Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[N:5][N:4]=[C:3]1[SH:13].[OH-].[Na+].[CH3:16]I>O>[NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]([CH3:10])([CH3:12])[CH3:11])=[N:5][N:4]=[C:3]1[S:13][CH3:16]
Reactant: CI
Reactant: CC(C)(C)c1nnc(S)n(N)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1nnc(C(C)(C)C)c(=O)n1N
Yield: 81.6 %

Procedure:
48.6 g (0.243 mol) of 4-amino-6-tert.-butyl-3-mercapto-1,2,4-triazin-5(4H)-one (V) were introduced into a mixture of 236 g of 45% strength sodium hydroxide solution and 160 g of water, while stirring. When all of the product had dissolved, 40.2 g of methyl iodide were added in a manner such that the internal temperature did not exceed 30° C. When the addition had ended, the reaction mixture was stirred at room temperature for a further 2 hours. The reaction product which had precipitated was then filtered off, washed with 100 ml of water and dried. 42.5 g (82% of theory) of 4-amino-6-tert.-butyl-3-methylthio-1,2,4-triazin-5(4H)-one (I) of melting point 123°-125° C. were obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][C:14]3[N:15]=[CH:16][N:17](C(OC(C)(C)C)=O)[CH:18]=3)[CH2:11][C@@H:10]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:9]([S:33](C)(=[O:35])=[O:34])[CH2:8][C:7]=2[CH:37]=1)#[N:2].Cl.N1C=C(CN2C3C=CC=CC=3CN([C:56]([C:58]3C4C(=CC=CC=4)C=CC=3)=[O:57])CC2)N=C1.[Cl:68]C(Cl)C>>[ClH:68].[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)[CH2:11][C@@H:10]([CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:9]([S:33]([O:57][CH2:56][CH3:58])(=[O:34])=[O:35])[CH2:8][C:7]=2[CH:37]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)n1cnc(CN2C[C@@H](Cc3ccccc3)N(S(C)(=O)=O)Cc3cc(C#N)ccc32)c1
Reactant: CC(Cl)Cl
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccccc2C1
Agent: Cl
Product: CCOS(=O)(=O)N1Cc2cc(C#N)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1

Procedure:
Example 256 was prepared from Compound A as described for Compound D of Example 1, using dichioroethane and 3A sieves. Purification by preparative HPLC followed by conversion to the HCl salt and lyophilization afforded Example 256.
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[C:20]([CH2:21][CH2:22][CH3:23])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[OH:4].[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[C:36]([OH:38])=[O:37].C1CCN2C(=NCCC2)CC1>CS(C)=O>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[C:20]([CH2:21][CH2:22][CH3:23])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[C:36]([OH:38])=[O:37]
Reactant: CCCc1c(-c2nc(-c3ccc(C(O)CBr)cc3)no2)noc1-c1ccccc1
Reactant: O=C(O)C1CCCCN1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: CCCc1c(-c2nc(-c3ccc(C(O)CN4CCCCC4C(=O)O)cc3)no2)noc1-c1ccccc1
Temperature: 80 °C

