Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]2)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:33][CH:32]([N:34]5[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]5)[CH2:31]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: OC1CCN(C2CNC2)CC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCC(O)CC4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 53.8 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.167 g, 0.43 mmol), 1-azetidin-3-ylpiperidin-4-ol (0.1 g, 0.64 mmol) and 4 Å molecular sieves (0.8 g) in DCE (8 mL) was stirred for 6 h at room temperature. Sodium triacetoxyborohydride (0.272 g, 1.28 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 5:95) to give 486 as a yellow solid (0.123 g, 55%). LCMS (Method I): RT=2.31 min, [M+H]+ 532.3. 1H NMR (400 MHz, DMSO-d6): δ 8.03-7.99 (m, 1 H); 7.65-7.61 (m, 1 H); 7.27-7.20 (m, 2 H); 4.54 (d, J=4.0 Hz, 1 H); 4.29-4.22 (m, 4 H); 3.86 (s, 2 H); 3.82-3.73 (m, 7 H); 3.42 (t, J=6.5 Hz, 2 H); 3.30-3.27 (m, 3 H); 3.27 (q, J=7.4 Hz, 2 H); 2.96 (t, J=6.5 Hz, 2 H); 2.89-2.86 (m, 1 H); 1.88-1.85 (m, 2 H); 1.71-1.68 (m, 2 H); 1.39-1.35 (m, 2 H); 1.33 (t, J=7.4 Hz, 3 H)
Reaction SMILES: [C:1]1([CH:7]([CH:13]([N:15]([CH3:17])[CH3:16])[CH3:14])[C:8](OCC)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[C:29]([Cl:31])=[O:30]>>[ClH:31].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[C:29]([O:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:13]([N:15]([CH3:17])[CH3:16])[CH3:14])=[O:30]
Reactant: CCOC(=O)C(c1ccccc1)C(C)N(C)C
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1cc(C(=O)OCC(c2ccccc2)C(C)N(C)C)cc(OC)c1OC
Product: Cl

Procedure:
The title compound is prepared from ethyl 2-phenyl-3-dimethylaminobutyrate and lithium aluminum hydride according to the procedure of Example 2 followed by reaction with 3,4,5-trimethoxybenzoyl chloride according to the procedure of Example 3. Fractional crystallization from isopropanol gives the β-isomer as the main product. It melts at 165°-166° C.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[K+].CN(C=O)C.[CH3:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][Cl:34])=[CH:31][CH:30]=1>O>[ClH:34].[ClH:34].[CH3:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]4)[CH2:2][CH2:3]2)=[CH:31][CH:30]=1
Reactant: Cc1ccc(CCl)cc1
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(CN2CCN(c3ccc4c(c3)CCC(=O)N4)CC2)cc1
Product: Cl
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 18.1 %

Procedure:
To a mixture of 1.2 g of 6-(1-piperazinyl)-3,4-dihydrocarbostyril, 1.17 g of potassium bicarbonate and 20 ml of DMF was added 646 mg of 4-methylbenzyl chloride and the mixture was stirred at 80° C. for 2.5 hours. The reaction mixture was poured into a large amount of water and extracted with chloroform. After washing with water the extract was dried over anhydrous sodium sulfate. Chloroform was distilled off and the residue was purified through silica gel column chromatography. After conversion to hydrochloric acid salt with methanol-hydrochloric acid, the product was recrystallized from methanol-water to give 0.17 g of 6-[4-(4-methylbenzyl)-1-piperazinyl]-3,4-dihydrocarbostyril dihydrochloride, m.p. 272°-273° C. (decomp.), colorless powders.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:9]=[C:8]([Cl:21])[CH:7]=1)[CH3:2].Br[C:24]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:25]=1[CH:26]=[O:27]>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[C:10]([C:24]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:25]=2[CH:26]=[O:27])[CH:9]=[C:8]([Cl:21])[CH:7]=1)[CH3:2]
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Reactant: CCOC(=O)Cc1cc(Cl)cc(B2OC(C)(C)C(C)(C)O2)c1
Product: CCOC(=O)Cc1cc(Cl)cc(-c2ccc(C(F)(F)F)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: [3-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester and 2-bromo-5-(trifluoromethyl)benzaldehyde.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:8]=[CH:7][NH:6][C:5]=1[C:9]([O:11][CH3:12])=[O:10].C1(P(O[NH2:28])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C=O)C>[NH2:28][N:6]1[CH:7]=[CH:8][C:4]([Cl:3])=[C:5]1[C:9]([O:11][CH3:12])=[O:10]
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1[nH]ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)ccn1N
Reaction time: 0.42 h
Yield: 91.5 %

