Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[N:12]([CH2:14][CH:15]=[CH2:16])[CH3:13])[CH:7]=O)[CH:2]=[CH2:3].C1COCC1.[Br-].[N+:23]([C:26]1[CH:51]=[CH:50][C:29]([CH2:30][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:28][CH:27]=1)([O-:25])=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:14]([N:12]([CH3:13])[C:11]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:30][C:29]2[CH:50]=[CH:51][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=2)=[CH:5][C:4]=1[CH2:1][CH:2]=[CH2:3])[CH:15]=[CH2:16]
Reactant: C=CCc1cc(C=O)ccc1N(C)CC=C
Reactant: O=[N+]([O-])c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCc1cc(C=Cc2ccc([N+](=O)[O-])cc2)ccc1N(C)CC=C
Reaction time: 2 h

Procedure:
A mixture of 3-allyl-4-(N-allyl-N-methylamino)benzaldehyde (10.25 g, 0.05 mol), THF (100 ml), p-nitrobenzyl triphenyiphosphonium bromide (27.4 g, 0.55 mol) and water (50 ml) is mixed at room temperature while 2 M sodium carbonate solution (50 ml) is added over 5 minutes. The mixture is stirred mechanically for 2 hours. The mixture is diluted with water (300 ml) and extracted two times with ether (250 ml portions). The extracts are washed with water and brine, dried over magnesium sulfate and concentrated. The mixture is diluted with toluene (100 ml) and hexane (200 ml) and the triphenyl phosphine oxide filtered off. The filtrate is concentrated and chromatographed on silica with hexaneethyl acetate to give pure N,2-diallyl-N-methyl-4-[2-(4-nitrophenyl)ethenyl]aniline.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[C:8]([CH3:11])[CH:7]=[CH:6][C:5]=2[CH3:12].[Li]CCCC.CCCCCC.[Si:24]([CH3:28])([CH3:27])(Cl)[Cl:25]>CCOCC.C1COCC1>[Cl:25][Si:24]([CH:3]1[C:4]2[C:9](=[C:8]([CH3:11])[CH:7]=[CH:6][C:5]=2[CH3:12])[CH:10]=[C:2]1[CH3:1])([CH3:28])[CH3:27]
Reactant: C[Si](C)(Cl)Cl
Reactant: CC1=Cc2c(C)ccc(C)c2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1=Cc2c(C)ccc(C)c2C1[Si](C)(C)Cl
Temperature: 0 °C
Yield: 102.7 %

Procedure:
7.24 g of 2,4,7 trimethylindene (45.8 mmol) were suspended in 70 ml of Et2O, cooled to 0° C., and to it were added 19.2 ml of a 2.5 M BuLi solution in hexane (48.0 mmol) with stirring. A slightly yellow cream is obtained. After allowing the reaction mixture to reach ambient temperature, additional 10 ml of Et2O were added, to improve stirring. After about 1 h the mixture was cooled again to 0° C. and 7.20 g of Me2SiCl2 (55.2 mmol, 1.2 eq) in 30 ml di THF, previously cooled to 0° C., were added to it. At the end of the addition, the reaction mixture was allowed to reach ambient temperature. At this point the reaction mixture, which appeared as a white suspension, was filtered to remove LiCl, and then all solvents and excess Me2SiCl2 were removed under reduced pressure to leave 11.8 g of pale yellow oil (98% yield).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C[C@H]1CCC[C@@H](C)N1C1N2C=C(O[C@H]3C4C(=CC=CC=4)[C@@H](NC(=O)[NH:39][C:40]4[N:44](C5C=NN(CCOS(C)(=O)=O)C=5)[N:43]=[C:42]([CH:57](C)C)[CH:41]=4)CC3)C=CC2=NN=1>>[NH2:39][C:40]1[N:44]([C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)[N:43]=[C:42]([CH3:57])[CH:41]=1
Reactant: Oc1cccc(I)c1
Reactant: CC(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5[C@H](C)CCC[C@@H]5C)n4c3)c3ccccc32)n(-c2cnn(CCOS(C)(=O)=O)c2)n1
Product: Cc1cc(N)n(-c2cccc(O)c2)n1