Procedure:
To a mixture of 2-bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol, Preparation 1C (30 mg, 0.066 mmol) and piperidine-2-carboxylic acid (25.6 mg, 0.198 mmol) in DMSO (2 mL) was added DBU (0.030 mL, 0.198 mmol). The reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 19 mg of 1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-2-carboxylic acid as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.10 (2H, dd, J=8.35, 2.20 Hz), 7.77 (2H, dd, J=7.91, 1.54 Hz), 7.52-7.64 (5H, m), 5.20 (1H, d, J=18.24 Hz), 3.67 (2H, br. s.), 2.87-3.01 (2H, m), 1.99-2.21 (2H, m), 1.69-1.88 (4H, m), 1.64 (2H, dq, J=15.24, 7.59 Hz), 1.39-1.56 (3H, m), 0.92 (3H, t, J=7.36 Hz). MS (m+1)=503. HPLC Peak RT=3.47 minutes (Analytical Method A). Purity=88%.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([N:12]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24](O)[CH3:25])=[CH:20][CH:19]=2)=[CH:15][C:14]([C:27]2[CH:28]=[C:29]([C:33]([NH:36][S:37]([CH2:40][C:41]([F:44])([F:43])[F:42])(=[O:39])=[O:38])([CH3:35])[CH3:34])[CH:30]=[CH:31][CH:32]=2)=[N:13]1)[CH3:11].C(=O)([O-])O.[Na+]>ClCCl>[CH2:10]([N:12]1[C:16]([O:17][C:18]2[CH:19]=[CH:20][C:21]([CH:24]([F:7])[CH3:25])=[CH:22][CH:23]=2)=[CH:15][C:14]([C:27]2[CH:28]=[C:29]([C:33]([NH:36][S:37]([CH2:40][C:41]([F:42])([F:44])[F:43])(=[O:39])=[O:38])([CH3:35])[CH3:34])[CH:30]=[CH:31][CH:32]=2)=[N:13]1)[CH3:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C(C)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C(C)F)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 64.9 %

Procedure:
N-ethyl-N-(trifluoro-λ4-sulfanyl)ethanamine (DAST, 0.020 mL, 0.15 mmol, 1.3 equiv) was added to a solution of N-[1-(3-{1-ethyl-5-[4-(1-hydroxyethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)-1-methylethyl]-2,2,2-trifluoroethanesulfonamide (62 mg, 0.12 mmol, 1 equiv) in dichloromethane (1.2 mL) at −78° C. The reaction mixture was stirred at −78° C. for 5 minutes, then saturated sodium hydrogencarbonate was added. The crude mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, and the washed solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash-column chromatography (hexanes, grading to 50% ethyl acetate-hexanes) to afford N-[1-(3-{1-ethyl-5-[4-(1-fluoroethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)-1-methylethyl]-2,2,2-trifluoroethanesulfonamide (40 mg, 64%). Calcd (M+1)+: 514.2. Found: 514.1.
Reaction SMILES: [Cl:1][C:2]1(Cl)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH2:15])=[O:14])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[CH:3]1[Cl:20].N12CCCCC1C=NCCC2.O>CN(C)C=O>[Cl:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH2:15])=[O:14])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[C:3]=1[Cl:20]
Reactant: NC(=O)N1c2ccccc2C(Cl)C(Cl)(Cl)c2ccccc21
Agent: C1=NCCCN2CCCCC12
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)N1c2ccccc2C(Cl)=C(Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 8.33 g of crude 10,11-dihydro-10,10,11-trichloro-5H-dibenz[b,f]azepine-5-carboxamide in 35 ml of dimethyl formamide is treated at 0°-10° C with 9.1 ml (0.61 mole) of 1,5-diazabicyclo[5.4.0]undec-5-ene and stirred for 1 hour at room temperature. The brown solution is then poured into a mixture of water and ice and the resultant suspension is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The crude product is chromatographed over silica gel (particle size: 0.063-0.2 mm) with ethyl acetate as eluant. The homogeneous fractions are combined, concentrated by evaporation and recrystallised from ethyl acetate to yield 10,11-dichloro-5H-dibenz[b,f]azepine-5-carboxamide which melts at 265°-270° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][O:25][C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:33].CCCCCC.C(OCC)(=O)C>C(O)CCC>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH2:23][CH2:24][O:25][C:26]3[C:27]([Cl:33])=[CH:28][CH:29]=[CH:30][C:31]=3[Cl:32])[CH2:11][CH2:10]2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)C2CCNCC2)cc1
Reactant: Clc1cccc(Cl)c1OCCBr
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: CCCCCC
Product: Fc1ccc(C(c2ccc(F)cc2)C2CCN(CCOc3c(Cl)cccc3Cl)CC2)cc1

