Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42](Br)=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.[C:52]1(B(O)O)[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)C.O.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>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Br)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(-c5ccccc5)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 60 °C

Procedure:
To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (300 mg, 0.4 mmol, Step 2) in ethanol (2 mL) and water (0.5 mL) was added phenylboronic acid (143 mg, 0.8 mmol), PdCl2(PPh3)2 (41 mg, 0.058 mmol), and Cs2CO3 (390 mg, 1.2 mmol). The reaction was heated to 60° C. for 16 h, then cooled to RT, filtered through celite and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:6]=1[C:20]1[NH:29][C:28](=[O:30])[C:27]2[C:22](=[C:23](Br)[CH:24]=[CH:25][CH:26]=2)[N:21]=1)[CH2:2][CH3:3].[CH2:32]=[CH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:6]=1[C:20]1[NH:29][C:28](=[O:30])[C:27]2[C:22](=[C:23]([CH:32]=[CH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:24]=[CH:25][CH:26]=2)[N:21]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(S(=O)(=O)N2CCOCC2)cc1-c1nc2c(Br)cccc2c(=O)[nH]1
Reactant: C=CCCCCC
Product: CCCCCC=Cc1cccc2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCOCC4)ccc3OCCC)nc12
Yield: 53.2 %

Procedure:
The title compound is prepared analogously to the method of Example 1, starting with 2-(2-n-propoxy-5-morpholinosulfonylphenyl)-8-bromoquinazolin-4(3H)-one and 1-heptene.
Reaction SMILES: O[CH:2]([C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([CH:14]([CH3:16])[CH3:15])=[CH:7][C:6]=1[CH:17]([CH3:19])[CH3:18])[CH2:3][CH3:4].S(Cl)([Cl:22])=O>CCCCCC>[Cl:22][CH:2]([C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([CH:14]([CH3:16])[CH3:15])=[CH:7][C:6]=1[CH:17]([CH3:19])[CH3:18])[CH2:3][CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CCC(O)c1c(C(C)C)cc(C(C)C)cc1C(C)C
Solvent: CCCCCC
Product: CCC(Cl)c1c(C(C)C)cc(C(C)C)cc1C(C)C
Temperature: 25 °C
Yield: 87.4 %

Procedure:
A 100 milliliter flask was equipped with a magnetic stirrer and a pressure equalized addition funnel/drying tube. The flask was filled with a solution containing 50 milliliters of hexane and 15 grams (0.057 mole) of 1-(1-hydroxypropyl)-2,4,6-triisopropylbenzene (1-ethyl-2',4',6'-triisopropylbenzyl alcohol). The addition funnel was filled with a solution containing 10 milliliters of hexane and 8.9 grams (0.075 mole) of thionyl chloride. The solution of the thionyl chloride was slowly added to the solution of the 1-ethyl-2',4',6'-triisopropylbenzyl alcohol over a 45 minute period while stirring the reaction mixture. During the addition there was vigorous gas evolution, and after the addition the reaction mixture was left standing over night and then was cooled in an ice bath. After the reaction mixture was cooled, about 20 milliliters of ice water was rapidly added with stirring. After warming the reaction mixture to room temperature, the organic phase and water phase were separated, and the organic phase was washed with 5 portions of 20 milliliters of water, and then with a 20 milliliter solution of saturated sodium chloride. Then the organic phase was dried over magnesium sulfate and filtered. The solvent was evaporated from the organic phase using a rotary evaporator, to give 14.0 grams (92 percent) of a pale yellow liquid of the composition 1-(1-chloropropyl)-2,4,6-triisopropylbenzene.
Reaction SMILES: ClC1C=C(C)C2N=C(C3C=CC(OCCCN4C(=O)CCNCC4)=CC=3C)NC=2C=1.[C:31]([O:35][C:36]([N:38]1[CH2:44][CH2:43][C:42](=[O:45])[NH:41][CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].[H-].[Na+].I[CH2:49][CH2:50][CH2:51][O:52][C:53]1[CH:60]=[CH:59][C:56]([CH:57]=[O:58])=[C:55]([CH3:61])[CH:54]=1>CN(C=O)C.O>[C:31]([O:35][C:36]([N:38]1[CH2:44][CH2:43][C:42](=[O:45])[N:41]([CH2:49][CH2:50][CH2:51][O:52][C:53]2[CH:60]=[CH:59][C:56]([CH:57]=[O:58])=[C:55]([CH3:61])[CH:54]=2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)CC1
Reactant: Cc1cc(OCCCI)ccc1C=O
Agent: Cc1cc(OCCCN2CCNCCC2=O)ccc1-c1nc2c(C)cc(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCCCN2CCN(C(=O)OC(C)(C)C)CCC2=O)ccc1C=O
Reaction time: 0.5 h