Procedure:
To a suspension of sodium hydride (60 percent, 1.5 g, 37.5 mmol) in DMF (250 mL) was added methyl 3-chloro-1H-pyrrole-2-carboxylate (5.0 g, 31.3 mmol) at 0° C., and the mixture was stirred for 25 min, followed by the addition of O-(diphenylphosphoryl)hydroxylamine (10.0 g, 43.75 mmol). The reaction mixture was stirred at RT for 4 h and quenched by aq. Na2SO3 solution. After stirred for another 5 min, the mixture was extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give crude product as a brown oil, which was purified by chromatography purification on silica gel (PE:EA=4:1) to obtain the title compound (5.00 g, 91%) as a white solid. MS (ES+) C6H7ClN2O2 requires: 174, 176. found: 175, 177 [M+H]+.
Reaction SMILES: C(OC1C=CC=CC=1C[N:12]([C@H:16]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C@@H:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)[CH:18]=[CH2:19])[C:13](=[O:15])[CH3:14])(=O)C.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:26][C:22]1[CH:21]=[C:20]([C@@H:17]([CH:18]=[CH2:19])[C@H:16]([NH:12][C:13](=[O:15])[CH3:14])[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: C=C[C@H](c1cccc(Cl)c1)[C@@H](c1ccc(Cl)cc1)N(Cc1ccccc1OC(C)=O)C(C)=O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=C[C@H](c1cccc(Cl)c1)[C@H](NC(C)=O)c1ccc(Cl)cc1

Procedure:
A solution of 1.05 g (2.18 mmol) of 2-((N-((1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-enyl)acetamido)methyl)phenyl acetate (Example 115, Step C) and toluenesulfonic acid monohydrate (1.66 g, 8.71 mmol) in toluene (15.0 mL) was heated to reflux for about 2 h. 120 ml of ethyl acetate was added, and the combined organics were washed consecutively with NaHCO3 solution and sat. NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The crude mixture was purified by preparative HPLC to give the title compound.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:18]#[N:19])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([OH:17])[CH:10]=2)=[O:5])C.[NH2:20][CH2:21][C:22]([OH:24])=[O:23].Cl.O>C[O-].[Na+].CO>[C:18]([C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([OH:17])[CH:10]=2)[C:15]([OH:16])=[C:6]([C:4]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:5])[N:7]=1)#[N:19]
Reactant: CCOC(=O)c1nc(C#N)c2cc(O)ccc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2ccc(O)cc12
Yield: 86 %

Procedure:
[(1-Cyano-4,7-dihydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid was prepared by heating a mixture of 42 mg (0.162 mmol) of 1-Cyano-4,7 dihydroxy-isoquinoline-3-carboxylic acid ethyl ester and 97 mg (1.29 mmol) of glycine in 2.25 mL of 0.5 N NaOMe in methanol at reflux temperature for 26 hours. The reaction mixture was cooled and acidified with 3 mL of 1 N HCl and water. A white solid was collected on a medium glass fritted filter to provide 40 mg of the title compound; MS (ESI+): 288.2 e/z (M+1)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:32])/[CH:10]=[CH:11]/[C:12]1[CH:16]=[CH:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[C:27][Si](C)(C)C)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:13]=1.[F-].[K+]>CO>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([S:17]([N:14]2[CH:15]=[CH:16][C:12](/[CH:11]=[CH:10]/[C:9]([NH:8][O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[O:32])=[CH:13]2)(=[O:19])=[O:18])=[CH:21][CH:22]=1)#[CH:27]
Reactant: C[Si](C)(C)C#Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NOC3CCCCO3)c2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NOC3CCCCO3)c2)cc1