Procedure:
A mixture of 6.13 g (0.021 mole) of 4-[bis(4-fluorophenyl)methyl]piperidine, 5.38 g (0.03 mole) of 2-(2-bromoethoxy)-1,3-dichlorobenzene was heated overnight at gentle reflux in 200 ml of 1-butanol. The reaction mixture was filtered and stripped to dryness. The residue was dissolved in chloroform and extracted with water and 5% sodium hydroxide solution. The oil which was obtained was chromotagraphed on 300 g of silica gel using hexane-ethyl acetate (50/50 v/v) as eluant. The fractions containing product were combined and solvent removed to furnish an oil. The oil was dried overnight in vacuo at 80° C. This furnished 5.99 g (59%) of product oil.
Reaction SMILES: C[C:2]1[C:7](Br)=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH2:10]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)[CH3:11]>>[Br:9][C:5]1[CH:4]=[N:3][CH:2]=[C:7]([C:15]2[CH:16]=[CH:17][C:12]([CH2:10][CH3:11])=[CH:13][CH:14]=2)[CH:6]=1
Reactant: CCc1ccc(B(O)O)cc1
Reactant: Cc1ncc(Br)cc1Br
Product: CCc1ccc(-c2cncc(Br)c2)cc1

Procedure:
23 g (97 mmol) of methyl 3,5-dibromopyridine and 18 g (117 mmol, 1.2 eq.) of 4-ethylphenylboronic acid were reacted according to General Method 1A. Yield: 17 g (66% of theory)
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[ClH:8].Cl.[Cl:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][SH:25])[CH2:18][CH2:17]2)=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[OH2:7].[ClH:10].[ClH:8].[C:1]([NH:5][C:6](=[SH:25][CH2:24][CH2:23][CH2:22][N:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:14]2[CH:13]=[CH:12][C:11]([Cl:10])=[CH:27][CH:26]=2)[CH2:17][CH2:18]1)[OH:7])([CH3:4])([CH3:3])[CH3:2].[OH2:7].[OH2:7].[C:1]([NH:5][C:6](=[SH:25][CH2:24][CH2:23][CH2:22][N:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:14]2[CH:13]=[CH:12][C:11]([Cl:10])=[CH:27][CH:26]=2)[CH2:17][CH2:18]1)[OH:7])([CH3:4])([CH3:3])[CH3:2].[ClH:10].[ClH:10]
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(O)=[SH]CCCN1CCN(Cc2ccc(Cl)cc2)CC1
Product: O
Yield: 140.2 %

Procedure:
The procedure described in Example 2 was followed, using 0.8 g of t-butyl isocyanate, 3.0 g of 3-[4-(4-chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 1.6 g of triethylamine and 75 ml of methylene chloride, to give 2.2 g (60% of theory) of N-(t-butyl)-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride sesquihydrate as a white crystalline solid, M.p. 246°-248° C.
Reaction SMILES: [NH2:1][CH:2]([CH:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[CH3:7])[C:3]([OH:5])=[O:4].C(=O)([O-])O.[Na+].Cl[C:23]([O:25][CH:26]1[CH:33]2[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:35][CH:27]1[CH2:28]3)[CH2:32]2)=[O:24].CO>[OH-].[Na+].O1CCOCC1.ClCCl>[CH:33]12[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:35][CH:27]([CH2:28]3)[CH:26]1[O:25][C:23]([NH:1][CH:2]([CH:6]([C:8]1[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=1)[CH3:7])[C:3]([OH:5])=[O:4])=[O:24])[CH2:32]2
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Reactant: CC(c1c[nH]c2ccccc12)C(N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: CC(c1c[nH]c2ccccc12)C(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Yield: 62.8 %

