Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1(C)C(O)C[CH2:24][C@@:23]2(C)[CH:3]1CC[C:6]1[C:7]3[C@:19]([CH3:29])([CH2:20][CH2:21][C:22]=12)[C@@H:10]([C@H:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:9][CH:8]=3.[C:31]([O:34][C:35](=[O:37])[CH3:36])(=O)[CH3:32].N1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:35]([O:34][CH:31]1[CH2:2][CH2:3][C@@:23]2([CH3:24])[CH:39]([CH2:40][CH2:41][C@:42]3([CH3:43])[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:29])[C@@:7]3([CH3:6])[CH2:8][CH2:9][C@@H:10]2[C@H:11]([CH3:18])[CH2:12][CH:13]=[CH:14][C:15]([CH3:17])=[CH2:16])[CH2:32]1)(=[O:37])[CH3:36]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CCC(O)C(C)(C)C1CC3
Reactant: CC(=O)OC(C)=O
Reactant: c1ccncc1
Product: C=C(C)C=CC[C@@H](C)[C@H]1CC[C@]2(C)[C@]1(C)CC[C@@H]1[C@@]3(C)CCC(OC(C)=O)CC3CC[C@]12C

Procedure:
1.3 g of 4,4-dimethylcholesta-8,14-diene-3-ol (Schroepfer et al., Chemistry and Physics of Lipids 47, p. 187 (1988)) were dissolved in 7.5 ml of pyridine and 7.5 ml of acetic anhydride and stirred at 22° C. overnight. The mixture was evaporated in vacuo, stripped twice with toluene, and purified by flash chromatography on SiO2 (toluene). The first 300 ml of eluate was evaporated, and the product crystallized from diethyl ether to yield 140 mg of 3-acetoxy-8,14-dimethylcholestadiene. Melting point: 120°-125° C. (with destruction). MS (molecular ion): 454.4.
Reaction SMILES: Br[CH:2]([Br:8])[CH2:3][CH2:4][CH2:5]CC.[NH:9]1[C:17]2C(=C[CH:14]=[CH:15][CH:16]=2)C=[CH:10]1.[Na].CN(C=[O:23])C>>[Br:8][CH2:2][CH2:3][CH2:4][C:5]([N:9]([CH2:17][CH2:16][CH2:15][CH3:14])[CH3:10])=[O:23]
Reactant: CCCCCC(Br)Br
Reactant: c1ccc2[nH]ccc2c1
Reactant: CN(C)C=O
Agent: [Na]
Product: CCCCN(C)C(=O)CCCBr

Procedure:
Synthesis is performed basically analogously to 5., but with the following changes: the dibromohexane that is used in 4× excess is dissolved in a second reaction flask also while being exposed to nitrogen gassing and while being stirred in an ice bath, and then the indole-sodium salt that is dissolved in DMF is allowed to quickly flow in. The mixture is stirred for two hours at room temperature and then worked up as described under item 5.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][CH:7]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([NH:19][C@@H:20]([CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:21][NH:22]C(=O)OC(C)(C)C)=[CH:15][N+:16]([O-:18])=[O:17])[CH2:9]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][CH:7]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([NH:19][C@@H:20]([CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:21][NH2:22])=[CH:15][N+:16]([O-:18])=[O:17])[CH2:9]1
Reactant: COCCCOC(c1ccccc1)C1CCCN(C(=C[N+](=O)[O-])N[C@H](CNC(=O)OC(C)(C)C)CC2CCCCC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCOC(c1ccccc1)C1CCCN(C(=C[N+](=O)[O-])N[C@H](CN)CC2CCCCC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 126.9 %