Procedure:
To a stirred solution of (E-N-(Tetrahydro-pyran-2-yloxy)-3-[1-(4-trimethylsilanylethynyl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide (0.139 mmol) in methanol (1.2 ml) is added KF (0.26 mmol). After 15 min the solvent is evaporated and the residue is taken up in DCM and filtered over alumina (1 g, neutral, activity II-III) using DCM as eluent. After evaporation of the solvent 0.0801 mmol of the title compound are obtained.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:21][C:20](=[O:22])[CH:19]=[C:18]([OH:23])[CH2:17]2)=[CH:12][CH:11]=1)(C)(C)C.[C:34]([C:38]1[CH:43]=[C:42]([O:44][Si](C(C)(C)C)(C)C)[C:41]([CH3:52])=[CH:40][C:39]=1[S:53]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:37])([CH3:36])[CH3:35].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:34]([C:38]1[CH:43]=[C:42]([OH:44])[C:41]([CH3:52])=[CH:40][C:39]=1[S:53][C:19]1[C:20](=[O:22])[O:21][C:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][OH:6])=[CH:15][CH:14]=2)([CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][C:18]=1[OH:23])([CH3:37])([CH3:36])[CH3:35]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(O[Si](C)(C)C(C)(C)C)cc2C(C)(C)C)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(C2(CCc3ccccc3)CC(O)=CC(=O)O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccccc3)(c3ccc(OCCO)cc3)OC2=O)c(C(C)(C)C)cc1O
Reaction time: 0.33 h

Procedure:
The title compound was prepared as described in General Method 9 using 6-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenyl }-4-hydroxy-6-phenethyl-5,6-dihydro-pyran-2-one (prepared in Example SS; 0.200 g, 0.43 mmol), toluene-4-thiosulfonic acid S-[2-tert-butyl-4-(tert-butyl-dimethyl-silanyloxy)-5-methyl-phenyl] ester prepared in Example JJJ (0.26 g, 0.56 mmol), K2CO3 (0.24 g, 1.7 mmol), and DMF (2.0 mL). After consumption of starting material, the mixture was diluted with MeOH and treated with 10 drops of concentrated HCl. The mixture was stirred for 20 minutes and then diluted with 15 mL of H2O and extracted with CH2Cl2. The organic layers were combined, dried (Na2SO4) and concentrated. The product was purified by column chromatography (CH2Cl2 to 4% MeOH in CH2Cl2) to provide a solid, m.p. 168°-170° C. (dec.). 1H NMR (DMSO-d6) δ 1.41 (s, 9 H), 1.63 (s, 3 H), 2.29-2.16 (m, 4 H), 3.32 (d, 1 H, partially obscured by H2O), 3.38 (d, 1 H, partially obscured by H2O), 3.98 (t, 2 H), 3.72 (br d, 2 H), 4.88 (br s, 1 H), 6.07 (s, 1 H), 6.71 (s, 1 H), 6.83 (d, 2 H), 7.09 (d, 2 H), 7.17-7.13 (m, 1 H), 7.26-7.22 (m, 2 H), 7.31 (d, 2 H), 8.91 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[O:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[N:11]([C:25](=[O:26])[C:24]3[C:23]([F:22])=[CH:31][CH:30]=[CH:29][C:28]=3[F:32])[C:10](=[O:14])[O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: O=c1[nH]c(=O)n(-c2cccc(Cl)c2)o1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1c(F)cccc1F)n1c(=O)on(-c2cccc(Cl)c2)c1=O
Reaction time: 24 h

