Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:24]([NH:26][C:27]([C:29]2[N:30]=[C:31](Cl)[O:32][CH:33]=2)=[O:28])[CH3:25])[CH:15]=[C:16]([F:23])[C:17]=1[NH:18][S:19]([CH3:22])(=[O:21])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:23][C:16]1[CH:15]=[C:14]([CH:24]([NH:26][C:27]([C:29]2[N:30]=[C:31]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[O:32][CH:33]=2)=[O:28])[CH3:25])[CH:13]=[C:12]([F:11])[C:17]=1[NH:18][S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: OB(O)c1cccc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1coc(-c2cccc(Cl)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 33.7 %

Procedure:
3-Chlorophenylboronic acid (40.7 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (20 mg, 34%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1). 1H NMR (300 MHz, CDCl3): δ8.31 (s, 1H), 8.05 (s, 1H), 7.93 (d, 1H, J=7.2 Hz), 7.45 (m, 2H), 7.29 (bs, 1H), 7.01 (d, 2H, J=8.7 Hz), 6.67 (s, 1H), 5.22 (m, 1H), 3.18 (s, 3H), 1.60 (d, 3H, J=6.9 Hz)
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28](O)=[O:29])[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1.Cl.[NH:32]1[CH2:36][CH2:35][CH:34]([C:37]#[N:38])[CH2:33]1>>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([N:32]4[CH2:36][CH2:35][CH:34]([C:37]#[N:38])[CH2:33]4)=[O:29])[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)O)c4)c3cn2)c1Cl
Reactant: N#CC1CCNC1
Agent: Cl
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)N5CCC(C#N)C5)c4)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 36, Step 2, starting from {4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetic acid and pyrrolidine-3-carbonitrile hydrochloride. LCMS (M+H)+=526.2/528.1.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH:4]=C1C=CC=CC1[PH+](C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[O:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[O:36][C:37]1[CH:50]=[CH:49][CH:48]=[CH:47][C:38]=1[C:39]([C:41]1[O:46][CH2:45][CH2:44][O:43][N:42]=1)=O>O1CCCC1>[O:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[O:36][C:37]1[CH:50]=[CH:49][CH:48]=[CH:47][C:38]=1[C:39]([C:41]1[O:46][CH2:45][CH2:44][O:43][N:42]=1)=[CH:2][O:3][CH3:4]
Reactant: COC=C1C=CC=CC1[PH+](c1ccccc1)c1ccccc1
Reactant: O=C(C1=NOCCO1)c1ccccc1OC1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=C(C1=NOCCO1)c1ccccc1OC1CCCCO1
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 63 %

