Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[CH2:10][NH:9][CH2:8][CH2:7][NH:6]1)=[O:4].Cl[CH2:12][C:13]([NH:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=1[Cl:24])=[O:14].C(N(CC)CC)C>COCCO>[CH3:1][NH:2][C:3]([CH:5]1[NH:6][CH2:7][CH2:8][N:9]([CH2:12][C:13]([NH:15][C:16]2[C:17]([Cl:24])=[CH:18][C:19]([Cl:23])=[CH:20][C:21]=2[Cl:22])=[O:14])[CH2:10]1)=[O:4]
Reactant: O=C(CCl)Nc1c(Cl)cc(Cl)cc1Cl
Reactant: CNC(=O)C1CNCCN1
Solvent: CCN(CC)CC
Solvent: COCCO
Product: CNC(=O)C1CN(CC(=O)Nc2c(Cl)cc(Cl)cc2Cl)CCN1
Temperature: 60 °C
Reaction time: 3 h
Yield: 24.4 %

Procedure:
A mixture of 15.33 parts of N-methyl-2-piperazinecarboxamide, 27.2 parts of 2-chloro-N-(2,4,6-trichlorophenyl)acetamide, 9.8 parts of N,N-diethylethanamine and 300 parts of 2-methoxyethanol was stirred for 3 hours at 60° C. The reaction mixture was evaporated. The residue was taken up in a small amount of water and treated with sodium carbonate. The product was extracted three times with dichloromethane. The combined extracts were dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off (the filtrate was set aside) and dried, yielding a first fraction of 9.27 parts (24.4%) of 3-[(methylamino)carbonyl]-N-(2,4,6-trichlorophenyl)-1-piperazineacetamide. The filtrate, which was set aside (see above) was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and 2-propanol (90:10 by volume) as eluent. The desired fraction was collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding a second fraction of 5.93 parts (15.6%) of 3-[(methylamino)carbonyl]-N-(2,4,6-trichlorophenyl)-1-piperazineacetamide; mp. 168.9° C.
Reaction SMILES: Cl[C:2]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1/[CH:6]=[CH:7]\[C:8]#[N:9])=[O:3].[O:14]1CCOCC1>CC(C)=O>[OH:14][C:8]1[CH:7]=[CH:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[C:2](=[O:3])[N:9]=1
Reactant: C1COCCO1
Reactant: N#C/C=C\c1ccccc1C(=O)Cl
Solvent: CC(C)=O
Product: O=c1nc(O)ccc2ccccc12
Reaction time: 8 h
Yield: 36.9 %

Procedure:
59.0 g (0.308 mole) of (I) is taken up in dry dioxane (800 ml) and purged with HCl gas at 70° for 5 hours. Solvent is removed, the residue is azeotropically distilled three times with benzene and the residue taken up in dimethoxyethane (200 ml) and water (22 ml). After standing overnight at room temperature, the reaction mixture is evaporated to dryness, taken up in ethyl acetate (1.5 liters) and washed twice with saturated NaHCO3 solution (630 ml portions). The NaHCO3 phase is back-washed with ethyl acetate (1.0 liter), the organic extracts are combined and washed 3 times with 500 ml portions of water. The organic layer is evaporated. The solid obtained is taken up in acetone (1.0 liter), charcoaled and evaporated. The product is recrystallized from benzene (500 ml) and petroleum ether (650 ml). Yield: 20.7 g, percent yield: 36.9%, single spot, Rf 0.30 (alumina, CHCl3 :EtOAc-6:4). mp=129°-131° (crude); mp on recrystallization: 135°-136°.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[N:29]=[C:17]2[N:18]=[C:19]([N:23]([CH3:28])[CH2:24][CH2:25][NH:26][CH3:27])[N:20]=[C:21]([NH2:22])[N:16]2[N:15]=1.CCN(CC)CC>CC#N>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[N:29]=[C:17]2[N:18]=[C:19]([N:23]([CH3:28])[CH2:24][CH2:25][N:26]([CH3:27])[CH2:2][C:3]3[CH:7]=[C:6]([CH3:8])[O:5][N:4]=3)[N:20]=[C:21]([NH2:22])[N:16]2[N:15]=1
Reactant: CNCCN(C)c1nc(N)n2nc(-c3ccco3)nc2n1
