:30][CH:29]([O:28][C:27]3[CH:40]=[CH:41][C:24]([O:23][C:22]([F:21])([F:42])[F:43])=[CH:25][CH:26]=3)[CH2:34][CH2:33]1)[CH2:8][O:7]2)([O-:3])=[O:2]
Reactant: O=C(Cl)CCN1CCC(Oc2ccc(OC(F)(F)F)cc2)CC1
Reactant: NC1COc2nc([N+](=O)[O-])cn2C1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(CCN1CCC(Oc2ccc(OC(F)(F)F)cc2)CC1)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
Under Ar, (S)-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine-6-amine (110 mg, 0.6 mmol) was dissolved in DMF (6 mL), cooled to 0° C., added Et3N (0.21 mL, 2 mmol), added 3-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl) propionyl chloride (291 mg, 0.75 mmol) in batches, naturally rose to room temperature and stirred for 3 h, added an appropriate amount of dichloromethane, washed by distilled water for 3 times, followed by anhydrous sodium sulphate drying, filtrated out drying agent and spinning dry, residuals were purified by column chromatography (eluent CH2Cl2: MeOH=30:1) to give 70 mg target product, yield was 23%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[S:13][C:12]([CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:11][N:10]=1.[C:31]([N:39]=[C:40]=[S:41])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[C:31]([NH:39][C:40]([N:11]1[N:10]=[C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[S:13][C:12]1([CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[S:41])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)NCCCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=S)NC(=O)c1ccccc1
Temperature: 60 °C
Yield: 83.6 %

Procedure:
To a solution of tert-butyl 3-(5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate (1.60 g, 3.69 mmol) in THF (37 mL) was added benzoyl isothiocyanate (0.595 mL, 4.43 mmol). After heating to reflux for 5 hours and to 60° C. for 16 hours, the reaction mixture was concentrated under reduced pressure. The residue was chromatographed (30% ethyl acetate in hexanes) to provide the product (1.84 g, 84%) as an orange-yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]([OH:22])[N:6]([C:13]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[C:7]2=[O:12].CN(CCN(C)C)C.C([Li])(CC)C.CCCCCC.[I:42]I>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([I:42])=[C:8]2[C:4]=1[CH:5]([OH:22])[N:6]([C:13]([CH3:14])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:21])[C:7]2=[O:12]
Reactant: COc1cccc2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Reactant: II
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(I)c2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Yield: 77 %

Procedure:
In a similar manner to Step 3 of Example 16, 4-methoxy-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (3.55 g, 11.9 mmol) was dissolved in THF (140 mL), and the solution was treated with TMEDA (4.00 mL, 26.2 mmol), sec-butyllithium-hexane solution (0.99 mol/L, 26.4 mL, 26.2 mmol) and iodine (3.62 g, 14.3 mmol), followed by purification by flash column chromatography (hexane/ethyl acetate=9/1, 7/3) to obtain 4-methoxy-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (3.88 g, yield 77%).
Reaction SMILES: [CH:1]1([C:4](=[O:9])[CH2:5][C:6](=O)[CH3:7])[CH2:3][CH2:2]1.Cl.[NH2:11]O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH:1]1([C:4]2[O:9][N:11]=[C:6]([CH3:7])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: NO
Reactant: CC(=O)CC(=O)C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cc(C2CC2)on1
Yield: 81.3 %

Procedure:
A mixture of 1-cyclopropylbutan-1,3-dione (65.3 g), hydroxylamine hydrochloride (36.6 g) and anhydrous potassium carbonate (71.8 g) in ethanol (375 ml) was stirred and heated at reflux for 2 hours. The mixture was cooled and filtered and the filtrate was evaporated to dryness. The residue was distilled under reduced pressure to give 5-cyclopropyl-3-methyl isoxazole containing approximately 20% 3-cyclopropyl-5-methylisoxazole (51.85 g) as a clear oil, b.p. 74° C. /12 mm.Hg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].CC1C=CC(S([CH2:26][N+:27]#[C-:28])(=O)=O)=CC=1>CO>[Br:1][C:2]1[CH:9]=[C:6]([C:7]2[O:8][CH:28]=[N:27][CH:26]=2)[CH:5]=[N:4][CH:3]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Brc1cncc(-c2cnco2)c1
Temperature: 85 °C
Yield: 53.3 %

Procedure:
To a solution of 5-bromonicotinaldehyde (0.2 g, 1 mmol) in MeOH (5 mL) was added K2CO3 (0.3 g, 2 mmol) followed by TOSMIC (0.27 g, 1.39 mmol). The mixture was heated to 85° C. for 2 h. Methanol was evaporated under reduced pressure and the residue was dissolved in DCM then washed with water. The organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography using 2.1% MeOH in DCM as the eluent to provide 5-(5-bromopyridin-3-yl)oxazole (0.12 g. 50%). LCMS Method Y: retention time 1.39 min; [M+1]=225.0.