Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[OH:11][CH2:12][CH2:13][C:14]1([CH2:32][C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[NH:18][C:17](=[S:19])[N:16]([CH2:20][CH:21]2[CH2:26][CH:25]3[CH2:27][CH:23]([C:24]3([CH3:29])[CH3:28])[CH:22]2[CH3:30])[C:15]1=[O:31].[C:39]([C:41]1[CH:50]=[CH:49][C:44]([C:45](=[O:48])[CH2:46]Br)=[CH:43][CH:42]=1)#[N:40]>C1COCC1>[OH:11][CH2:12][CH2:13][C:14]1([CH2:32][C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[C:15](=[O:31])[N:16]([CH2:20][CH:21]2[CH2:26][CH:25]3[CH2:27][CH:23]([C:24]3([CH3:29])[CH3:28])[CH:22]2[CH3:30])[C:17]([S:19][CH2:46][C:45]([C:44]2[CH:49]=[CH:50][C:41]([C:39]#[N:40])=[CH:42][CH:43]=2)=[O:48])=[N:18]1
Reactant: CC1C(CN2C(=O)C(CCO)(Cc3ccncc3)NC2=S)CC2CC1C2(C)C
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC1C(CN2C(=O)C(CCO)(Cc3ccncc3)N=C2SCC(=O)c2ccc(C#N)cc2)CC2CC1C2(C)C
Temperature: 40 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
Potassium bis-(trimethylsilyl)amide (286 mg, 1.43 mMol) was dissolved in anhydrous THF (20 mL) under an atmosphere of dry N2. The mixture was cooled to 40° C. and then 5-(2-hydroxy-ethyl)-5-pyridin-4-ylmethyl-2-thioxo-3-((+)-(2,6,6-trimethyl-bicyclo[3.1.1]-hept-3-ylmethyl))-imidazolidin-4-one (548 mg, 1.37 mMol) was added. The mixture was warmed to ambient temperature and 4-cyanophenacyl bromide (350 mg, 1.43 mMol) was added. The reaction mixture was stirred for one hour after which time it was partitioned between CH2Cl2 and saturated aqueous NaHCO3 solution. The CH2Cl2 layer was dried over Na2SO4, filtered and concentrated under vacuum to give a red foam. The foam was chromatographed on flash silica gel eluting with EtOAc-hexanes (50:50 ) to give 700 mg of the titled compound as a yellow foam as a 1:1 mixture of diastereomers.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][C:16]([CH3:18])=[N:15][CH:14]=2)=[C:9]([O:19][CH3:20])[CH:8]=1.C1(C(C2C=CC=CC=2)=[N:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C.C(OCC)(=O)C>[NH2:28][CH:29]([CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][C:16]([CH3:18])=[N:15][CH:14]=2)=[C:9]([O:19][CH3:20])[CH:8]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: COc1cc(C#CCCCCl)ccc1-c1cnc(C)o1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C(N)CCCC#Cc1ccc(-c2cnc(C)o2)c(OC)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
A mixture of 5-[4-(5-chloropent-1-yn-1-yl)-2-methoxyphenyl]-2-methyl-1,3-oxazole (500 mg), ethyl N-(diphenylmethylene)glycinate (461 mg), potassium carbonate (1.2 g) and tetrabutylammonium iodide (637 mg) in acetonitrile (5 mL) was stirred at 80° C. overnight under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, the insoluble material was separated by filtration, and the filtrate was concentrated. A mixture of the residue and 6N hydrochloric acid (0.5 mL) in acetonitrile (5 ml) was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (362 mg).
Reaction SMILES: C1(C2C(OCC3(C(F)(F)F)CCCCC3)=CC(F)=C(C=2)C(O)=O)CC1.[CH:26]1([C:29]2[C:30]([O:39][CH2:40][CH:41]3[CH2:46][CH2:45][C:44]([CH3:48])([CH3:47])[CH2:43][CH2:42]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34]([OH:36])=O)[CH2:28][CH2:27]1.CS(N)(=O)=O.[N:54]1([S:58]([NH2:61])(=[O:60])=[O:59])[CH2:57][CH2:56][CH2:55]1>>[N:54]1([S:58]([NH:61][C:34](=[O:36])[C:33]2[CH:37]=[C:29]([CH:26]3[CH2:27][CH2:28]3)[C:30]([O:39][CH2:40][CH:41]3[CH2:46][CH2:45][C:44]([CH3:47])([CH3:48])[CH2:43][CH2:42]3)=[CH:31][C:32]=2[F:38])(=[O:60])=[O:59])[CH2:57][CH2:56][CH2:55]1
Reactant: NS(=O)(=O)N1CCC1
Reactant: CC1(C)CCC(COc2cc(F)c(C(=O)O)cc2C2CC2)CC1
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: CC1(C)CCC(COc2cc(F)c(C(=O)NS(=O)(=O)N3CCC3)cc2C2CC2)CC1