Procedure:
2-(3-Chlorophenyl)-1,2,4-oxadiazolidin-3,5-dione (0.03 mole), toluene (100 ml) and triethylamine (5 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,6-Difluorobenzoyl chloride (0.03 mole) dissolved in toluene (20 ml) is then added to the reaction flask and the resulting mixture is heated at reflux with stirring for a period of about 24 hours. After this time the reaction mixture is filtered and the filtrate is washed with water, dilute hydrochloric acid and with aqueous sodium bicarbonate. The washed solution is then dried over anhydrous magnesium sulfate. The dried solution is stripped of solvent under reduced pressure leaving a solid residue. The residue is recrystallized to yield the desired product 2-(3-chlorophenyl)-4-(2,6-difluorobenzoyl)-1,2,4-oxadiazolidin-3,5-dione.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:15]2[C@H:24]3[C@H:19]([CH2:20][CH2:21][CH2:22][CH2:23]3)[C:18](=[O:25])[N:17]([CH2:26][C:27]3[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=3)[N:16]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].[CH3:36]O>>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:15]2[C@H:24]3[C@H:19]([CH2:20][CH2:21][CH2:22][CH2:23]3)[C:18](=[O:25])[N:17]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([C:31]([O:33][CH3:36])=[O:32])=[CH:34][CH:35]=3)[N:16]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: COc1ccc(C2=NN(Cc3ccc(C(=O)O)cc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(CN2N=C(c3ccc(OC)c(OC)c3)[C@@H]3CCCC[C@@H]3C2=O)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3 ml of thionyl chloride was added slowly to a solution of 1 g of compound 83 in methanol at -20° C. After complete addition, the mixture was stirred for 6 hours at room temperature and subsequently evaporated. The compound was crystallized from diethyl ether at -20° C. M.p. 90°-92° C.
Reaction SMILES: C([NH:8][CH:9]1[CH2:12][CH:11]([CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]1[F:22])C1C=CC=CC=1.CCN(CC)CC.[N+](C1C=CC([N:39]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:40](=[O:42])[O-])=CC=1)([O-])=O>C(Cl)Cl>[CH2:43]([NH:39][C:40]([NH:8][CH:9]1[CH2:12][CH:11]([CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]1[F:22])=[O:42])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: FC1C(COCc2ccccc2)CC1NCc1ccccc1
Reactant: O=C([O-])N(Cc1ccccc1)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1)NC1CC(COCc2ccccc2)C1F
Reaction time: 0.08 h
Yield: 92.5 %

