Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([C:17](O)=[O:18])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl.[CH3:21][O:22][C:23](=[O:43])[C@@H:24]([NH2:42])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:21][O:22][C:23](=[O:43])[CH:24]([NH:42][C:17]([C:11]1[CH:10]=[N:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]=1[C:13]([F:16])([F:14])[F:15])=[O:18])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:40])([F:39])[F:41])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: O=C(O)c1cnn(-c2ccc(F)cc2)c1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)NC(=O)c1cnn(-c2ccc(F)cc2)c1C(F)(F)F
Yield: 47.2 %

Procedure:
A solution of 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (0.300 g, 1.097 mmol, prepared in example 635) in DMF (4.0 mL) was reacted with (2S)-amino-3-(4′-trifluoromethyl-biphenyl-4-yl)propionic acid methyl ester Hydrochloride (0.394 g, 1.097 mmol), HBTU (0.416 g, 1.097 mmol), and DIEA (0.585 mL, 3.29 mmol) as described in general procedure A. The crude compound was purified by washing with ethyl ether to give 0.300 g (47%) of 2-{[1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester. A solution of this ester (0.125 g, 0.215 mmol) in THF (4.0 mL) was treated with LiOH (0.031 g) by general procedure I to afford (0.105 g, 87%) the title compound 2-{[1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid as a white solid. LCMS: 565 (M+1)+. 1H NMR (DMSO-d6) 8.92 [d, 1H], 8.39 [s, 1H], 8.18 [d, 2H], 8.09 [d, 2H], 7.96 [d, 2H], 7.87 [m, 2H], 7.71 [m, 4H], 4.83 [m, 1H], 3.58 [m, 1H], 3.36 [m, 1H].
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>CN1C(=O)CCC1.CCOC(C)=O>[F:24][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([N:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: CN1CCNCC1
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCN(C)CC3)nn12
Temperature: 170 °C
Reaction time: 2 h

Procedure:
(rac)-6-[1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate C, 69 mg, 0.20 mmol), KF (58 mg, 1.0 mmol) and N-methyl-piperazine (60 mg, 0.60 mmol) were suspended in NMP (1.0 mL). The RM was stirred at 170° C. for 2 h. The mixture was diluted with EtOAc and washed with 1M Na2CO3 (1×) and water (2×). The aqueous was further extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography and afforded the title compound as a yellow foam (tR 2.83 min (conditions 1), MH+=409.1).
Reaction SMILES: [CH3:1][N:2]([C:18]([CH2:23][OH:24])([CH2:21][OH:22])[CH2:19][OH:20])[C:3](=[O:17])[C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+]>CO>[CH3:1][N:2]([C:18]([CH2:23][OH:24])([CH2:19][OH:20])[CH2:21][OH:22])[C:3](=[O:17])[C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(C(=O)N(C)C(CO)(CO)CO)cc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1)C(CO)(CO)CO

Procedure:
Methyl N-methyl-5-nitro-N-[tris(hydroxymethyl)methyl]isophthalamate is stirred with one equivalent of sodium hydroxide in aqueous methanol. The reaction mixture is concentrated to remove the methanol, diluted with water and acidified with mineral acid to provide crystalline N-methyl-5-nitro-N-[tris (hydroxymethyl)methyl]isophthalamic acid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=2)=[CH2:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.CS(Cl)(=O)=O.[CH3:31][C:32]1([CH3:39])[NH:36][C:35](=[O:37])[NH:34][C:33]1=[O:38].[H-].[Na+]>CCN(CC)CC>[CH3:31][C:32]1([CH3:39])[NH:36][C:35](=[O:37])[N:34]([CH2:24][C:21]2[CH:22]=[CH:23][C:18]([C:16]([C:3]3[C:2]([CH3:1])=[CH:11][C:10]4[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=4[CH:4]=3)=[CH2:17])=[CH:19][CH:20]=2)[C:33]1=[O:38]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: C=C(c1ccc(CO)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: C=C(c1ccc(CN2C(=O)NC(C)(C)C2=O)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Yield: 60 %