Procedure:
Tert-butyl (S)-2-(1-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)-2-nitrovinylamino)-3-cyclohexylpropylcarbamate (12 mg, 0.02 mmol) was dissolved in 1:1 TFA/CH2Cl2 (3 mL) and stirred for 30 min at rt. LC-MS showed the reaction was complete. After concentration, the mixture was purified by prep HPLC to afford (2S)—N2-(1-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)-2-nitrovinyl)-3-cyclohexylpropane-1,2-diamine (12.4 mg, 68%). LC-MS (3 min) tR=1.38 min. m/z 489 (M+1).
Reaction SMILES: [F:1][C@H:2]1[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([C:14]([O:16]C)=O)[CH2:3]1.F[C@H]1C[N:22](C(OC(C)(C)C)=O)[C@H:21]([C:31](=O)[NH:32][C:33]2[CH:38]=NC=CN=2)[CH2:20]1.[F:40][C@H]1CN[C@H](C(NC2C=NC=CN=2)=O)C1>>[F:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:14]([NH:22][C:21]2[CH:31]=[N:32][C:33]([F:40])=[CH:38][CH:20]=2)=[O:16])[CH2:3]1
Reactant: COC(=O)[C@@H]1C[C@@H](F)CN1C(=O)OC(C)(C)C
Reactant: O=C(Nc1cnccn1)[C@@H]1C[C@@H](F)CN1
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)Nc1cnccn1
Product: O=C(Nc1ccc(F)nc1)[C@@H]1C[C@@H](F)CN1

Procedure:
(2S,4R)-4-Fluoro-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide 79A was prepared from (2S,4R)-1-tert-butyl 2-methyl 4-fluoropyrrolidine-1,2-dicarboxylate as described for 65A and 65B. LC/MS [M+H]+: 228; Ret time (Method C): 0.57 min.
Reaction SMILES: [CH3:1][SiH:2]([Cl:4])[Cl:3].[SiH:5]([Cl:8])([CH3:7])[CH3:6].[CH2:9]([Cl:13])[C:10](=[CH2:12])[CH3:11]>>[Si:5]([CH2:11][CH:10]([CH2:9][Cl:13])[CH3:12])([CH3:7])([CH3:6])[Cl:8].[CH3:1][Si:2]([CH2:11][CH:10]([CH2:9][Cl:13])[CH3:12])([Cl:4])[Cl:3]
Reactant: C[SiH](C)Cl
Reactant: C=C(C)CCl
Reactant: C[SiH](Cl)Cl
Product: CC(CCl)C[Si](C)(C)Cl
Product: CC(CCl)C[Si](C)(Cl)Cl
Reaction time: 0.17 h
Yield: 19.6 %
Yield: 54 %

Procedure:
In a 100 ml apparatus, there were combined 8.6 g (0.75 mol) of MeSiHCl2, 7.1 g (0.075 mol) of Me2SiHCl, and 6.8 g (0.075 mol) of methallyl chloride. Pt catalyst solution (0.01 ml) was added at 32° causing an exothermic reaction to 57° C. and completion in 10 min. Distillation yielded 54.0% of Me2SiClCH2CHMeCH2Cl and 19.6% of MeSiCl2CH2CHMeCH2Cl, indicating that at the equimolar level, neither MeSiHCl2 nor Me2SiHCl is a very effective promoter for reactions of the other with methallyl chloride, in terms of yield, but that reaction rates are increased.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH:13][C:14]2[CH:15]=[C:16]([N:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)[CH:17]=[CH:18][C:19]=2[N+:20]([O-:22])=[O:21])[CH3:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[ClH:36]>ClCCl.C(OCC)C>[ClH:36].[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH:11]([NH:13][C:14]2[CH:15]=[C:16]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:17]=[CH:18][C:19]=2[N+:20]([O-:22])=[O:21])[CH3:12])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(OC)cc(C(C)Nc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2[N+](=O)[O-])c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc(OC)cc(C(C)Nc2cc(N3CCNCC3)ccc2[N+](=O)[O-])c1
Reaction time: 4 h
Yield: 76 %

