Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH:3]([OH:12])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[K+]>O1CCOCC1.CCOC(C)=O>[O:12]1[CH2:2][CH:3]1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OC(CCl)CNc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: c1ccc(NCC2CO2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
To a solution of the product of Step 3 (185.7 mg, 1.0 mmol, 1 equiv) in 1,4-dioxane (3.3 mL) was added KOH powder (67.3 mg, 1.2 mmol, 1.2 equiv). The mixture was stirred at room temperature for 24 hours. The mixture was diluted with EtOAc and washed with 1M HCl and brine. The organic layer was dried with MgSO4 and concentrated to give crude product. It was further purified by silica gel chromatography using 20% EtOAc/Hex to afford 141.8 mg colorless oil as product, yield 95.0%. 1H NMR (CDCl3, 400 MHz) δ=2.70 (dd, J=4.9, 2.3 Hz, 1H) 2.87-2.77 (m, 1H) 3.23-3.18 (m, 1H) 3.26 (t, J=4.9 Hz, 1H) 3.59-3.48 (m, 1H) 3.87 (s, 1H) 6.64 (d, J=7.7 Hz, 2H) 6.73 (t, J=7.3 Hz, 1H) 7.18 (dd, J=8.3, 7.5 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](Br)[C:9]2[N:10]([CH3:20])[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)CCC>CN(C=O)C.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>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]2[N:10]([CH3:20])[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c1ccccc1n2C
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(-c2ccccc2)c2c(c1O)c1ccccc1n2C
Temperature: 120 °C

Procedure:
A mixture of 1-bromo-4-hydroxy-9-methyl-9H-beta-carboline-3-carboxylic acid ethyl ester (150 mg), tributyl phenyl tin (0.169 mL), and Pd(PPh3)2Cl2 (15 mg) in DMF (1.5 mL) was heated at 120° C. for 41 min. The reaction was then partitioned between EtOAc and water, the organic phase was subsequently washed with sat. NaCl solution, dried over anhydrous sodium sulfate and then filtered, concentrated; the residue was purified with column to give the title compound (94 mg). ESI MS (m/z): 347 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:14]=[C:15]([OH:30])[C:16]3[C:21]4[CH2:22][CH:23]([CH3:26])[CH2:24][CH2:25][C:20]=4[C:19]([CH3:28])([CH3:27])[O:18][C:17]=3[CH:29]=2)([CH3:12])[CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.[ClH:31].[N:32]1([CH2:38][CH2:39][CH2:40][C:41](O)=[O:42])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:31].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:12])([C:13]2[CH:14]=[C:15]([O:30][C:41](=[O:42])[CH2:40][CH2:39][CH2:38][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[C:16]3[C:21]4[CH2:22][CH:23]([CH3:26])[CH2:24][CH2:25][C:20]=4[C:19]([CH3:28])([CH3:27])[O:18][C:17]=3[CH:29]=2)[CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CCCN1CCCCC1
Reactant: CCCC(C)(c1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CC(C)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCC(C)(c1ccc(F)cc1)c1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)C1=C2CC(C)CC1

