Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.CC([CH2:9][CH2:10][CH2:11][C@H:12]([C@@H:14]1[C@:32]2([CH3:33])[C@H:17]([C@H:18]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:21](C[C@H](C[CH2:26]2)O)=[CH:20][CH2:19]3)CC1)C)C.[C:34]([O-:37])(=[O:36])[CH3:35]>CO>[CH3:17][C:18]1[CH2:19][CH2:20][CH2:21][C:27]([CH3:26])([CH3:28])[C:29]=1/[CH:30]=[CH:31]/[C:32](/[CH3:33])=[CH:14]/[CH:12]=[CH:11]/[C:10](/[CH3:9])=[CH:35]/[C:34]([OH:37])=[O:36]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CO
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC1

Procedure:
40 mg of hapten are solubilized in 2 ml of anhydrous methanol and 2 ml of anhydrous DMF containing 1 μl of radioactive tracer (cholesterol: ref. NET 725, Dupont de Nemours). 80 mg of PL dissolved in 2 ml of 1.5 M acetate buffer are then added dropwise. After thorough stirring, the conjugates are purified by dialysis. The first dialysis solution consists of a mixture of 1/3 of methanol, 1/3 of DMF and 1/3 of water. The following two solutions consist solely of water.
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[CH2:6][CH2:5][CH:4]=[N:3]1.C(#N)C.C1COCC1.C[Si](C)(C)[O:18][C:19]([CH:21]=[CH2:22])=[CH2:20]>ClCCl.Cl.[Cl-].[Cl-].[Zn+2]>[CH3:1][C:2]1([CH3:7])[N:3]2[CH:4]([CH2:20][C:19](=[O:18])[CH2:21][CH2:22]2)[CH2:5][CH2:6]1
Reactant: C=CC(=C)O[Si](C)(C)C
Reactant: CC1(C)CCC=N1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC#N
Product: CC1(C)CCC2CC(=O)CCN21
Temperature: 60 °C
Yield: 10.9 %

Procedure:
3,4-Dihydro-2,2-dimethyl-2H-pyrrole (900 mg, 9.3 mmol) was added to acetonitrile (90 ml) in a 250 ml round bottom flask, fitted with water condenser. ZnCl2 (0.5M) in THF (23 ml, 11.6 mmol) was added to the solution and warmed to 60° C. 2-(Trimethylsiloxy)-1,3-butadiene (2.6 g, mmol, 18.4 mmol) was added to the mixture and heated at 90° C. overnight. The solution was cooled to room temperature and diluted with dichloromethane (90 ml) and 1N HCl (90 ml). The two layers were separated, the aqueous layer was basified with NH3 (28%) in H2O, and extracted with dichloromethane. The organic layer was washed with brine and dried with Na2SO4. Solid was removed by filtration and mother liquor was concentrated in vacuo to give 250 mg brown color oil. This oil was further purified by column chromatography (100% ethyl acetate to 95% ethyl acetate: 5% methanol) to give a light yellow oil (170 mg, 11% yield).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]([CH3:15])([C:12](Cl)=[O:13])[C:9](Cl)=[O:10].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[CH2:24][NH:25][OH:26]>C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[CH2:24][N:25]1[C:9](=[O:10])[C:8]([CH3:15])([CH3:7])[C:12](=[O:13])[O:26]1
Reactant: CC(C)(C(=O)Cl)C(=O)Cl
Reactant: ONCc1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)C(=O)ON(Cc2ccc(Cl)cc2Cl)C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
Seventy-five ml of methylene chloride and 9.6 ml (0.12 mole) of pyridine were placed in a flask under argon and cooled to 0° C. To this solution 8.4 grams (0.05 mole) dimethylmalonylchloride in 20 ml methylene chloride was added dropwise with stirring. This mixture was cooled to -70° C. and 9.6 g (0.05 mole) of N-(2,4-dichlorophenylmethyl)hydroxylamine (Intermediate E) was added in a single portion, and the temperature rose to 35° C. Stirring was continued for two hours at -10° C., and at ambient temperature for about 18 hours. The reaction mixture was washed with 2 N hydrochloric acid and saturated aqueous sodium chloride solution, and the methylene chloride layer was dried over sodium sulfate, which was removed by filtration. The filtrate was evaporated under reduced pressure and the resulting viscous liquid was subjected to column chromatography on silica gel. Elution was accomplished with 25% ethyl acetate in hexane. Cuts 3-11 were combined and solvent was removed under reduced pressure, yielding a light orange viscous liquid. This solidified as 6.5 grams of product (45% yield); mp 68°-69.5° C. The nmr and ir spectra were consistent with the assigned structure.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[N:5]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@H:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[NH:9][C@@H:8]([CH3:20])[CH2:7]1)[CH3:2].N1C=CC=CC=1.Cl[C:36]([O:38][CH3:39])=[O:37].[OH-].[K+]>ClCCl.O>[CH3:39][O:38][C:36]([N:9]1[C:10]2[C:15](=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[C@H:6]([N:5]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:4]([O:3][CH2:1][CH3:2])=[O:28])[CH2:7][C@@H:8]1[CH3:20])=[O:37]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)N(Cc1ccccc1)[C@@H]1C[C@H](C)Nc2cc(OC)c(OC)cc21
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N(Cc1ccccc1)[C@@H]1C[C@H](C)N(C(=O)OC)c2cc(OC)c(OC)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.8 %