Procedure:
A mixture of 31.2 g (0.091 mol) of methoxymethylene-triphenyl-phosphonium chloride and 10.2 g (0.091 mol) of potassium tert-butoxide in 100 ml of tetrahydrofuran is stirred for 20 minutes at 20° C. A solution of 13.3 g (0.0457 mol) of 3-[2-(tetrahydropyran-2-yloxy)-benzoyl]-5,6-dihydro-1,4,2-dioxazine in 100 ml of tetrahydrofuran is then added, and the mixture is refluxed at the boil for 12 hours. The mixture is concentrated under reduced pressure and the residue is partitioned between water and ethyl acetate. The organic phase is separated off and dried over sodium sulphate. The residue is chromatographed on silica gel using cyclohexane/ethyl acetate (1:1). 9.2 g (63% of theory) of 3-{1-[2-(tetrahydropyran-2-yloxy)-phenyl]-2-methoxyethen-1-yl}-5,6-dihydro-1,4,2-dioxazine are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:8]=2)[O:3]1.OS(O)(=O)=O.[N+:25]([O-])([OH:27])=[O:26]>>[N+:25]([C:5]1[CH:6]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:8]=[C:9]2[C:4]=1[O:3][C:2]([CH3:19])([CH3:1])[CH2:11][C:10]2([CH3:12])[CH3:13])([O-:27])=[O:26]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc([N+](=O)[O-])c2c(c1)C(C)(C)CC(C)(C)O2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Ethyl 2,2,4,4-tetramethyl-6-chromanoate (150 mg, 0.57 mmol) was slowly added to 0.3 ml of conc. H2SO4 at 0° C. To this mixture was added very slowly 0.03 ml of HNO3. The reaction mixture was stirred at 0° C. for 30 min and poured into ice-water. The product was extracted into 5 ml of ethyl acetate, washed with NaHCO3 (sat.), brine and dried over MgSO4. After concentration, the product was purified by column chromatography (ethyl acetate/hexane 1/10) to yield 74 mg of light-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][C@H:18]([CH2:22][CH2:23][CH2:24][N:25]3[C:33](=[O:34])[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]3=[O:35])[C:19]([OH:21])=O)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CN1CCOCC1.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:65]([O:84][NH2:85])([C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)([C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>ClCCl>[C:65]([O:84][NH:85][C:19](=[O:21])[C@H:18]([NH:17][S:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)(=[O:15])=[O:16])[CH2:22][CH2:23][CH2:24][N:25]1[C:26](=[O:35])[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]1=[O:34])([C:72]1[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=1)([C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: O=C(O)[C@@H](CCCN1C(=O)c2ccccc2C1=O)NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: NOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(NOC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](CCCN1C(=O)c2ccccc2C1=O)NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A solution of the title compound of Example 1, (2R)-(4′-chlorobiphenyl-4-sulfonylamino)-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid (304 mg, 0.593 mmol) and NMM (0.330 mL, 3.00 mmol) in 10 mL of dichloromethane is treated with 1-hydroxy-7-azabenzotriazole (89 mg, 0.654 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (170 mg, 0.886 mmol) at RT. After stirring for 30 min, O-tritylhydroxylamine (489 mg, 1.776 mmol) is added, and the reaction is stirred for 16 h. The mixture is partitioned between 60 mL of dichloromethane and 40 mL of water. The organic solution is washed with 30 mL of 1M aqueous NaHCO3, dried over anhydrous Na2SO4 and concentrated. Chomatography on silica gel (eluant; 4/6—ethyl acetate/hexane) affords 293 mg (64%) of (2R)-(4′-chlorobiphenyl-4-sulfonylamino)-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid O-tritylhydroxyamide as a waxy solid: NMR(CDCl3) 0.62-0.76 (br m, 1H), 1.08-1.24 (br m, 1H), 1.46-1.65 (br m, 1H), 1.72-1.87 (br m, 1H), 3.65-3.73 (m, 2H), 3.94 (t, 1H, J=8.7), 5.31 (d, 1H, J=9.2), 7.20-7.27 (m, 15H), 7.48 (d, 4H, J=8.4), 7.59 (d, 2H, J=8.5), 7.70 (d, 4H, J=8.3), 7.91 (d, 2H, J=8.3), 8.27 (s, 1H); IR 1770, 1710, 1349, 1166; ESI-MS 770 (M++1).
Reaction SMILES: C(OC([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:44])[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[C:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:31]=3)[CH2:25][CH2:24]2)[CH:18]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.[ClH:45]>CO>[ClH:45].[C:38]1([C:37]#[C:36][C:32]2[CH:31]=[C:30]([CH:35]=[CH:34][CH:33]=2)[C:29]([N:26]2[CH2:25][CH2:24][CH:23]([C:19]3[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=3)[CH2:16][NH2:8])[CH2:28][CH2:27]2)=[O:44])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(C2CCN(C(=O)c3cccc(C#Cc4ccccc4)c3)CC2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: NCc1cccc(C2CCN(C(=O)c3cccc(C#Cc4ccccc4)c3)CC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of N,N-Bis-(tert-butoxycarbonyl)-3-[1-(3-phenylethynyl-benzoyl)-piperidin-4-yl]-benzylamine (100 mg, 0.17 mmol) in methanol (10 ml), cooled to 0° C., was saturated with hydrogen chloride gas. The mixture was stirred at ambient temperature for 4 hours then concentrated to dryness under vacuum. The residue was triturated with a mixture of dichloromethane and diethyl ether to give 3-[1-(3-phenylethynyl-benzoyl)-piperidin-4-yl]-benzylamine hydrochloride as a white amorphous solid (46 mg). 1H NMR [(CD3)2SO, 500 MHz]: δ 7.61-7.30 (m, 13H), 4.62 (br m, 1H), 4.00 (s, 2H), 3.62 (br m, 1H), 3.25 (br m, 1H), 2.85 (br m, 2H), 1.88 (br m, 1H), 1.70 (br m, 3H). MS(EI): 395(M++H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[NH2:16][C:17]([NH2:19])=[S:18]>>[CH3:1][O:2][C:3]([C:4]1[N:16]=[C:17]([NH2:19])[S:18][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:15]
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Reactant: NC(N)=S
Product: COC(=O)c1nc(N)sc1-c1ccc(F)cc1

