Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[N:32]=[C:33]=[O:34].C(N(CC)CC)C>C1COCC1>[O:21]=[C:15]1[CH:14]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:33]([NH:32][C:23]3[CH:24]=[CH:25][C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:22]=3)=[O:34])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1ccc2ccccc2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3c(CNC(=O)Nc4ccc5ccccc5c4)cccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.6 %

Procedure:
A heterogeneous mixture of 3-(4-aminomethyl-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.50 g, 1.6 mmol), 2-naphthyl isocyanate (0.26 g, 1.6 mmol), and triethylamine (4.9 g, 4.9 mmol) in 25 mL THF was stirred under nitrogen at ambient temperature for 18 hours. The solvent was removed under vacuum. The residue was triturated with 3% aqueous HCl (100 mL) for 1 hour and then filtered, and the filter was washed with additional 3% HCl. The resulting solid was dried, triturated with 30 mL refluxing acetone for 1 hour, and filtered, and the filter was washed with additional hot acetone. The resulting solid was dried and then triturated with 30 mL refluxing acetonitrile, filtered, and dried, to provide 0.45 g of the product in 63% yield: 1H NMR (DMSO-d6) δ 2.01-2.08 (m, 1H), 2.38-2.45 (m, 1H), 2.57-2.65 (m, 1H), 2.86-2.93 (m, 1H), 4.41 (d, J=5.0 Hz, 2H), 4.43 (d, J=17.4 Hz, 1H), 4.57 (d, J=17.4 Hz, 1H), 5.16 (dd, J=13.2 Hz, J=5.1 Hz, 1H), 6.83 (t, J=5.8 Hz, 1H), 7.28-7.79 (m, 9H), 8.02 (d, J=1.8 Hz, 1H), 8.85 (s, 1H), 11.03 (s, 1H); 13C NMR (DMSO-d6) δ 22.6, 31.2, 39.8, 46.2, 51.6, 112.8, 119.6, 121.6, 123.6, 126.2, 126.8, 127.4, 128.2, 128.3, 128.8, 130.4, 131.7, 133.8, 135.6, 138.0, 139.9, 155.3, 168.1, 171.0, 172.8; Anal. calcd for C25H22N4O4.0.2H2O: C, 67.31; H, 5.06; N, 12.56. Found: C, 67.37; H, 4.90; N, 12.53.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14]Br)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.C(N(CC)CC)C.[OH-].[Na+].[Cl-].[Na+]>O.O1CCCC1>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH2:14][CH2:13][CH2:12][O:11][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[CH2:26][CH2:25]2)=[CH:22][CH:23]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: BrCCCOc1cccc2ccccc12
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(CCCOc3cccc4ccccc34)CC2)cc1
Yield: 67.7 %

Procedure:
10.6 g (40 mMol) 1-(naphth-1-yloxy)-3-bromopropane were mixed with 7.7 g (40 mMol) 1-(4-methoxyphenyl)-piperazine, 8.1 g (80 mMol) anhydrous triethylamine and 40 ml. anhydrous tetrahydrofuran and the reaction mixture subsequently maintained at reflux temperature for 10 hours. After cooling, the precipitated triethylamine hydrobromide was filtered off with suction. The filtrate was substantially evaporated in a vaccum, the residue was taken up in chloroform and the solution obtained was shaken with dilute aqueous sodium hydroxide solution, then with an aqueous solution of sodium chloride and thereafter with water. The organic phase was dried over anhydrous sodium sulfate, filtered through active charcoal and finally freed from chloroform in a vacuum. The oily residue was brought to crystallization by the addition of isopropanol. After recrystallization from methanol, with the addition of active charcoal, there were obtained 10.2 g (68% of theory) 1-(4-methoxyphenyl)-4-[3-(naphth-1-yloxy)-propyl]-piperazine, which had a melting point of 68° - 69° C. The corresponding hydrochloride was obtained by passing dry hydrogen chloride through a dioxan solution of the base. It had a melting point of 235° - 238° C.
Reaction SMILES: [F:1][CH:2]([F:6])[C:3](O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[F:47][CH:48]([F:77])[CH2:49][NH:50][C:51]1[N:56]=[C:55]2[CH:57]([CH3:61])[NH:58][CH2:59][CH2:60][C:54]2=[N:53][C:52]=1[N:62]1[CH2:67][CH2:66][CH:65]([O:68][C:69]2[CH:74]=[CH:73][C:72]([F:75])=[CH:71][C:70]=2[F:76])[CH2:64][CH2:63]1>CN(C=O)C>[F:77][CH:48]([F:47])[CH2:49][NH:50][C:51]1[N:56]=[C:55]2[CH:57]([CH3:61])[N:58]([C:3](=[O:4])[CH:2]([F:6])[F:1])[CH2:59][CH2:60][C:54]2=[N:53][C:52]=1[N:62]1[CH2:67][CH2:66][CH:65]([O:68][C:69]2[CH:74]=[CH:73][C:72]([F:75])=[CH:71][C:70]=2[F:76])[CH2:64][CH2:63]1
Reactant: CC1NCCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NCC(F)F)nc21
Reactant: O=C(O)C(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1c2nc(NCC(F)F)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2CCN1C(=O)C(F)F
Reaction time: 8 h

