Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6](B(O)O)=[CH:5][CH:4]=[N:3]1.Br[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].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>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(Br)cc1
Reactant: Cn1nccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(-c2ccnn2C)cc1
Reaction time: 3 h

Procedure:
A mixture of (1-methyl-1H-pyrazol-5-yl)boronic acid (C1) (60.0 g, 0.476 mol) and 1-bromo-4-methylbenzene (75.0 g, 0.438 mol) in a mixture of 1,2-dimethoxyethane (1.2 L) and 2 M aqueous sodium carbonate solution (550 mL) was degassed and purged with N2; this procedure was then repeated twice. Dichlorobis(triphenylphosphine)palladium(II) (3.1 g, 4.4 mmol) was added and the mixture was purged twice with N2. The reaction mixture was heated to reflux and stirred under N2 for 3 hours. The mixture was cooled and 1,2-dimethoxyethane was removed under reduced pressure; water (500 mL) was added to the residue, and the resulting mixture was extracted with dichloromethane (3×500 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Eluent: 100:1 petroleum ether/ethyl acetate) provided the product as a yellow liquid. Yield: 55.0 g, 319 mmol, 73%. 1H NMR (400 MHz, CDCl3) δ 2.42 (s, 3H), 3.89 (s, 3H), 6.29 (d, J=1.8 Hz, 1H), 7.29 (br AB quartet, JAB=8 Hz, ΔνAB=18 Hz, 4H), 7.52 (d, J=2.0 Hz, 1H).
Reaction SMILES: N1CCCCC1.[CH2:7]([N:9]([CH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:16]=O)[CH2:10][CH3:11])[CH3:8].C([CH2:26][C:27]([NH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=[O:33])=[O:28])(O)=O.CC(O)=O>C1(C)C=CC=CC=1>[CH2:7]([N:9]([CH2:12][C:13]1[CH:14]=[C:15](/[CH:16]=[CH:26]/[C:27]([NH:29][C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([OH:34])=[O:33])=[O:28])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:10][CH3:11])[CH3:8]
Reactant: CCN(CC)Cc1cc(C=O)ccc1OC
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCN(CC)Cc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1OC
Yield: 49.4 %

Procedure:
Piperidine (97 μL, 0.99 mmol) was added to a suspension of 3-((diethylamino)methyl)-4-methoxybenzaldehyde (0.22 g, 0.99 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.20 g, 0.90 mmol) in toluene (5 mL) and treated according to Procedure 2, neutralizing with 20% AcOH. The resulting precipitate was filtered and washed with water providing (E)-2-[[3-(3-((diethylamino)methyl)-4-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.17 g, 50%) as a colourless crystalline solid; mp 202-205° C.; δH (400 MHz, DMSO-d6) 1.14 (t, J=7.2 Hz, 4H, CH2CH3), 2.87 (q, J=7.2 Hz, 6H, CH2CH3), 3.79 (s, 3H, OCH3), 3.98 (s, 2H, NCH2), 6.51 (d, J=15.6 Hz, 1H, CH═CHCO), 6.98 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.03 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.34 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 7.46 (d, J=15.6 Hz, 1H, CH═CHCO), 7.57 (dd, J5′,6′=8.0, J2′,6′=1.6 Hz, 1H, H6′), 7.76 (d, J2′,6′=1.6 Hz, 1H, H2′), 7.98 (d, J3,4=8.0 Hz, 1H, H3), 8.54 (d, J5,6=8.0 Hz, 1H, H6), 13.34 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 9.38, 46.4, 49.8, 55.6, 111.4, 118.9, 121.2, 121.5, 122.1, 126.9, 130.2, 130.8, 130.9, 139.2, 140.7, 158.8, 163.3, 169.7; HRMS (ESI) calculated for C22H26N2O4 [M+H]+ 383.1965. found 383.1964; vmax 823, 1264, 1366, 1500, 1579, 1609, 1674, 2943, 3478 cm−1.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38](O)=[O:39])=[CH:30][CH:29]=1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:38]([C:31]5[C:32]6[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=6)[N:28]=[CH:29][CH:30]=5)=[O:39])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: O=C(O)c1ccnc2ccccc12
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)c1ccnc2ccccc12