Procedure:
prepared by reaction of 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methyl ester with thiourea. LC-MS: tR=0.75 min; [M+H]+=253.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20](=[O:21])[CH2:19][CH:18]([C:22]([OH:24])=O)[CH2:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:25][NH2:26]>>[CH3:25][NH:26][C:22]([CH:18]1[CH2:19][C:20](=[O:21])[N:16]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[CH:11][CH:12]=2)[CH2:17]1)=[O:24]
Reactant: O=C(O)C1CC(=O)N(c2ccc(CCc3cccc(F)c3)cc2)C1
Reactant: CN
Product: CNC(=O)C1CC(=O)N(c2ccc(CCc3cccc(F)c3)cc2)C1

Procedure:
In an analogous manner to that described in Example 36d), the esterification of (RS)-1-{4-[2-(3-fluoro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid and reaction of the intermediate acid chloride with methylamine yields the (RS)-1-{4-[2-(3-fluoro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid methylamide as a light yellow solid; MS: m/e=341 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:18])/[C:4](/[CH2:15][CH2:16][CH3:17])=[CH:5]/[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7].[OH-].[Li+]>C1COCC1.O>[C:9]1([S:6](/[CH:5]=[C:4](\[CH2:15][CH2:16][CH3:17])/[C:3]([OH:18])=[O:2])(=[O:8])=[O:7])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCC/C(=C\S(=O)(=O)c1ccccc1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC/C(=C\S(=O)(=O)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
(E)-3-benzenesulfonyl-2-propylacrylic acid methyl ester (5.0 g, 16.84 mmol) was dissolved in THF/water 3:1 (20 ml). Lithium hydroxide (0.86 g, 20.49 mmol) was added and the solution was stirred at room temperature overnight. The solvent was evaporated and the mixture was partitioned between ethyl acetate (50 ml) and water (40 ml). The aqueous layer was acidifed with 2M H2SO4 (6 ml) and the product was extracted into ethyl acetate (2×30 ml). The combined organic layers were washed with 2M H2SO4 (20 ml), brine, dried over magnesium sulfate, filtered and evaporated to give the title compound in 83% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]=[C:38]=[S:39]>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:38]([NH:37][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[F:30])=[S:39])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Fc1ccccc1N=C=S
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(NC(=S)Nc2ccccc2F)c1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 2-fluorophenyl isothiocyanate according to the procedure of Example 65. MS (ESI) m/z 546.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[CH2:13]([CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:30])[C:27](O)=[O:28])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)C>[CH2:13]([CH:20]1[CH2:21][CH2:22][N:23]([C:26](=[O:30])[C:27]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[C:5]3=[O:12])=[O:28])[CH2:24][CH2:25]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Reactant: Nc1ccc2c(c1)C(=O)C(=O)N2
Solvent: CCOCC
Product: O=C1Nc2ccc(NC(=O)C(=O)N3CCC(Cc4ccccc4)CC3)cc2C1=O

Procedure:
The title compound is prepared from 5-amino-1H-indole-2,3-dion [Helv. Chim-Acta 19, 1327. (1936)] and (4-benzyl-piperidin-1-yl)-oxo-acetic-acid (Example 5b) according to the method described in Example 1c. Melting Point: 234-236° C. (diethylether)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N:13]=[C:14]=[N:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1/[CH:22]=[CH:23]/[C:24]([O:26][CH3:27])=[O:25].[F:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:31][CH:30]=1>>[F:28][C:29]1[CH:30]=[CH:31][C:32]([N:35]2[CH2:40][CH2:39][N:38]([C:14]3[N:13]([C:4]4[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH:22]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:17]4[CH:18]=[N:19][CH:20]=[CH:21][C:16]=4[N:15]=3)[CH2:37][CH2:36]2)=[CH:33][CH:34]=1
Reactant: COC(=O)/C=C/c1cnccc1N=C=Nc1cc(C(F)(F)F)ccc1OC
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: COC(=O)CC1c2cnccc2N=C(N2CCN(c3ccc(F)cc3)CC2)N1c1cc(C(F)(F)F)ccc1OC

Procedure:
Starting from 565 mg (1.50 mmol) of the carbodiimide from Example 18A and 297 mg (1.65 mmol) of 4-fluorophenylpiperazine, general procedure [C] and purification by preparative
Reaction SMILES: [ClH:1].C([O:5][C:6]1[C:15]([O:16]C(=O)C)=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:10]=[C:11]2[CH2:20][NH2:21])(=O)C>CO.Cl>[ClH:1].[NH2:21][CH2:20][C:11]1[C:12]2[C:7](=[C:6]([OH:5])[C:15]([OH:16])=[CH:14][CH:13]=2)[CH:8]=[C:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:10]=1
Reactant: CC(=O)Oc1ccc2c(CN)cc(-c3ccccc3)cc2c1OC(C)=O
Agent: Cl
Solvent: CO
Product: NCc1cc(-c2ccccc2)cc2c(O)c(O)ccc12
Yield: 75 %