Procedure:
Percent amino acid (75) (449 mg, 2.29 mmol) in 1N sodium hydroxide (2.29 mL) was added to sodium hydrogen carbonate (211 mg, 2.5 mmol). This mixture was cooled to 0° C. (ice bath), dioxan. (2.29 mL) was added, followed by dropwise addition with stirring of a solution of the chloroformate (76) (742 mg, 34.46 mmol) in dioxan (2.29 mL). When all the amino acid had gone (TLC SiO2 :4% methanol in dichloromethane), the dioxan was removed in vacuo and the residue partitioned between 10% citric acid and ethyl acetate. The aqueous phase was extracted further with ethyl acetate. The organic extracts were combined, dried (MgSO4), and evaporated to dryness. The crude acid was purified by column chromatography on normal silica [hexane:ethyl acetate (3:20+0.5% acetic acid as eluant] to give 2-(2-adamantyloxy-carbonyl)amino-3-(3-indolyl) butanoic acid (77) (570 mg, 63%); δ H (300 M Hz, d6 -DMSO), 1.34 (3H, d, J 8Jz. CH3), 1.68-2.00 (14H, m, adamantyl), 3.40-3.53 (1H, m, indCH(CH3)), 4.36 (1H, brt, CH(CO2H)), 4.59 (1H, s, adamantyl 2-H), 6.73 (1H, d, J 9 Hz, urethane NH), 6.96 (1H, t, J 7 Hz, indole 5-H), 7.06m (1H, t, J 7 Hz, indole 6-H), 7.17 (1H, brs, indole 2-H), 7.33 (1H, d, J 8 Hz, indole 7-H), 7.60 (1H, d, J 8 Hz, indole 4-H), 10.83 (1H, s, indole NH)m, ca 12.6 (vbrs, CO2H).
Reaction SMILES: [OH:1][CH:2]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].C1([O:24][C:25](=O)[NH:26][C:27]2[N:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[N:28]=2)C=CC=CC=1.C1CCN2C(=NCCC2)CC1.CCCCCl>Cl.C(Cl)Cl>[CH3:34][O:33][C:31]1[CH:30]=[C:29]([O:35][CH3:36])[N:28]=[C:27]([NH:26][C:25]([NH:12][S:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:2]([OH:1])[C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:11])=[O:24])[N:32]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: NS(=O)(=O)c1ccccc1C(O)c1cccs1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCCCCl
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C(O)c2cccs2)n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 35.9 %

Procedure:
To 0.5 g of the product of Example 6, dissolved in 30 mL of p-doxane, was added 0.51 g of phenyl(4,6-dimethoxypyrimidin-2-yl)carbamate followed by 0.27 mL of "DBU". The reaction was stirred for 1.5 hours, diluted with 45 mL of ice-water and acidified with 10 drops of concentrated hydrochloric acid to obtain an oily precipitate. The water was decanted from the oil and the oily residue was dissolved in methylene chloride, washed with water and brine, and finally dried (MgSO4). Filtration and concentration of the filtrate, in vacuo, yielded an oil. Trituration with a 10:1 mixture of n-chlorbutane and methylene chloride provided 0.3 g of the subject compound as an off-white solid, m.p. 152°-54°.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:28](C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.COC1CCNC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH:24]([O:25][CH3:28])[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: COC1CCNC1
Agent: Cl
Product: COC1CCN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-methoxypyrrolidine hydrochloride and isolated as colorless gum (13.2 mg, 70%), MS(m/e): 401.4 (MH+).
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].[H-].[Na+].[CH3:12][O:13][C:14](=[O:26])[C:15]1[C:16](=[C:21](I)[CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH3:20])=[O:18]>N1C=CC=CC=1.[Cu]Br>[CH3:12][O:13][C:14](=[O:26])[C:15]1[C:16](=[C:21]([O:3][C:2]2[CH:4]=[CH:5][CH:6]=[CH:7][C:1]=2[O:8][CH3:9])[CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Reactant: COc1ccccc1O
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: COC(=O)c1cccc(Oc2ccccc2OC)c1C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.2 %