Procedure:
The title compound, white solid (14.2 mg, 35.8%), MS (ISP) m/z=487.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (x mg, x mmol) and quinoline-4-carboxylic acid.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:20])([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:10][N:9]=2)[CH2:6][CH2:5][N:4](C([O-])=O)[CH2:3]1.CCOC(C)=O.[ClH:30]>O1CCOCC1>[ClH:30].[ClH:30].[F:18][C:15]([F:16])([F:17])[C:14]([C:11]1[CH:10]=[N:9][C:8]([N:7]2[CH2:6][CH2:5][NH:4][CH2:3][C@@H:2]2[CH3:1])=[N:13][CH:12]=1)([OH:20])[CH3:19]
Reactant: C[C@H]1CN(C(=O)[O-])CCN1c1ncc(C(C)(O)C(F)(F)F)cn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H]1CNCCN1c1ncc(C(C)(O)C(F)(F)F)cn1
Temperature: 80 °C

Procedure:
A 100 mL round-bottomed flask was charged with ((3S)-3-methyl-4-(5-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-2-pyrimidinyl)-1-piperazinecarboxylate (1.12 g, 2.87 mmol), 10 mL of EtOAc, and 3 mL of 4N HCl in dioxane. The mixture was heated at 80° C. for 3 h. The resulting white precipitate was collected by filtration to give 1,1,1-trifluoro-2-(2-((2S)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-2-propanol dihydrochloride (1.05 g)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[O:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl.O>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)(=[O:32])=[O:31])=[CH:7][CH:6]=3)=[CH:9][O:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc(-c2coc3ncnc(N)c23)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Nc1ncnc2occ(-c3ccc(NS(=O)(=O)c4ccccc4)cc3)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
A 0° C. suspension of Example 13E (0.05 g, 0.22 mmol) in dichloromethane (4 mL) was treated with pyridine (0.022 mL, 0.26 mmol) and benzenesulfonyl chloride (0.03 mL, 0.23 mmol), stirred at 0° C. for 1 hour, warmed to room temperature, and stirred overnight. The reaction mixture was diluted with water and extracted twice with dichloromethane. The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The concentrate was triturated with dichloromethane/hexanes to provide 52 mg (64%) of the desired product. MS (ESI(+)) m/e 367 (M+H)+; 1H NMR (DMSO-d6) δ 10.51 (s, 1H), 8.23 (s, 1H), 7.88 (s, 1H), 7.84-7.81 (m, 2H), 7.64-7.54 (m, 3H), 7.38 (d, J=8.5 Hz, 2H), 7.22 (d, J=8.5 Hz, 2H), 6.45 (br s, 2H); Anal. Calcd. for C18H14N4O3S: C, 59.01; H, 3.85; N, 15.29. Found: C, 58.77; H, 3.88; N, 15.18.
Reaction SMILES: CO[CH:3](OC)/[C:4](=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[CH3:15])/[C:5]#[N:6].CC1C(C)=CC=CC=1CC(C(OC)OC)C#N.O.[NH2:36][NH2:37].Cl>CO.C(O)C.[Pd]>[CH3:15][C:9]1[C:10]([CH3:14])=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][C:4]1[C:5]([NH2:6])=[N:36][NH:37][CH:3]=1
Reactant: COC(OC)/C(C#N)=C/c1cccc(C)c1C
Reactant: NN
Agent: [Pd]
Agent: COC(OC)C(C#N)Cc1cccc(C)c1C
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CO
Product: Cc1cccc(Cc2c[nH]nc2N)c1C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
The suspension of (2E)-2-[bis(methyloxy)methyl]-3-(2,3-dimethylphenyl)-2-propenenitrile (1.55 g, 9.2 mmol) and 10% Pd/C (36 mg, 0.33 mmol) in methanol (25 mL) was hydrogenated using the Parr shaker (23° C., 50 bar) overnight. The catalyst was removed by filtration. Concentration of filtrate gave desire product. (0.26 g, 17%). To a solution of 2-[(2,3-dimethylphenyl)methyl]-3,3-bis(methyloxy)propanenitrile (257 mg, 1.1 mmol) and hydrazine monohydrate (55.1 mg, 1.1 mmol) in ethanol (15 ml) stirred under nitrogen at room temperature was added a solution of 36% HCl (558 mg, 5.51 mmol) dropwise. The reaction mixture was stirred at 100° C. for overnight. Reaction mixture was concentrated and dissolved with ethyl acetate (30 mL) and water (10 mL). pH of aqueous layer was adjusted to 8˜9. Two layers were separated. Organic layer was washed with brine (5 mL), dried and concentrated. Crude product was purified with silica gel column (0-10 methanol/DCM). Product was obtained and used in next step. (191 mg, 86%); LC/MS: MS (ES+) m/e 202 (MH+).
Reaction SMILES: C.C1C(Br)=C(Br)[NH:4]C=1C(O)=O.N([O-])=O.[Na+].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[N+:23]([O-:26])([OH:25])=[O:24]>O>[N+:23]([O-:26])([O-:25])=[O:24].[C:17]1([N+:16]#[N:4])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1cc(Br)c(Br)[nH]1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])O
Agent: C
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#[N+]c1ccccc1
Product: O=[N+]([O-])[O-]