Procedure:
In a 25 mL flask with benzyl-(3-benzyloxymethyl-2-fluoro-cyclobutyl)-amine (25.8 mg, 0.12 mmol) inside, dry CH2Cl2 2 mL was added under argon at room temperature to give a colorless solution, followed by the addition of Et3N (0.02 mL, 0.14 mmol). After stirring for 5 min, 4-nitrophenyl-N-benzylcarbamate (32.1 mg, 0.12 mmol) was added to give a yellow solution. This was left stirring at room temperature for 10 hr and the reaction was quenched by adding 10 mL CH2Cl2. The organic phase was washed with 1 M NaOH 10 mL, H2O 10 mL and brine 10 mL and was dried over MgSO4. Solvent evaporation gave the crude product 42 mg that is pure enough and crystallization gave the pure product 38 mg (90%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 1.96-2.01 (m, 2H), 2.65-2.80 (m, 1H), 3.48-3.58 (m, 2H), 4.31-4.36 (m, 3H), 4.52 (s, 2H), 4.82-4.99 (td, 1H, J=54.8, 5.2), 7.19-7.39 (m, 10H). 13C NMR (CDCl3, 100 MHz): δ 27.11-27.19 (d, J=7.6), 41.75-41.96 (d, J=21), 47.92, 48.44-48.51 (d, J=7.0), 71.12-71.16 (d, J=4.0), 74.26, 90.34-92.48 (d, J=214), 128.14, 128.30, 128.84, 128.96, 129.56, 129.62, 139.81, 141.35, 160.85. MS (FAB): expected for C20H23FN2O2 (M+H)+ 343.41. Found 343.18178. IR (neat) νmax 2923, 2851, 1558, 1458, 1378, 1265, 895, 740, 704. The absolute stereochemistry was established by X-ray crystallographic analyses.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15](=[O:17])[CH3:16].[CH3:18][Mg]Br.[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH3:18])([CH3:16])[OH:17]
Reactant: CC(=O)c1cc(-c2cccc(Cl)c2)ccc1N
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(-c2cccc(Cl)c2)ccc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanone (.55 g, 2.2 mmol) in anhydrous THF under nitrogen was added a solution of methyl magnesium bromide (3.0 M in diethyl ether, 1 mL, 3 mmol) at 0° C. The mixture was slowly warmed to room temperature and kept stirring under nitrogen for 18 hours. The mixture was treated with 10 mL of saturated ammonium chloride aqueous solution and ethyl acetate (50 mL) was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine (20 mL) and dried (MgSO4). After removal of the solvent, the residue was purified by a flash chromatography (silica gel, hexane:ethyl acetate/2:1) to afford the title compound as an off-white solid: 186-188° C. (HCl salt). Anal. Calc. For C15H17Cl2NO: C, 60.42, H, 5.75, N, 4.7. Found: C, 60.51, H, 5.62, N, 4.56.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[CH:8]=1)[C:5]#[N:6].O.[NH2:16]N>C(O)C>[CH3:13][C:9]1[CH:8]=[C:7]([C:4]2[CH:5]=[N:6][NH:2][C:3]=2[NH2:16])[CH:12]=[CH:11][N:10]=1
Reactant: Cc1cc(C(C#N)=CN(C)C)ccn1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(-c2cn[nH]c2N)ccn1
Yield: 35.8 %

Procedure:
To stirred solution of 3-dimethylamino-2-(2-methyl-pyridin-4-yl)-acrylonitrile (1.8 g, 9.61 mmol) in ethanol (18 ml) was added at room temperature hydrazine monohydrate (1.03 ml, 21.1 mmol), the reaction mixture was heated under reflux conditions for 16 h and evaporated. Purification by column chromatography on silica gel (dichloromethane/methanol/NH4OH 80:10:1) and crystallization from diethyl ether yielded 4-(2-methyl-pyridin-4-yl)-2H-pyrazol-3-ylamine (0.6 g, 36%) as an orange solid. MS (ISP) 175.1 [(M+H)+]; mp 230° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:5]2[NH:6][N:7]=[N:8][C:4]=2[C:3]=1[F:12].[Cl:13][C:14]1[CH:20]=[C:19]([Cl:21])[C:17]([NH2:18])=[C:16]([N+:22]([O-:24])=[O:23])[C:15]=1[F:25].Cl[C:27]1C=C(Cl)C(F)=CC=1N>>[NH2:18][C:17]([CH3:27])([CH2:19][N:7]1[N:6]=[C:5]2[C:9]([Cl:11])=[CH:10][C:2]([Cl:1])=[C:3]([F:12])[C:4]2=[N:8]1)[C:16]#[N:22].[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:5]2[NH:6][N:7]=[N:8][C:4]=2[C:3]=1[F:12].[Cl:13][C:14]1[CH:20]=[C:19]([Cl:21])[C:17]([NH2:18])=[C:16]([N+:22]([O-:24])=[O:23])[C:15]=1[F:25]
Reactant: Nc1cc(F)c(Cl)cc1Cl
Agent: Fc1c(Cl)cc(Cl)c2[nH]nnc12
Agent: Nc1c(Cl)cc(Cl)c(F)c1[N+](=O)[O-]
Product: CC(N)(C#N)Cn1nc2c(Cl)cc(Cl)c(F)c2n1