Procedure:
A solution of cis-benzyl-(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid ethyl ester (Example 66) (111 mg, 0.29 mmol) in anhydrous dichloromethane (2 mL), was treated sequentially with anhydrous pyridine (1 mL), and methyl chloroformate (38 μL, 0.49 mmol). After stirring at room temperature overnight, water (10 mL) and an aqueous 10% KOH solution (10 mL) were added, and the mixture was extracted with ethyl acetate (3×10 mL). The combined organic phases were then washed with 1N HCl (2×10 mL), and then a saturated sodium bicarbonate solution (10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give 112 mg crude product. Purification by silica gel chromatography using 0-50% ethyl acetate/hexanes as eluent afforded the desired final product (12.6 mg, 10%): MS m/z 443 (M++1), 460 (M++18); 1H NMR (CDCl3) δ7.02 (C8, s, 1H), 6.42 (C5, s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:18][C:19]1[S:34][C:22]2[CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26][C:21]=2[C:20]=1[C:35](=[O:37])[NH2:36]>C1COCC1.C(Cl)Cl>[C:35]([C:20]1[C:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH2:23][C:22]=2[S:34][C:19]=1[NH:18][C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:10])(=[O:37])[NH2:36]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc(N)c2C(N)=O)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2c(sc(NC(=O)Nc3ccc(Cl)cc3)c2C(N)=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a stirred solution of 4-chlorophenyl isocyanate (325 mg, 2.12 mmol) and triethylamine (444 μL, 3.18 mmol) in anhydrous THF (10 mL) was added tert-butyl 2-amino-3-carbamoyl-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate (632 mg, 2.12 mmol) and the reaction mixture was stirred at rt for 8 h. The reaction mixture was concentrated in vacuo to afford oil, which was taken up in DCM and washed with water (×2). The organics were then dried with anhydrous Na2SO4 and concentrated in vacuo. The product was purified by Isolera system (SiO2 gel as stationary phase, 25 g HP column, dry loading) using DCM-DCM/MeOH (0%-8% MeOH in DCM) to afford the title compound as a tan solid (633 mg, 57% yield). LRMS [M+H]451.
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[CH:12]1([C:17]2[C:26]([CH:27]([OH:38])[C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[C:25]([CH:39]([CH3:41])[CH3:40])[CH:24]=[C:23]3[C:18]=2[C:19](=[O:44])[CH2:20][C:21]([CH3:43])([CH3:42])[O:22]3)[CH2:16][CH2:15][CH2:14][CH2:13]1.CO>O1CCCC1>[CH:12]1([C:17]2[C:26]([C@H:27]([OH:38])[C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][CH:29]=3)=[C:25]([CH:39]([CH3:40])[CH3:41])[CH:24]=[C:23]3[C:18]=2[C@@H:19]([OH:44])[CH2:20][C:21]([CH3:42])([CH3:43])[O:22]3)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC(C)c1cc2c(c(C3CCCC3)c1C(O)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(C3CCCC3)c1[C@H](O)c1ccc(C(F)(F)F)cc1)[C@@H](O)CC(C)(C)O2
Reaction time: 0.5 h