Procedure:
A solution of 2,2-difluoroacetic acid (2.86 mg, 0.030 mmol), HATU (11.3 mg, 0.030 mmol), and DIPEA (14.2 μL, 0.081 mmol) in DMF (136 μL) was stirred at room temperature for 10 min. Then, N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (15 mg, 0.027 mmol) was added and stirring was continued overnight. No desired product was detected by LCMS. To this was added 2,2-difluoroacetic anhydride (7.08 mg, 0.041 mmol) and after 1 h, purification by HPLC Method A afforded the title compound as a TFA salt (4.4 mg) as an off-white film. 1H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm 1.51 (d, J=6.8 Hz, 2.1H), 1.62 (d, J=6.8 Hz, 0.9H), 1.94-2.02 (m, 2H), 2.10-2.18 (m, 2H), 2.68-2.78 (m, 1H), 2.82-3.06 (m, 3.2H), 3.36-3.44 (m, 2H), 3.53-3.61 (m, 0.7H), 3.71-3.88 (m, 2.1H), 4.16 (dd, J=14.2, 5.4 Hz, 0.7H), 4.46 (dt, J=7.4, 3.8 Hz, 1H), 4.67 (dd, J=13.2, 5.9 Hz, 0.3H), 4.97 (q, J=6.7 Hz, 0.3H), 5.27 (q, J=6.8 Hz, 0.7H), 5.93-6.20 (m, 1H), 6.43-6.70 (m, 1H), 6.85-6.92 (m, 1H), 6.99 (ddd, J=11.3, 8.4, 3.2 Hz, 1H), 7.18 (td, J=9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 518.80.
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:33])[C:14]([NH:29][C:30](=[O:32])[CH3:31])([CH2:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl.C(OCC)(=O)C>[CH3:27][C:25]([CH3:28])([CH3:26])[CH2:24][CH2:23][C:14]1([NH:29][C:30](=[O:32])[CH3:31])[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]([OH:22])=[C:12]([C:7]2[NH:6][C:5]3[CH:34]=[CH:35][C:2]([NH:1][S:44]([CH3:43])(=[O:46])=[O:45])=[CH:3][C:4]=3[S:9](=[O:10])(=[O:11])[N:8]=2)[C:13]1=[O:33]
Reactant: CC(=O)NC1(CCC(C)(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)NC1(CCC(C)(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.2 %