Reactant: Cc1cc(CCl)no1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(CN(C)CCN(C)c2nc(N)n3nc(-c4ccco4)nc3n2)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Chloromethyl-5-methyl-isoxazole (1.5 eq.) was directly added to a solution of 2-furan-2-yl-N5-methyl-N5-(2-methylamino-ethyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine (0.14 mmol) and Et3N (0.3 mmol), in 3 mL of CH3CN. The resulting reaction mixture was stirred at room temp for 18 hours. It was then concentrated and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA. 1H NMR (DMSO-d6) δ 7.90 (br s, 2H), 7.80 (d, J=1.0 Hz, 1H), 7.05 (d, J=3.6 Hz, 1 H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H), 6.30 (s, 1H), 3.65 (m, 2H), 3.20-2.75 (m, 4H), 2.5 (s, 3H), 2.35 (s, 3H), 2.3 (s, 3H) ppm. MS: m/z: 385 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH3:14])[C:10](=[S:13])[NH:11][N:12]=1.[C:15]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH3:14])[C:10]([S:13][CH3:15])=[N:11][N:12]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1c(-c2ccccc2F)n[nH]c1=S
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CSc1nnc(-c2ccccc2F)n1C
Yield: 72.9 %

Procedure:
A mixture of 5-(2-fluorophenyl)-2 4-dihydro-4-methyl-3H-1,2,4-triazole-3-thione (4.56 g 2.18×10-2 mole), K2CO3 (3.01 g, 2.18×10-2 mole), methyl iodide (1 5 ml 2.4×10-2 mole), and acetone (65 ml) was stirred and warmed to reflux. After refluxing overnight, the solvent was evaporated and the concentrate was treated with water. The aqueous mixture was extracted three times with EtOAc. The EtOAc extracts were combined washed with saturated aqueous NaCl, and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure affording a pale yellow oil which was purified by chromatography and kugel rohr distillation, affording a pale yellow oil 3.55 g (73%), bp=190°-197° C. (0.3 mm).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.[O:38]1C(C(Cl)=O)=C[CH:40]=[N:39]1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17]([C:18]3[O:38][N:39]=[CH:40][CH:19]=3)=[O:20])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:3]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(Cl)c1ccno1
Product: O=C(N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O)c1ccno1

Procedure:
This compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (Intermediate JJ4) by replacing propionyl chloride with isoxazole-5-carbonyl chloride. (MH+ 560.28)
Reaction SMILES: [C:1]([C:4]1[C:9](F)=[CH:8][C:7](C2C=CC3C(=CC=C([C@H]4CC[C@H](CCC)CC4)C=3)C=2)=[CH:6][C:5]=1F)(=[O:3])N.FC1C2C(=CC([C@H]3CC[C@H](CCC)CC3)=CC=2)C=CC=1C1C=C(F)C=C(F)C=1.C([Li])CCC.C(=O)=[O:65]>>[C:1]([OH:3])(=[O:65])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCC[C@H]1CC[C@H](c2ccc3cc(-c4cc(F)c(C(N)=O)c(F)c4)ccc3c2)CC1
Reactant: O=C=O
Agent: CCC[C@H]1CC[C@H](c2ccc3c(F)c(-c4cc(F)cc(F)c4)ccc3c2)CC1
Agent: [Li]CCCC
Product: O=C(O)c1ccccc1

Procedure:
10 g of 2-(4-carbamoyl-3,5-difluorophenyl)-6-(trans-4-propylcyclohexyl)naphthalene (synthesized by lithioating 1-fluoro-2-(3,5-difluorophenyl)-6-(trans-4-propylcyclohexyl)naphthalene obtained in Example 5 with butyl lithium, blowing carbon dioxide through the material to produce benzoic acid, reacting the product with thionyl chloride to produce acid chloride, and then blowing ammonia gas through the material) was dissolved in 40 ml of DMF. To the solution was then added 2.5 ml of phosphorus oxychloride. The reaction mixture was then allowed to undergo reaction at a temperature of 25° C. for 2 hours. The reaction solution was then poured into ice water. To the reaction solution was then added diluted hydrochloric acid. The resulting aqueous phase was then extracted with toluene. The material thus extracted and the organic phase were together washed with water, saturated aqueous solution of sodium bicarbonate and saturated brine, and then dehydrated and dried over anhydrous sodium sulfate. The residue was purified through silica gel column chromatography (hexane/dichloromethane=6/4) and then recrystallized from ethanol to obtain 7.4 g of 1-fluoro-2-(3,5-difluoro-4-cyanophenyl)-6-(trans-4-propylcyclohexyl)naphthalene.