Procedure:
To a solution of t-butyl 4-(3-(1-(3,5-dimethoxyphenyl)ethylamino)-4-nitrophenyl)piperazine-1-carboxylate (327 mg, 0.67 mmol) in dry dichloromethane (2.0 mL) was added a saturated solution of HCl in diethyl ether (15 mL). The reaction mixture was stirred for 4 hours. The product was collected by filtration and dried in vacuo to afford the title compound (216 mg, 76% yield). 1H NMR (400 MHz, CD3OD): δ 8.03 (d, 1H), 6.55 (s, 2H), 6.36 (m, 2H), 5.95 (s, 1H), 4.67 (m, 1H), 3.73 (s, 6H), 3.49 (m, 4H), 3.29 (m, 4H), 1.60 (d, 3H); MS (ESI) m/z: Calculated for C20H27N4O4: 387.2; Observed: 387.3 (M++1) [corresponding to the free base].
Reaction SMILES: C([C@H:4]1[CH2:8][NH:7][C:6](=[S:9])[CH2:5]1)(=O)C.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:11].O.[C:25]([O:28]CC)(=O)[CH3:26]>C1(C)C=CC=CC=1>[C:25]([S:11][C@H:4]1[CH2:8][NH:7][C:6](=[S:9])[CH2:5]1)(=[O:28])[CH3:26]
Reactant: CC(=O)[C@H]1CNC(=S)C1
Reactant: CCOC(C)=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)S[C@H]1CNC(=S)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72 %

Procedure:
(4R)-4-Acetylthio-2-pyrrolidone (10 g) is dissolved in toluene (100 ml), and thereto is added gradually phosphorus pentasulfide (9.5 g), and the mixture is stirred at room temperature for 20 minutes. To the reaction solution are added water and ethyl acetate, and the mixture is stirred at room temperature for 1.5 hour. The insoluble materials are removed by filtration, and the organic layer is washed with water, dried, and evaporated to remove the solvent. The residue is recrystallized from toluene to give (+)-(4R)-4-acetylthiopyrrolidine-2-thione (7.9 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([N:15]([CH3:17])[CH3:16])=[N:11][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[H-].[Na+].IC.[C:22](O)(=O)C>O1CCCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:22])[C:10]([N:15]([CH3:17])[CH3:16])=[N:11][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1
Reactant: CN(C)C(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(C)C(=N[N+](=O)[O-])N(C)Cc1ccc(Cl)nc1
Reaction time: 0.5 h

Procedure:
To a mixture of 0.24 g of 1-(6-chloro-3-pyridylmethyl)-3,3-dimethyl-2-nitroguanidine (Compound No. 6) and 6 ml of dry tetrahydrofuran (THF) was added 0.045 g of 60% sodium hydride (in mineral oil) at room temperature, followed by stirring for 30 minutes. A solution of 0.16 g of iodomethane in 1 ml of THF was added to the reaction mixture and allowed to react for 3 days. After adding 0.1 ml of acetic acid, the mixture was filtered to remove insoluble materials and the filtrate was concentrated. The residue was purified by a column chromatography [developing solvent: dichloromethanemethanol (20:1)] to obtain 0.17 g of 1-(6-chloro-3-pyridylmethyl)-1,3,3-trimethyl-2-nitroguanidine (Compound No. 14) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH3:19][O:20][C:21](=[O:27])[C@H:22]([CH:24]([CH3:26])[CH3:25])[NH2:23]>>[CH3:19][O:20][C:21](=[O:27])[C@H:22]([CH:24]([CH3:26])[CH3:25])[NH:23][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Product: COC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)C(C)C

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-valine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH:9]=[C:10]([C:14]([O-:16])=O)[C:11]([O-:13])=[O:12])=[CH:4][CH:3]=1.[C:17]1(OC2C=CC=CC=2)C=CC=C[CH:18]=1>C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:17][CH3:18])=[O:12])=[C:14]2[OH:16]
Reactant: O=C([O-])C(=CNc1ccc(Br)nc1)C(=O)[O-]
Reactant: c1ccc(Oc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2ccc(Br)nc2c1O

