Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=[C:4]([NH:8][C:9]([NH:11][S:12]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:14])=[O:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.N1CCCC1>C(O)C>[N:8]1([C:9]([NH:11][S:12]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:14])=[O:13])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(Nc1cccc(Cl)c1)NS(=O)(=O)C=Cc1ccccc1
Solvent: C1CCNC1
Solvent: CCO
Product: O=C(NS(=O)(=O)C=Cc1ccccc1)N1CCCC1

Procedure:
A mixture of 3.4 g. of N-(N-[m-chlorophenyl]carbamoyl)-2-phenylethenesulfonamide and 2.15 g. of pyrrolidine in 100 ml. of ethanol is heated under reflux for 20 hours. The solution is cooled, and then it is concentrated in vacuo to ca. 25 ml. A small amount of starting material precipitates and it is filtered off. To the ethanol filtrate is then added 75 ml. of ether and 75 ml. of water. The layers are separated, and the aqueous layer is acidified using concentrated hydrochloric acid. This causes the crude product to precipitate. It is filtered off, and when dry it weighs 1.5 g. The ether layer is washed with 50 ml. of 1N hydrochloric acid, followed by 25 ml. of water. After being dried using anhydrous sodium sulfate, the ether is evaporated in vacuo to give a second crop of product (0.70 g.). The first crop of product is recrystallized from acetone to 0.60 g. of pure-N-(pyrrolidinocarbonyl)-2-phenylethenesulfonamide, m.p. 201°-204° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8](Br)[C:9]#[CH:10].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:10]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]#[CH:8]
Reactant: C#CCBr
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1ccccc1
Temperature: 85 °C
Yield: 84 %

Procedure:
Referring to FIG. 39, phenol (14.6 g. 0.155 mol), propargyl bromide (19 m 0.171 mol) and potassium carbonate (32.1 g, 0.232 mol) in DMF (100 mL) were heated at 85° C. overnight. The reaction was diluted with water and extracted with ether. The extract was washed with brine, dried (MgSO4) and evaporated. The residue was purified by Biotage flash column chromatography (10% EtOAc/Hep) to give product as an oil (17.2 g, 84%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.Cl[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[CH3:23]>>[CH3:23][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:17]=1[O:14][CH:11]1[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]1
Reactant: Cc1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: Cl
Product: Cc1cnccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 72 h

Procedure:
The title compound was prepared from 1-Boc-4-hydroxypiperidine and 4-chloro-3-methylpyridine hydrochloride, using a similar method to preparation 27. The reaction mixture was stirred for 72 hours to afford the title compound the desired product in 87% yield. 1H NMR (CDCl3, 400 MHz) δ: 1.44 (s, 9H), 1.75-1.85 (m, 2H), 1.87-1.97 (m, 2H), 2.18 (s, 3H), 3.42-3.53 (m, 2H), 3.56-3.65 (m, 2H), 4.57-4.65 (m, 1H), 6.72 (d, 1H), 8.29 (s, 1H), 8.35 (d, 1H); LRMS APCI m/z 293 [M+H]+
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]([O:16][CH2:17][CH:18]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:10][C@H:9]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])=O)(C)(C)C.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42].C(Cl)Cl>>[F:44][C:43]([F:46])([F:45])[C:41]([OH:47])=[O:42].[CH2:34]([O:33][C:31]([C@@H:9]1[CH2:10][C@H:11]([NH:13][C:14]([O:16][CH2:17][CH:18]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:12][NH:8]1)=[O:32])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1CN[C@H](C(=O)OCc2ccccc2)C1)OCC1c2ccccc2-c2ccccc21
Reaction time: 2 h