Procedure:
23 μl (130 μmol) of borane/N,N-diethylaniline complex are added to a solution of 0.1 mg (6.7 μmol) of (1R,2S)-1-aminoindan-2-ol in 1.0 ml of tetrahydrofuran, and the mixture is stirred for 30 min. A solution of 15 mg (33 μmol) of 5-cyclopent-1-yl-6-{hydroxy[4-(trifluormethyl)phenyl]methyl}-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 38A) in 1.0 ml of tetrahydrofuran is then added dropwise, and the mixture is stirred for 2 h. Methanol is then added, and the mixture is concentrated under reduced pressure. The residue is taken up in ethyl acetate and washed in each case twice with 1 M hydrochloric acid and saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. Purification of the crude product by preparative HPLC (method 1) gives the diastereomerically pure target compounds.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.O.Cl>CS(C)=O>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15]([N:28]5[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2nc3cc(F)c(F)cc3cc2c1=O
Reactant: CN1CCNCC1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: CN1CCN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C2CC2)CC1
Yield: 49.2 %

Procedure:
A suspension of 0.47 g of 1-cyclopropyl-7,8-difluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 0.6 g of 1-methylpiperazine in 7 cm3 of dimethyl sulphoxide is heated at a temperature close to 80° C. for 15 minutes. The reaction mixture is poured into 25 cm3 of water and 9 cm3 of N hydrochloric acid are added. The solid obtained is drained and washed with 3 times 5 cm3 of water. After recrystallizing once from a mixture of 4.5 cm3 of ethanol and 4.5 cm3 of dimethylformamide, 0.29 g of 1-cyclopropyl-7-fluoro-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a yellow solid melting at 250° C.
Reaction SMILES: [NH:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2][C:3]([OH:5])=O.CN1CCOCC1.ClC(OCC)=O.[NH2:29][C@H:30]([C:38]([NH:40][C@H:41]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:39])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[NH:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2][C:3]([NH:29][C@H:30]([C:38]([NH:40][C@H:41]([C:46]([O:48][C:49]([CH3:51])([CH3:50])[CH3:52])=[O:47])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:39])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:5]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OC(C)(C)C
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.05 h

Procedure:
Z-Gly-OH (25.2 g., 132 mM) was dissolved in DMF (300 ml.) and the solution was cooled to -10° C. N-methylmorpholine (14.8 ml., 132 mM) was added, followed by ethyl chloroformate (12.1 ml., 126 mM). After 3 minutes at -10° C., a solution of H-Phe-Leu-OBut (40.1 g., 120 mM) in DMF (100 ml.) was added, and the mixture was stirred at 0° C. overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate (600 ml.) and washed successively with water (2×60 ml.), 2 N-aqueous potassium bicarbonate (3×60 ml.), and water (3×60 ml.). The solution was dried (MgSO4) and filtered. The solvent was evaporated to give Z-Gly-Phe-Leu-OBut.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH:3]=1.[CH:18]1([C:21](=O)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:20][CH2:19]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CCO>[CH2:26]([O:25][C:23]([C:22]1[C:21]([CH:18]2[CH2:20][CH2:19]2)=[N:8][C:5]2[C:4]([C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:24])[CH3:27]
Reactant: Nc1ccc(Cl)cc1C#Cc1ccccc1Cl
Reactant: CCOC(=O)CC(=O)C1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(C2CC2)nc2ccc(Cl)cc2c1Cc1ccccc1Cl
Yield: 21.7 %