Procedure:
Adopting the procedure outlined for example 9 using 40.0 mg (0.12 mmol) of {4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-phenyl}-methanol, 0.05 mL of methanesulfonyl chloride, 0.10 mL of NEt3, 300 mg of 5,5-dimethylhydantoin, and 56 mg of NaH, 32.0 mg of the product was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:15][N:16]=[C:17]=[S:18]>C(O)C>[SH:18][C:17]1[N:16]([CH3:15])[C:4](=[O:5])[C:3]2[C:2](=[CH:10][C:9]([O:11][CH3:12])=[C:8]([O:13][CH3:14])[CH:7]=2)[N:1]=1
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Reactant: CN=C=S
Solvent: CCO
Product: COc1cc2nc(S)n(C)c(=O)c2cc1OC

Procedure:
A solution of 2-amino-4,5-dimethoxybenzoic acid (20.0 g) and methyl isothiocyanate (7.23 g) in ethanol was refluxed for 30 minutes. The precipitate was collected by filtration to provide the title compound as colorless needles. Yield 11.77 g (47%) 1H-NMR (CDCl3) δ: 3.67(3H,s), 3.85(3H,s), 3.89(3H,s), 6.93(1H,s), 7.31(1H,s).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:22]([NH2:24])=S)[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CI>CC(C)=O.O1CCCC1>[CH2:1]([NH:10][C:22]([NH:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([NH:10][C@H:1]1[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]1)[CH:20]=[CH:19]2)=[NH:24])[C:9]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NC(=S)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Solvent: CI
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: N=C(NCc1ccccc1)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 196.3 %

Procedure:
[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-thiourea (600 mg, 1.8 mmol) was dissolved in 20 mL acetone and 10 mL tetrahydrofurane. Methyliodide (306 mg, 2.2 mmol) was added and the reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated and the residue was recrystallized from dichloromethane and diethylether. The title compound (720 mg, 84%) was obtained as a yellow solid; MS: m/e=349.4 (M+H+).
Reaction SMILES: C(OC([O:6][CH2:7][C:8]#[C:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[O:11])C)C.Cl>O1CCCC1>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C:10](=[O:11])[C:9]#[C:8][CH2:7][OH:6])=[CH:17][CH:16]=1
Reactant: CCOC(C)OCC#CC(=O)c1ccc(F)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(C#CCO)c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
A solution of 7.3 g (29 mmol) of 4-(1-ethoxyethoxy)-1-(4-fluorophenyl)-2-butyn-1-one in 100 ml of tetrahydrofuran was treated at room temperature with 29 ml of 2N hydrochloric acid, whereupon the mixture was stirred for 30 minutes. The reaction mixture was then extracted twice with ethyl acetate. The combined organic phases were washed in succession with saturated sodium carbonate solution and with water, dried over magnesium sulphate and concentrated. Crystallization of the residue from ethyl acetate/ hexane yielded 1-(4-fluorophenyl)-4-hydroxy-2-butyn-1-one of melting point 63°.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][O:5][NH:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@:11]2([OH:28])[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C@@H:17]([CH2:18][C@@H:19]([OH:27])[CH2:20][CH2:21]1)[CH2:16][CH2:15]3.C=O.[BH3-][C:33]#N.[Na+]>C(#N)C.Cl>[CH3:33][N:6]([CH2:7][C@H:8]1[CH2:13][CH2:12][C@:11]2([OH:28])[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C@@H:17]([CH2:18][C@@H:19]([OH:27])[CH2:20][CH2:21]1)[CH2:16][CH2:15]3)[O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:29]
Reactant: CN(C)CCONC[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: CN(C)CCON(C)C[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 28 h

Procedure:
To a stirred solution of 0.41 g of 17β-(2-dimethylaminoethoxyamino)methyl-5β-androstane-3β,14β-diol (I-am) and 1.0 ml of 37% aqueous formaldehyde in 10 ml of acetonitrile 0.20 g of NaBH3CN was added. The reaction was stirred for 28 hr and then diluted with 0.1N hydrochloric acid and extracted with ethyl acetate. The aqueous layer was basified to pH 9.5 with 2.5N NaOH and extracted with ethyl acetate; the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by flash-chromatography (SiO2) using chloroform/methanol/26% aqueous ammonium hydroxide 90/9/1 as the eluant; the fractions containing the title compound were collected and evaporated to dryness under reduced pressure. The residue was dissolved with ethyl acetate and the stoichiometric amount of oxalic acid was added to give 0.33 g of the title compound (I-ap), as a white solid, oxalate.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:18]([NH:20][CH:21]3[C:30]4[C:25](=[C:26]([O:31]C)[CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23][CH2:22]3)[CH3:19])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]([NH:20][CH:21]3[C:30]4[C:25](=[C:26]([OH:31])[CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23][CH2:22]3)[CH3:19])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cccc2c1CCCC2NC(C)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(NC1CCCc2c(O)cccc21)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reaction time: 3 h
Yield: 72.1 %