Procedure:
Following the procedure as described in Example 158 step 5, and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoic acid with 5-cyclopropyl-4-((4,4-dimethylcyclohexyl)-methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained (0.16 g, 51%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.71-8.58 (m, 1H), 7.64-7.56 (m, 1H), 6.64-6.52 (m, 1H), 4.34-4.18 (m, 4H), 3.92-3.80 (m, 2H), 2.36-2.18 (m, 2H), 2.12-1.97 (m, 1H), 1.87-1.66 (m, 3H), 1.51-1.19 (m, 6H), 1.01-0.84 (m, 8H), 0.74-0.62 (m, 2H); MS (ES+) m/z 439.2 (M+1).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[NH:19][C:18]([C@@H:20]4[CH2:24][CH2:23][CH2:22][N:21]4[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[N:17][CH:16]=3)=[CH:11][CH:10]=2)O1.Cl[C:34]1[N:39]=[CH:38][C:37]([C:40]2[N:44]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:43]([C@@H:53]3[CH2:57][CH2:56][CH2:55][N:54]3[C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])=[N:42][CH:41]=2)=[CH:36][N:35]=1.C([O-])(O)=O.[Na+].COCCOC>C(OCC)(=O)C.[Pd].O>[C:61]([O:60][C:58]([N:54]1[CH2:55][CH2:56][CH2:57][C@H:53]1[C:43]1[N:44]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:40]([C:37]2[CH:36]=[N:35][C:34]([C:9]3[CH:10]=[CH:11][C:12]([C:15]4[NH:19][C:18]([C@@H:20]5[CH2:24][CH2:23][CH2:22][N:21]5[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[N:17][CH:16]=4)=[CH:13][CH:14]=3)=[N:39][CH:38]=2)=[CH:41][N:42]=1)=[O:59])([CH3:64])([CH3:63])[CH3:62]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2cnc(Cl)nc2)n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ncc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)n4COCC[Si](C)(C)C)cn3)cc2)[nH]1
Temperature: 80 °C
Yield: 98.3 %

Procedure:
Pd (Ph3)4 (0.12 g, 0.103 mmol) was added in one portion to a stirred suspension of (S)-tert-butyl 2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (1c, 1.00 g, 2.27 mmol), (S)-tert-butyl 2-(5-(2-chloropyrimidin-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (152c-1, 0.99 g, 2.06 mmol) and NaHCO3 (0.87 g, 10.3 mmol) in a solution of DME (20 mL) and H2O (6 mL) at room temperature under N2. The vessel was sealed and the mixture was placed into a preheated (80° C.) oil bath and stirred at 80° C. for 16 h before additional catalyst (0.12 g) was added. After heating the mixture for an additional 12 h at 80° C., the mixture was cooled to ambient temperature, diluted with ethyl acetate and washed with sat'd NaHCO3 soln and brine prior to drying over anhydrous sodium sulfate and solvent concentration. Purification of the residue by Biotage™ flash chromatography on silica gel using a 40M column (preequilibrated with 40% B followed by step gradient elution with 40% B to 40% B for 150 mL, 40% B to 100% B for 1500 mL, 100% B to 100% B for 1000 mL where B=ethyl acetate and A=hexanes) furnished the title compound as a yellow foam (1.533 g, 98%). A small amount of the yellow foam was further purified for characterization purposes by pHPLC (Phenomenex GEMINI, 30×100 mm, S10, 10 to 100% B over 13 minutes, 3 minute hold time, 40 mL/min, A=95% water, 5% acetonitrile, 10 mM NH4OAc, B=10% water, 90% acetonitrile, 10 mM NH4OAc) to yield 95% pure title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1.[C:23]([C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][C@H:33]2[CH2:35][O:34]2)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[Br:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][N:14]([CH2:35][C@@H:33]([OH:34])[CH2:32][O:31][C:30]5[CH:36]=[CH:37][C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:28][CH:29]=5)[CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1
Reactant: O=C1C(=O)c2ccc(Br)cc2C2=C1SCC1(CCNCC1)O2
Reactant: CC(C)(C)c1ccc(OC[C@H]2CO2)cc1
Product: CC(C)(C)c1ccc(OC[C@H](O)CN2CCC3(CC2)CSC2=C(O3)c3cc(Br)ccc3C(=O)C2=O)cc1