Procedure:
To a solution of 4-chloro-2-(2-chloro-phenylethynyl)-phenylamine (100 mg, 0.38 mmol, 1 eq) and ethyl 3-cyclopropyl-3-oxopropanoate (89.4 mg, 0.57 mmol, 1.5 eq) in anhydrous EtOH (5 ml), was added p-TsOH.H2O (72.6 mg, 0.38 mmol, 1 eq) and the mixture was refluxed for 16 h. After cooling, the reaction mixture was concentrated in vacuo and then diluted with ethyl acetate. The mixture was washed with saturated sodium bicarbonate solution, brine, dried over sodium sulfate and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (elution with 3% ethyl acetate in hexane) to give 6-chloro-4-(2-chloro-benzyl)-2-cyclopropyl-quinoline-3-carboxylic acid ethyl ester (33 mg, 22%) as a pale yellow solid. MS (ESI): 400.0 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])=[N:5][C:6]([CH3:15])=[CH:7][C:8]=1[NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12].Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH2:13]([CH:10]([N:9]1[C:8]2[CH:7]=[C:6]([CH3:15])[N:5]=[C:4]([O:16][C:17]3[C:18]([CH3:25])=[CH:19][C:20]([CH3:24])=[CH:21][C:22]=3[CH3:23])[C:3]=2[CH2:2][NH:1][C:27]1=[O:29])[CH2:11][CH3:12])[CH3:14]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1CN
Solvent: C1CCOC1
Product: CCC(CC)N1C(=O)NCc2c1cc(C)nc2Oc1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 310.3 %

