Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][C:9]2[N:10]=[CH:11][N:12]=[C:13](Cl)[C:8]=2[CH2:7]1)=[O:5])[CH3:2].[OH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[CH:28]2.C1CCN2C(=NCCC2)CC1>CC#N>[CH2:1]([O:3][C:4]([CH:6]1[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][C:9]2[N:10]=[CH:11][N:12]=[C:13]([O:24][C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[NH:30][CH:29]=[CH:28]4)[C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1Cc2c(Cl)ncnc2CN1C(=O)OC(C)(C)C
Reactant: Oc1ccc2[nH]ccc2c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)C1Cc2c(ncnc2Oc2ccc3[nH]ccc3c2)CN1C(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
To a solution of 4-chloro-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-6,7-dicarboxylic acid 7-tert-butyl ester 6-ethyl ester (1 g, 2.93 mmol) in CH3CN (30 mL), 5-hydroxy-indole (0.779 g, 5.85 mmol) and DBU (0.88 mL, 5.85 mmol) are added. After heating at 60° C. for 5 h the reaction is evaporated and the product isolated using FCC eluting with heptane:EtOAc 1:1. MS (ESI) m/z 439.1 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([Cl:18])=[CH:11][N:12]2[CH:15]2[CH2:17][CH2:16]2)=[C:8]([O:19][CH3:20])[CH:7]=1)=[O:5])C>CO.C1COCC1>[Cl:18][C:10]1[C:9]2[C:13](=[CH:14][C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]=2[O:19][CH3:20])[N:12]([CH:15]2[CH2:17][CH2:16]2)[CH:11]=1
Reactant: CCOC(=O)c1cc(OC)c2c(Cl)cn(C3CC3)c2c1
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)cc2c1c(Cl)cn2C1CC1
Temperature: 60 °C
Reaction time: 9 h
Yield: 85.7 %

Procedure:
To a stirred solution of 1.03 g of ethyl-3-chloro-1-cyclopropyl-4-(methyloxy)-1H-indole-6-carboxylate in 15 ml of MeOH and 10 ml of THF was added 2 ml of 5N NaOHaq and the mixture was stirred at 60° C. for 9 hrs. After evaporation of MeOH and THF, the mixture was diluted with water and 2 ml of 5N HClaq was added thereto. The precipitate was collected by filtration and dried in vacuo to give 798 mg of 3-chloro-1-cyclopropyl-4-(methyloxy)-1H-indole-6-carboxylic acid as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:28]=[CH:27][C:6]([CH2:7][NH:8][CH:9]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH2:10]/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1.N1C2C=CC=C(CO)[C:34]=2N=N1.C(O)(C)(C)C.[I-].[I-].[Sm+2]>C1C=CC=CC=1>[CH3:16][O:15][C:13](=[O:14])[CH2:12][CH:11]1[CH2:10][CH:9]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=2)[N:8]([CH2:7][C:6]2[CH:27]=[CH:28][C:3]([C:2]([F:29])([F:30])[F:1])=[CH:4][CH:5]=2)[CH2:34]1
Reactant: OCc1cccc2[nH]nnc12
Reactant: COC(=O)/C=C/CC(NCc1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Agent: [I-]
Agent: [Sm+2]
Solvent: c1ccccc1
Solvent: CC(C)(C)O
Product: COC(=O)CC1CC(c2ccc(C(F)(F)F)cc2)N(Cc2ccc(C(F)(F)F)cc2)C1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
The amine from Step 4 (400 mg, 0.9 mmol) was dissolved in benzene and benzotriazolemethanol (135 mg, 0.9 mmol) was added followed by powdered molecular sieves (470 mg). This was stirred overnight, the molecular sieves removed by filtration through Celite and the filtrate concentrated in vacuo. The residue was dissolved in THF (25 mL) and anhydrous t-butanol (0.17 mL, 0.9 mmol) was added. This solution was added dropwise via cannula onto a solution of samarium diiodide (27 mL, 2.7 mmol, 0.1M in THF) which was pre-cooled to −78° C. The mixture was stirred (−78° C. 0° C.) overnight then quenched with aq. K2CO3 and extracted with ethyl acetate. The organic extracts were washed with water, dried (MgSO4) and evaporated. The residue was purified on silica using 30-50% CH2Cl2 in iso-hexane to elute isomer a (245 mg) and isomer b (100 mg).
Reaction SMILES: C(O[C@@:5]1([OH:33])[C@:9](OC(=O)C)([OH:10])[C@@H:8]([CH:15](OC(=O)C)[OH:16])[O:7][C@H:6]1[N:21]1[C:30]2[C:24]([C:25](Cl)([N:27]=[C:28]([Cl:31])[N:29]=2)[NH2:26])=[N:23][CH2:22]1)(=O)C.[CH:34]1(N)[CH2:38][CH2:37][CH2:36][CH2:35]1.C(O)C>C(OCC)(=O)C.O>[Cl:31][C:28]1[N:27]=[C:25]([NH:26][CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[C:24]2[N:23]=[CH:22][N:21]([C:30]=2[N:29]=1)[C@@H:6]1[O:7][C@H:8]([CH2:15][OH:16])[C@@H:9]([OH:10])[C@H:5]1[OH:33]
Reactant: NC1CCCC1
Reactant: CC(=O)OC(O)[C@H]1O[C@@H](N2CN=C3C2=NC(Cl)=NC3(N)Cl)[C@@](O)(OC(C)=O)[C@@]1(O)OC(C)=O
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: OC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C