Procedure:
A carbon black with a surface area of 58 m2 /g and a DBPA of 46 ml/100 g was used. A suspension of 50 g of this carbon black was prepared by stirring it into 450 g of water. A solution of 0.85 g of NaNO2 in 4 g of cold water was slowly added to a solution of 0.94 g of aniline and 1.98 g of concentrated nitric acid in 5 g of water that was cooled in an ice bath. Benzenediazonium nitrate was formed. After 15 minutes of stirring, the mixture was added to the stirring carbon black suspension. Bubbles were released. When the bubbling had stopped, the product was collected by filtration, washed twice with water and dried in an oven at 125° C. The carbon black product had attached phenyl groups.
Reaction SMILES: [CH2:1](NC1C(C(OCC)=[O:13])=C(C)N=C2NC=NC=12)[CH2:2]CC.[CH2:21]([O:23][C:24]([C:26]1[C:27]([NH:37][CH2:38][CH2:39][CH2:40][CH3:41])=[C:28]2[N:35]=[C:34]([CH3:36])[NH:33][C:29]2=[N:30][C:31]=1[CH3:32])=[O:25])[CH3:22]>>[OH2:13].[CH2:38]([NH:37][C:27]1[C:26]([C:24]([O:23][CH2:21][CH3:22])=[O:25])=[C:31]([CH3:32])[N:30]=[C:29]2[N:33]([CH2:1][CH3:2])[C:34]([CH3:36])=[N:35][C:28]=12)[CH2:39][CH2:40][CH3:41]
Reactant: CCCCNc1c(C(=O)OCC)c(C)nc2[nH]c(C)nc12
Reactant: CCCCNc1c(C(=O)OCC)c(C)nc2[nH]cnc12
Product: CCCCNc1c(C(=O)OCC)c(C)nc2c1nc(C)n2CC
Product: O

Procedure:
The following additional compounds are prepared by the procedure of Example 2: 7-butylamino-5-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester, m.p. 120°-122°, and 7-butylamino-2,5-dimethyl-3H-imidazo[4,5-b]-pyridine-6-carboxylic acid ethyl ester, m.p. 148°-149°.
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][O:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11]#[N:12].[C:13]([N:21]=[C:22]=[O:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCOCC1>[C:11]([C:3]1[C:4]2[CH2:9][CH2:8][O:7][CH2:6][C:5]=2[S:10][C:2]=1[NH:1][C:22]([NH:21][C:13](=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:23])#[N:12]
Reactant: N#Cc1c(N)sc2c1CCOC2
Reactant: O=C=NC(=O)c1ccccc1
Solvent: C1COCCO1
Product: N#Cc1c(NC(=O)NC(=O)c2ccccc2)sc2c1CCOC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
To a solution of 2-amino-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carbonitrile (Example 159b) (400 mg, 2.22 mmol) in 1,4-dioxane (30 mL) was added benzoyl isocyanate (327 mg, 2.22 mmol). The reaction mixture was then stirred at room temperature under nitrogen overnight. The precipitate was collected by filtration, washed with 1,4-dioxane, and dried in the air to give the title compound (577 mg, 80%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 2.62 (t, J=5.2 Hz, 2H), 3.87 (t, J=5.2 Hz, 2H), 4.62 (s, 2H), 7.56-7.53 (m, 2H), 7.67-7.65 (m, 1H), 8.04-8.01 (m, 2H), 11.60 (brs, 1H), 12.13 (brs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](Cl)=[O:8].[N:10]#[C:11][NH2:12]>>[C:11]([NH:12][C:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[Cl:1])=[O:8])#[N:10]
Reactant: O=C(Cl)c1sccc1Cl
Reactant: N#CN
Product: N#CNC(=O)c1sccc1Cl