Procedure:
4-{3-[4-(6-Chloro-4-methyl-1H-benzoimidazol-2-yl)-3-methyl-phenoxy]-propyl}-[1,4]diazepan-5-one. To a stirred solution of 5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester (3.0 g, 14.0 mmol, 1.0 equiv) in DMF (45 mL) at rt was added 60% sodium hydride (560 mg, 14.0 mmol, 1.0 equiv). After stirring for 30 min, 4-(3-iodo-propoxy)-2-methyl-benzaldehyde (4.26 g, 14.0 mmol, 1.0 equiv) was added as a solution in DMF (5 mL). The mixture was stirred for 16 h and then poured into water and extracted with ethyl acetate. The combined extracts were dried (Na2SO4), filtered, and concentrated. The residue was partially purified by column chromatography (silica gel, 5-50% ethyl acetate in hexanes) to afford 4-[3-(4-formyl-3-methyl-phenoxy)-propyl]-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester as a mixture with several unidentified products. This impure mixture (200 mg), 5-chloro-3-methyl-benzene-1,2-diamine (80.1 mg), and Na2S2O5 (97 mg) were stirred in DMF (1.0 mL) at 90° C. for 3 h. After cooling to rt, the reaction mixture was loaded on silica gel and was purified by Method 2 to afford 4-{3-[4-(6-chloro-4-methyl-1H-benzoimidazol-2-yl)-3-methyl-phenoxy]-propyl}-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester as a mixture with several unidentified products. This mixture was dissolved in dichloromethane (1.0 mL) and TFA (1.0 mL) and stirred at rt for 1 h. The reaction mixture was loaded on silica gel and purified by Method 2 to afford 91.0 mg (42%) of the title compound. MS (electrospray): mass calculated for C23H27ClN4O2, 426.18. m/z found, 427.4 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.55 (d, J=8.5 Hz, 1H), 7.42 (br s, 1H), 7.09-7.06 (m, 1H), 6.97 (d, J=2.4 Hz, 1H), 6.93 (dd, J=8.5, 2.5 Hz, 1H), 4.10 (t, J=6.1 Hz, 2H), 3.67-3.56 (m, 4H), 2.98-2.89 (m, 4H), 2.72-2.66 (m, 2H), 2.59 (s, 3H), 2.50 (s, 3H), 2.12-2.01 (m, 2H).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:11](=[O:40])[C:12](=[C:31]2[NH:35][C:34]3[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=3[NH:32]2)[C:13]([C:15]2[CH:16]=[C:17]([S:21]([NH:24][CH2:25][C:26]([O:28]CC)=[O:27])(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=2)=[O:14])[CH:7]=[C:8]([F:10])[CH:9]=1>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([C:11](=[O:40])[C:12](=[C:31]2[NH:32][C:33]3[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=3[NH:35]2)[C:13]([C:15]2[CH:16]=[C:17]([S:21]([NH:24][CH2:25][C:26]([OH:28])=[O:27])(=[O:22])=[O:23])[CH:18]=[CH:19][CH:20]=2)=[O:14])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: CCOC(=O)CNS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CNS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 87.9 %

Procedure:
An aqueous 1 M sodium hydroxide solution (3.1 mL) was added to a THF (10 mL) solution of the compound (300 mg) obtained in Example 2, followed by stirring at room temperature for 3.5 hours. THF was evaporated under reduced pressure, and 1 M hydrochloric acid was excessively added. The precipitate was collected by filtration and dried under reduced pressure to obtain [({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)amino]acetic acid (250 mg).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C:6]=2[N:7]=1.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=1.O(C(C)(C)C)[Na]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(C)C=CC=CC=1>[CH3:26][C:22]1[CH:21]=[C:20]([NH:1][C:2]2[N:3]=[CH:4][C:5]3[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C:6]=3[N:7]=2)[CH:25]=[CH:24][N:23]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cnc(N)nc2C1
Reactant: Cc1cc(Cl)ccn1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cc(Nc2ncc3c(n2)CN(C(=O)OC(C)(C)C)CC3)ccn1
Temperature: 90 °C
Yield: 33.2 %