Procedure:
To a mixture of [3-Aminomethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-propyl)-amine (100 mg, 0.292 mmol) in dry THF was added triphosgene (34 mg, 0.114 mmol) at 0° C. The reaction mixture was allowed to gradually warm to rt and stir for 2 h. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to dryness to give 130 mg of a clear oil. The solid was purified through silica gel column chromatography using 10% EtOAc in hexane as eluent to give 89 mg (82.4%)of the title compound as a white crystalline solid, mp 197-199° C. 1H NMR (CDCl3) d 6.86(s,2H), 6.44(s,1H), 5.14(brs,1H), 4.49(s,2H), 4.20(m,1H), 2.28(s,3H), 2.22(s,3H), 2.04(s,6H), 1.67(m,4H), 0.94(t,6H)ppm.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:24](=O)([O-])[O-].[K+].[K+].I[CH:31]([CH2:35][CH3:36])[C:32]([O-:34])=[O:33]>CC(C)=O>[CH3:24][O:34][C:32](=[O:33])[CH2:31][CH2:35][CH2:36][N:6]1[CH2:7][CH2:8][N:3]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])[CH2:4][CH2:5]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCNCC1
Reactant: CCC(I)C(=O)[O-]
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CCCN1CCN(CCCCN2C(=O)c3ccccc3C2=O)CC1
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
Compound 10 (3.30 g, 9.30 mmol) was added slowly to a stirred suspension of potassium carbonate (4.10 g, 29.7 mmol) in acetone (120 mL). After 0.5 hour, iodobutyrate (4.0 mL, 29.60 mmol) was added and the reaction was stirred at reflux for 14 hours. The reaction mixture was concentrated to dryness and the residue was taken up in water (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic extracts were successively washed with water and brine, dried over anhydrous sodium sulfate and concentrated to an oil. Purification by column chromatography (silica gel, dichloromethane, then 95:5 dichloromethane/methanol, v/v) gave 11 (3.27 g, 91%) as an orange oil: 1H NMR (500 MHz, CDCl3) δ 1.62-1.71 (m, 4H), 3.11-3.17 (m, 5H), 2.39-3.41 (m, 2H), 3.48-3.77 (m, 4H), 7.83-7.91 (m, 4H), 9.33 (br, 2H), 11.54 (br, 1H); ESI MS m/z 288 [C16H21N3O2+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[N:4][CH:5]=[C:6]([CH2:8]SC)[CH:7]=1.O[O:21][S:22]([O-:24])=O.[K+].[CH3:26]O>O>[Br:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[N:4][CH:5]=[C:6]([CH2:8][S:22]([CH3:26])(=[O:24])=[O:21])[CH:7]=1
Reactant: O=S([O-])OO
Reactant: CO
Reactant: CSCc1cnc(Oc2ccc(F)cc2F)c(Br)c1
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)Cc1cnc(Oc2ccc(F)cc2F)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A solution of the product from Example 311d (0.66 g, 1.906 mmol) at 0° C. in methanol (7.33 mL) was treated with a solution of Oxone (2.461 g, 4.00 mmol) in water (7.33 mL), stirred at ambient temperature for two hours and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (Na2SO4), filtered, and concentrated. Purification by chromatography (silica gel, 0-5% methanol in dichloromethane) afforded the title compound (0.433 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([NH:23][S:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[C:9]1[S:13][C:12]([NH:14]C(=O)OC(C)(C)C)=[N:11][C:10]=1[CH3:22].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:14][C:12]1[S:13][C:9]([C@@H:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[NH:23][S@@:24]([C:26]([CH3:29])([CH3:27])[CH3:28])=[O:25])=[C:10]([CH3:22])[N:11]=1.[NH2:14][C:12]1[S:13][C:9]([C@H:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[NH:23][S@@:24]([C:26]([CH3:29])([CH3:27])[CH3:28])=[O:25])=[C:10]([CH3:22])[N:11]=1
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1[C@H](NS(=O)C(C)(C)C)c1ccccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)sc1[C@@H](N[S@](=O)C(C)(C)C)c1ccccc1Cl
Product: Cc1nc(N)sc1[C@H](N[S@](=O)C(C)(C)C)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-tert-Butyl 5-((2-chlorophenyl)(1,1-dimethylethylsulfinamido) methyl)-4-methylthiazol-2-ylcarbamate, (19.0 g, 41.6 mmol) in CH2Cl2 (83 mL) was added TFA (83 mL). The reaction was stirred at room temperature for 1 h. The reaction was concentrated and then partitioned between CH2Cl2 and saturated aqueous NaHCO3 solution. The aqueous layer was basified to pH>12 by adding 1 N NaOH solution and extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated. The crude product was adsorbed onto silica gel and purified by column chromatography (70-100% EtOAc/hexanes. The EtOAc contained 2% NH4OH and was stirred to maintain the mixture) to provide (R)—N—((R)-(2-amino-4-methylthiazol-5-yl)(2-chlorophenyl)methyl)-2-methylpropane-2-sulfinamide and (R)—N—((S)-(2-amino-4-methylthiazol-5-yl)(2-chlorophenyl)methyl)-2-methylpropane-2-sulfinamide and a mixture of both diastereomers (7.1 g, 47%). First eluted product (Isomer A) (white solid, 3.0 g, 20%, >99% de); 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J=1.6, 7.7 Hz, 1H), 7.38-7.22 (m, 3H), 6.15 (d, J=2.5 Hz, 1H), 4.94 (s, 2H), 3.87 (d, J=2.3 Hz, 1H), 2.34 (s, 3H), 1.27 (s, 9H); HPLC ret. time 3.08 min, 10-99% CH3CN, 15 min run; ESI-MS 358.3 m/z (MH+). Second eluted product (Isomer B) (yellow waxy solid, 5.0 g, 33%. 98% de); 1H NMR (400 MHz, CDCl3) δ 7.64 (dd, J=7.7, 1.7 Hz, 1H), 7.36 (dd, J=7.8, 1.4 Hz, 1H), 7.32-7.21 (m, 2H), 6.19 (d, J=1.8 Hz, 1H), 4.86 (s, 2H), 3.65 (d, J=1.2 Hz, 1H), 2.33 (s, 3H), 1.26 (s, 9H); HPLC ret. time 3.77 min, 10-99% CH3CN, 15 min run; ESI-MS 358.3 m/z (MH+).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[C:18](I)=[CH:17][N:16]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:11]=2[N:12]=[C:13]([Cl:15])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([NH:8][C:9]1[C:10]2[C:18]([C:33]3[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=3)=[CH:17][N:16]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:11]=2[N:12]=[C:13]([Cl:15])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccncc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(NCc4ccccc4)nc(Cl)nc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccncc3)c3c(NCc4ccccc4)nc(Cl)nc32)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 9.9 %