Procedure:
5,6-Bis(acetoxy)-1-aminomethyl-3-phenylnaphthalene hydrochloride (130 mg, 0.34 mmol) from Step 3 was dissolved in 10 mL of methanol saturated with hydrogen chloride. The resultant solution was stirred at ambient temperature for 3 h and then concentrated in vacuo. The solid residue was dissolved in a minimal amount of ethanol. The ethanol solution was added slowly to 30 mL of dry diethyl ether and the precipitate was collected by filtration. The solid was dried at 60° C. in vacuo to give 77 mg (76% yield) of the title compound as a white solid, m.p. 205-°212° C. (dec); DCI MS M/Z: 266 (M+H)+, 283 (M+NH4)+; 1H NMR (d6 -DMSO) δ: 4.50 (d, 2H), 7.28 (d, 1H), 7.36-7.60 (m, 4H), 7.77 (s, 1H), 7.83 (d, 2H), 8.35 (s, 1H), 8.49 (br s, 3H), 9.22 (br s, 1H), 9.60 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([Br:12])[C:9]=1[CH2:10]Br)=[O:4].[CH2:13]([O:15][C:16](=[O:30])[CH2:17][NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[O:28][CH3:29])C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([Br:12])[C:9]=1[CH2:10][N:18]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[O:28][CH3:29])[CH2:17][C:16]([O:15][CH3:13])=[O:30])=[O:4]
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Reactant: COC(=O)c1scc(Br)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CN(Cc1ccc(OC)cc1OC)Cc1c(Br)csc1C(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
4-Bromo-3-bromomethyl-thiophene-2-carboxylic acid methyl ester (2.28 g, 7.31 mmol), example 31-b, was dissolved in 18 mL of dry N,N-dimethylformamide. N-(2,4-dimethoxy-benzyl)glycine ethyl ester (1.75 g, 7.31 mmol) and potassium carbonate (1.11 g, 8.04 mmol) were added and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic fraction was dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-60% ethyl acetate in hexanes to produce 3.18 g of a tan oil. MS: (+) m/z 494.1, 496.1 (M+Na+, 79Br/81Br).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:24]=[C:11]3[N:12]=[C:13]([CH3:23])[C:14]([C@H:17]([OH:22])[C:18]([O:20][CH3:21])=[O:19])=[C:15]([I:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl(O)(=O)(=O)=O>C(Cl)Cl.C(OC(C)(C)C)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:24]=[C:11]3[N:12]=[C:13]([CH3:23])[C:14]([C@H:17]([O:22][C:4]([CH3:8])([CH3:5])[CH3:3])[C:18]([O:20][CH3:21])=[O:19])=[C:15]([I:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](O)c1c(C)nc2cc(-c3cccc(Br)c3)nn2c1I
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Solvent: CC(=O)OC(C)(C)C
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Br)c3)nn2c1I
Reaction time: 3 h
Yield: 143.9 %

Procedure:
To a stirred solution of (S)-methyl 2-(2-(3-bromophenyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (1 g, 1.992 mmol) in CH2Cl2 (30 mL) and t-butyl acetate (21.00 mL) at rt was added 70% perchloric acid (0.513 mL, 5.97 mmol). After 3 h, the reaction mixture was diluted with CH2Cl2 (100 mL), carefully quenched with sat. NaHCO3 (50 mL), organic layer separated and washed with brine (100 mL), dried (Na2SO4), filtered and concentrated to give yellow liquid. This was purified by flash column chromatograpgy on silica gel column using (10-50% EtOAc/Hex as eluant) to afford (S)-methyl 2-(2-(3-bromophenyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (800 mg, 1.433 mmol, 72.0% yield) as yellow solid. 1H NMR (500 MHz, CDCl3) δ: 8.20 (s, 1H), 7.95 (d, J=7.7 Hz, 1H), 7.56 (d, J=7.9 Hz, 1H), 7.37 (t, J=7.9 Hz, 1H), 7.08 (s, 1H), 5.59 (s, 1H), 3.76 (s, 3H), 2.70 (s, 3H), 1.32 (s, 9H). LCMS (M+H)=560.15.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:18][C:19]3[N:24]=[C:23]([CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH2:33][C:34]([O-:36])=O)[C:22]([C:37]([F:40])([F:39])[F:38])=[CH:21][N:20]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].C[N:43](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)([O-])[O-].[NH4+].[NH4+].CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>CN(C=O)C.O>[NH2:43][C:34](=[O:36])[CH2:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][CH2:25][C:23]1[C:22]([C:37]([F:39])([F:38])[F:40])=[CH:21][N:20]=[C:19]([NH:18][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:17][CH2:16]3)[N:24]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)[O-])n3)ccc2C1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2cc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)ccc2C1
Reaction time: 0.05 h
Yield: 67.1 %