Procedure:
A mixture of 20 mL TFA/DCM (1:1) at 0° C. was added to (2S,4S)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (0.92 g, 0.17 mmol) at 0° C., the cooling bath was removed and the mixture stirred for 2 h. The mixture was concentrated and triturated with diethyl ether to give (2S,4S)-4-(9H-Fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-2-carboxylic acid benzyl ester trifluoroacetate (0.94 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]([NH:11][CH2:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=2[O:21][CH3:22])=[NH:10])[CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](OB(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].C([O-])(=O)C>>[CH3:22][O:21][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:13]=1[CH2:12][NH:11][C:9]([NH:8][C:4]1[CH:3]=[C:2]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[CH:7]=[CH:6][N:5]=1)=[NH:10]
Reactant: OB(O)Oc1ccc(F)cc1
Reactant: COc1cccc(OC)c1CNC(=N)Nc1cc(Br)ccn1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cccc(OC)c1CNC(=N)Nc1cc(-c2ccc(F)cc2)ccn1
Temperature: 110 °C
Yield: 55.3 %

Procedure:
The preparation was carried out analogously to Example 56, using 0.160 g (0.438 mmol) N-(4-bromopyridin-2-yl)-N′-(2,6-dimethoxybenzyl)guanidine, 0.091 g (0.657 mmol) (4-fluorophenyl)boric acid, 0.139 g (1.314 mmol) sodium carbonate, and 0.035 g (0.031 mmol) tetrakis-(triphenylphosphine)palladium(0). The mixture was likewise heated in a reaction block for 18.5 hr at 110° C. under a nitrogen atmosphere. After appropriate workup and purification via preparative HPLC, 106.5 mg (0.242 mmol, 55%) pure N-(2,6-dimethoxybenzyl)-N′-[4-(4-fluorophenyl)pyridin-2-yl]guanidine was obtained in the form of the acetate salt (base/acetate in a ratio of 1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34](O)=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:9][CH:8]=1.Cl.C[O:45][C:46](=[O:64])[C@@H:47]([NH2:63])[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][C:58]([C:61]#[N:62])=[CH:57][CH:56]=2)=[CH:51][CH:50]=1>>[C:61]([C:58]1[CH:57]=[CH:56][C:55]([C:52]2[CH:51]=[CH:50][C:49]([CH2:48][C@H:47]([NH:63][C:34]([C@@H:20]3[CH2:19][C:18]4[CH:17]=[C:16]5[O:37][CH2:38][C@H:13]([C:10]6[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]7[CH:39]=[CH:40][C:41]([Cl:42])=[C:2]([Cl:1])[CH:3]=7)=[CH:12][CH:11]=6)[O:14][C:15]5=[CH:24][C:23]=4[CH2:22][N:21]3[C@H:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:26][CH3:27])=[O:35])[C:46]([OH:45])=[O:64])=[CH:54][CH:53]=2)=[CH:60][CH:59]=1)#[N:62]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: Cl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
The title compound (193 mg) was prepared from (3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (272 mg) and (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester hydrochloride according to General Procedures L and B. LCMS (m/z): 853.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N+:21]=2[O-])=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].C1CCCCC=1>[Pd].C(O)(C)C>[CH3:1][C:2]([CH3:27])([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(C)(C)Cc1ccc(OCCCNc2cccc[n+]2[O-])cc1
Agent: [Pd]
Solvent: CC(C)O
Solvent: C1=CCCCC1
Product: COC(=O)CC(C)(C)Cc1ccc(OCCCNc2ccccn2)cc1