Procedure:
A tube was charged with 187 (300 mg, 1.20 mmol), Pd(dba)2 (34.5 mg, 0.0599 mmol), Binap-rac (74.6 mg, 0.120 mmol), 4-chloro-2-methylpyridine (229 mg, 1.80 mmol), and NaO-tert-Bu (230 mg, 2.40 mmol) and toluene (3 mL), sealed, degassed with nitrogen for 5 min then heated to 90° C. for 4 h. The reaction was cooled and filtered through a plug of CELITE®. The filtrate was concentrated and purified by reverse phase column chromatography (SP4) eluting with a MeCN/H2O gradient (5 to 85% MeCN) to afford 136 mg (33.2%) of tert-butyl 2-(2-methylpyridin-4-ylamino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (188).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH2:38])=[N:5][CH:6]=[N:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[N:16]([CH2:31][CH2:32][N:33]3[CH2:36][CH:35]([F:37])[CH2:34]3)[CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)[N:19]=2)[CH2:11][CH2:10]1)[CH3:2].[F:39]C1(F)CN(CCN2C=C(C3C=CC(F)=C(C(F)(F)F)C=3)N=C2C2CCNCC2)C1>>[F:37][C:35]1([F:39])[CH2:34][N:33]([CH2:32][CH2:31][N:16]2[CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([C:27]([F:28])([F:30])[F:29])[CH:21]=3)[N:19]=[C:15]2[CH:12]2[CH2:11][CH2:10][N:9]([C:8]3[N:7]=[CH:6][N:5]=[C:4]([NH2:38])[C:3]=3[CH2:1][CH3:2])[CH2:14][CH2:13]2)[CH2:36]1
Reactant: Fc1ccc(-c2cn(CCN3CC(F)(F)C3)c(C3CCNCC3)n2)cc1C(F)(F)F
Reactant: CCc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN2CC(F)C2)CC1
Product: CCc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN2CC(F)(F)C2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-ethyl-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-(3-fluoroazetidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine using 4-(1-(2-(3,3-difluoroazetidin-1-yl)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine instead of 4-[1-[2-(3-Fluoro-azetidin-1-yl)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C([Sn](CCCC)(CCCC)[C:17]1[O:18][CH:19]=[CH:20][CH:21]=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>[Cl:1][C:2]1[N:3]=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2sccc2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: Clc1nc(-c2ccco2)c2sccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.5 %

Procedure:
A solution of 2,4-dichlorothieno[3,2-d]pyrimidine (205 mg, 1 mmol) in DMF (4 mL) was treated with PdCl2(PPh3)2 (35 mg, 0.05 mmol) and 2-(tributylstannyl)-furan (315 μL, 1 mmol), stirred at room temperature for 16 h, the reaction mixture purified directly by chromatography (SiO2:EtOAc:Heptane, 1:9) and the resulting cream solid recrystallised (EtOAc/Heptane) to give the title compound (122 mg, 52%) as a cream solid.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:17])[N:3]=1)=[CH:11][CH:10]=[C:9]([F:16])[CH:8]=3.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([Cl:25])[CH:24]=1.C([O-])([O-])=O.[K+].[K+]>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>[Cl:18][C:19]1[CH:20]=[C:21]([C:2]2[N:6]3[C:7]4[C:12]([N:13]=[C:14]([CH3:15])[C:5]3=[C:4]([CH3:17])[N:3]=2)=[CH:11][CH:10]=[C:9]([F:16])[CH:8]=4)[CH:22]=[C:23]([Cl:25])[CH:24]=1
Reactant: Cc1nc(Br)n2c1c(C)nc1ccc(F)cc12
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
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+]
Product: Cc1nc(-c2cc(Cl)cc(Cl)c2)n2c1c(C)nc1ccc(F)cc12
Yield: 77.7 %

Procedure:
Following the general Suzuki coupling procedure, reaction of bromide 5A (75 mg, 0.25 mmol), 3,5-dichlorophenylboronic acid (58 mg, 0.30 mmol), K2CO3 (105 mg, 0.75 mmol) and Pd(PPh3)4 (5.8 mg, 0.005 mmol) provided the coupling product as a white powder (70 mg, 78% yield). EIMS 360.0 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH2:37].[CH3:39][N:40]=[C:41]=[O:42]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:41]([NH:40][CH3:39])=[O:42]
Reactant: Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: CN=C=O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 52 %