Procedure:
Lithium 2-(2-(2-(2-((2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I81) (205 mg, 0.37 mmol) was dissolved in DMF (3 mL) and HATU (154 mg, 0.41 mmol) was added. After stirring for 3 minutes, ammonium carbonate (212 mg, 2.20 mmol) and DIPEA (0.26 mL, 1.5 mmol) were added and the mixture was stirred at room temperature for 18 hours. The resulting mixture was added to water (50 mL) and saturated sodium bicarbonate (10 mL) then extracted with ethyl acetate (3×50 mL). The organic extracts were washed with brine (2×50 mL), dried (sodium sulphate) and evaporated to dryness. The residue was chromatographed (12 g silica cartridge, 0-100% ethyl acetate/petroleum benzine 40-60° C.) and the product triturated with diethyl ether to give the title compound (I82) (138 mg, 67%) as an off-white foam; 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 7.57 (s, 1H), 7.43 (d, J=8.9 Hz, 2H), 7.29-7.26 (m, overlaps with CHCl3), 7.10 (d, J=8.4 Hz, 1H), 5.36 (d, J=14.4 Hz, 2H), 4.55 (s, 2H), 3.73 (s, 2H), 3.65 (s, 2H), 3.15-3.04 (m, 4H), 2.85 (t, J=5.8 Hz, 2H), 1.50 (s, 9H). LCMS Method C: rt 6.36 min; m/z 556.1 [M+H]+, 500.0 [M-tBu+2H]+, 456.1 [M-Boc+2H]+; m/z 554.2 [M−H]−.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19](=[O:20])[C:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)=[C:17]([CH2:36][CH2:37][CH3:38])[N:16]3[N:39]=[CH:40][N:41]=[C:15]23)[CH2:10][CH2:9]1)[C:2]1C=CC=CC=1.O1CCCC1>[C].[Pd].C(O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:19](=[O:20])[C:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)=[C:17]([CH2:36][CH2:37][CH3:38])[N:16]3[N:39]=[CH:40][N:41]=[C:15]23)[CH2:12][CH2:13]1)[CH3:2]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCN(Cc3ccccc3)CC2)c2ncnn12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCN(CC)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4′-{[4-(1-benzylpiperidin-4-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (4.82 g), 10% palladium-carbon (2.39 g), tetrahydrofuran (30 mL) and ethanol (60 mL) was stirred at room temperature for 2 days under a hydrogen atmosphere. The reaction mixture was filtered, and the solvent was evaporated. The residue was purified by basic silica gel chromatography [eluent: methanol/ethyl acetate=0/100→5/95 (volume ratio)] to give the title compound as a colorless amorphous compound (146 mg, 3%).
Reaction SMILES: C(C1OC2C=CC=CC=2C=1C(=O)C1C=CN=CC=1)CCC.C(NN)CCC.[CH2:28]([N:32]1[C:36]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)=[C:35]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[OH:49])[C:34]([CH2:50][CH2:51]CC)=[N:33]1)CCC>>[CH3:28][N:32]1[C:36]([C:37]2[CH:38]=[CH:39][N:40]=[CH:41][CH:42]=2)=[C:35]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[OH:49])[C:34]([CH2:50][CH3:51])=[N:33]1
Reactant: CCCCc1nn(CCCC)c(-c2ccncc2)c1-c1ccccc1O
Agent: CCCCNN
Agent: CCCCc1oc2ccccc2c1C(=O)c1ccncc1
Product: CCc1nn(C)c(-c2ccncc2)c1-c1ccccc1O

Procedure:
From 2-n-butyl-3-isonicotinoyl-benzofuran M.P. 52° C. and n-butylhydrazine, 2,5-di-n-butyl-3-(4-pyridyl)-4-(2-hydroxyphenyl)-pyrazole M.P. 121° C.