Procedure:
The title compound was prepared starting from 5-methyl-2H-amino pyrazol (500 mg, 5.1 mmol) and 3-iodo-phenol (1.25 g, 5.7 mmol) by using an analogous procedure to that described for Intermediate A step b. LCMS (Method 3): Rt 0.99 min, m/z=190 [MH+].
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=[O:19])C=C.C1(CO)C2C(=CC3C(C=2)=CC=CC=3)C=CC=1>CN(C1C=CC=CN=1)C.CN(C1C=CN=CC=1)C.O1CCCC1>[C:8]([NH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:19]
Reactant: C=CC(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: CN(C)c1ccncc1
Agent: OCc1cccc2cc3ccccc3cc12
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 24 h

Procedure:
The adhesive was converted to a switchable adhesive. The method used for esterification of the carboxylic acid groups pendant to the prepolymer chain employed a dehydrating agent, dicyclohexylcarbodiimide (DCC). This was used in conjunction with a dimethylaminopyridine catalyst with the reaction proceeding at room temperature. The following general procedure was initially used for the esterification reaction. For Example 9a), 6.09 g of base PSA (containing 0.0068 moles acrylic acid) was placed in a dry jar along with 1.41 g of anthracenemethanol (0.0068 moles), 1.39 g DCC (0.0068 moles) and 0.33 g DMAP (0.00027 moles). Approximately 100 ml of anhydrous tetrahydrofuran (THF) was added to the reaction mixture which was left stirring overnight (˜24 hours). A precipitate was formed as a by-product of the esterification (dicyclohexylurea, DHU) which was insoluble in THF and was therefore filtered from the PSA solution. A viscous yellow liquid was produced which was then spread thinly onto Melinex for UV irradiation.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(O[C:26]1[CH2:40][C@@H:39]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[C@H:38](/[CH:49]=[CH:50]/[C@@H:51]([O:59][Si:60]([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61])[CH2:52][C@H:53]([CH3:58])[CH2:54][CH2:55][CH2:56][CH3:57])[C:27]=1[S:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])(=O)=O.[O-][Si]([O-])=O.[Mg+2].[F:74][C:75](I)([F:77])[F:76]>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Zn]>[F:74][C:75]([F:77])([F:76])[C:26]1[CH2:40][C@@H:39]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:43])[CH3:44])[C@H:38](/[CH:49]=[CH:50]/[C@@H:51]([O:59][Si:60]([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:61])[CH3:62])[CH2:52][C@H:53]([CH3:58])[CH2:54][CH2:55][CH2:56][CH3:57])[C:27]=1[S:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35]
Reactant: FC(F)(F)I
Reactant: CCCC[C@@H](C)C[C@@H](/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(OS(=O)(=O)C(F)(F)F)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=[Si]([O-])[O-]
Solvent: C1CCOC1
Product: CCCC[C@@H](C)C[C@@H](/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(C(F)(F)F)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Yield: 36 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) (11.4 mg, 0.0125 mmol), triphenylphosphine (13.1 mg, 0.05 mmol), zinc (powder) (36.8 mg, 56.3 mmol), and methyl (11R,12S,13E,15S,17R)-9-trifluoromethanesulfonyloxy-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate (218 mg, 0.282 mmol) in tetrahydrofuran (5 mL) were placed in an autoclave reactor, a small sized container of trifluoromethyl iodide was connected, and the inside of the reaction vessel was made the same pressure as the inside of the small sized container. The reaction vessel was made to vibrate in trifluoromethyl iodide atmosphere for 1 hour by an ultrasonic wave washer. Next, the unreacted trifluoromethyl iodide in the reaction vessel was removed to obtain the reaction solution which was passed through Florisil column. The solution thus obtained was concentrated under reduced pressure, then was purified by silica gel column chromotography (4to 10% ethyl acetate/hexane) to obtain methyl (11R,12S,13E,15S,17R)-9-trifluoromethyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate (72 mg, 36%).
Reaction SMILES: [P:1]([O:39]C)([O:37]C)([O:3][CH2:4][CH2:5][C@@H:6]([NH:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[C:28]([Cl:36])[CH:27]=1)=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([C:20](=[O:22])[CH3:21])[N:17]([CH3:19])[CH:18]=2)=[CH:10][CH:9]=1)=[O:2]>Br.CC(O)=O>[P:1]([OH:37])([OH:39])([O:3][CH2:4][CH2:5][C@@H:6]([NH:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[C:28]([Cl:36])[CH:27]=1)=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([C:20](=[O:22])[CH3:21])[N:17]([CH3:19])[CH:18]=2)=[CH:10][CH:9]=1)=[O:2]
Reactant: COP(=O)(OC)OCC[C@H](Cc1ccc(-c2cn(C)c(C(C)=O)n2)cc1)NC(=O)c1ccc(OC(C)C)c(Cl)c1
Agent: Br
Solvent: CC(=O)O
Product: CC(=O)c1nc(-c2ccc(C[C@@H](CCOP(=O)(O)O)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
A yellow solution of (3S)-4-[4-(2-acetyl-1-methyl-1H-imidazol-4-yl)phenyl]-3-[({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]butyl dimethyl phosphate (475 mg, 0.804 mmol) in 30% HBr in AcOH was placed in a pre-heated (60° C.) bath for 10 min, then immediately allowed to cool to rt. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in DMSO (6 mL), filtered and purified by Gilson reverse phase HPLC (MeCN/H2O with 0.1% TFA). The MeCN of the clean fractions was removed under reduced pressure and the remaining aqueous solution was frozen and lyophilized overnight to give 84 mg (19%) of the title compound as a yellow powder. LC/MS (ES) m/e 564.2 (M+H)+.
Reaction SMILES: [N:1](OCCC(C)C)=[O:2].C[O-].[Na+].[C:12]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)(=[O:15])[CH2:13][CH3:14].Cl>CO>[OH:2][N:1]=[C:13]([CH3:14])[C:12]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[O:15]
Reactant: CC(C)CCON=O
Reactant: CCC(=O)c1ccncc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(=NO)C(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of isoamyl nitrite (2.6 ml) and sodium methoxide (28% in methanol, 3.4 ml) in methanol (40 ml) was added dropwise a solution of 4-propionylpyridine (2.0 g) in methanol (10 ml) under ice-cooling. The reaction mixture was stirred at ambient temperature for 3 hours, and then neutralized with 1N hydrochloric acid. After evaporation to remove methanol, the organic layer was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, evaporated and triturated with diisopropyl ether to give 4-(2-hydroxyiminopropionyl)pyridine (0.95 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:19]=1.[Cl:31][C:32]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[C:34]([Cl:47])[C:33]=1[OH:48]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][CH2:29][CH2:30]4)[CH:19]=2)=[CH:3][C:2]([C:36]2[CH:35]=[C:34]([Cl:47])[C:33]([OH:48])=[C:32]([Cl:31])[CH:37]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: O=C(c1cnc2ccc(Br)cc2c1Nc1cccc(CCN2CCCC2)c1)C1CC1
Product: O=C(c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1cccc(CCN2CCCC2)c1)C1CC1
Yield: 15.2 %