Procedure:
2.5 g. (6.76 mmole) of 3-(4-fluorophenyl-1-methylbutyl)-1-hydroxy-6,6,9-trimethyl-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran is combined with 1.41 g. (6.76 mmole) of γ-piperidinobutyric acid hydrochloride and 1.48 g. (7.16 mmole) of dicyclohexylcarbodiimide in 125 ml. of methylene chloride and stirred at room temperature for 16 hours. The by-product of dicyclohexylurea is removed by filtration and the filtrate is evaporated to a residue. The residue is dissolved in ether and the small amount of solid which appears is removed by filtration. The ether is removed on a rotary evaporator and the gummy residue which remains is triturated several times with small quantities of hexane. The material is thoroughly dried to yield the product as a powder.
Reaction SMILES: O[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:30]>ClCCl>[Br:30][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: N#Cc1csc(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1csc(CBr)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
To a cooled (0° C.) solution of 2-(hydroxymethyl)thiophene-4-carbonitrile (1.14 g, 8.2 mmol) in dichloromethane (50 mL) was added triphenylphosphine (2.8 g, 10.6 mmol) and carbon tetrabromide (3.3 g, 9.9 mmol). After stirring for 3 h at rt, the solvent was removed in vacuo and the residue chromatographed using EtOAc and n-hexane (1:4) to give the title compound (1.6 g, 96%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][CH2:21][CH2:22][C:23]1[O:24][C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:28]([C:26]3[N:27]=[C:23]([CH2:22][CH2:21][O:20][CH3:19])[O:24][C:25]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:29])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: COCCc1nc(C(=O)O)c(-c2ccccc2)o1
Product: COCCc1nc(C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)c2)c(-c2ccccc2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-(2-methoxy-ethyl)-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.97 min; [M+H]+=435.13.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[N:5]=[C:4]2[N:19]([C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])[C:20](=[O:23])[NH:21][CH2:22][C:3]=12.O.C(=O)([O-])[O-].[K+].[K+].[F:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:47](=[O:64])[C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[C:50](B3OC(C)(C)C(C)(C)O3)[CH:49]=2)=[CH:42][CH:41]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:30][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([F:31])[C:24]=1[N:19]1[C:4]2[N:5]=[C:6]([N:8]3[CH2:9][CH2:10][CH:11]([N:14]4[CH2:15][CH2:16][CH2:17][CH2:18]4)[CH2:12][CH2:13]3)[N:7]=[C:2]([C:50]3[CH:49]=[C:48]([CH:53]=[CH:52][C:51]=3[CH3:54])[C:47]([NH:46][C:43]3[CH:44]=[CH:45][C:40]([F:39])=[CH:41][CH:42]=3)=[O:64])[C:3]=2[CH2:22][NH:21][C:20]1=[O:23]
Reactant: O=C1NCc2c(Cl)nc(N3CCC(N4CCCC4)CC3)nc2N1c1c(F)cccc1F
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(N2CCC(N3CCCC3)CC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 54.5 %

Procedure:
To a solution of 5-chloro-1-(2,6-difluorophenyl)-7-[4-(1-pyrrolidinyl)-1-piperidinyl]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (18 mg, 0.04 mmol) in dioxane (1.5 mL)/water (0.5 mL) were added potassium carbonate (34 mg, 0.25 mmol), tetrakis(triphenylphosphine)palladium(0) (2.3 mg, 0.002 mmol) and N-(4-fluorophenyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (22 mg, 0.062 mmol). The reaction mixture was bubbled with N2 for 5 mins, then microwaved at about 150° C. for about 30 mins. The reaction mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (14 mg, 54%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[F:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[C:18]([F:20])[CH:19]=1>>[N+:10]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:21][C:16]1[CH:15]=[C:14]([F:13])[CH:19]=[C:18]([F:20])[CH:17]=1)[C:6]#[N:7])([O-:12])=[O:11]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Oc1cc(F)cc(F)c1
Product: N#Cc1ccc(Oc2cc(F)cc(F)c2)c([N+](=O)[O-])c1

Procedure:
In a similar manner, 4-chloro-3-nitrobenzonitrile (4.6 g, 25 mmol) and 3,5-difluorophenol were combined to produce 6.9 g of 3-nitro-4-(3,5-difluorophenoxy)benzonitrile (26.2), mp 132-136° C.
Reaction SMILES: [C:1]([C:9]1[CH:16]=[CH:15][C:12]([CH2:13][Br:14])=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(OCC)(=O)C>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][Br:14])=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: BrCc1ccc(Cc2ccccc2)cc1
Yield: 52.5 %

Procedure:
4-Benzoylbenzyl bromide (2.75 grams, 10.0 mmole) and triethylsilane (2.33 grams, 20 mmole) in trifluoroacetic acid (4.56 grams, 40 mmole) were warmed to 60° C. for 18 hours. The cooled mixture was diluted with ethyl acetate (50 ml) and carefully washed with saturated sodium bicarbonate solution (2×50 ml). After drying with magnesium sulfate, the extract was filtered and concentrated. The residue was chromatographed (0.5:99.5 to 2:98--ethyl acetate:hexane) to give 1.37 grams (52%) of 4-benzylbenzyl bromide as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[N:34]=[CH:33][N:32]=[C:31]2[S:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:44][C:43]2[CH:45]=[CH:46][CH:47]=[C:41]([S:40][C:31]3[C:30]4[C:35](=[CH:36][C:37]([O:38][CH3:39])=[C:28]([O:27][CH3:26])[CH:29]=4)[N:34]=[CH:33][N:32]=3)[CH:42]=2)=[O:19])[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccccc4)c3)c2cc1OC
Temperature: 50 °C
Yield: 49.9 %