Procedure:
To a solution of product of Example 74D (1.16 g, 2.33 mmol) in dichloromethane (20 mL) was added triethylamine (1.6 mL, 11.7 mmol) followed by dropwise addition of methanesulfonyl chloride (0.45 mL, 5.84 mmol). The reaction mixture was stirred at room temperature for 18 h. The solution was diluted with ethyl acetate (30 mL), washed with aqueous 1 N HCl (2×15 mL), dried (Na2SO4), and concentrated in vacuo. The resulting residue was taken up in methanol (20 mL) and treated with excess K2CO3 for 2 h. The mixture was filtered. The filtrate was concentrated in vacuo and the resulting residue was taken up in 3:1 dichloromethane:isopropanol (15 mL) and washed with aqueous 1 N HCl (2×10 mL), dried (Na2SO4), and concentrated in vacuo to afford the title compound as a light yellow solid (1.1 g, 82%). 1H NMR (500 MHz, DMSO-d6), δ ppm 0.44-0.54 (m, 1H), 0.66 (s, 9H), 0.87-0.98 (m, 1H), 1.80-1.89 (m, 4H), 1.95-2.05 (m, 1H), 3.08 (s, 3H), 7.53 (t, J=7.25 Hz, 2H), 7.58 (dd, J=8.69, 2.32 Hz, 1H), 7.64 (d, J=2.32 Hz, 1H), 7.70-7.78 (m, 2H), 8.12 (d, J=7.54 Hz, 1H), 9.14 (s, 1H), 10.24 (s, 1H), 13.61 (s, 1H); MS m/z 575.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9]CC=C)[CH:5]=[CH:4][C:3]=1[C:13]([C:15]1[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=1)=[O:14].CN(C)[C:23]1[CH:28]=CC=C[CH:24]=1>CCOCC>[CH2:28]([C:5]1[C:6]([OH:9])=[C:7]([Cl:8])[C:2]([Cl:1])=[C:3]([C:13]([C:15]2[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=2)=[O:14])[CH:4]=1)[CH:23]=[CH2:24]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1ccc(C(=O)c2ccnn2C)c(Cl)c1Cl
Solvent: CCOCC
Product: C=CCc1cc(C(=O)c2ccnn2C)c(Cl)c(Cl)c1O
Temperature: 200 °C
Reaction time: 25 h

Procedure:
A suspension of 8.20 g of (2,3-dichloro-4-allyloxyphenyl)(1-methyl-5-pyrazolyl)methanone in N,N-dimethylaniline is stirred at 200° C. under argon gas atmosphere for 25 hours and cooled. The reaction mixture is diluted with ether and extracted with an aqueous 5% sodium hydroxide solution. The aqueous extract is washed with ether, adjusted to pH 5-6 with acetic acid and then extracted with chloroform. The organic layer is washed with water, dried and evaporated to give a solid, which is then purified by silica gel column chromatography to give 5.16 g of 6-allyl-2,3-dichloro-4-(1-methyl-5-pyrazolylcarbonyl)phenol.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29](C(OC(C)(C)C)=O)[CH3:30])[CH:24]=2)[S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1>[CH:1]([N:14]1[CH2:15][C:16](=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][CH3:30])[CH:24]=2)[S:19]([CH3:22])(=[O:21])=[O:20])[CH2:17]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(C(=C2CN(C(c3ccccc3)c3ccccc3)C2)S(C)(=O)=O)c1
Solvent: C1COCCO1
Product: CNc1cccc(C(=C2CN(C(c3ccccc3)c3ccccc3)C2)S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.1 %

Procedure:
A mixture of 0.3 g of 1-benzhydryl-3-{[3-(N-tert-butyloxycarbonyl-N-methylamino)phenyl](methylsulfonyl)methylene}azetidine, 4 cm3 of a 4.7 N solution of hydrochloric dioxane and 4 cm3 of dioxane is stirred for 18 hours at room temperature. The reaction medium is concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 100 cm3 of water and 20 cm3 of diethyl ether. The aqueous phase is alkalinized with 30 cm3 of an aqueous sodium bicarbonate solution. The organic phase is extracted with twice 40 cm3 of ethyl acetate, washed with twice 30 cm3 of water, decanted off, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from 20 cm3 of diethyl ether. 0.16 g of 1-benzhydryl-3-[(3-methylaminophenyl)(methylsulfonyl)methylene]azetidine is obtained in the form of a solid melting at 161° C. [NMR spectrum in DMSO-d6, T=300K, δ in ppm (250 MHz): 2.65 (3H, d, J=5 Hz, NCH3), 2.95 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), 5.80 (1H, q, J=5 Hz, NH), 6.60 (3H, m, 3CH arom.), 7.15 (1H, t, J=7 Hz, CH arom.), 7.22 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz, 4CH arom.), 7.48 (4H, d, J=7 Hz, 4 CH arom.)].
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[C:32][CH2:33][CH3:34])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[Br:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:9]2[CH2:10][CH2:11][C:6]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]#[C:32][CH2:33][CH3:34])=[CH:27][CH:28]=3)(=[O:22])=[O:21])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[CH:18][CH:17]=1
Reactant: CCC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(Br)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(Br)cc3)CC2)cc1