Procedure:
A mixture of the product of STEP 1 (0.95 g), cyclohexene (Aldrich, 7 mL), 10% Pd/C (0.2 g) and isopropanol (10 mL) was heated to reflux for 20 hours. The mixture was filtered through celite and concentrated in vacuo. The residue was purified by chromatography using ethyl acetate as eluant to provide the above product as a thick gum.
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1/[CH:29]=[CH:30]/[CH:31]=[O:32]>>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH:30]1[C:31](=[O:32])[O:13][C:12]2[NH:11][C:10]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=3[F:21])=[N:9][C:8]=2[CH:1]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(c2cc(F)ccc2F)=N/C1=C\c1ccccc1
Reactant: O=C/C=C/c1ccccc1Cl
Product: O=C1Oc2[nH]c(-c3cc(F)ccc3F)nc2C(c2ccccc2)C1Cc1ccccc1Cl
Yield: 48 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,5-difluorophenyl)-1H-imidazol-5(4H)-one and (E)-3-(2-chlorophenyl)acrylaldehyde. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 14 as a white solid (65 mg, 48%). Analytical data for 14: 1H NMR (500 MHz, CDCl3) δ 9.40 (d, J=8.0 Hz, 1H), 7.88 (ddd, J=9.2, 6.1, 3.2 Hz, 1H), 7.39-7.32 (m, 3H), 7.28-7.22 (m, 2H), 7.10-7.03 (m, 2H), 7.01-6.94 (m, 4H), 4.09 (d, J=6.9 Hz, 1H), 3.58 (ddd, J=9.8, 6.8, 4.9 Hz, 1H), 3.31 (dd, J=14.9, 4.9 Hz, 1H), 2.42 (dd, J=14.9, 9.8 Hz, 1H); 13C NMR (CDCl3, 126 MHz) δ 168.6, 159.1 (d, JCF=243.3 Hz), 155.4 (d, JCF=240.2 Hz), 148.9, 140.0, 136.8, 136.5, 134.4, 129.9, 129.3, 129.1, 128.5, 127.9, 127.3, 127.0, 118.3 (dd, JCF=13.0, 9.3 Hz), 117.1 (dd, JCF=25.8, 8.7 Hz), 116.6 (dd, JCF=24.8, 9.5 Hz), 114.5 (dd, JCF=26.8, 3.7 Hz), 110.7 (d, JCF=3.8 Hz), 47.0, 38.6, 32.6; IR (film) cm−1 1772, 1636, 1619, 1598, 1529, 1481, 1463, 1172, 1118, 1079, 875, 813, 766, 741, 697; LRMS (ESI): Mass calcd for [M+H]+ C25H18ClF2N2O2: 451.1. found 451.3; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 4% IPA/2% MeOH/hexanes 1.0 mL/min, 280 nm), Rt1 (major)=20.7, Rt2 (minor)=23.6 min; er=92:8.
Reaction SMILES: COC[N:4]1[C:9]2[CH:10]=[C:11]([C:14]3[S:15][CH2:16][CH:17](O)[N:18]=3)[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:20]=[CH:21][CH:22]=[N:23][C:5]1=2.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>COCCOC.C(OCC)(=O)C>[S:15]1[CH:16]=[CH:17][N:18]=[C:14]1[C:11]1[CH:12]=[CH:13][C:8]2[S:7][C:6]3[N:20]=[CH:21][CH:22]=[N:23][C:5]=3[NH:4][C:9]=2[CH:10]=1
Reactant: COCN1c2cc(C3=NC(O)CS3)ccc2Sc2nccnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Product: c1csc(-c2ccc3c(c2)Nc2nccnc2S3)n1
Yield: 62.3 %

Procedure:
450 mg of 2-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-4,5-dihydro-1,3-thiazol-4-ol and 0.83 ml of pyridine were dissolved in 15 ml of 1,2-dimethoxyethane. While stirring the reaction mixture under ice-cooling, 300 mg of trifluoroacetic anhydride was dropped thereinto and the resulting mixture was stirred for 1 hour. Then the reaction mixture was distributed into an aqueous solution of sodium bicarbonate and ethyl acetate. The organic layer was extracted, washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the oily residue thus obtained was treated in the same manner as the one of Example 434 and purified by silica gel column chromatography (eluted with dichloromethane/methanol). Thus 230 mg of the title compound was obtained as yellow crystals.
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=1)[CH2:3][C:4]#[CH:5].[N:12]([CH2:15][CH2:16][C:17]1[CH:21]=[CH:20][S:19][CH:18]=1)=[N+:13]=[N-:14]>>[ClH:1].[S:19]1[CH:20]=[CH:21][C:17]([CH2:16][CH2:15][N:12]2[CH:5]=[C:4]([CH2:3][CH2:2][C:6]3[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=3)[N:14]=[N:13]2)=[CH:18]1
Reactant: C#CCCc1c[nH]c(N)n1
Reactant: [N-]=[N+]=NCCc1ccsc1
Agent: Cl
Product: Nc1nc(CCc2cn(CCc3ccsc3)nn2)c[nH]1
Yield: 47.2 %