Procedure:
According to the procedure described in Example 138B, phenyl 3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate (151 mg, 0.45 mmol) from Example 153A was reacted with 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (89 mg, 0.30 mmol). To this solution was added diisopropylethyl amine (80 μL, 0.45 mmol) and DMAP (4 mg, 0.03 mmol). After heating for 2 hours at 50° C., the reaction was concentrated to dryness. The resulting solid was triturated with 1:1 dichloromethane/hexane and the solid removed by filtration to afford the title compound (83 mg, 50% yield). 1H NMR (300 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.68 (s, 1H), 8.47 (s, 1H), 7.55 (m, 4H), 7.40 (m, 5H), 7.20 (s, 1H), 6.95 (m, 1H), 6.36 (s, 1H), 3.98 (s, 6H), 1.25 (s, 9H); LCMS (ESI) m/z 555 (M+H)+.
Reaction SMILES: Cl.Cl.[CH:3]1([NH:9][C:10]2[C:14]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:13]([CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24])[C:12](=[O:25])[N:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[I:49][C:50]1[CH:51]=[C:52]([CH:55]=[CH:56][CH:57]=1)[CH:53]=O>ClCCCl>[CH:3]1([NH:9][C:10]2[C:14]3([CH2:15][CH2:16][N:17]([CH2:53][C:52]4[CH:55]=[CH:56][CH:57]=[C:50]([I:49])[CH:51]=4)[CH2:18][CH2:19]3)[N:13]([CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24])[C:12](=[O:25])[N:11]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=Cc1cccc(I)c1
Reactant: C=CCCCN1C(=O)N=C(NC2CCCCC2)C12CCNCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCN1C(=O)N=C(NC2CCCCC2)C12CCN(Cc1cccc(I)c1)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(cyclohexylamino)-1-pent-4-en-1-yl-1,3,8-triazaspiro[4.5]dec-3-en-2-one dihydrochloride (1 g, 2.56 mmol, intermediate I.1.c.1) in DCE (16 mL), was added Hunig's base (0.67 mL, 1.42 mmol), sodium triacetoxyborohydride (0.25 g, 1.18 mmol) and 3-iodo-benzaldehyde (329 mg, 3.83 mmol) in DCE (0.5 mL) dropwise. The reaction mixture was stirred at rt for 18 h, quenched with aq NaHCO3, extracted twice with EtOAc, washed with brine, concentrated in vacuo and purified flash chromatography (silica gel, EtOAc) to provide the desired product LRMS (M+1)=535.
Reaction SMILES: [CH2:1]([N:3]([CH2:34][CH3:35])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[CH:15][C:16]([C:23](=[O:33])[CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:17][CH:18]=3)[CH2:13][C:12]=2[CH:11]=1)=[O:9])[CH3:2].[OH-:36].C([N+](C)(C)C)C1C=CC=CC=1.O=O>N1C=CC=CC=1>[CH2:34]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[CH:15][C:16]([C:23](=[O:33])[CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:29][CH3:30])[CH2:31][CH3:32])=[CH:17][CH:18]=3)[C:13](=[O:36])[C:12]=2[CH:11]=1)=[O:9])[CH3:35]
Reactant: CCN(CC)CCCCC(=O)c1ccc2c(c1)Cc1cc(C(=O)CCCCN(CC)CC)ccc1-2
Reactant: [OH-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=O
Solvent: c1ccncc1
Product: CCN(CC)CCCCC(=O)c1ccc2c(c1)C(=O)c1cc(C(=O)CCCCN(CC)CC)ccc1-2