Procedure:
1-(4-Bromo-benzyl)-4-(4-pent-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid was prepared starting from 1-(4-bromo-benzyl)-4-(4-pent-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid ethyl ester (2.64 g 4.8 mmol) dissolved in THF:methanol (100:50 ml) and 10 N NaOH (10 ml). The resulting reaction mixture was worked up as outlined in Example 1 (Step 7). Yield 1.6 g (65%); off white solid; mp 217° C.; MS: 521.9 (M+H)+
Reaction SMILES: FC(F)(F)C([O-])=O.[CH:8]1([C@H:14]2[C:47](=[O:48])[N:46]3[CH2:49][C@@H:43]([CH2:44][C@H:45]3[C:50](=[O:67])[NH:51][C@:52]3([C:57](=[O:66])[NH:58][S:59]([C:62]4([CH3:65])[CH2:64][CH2:63]4)(=[O:61])=[O:60])[CH2:54][C@H:53]3[CH:55]=[CH2:56])[O:42][C:26]3=[N:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=4[C:34]([O:35][CH:36]4[CH2:41][CH2:40][NH2+:39][CH2:38][CH2:37]4)=[C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]3[CH2:68][C@H:18]3[O:17][C:16](=[O:69])[NH:15]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.CCN(C(C)C)C(C)C.[CH:79]([S:81]([CH3:84])(=[O:83])=[O:82])=[CH2:80]>C(Cl)Cl>[CH:8]1([C@H:14]2[C:47](=[O:48])[N:46]3[CH2:49][C@@H:43]([CH2:44][C@H:45]3[C:50]([NH:51][C@:52]3([C:57](=[O:66])[NH:58][S:59]([C:62]4([CH3:65])[CH2:63][CH2:64]4)(=[O:61])=[O:60])[CH2:54][C@H:53]3[CH:55]=[CH2:56])=[O:67])[O:42][C:26]3=[N:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=4[C:34]([O:35][CH:36]4[CH2:37][CH2:38][N:39]([CH2:80][CH2:79][S:81]([CH3:84])(=[O:83])=[O:82])[CH2:40][CH2:41]4)=[C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]3[CH2:68][C@H:18]3[O:17][C:16](=[O:69])[NH:15]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCCC1)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OC1CC[NH2+]CC1)O2)C(=O)NS(=O)(=O)C1(C)CC1
Reactant: C=CS(C)(=O)=O
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCCC1)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OC1CCN(CCS(C)(=O)=O)CC1)O2)C(=O)NS(=O)(=O)C1(C)CC1
Reaction time: 16 h

Procedure:
To a solution of the product from Step 1, Example 236 (50 mg, 0.057 mmol) in CH2Cl2 (3 ml) was added DIPEA (0.030 ml, 0.171 mmol) followed by methyl vinyl sulfone (12.10 mg, 0.114 mmol). The reaction was stirred in a sealed vial for 16 h at which stage LCMS indicated complete conversion to one peak corresponding to a product with desired mass. After removing the solvent the crude mixture was purified by PTLC (5% MeOH in CH2Cl2) and then repurified by PTLC using 40% acetone in hexane to furnish the title compound. LRMS m/z 981.6 (M+H)+.
Reaction SMILES: Cl[C:2](=[O:16])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1.CC1C=CC=C(C)N=1.[H][H]>[Pd].O1CCCC1>[O:16]=[CH:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: [H][H]
Reactant: CCOC(=O)N1CCC(CCC(=O)Cl)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)N1CCC(CCC=O)CC1
Yield: 81 %