Procedure:
Following general procedure A-1, {6-bromo-4-[3-(2-(pyrrolidin-1-yl)ethyl)phenylamino]quinolin-3-yl}(cyclopropyl)methanone (56 mg, 0.120 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (52 mg, 0.180 mmol) to afford the desired product (10 mg, 15%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.46 (s, 1H), 8.22 (dd, J=8.8, 1.9 Hz, 2H), 8.02 (d, J=8.8 Hz, 2H), 7.90-7.85 (m, 1H), 7.66-7.59 (m, 1H), 7.58-7.53 (m, 1H), 7.47 (s, 1H), 7.42-7.36 (m, 1H), 7.19 (s, 2H), 3.72-3.63 (m, 2H), 3.45-3.37 (m, 2H), 3.18-3.04 (m, 4H), 2.92-2.84 (m, 1H), 2.20-2.08 (m, 2H), 2.08-1.97 (m, 2H), 1.31-1.13 (m, 4H); ESI MS m/z 546 [C31H29Cl2N3O2+H]+; HPLC 97.3% (AUC), tR=11.04 min.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:14]=[C:13]([C:15]2[CH:34]=[CH:33][C:18]3[NH:19][CH:20]([CH2:28][C:29]([O:31]C)=[O:30])[C:21](=[O:27])[N:22]([CH:24]4[CH2:26][CH2:25]4)[CH2:23][C:17]=3[CH:16]=2)[O:12][N:11]=1.O.[Li+].[OH-]>COCCOC>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]1[N:14]=[C:13]([C:15]2[CH:34]=[CH:33][C:18]3[NH:19][CH:20]([CH2:28][C:29]([OH:31])=[O:30])[C:21](=[O:27])[N:22]([CH:24]4[CH2:25][CH2:26]4)[CH2:23][C:17]=3[CH:16]=2)[O:12][N:11]=1
Reactant: COC(=O)CC1Nc2ccc(-c3nc(-c4nc5ccccc5[nH]4)no3)cc2CN(C2CC2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: O=C(O)CC1Nc2ccc(-c3nc(-c4nc5ccccc5[nH]4)no3)cc2CN(C2CC2)C1=O