Procedure:
The desired compound was prepared according to the procedure of Example B83, using 6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine bis(trifluoroacetate) and methyl isocyanate as the starting materials in 52% yield. LCMS for C19H19ClN7O (M+H)+: m/z=396.1. 1H NMR (400 MHz, DMSO-d6): δ 9.97 (s, 1H), 9.31 (s, 1H), 8.99 (m, 1H), 8.30 (m, 2H), 8.18 (s, 1H), 7.84 (m, 1H), 7.65 (d, 1H), 7.56 (d, 1H), 6.98 (dd, 1H), 6.40 (bs, 1H), 2.96 (m, 4H), 2.64 (d, 3H).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[NH:20]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1CN([P+](Cl)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([N:20]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:12])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: Cl[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N)C(=O)N(Cc1ccccc1)Cc1ccccc1

Procedure:
A solution of Boc-Arg-OH(1 eq), NH(CH2Ph)2 (1.1 eq) and PyCloP (1 eq) in dry DCM (filtered through alumina) (2 ml) and DMF (1 ml). The solution was cooled on ice and DIPEA (2 eq) was added under stirring. The solution was stirred for 1 h at room temperature. The reaction mixture was evaporated, and redissolved in ethyl acetate and washed with citric acid, sodium bicarbonate and brine. The solvent was removed under vacuum and the Boc protecting group of the resulting peptide was deprotected in the dark using 95% TFA.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([OH:24])[CH:20]=[C:21]([CH:23]=1)[OH:22]>>[CH3:15][O:16][C:17]1[CH:23]=[C:21]([O:22][S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:2]([CH3:1])(=[O:4])=[O:3])(=[O:13])=[O:12])[CH:20]=[C:19]([OH:24])[CH:18]=1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: COc1cc(O)cc(O)c1
Product: COc1cc(O)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Yield: 80 %

Procedure:
The title compound was prepared in 80% yield from 2-methylsulfonylbenzenesulfonyl chloride and 5-methoxyresorcinol in a manner analogous to step a of Example 1. 1H-NMR (300 MHz, CDCl3) δ8.42 (d, J=7.8 Hz, 1H), 8.13 (d, J=7.8 Hz, 1H), 7.88 (t, J=7.8 Hz, 1H), 7.75 (t, J=7.7 Hz, 1H), 6.36 (s, 1H), 6.31 (s, 1H), 6.28 (s, 1H), 3.68 (s, 3H), 3.45 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[O:5][CH2:6][CH:7]1[O:11][C:10](=[O:12])[N:9]([C:13]([CH3:26])([CH3:25])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[CH2:8]1.C(OCC)(=O)C.[BH4-].[Na+]>C(O)(C)(C)C>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:13]([N:9]2[CH2:8][CH:7]([CH2:6][O:5][C:4]3[CH:27]=[CH:28][CH:29]=[C:2]([Cl:1])[CH:3]=3)[O:11][C:10]2=[O:12])([CH3:25])[CH3:26])=[CH:17][CH:18]=1
Reactant: CC(C)(COc1ccc([N+](=O)[O-])cc1)N1CC(COc2cccc(Cl)c2)OC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CC(C)(COc1ccc(N)cc1)N1CC(COc2cccc(Cl)c2)OC1=O
Reaction time: 6 h
Yield: 90.2 %

Procedure:
6.32 g of stannous chloride dihydrate were added to a solution of 2.34 g of 5-(3-chlorophenoxymethyl)-3-[2-(4-nitrophenoxy)-1,1-dimethylethyl]oxazolidin-2-one (prepared as described in Preparation 108) in 70 ml of a 9:1 by volume mixture of ethyl acetate and t-butanol. 0.11 g of sodium borohydride was then added to the mixture over an oil bath at 66° C. The mixture was stirred at the same temperature for 6 hours. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and the residue was neutralized by adding an aqueous sodium hydrogencarbonate solution. The insolubles which had precipitated were removed by filtration, and the filtrate was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extract by evaporation under reduced pressure, to give 1.96 g of the title compound having an Rf value of 0.34 (on silica gel thin layer chromatography, using a 4:1 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6](=[O:10])[CH:7]([CH3:9])[CH3:8])[CH3:2].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH:24]=[CH:23][CH:22]=[N:21]2)=[CH:16][CH:15]=1>>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH:24]=[CH:23][CH:22]=[N:21]2)=[CH:18][CH:19]=1)[C:6](=[O:10])[CH:7]([CH3:8])[CH3:9])[CH3:2]
Reactant: BrCc1ccc(-n2cccn2)cc1
Reactant: CCOC(=O)CC(=O)C(C)C
Product: CCOC(=O)C(Cc1ccc(-n2cccn2)cc1)C(=O)C(C)C