Procedure:
Compounds of this invention with a linker between middle ring and Ar2 may be prepared as illustrated by the exemplary reaction in Scheme 11. Reaction of 3-chloro-thiophene-2-carbonyl chloride with cyanamide produces N-cyano-3-chloro-thiophene-2-carboxylic acid amide, followed by treating with hydroxyamine to give 3-amino-5-(3-chloro-2-thienyl)-1,2,4-oxadiazole.
Reaction SMILES: C(N[C:5]([C:7](NC(=O)C)=[O:8])=[O:6])(=O)C.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:20][O-:21].[Na+]>C(OCC)C>[C:20]1([O:21][C:5](=[O:6])[C:7]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:8])[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1
Reactant: CC(=O)NC(=O)C(=O)NC(C)=O
Reactant: C[O-]
Reactant: Oc1ccccc1
Agent: [Na+]
Solvent: CCOCC
Product: O=C(Oc1ccccc1)C(=O)Oc1ccccc1
Yield: 502.7 %

Procedure:
N,N'-diacetyloxamide (10 g, 0.058 mol), phenol (27.91 g, 0.297 mol) and sodium methoxide (0.2 g, 3.7 mmol) are charged into a three-necked flask equipped with a reflux condenser, a thermometer, an inlet tube for nitrogen, and a magnetic stirrer. The temperature is brought to 130° C., and after two hours the complete disappearance of the N,N'-diacetyloxamide is observed. The reaction mixture is then cooled and ethyl ether (30 ml) is added thereto. The compound of the title is separated from the reaction mixture by crystallization, recovered by filtration and recrystallized from absolute ethyl alcohol, yielding 4.5 g (18.6 mmol) of oxalic acid diphenyl ester with m.p. 132°-5° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C@@H:16]([CH:20]([CH3:22])[CH3:21])[C:17]([NH2:19])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.I.[NH2:33][C:34]1[C:35]([C:42]([NH:44][C:45](=[NH:48])SC)=[O:43])=[N:36][C:37]([Cl:41])=[C:38]([NH2:40])[N:39]=1>C(O)C>[NH2:33][C:34]1[C:35]([C:42]([N:44]=[C:45]([NH2:48])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:7]=[CH:8][C:9]([S:12]([NH:15][C@@H:16]([CH:20]([CH3:22])[CH3:21])[C:17]([NH2:19])=[O:18])(=[O:14])=[O:13])=[CH:10][CH:11]=2)=[O:43])=[N:36][C:37]([Cl:41])=[C:38]([NH2:40])[N:39]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(CCCCN)cc1)C(N)=O
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)[C@H](NS(=O)(=O)c1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1)C(N)=O
Temperature: 25 °C
Yield: 54 %

Procedure:
A solution of (2S)-[4-(4-aminobutyl)benzenesulfonylamino]-3-methylbutyramide 15 (156 mg, 0.47 mmol), diisopropylethylamine (0.60 mL, 3.0 mmol), and 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (230 mg, 0.61 mmol) in absolute ethanol (8 mL) was stirred at 70° C. for 5 h and then cooled to room temperature. The reaction mixture was concentrated by rotary evaporation. The crude residue was washed with water, filtered and the crude solid product was purified by flash silica gel column chromatography eluting with chloroform/methanol/concentrated ammonium hydroxide (5:1:0.1, v/v) to give the desired product as a yellow solid (137 mg, 54% yield). Part of the solid (86 mg) was further purified by semi-preparative HPLC (acetonitrile/water/0.1% TFA) to give the analytical pure sample which was then co-evaporated with 5% aqueous HCl to give the hydrochloride salt 16. mp 154-156° C. (decomposed). 1H NMR (300 MHz, CD3OD) δ 0.85 (d, 3H), 0.86 (d, 3H), 1.70 (m, 4H), 1.90 (m, 1H), 2.75 (m, 2H), 3.32 (m, 2H), 3.52 (d, 1H), 7.35 (d, 2H), 7.75 (d, 2H). m/z (ESI): 540 [C21H30ClN9O4S+H]+. [α]D25+5.20 (c 0.50, MeOH).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=1)[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])=[CH:16][CH:15]=1)O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].S(Cl)([Cl:31])=O>ClCCl>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=1)[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[Cl:31])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CN(C)S(=O)(=O)c1ccc(C(O)c2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1ccc(C(Cl)c2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1