Procedure:
2′,3′,5′-triacetoxy-2,6-dichloroadenosine (1.5 g) and cyclopentylamine (8 eq.) were diluted with ethanol (50 eq.) and the resulting solution was heated at reflux for about 15 hours, then cooled to room temperature and concentrated in vacuo to provide a crude residue which was diluted with a mixture of ethyl acetate and water and transferred to a separatory funnel. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to provide a crude residue which was purified using flash column chromatography on silica gel (8% MeOH-dichloromethane as eluent) to provide 2-chloro-N6-cyclopentyladenosine (0.948 g). MS m/z 370.32 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[C:21]1([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=2[CH:37]=[O:38])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1.CCCCCC.O1CCCC1>[OH:38][CH:37]([C:36]1[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(=O)OC(C)(C)C
Reactant: O=Cc1ccccc1CCCCCCCCc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)CC(O)c1ccccc1CCCCCCCCc1ccccc1
Reaction time: 0.17 h

Procedure:
A solution of diisopropylamine (4.8 ml, 0.03 mole) in tetrahydrofuran/hexane (100 ml, 1/1) was cooled to -60° C. and n-butyllithium (2.5M solution in hexane, 13.6 ml, 0.03 mole) was added. This solution was stirred for 10 minutes followed by addition of t-butyl acetate (4.6 ml, 0.03 mole). The mixture was stirred for an additional 10 minutes before addition of a solution of 2-(8-phenyloctyl)benzaldehyde (10 gm, 0.03 mole) in tetrahydrofuran (25 ml) was added dropwise. The whole was stirred first for 30 minutes at -50° C. and then for 30 minutes at -20° C. The reaction mixture was poured into aqueous acid and extracted twice with diethyl ether. The combined extracts were washed with 5% aqueous sodium bicarbonate solution and saturated aqueous sodium chloride sodium and then dried over anhydrous magnesium sulfate, filtered and evaporated. Chromatography on silica gel using hexane-ethyl acetate (95/5) to elute gave the product as an oil. 90 MHz NMR (CDCl3)δ1.29-1.52 (12H,m) 2.52-2.78 (6H,m) 5.39 (1H,dd) 7.10-7.60 (9H,m).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[N:7][N:6]2[C:13]=1[CH2:14][OH:15])[CH3:2].CCOC(C)=O.CCCCCC>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([C:3]1[N:4]=[C:5]2[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[N:7][N:6]2[C:13]=1[CH:14]=[O:15])[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nn2c1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCc1nc2c(C)cc(C)nn2c1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
To a solution of 0.886 g (4.32 mmol) of the product of Step B dissolved in 15 mL of CH2Cl2 was added 1.772 g of powdered 4A molecular sieves and 4.430 g (51 mmol) of manganese dioxide and the reaction mixture was magnetically stirred at room temperature. After 16 h, TLC analysis (50% EtOAc-hexane) indicated complete reaction and the mixture was filtered. The filtrate was concentrated in vacuo, and the residue was redissolved in 50% EtOAc-hexane and purified by filtration through a short plug of silica gel. Evaporation of the filtrate and drying in vacuo afforded 0.781 g (89%) of the title compound as a tan solid.
Reaction SMILES: S([C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH3:12])=[C:7]([Cl:13])[C:6]=1[OH:14])(O)(=O)=O.[N+:15]([O-])([OH:17])=[O:16]>>[N+:15]([C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH3:12])=[C:7]([Cl:13])[C:6]=1[OH:14])([O-:17])=[O:16]
Reactant: Cc1c(Cl)cc(S(=O)(=O)O)c(O)c1Cl
Reactant: O=[N+]([O-])O
Product: Cc1c(Cl)cc([N+](=O)[O-])c(O)c1Cl