Procedure:
Compound 223 was synthesized using 9-bromospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2R)-2-[(4-tert-butylphenoxy)methyl]oxirane and conditions outlined in procedure Y. 400 MHz 1H NMR (DMSO) δ: 7.83 (s, 1H), 7.79 (m, 2H), 7.29 (d, 2H), 6.86 (d, 2H), 4.86 (br s, 1H), 3.99-3.94 (m, 2H), 3.89-3.86 (m, 1H), 3.19 (s, 2H), 2.87-2.72 (m, 2H), 2.56-2.50 (m, 2H), 2.47-2.35 (m, 2H), 2.04-1.96 (m, 2H), 1.87-1.78 (m, 2H), 1.25 (s, 9H); LCMS: 587 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[CH3:17])[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]([CH3:26])([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[NH2:20]>>[CH3:18][C:19]([NH:20][C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH3:17])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[CH3:26]
Reactant: Cc1ccc(C(=O)O)nc1-c1cccc(Cl)c1
Reactant: CC(C)(N)c1nccs1
Product: Cc1ccc(C(=O)NC(C)(C)c2nccs2)nc1-c1cccc(Cl)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-methyl-pyridine-2-carboxylic acid (Example 49 e) and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): 372.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:3]=1.[F:20][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1I.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:20][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[NH:11][C:9]1[C:10]2[C:2]([CH3:1])=[CH:3][N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:18])([CH3:17])[CH3:19])[C:5]=2[N:6]=[CH:7][CH:8]=1
Reactant: Cc1cn(COCC[Si](C)(C)C)c2nccc(N)c12
Reactant: O=[N+]([O-])c1ccc(I)c(F)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1cn(COCC[Si](C)(C)C)c2nccc(Nc3ccc([N+](=O)[O-])cc3F)c12
Temperature: 25 °C

Procedure:
A solution of 29 mg (100 μmol) of 3-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-4-amine, 33 mg (130 μmol) of 2-fluoro-1-iodo-4-nitrobenzene, 5 mg (10 μmol) of tris-(dibenzylideneacetone)dipalladium, 6 mg (10 mmol) of 1,1′-bis(diphenylphosphino)ferrocene and 14 mg (150 mmol) of sodium tert-butoxide in 3 ml of degassed toluene is stirred at 100° C. overnight. After cooling to RT, the reaction mixture is directly applied to a silica gel column and separated (mobile phase: cyclohexane/ethyl acetate 10:1 to 8:2).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:28][N:29]([CH:38]=[O:39])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([N:10]2[C@H:14]([C:15]([OH:17])=O)[CH2:13][CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1C=CN=C1.S(Cl)(C)(=O)=O.[NH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][N+:53]=1[O-:58]>CN(C=O)C>[CH:1]1([CH2:6][C@H:7]([CH2:28][N:29]([CH:38]=[O:39])[O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][N+:53]=3[O-:58])=[O:17])[CH2:13][CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cccc[n+]1[O-]
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: CS(=O)(=O)Cl
Agent: Cn1ccnc1
Solvent: CN(C)C=O
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)Nc2cccc[n+]2[O-])CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.1 %