Procedure:
A mixture of guaiacol (0.77 g, 6.2 mmol), copper (I) bromide (0.89 g, 6.2 mmol), and sodium hydride (0.3 g of a 60% dispersion, 7.5 mmol) in 100 mL pyridine was heated to reflux and stirred under nitrogen for 15 min. 3-Iodophthalic acid dimethyl ester (2.0 g, 6.2 mmol) was added, and the resulting mixture was stirred at reflux for 20 h. The mixture was cooled to room temperature and quenched by the addition of saturated NH4Cl (15 mL). Volatiles were removed under reduced pressure. The residue was partitioned between dilute aqueous HCl (100 mL) and ethyl acetate (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic extracts were washed with dilute aqueous HCl (2×100 mL), saturated Na2CO3 (2×100 mL), again with dilute aqueous HCl (2×100 mL) and finally with water (100 mL), and were evaporated. Chromatography in hexanes-ethyl acetate gradient provided 0.75 g of 3-(2-methoxy-phenoxy)-phthalic acid dimethyl ester, eluting at 25-30% ethyl acetate, in 38% yield; 1H NMR (CDCl3) δ 3.79 (s, 3H), 3.91 (s, 3H), 3.95 (s, 3H), 6.86-6.91 (m, 1H), 6.93-7.01 (m, 2H), 7.05 (dd, J=7.9 Hz, J=1.6 Hz, 1H), 7.13-7.20 (m, 1H), 7.30 (t, J=8.0 Hz, 1H), 7.66-7.69 (m, 1H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=2)[CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(Cl)(=O)C([Cl:35])=O.CN(C)C=O>ClCCl>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=2)[CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([Cl:35])=[O:18])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C(Cc2ccc(C(=O)O)cc2)c2ccc(CC(C)C)cc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)Cc1ccc(C(Cc2ccc(C(=O)Cl)cc2)c2ccc(CC(C)C)cc2)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[2,2-bis(4-isobutylphenyl)ethyl]benzoic acid (400 mg) in dichloromethane (10 ml) were added oxalyl chloride (0.1 ml) and a drop of N,N-dimethylformamide at 0° C. After stirred at 20° C. for 1 hour, the,mixture was evaporated to give 4-[2,2-bis(4-isobutylphenyl)ethyl]benzoyl chloride (450 mg) as pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:14]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[CH:21]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[B:33](OC(C)C)([O:38]C(C)C)[O:34]C(C)C.Cl>C1(C)C=CC=CC=1.C1COCC1>[CH:19]1[C:20]2[CH:21]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([B:33]([OH:38])[OH:34])=[CH:3][CH:4]=3)[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: Brc1ccc(-c2cc3ccccc3c3ccccc23)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OB(O)c1ccc(-c2cc3ccccc3c3ccccc23)cc1
Temperature: -60 °C
Yield: 72.4 %

Procedure:
Under an argon gas atmosphere, a mixture of 21.3 g (63.9 mmol) of 9-(4-bromophenyl)phenanthrene and 200 mL of dehydrated THF was cooled down to −60 degrees C., and added with 49.2 mL (76.7 mmol) of hexane solution of 1.56M n-butyllithium in drops while being stirred. Then, the reaction mixture was stirred for two hours at −60 degrees C. The reaction solution was further cooled down to −60 degrees C. and added with 36.1 g (192 mol) of triisopropyl borate in drops. Subsequently, the reaction mixture was warmed up to room temperature, and stirred for 17 hours. The reaction mixture was cooled down to 0 degree C. to be further added with solution of hydrochloric acid, and then stirred for one hour at room temperature. After the reaction, the reaction mixture was further added with toluene, so that aqueous phase thereof was eliminated. After organic phase thereof was dried with magnesium sulfate, the solvent was distilled away under reduced pressure. By recrystallizing residue by toluene and hexane, 13.8 g of 4-(9-phenanthrenyl)phenylboronic acid was obtained at an yield of 72%.
Reaction SMILES: [F:1][C:2]1[N:3]=[C:4]([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([F:28])[CH:27]=2)[S:5][C:6]=1[N:7](C(OC(C)(C)C)=O)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].FC(F)(F)C(O)=O>ClCCl>[C:11]([O:10][C:8](=[O:9])[NH:7][C:6]1[S:5][C:4]([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([F:28])[CH:27]=2)=[N:3][C:2]=1[F:1])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1sc(-c2cncc(F)c2)nc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)Nc1sc(-c2cncc(F)c2)nc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.8 %