Procedure:
A solution of 12.0g (0.025 mole) 2,7-bis[5-(diethylamino)valeryl]-fluorene, prepared in Example 16, 2.0 ml 40% benzyltrimethylammonium hydroxide in pyridine and 200 ml pyridine was stirred at room temperature while oxygen was bubbled through the solution at a rate of 500 ml/min. for a total of four hours. The reaction mixture was evaporated to dryness leaving a residue which was chromatographed on alumina using chloroform as the eluant. The solvent was removed from the fraction collected leaving a solid which was recrystallized once from chloroform-petroleum ether to yield the desired product. M.P. 108°-109.5° C, λmaxEtOH 280, E1cm1% 1530.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:19](Cl)(=[O:29])[C:20]1[CH:28]=[CH:27][C:26]2[O:25][CH2:24][O:23][C:22]=2[CH:21]=1>>[O:25]1[C:26]2[CH:27]=[CH:28][C:20]([C:19]([N:4]3[CH2:5][CH2:6][N:1]([C:7]4[CH:16]=[CH:15][CH:14]=[C:13]5[C:8]=4[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]5)[CH2:2][CH2:3]3)=[O:29])=[CH:21][C:22]=2[O:23][CH2:24]1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(N3CCN(C(=O)c4ccc5c(c4)OCO5)CC3)cccc2n1
Yield: 54 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and piperonyloyl chloride (75.7 mg; 0.41 mmol) to obtain 42.5 mg. (54% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 7.39 (t, J=8.0 Hz, 1H), 7.15 (br s, 1H), 7.03 (s, 1H), 6.99 (m, 3H), 6.89 (dd, J=7.6, 0.8 Hz, 1H), 6.08 (s, 2H), 5.93 (br s, 2H), 3.27 (m, 4H), 3.06 (m, 2H), 2.76 (m, 2H). ESIMS+394.2 m/z
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:14][CH2:13][C@@:12]34[C:15]5[C:21]6[CH2:22][C@@H:6]2[C@@:7]23[CH2:34][CH2:33][C@:10]([O:35][CH3:36])([C@@H:11]4[O:17][C:16]=5[C:18]([O:23]CC3C=CC(OC)=CC=3)=[CH:19][CH:20]=6)[C@@H:9]([CH2:37][NH2:38])[CH2:8]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:46]1([CH3:56])[CH:51]=[CH:50][C:49]([S:52](Cl)(=[O:54])=[O:53])=[CH:48][CH:47]=1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]2[CH2:14][CH2:13][C@@:12]34[C:15]5[C:21]6[CH2:22][C@@H:6]2[C@@:7]23[CH2:34][CH2:33][C@:10]([O:35][CH3:36])([C@@H:11]4[O:17][C:16]=5[C:18]([OH:23])=[CH:19][CH:20]=6)[C@@H:9]([CH2:37][NH:38][S:52]([C:49]3[CH:50]=[CH:51][C:46]([CH3:56])=[CH:47][CH:48]=3)(=[O:54])=[O:53])[CH2:8]2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(COc2ccc3c4c2O[C@H]2[C@@]5(OC)CC[C@@]6(C[C@@H]5CN)[C@@H](C3)N(CC3CC3)CC[C@]426)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CO[C@]12CC[C@@]3(C[C@@H]1CNS(=O)(=O)c1ccc(C)cc1)[C@H]1Cc4ccc(O)c5c4[C@@]3(CCN1CC1CC1)[C@H]2O5
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Compound 5 (31 mg, 0.06 mmol, 1 eq) in DCM (2 mL) at 0° C. was added triethylamine (86 μL, 6.0 mmol, 10 eq.) followed by p-toluenesulfonyl chloride (34.3 mg, 0.18 mmol, 3 eq.). The reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with DCM and washed with saturated sodium bicarbonate solution. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated and the crude material dissolved in DCM (2 mL), TFA (0.5 mL) was added and the mixture stirred at 0° C. for 1 h. The residue, after evaporating the solvent, was purified by flash chromatography (SiO2, 1-5% MeOH (with 7% ammonia)/DCM) to provide Compound 124 as the free base. The free base was dissolved in DCM (1 mL) and 1M HCl in Et2O (1 mL) was added and the mixture stirred at 0° C. for 1 h. The solvents were evaporated and the residue was triturated with Et2O to give Compound 124 HCl salt as a white solid
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.[C:22]1([C:28](Cl)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[CH3:1][O:2][C:3]([CH:5]1[C:14]2[N:13]=[CH:12][N:11]([C:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:10]=2[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCCCc2[nH]cnc21
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCCCc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
To a solution of crude 1,4,5,6,7,8-hexahydrocycloheptaimidazole-4-carboxylic acid methyl ester (8.75 g, approx. 45.0 mmol, J. Am. Chem. Soc. 1976, 98, 984) in dichloromethane (100 ml) were added triethylamine (15.4 ml, 111 mmol) and a solution of triphenylmethyl chloride (18.5 g, 66.4 mmol) in dichloromethane (100 ml). The resulting mixture was stirred at 20° C. overnight. The mixture was washed with water and dried with magnesium sulfate. Filtration, concentration, and column chromatography (silica gel, gradient elution with heptane/ethyl acetate 9:1 to 1:1) yielded 5.5 g (28%) of the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29]C(=O)OCCCC)=[CH:25][CH:24]=3)[C:18]2=[O:37])[S:5][C:6]=1[C:7](=[O:16])[NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:19]2[CH2:20][CH2:21][N:17]([C:4]3[S:5][C:6]([C:7]([NH:8][CH2:9][C:10]4[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=4)=[O:16])=[C:2]([CH3:1])[CH:3]=3)[C:18]2=[O:37])=[CH:28][CH:27]=1
Reactant: CCCCOC(=O)Nc1ccc(CN2CCN(c3cc(C)c(C(=O)NCc4cccnc4)s3)C2=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N2CCN(Cc3ccc(N)cc3)C2=O)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A mixture of tent-butyl 4-((3-(4-methyl-5-(pyridin-3-ylmethylcarbamoyl)-thiophen-2-yl)-2-oxoimidazolidin-1-yl)methyl)phenylcarbamate (0.18 g, 0.34 mmol) and trifluoroacetic acid (2 mL) in dichloromethane (2 mL) was stirred at ambient temperature for 2 h and concentrated. The residue was taken up in saturated aqueous sodium bicarbonate solution (25 mL) and extracted with dichloromethane (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 0-10% methanol in dichloromethane to afford the title compound as a cream solid in 46% yield (0.07 g): mp 118-120° C.: 1H NMR (300 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.44 (s, 1H), 8.30 (t, J=5.9 Hz, 1H), 7.70 (d, J=7.9 Hz, 1H), 7.53 (dd, J=7.9, 4.8 Hz, 1H), 6.93 (d, J=8.4 Hz, 2H), 6.52 (d, J=8.4 Hz, 2H), 6.18 (s, 1H), 5.09 (br s, 2H), 4.38 (d, J=5.9 Hz, 2H), 4.18 (s, 2H), 3.80-3.72 (m, 2H), 3.40-3.32 (m, 2H), 2.36 (s, 3H): 13C NMR (75 MHz, DMSO-d6) δ 162.9, 155.3, 148.8, 148.0, 147.8, 142.7, 139.1, 135.4, 135.0, 128.9, 123.4, 123.0, 119.7, 113.8, 111.8, 46.8, 42.4, 40.9, 15.7; MS (ES+) m/z 422.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20]>CN(C=O)C>[C:11]1(=[O:20])[N:10]([CH2:9][O:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]12
Reactant: Oc1ccncc1
Reactant: O=C1c2ccccc2C(=O)N1CCl
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1COc1ccncc1
Temperature: 25 °C
Yield: 21 %