Procedure:
The alcohol (88.8 g, 0.21 mol) was treated with thionyl chloride in dichloromethane as described in Example 1 to give 93.7 g of 4-(3-(tert-butyldimethylsilyloxy)-α-chlorobenzyl)-N,N-dimethylbenzenesulfonamide as a brown oil. The crude benzhydryl chloride (93.7 g, 0.21 mol) was combined with trans-2,5-dimethylpiperazine (71.8 g, 0.63 mol) in 400 mL of dimethylformamide and heated to 140° C. for 1 hour. The mixture was cooled to room temperature, poured into ice water and extracted with diethyl ether. The ether extracts were washed with 1M sodium hydroxide, water, and saturated aqueous sodium chloride, and dried over sodium sulfate. The solvent was removed and the residue was purified by chromatography on silica gel with dichloromethane:methanol to give 28.9 g (27%) of trans-4-(α-(2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)-N,N-dimethylbenzenesulfonamide as a brown oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.[CH3:16][C:17]1[N:21]([CH:22](S(OC)(=O)=O)[CH3:23])[C:20]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:19][CH:18]=1>CN(C)C=O.O>[CH3:16][C:17]1[N:21]([CH2:22][CH2:23][O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[C:20]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:19][CH:18]=1
Reactant: COS(=O)(=O)C(C)n1c(C)ccc1-c1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2ccccc2)n1CCOc1ccc(C=O)cc1
Reaction time: 4 h

Procedure:
To a suspension of potassium carbonate (16.43 g) in dimethyl formamide (50 mL), 4-hydroxy benzaldehyde (4.37 g) was added and warmed to 90° C. to 95° C. To the solution, methyl 1-[5-methyl-2-phenyl-1H-pyrrol-1-yl]ethane sulfonate (10 g) (compound no. 41) dissolved in dimethyl formamide (50 mL) was added within 30 min and the reaction was continued for further 4 hours. The reaction mixture was diluted with water (100 mL) and was extracted with ethyl acetate (3×100 mL), washed with water (3×100 mL), brine (200 mL), and was dried over sodium sulfite. The solvent was evaporated under reduced pressure, to yield the title compound.
Reaction SMILES: N(CCO)CCO.CCOCC.[C:13]([CH2:18][C:19]([OH:21])=[O:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].[N+]([O-])([O-])=O.[Ag+:26]>O>[C:13]([CH2:18][C:19]([O-:21])=[O:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].[Ag+:26]
Reactant: CC(C)C(=O)CC(=O)O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: OCCNCCO
Solvent: CCOCC
Product: CC(C)C(=O)CC(=O)[O-]
Temperature: 15 °C

Procedure:
Diethanolamine (0.33 g) was dissolved in water (5 ml) and an ether solution (10 ml) containing the isobutyrylacetic acid (0.43 g) was added thereto. Next, while stirring the obtained mixture at 15° C., an aqueous solution (5 ml) containing silver nitrate (0.51 g) was added dropwise thereto and further stirred for 15 minutes. The precipitated white precipitate was filtered out, thereby obtaining silver isobutyrylacetate (yield: 0.37 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:60])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:22]=CC3C4C(=C5C=CC(C6NC(C7CCCN7C(=O)C(NC(OC)=O)C(C)C)=NC=6)=CC5=CC=4)[O:27][CH2:26][C:25]=3[CH:59]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].FC(F)(F)S([O:66][C:67]1C=CC2[C:71]([CH:92]=1)=[CH:72][CH:73]=[C:74]1C=2OCC2C=C(OS(C(F)(F)F)(=O)=O)[CH:82]=[CH:83][C:75]1=2)(=O)=O>>[CH3:1][O:2][C:3](=[O:60])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:59]=[C:25]3[CH2:26][O:27][C:74]4[C:75]5=[C:92]([CH:71]=[C:72]([C:19]6[NH:20][C:16]([CH:12]7[CH2:13][CH2:14][CH2:15][N:11]7[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:60])[CH:6]([CH3:7])[CH3:8])=[N:17][CH:18]=6)[CH:73]=4)[CH2:67][O:66][C:82]([CH:22]=2)=[C:83]35)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3c(c2)COc2c-3ccc3cc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)ccc23)[nH]1)C(C)C
Reactant: O=S(=O)(Oc1ccc2c(c1)COc1c-2ccc2cc(OS(=O)(=O)C(F)(F)F)ccc12)C(F)(F)F
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2cc3c4c(c2)OCc2cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc(c2-4)OC3)[nH]1)C(C)C