Procedure:
A mixture of 102 parts of ethyl 4-(3-chloro-3-oxopropyl)-1-piperidinecarboxylate, 45 parts of 2,6-dimethylpyridine and 630 parts of tetrahydrofuran was hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in 650 parts of dichloromethane. The solution was washed twice with 100 parts of a hydrochloric acid solution 5% and twice with 100 parts of water, dried, filtered and evaporated. The residue was distilled, yielding 71.1 parts (81%) of ethyl 4-(3-oxopropyl)-1-piperidinecarboxylate; bp. 130°-135° C. at 133 Pa (int. 46).
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@H:9]([CH2:28][F:29])[C@@H:10]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:27])(=[N:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[O:19])=[CH:14][CH:13]=1)[OH:11].C([O:32][C:33](=O)[CH:34]([Cl:36])[Cl:35])C>CO>[Cl:35][CH:34]([Cl:36])[C:33]([NH:8][C@H:9]([CH2:28][F:29])[C@H:10]([OH:11])[C:12]1[CH:13]=[CH:14][C:15]([S:18]([CH3:27])(=[N:20][C:21](=[O:26])[C:22]([F:24])([F:25])[F:23])=[O:19])=[CH:16][CH:17]=1)=[O:32]
Reactant: CCOC(=O)C(Cl)Cl
Reactant: CS(=O)(=NC(=O)C(F)(F)F)c1ccc([C@@H](O)[C@H](N)CF)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CS(=O)(=NC(=O)C(F)(F)F)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.6 %

Procedure:
To a solution of (1R,2S)-2-Amino-3-fluoro-1-(4-(methyl-N-(2,2,2-trifluoroacetyl)sulfonimidoyl)phenyl)-propan-1-ol TFA salt (426 mg, 1.479 mmol) in Methanol (5 mL) is added TEA (0.299 mL, 2.95 mmol) followed by addition of ethyldichloroacetate (0.279 mL, 1.775 mmol) The resulting reaction mixture is stirred at room temperature for 16 h. Solvent is evaporated in vacuo to get crude which is purified by combi-flash chromatography using 10.3% MeOH in DCM as an eluent to afford title compound (212 mg) as yellow oil. 1H-NMR (400 MHz, DMSO) δ: 3.02 (s, 3H), 4.19-4.13 (m, 1H), 4.15 (bs, 1H), 4.36-4.41 (m, 1.5H), 4.44-4.56 (m, 1H), 4.66-4.69 (m, 0.5H), 4.93 (t, J=4.56 Hz, 1H), 6.0 (d, J=4.64 Hz, 1H), 7.54 (d, J=8.28 Hz, 2H), 7.87 (d, J=8.36 Hz, 2H), 9.49 (d, J=8.36 Hz, 1H). LC-MS (m/z): M+H=343.1 (fragment).
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].Br[C:10]1[C:15]([Br:16])=[CH:14][CH:13]=[CH:12][N:11]=1>C1COCC1>[Br:16][C:15]1[C:10]([CH2:7][C:6]#[N:8])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: Brc1cccnc1Br
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCc1ncccc1Br
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
Dry THF (100 mL) was cooled to −78° C. and n-butyllithium (2.5 M in hexanes; 23 mL, 58 mmol) was added. Acetonitrile (3.3 mL, 64 mmol) was added dropwise maintaining the temperature below −60° C. A white precipitate formed and the reaction mixture was stirred at −78° C. for 45 min. A solution of 2,3-dibromopyridine (2.0 g, 8 4 mmol) in dry THF (10 mL) was added dropwise and the reaction mixture stirred at −78° C. for 1.5 h then allowed to warm to room temperature. The reaction was quenched by the dropwise addition of water. The aqueous was extracted with DCM (×3) and the combined organics washed with brine, dried (MgSO4) and concentrated in vacuo. (3-Bromo-pyridin-2-yl)-acetonitrile (Intermediate 1) was purified by flash column chromatography.
Reaction SMILES: B(Br)(Br)Br.C([O:12][C:13]1[CH:14]=[C:15]([F:31])[CH:16]=[C:17]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=2)[CH:18]=1)C1C=CC=CC=1.CO>C(Cl)Cl>[C:28]([O:27][C:24]1[CH:25]=[CH:26][C:21]([CH:20]=[CH:19][C:17]2[CH:18]=[C:13]([OH:12])[CH:14]=[C:15]([F:31])[CH:16]=2)=[CH:22][CH:23]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)Oc1ccc(C=Cc2cc(F)cc(OCc3ccccc3)c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC(=O)Oc1ccc(C=Cc2cc(O)cc(F)c2)cc1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 61.2 %