Procedure:
To a solution of (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidine carboxylic acid (176 mg, 0.327 mmol) in DMF (2 ml) was added 1-methylimidazole (52 μl, 0.655 mmol) and cooled to 0° C. Mesyl chloride (27 μL, 0.344 mmol) was added dropwise at 0° C., and the resulting mixture was stirred for 30 min followed by the addition of 2-amino pyridine N-oxide (36 mg, 0.327 mmol). The reaction was warmed to rt. After 2 h, the reaction mixture was concentrated, diluted with methanol, and purified by reverse phase HPLC to afford 105 mg (0.167 mmol, 51%) of the title compound. LC/MS: (M+H)+: 629.8.
Reaction SMILES: [N+]([O-])([O-])=O.[Ag+:5].[C:6](=[O:9])([O-:8])[O-:7].[Ca+2:10]>>[C:6](=[O:7])([O-:9])[O-:8].[Ag+2:5].[C:6](=[O:7])([O-:9])[O-:8].[Ca+2:10]
Reactant: [Ag+]
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])[O-]
Agent: [Ca+2]
Product: [Ag+2]
Reaction time: 3 h

Procedure:
200 g of an aqueous silver nitrate solution containing 52 g of silver nitrate was added dropwise to 1,200.0 g of a slurry solution containing 115.3 g of calcium carbonate having a surface area of 0.4 m2/g and an alkali metal content of 20 ppm or less (reagent distributed by Nacalai Tesque, Inc.) as alkaline earth metal carbonate at 20° C. to 25° C., followed by stirring for 3 hours. The solid was collected by filtration, washed with 200 mL of ion exchanged water four times to obtain 193 g of a silver carbonate/calcium carbonate mixture. Then, 48.3 g of the resulting silver carbonate/calcium carbonate mixture and 25 g of ion exchanged water were put into a flask, and adding 5.2 g of ethylenediamine, 5.4 g of oxalic acid and 1.8 g of monoethanolamine, followed by stirring for one hour, and further dried at 70° C. under reduced pressure. Then, a silver catalyst was prepared by filling the obtained powder into a calcination glass tube, and subjecting the powder to calcination at 350° C. for 3 hours under air flow of 100 mL/min.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.C[O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][N:31]=1.B(O)O.Br>C(O)(=O)C>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:33]3[CH:34]=[CH:35][C:30]([OH:29])=[N:31][CH:32]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: COc1ccc(B(O)O)cn1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: Br
Agent: OBO
Solvent: CC(=O)O
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccc(O)nc4)nc(N4CCOCC4)c3s2)CC1
Temperature: 125 °C

Procedure:
2-Chloro-6-((4-methanesulfonylpiperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidine, prepared via General Procedure B-3, (100 mg) was used in General Procedure A using 2-methoxypyridine-5-boronic acid as the boronic acid. The resulting crude (60 mg) was treated with 1 mL of 48% HBr in acetic acid and heated to 125° C. for 6 min in the microwave. The 2-hydroxy pyridine was extracted into ethylacetate and washed with water. After evaporation of the organic layer the crude was purified by reversed phase HPLC purification to yield 17 mg of 189. NMR (CDCl3): 2.67 (m, 4H, 2×CH2), 2.80 (s, 3H, CH3), 3.30 (m, 4H, 2×CH2), 3.87-3.89 (m, 6H, 3×CH2), 3.98-4.00 (m, 4H, 2×CH2), 6.65 (d, H, ArH, J=10.27 Hz), 7.25 (s, H, ArH) 8.50-8.53 (m, 2H, 2×ArH), 11.6 (sbr, H, OH). MS: (ESI+): MH+ 491.22
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:42]/[O:43]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15](/[CH:23]=[C:24]2/[C:25](=[O:41])[N:26]([C@@H:29]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]4)[CH2:27][CH2:28]/2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:3]=1.C1(OC)C=CC=CC=1.ClCCl.FC(F)(F)C(O)=O>C(O)=O.C1(C)C=CC=CC=1>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:42]/[OH:43])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15](/[CH:23]=[C:24]2/[C:25](=[O:41])[N:26]([C@@H:29]4[CH2:33][CH2:32][NH:31][CH2:30]4)[CH2:27][CH2:28]/2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N2CC/C(=C\C3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)/C(=N\OC(c5ccccc5)(c5ccccc5)c5ccccc5)c5nsc(N)n5)[C@H]4SC3)C2=O)C1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=CO
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(/C=C4\CCN([C@@H]5CCNC5)C4=O)CS[C@H]23)ns1
Temperature: 30 °C
Yield: 80.4 %