Procedure:
2-Amino-3-(5,7-dichloro-4-fluoro-2H-benzotriazol-2-yl)-2-methylpropionitrile [1.3 g, Rf=0.2 (1:1 EA/heptane)] was prepared using a procedure similar to that described in Example 1, part a and b, except starting from 5,7-dichloro-4-fluoro-1H-benzotriazole. 5,7-Dichloro-4-fluoro-1H-benzotriazole (4 g, 85%) was prepared using a procedure similar to that described in Example 11, part a, except starting from 4,6-dichloro-3-fluoro-2-nitroaniline. 4,6-Dichloro-3-fluoro-2-nitroaniline (6.1 g) was prepared using a procedure similar to that described in Example 39, part a, b and c, except starting from 2,4-dichloro-5-fluoroaniline (10 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:8]([O:10][CH3:11])=O)([CH3:4])([CH3:3])[CH3:2].[CH3:17]I.O=O>>[C:1]([C:5]1[CH:14]=[C:13]([C:15](=[O:16])[CH3:17])[CH:12]=[C:7]([CH2:8][O:10][CH3:11])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: COC(=O)c1cc(CO)cc(C(C)(C)C)c1
Agent: O=O
Product: COCc1cc(C(C)=O)cc(C(C)(C)C)c1

Procedure:
Methyl 3-tert-butyl-5-hydroxymethylbenzoate was reacted with methyl iodide analogously to O5.043, and converted to the title compound analogously to the sequence O4.008 to O2.008. 1.54 g were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[CH2:10][C:11](O)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].NN.O.O[N:27]1C2C=CC=CC=2N=[N:28]1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[CH2:10][C:11]([NH:27][NH2:28])=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)NN)Cc1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 94.6 mg (0.3 mmol) of (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoic acid (Intermediate 1) in 1.5 mL of anhydrous dichloromethane, stirred in an ice bath under protection from moisture, was added 0.0106 mL (10.8 mmol) of anhydrous 98% hydrazine. Then 91.8 mg of 1-hydroxybenzotriazole hydrate was added, followed by 63.4 mg (0.33 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and finally 0.0574 mL (42.6 mg, 0.33 mmol) of N,N-diisopropylethylamine. After 15 minutes, an additional 0.0574 mL (42.6 mg, 0.33 mmol) of N,N-diisopropylethylamine was added. After 2 h, the mixture was removed from the ice bath and allowed to warm to room temperature, and precipitation gradually increased. After 22 h, the precipitated solid was collected on a filter, washed with small volumes of dichloromethane, and dried to give the title compound as a white solid, mp 168-169° C. LC-MS 230 (M+1-Boc).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[CH3:24])/[C:17]([O:19]C(C)(C)C)=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[CH3:24])/[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: C/C(=C\c1ccc(C(=C2CCOCC2)c2ccc(O)cc2)cc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C/C(=C\c1ccc(C(=C2CCOCC2)c2ccc(O)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.8 %

Procedure:
tert-Butyl (2E)-3-{4-[(4-hydroxyphenyl)(tetrahydro-4H-pyran-4-ylidene)methyl]phenyl}-2-methylprop-2-enoate (59) (0.0702 g, 0.173 mmole) was dissolved in CH2Cl2 (1 mL) and TFA (1 mL). The solution was stirred at RT for 4 h, then was concentrated. The residue was triturated with CH2Cl2 to provide compound 60 (0.029 g, 47%) as a tan solid. 1H NMR (DMSO-d6): δ 12.49 (br s, 1H), 9.38 (s, 1H), 7.54 (s, 1H), 7.40 (d, J=8.1 Hz, 2H), 7.11 (d, J=8.1 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 6.68 (d, J=8.4 Hz, 2H), 3.60 (m, 4H), 2.25 (m, 4H), 2.01 (s, 3H). LRMS (ESI): m/z 349 (M−H)−.