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[CH:15]([CH3:16])[C:14](=[O:17])[C:13]([CH3:19])([CH3:18])[C:12]2=[O:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:21][Mg]Br.C1COCC1>>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C:12](=[O:20])[C:13]([CH3:19])([CH3:18])[C@:14]([OH:17])([CH3:21])[C@H:15]2[CH3:16])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(N2C(=O)C(C)(C)C(=O)C2C)ccc(C#N)c1Cl
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: Cc1c(N2C(=O)C(C)(C)[C@@](C)(O)[C@H]2C)ccc(C#N)c1Cl

Procedure:
Using 2-chloro-3-methyl-4-(3,3,5-trimethyl-2,4-dioxopyrrolidin-1-yl)benzonitrile (40 mg) and methylmagnesium bromide-THF solution (1.38 mL, 1.0 mol/L), and in the same manner as in Example 2, the title compound was obtained as a colorless solid (yield: 24 mg, 57%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][OH:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23](=O)[CH2:24][CH3:25])[CH2:17][CH2:16]1.Cl.O>O1CCOCC1>[CH2:24]([C:23]1([CH2:22][CH2:21][N:18]2[CH2:17][CH2:16][N:15]([CH3:14])[CH2:20][CH2:19]2)[C:6]2[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH2:11][CH2:12][O:13]1)[CH3:25]
Reactant: CCC(=O)CCN1CCN(C)CC1
Reactant: COc1ccc(CCO)cc1OC
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCC1(CCN2CCN(C)CC2)OCCc2cc(OC)c(OC)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.6 %

Procedure:
A mixture of 34,8 g of 3,4-dimethoxybenzeneethanol and 32 g of crude 1-(4-methylpiperazinyl)pentane-3-one in 400 ml of dioxane, which is saturated with anhydrous hydrochloric acid, was stirred at ambient temperature for 24 h. After addition of water the mixture was extracted with dichloromethane. The organic phase was washed, dried and evaporated to yield 41,5 g (68,5%) of crude 1-[2-(1-ethyl-3,4-dihydro-6,7-dimethoxy-1H-2-benzopyran-1-yl)ethyl]-4-methylpiperazine.
Reaction SMILES: [C:1]([CH2:3][C:4](=[S:6])[NH2:5])#[N:2].[CH:7]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:11][C:10]=1[N+:28]([O-:30])=[O:29])=O>N1CCCCC1.C(O)C>[NH2:5][C:4](=[S:6])[C:3]([C:1]#[N:2])=[CH:7][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH2:17][CH2:16]2)=[CH:11][C:10]=1[N+:28]([O-:30])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)c([N+](=O)[O-])c2)CC1
Reactant: N#CCC(N)=S
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=C(C#N)C(N)=S)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
1.5 g (15 mmol) of 2-cyanoethanethioamide, 60 ml of ethanol and one drop of piperidine are added respectively to 5 g (15 mmol) of tert-butyl 4-(4-formyl-3-nitrophenyl)piperazine-1-carboxylate. The reaction mixture is stirred at room temperature for 12 hours. The precipitate obtained is filtered to yield 5.2 g (83%) of tert-butyl 4-(4-(3-amino-2-cyano-3-thioxoprop-1-enyl)-3-nitrophenyl)piperazine-1-carboxylate in the form of a yellow solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]3[CH:13]=[C:14]([C@H:20]4[C@H:25]([OH:26])[C@@H:24]([OH:27])[C@H:23]([OH:28])[C@@H:22]([CH2:29][OH:30])[O:21]4)[CH:15]=[CH:16][C:17]=3[CH2:18][CH3:19])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[C:31]([O:35][P:36](N(CC)CC)(=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:34])([CH3:33])[CH3:32].N1C=NN=N1.C1C=C(Cl)C=C(C(OO)=O)C=1>C1COCC1.C(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]3[CH:13]=[C:14]([C@@H:20]4[O:21][C@H:22]([CH2:29][O:30][P:36](=[O:42])([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[O:35][C:31]([CH3:33])([CH3:34])[CH3:32])[C@@H:23]([OH:28])[C@H:24]([OH:27])[C@H:25]4[OH:26])[CH:15]=[CH:16][C:17]=3[CH2:18][CH3:19])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCc1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc2c(c1)OCCO2