Procedure:
130 mg of methyl 7-[3-(1H-benzimidazol-2-yl)-[1,2,4]oxadiazol-5-yl]-4-cyclopropyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-2-acetate are hydrolyzed in 4 ml of ethylene glycol dimethyl ether and 3 ml of water and also 90 mg of LiOH analogously to Preparation Example 2. 80 mg are obtained as a colorless solid. 1H NMR (400 MHz, DMSO): 0.59 (m, 1H), 0.77 (m, 1H), 2.58 (1 H, dd, J=5.2 Hz, 16.7 Hz) 2.75-2.85 (m, 2H), 2.96 (s, 3H), 4.09 (d, 1H, 16.9 Hz), 5.13 (m, 1H), 5.47 (d, 1H, 16.9 Hz), 6.76 (d, 1H, 8.6 Hz), 6.92 (m, 1H), 7.25-7.90 (m, 6H), 12.5 (broad s, 1H), 13.52 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([NH:13]C(=O)CCl)([CH3:12])[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(O)(=O)C.NC(N)=S>C(O)C>[CH3:12][C:2]([NH2:13])([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(CCCc1ccccc1)NC(=O)CCl
Agent: NC(N)=S
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(N)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
A 1008 g quantity of N-(1,1-dimethyl-4-phenylbutyl)-2-chloroacetamide (3.98 moles) was dissolved in 8.4 L of ethanol and 1080 mL gl. acetic acid in a 22 L 3-necked, round-bottomed flask equipped with stirrer, thermometer and reflux condenser and 370 g (4.86 moles) of thiourea was added. The reaction was heated to reflux to dissolve the thiourea. A white crystalline precipitate began to form after about two hours of reflux. The reflux was continued for additional 8 h. The reaction mixture was allowed to cool to ambient temperature and was filtered and the filtrate diluted with 8 L of water, extracted with 2×1 L of hexane and neutralized by the addition of 220 mL 50% sodium hydroxide. This caused an oil to form which was separated and the aqueous phase extracted with 2×2 L of ether/hexane. The extracts were combined with the oil and concentrated to give 590 g of reddish oil, LC/MS single peak, m/e 179, NMR (CDCl3) consistent with the desired product, 1,1-Dimethyl-4-phenylbutylamine, 84% crude yield. This material was vacuum distilled to give 518 g of clear oil, bp(1 torr) 71-74°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[N:10]([CH:19]([CH3:21])[CH3:20])[C:9]=2/[CH:22]=[CH:23]/[C:24]([OH:26])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:30])=O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[N:10]([CH:19]([CH3:21])[CH3:20])[C:9]=2/[CH:22]=[CH:23]/[C:24]([Cl:30])=[O:26])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)n1c(/C=C/C(=O)O)c(-c2ccc(F)cc2)c2ccccc2c1=O
Solvent: C1CCOC1
Product: CC(C)n1c(/C=C/C(=O)Cl)c(-c2ccc(F)cc2)c2ccccc2c1=O