Procedure:
To a solution of 1-[1-(4,5-diphenyloxazol-2-yl)ethylamino]-1,2,3,4-tetrahydro-5-methoxynaphthalene (0.33 g) in CH2Cl2 (7 ml) was added 1M BBr3 -CH2Cl2 solution (1.5 ml) at 0° C. After being stirred for 3 hours at the same temperature, the solvent was evaporated in vacuo. The residue was partitioned between ethyl acetate and sat. NaHCO3. The organic layer was washed with water and brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-[1-(4,5-diphenyloxazol-2-yl)ethylamino]-1,2,3,4-tetrahydro-5-hydroxynaphthalene (0.23 g). MS (m/z): 411 (M+ +1) NMR (CDCl3, δ): 1.57 (3H, d, J=6.8 Hz), 1.64-2.20 (4H, m), 2.44-2.86 (2H, m), 3.89 (0.5H, m), 4.12 (0.5H, q, J=6.8 Hz), 4.29 (0.5H, q, J=6.8 Hz), 4.78 (0.5H, m), 6.62-6.72 (1H, m), 6.97-7.14 (2H, m), 7.32-7.41 (6H, m), 7.58-7.68 (4H, m)
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[F:20][C:21]1([F:29])[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][NH2:28])[CH2:22]1>>[F:20][C:21]1([F:29])[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][NH:28][S:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:22]1
Reactant: NCCN1CCC(F)(F)C1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCN3CCC(F)(F)C3)s2)c(C)[nH]c1=O
Yield: 43 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 2-(3,3-difluoro-pyrrolidin-1-yl)-ethylamine as described in Step 5, Example 24 to give the title compound (43% yield). LC/MS: RT 1.32 min; m/e 432 (M+H).
Reaction SMILES: ClC1N=C(Cl)N=C(Cl)N=1.[CH2:10]([O:17][C:18]1[C:23](=[O:24])[N:22]2[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:21]2=[N:20][C:19]=1[CH:30]=[N:31]O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:10]([O:17][C:18]1[C:23](=[O:24])[N:22]2[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:21]2=[N:20][C:19]=1[C:30]#[N:31])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1ccc2nc(C=NO)c(OCc3ccccc3)c(=O)n2c1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc2nc(C#N)c(OCc3ccccc3)c(=O)n2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
Trichloro-1,3,5-triazine (576 mg, 3.15 mmol) was dissolved in anhydrous N,N-dimethylformamide (DMF) (1 mL) and stirred at room temperature for 30 min. To this solution was added dropwise a solution of the product from Example 11.1 (927 mg, 3 mmol) in DMF (5 mL). The mixture was kept at room temperature for 2 h, then ethyl acetate (50 mL) was added and the organic phase separated and washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by short flash chromatography afforded the desired compound (530 mg, 60.7%).
Reaction SMILES: C(OC[O:10][CH2:11][CH2:12][C:13]([CH3:27])([CH3:26])[CH2:14][CH2:15][S:16][C:17]1[N:22]2[CH:23]=[CH:24][N:25]=[C:21]2[CH:20]=[CH:19][CH:18]=1)C1C=CC=CC=1.Cl>CO>[OH:10][CH2:11][CH2:12][C:13]([CH3:27])([CH3:26])[CH2:14][CH2:15][S:16][C:17]1[N:22]2[CH:23]=[CH:24][N:25]=[C:21]2[CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(CCOCOCc1ccccc1)CCSc1cccc2nccn12
Agent: Cl
Solvent: CO
Product: CC(C)(CCO)CCSc1cccc2nccn12
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 0.71 g (1.85 mmol) of 5-(5-benzyloxymethyloxy-3,3-dimethylpentylthio)imidazo[1,2-a]pyridine in 10 ml of methanol, 0.33 ml (4.0 mmol) of concentrated hydrochloric acid was added, followed by stirring at 60° C. for 3 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in 10 ml of water; 3 ml of 1N aqueous sodium hydroxide was added. To this mixture, 1N hydrochloric acid was added to pH 5-6. The mixture was extracted with dichloromethane and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4→ethyl acetate) to yield 350 mg (71.6%, white crystal) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][CH:18]2[CH2:25][CH:21]3[CH2:22][NH:23][CH2:24][CH:20]3[CH2:19]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH2:14][CH2:15][OH:16])[CH:13]=2)=[N:6][CH:7]=1.[C:26]([CH2:28][C:29](O)=[O:30])#[N:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:17][CH:18]2[CH2:25][CH:21]3[CH2:22][N:23]([C:29](=[O:30])[CH2:28][C:26]#[N:27])[CH2:24][CH:20]3[CH2:19]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH2:14][CH2:15][OH:16])[CH:13]=2)=[N:6][CH:7]=1
Reactant: OCCn1cc(Nc2ncc(Cl)c(NC3CC4CNCC4C3)n2)cn1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCC(=O)N1CC2CC(Nc3nc(Nc4cnn(CCO)c4)ncc3Cl)CC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a solution of 2-(4-((5-chloro-4-((octahydrocyclopenta[c]pyrrol-5-yl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)ethanol (0.29 g, 0.80 mmol) and 2-cyanoacetic acid (87.2 mg, 1.03 mmol) in a mixture of DCM (20 mL) and DMF (5 mL) were added HATU (462.4 mg, 1.22 mmol) and Et3N (0.17 g, 1.68 mmol). After addition, the reaction mixture was stirred at rt for 1 h, then quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/20) to give the title compound as a beige solid (300.1 mg, 87%).
Reaction SMILES: S(O[CH2:12][CH2:13][CH:14]([OH:16])[CH3:15])(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[OH:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:34][CH:33]([CH2:35][O:36][CH3:37])[O:32][C:31]2=[O:38])=[CH:26][CH:25]=1>CC(CC)=O>[OH:16][CH:14]([CH3:15])[CH2:13][CH2:12][O:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:34][CH:33]([CH2:35][O:36][CH3:37])[O:32][C:31]2=[O:38])=[CH:28][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)O)cc1
Reactant: COCC1CN(c2ccc(O)cc2)C(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COCC1CN(c2ccc(OCCC(C)O)cc2)C(=O)O1
Yield: 70 %