Reactant: CCN(CC)P(=O)(OC(C)(C)C)OC(C)(C)C
Agent: O=C(OO)c1cccc(Cl)c1
Agent: c1nnn[nH]1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1ccc([C@@H]2O[C@H](COP(=O)(OC(C)(C)C)OC(C)(C)C)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc2c(c1)OCCO2
Temperature: -40 °C
Reaction time: 0.08 h
Yield: 47.9 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Intermediate 2, 1.0 g, 2.4 mmol) in THF (15 ml) was added a solution of Diethyl-phosphoramidic acid di-tert-butyl ester (780 mg, 3.12 mmol) in THF (5 ml) at 0° C. followed by a solution of tetrazole (435 mg, 6.2 mmol) in DCM (12.5 ml). After stirring for 5 min at same temperature, it was stirred at room temperature for 20 min. Reaction mixture was cooled to −40° C. and added a solution of m-CPBA (830 mg, 4.8 mmol) in DCM (5 ml). The reaction mixture was stirred at same temperature for 5 min and then at room temperature for 2 h. Reaction mixture was cooled to 0° C. and quenched by the addition of 10% sodium bisulfite solution (5 ml). This was extracted with ether (3×10 ml). Combined organic layer was washed with brine (5 ml), dried over sodium sulfate and concentrated to give 700 mg of phosphoric acid di-tert-butyl ester (2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester.
Reaction SMILES: OCC(OC1C(C(C)C)CCC(C)C1)=O.C([Si](Cl)(C)C)(C)(C)C.[OH:24][CH2:25][C:26]([O:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:27].OCC(O[C@H]1CCCC[C@@H]1C1C=CC=CC=1)=O.[CH:58]([Si:61](Cl)([CH:65]([CH3:67])[CH3:66])[CH:62]([CH3:64])[CH3:63])([CH3:60])[CH3:59]>>[CH:58]([Si:61]([CH:65]([CH3:67])[CH3:66])([CH:62]([CH3:64])[CH3:63])[O:24][CH2:25][C:26]([O:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:27])([CH3:60])[CH3:59]
Reactant: O=C(CO)O[C@@H]1CCCC[C@H]1c1ccccc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: CC1CCC(C(C)C)C(OC(=O)CO)C1
Agent: O=C(CO)O[C@H]1CCCC[C@@H]1c1ccccc1
Product: CC(C)[Si](OCC(=O)O[C@@H]1CCCC[C@H]1c1ccccc1)(C(C)C)C(C)C

Procedure:
In the same manner, 1a, 1b, and 1c(+) were prepared from the combinations of (-)-menthyl hydroxyacetate with tertbutyldimethylsilyl chloride, (-)-(1R,2S)-2-phenyl-1-cyclohexyl hydroxyacetate with tert-butyldimethylsilyl chloride, and (+)-(1S,2R)-2-phenyl-1-cyclohexyl hydroxyacetate with triisopropylsilyl chloride, respectively, in 90-95% yields.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]([NH2:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:19][C:20]([Cl:25])([Cl:24])[C:21](Cl)=[O:22]>C(Cl)Cl>[Cl:19][C:20]([Cl:25])([Cl:24])[C:21]([NH:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2)=[O:22]
Reactant: Cc1ccc(N)c2cn[nH]c12
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)C(Cl)(Cl)Cl)c2cn[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-Methyl-1H-indazol-4-amine (J. Chem. Soc. 1955, 2412; 550 mg, 3.74 mmol) and triethylamine (1.6 mL, 11.5 mmol) were combined in CH2Cl2 (22 mL) and treated with trichloroacetyl chloride (0.54 mL, 4.84 mmol) dropwise at 0° C. The mixture was allowed to gradually warm to ambient temperature and stir overnight. The mixture was concentrated and the residue was purified by flash chromatography (98:2, CH2C12:CH3OH), to provide the title compound.