Procedure:
4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.078 g, 0.45 mmol) was reacted with 3-(2-Azido-ethyl)-thiophene (0.083 g, 0.543 mmol) following the general procedure for click reactions outlined above to produce 4-{2-[1-(2-Thiophen-3-yl-ethyl)-1H-[1,2,3]triazol-4-yl]-ethyl}-1H-imidazol-2-ylamine hydrochloride (0.069 g, 47%) of a pale yellow oil. 1H NMR (300 MHz, CD3OD) δ 7.33 (s, 1H), δ 7.19 (dd, 1H), δ 6.85 (d, 1H), δ 6.72 (d, 1H), δ 6.06 (s, 1H), δ 4.45 (t, 2H), δ 3.08 (t, 2H), δ 2.79 (t, 2H), δ 2.59 (t, 2H), ppm 13C (75 MHz, CD3OD) δ 149.3, 147.0, 137.7, 132.1, 127.7, 125.8, 122.4, 121.9, 110.6, 50.8, 30.7, 26.6, 24.8 ppm; HRMS (ESI) calcd for C13H17N6S (M+) 289.1229. found 289.1231.
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]1[F:22])C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CCO>[NH2:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:11][C@H:10]1[F:22]
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)C(F)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](F)C1
Reaction time: 15 h
Yield: 97.4 %

Procedure:
To a 250 mL glass Parr vessel was added the product from Step C (14.8 g, 48.0 mmol) and EtOH (100 mL). Pearlman's Catalyst (4.72 g, 3.36 mmol) was added and the mixture was shaken in a Parr reactor under 40-45 psi H2 for 15 hours. The reaction was filtered through celite and the celite was washed with EtOAc. The filtrate was concentrated and the residue was dissolved in CH2Cl2 and filtered through celite, and the celite was washed with CH2Cl2 and EtOAc. The filtrate was concentrated to afford 10.2 g (92%) of the desired product as a thick oil that slowly solidified to a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[N:7]([C@H:9]([C:11](=[O:30])[NH:12][C@H:13]([C:17]([N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21][CH:20]1[CH2:28][OH:29])=[O:18])[CH:14]([CH3:16])[CH3:15])[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[K+].[Br-].[O-]Cl.[Na+]>C(Cl)Cl.CC1(C)N([O])C(C)(C)CCC1>[C:1]([O:5][C:6](=[O:31])[N:7]([C@H:9]([C:11](=[O:30])[NH:12][C@H:13]([C:17]([N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21][C@H:20]1[CH:28]=[O:29])=[O:18])[CH:14]([CH3:16])[CH3:15])[CH3:10])[CH3:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2CC1CO
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1C=O
Reaction time: 1 h
Yield: 73 %

Procedure:
To {(S)-1-[(S)-1-(2-hydroxymethyl-2,3-dihydro-pyrrolo[2,3-b]pyridine-1-carbonyl)-2-methyl-propylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (16.5 mg, 0.038 mmol) in DCM (0.4 mL) at 0° C. was added sequentially KBr (3.1 g, 0.027 mmol), TEMPO (0.3 mg) and 8% NaOCl solution (0.35 mL, 10 eq) and the reaction was stirred vigorously for 1 h. The reaction mixture was diluted with DCM and washed with water and brine and then concentrated in vacuo to give {(S)-1-[(S)-1-((S)-2-formyl-2,3-dihydro-pyrrolo[2,3-b]pyridine-1-carbonyl)-2-methyl-propylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (12 mg).
Reaction SMILES: ClC(Cl)C.[CH3:5][O:6][C:7]1[CH:44]=[CH:43][C:10]([CH2:11][N:12]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:13]2[N:18]=[CH:17][C:16]([C:19]3[C:20]4[CH2:33][CH2:32][NH:31][C:21]=4[N:22]=[C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[N:24]=3)=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH2:45]([O:47][C:48](=[O:53])[CH2:49][N:50]=[C:51]=[O:52])[CH3:46].[Cl-].[NH4+]>C(N(CC)CC)C>[CH2:45]([O:47][C:48](=[O:53])[CH2:49][NH:50][C:51]([N:31]1[C:21]2[N:22]=[C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:24]=[C:19]([C:16]3[CH:15]=[N:14][C:13]([N:12]([CH2:11][C:10]4[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:44][CH:43]=4)[CH2:34][C:35]4[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=4)=[N:18][CH:17]=3)[C:20]=2[CH2:33][CH2:32]1)=[O:52])[CH3:46]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CCOC(=O)CN=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CCOC(=O)CNC(=O)N1CCc2c(-c3cnc(N(Cc4ccc(OC)cc4)Cc4ccc(OC)cc4)nc3)nc(N3CCOCC3)nc21
Temperature: 25 °C