Procedure:
5.1 (small scale): A suspension of 149 mg of (6R,7R)-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-trityloxyimino-acetylamino]-3-[(E)-(R)-1′-tert.-butoxycarbonyl-2-oxo-[1,3′]bipyrrolidinyl-3-ylidene-methyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 0.24 ml of methyl phenyl ether in 0.8 ml of formic acid was treated with 0.26 ml of dichloromethane containing 2% of trifluoroacetic acid and the solution was heated to 30° C. for 3 h after which time HPLC indicated completion of the reaction. The mixture was diluted with 3 ml of toluene and evaporated to dryness. The residue was diluted with 2 ml of methanol and 6 ml of water, the pH was adjusted to 9 by adding diluted ammonia and the aqueous layer was washed three times with ethyl acetate. The pH of the aqueous layer was adjusted to 3 by adding diluted hydrochloric acid and the solution was evaporated to dryness. The residue was digested with t-butyl methyl ether, filtered and the residue dried to give 73 mg of the NMR-pure title compound as a pale yellow solid. 1H-NMR (d6-DMSO+1 equivalent of CF3COOH, only some selected signals given): 7.26 (s, 1H, CH—C(3)); 5.88 (d, J=4.8, 1H, H—C(7)); 5.18 (d, J=4.8, 1H, H—C(6)); 3.88 and 3.86 (d each, J=18 each, 2H, CH2—S(5)); 3.5-2.8 (m, 8H, 4×CH2); 2.2-2.0 (m, 2H, CH2).
Reaction SMILES: [F:1][CH:2]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4][CH:3]1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C.Cl[C:27]1[N:31]([CH3:32])[N:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34]>CCO>[F:1][CH:2]1[CH2:8][CH2:7][N:6]([C:27]2[N:31]([CH3:32])[N:30]=[CH:29][C:28]=2[N+:33]([O-:35])=[O:34])[CH2:5][CH2:4][CH:3]1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14]
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: CC(C)(C)OC(=O)NC1CCNCCC1F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc([N+](=O)[O-])c1N1CCC(F)C(NC(=O)OC(C)(C)C)CC1
Temperature: 130 °C
Yield: 13.6 %

Procedure:
To a solution of tert-butyl 5-fluoroazepan-4-ylcarbamate (310 mg, 1.34 mmol) in EtOH (4 mL) was added DIPEA (1 ml, 5.7 mmol) and 5-chloro-1-methyl-4-nitro-1H-pyrazole (216 mg, 1.34 mmol). The reaction mixture was heated at 130° C. in a microwave for 8 hr. The solvent was removed under reduced pressure and the residue was purified via silica gel column chromatography (30-40% EtOAc/isohexane) to give the two trans (anti) isomers, tert-butyl 5-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate as a yellow glass (65 mg) contaminated with some of the cis (syn) isomer.
Reaction SMILES: Br[CH2:2][C@H:3]([CH3:6])[CH2:4][OH:5].[Cl:7][C:8]1[CH:9]=[C:10]2[C:16]([C:17]3[N:22]=[C:21]([NH:23][CH2:24][C@@H:25]4[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]4)[C:20]([F:31])=[CH:19][N:18]=3)=[CH:15][NH:14][C:11]2=[N:12][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:7][C:8]1[CH:9]=[C:10]2[C:16]([C:17]3[N:22]=[C:21]([NH:23][CH2:24][C@@H:25]4[CH2:30][CH2:29][CH2:28][N:27]([CH2:2][C@H:3]([CH3:6])[CH2:4][OH:5])[CH2:26]4)[C:20]([F:31])=[CH:19][N:18]=3)=[CH:15][NH:14][C:11]2=[N:12][CH:13]=1
Reactant: C[C@H](CO)CBr
Reactant: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1NC[C@@H]1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H](CO)CN1CCC[C@@H](CNc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 80 °C