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH:31]([NH2:34])([CH3:33])[CH3:32]>C1COCC1>[CH2:4]([O:3][C:1](=[O:2])[NH:11][CH2:12][C:13](=[O:15])[NH:34][CH:31]([CH3:33])[CH3:32])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC(C)N
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)NC(=O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a solution of N-Cbz-glycine (20.9 g, 100 mmol) in THF (400 mL) at 0° C. was added N-methylmorpholine (NMM) (12.1 mL, 110 mmol) and i-butylchloroformate (13 mL, 100 mmol). The resultant mixture was stirred at 0° C. for 2 min and then i-propylamine (9.4 mL, 110 mmol) was added. The reaction mixture was warmed to room temperature and stirred at this temperature for 16 h. The mixture was filtered through a pad of CELITE™ and concentrated in vacuo. The crude residue was dissolved in ethyl acetate (500 mL) and washed with 1N HCl (aq.) (1×100 mL), sat. NaHCO3 (aq.) (1×100 mL) and brine (1×100 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to afford (isopropylcarbamoylmethyl)carbamic acid benzyl ester as a white solid (24.5 g, 98 mmol, 98%) which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.Br[C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1.COC1C=C(C2C=NC=CC=2)C=CC=1>>[CH3:15][C:11]1[CH:10]=[C:9]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Brc1cccnc1
Reactant: Cc1cccc(Br)c1
Agent: COc1cccc(-c2cccnc2)c1
Product: Cc1cccc(-c2cccnc2)c1

Procedure:
3-(3-methylphenyl)-pyridine was prepared from 81.5 g (0.52 mol) 3-bromopyridine and 120 g (0.70 mol) 3-bromo-toluene as described for the preparation of 3-(3-methoxyphenyl)-pyridine. (Example I7.) B.p. 87°/0.05 mmHg. Yield 61.7 g (69%).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:21]2[CH:9]3[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:11](=[O:13])[CH2:12][CH:8]3[CH2:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.CC(O[CH:28](N(C)C)[N:29]([CH3:31])[CH3:30])(C)C.O>C1(C)C=CC=CC=1>[CH3:28][N:29](/[CH:31]=[C:12]1\[CH:8]2[CH2:7][C:6]3[CH2:5][CH2:4][CH2:3][C:2]([CH3:22])([CH3:1])[C:21]=3[CH:9]2[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:11]\1=[O:13])[CH3:30]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(C)(C)OC(=O)N1C(=O)CC2CC3=C(C21)C(C)(C)CCC3
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)/C=C1/C(=O)N(C(=O)OC(C)(C)C)C2C3=C(CCCC3(C)C)CC12
Temperature: 110 °C
Yield: 64 %

Procedure:
To a solution of tert-butyl 8,8-dimethyl-2-oxo-3a,4,5,6,7,8b-hexahydro-3H-indeno[1,2-b]pyrrole-1-carboxylate (110 mg, 0.36 mmol) in toluene (2 mL) was added Bredereck reagent ((t-butoxybis(dimethylamino)methane) (0.30 mL, 1.44 mmol). The solution was heated to 110° C. for 5 h. The solution was cooled down to room temperature, and water was added. The solution was extracted with ethyl acetate, washed with brine, dried and concentrated. The residue was purified by flash chromatography eluting with cyclohexane and ethyl acetate (7/3 to 1/1) to give a white solid (83 mg, 64%). Mp 170-172° C.; LCMS (Method B) RT=1.14 min, 361 (M+H+); 1H NMR (400 MHz, CDCl3) δ 7.10 (1H, d, J=1.8 Hz), 5.27 (1H, d, J=8.1 Hz), 3.65 (1H, tt, J=8.1, 1.8 Hz), 2.99 (6H, s), 2.24 (1H, d, J=15.4 Hz), 1.75-1.97 (2H, m), 1.49-1.60 (11H, m), 1.38-1.46 (1H, m), 1.32 (1H, m), 1.19 (3H, s), 0.97 (3H, s) ppm.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[NH2:11][OH:12].C([O-])(=O)C.[Na+]>C(O)C>[Br:1][C:2]1[C:7]([CH:8]=[N:11][OH:12])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cccnc1Br