Procedure:
To a dichloroethane solution (2 ml) of bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg), triethylamine (260 μl) and isocyanato-acetic acid ethyl ester (208 μl) were added, followed by refluxing for 3 hours. After this was cooled to room temperature, saturated aqueous ammonium chloride solution was added, and passed through Whatman tube. The resulting organic layer was concentrated under reduced pressure, followed by purification by silica gel column chromatography (dichloromethane/methanol=/) column chromatography (dichloromethane/methanol=1/0 to 100/1), to obtain a crude product of the desired compound (127 mg, quant.).
Reaction SMILES: [K+].[C:2]([N:9]1[C@@H:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:12]([C:20]([O-:22])=[O:21])[O:11][CH:10]1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3]>C(OCC)(=O)C>[C:2]([N:9]1[C@@H:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:12]([C:20]([OH:22])=[O:21])[O:11][CH:10]1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3]
Reactant: COc1ccc(C2O[C@@H](C(=O)[O-])[C@H](c3ccccc3)N2C(=O)OC(C)(C)C)c(OC)c1
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1ccc(C2O[C@@H](C(=O)O)[C@H](c3ccccc3)N2C(=O)OC(C)(C)C)c(OC)c1
Reaction time: 2.5 h

Procedure:
(4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid (4a,b) is prepared from the side chain salt as follows. The (4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid potassium salt (1.5 mM) is suspended in ethyl acetate, and the solution washed twice with 5% aqueous sodium bisulfate, once with brine, dried and evaporated. The carboxylic acid is treated with methylene chloride (2 mL), 4-dimethylaminopyridine (48 mg), a solution of the 7-TES-Δ12,13 -iso-baccatin III (3, 0.492 g, 0.702 mM) in toluene (5 mL) plus methylene chloride (8 mL), and 1,3-dicyclohexylcarbodiimide (0.316 g, 1.53 mM). The solution is stirred under an inert atmosphere 2.5 h. The reaction is diluted with ethyl acetate and washed with aqueous sodium bisulfate and aqueous bicarbonate plus brine. The layers are filtered and separated, and the organic layer dried and evaporated. The product is purified by silica gel chromatography in acetone-hexane mixtures. 7-TES-Δ12,13 -iso-baccatin III-13-(4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid ester (5a,b) is obtained.
Reaction SMILES: [OH-].[Na+].CC1(C)C(C)(C)OB([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)O1.Br[C:22]1[S:23][CH:24]=[CH:25][N:26]=1>[Pd].C1COCC1>[S:23]1[CH:24]=[CH:25][N:26]=[C:22]1[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2
Reactant: Brc1nccs1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: c1cc(-c2nccs2)c2cc[nH]c2c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 42.5 %

Procedure:
Palladium catalyst Pd(PPh3)4 (142 mg, 0.12 mmol) and freshly prepared aqueous sodium hydroxide (493 mg, 12.33 mmol in 6 mL of water) were added to a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (1 g, 4.11 mmol) and 2-bromothiazole (809 mg, 4.93 mmol) in THF (20 mL). The system was degassed and then purged three times with nitrogen. The mixture was stirred under nitrogen at 70° C. in an oil bath for 4 hours. It was then cooled to room temperature and ethyl acetate (300 mL) was added. The organic layer was isolated, washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was triturated with dichloromethane to give 350 mg (42%) of 4-thiazol-2-yl-1H-indole as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C@H:9]([CH3:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=1.[C:18]1([C:24]#[CH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.C(NCC)C.[Cu]I.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O(C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1>[N+:15]([C:5]1[CH:4]=[CH:3][C:2]([C:25]#[C:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][C:6]=1[NH:8][C@H:9]([CH3:14])[C:10]([CH3:13])([CH3:12])[CH3:11])([O-:17])=[O:16]
Reactant: C[C@@H](Nc1cc(Cl)ccc1[N+](=O)[O-])C(C)(C)C
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCNCC
Product: C[C@@H](Nc1cc(C#Cc2ccccc2)ccc1[N+](=O)[O-])C(C)(C)C
Temperature: 25 °C
Yield: 129.2 %