Procedure:
Diethyl(2-(((6-bromopyridin-3-yl)amino)methylene)malonate (40 g, 0.117 mol) was added to boiling diphenyl ether (214 mL) in batches over 5 min, heated under reflux for 45 min. After confirming a disappearance of the raw materials by a thin layer chromatography plate (ethyl acetate:petroleum ether=1:3), the reaction mixture was cooled and poured into petroleum ether to precipitate a solid, suction filtered to give 24.6 g of a khaki solid.
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[C:10]4(C)[NH:16][CH:13]([CH2:14][CH:15]=3)[CH2:12][CH2:11]4)[O:6][N:5]=2)[CH2:3][CH2:2]1.[Cl:18]C(OC(Cl)C)=O>ClC(Cl)C>[ClH:18].[CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[CH:10]4[NH:16][CH:13]([CH2:14][CH:15]=3)[CH2:12][CH2:11]4)[O:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: CC12CCC(CC=C1c1nc(C3CC3)no1)N2
Reactant: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: C1=C(c2nc(C3CC3)no2)C2CCC(C1)N2
Product: Cl

Procedure:
2-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-methyl-8-azabicyclo[3.2.1]oct-2-ene (525 mg, 2.3 mmol) was dissolved in dry dichlorethane (10 ml). The solution was cooled on ice and 1-chloroethyl chloroformate (370 μl, 3.4 mmol was added). The reaction mixture was heated under reflux for 1.5 h and the solvent evaporated. Methanol (20 ml) was added and the mixture heated under reflux for further 1.5 h. The mixture was treated with charcoal, filtered and concentrated in vacuo.
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].Br[CH2:13][CH2:14][O:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[O:15]1[CH2:16][CH2:17][N:1]([C@H:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([OH:5])=[O:4])[CH2:13][CH2:14]1
Reactant: BrCCOCCBr
Reactant: N[C@@H](C(=O)O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)[C@@H](c1ccccc1)N1CCOCC1

Procedure:
To (R)-2-amino-2-phenylacetic acid (1.0 g, 6.62 mmol), 1-bromo-2-(2-bromoethoxy)ethane (1.686 g, 0.727 mmol) and sodium carbonate (2.103 g, 19.85 mmol) was added ethanol (40 mL) and the resultant mixture heated at 100° C. for 45 hours. After cooling, the resultant solid was removed by filtration and washed with ethanol. The filtrate was concentrated, and then dissolved in ethanol then a solution of 4N aqueous hydrochloric acid added until the pH of the solution was 3. The resultant solid was removed and discarded. The filtrate was concentrated and purified by reversed phase chromatography (C18), eluting with 10-100% acetonitrile in water (0.1% TFA) to give the title compound. MS (ESI) m/z 222 (MA)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(O)(=O)C.[N+:13]([O-])([OH:15])=[O:14]>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:13]([O-:15])=[O:14])[C:3]=1[OH:8]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccccc1Br
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cccc(Br)c1O
Reaction time: 1 h
Yield: 34.1 %

Procedure:
51.9 g (0.3 mol) of 2-bromophenol and 300 ml of acetic acid were fed into a 1-liter four-necked flask provided with a reflux condenser, a stirrer and a thermometer. Thereto was dropwise added 29.7 g (0.33 mol) of 70% nitric acid at a temperature of 15° C. or below, with ice-cooling. The reaction mixture was stirred at a temperature of 10° C. or below for 1 hour and poured into 600 ml of water. The mixture was subjected to extraction with 400 ml of ether. The ether layer was washed with 150 ml of water. The ether layer was subjected to distillation. The residue was transferred into a 1-liter flask provided with a stirrer and a distillation apparatus. Azeotropic distillation was conducted while water was added gradually. The amount of water required for azeotropic distillation was 2,100 ml. The distillate obtained was subjected to extraction two times using 500 ml of ether. The ether layer was dried over anhydrous sodium sulfate and subjected to distillation to remove ether. The resulting crude product was mixed with 10 ml of ethanol. The mixture was heated and then allowed to cool. The formed crystals were collected by filtration and then dried to obtain 22.3 g of 2-bromo-6-nitrophenol (yield: 34.1%, purity: 99.6%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[CH:27]=[C:28]([CH:45]=[C:46]([F:48])[CH:47]=1)[O:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:45]=[C:46]([F:48])[CH:47]=[C:26]([F:25])[CH:27]=4)=[CH:35][CH:34]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(I)c3c(N)ncnc32)C1
Reactant: CC1(C)OB(c2ccc(Oc3cc(F)cc(F)c3)cc2)OC1(C)C
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cc(F)cc(F)c4)cc3)c3c(N)ncnc32)C1
Temperature: 80 °C
Reaction time: 12 h
Yield: 72.3 %