Procedure:
The reaction of the 2-sulpho-4,6-dichloro-5-methylphenol, prepared in the second stage, with nitric acid in the third process stage to give 2-nitro-4,6-dichloro-5-methylphenol can be illustrated by the following equation: ##STR3##
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1([P:15](Cl)Cl)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH:18]([Mg]Br)([CH3:20])[CH3:19].O>CCOCC>[CH:1]1([P:15]([CH:18]([CH3:20])[CH3:19])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClP(Cl)c1ccccc1
Reactant: CC(C)[Mg]Br
Reactant: Cl[Mg]C1CCCCC1
Solvent: O
Solvent: CCOCC
Product: CC(C)P(c1ccccc1)C1CCCCC1
Temperature: -25 °C
Yield: 67 %

Procedure:
A Grignard mixture of 55 mmoles of cyclohexylmagnesium chloride (prepared from 1.5 g of magnesium turnings and 6.5 g of cyclohexylchloride in 20 ml of anhydrous ether) was added dropwise to a stirred solution of 8.9 g (50 mmoles) of phenyldichlorophosphine in 50 ml of anhydrous ether maintained under an inert atmosphere at -25° C. After the addition was complete, the resulting mixture was allowed to gradually warm to ambient temperature and then was refluxed for 15 minutes. The stirred mixture was cooled and a solution of 75 mmoles of isopropylmagnesium bromide (prepared from 2.1 g of magnesium turnings and 9.5 g of isopropyl bromide in 29 ml of anhydrous ether) was added dropwise at temperatures between 0° C. and +30° C. After refluxing for 4 hours, the reaction mixture was cooled to 0° C. and treated dropwise with 25 ml of water, thereby giving two phases. The ether phase was separated, dried over magnesium sulfate, concentrated, and distilled to give cyclohexylisopropylphenylphosphine: 31P-NMR δ=6.08 ppm; boiling point ("BP")=104°-105° C. at 0.05 torr, Chemical Ionization Mass Spec [M+H+ =235, yield=about 67%.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C:6]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([O:17]CC)=[O:16])[CH2:10]2)=[CH:5][CH2:4][C@H:3]1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27].[Li+].[OH-].Cl>O1CCCC1.O.CCOCC>[NH2:1][C@@H:2]1[CH2:7][C:6]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([OH:17])=[O:16])[CH2:10]2)=[CH:5][CH2:4][C@H:3]1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27]
Reactant: CCOC(=O)[C@H]1CCCN(CC2=CC[C@@H](c3ccc(Cl)cc3Cl)[C@H](N)C2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: N[C@@H]1CC(CN2CCC[C@H](C(=O)O)C2)=CC[C@H]1c1ccc(Cl)cc1Cl
Reaction time: 8 h
Yield: 64.2 %