Procedure:
Stir (5-Chloro-2-nitrophenyl)-(1-(R)-methyl-2,2-dimethylpropyl)amine (17.23 g, 0.067 mol), copper (I) iodide (0.64 g, 0.0034 mol), (oxydi-2,1-phenylene)bis(diphenylphosphine) (3.61 g, 0.0067 mol), phenylacetylene (12.5 mL, 0.114 mol) in DMF (200 mL) and diethylamine (50 mL) for 5 minutes. Add palladium (II) acetate (0.753 g, 0.0034 mol) and heat to 95° C. for 4 h. Cool to ambient temperature and evaporate off diethylamine under reduced pressure and pour into hexane. Filter insolubles and evaporate off hexane. Dilute with ethyl ether (1 L), filter and wash filtrate with water (2×1 L), saturated sodium chloride, dry magnesium sulfate, concentrate and purify (silica gel chromatography eluting with hexane/dichloromethane mixtures) to give 27.9 g of crude (2-nitro-5-phenylethynylphenyl)-(1-(R)-methyl-2,2-dimethylpropyl)amine that was used in the next step without further purification. To a solution of impure (2-nitro-5-phenylethynylphenyl)-(1-(R)-methyl-2,2-dimethylpropyl)amine (27.9 g) in THF (350 mL), water (100 mL), concentrated ammonium hydroxide (150 mL), Na2S2O4 (73.6 g, 0.423 mol) and stir for about 18 hours. Dilute with ethyl acetate and wash with saturated sodium chloride, dry with magnesium sulfate, concentrate and purify (silica gel chromatography with hexane/dichloromethane mixtures to give 14.51 g of the desired compound (75% for 2 Steps).
Reaction SMILES: S(Cl)(C)(=O)=O.[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)(=[O:9])[CH:7]=[CH2:8].C(N(CC)CC)C.[C:34]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][O:45][C:46](=[O:55])[C:47]1[CH:52]=[C:51](O)[CH:50]=[CH:49][C:48]=1[OH:54])(=[O:37])[CH:35]=[CH2:36]>C1COCC1>[C:34]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][O:45][C:46](=[O:55])[C:47]1[CH:52]=[C:51]([O:23][C:22](=[O:24])[C:21]2[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6](=[O:9])[CH:7]=[CH2:8])=[CH:26][CH:25]=2)[CH:50]=[CH:49][C:48]=1[OH:54])(=[O:37])[CH:35]=[CH2:36]
Reactant: C=CC(=O)OCCCCCCOC(=O)c1cc(O)ccc1O
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCCCCCOC(=O)c1cc(OC(=O)c2ccc(OCCCCCCOC(=O)C=C)cc2)ccc1O
Temperature: -25 °C
Reaction time: 0.5 h

Procedure:
A solution of mesyl chloride (3.44 g) in 50 ml of dry THF was added dropwise under argon to a cooled (−25° C.) solution of 4-(6-acryloyloxyhexyloxy)benzoic acid (8.35 g) and triethylamine (6.07 g) in 100 ml of dry THF. After complete addition (15 min), the reaction mixture was stirred for a further 30 min at −25° C., treated with a solution of 2,5-dihydroxybenzoic-6-acryloyloxyhexyl ester in 50 ml of dry THF and further stirred at −25° C. for 4 h. The reaction mixture was then filtered through celite and the solvent was removed by evaporation. The filtrate was purified by flash chromatography using a short silica-gel column and dichloromethane/diethylether (39/1) as eluent to give 10.8 g of 5-[4-(6-acryloyloxyhexyloxy)benzoyloxy]-2-hydroxybenzoic acid 6-acryloyloxyhexyl ester as a slightly beige oil.