Procedure:
To a mixture of N-benzyl-2-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (300 mg, 0.557 mmol), pyridine-4-boronic acid (137 mg, 1.111 mmol) and Pd(Ph3P)2Cl2 (40 mg, 0.042 mmol) in dioxane (3 mL), aq. Na2CO3 (120 mg, 1.13 mmol) (1.0 mL) was added. The mixture was stirred at 100° C. for 4 h. It was concentrated in vacuo. The residue was purified by HPLC to give N-benzyl-2-chloro-5-(pyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (27 mg).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.[NH2:14][CH2:15][CH:16]1[CH2:20][CH2:19][CH:18]([CH3:21])[N:17]1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:17]1[CH:18]([CH3:21])[CH2:19][CH2:20][CH:16]1[CH2:15][NH:14][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([Cl:11])[C:2]([NH2:1])=[CH:3][C:4]=1[O:12][CH3:13])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC1CCC(CN)N1Cc1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCC(C)N1Cc1ccccc1

Procedure:
By following general method B using 1.01 g. of 4-amino-5-chloro-2-methoxybenzoic acid and 1.0 g. of 2-aminomethyl-1-benzyl-5-methylpyrrolidine, 1.5 g. of N-(1-benzyl-5-methyl-2-pyrrolidinylmethyl)-4-amino-5-chloro-2-methoxybenzamide was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccccc1
Product: c1ccc(-c2ccccc2)cc1

Procedure:
Table 2 summarizes the coupling experiments of bromobenzene and benzeneboronic acid to give biphenyl under bis(N-pivaloyl-N′-butylbenzamidine)palladium(II) chloride catalysis.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:18]2[O:19][C:20]([CH3:23])=[CH:21][N:22]=2)[CH:12]=[C:13]([O:16][CH3:17])[C:14]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[B:29](OC)([O:32]C)[O:30]C>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:18]2[O:19][C:20]([CH3:23])=[CH:21][N:22]=2)[CH:12]=[C:13]([O:16][CH3:17])[C:14]=1[B:29]([OH:32])[OH:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2ncc(C)o2)cc(OCc2ccccc2)c1Br
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(-c2ncc(C)o2)cc(OCc2ccccc2)c1B(O)O
Temperature: 25 °C
Yield: 35.3 %

Procedure:
To a stirred solution of 2-(3-(benzyloxy)-4-bromo-5-methoxyphenyl)-5-methyloxazole (197 mg, 0.526 mmol) in THF (1.3 mL) cooled to −78° C. was added n-butyl lithium (2.5 M in hexanes, 232 uL, 0.579 mmol). The solution was stirred for 15 minutes after which time trimethyl borate (235 uL, 2.11 mmol) was added and the solution was allowed to slowly warm to room temperature overnight. The reaction was quenched by addition of 0.1 M HCl and was diluted with ethyl acetate, washed with water, brine, dried over magnesium sulfate and concentrated. Flash column chromatography (12 g silica, 0-100% ethyl acetate in DCM over 30 column volumes) provided (2-(benzyloxy)-6-methoxy-4-(5-methyloxazol-2-yl)phenyl)boronic acid (63 mg) as a white foam. MS=340.1 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.28-7.46 (m, 5H), 7.25 (d, J=1.01 Hz, 1H), 7.08 (br. s, 1H), 6.85 (d, J=1.01 Hz, 1H), 5.17 (s, 2H), 3.95 (s, 3H), 2.38 (d, J=1.52 Hz, 3H).