Procedure:
To a solution of Example 17B (55 mg, 0.13 mmol) in a mixture of tetrahydrofuran/H2O (1.0 mL/0.5 mL), LiOH (19 mg, 0.80 mmol) was added at room temperature. The reaction mixture was stirred overnight. It was acidified with 2N HCl in ether until pH=3 and purified by high pressure liquid chromotography (eluting with 0-70% acetonitrile/water and 0.1% trifluoroacetic acid) to provide the title compound (32 mg, 63%). 1H NMR (400 MHz, methanol-d4) δ ppm 7.78 (s, 1H), 7.55-7.52 (m, 1H), 7.42-7.38 (m, 1H), 6.21 (s, 1H), 4.0-3.90 (m, 1H) 3.85-3.70 (m, 2H), 3.65-3.50 (m, 1H), 3.20-2.8 (m, 3H), 2.75-2.55 (m, 3H), 2.50-2.40 (m, 3H), 2.35-2.20 (m, 2H), 2.05-1.85 (m, 2H). MS (APCI) m/z 383 (M+H)+.
Reaction SMILES: C1(CN2CCC(C[CH2:15][C:16]3[C:20]4[CH:21]=[C:22]5[NH:27][C:26](=[O:28])[CH2:25][C:23]5=[CH:24][C:19]=4[O:18][N:17]=3)CC2)C=CC=CC=1.N1C=CC=CC=1>CN(C=O)C>[CH3:15][C:16]1[C:20]2[CH:21]=[C:22]3[NH:27][C:26](=[O:28])[CH2:25][C:23]3=[CH:24][C:19]=2[O:18][N:17]=1
Reactant: O=C1Cc2cc3onc(CCC4CCN(Cc5ccccc5)CC4)c3cc2N1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1noc2cc3c(cc12)NC(=O)C3
Yield: 11.9 %

Procedure:
The procedure described in Example 33d was followed with the oxime acetate obtained in step c (2.75 g, 10.97 mmol) and pyridine (8.9 mL, 109.7 mmol) in DMF (110 m). After concentration in vacuo, the residue was purified by silica gel flash chromatography (2% MeOH—CH2Cl2) to give the title compound (0.245 g, 12%) as a pastel yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([O:12][CH3:13])[CH:6]=1)=[O:4].[C:14]([O-:17])(=[O:16])[CH3:15].[K+]>C(O)C.C(O)(=O)C>[C:14]([O:17][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([O:12][CH3:13])[CH:6]=1)=[O:4])(=[O:16])[CH3:15]
Reactant: COc1cc(C(=O)CCl)ccc1O
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(C(=O)COC(C)=O)ccc1O
Yield: 36.1 %

Procedure:
To a slurry of 80.2 g (0.4 mole) of 2-chloro-1-(4-hydroxy-3-methoxyphenyl)ethanone in 576 ml of absolute ethanol and 24 ml of glacial acetic acid was added 73.6 g (0.75 mole) of potassium acetate, and the mixture was heated at reflux temperature for 1 hr. The mixture was cooled, filtered, and the filtrate concentrated to a gummy residue. The residue was triturated with four 200 ml portions of hot benzene. The combined extracts were washed with three 200 ml portions of saturated aqueous sodium bicarbonate solution and once with brine, dried over sodium sulfate, and concentrated to give a solid residue. The solid was recrystallized from benzene (with charcoal treatment) to yield 32.4 g (36% yield) of the title compound as a white solid, mp 115°-117° C.
Reaction SMILES: C([O:8][C:9]1[CH:35]=[C:34]([Cl:36])[C:12]([CH2:13][CH:14]2[CH2:18][CH2:17][N:16]([C@H:19]3[CH2:24][CH2:23][C@@H:22]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:21][CH2:20]3)[C:15]2=[O:33])=[C:11]([Cl:37])[CH:10]=1)C1C=CC=CC=1.[H][H]>O1CCCC1.[OH-].[OH-].[Pd+2]>[C:29]([Si:26]([CH3:28])([CH3:27])[O:25][C@@H:22]1[CH2:23][CH2:24][C@H:19]([N:16]2[CH2:17][CH2:18][CH:14]([CH2:13][C:12]3[C:11]([Cl:37])=[CH:10][C:9]([OH:8])=[CH:35][C:34]=3[Cl:36])[C:15]2=[O:33])[CH2:20][CH2:21]1)([CH3:31])([CH3:30])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC(Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC(Cc3c(Cl)cc(O)cc3Cl)C2=O)CC1

Procedure:
Add a solution of 3-(4-benzyloxy-2,6-dichloro-benzyl)-cis-1-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-pyrrolidin-2-one (8.5 g 15.1 mmol) in 25 mL tetrahydrofuran to 0.5 g Pearlman's catalyst and hydrogenate the resulting mixture under a balloon of hydrogen gas 2 hr. Filter through Celite® and concentrate to get a solid. Purify by silica gel chromatography using hexanes/ethyl acetate to recover 4.4 g (61%) of product.
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].C(O)(=O)C(O)=O.[CH2:30]([NH:32][NH2:33])[CH3:31]>O>[CH2:30]([N:32]1[C:2]2[C:3](=[CH:14][CH:15]=[C:16]([OH:18])[CH:17]=2)[C:4]([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=2[OH:13])=[N:33]1)[CH3:31]
Reactant: CCNN
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Agent: CC(=O)[O-]
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: O
Product: CCn1nc(-c2ccc(O)cc2O)c2ccc(O)cc21
Temperature: 90 °C
Yield: 18.5 %