Procedure:
Into a 100 mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (400 mg, 0.90 mmol, 1.00 equiv), 2-[4-(3,5-difluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (360 mg, 1.08 mmol, 1.20 equiv), sodium carbonate (190 mg, 1.79 mmol, 1.99 equiv), ethylene glycol dimethyl ether (50 mL), water (15 mL), and Pd(PPh3)4 (52 mg, 0.04 mmol, 0.05 equiv). The resulting solution was stirred for 12 h at 80° C. and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100/1) to give 340 mg (72%) of tert-butyl (3R)-3-[4-amino-3-[4-(3,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a yellow solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[C:13]([OH:15])=O)[CH3:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.[NH2:63][C@@H:64]([CH2:78][C:79]1[CH:84]=[C:83]([F:85])[CH:82]=[C:81]([F:86])[CH:80]=1)[C@H:65]([OH:77])[CH2:66][NH:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([CH2:75][CH3:76])[CH:70]=1.C(Cl)[Cl:88]>>[ClH:88].[ClH:88].[F:85][C:83]1[CH:84]=[C:79]([CH:80]=[C:81]([F:86])[CH:82]=1)[CH2:78][C@H:64]([NH:63][C:13](=[O:15])[C:12]1[CH:16]=[C:17]([CH3:19])[CH:18]=[C:10]([CH2:9][N:7]([CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH3:8])[CH:11]=1)[C@H:65]([OH:77])[CH2:66][NH:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([CH2:75][CH3:76])[CH:70]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: Cc1cc(CN(C)Cc2ccco2)cc(C(=O)O)c1
Reactant: ClCCl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C)cc(CN(C)Cc3ccco3)c2)c1
Product: Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 3-{[(2-furylmethyl)(methyl)amino]methyl}-5-methylbenzoic acid (170 mg, 0.66 mmol) in methylene chloride (3 mL) is added HBTU (375 mg, 0.99 mmol), HOBt (134 mg, 0.99 mmol), and N,N-diisopropylethylamine (0.334 mL, 1.98 mmol), followed by (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol prepared by the method in EXAMPLE SP-272 (269 mg, 0.66 mmol), and the reaction mixture is stirred for 12 h at room temperature. The reaction mixture is diluted with methylene chloride, washed with water, and saturated sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 10% methanol/chloroform) affords the title compound as the free base. The compound is dissolved in methanol (2 mL), and to this solution is added hydrochloric acid (5 mL, 4 N dioxane, 20 mmol). The reaction mixture is stirred for 1 h at room temperature. The reaction mixture is then diluted with ethyl ether (10 mL). The precipitate that is formed is collected by filtration to provide the title compound. ESI MS m/z 576 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.[C:19]([C:28]1[CH:33]=[CH:32][C:31](O)=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:21])[CH3:20]>>[CH3:18][O:17][C@@H:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][C:31]2[CH:32]=[CH:33][C:28]([C:19]([CH3:21])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:20])=[CH:29][CH:30]=2)=[CH:7][CH:8]=1)[C:14]([OH:16])=[O:15]
Reactant: CO[C@@H](Cc1ccc(OCCCO)cc1)C(=O)O
Reactant: CC(C)(c1ccccc1)c1ccc(O)cc1
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(C(C)(C)c3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling with 4-cumylphenol and cleavage from the resin (Standard Procedure G) gave an oily solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:6]1[C:11]([OH:12])=[CH:10][C:9]([OH:13])=[CH:8][C:7]=1[OH:14])=[O:5].[CH2:15](Br)[CH2:16][C:17]([CH3:19])=[CH2:18]>[OH-].[K+]>[CH3:1][O:2][CH2:3][C:4]([C:6]1[C:7]([OH:14])=[C:8]([CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[C:9]([OH:13])=[C:10]([CH2:3][CH:4]=[C:6]([CH3:11])[CH3:7])[C:11]=1[OH:12])=[O:5]
Reactant: COCC(=O)c1c(O)cc(O)cc1O
Reactant: C=C(C)CCBr
Agent: [K+]
Agent: [OH-]
Product: COCC(=O)c1c(O)c(CC=C(C)C)c(O)c(CC=C(C)C)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
2-methoxy-1-(2,4,6-trihydroxyphenyl)ethanone (8.3 g, 42 mmol) was dissolved in a 5% potassium hydroxide aqueous solution (84 ml). After the reaction mixture was cooled below 0° C., Isopentenyl bromide (12.48 g, 84 mmol) was slowly added dropwise to within 30 minutes. The reaction mixture was stirred at room temperature (RT) for 2 hours, then poured into an ice water and acidified to pH 2. The reaction mixture was extracted with ethyl acetate. The extract was collected and dried over anhydrous sodium sulfate, followed by removing solvent. The desired compound was obtained by purifying the residue by silica gel column chromatography (dichloromethane as eluent) (5.7 g, yield 41%). 1H NMR (400 MHz, DMSO-d6): δ=11.44 (s, 2H), 9.24 (s, 1H), 5.00 (t, 2H, J=6.8 Hz), 4.63 (s, 2H,), 3.31 (s, 3H), 3.22 (d, 4H, J=6.8 Hz), 1.67 (s, 6H), 1.58 (s, 6H).
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:4]#[CH:5].[CH2:14](I)[CH3:15]>CN(C=O)C.O.C(OCC)C>[CH2:14]([N:6]([CH2:3][C:4]#[CH:5])[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH3:15]
Reactant: CCI
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C#CCN(CC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
A suspension of sodium hydride (354 mg, 14.2 mmol) in DMF (33 mL) at room temperature was treated with a solution of Example 516A (2.0 g, 12.9 mmol) in DMF (10 mL) and stirred for one hour at room temperature. The solution was cooled to 0° C., treated with ethyl iodide (1.24 mL, 15.5 mmol), stirred for one hour at 0° and overnight at room temperature. The solution was diluted with water (25 mL),extracted with diethyl ether (2×50 mL) and the combined organic layers were washed with brine (30 mL0, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel using 5–10% ethyl acetate/hexanes to give the 1.1 g (47% yield) of the desired product. MS (ESI(+)) m/e 184 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.Cl[C:12]1[N:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:12]3[C:13]([C:14]([OH:16])=[O:15])=[CH:17][CH:18]=[CH:19][N:20]=3)[CH:10]=2)[CH:6]=[N:7]1
Reactant: O=C(O)c1cccnc1Cl
Reactant: Nc1ccc2cn[nH]c2c1
Product: O=C(O)c1cccnc1Nc1ccc2cn[nH]c2c1
Temperature: 150 °C