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=Cc1cccnc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
To a solution of 2-bromopyridine-3-carbaldehyde (2.04 g) in ethanol (25 mL) is added hydroxylamine hydrochloride (948 mg, 13.16 mmol) and sodium ethanoate (1.09 g, 13.16 mmol). The mixture is stirred at room temperature overnight. The solvent is evaporated under reduced pressure and the residue partitioned between dichloromethane and water. The organic layer is separated, dried over sodium sulfate, filtered and solvent evaporated in vacuo to give 2 g of 2-bromopyridine-3-carbaldehyde oxime. MS (m/z): 201/203 (M+1/M+3)
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[N:19]=[CH:18][C:17]([CH2:20][N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:16][CH:15]=1.[Li+].CC([N-]C(C)C)C.[B:42](OC(C)C)([O:47]C(C)C)[O:43]C(C)C>C1COCC1>[C:30]([O:29][C:27]([N:24]1[CH2:23][CH2:22][N:21]([CH2:20][C:17]2[CH:16]=[C:15]([B:42]([OH:47])[OH:43])[C:14]([F:13])=[N:19][CH:18]=2)[CH2:26][CH2:25]1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(F)nc2)CC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cnc(F)c(B(O)O)c2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 36.1 mL, 90 mmol) was added to a stirred solution of diisopropylamine (12.8 mL, 90 mmol) in tetrahydrofuran (150 mL, 75 mmol) at −40° C. and the slightly yellow solution was stirred at the same temperature for 1 h, and then cooled to −78° C. A solution of tert-butyl 4-((6-fluoropyridin-3-yl)methyl)piperazine-1-carboxylate (22.22 g, 75 mmol) in THF (100 mL) was cannulated slowly into the LDA solution over 30 min. The brown mixture was stirred at the same temperature for 1.5 h and then a solution of triisopropyl borate (25.9 mL, 113 mmol) in THF (50 mL) was added slowly. The resulting mixture was stirred at the same temperature for 30 min and then the cooling bath was removed. After the reaction mixture had warmed up to room temperature, the yellow heterogeneous mixture was quenched with 1.0 M NaOH(aq) (50 mL) and stirred for an additional 30 min. The separated aqueous layer was carefully acidified with 5 N aqueous HCl until acidic (pH 4 to about 5) and the resulting cloudy mixture was diluted with EtOAc (150 mL). The separated aqueous layer was extracted with EtOAc (2×150 mL) and the combined organic phases were dried (Na2SO4), filtered, and concentrated to give 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-2-fluoropyridin-3-ylboronic acid (21.93 g, 64.7 mmol, 86% yield) as a pale yellow solid. LCMS (API-ES) m/z 340 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-:18][CH2:19][CH3:20].[Na+].C(Cl)(=O)C.Cl>O1CCCC1>[C:19]([C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:18])[CH3:20]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: C1CCOC1
Product: CCOC(=O)C(C(C)=O)(C(=O)OCC)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of diethyl 2-phenylmalonate (100 mmol) in anhydrous tetrahydrofuran (300 mL) is added sodium ethoxide (110 mmol). The mixture is stirred at room temperature for 30 min, followed by the addition of a solution of acetyl chloride (110 mmol) in tetrahydrofuran (50 mL). After the addition is complete, the mixture is heated to reflux for 3 hours, cooled to room temperature, neutralized with 2 N HCl, then concentrated in vacuo. The residue is partitioned between H20 and CHCl3, the organic extracts washed with sodium bicarbonate, water, and brine, dried (MgS04), filtered and concentrated.