Procedure:
A mixture of 2,2′,4,4′-tetrahydroxybenzophenone (0.123 g, 0.5 mmol), sodium acetate (0.164 g, 2.0 mmol) and ethylhydrazine oxalate (0.30 g, 2.0 mmol) in 2 mL H2O was heated at 90° C. overnight. The cooled reaction mixture was partitioned with EtOAc and 1 N HCl. The organic layer was dried (Na2SO4) and concentrated in vacuo to give the crude product. The residue was purified by HPLC chromatography using a silica gel column 150×12 mm (Biotage) at 10 mL/min with methyl-t-butyl ether/hexane (1:3, v/v) to give 0.025 g of product as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH:18]([CH3:22])[CH2:17]3)=[CH:11][C:10]=2[F:23])=[N:6][CH:7]=1.N>C(Cl)Cl.CO>[Cl:1][C:2]1[C:3]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([C@@H:16]3[CH2:21][CH2:20][NH:19][C@@H:18]([CH3:22])[CH2:17]3)=[CH:11][C:10]=2[F:23])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNC(C)C4)cc3F)ncc2Cl)n[nH]1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(Nc2nc(Nc3cc(C)c([C@@H]4CCN[C@@H](C)C4)cc3F)ncc2Cl)n[nH]1

Procedure:
5-Chloro-N2-(2-fluoro-5-methyl-4-(2-methylpiperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (20 mg, 0.046 mmol) was dissolved in a solvent mixture of DCM and methanol (0.5 mL, 10/1 v/v+0.175N NH3). The mixture was applied to preparative TLC in order to separate the cis and trans stereoisomers (eluent: 6% MeOH in DCM with 0.1N NH3) of 5-Chloro-N2-(2-fluoro-5-methyl-4-(2-methylpiperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as white solids. The trans isomer was the preparative TLC top band and the cis isomer was the preparative TLC bottom band; ESMS m/z 430.1 (M+H+); cis stereoisomer 1H NMR (400 MHz, MeOD-d4): δ 8.03 (s, 1H), 7.84 (d, 1H), 7.02 (d, 1H), 6.24 (d, 1H), 3.90-3.85 (m, 1H), 2.32 (s, 3H), 2.27 (s, 3H), 2.03-1.84 (m, 2H), 1.65-1.54 (m, 1H), 1.55 (d, 3H), 1.38-1.19 (m, 4H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[C:27](Cl)(=O)[CH:28]=C.[O:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37][NH2:38]>>[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][C@H:9]1[C:24]([NH:38][CH2:37][C:33]1[O:32][CH:36]=[CH:35][CH:34]=1)=[O:26])(=[O:7])[CH:27]=[CH2:28]
Reactant: C=CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)O
Reactant: NCc1ccco1
Product: C=CC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)NCc1ccco1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, acryloyl chloride, and 2-furylmethylamine the title compound was obtained in 74% purity by LC/MS. MS(ESI+): m/z=436.8.
Reaction SMILES: [Si]([N:8]1[C:11](=[O:12])[C@H:10]([CH2:13][CH3:14])[C@H:9]1[C:15](O)=O)(C(C)(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+:26](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[C:42]([C:46]1[CH:47]=[C:48]([NH2:53])[C:49]([NH2:52])=[CH:50][CH:51]=1)([CH3:45])([CH3:44])[CH3:43]>CN(C)C=O.O>[NH2:26][C@H:9]([C:15]1[NH:53][C:48]2[CH:47]=[C:46]([C:42]([CH3:45])([CH3:43])[CH3:44])[CH:51]=[CH:50][C:49]=2[N:52]=1)[C@@H:10]([CH2:13][CH3:14])[C:11]([NH2:8])=[O:12]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1C(=O)O
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@@H](C(N)=O)[C@H](N)c1nc2ccc(C(C)(C)C)cc2[nH]1
Reaction time: 0.33 h