Procedure:
To a solution of 4.76 g (50 mmol) of 4-hydroxypyridine and 10.76 g (55 mmol) of N-chloromethylphthalimide. in 80 ml of DMF, 8.23 ml (55 mmol) of 1,8-diazabicyclo[5,4,0]-2-undecene was added. The mixture was stirred at room temperature for. 2 hours. After the solvent was distilled off, the reaction mixture was poured into water and extracted with ethyl acetate. The precipitate was filtered off. The aqueous layer was further extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 2.67 g of the desired compound (yield: 21%, colorless crystals). mp: 129.0°-131.0° C.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]4[N:28]=[CH:27][N:26](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:25]=4)=[O:23])=[CH:17][CH:16]=3)[NH:10][C:9]=2[C:8](=[O:48])[N:7]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[F:56])[C:6]1=[O:57])[CH2:2][CH2:3][CH3:4].[F:58][C:59]([F:64])([F:63])[C:60]([OH:62])=[O:61].C([SiH](CC)CC)C>ClCCl>[F:58][C:59]([F:64])([F:63])[C:60]([OH:62])=[O:61].[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22]([C:24]4[N:28]=[CH:27][NH:26][N:25]=4)=[O:23])=[CH:19][CH:20]=3)[NH:10][C:9]=2[C:8](=[O:48])[N:7]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[F:56])[C:6]1=[O:57])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NC(=O)c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc3)nc21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NC(=O)c4nc[nH]n4)cc3)nc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 40 %

Procedure:
A solution of 1-trityl-1H-[1,2,4]triazole-3-carboxylic acid {4-[3-butyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-amide (15 mg, 0.02 mmol) in dichloromethane (1.0 mL) at 25° C. was treated with trifluoroacetic acid (1.0 mL). The resulting solution was stirred at 25° C. for 45 min. At this time, the reaction was treated with triethylsilane (0.003 mL, 0.02 mmol). This solution was stirred at 25° C. for 5 min and then was concentrated in vacuo. The resulting residue was purified by HPLC (20–90% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 30 min). Fractions with the desired product were freeze dried to afford 1H-[1,2,4]triazole-3-carboxylic acid {4-[3-butyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-amide; compound with trifluoro-acetic acid (4.5 mg, 40%) as a white, fluffy solid: EI-HRMS m/e calcd for C26H25N8O3F (M+) 516.2033, found 516.2027.