Procedure:
Title compound was prepared according to the method employed to prepare (1-{2-[5-(2-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-6-H-dibenzo[c,h]chromen-8-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester, substituting trifluoro-methanesulfonic acid 7-trifluoromethane sulfonyloxy-5,10-dihydro-chromeno[5,4,3-cde]chromen-2-yl ester for trifluoro-methanesulfonic acid 2-trifluoromethanesulfonyloxy-6-H-dibenzo[c,h]chromen-8-yl ester.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH2:4][NH:3]1.Br.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.C(N(CC)CC)C>C1COCC1>[CH3:1][C@@H:2]1[N:3]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:4][CH2:5][N:6]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:7]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: BrCc1ccccn1
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1ccccn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of (S)-2-methyl-4-N—BOC-piperazine (400 mg, 1.997 mmol) and 2-(bromomethyl)pyridine hydrobromide (505 mg, 1.997 mmol) in anhydrous THF (5 ml) was added triethylamine (0.7 ml, 4.99 mmol) and the resulting mixture stirred at RT for 3 days. The mixture partitioned between water and EtOAc; organic layer washed with sat. NaCl, dried over MgSO4, filtered and evaporated. The residue purified by column chromatography (eluent: 5% MeOH in DCM) to give 320 mg (55%) to afford the title compound as a yellow oil. 1H NMR (CDCl3): 1.14 (d, J 6.2 Hz, 3H), 1.47 (s, 9H), 2.25 (t, J 9.5 Hz, 1H), 2.51 (m, 1H), 2.70 (d, J 11.6 Hz, 1H), 2.84 (brs, 1H), 3.15 (t, J 10.1, 1H), 3.47 (d, J 14.2 Hz, 1H), 3.69 (d, J 13.0 Hz, 1H), 3.75 (brs, 1H), 4.08 (d, J 14.0, 1H), 7.17 (dd, J 7.1 and 5.3, 1H), 7.45 (d, J 7.8, 1H), 7.66 (m, 1H), 8.56 (d, J=4.7 Hz, 1H).
Reaction SMILES: [C:1]([O:13][CH3:14])(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:15](O)[CH2:16]CCO>>[C:6]1(=[O:7])[O:8][CH2:9][CH2:16][CH2:15][CH2:14][O:13][C:1](=[O:12])[C:2]2[CH:11]=[CH:10][C:5]1=[CH:4][CH:3]=2
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Reactant: OCCCCO
Product: O=C1OCCCCOC(=O)c2ccc1cc2
Temperature: 160 °C
Reaction time: 1 h

Procedure:
474 g of dimethyl terephthalate and 660 g of 1,4-butanediol were placed into a 2 liter round bottomed flack fitted with a condenser, vigreux distillation column, nitrogen inlet and mechanical stirrer. The reactor was placed inside an isomantle and slowly heated to a temperature of 160° C. At this point 248 mg of tetrabutyl titanate catalyst pre-mixed with a small amount of pure 1,4-butanediol was injected, whilst the reactor contents were being stirred. The reaction was allowed to continue for 1 hour at 200° C. Methanol vapor which is produced during the reaction, was removed via the vigreux distillation column and combined condenser. The composition of the product was 82% by weight of butylene terephthalate (as confirmed by NMR) and 18% by weight of 1,4-butanediol.