Procedure:
To a solution of (R)-3-bromo-2-methylpropan-1-ol (0.006 mL, 0.055 mmol) and (R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-ylmethyl)-pyrimidin-4-amine, 12a, (0.020 g, 0.055 mmol) in CH3CN (2 mL) was added K2CO3 (0.023 g, 0.165 mmol). The reaction mixture was heated at 80° C. at for 24 h. The solvent was concentrated under reduced pressure and the resulting residue was purified by preparatory HPLC (0.1% TFA-H2O/acetonitrile) to afford the desired product, 135.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:5]([NH:7][C@H:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:9][OH:10])=[O:6])[CH2:3][OH:4].[H][H].[ClH:27]>CO.[Pd]>[NH2:1][C@H:2]([C:5]([NH:7][C@H:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:9][OH:10])=[O:6])[CH2:3][OH:4].[ClH:27]
Reactant: [H][H]
Reactant: COC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](CO)NC(=O)[C@@H](N)CO

Procedure:
2.5 Grams of Z-Ser-Ser-OMe was dissolved in 50 ml of methanol with 7.34 ml of 1N-hydrochloric acid, then in the presence of 500 mg of palladium balck, catalytic reduction was carried out at 20° C., under 1 atmospheric pressure of hydrogen gas, to obtain H-Ser-Ser-OMe.HCl.
Reaction SMILES: [OH-].[K+].[Mn]([O-])(=O)(=O)=O.[K+].[CH:9]12[CH2:15][CH:12]([CH2:13][CH2:14]1)[CH2:11][CH:10]2[C:16]([OH:18])=[O:17].S(=O)(=O)(O)[OH:20].S(=O)(O)[O-].[Na+]>O>[OH:20][C:10]1([C:16]([OH:18])=[O:17])[CH2:11][CH:12]2[CH2:15][CH:9]1[CH2:14][CH2:13]2
Reactant: O=C(O)C1CC2CCC1C2
Reactant: O=S(=O)(O)O
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=S([O-])O
Agent: [K+]
Solvent: O
Product: O=C(O)C1(O)CC2CCC1C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
107 g (1.63 mol) of potassium hydroxide (85%) and 85.7 g (542 mmol) of potassium permanganate were dissolved in 380 ml of water, and 37.9 g (271 mmol) of crude 2-norbornanecarboxylic acid in 380 ml of petroleum ether was added dropwise on ice cooling. After heating and refluxing for eight hours, the mixture was stirred at room temperature for 18 hours. The reaction mixture was slowly added to 544 ml of 6N sulfuric acid, to obtain acidified mixture, then 272 ml of an aqueous solution of 62.2 g of sodium bisulfite was added, and the mixture was stirred at room temperature for one hour. After the reaction mixture was extracted with ethyl acetate (200 ml×4), the extract was dried over anhydrous magnesium sulfate. The extract was filtered, the solvent was distilled off and 38.5 g of crude 2-hydroxy-2-norbornanecarboxylic acid was obtained. Crude yield: 92%.
Reaction SMILES: CN(C)CCN(C)C.[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:17][SiH:18]([Cl:20])[Cl:19]>>[CH2:9]([Si:18]([Cl:20])([Cl:19])[Cl:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: ClCc1ccccc1
Agent: CN(C)CCN(C)C
Product: Cl[Si](Cl)(Cl)Cc1ccccc1
Yield: 50.5 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.116 g (1.0 mmol) of N,N,N′,N′-tetramethylethylenediamine, 0.63 g (5.0 mmol) of benzyl chloride, and 3.41 g (25.2 mmol) of trichlorosilane were reacted at 200° C. for 7 hrs. The resulting mixture was distilled to give 0.57 g of benzyltrichlorosilane (yield; 52%).
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:6]=[CH:7][C:8](Cl)=[N:9][CH:10]=1>C(O)C.O>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([NH:2][NH2:3])=[N:9][CH:10]=1
Reactant: NN
Reactant: Clc1ccc(Br)cn1
Solvent: O
Solvent: CCO
Product: NNc1ccc(Br)cn1

Procedure:
9.3 ml (9.5 g, 190.2 mmol) hydrazine hydrate are added to a solution of 1.8 g (9.5 mmol) 5-bromo-2-chloropyridine in 25 ml ethanol at RT, while stirring, and the mixture is then stirred at 90° C. for 46 h. After concentration of the reaction mixture in vacuo, the residue is stirred in water and the solid is filtered off, washed with water and diethyl ether and dried in vacuo.