Procedure:
(2S,3R)-1-(tert-Butyldimethylsilyl)-3-ethyl-4-oxoazetidine-2-carboxylic acid (Tetrahedron, 46(7), 2255-62; 1990, 100 mg, 0.388 mmol) was dissolved in N,N-dimethylformamide (2 mL) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (418 mg, 1.10 mmol) was added. The reaction mixture was stirred for 20 minutes then 4-(tert-butyl)benzene-1,2-diamine (165 mg, 1.00 mmol) was added and the reaction mixture stirred at ambient temperature for 18 hours. The reaction mixture was diluted with water and extracted three times with ethyl ether. The combined organic phase was dried over anhydrous magnesium sulfate, filtered and the solvent removed in-vacuo. The residue was purified by silica gel column chromatography eluting with 0-100% ethyl acetate in hexanes to afford the amide as a mixture of isomers.
Reaction SMILES: [Si:1]([CH:18]([OH:25])[C@@H:19]1[O:23][C:22](=[O:24])[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Si](Cl)(C)(C)C.[C:41]1([Se:47]Br)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1.CCOCC>[Si:1]([CH:18]([OH:25])[C@@H:19]1[O:23][C:22](=[O:24])[C@@H:21]([Se:47][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([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
Reactant: CC(C)(C)[Si](c1ccccc1)(c1ccccc1)C(O)[C@H]1CCC(=O)O1
Reactant: Br[Se]c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](c1ccccc1)(c1ccccc1)C(O)[C@H]1C[C@H]([Se]c2ccccc2)C(=O)O1
Temperature: -78 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a solution of 4 (5 g, 14.1 mmol) in anhydrous THF (50 mL) at −78° C. was added lithium bis(trimethylsilyl)amide (1 M solution in THF, 15.8 mL, 15.8 mmol) over a period of 10 min. After being stirred at −78° C. for 1 h, Me3SiCl (1.918 g, 17.65 mmol) was added dropwise, and the reaction mixture was allowed to warm to room temperature. After being stirred at room temperature for 30 min, the mixture was cooled to −78° C., and a solution of PhSeBr (5 g, 21.19 mmol) in anhydrous THF (25 mL) was added rapidly. The mixture was diluted with ether (50 mL), washed with water until the color of organic layer changed from dark brown to light yellow, dried (Na2SO4), filtered, and evaporated. The resulting oily residue [containing 3S (α, 5) and 3R (β) isomers; TLC: hexane/EtOAc, 10:1; Rf=0.42 and 0.28, respectively] was purified by flash chromatography on silica gel, eluting with hexane/EtOAc (99:1 to 95:5) to give the title compound 5 as a light yellow oil (4.093 g, 57%). 1H NMR (CDCl3) δ 7.69-7.60 (m, 6H, arom.), 7.46-7.30 (m, 9H, arom.), 4.37-4.34 (m, 1H, H-5), 4.12-4.08 (m, 1H, H-3), 3.86-3.82 (dd, J=3 & 11 Hz, 1H, CH2OH), 3.62-3.59 (dd, J=3 & 11 Hz, 1H, CH2OH), 2.73-2.67 (m, 1H, H-4), 2.32-2.28 (m, 1H, H-4), 1.02 (s, 9H, t-Bu).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[N:17]=[CH:18][S:19][CH:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:33]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:30][O:31][C:32]1[CH:37]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:35]=[CH:34][C:33]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[N:17]=[CH:18][S:19][CH:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Reactant: COc1ccc(CN(c2cscn2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(CN(c2cscn2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4OC)nccc3c2)cc1
Temperature: 125 °C

Procedure:
To a solution of 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)isoquinoline-6-sulfonamide (0.10 g, 0.224 mmol), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (0.064 g, 0.292 mmol) and cesium carbonate (0.292 g, 0.897 mmol) in DME (2.437 ml) and Water (0.366 ml) was added Pd(PPh3)4 (0.026 g, 0.022 mmol) in one portion. The resulting mixture was heated to 125° C. in the microwave for 2 hours. The resulting mixture was transferred to a seperatory funnel and the aqueous layer was washed 3× with EtOAc. The organic layers were combined, dried with MgSO4, filtered and concentrated to an oil. The crude mixture was purified by the silica gel chromatography (100% hexanes to 25% EtOAc in hexanes to 90% EtOAc in heptanes). m/z (ESI) 586.2 (M+H)+.