Procedure:
To a solution of 27.5 g (0.112 mol) of 1-tosyloxy-3-butanol in 250 ml of methylethylketone, are added 28.2 g (0.2 mol) of K2CO3 and 22.8 g (0.102 mol) of 3-(4-hydroxyphenyl)-5-methoxymethyl-2-oxazolidinone (code number MD 780232). The mixture is heated under reflux for 4 h 30. After filtration and concentration, the residue is taken up in 200 ml of CH2Cl2, the organic phase is washed with NaCl saturated water, dried over Na2SO4 and concentrated. After purification by flash chromatography (silica, eluent: CH2Cl2 :98;CH3OH:2), the aimed product is obtained with a 70% yield, m.p.: 58° C.;
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])=[N:5][C:4]=1[C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)=O.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:4]1[N:5]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[S:7][C:3]=1[CH2:1][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: C1COCCN1
Reactant: O=Cc1sc(NC(=O)c2ccncc2)nc1-c1ccco1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: O=C(Nc1nc(-c2ccco2)c(CN2CCOCC2)s1)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
Compound 85 (250 mg, 0.836 mmol) was dissolved in 1,2-dichloroethane (4 mL), and morpholine (0.15 mL, 1.67 mmol) and sodium triacetoxyborohydride (531 mg, 2.51 mmol) were added thereto, followed by stirring overnight at room temperature. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=30:1) to afford the entitled Compound 86 (302 mg, 98%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][NH:18][CH2:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C(N(CC)CC)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][N:18]([C:24]4[CH:23]=[C:22]([CH3:31])[CH:27]=[CH:26][CH:25]=4)[CH2:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CNCC3)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(N2CCc3ncnc(Nc4ccc(C(F)(F)F)cc4)c3C2)c1
Reaction time: 6 h
Yield: 4.7 %