Procedure:
A mixture of 6-aminoindazole (6.7 g) and 2-chloronicotinic acid (8 g) was heated neat at 150° C. for 2 h. The reaction was cooled and washed with acetone to give 2-(1H-indazol-6-ylamino)pyridine-3-carboxylic acid.
Reaction SMILES: [C:1]([CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)#[N:2].[Li+].[CH3:16][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[C:1]([C:3]1([CH3:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)#[N:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)C1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C#N)CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
To a solution of tert-butyl 3-cyanopyrrolidine-1-carboxylate (1.0 g, 5.1 mmol) in THF (20 mL) at −78° C. was slowly added LiHMDS (1.0 M in THF, 5.6 mL, 5.6 mmol). The reaction mixture was stirred at −78° C. for 30 min then iodomethane (0.48 mL, 7.64 mmol) was slowly added. The reaction mixture was stirred at −78° C. for 30 min then warmed to room temperature and quenched with saturated aqueous NH4Cl. Diluted with H2O and extracted with EtOAc (2×) then dried over MgSO4 and concentrated. The residue was purified by SiO2 chromatography (20% to 40% EtOAc/hexanes) to afford 0.95 g (89%) of tert-butyl 3-cyano-3-methylpyrrolidine-1-carboxylate as a pale yellow solid.