Procedure:
To a solution of di(tert-butyl) 4-fluoro-2-(5-fluoropyridin-3-yl)-1,3-thiazol-5-ylimidodicarbonate (320 mg, 0.77 mmol) in DCM (7 mL) was added trifluoroacetic acid (TFA) (0.7 mL). The solution was stirred at room temperature for 10 minutes, before quenched slowly with saturated NaHCO3 solution. The organic layer was separated and the aqueous layer was extracted with dichloromethane (DCM). The combined organic layer was dried over Na2SO4, filtered and purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to give product as a pale yellow solid (166 mg, 68%): mp 188-191° C.; 1H NMR (300 MHz, CDCl3) δ 8.84 (s, 1H), 8.46 (d, J=2.7 Hz, 1H), 7.85 (ddd, J=9.1, 2.6, 1.7 Hz, 1H), 6.92 (br s, 1H), 1.55 (s, 9H); ESIMS m/z 312 (M−1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N:12]=[C:11]([NH2:18])[CH:10]=1.CCN(C(C)C)C(C)C>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N:12]=[C:11]([NH2:18])[CH:10]=2)[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2cc(N)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 90 h
Yield: 64.9 %

Procedure:
1-methylpiperazine (265.5 mg, 294.0 mL, 2.651 mmol) in THF (5 mL) was added to a stirred suspension of 4-chloro-5-nitro-pyridin-2-amine (400 mg, 2.305 mmol) and DIPEA (357.5 mg, 481.8 mL, 2.766 mmol) in THF (10 mL) at 0° C. under an atmosphere of nitrogen. The reaction was allowed to stir at ambient temperature for 90 hours before the solvent removed in vacuo. The residue was tritruated from DCM/MeOH and the resultant precipitate was washed with DCM/MeOH solutions. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (ISCO Companion, 40 g column, eluting with 0 to 10% 2M NH3 in MeOH/DCM) to give 4-(4-methylpiperazin-1-yl)-5-nitro-pyridin-2-amine as a yellow solid (355 mg, 65% Yield). MS (ES+) 238.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)[N:3]=1.[NH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]1[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].CCN(CC)CC>CC(N(C)C)=O>[C:29]([O:28][C:27]([NH:26][C@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][C@H:20]1[NH:19][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)[N:3]=1)=[O:33])([CH3:32])([CH3:30])[CH3:31]
Reactant: COC(=O)c1c(C)nc(Cl)nc1-c1cnn(C)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COC(=O)c1c(C)nc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1-c1cnn(C)c1
Temperature: 90 °C
Yield: 44.9 %

Procedure:
To a mixture of methyl 2-chloro-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxylate (0.227 g, 0.851 mmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (0.182 g, 0.851 mmol) in DMA (3 mL) was added Et3N (0.356 mL, 2.55 mmol). The reaction mixture was heated at 90° C. for 4 h. The reaction mixture was cooled to RT and poured onto ice. The solid was filtered and dried under high vacuum to yield the title compound as an off-white foam (170 mg). [M+H] calc'd for C22H32N6O4, 445. found, 445.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:9][CH:8]=[CH:7][N:6]=1)=O.[NH4+:22].[OH-]>C(O)C>[Br:19][C:17]1[CH:16]=[CH:15][C:14]([F:20])=[C:13]([CH:18]=1)[C:12]([NH:11][C:10]1[C:5]([C:3]([NH2:22])=[O:2])=[N:6][CH:7]=[CH:8][N:9]=1)=[O:21]
Reactant: COC(=O)c1nccnc1NC(=O)c1cc(Br)ccc1F
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1nccnc1NC(=O)c1cc(Br)ccc1F
Temperature: 25 °C

Procedure:
A mixture of 3-(5-bromo-2-fluorobenzoylamino)pyrazine-2-carboxylic acid methyl ester 102 (2.6 g, 7.34 mmol) and NH4OH (15 mL) in ethanol (50 mL) was heated at reflux for 10 min. Then, the reaction mixture was cooled at room temperature and the precipitate was filtered off, washed with ethanol and ether to give 2.1 g of the title product 103 as a white powder (LCMS analysis).