Procedure:
A solution of (E)-3-[4-(4-fluorophenyl)-2-isopropyl-1-oxo-1,2-dihydroisoquinolin-3-yl]prop-2-enoic acid (0.35 g) in dry tetrahydrofuran (10 ml) was treated with oxalyl chloride (0.26 ml) and heated at reflux for 2 hours. The solvent was then removed by distillation and the residual yellow solid was washed with petroleum ether (b.p. 40°-60° C.), to give (E)-3-[4-(4-fluorophenyl)-2-isopropyl-1-oxo-1,2-dihydroisoquinolin-3-yl]prop-2-enoyl chloride in the form of a pale yellow solid.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=[CH:13][CH:12]=1)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[Cl:25][C:26]1[C:27]([Cl:41])=[CH:28][C:29]2[O:34][CH2:33][C:32](=[O:35])[N:31]([CH2:36][C:37]([OH:39])=O)[C:30]=2[CH:40]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:25][C:26]1[C:27]([Cl:41])=[CH:28][C:29]2[O:34][CH2:33][C:32](=[O:35])[N:31]([CH2:36][C:37]([N:2]([CH3:1])[C@H:3]([C:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=4)=[CH:15][CH:16]=3)[CH2:4][N:5]3[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)=[O:39])[C:30]=2[CH:40]=1
Reactant: CN[C@@H](CN1CCOCC1)c1ccc(-c2cccc(OC)c2)cc1
Reactant: O=C(O)CN1C(=O)COc2cc(Cl)c(Cl)cc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cccc(-c2ccc([C@H](CN3CCOCC3)N(C)C(=O)CN3C(=O)COc4cc(Cl)c(Cl)cc43)cc2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46.2 %

Procedure:
(1R)—N-Methyl-1-[3′-(methyloxy)-4-biphenylyl]-2-(4-morpholinyl)ethanamine (3.3 g, 10 mmol) was dissolved in 100 mL of DMF at room temperature with magnetic stirring. The resulting solution was treated with (6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetic acid (4.3 g, 12 mmol, with 23 wt % LiCl) followed by triethylamine (2.8 mL, 20 mmol) and BOP (5.3 g, 12 mmol). The reaction mixture was maintained at room temperature for 16 h. The reaction mixture was filtered and the filtrate was added slowly to of H2O (300 mL) with vigorous stirring. The precipitate which formed was collected by filtration and further purified by silica gel chromatography (120 g Redisep column, silica, 40 um, 60 Å, 80 mL/min, A: MeOH (with 10% NEt3), B: CH2Cl2, A: 1% for 20 min, 2% for 20 min, 5% for 10 min; detection at 254 nm). The combined fractions were concentrated, and the resulting residue was triturated with MeOH. The white solid was collected by filtration to give the title compound (2.7 g, 46%). MS (ES) m/e 585 [M+H]+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][CH:14]([CH2:16][OH:17])[OH:15].Cl>N1C=CC=CC=1>[S:7]([O:12][CH2:13][CH:14]([CH2:16][O:17][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[OH:15])([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: OCC(O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(O)COS(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
Compound 2 was synthesized according to the previous reported method with modifications (Benbouzid et al., 1988). p-Toluenesulfonyl chloride (10.29 g, 54 mmol) dissolved in dry pyridine was added to a stirred solution of anhydrous glycerol (2.48 g, 27 mmol) in dry pyridine (30 ml at 0° C.). The solution was added slowly and left to react for 44 hours in the refrigerator (0°-3° C.). The pink mixture was poured over crushed ice and acidified with concentrated HCl. The organic layer was separated and the aqueous layer was washed with methylene chloride (2×50 ml). The combined organic extracts were washed successively with 2N HCl (2×10 ml) and distilled water (2×10 ml) and dried over anhydrous Na2SO4. The filtrate was evaporated and the residual crude product was purified by column chromatography on silica gel to afford Compound 2 as an oil: 9.72 g (24.3 mmol) yield 90%. 1H NMR [Chemical shift (d), multiplicity, coupling constant (Hz), number of protons, atom]: 7.75 (d; J=8.2 Hz; 4H, Har.); 7.35 (d; J=8.2 Hz; 4H; Har.); 4.1 (bs; 4H; H1,3); 3.35 (bs; 1H; H2); 2.4 (s; 6H; 2CH3). 13C NMR (ppm): 145 (C ar.); 131.7 (C ar.); 129.7 (CH ar.); 127.6 (CH ar.); 69.3 (C1,3); 66.7 (C2); 21.2 (CH3). Satisfactory 1H and 13C NMR data as well as mass spectral data were recorded for this compound. These spectra were consistent with the structures shown in FIG. 1.
Reaction SMILES: N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:15]([O-])([O-])=[O:16].[Cs+].[Cs+].I[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26].CO>[Cu]I.C1(C)C=CC=CC=1>[CH3:15][O:16][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cccc(I)c1
Agent: [Cu]I
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1cccc(C#N)c1
Temperature: 110 °C
Reaction time: 23 h
Yield: 83.4 %