Procedure:
A 1 M solution of BBr3 (9 ml, 9 mmol) in CH2Cl2 was added to a well-stirred solution of 5-benzyloxy-3-fluoro-4′-acetoxystilbene (1.09 g, 3 mmol) in dry CH2Cl2 (120 mL) at −78° C. The mixture was warmed to −20° C. and stirred for 10 minutes. Then MeOH was added at −78° C. The mixture was washed with saturated NaHCO3, and water, dried over Na2SO4, filtered and evaporated. The 4′-acetoxy-3-fluoro-5-hydroxystilbene (0.50 g, 61%) was obtained as white solid. To a solution of the crude 4′-acetoxy-3-fluoro-5-hydroxystilbene (0.50 g, 1.8 mmol) in MeOH (7.5 ml) was added 3.7 ml 4M HCl in 1,4-dioxane. The mixture was stirred for 20 minutes at ambient temperature. After purification by flash column, 3-fluoro-5,4′-dihydroxystilbene (0.33 g, 78%) was obtained. Data are: 1H NMR (Aceton-d6, 300 MHz) δ 8.624 (s, 2H), 7.46 (m, 2H), 7.06 (q, 2H), 6.84 (m, 4H), 6.66 (dt, 1H); 13C NMR (Aceton-d6, 75 MHz) δ 164.90 (d), 159.96 (d), 158.57, 142.02 (d), 130.84, 129.63, 129.10, 125.55 (d), 116.53, 110.28 (d), 104.44 (d), 102.00 (d); 19F NMR (Aceton-d6, 282 MHz) δ −32429.72 (t); HRMS (EI+) found 230.0738 M+, calcd 230.0743 for C14H11FO2.
Reaction SMILES: [SH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[N:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:46][O:47][C:48](=[O:55])/[CH:49]=[C:50](\[CH3:54])/[CH2:51][CH2:52]O>C(OCC)(=O)C.C1COCC1>[CH3:46][O:47][C:48](=[O:55])/[CH:49]=[C:50](\[CH3:54])/[CH2:51][CH2:52][S:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[N:4][N:3]=1
Reactant: COC(=O)/C=C(\C)CCO
Reactant: Sc1nnnn1-c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)/C=C(\C)CCSc1nnnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.7 %

Procedure:
5-Mercapto-1-phenyltetrazole (2.62 g, 14.60 mmol), triphenylphosphine (3.83 g, 14.60 mmol) and diisopropyl azodicarboxylate (95%, 2.96 g, 14.60 mmol) were added to a THF (36.8 ml) solution of methyl-(2E)-5-hydroxy-3-methylpent-2-enoate (1.16 g, 7.31 mmol) while ice cooling. The reaction solution was warmed to room temperature and stirred for two hours. After the reaction solution was diluted with ethyl acetate, it was washed with distilled water and brine. After the organic layer was dried over anhydrous sodium sulfate and the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Merck, commercial name Silica Gel 60, 230-400 mesh; hexane:ethyl acetate=5:1) to obtain the title compound (2.33 g) as a white solid.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]([CH3:19])([O-:18])[CH3:17].[K+].Cl[CH2:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[C:26](OC)=[O:27]>O1CCCC1>[CH:11]1[C:12]2[N:13]([CH2:22][C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([O:18][C:16]([CH3:19])([CH3:17])[CH3:15])=[O:27])[C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[S:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1cccc(CCl)c1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cccc(CN2c3ccccc3Sc3ccccc32)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 30.6 %

Procedure:
To a solution of phenothiazine (1.00 g) in tetrahydrofuran (10 ml) was added potassium tert-butoxide (617 mg) at 0° C. The mixture was stirred at 0° C. for 20 minutes, and then a solution of methyl 3-(chloromethyl)benzoate (1.02 g) in tetrahydrofuran (10 ml) was added. The mixture was stirred at 25° C. for 3 hours, and then potassium tert-butoxide (1.02 g) was added. The mixture was stirred at 25° C. for 1 hour, and then evaporated. The residue was partitioned between ethyl acetate and 0.1N hydrochloric acid. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (40:1) to give tert-butyl 3-(phenothiazin-10-ylmethyl)benzoate (598 mg) as crystals.