Procedure:
N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (100 mg, 0.34 mmol) was dissolved in anhydrous THF (2 mL). To the mixture was added m-tolylboronic acid (92 mg, 0.68 mmol), Cu(OAc)2 (124 mg, 0.68 mmol) and triethylamine (0.68 g, 0.095 mL). The mixture was agitated for 6 h and the solvent was removed under a vacuum. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as reddish powder (6.2 mg, 5%).
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][NH:4]1.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:15]>C1COCC1>[N+:23]([C:20]1[CH:19]=[CH:18][C:17]([O:16][C:14](=[O:15])[O:12][C:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][N:4]=2)=[CH:22][CH:21]=1)([O-:25])=[O:24]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C1NCc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OC1=NCc2ccccc21)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a suspension of NaH (18 mg, 60% dispension in mineral oil, 0.454 mmol) in THF (10 mL), 2,3-dihydro-isoindol-1-one (55 mg, 0.413 mmol) was added. The reaction mixture was stirred at room temperature for 1 hours. The p-nitrophenyl chloroformate (91.5 mg, 0.454 mmol) was added and the reaction mixture was stirred at room temperature for overnight. Solvent was concentrated and the residue was washed with methanol. White solid was collected as pure product carbonic acid 3H-isoindol-1-yl ester 4-nitro-phenyl ester (37 mg, 30% yield).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:12]([OH:13])=[C:11]2[C:7]([CH2:8][CH2:9][CH:10]2[CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])=[CH:6][CH:5]=1.I[CH2:22]I.Cl>CN(C)P(N(C)C)(N(C)C)=O.O>[O:13]1[C:12]2[C:11]3[CH:10]([CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH2:9][CH2:8][C:7]=3[CH:6]=[CH:5][C:4]=2[O:3][CH2:22]1
Reactant: CCC(=O)NCCC1CCc2ccc(O)c(O)c21
Reactant: ICI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCC(=O)NCCC1CCc2ccc3c(c21)OCO3
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.4 %

Procedure:
Hexamethyl phosphoramide (5 mL) was cooled with ice, to which was gradually added sodium hydride (0.28 g, 7.5 mmol.), content 65%). To this mixture was added dropwise a solution of N-[2-(6,7-dihydroxyindan-1-yl)ethyl] propionamide (0.85 g, 3.41 mmol.) in hexamethyl phosphoramide (5 mL) at room temperature over 6 minutes. At the time when the bubbling of hydrogen gas ceased, diiodomethane (1.1 g, 4.1 mmol.) was added dropwise to the reaction mixture, followed by stirring for two hours at room temperature. The reaction mixture was poured into water, which was neutralized with dilute hydrochloric acid, followed by extracting the organic matter with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution and water, which was then dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of silica gel column chromatography (ethyl acetate) to afford the title compound (yield 280 mg, 31%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])N.Cl.N([O-])=O.[Na+].[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]([CH3:22])=[O:21]>O.CC(C)=O>[CH3:22][C:20]([C:16]1[O:15][C:19]([C:4]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=2)=[CH:18][CH:17]=1)=[O:21]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)c1ccco1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1ccc(-c2ccc(Cl)c(Cl)c2)o1
Reaction time: 1 h
Yield: 35.3 %

Procedure:
A mixture of 81 g (0.50 mole) of 3,4-dichloroaniline, 100 ml of water and 75 ml of conc. HCl was heated on a steam bath to ca. 70°, and 150 ml of conc. HCl was added. White crystals separated and the mixture was cooled to 0°. A solution of 35 g (0.50 mole) of sodium nitrite in 150 ml of water was added at 0°-5° over 25 min and stirring was continued at 0°-5° for 1 hour. A solution of 55 g (0.50 mole) of methyl 2-furyl ketone in 50 ml of acetone was added quickly followed by the dropwise addition over 10 minutes at 4°-5° of a solution of 10 g (0.06 mole) of cupric chloride dihydrate in 20 ml of water. The cooling bath was removed, and the green solution was stirred overnight at ambient temperature. The solid which was deposited was collected by filtration and washed with water. Recrystallization from ca. 800 ml of MeOH gave 45 g (35%) of 5-(3,4-dichlorophenyl)-2-furyl methyl ketone A. Two additional recrystallizations from MeOH gave an analytical sample, m.p. 114°-117°.