Procedure:
A test tube was charged with CuI (20 mg, 0.10 mmol, 10 mol %), 1,10-phenanthroline (36 mg, 0.20 mmol, 20 mol %), Cs2CO3 (652 mg, 2.0 mmol), 3-iodobenzonitrile (229 mg, 1.0 mmol), methanol (162 μL, 4.0 mmol) and toluene (1 mL). The test tube was sealed and the reaction mixture was stirred at 110° C. for 23 h. The resulting suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with diethyl ether. The filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (2×20 cm; pentane/diethyl ether 5:1) provided 111 mg (84% yield) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:20])C(=O)C1.O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[C:5]([Br:20])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nccc2cc(F)ccc12
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1ncc(Br)c2cc(F)ccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.8 %

Procedure:
To a solution of 1-amino-6-fluoro-isoquinoline (0.41 g, 2.53 mmol) in CHCl3 (25 mL) is added NBS (0.45 g, 2.53 mmol), and the reaction mixture is stirred RT for 1.5 h. The reaction mixture is treated with water (10 mL). The aqueous phase is extracted with CH2Cl2 (2×). The combined organic layers are washed with brine, and dried over MgSO4. The solvent is evaporated and the residue is dried under vacuum. Purification of the crude material using a Biotage column (10-40% MeOH/CH2Cl2) afforded 0.395 g (65%) of 1-amino-4-bromo-6-fluoro-isoquinoline. LC/MS m/z=242 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.CCCCC.[Cl-].[C:17]([O:21][C:22](=[O:25])[CH2:23][Zn+])([CH3:20])([CH3:19])[CH3:18]>C1COCC1.CCOC(C)=O>[C:17]([O:21][C:22](=[O:25])[CH2:23][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: [Cl-]
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cc1ccc2cc[nH]c2c1

Procedure:
To a solution of 6-bromoindole (2 g, 10.2 mmol) in THF (20 mL) under nitrogen atmosphere was added KH (30% in mineral oil de-greased with pentane, 1.5 g, 11.22 mmol) and the mixture was stirred at RT for 30 min before addition of [P(t-Bu)3PdBr]2 (40 mg, 0.051 mmol) diluted in THF (20 mL). The resulting mixture was added to a solution of 2-tert-butoxy-2-oxoethylzinc chloride (0.5 M in Et2O, 22.4 mL, 11.2 mmol) stirred under nitrogen atmosphere and the mixture was further stirred at RT for 24 h. The reaction mixture was diluted with EtOAc, and washed with a saturated aqueous solution of NaHCO3, then with water. The organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 94:6 to c-hexane/EtOAc 8:2) to give the desired material. TLC, Rf (c-hexane/EtOAc 4:1)=0.3; MS (UPLC): 232.2 [M+H]+, 176.1 [MH−tBu]+, 249.2 [M+NH4]+, 463.4 [2M+H]+, 273.3 [M+HCOO]−.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([NH:10][CH:11]1[CH2:15][S:14](=[O:17])(=[O:16])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]1=2)[CH2:7][CH2:8][CH3:9].C(N(CC)CC)C>C1COCC1>[CH2:6]([N:10]([CH:11]1[CH2:15][S:14](=[O:17])(=[O:16])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]1=2)[S:2]([CH3:1])(=[O:4])=[O:3])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCNC1CS(=O)(=O)c2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCN(C1CS(=O)(=O)c2ccccc21)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 106 %

Procedure:
6.63 g (57 mmol) of methanesulfonyl chloride were added dropwise to a solution of 11.7 g (41 mmol) of butyl-(1,1-dioxo-2,3-dihydro-1H-benzo[b]thiophen-3-yl)-amine and 15.5 g (153 mmol) of triethylamine in 120 ml of THF, and the reaction mixture was stirred at RT overnight. Most of the THF was distilled off, the residue was diluted with 250 ml of water and the precipitate was filtered off with suction. Drying under reduced pressure gave 13.8 g of N-butyl-N-(1,1-dioxo-2,3-dihydro-1H-benzo[b]thiophen-3-yl)methanesulfonamide; m.p. 171-173° C.