Procedure:
The title compound was prepared by the method of Preparation 1b using 4-methyl-3-oxopentanoic acid ethyl ester and 1-(4-bromomethylphenyl)-1H-pyrazole.
Reaction SMILES: [CH:1](NC(=NC(C)C)OCC)(C)[CH3:2].[CH3:13][C:14]1([CH3:26])[C@@H:16]([CH:17]=[C:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C@H:15]1[C:23]([OH:25])=[O:24]>C(OCC)(=O)C>[CH3:13][C:14]1([CH3:26])[C@@H:16]([CH:17]=[C:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C@H:15]1[C:23]([O:25][CH2:1][CH3:2])=[O:24]
Reactant: CCOC(=NC(C)C)NC(C)C
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C=C1CCCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1[C@H](C=C2CCCC2)C1(C)C
Yield: 15.7 %

Procedure:
7.5 g of ethyl N,N'-diisopropyl-carbamimidate were added to a solution of 7.8 g of (1R,cis) 2,2-dimethyl-3-cyclopentylidenemethyl-cyclopropane-1-carboxylic acid in 20 ml of ethyl acetate and the mixture was refluxed for 2 hours and was filtered. The filtrate was evaporated to dryness and the 13 g of residue were chromatographed over silica gel. Elution with a 7-3 cyclohexane-ethyl acetate mixture and the fraction with a Rf=0.45 was evaporated to dryness under reduced pressure to obtain 1.4 g of ethyl (1R,cis) 2,2-dimethyl-3-cyclopentylidenemethyl-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+76°±2° (c=1% in ethanol).
Reaction SMILES: CC1[O:3][C@H:4]([C:10]([O:12]C)=[O:11])[C@H:5]([CH2:7][CH2:8][CH3:9])[N:6]=1.[ClH:14]>>[ClH:14].[NH2:6][C@@H:5]([CH2:7][CH2:8][CH3:9])[C@H:4]([OH:3])[C:10]([OH:12])=[O:11]
Reactant: CCC[C@@H]1N=C(C)O[C@@H]1C(=O)OC
Agent: Cl
Product: CCC[C@H](N)[C@H](O)C(=O)O
Temperature: 100 °C
Reaction time: 14 h
Yield: 90 %

Procedure:
Methyl (4S,5S)-2-methyl-4-propyl-4,5-dihydro-1,3-oxazole-5-carboxylate (0.68 g, 3 mmol) and 6 N hydrochloric acid (10 ml) were mixed, and the mixture was stirred at 100° C. for 14 hours. The solvent was evaporated away under reduced pressure to obtain the title compound as a white solid (0.50 g, yield: 90%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:19])[CH:10]([CH2:20][NH2:21])[N:9]=1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[C:31](Cl)=[O:32].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:19])[CH:10]([CH2:20][NH:21][C:31]([C:23]2[NH:22][C:30]3[C:25]([CH:24]=2)=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:32])[N:9]=1
Reactant: NCC1N=C(c2ccccc2F)c2ccccc2NC1=O
Reactant: O=C(Cl)c1cc2ccccc2[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1N=C(c2ccccc2F)c2ccccc2NC1=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 32.4 %

Procedure:
1,3-Dihydro-5-(2-fluorophenyl)-3(RS)-aminomethyl-2H-1,4-benzodiazepin-2-one (80 mg, 0.282 mmole) and indole-2-carbonyl chloride (53 mg, 0.30 mmol) were mixed in 5 ml of methylene chloride at room temperature. The homogeneous reaction mixture was protected from moisture and treated with 42 l (0.30 mmole) of triethylamine. Within five min., triethylamine hydrochloride precipitated. The reaction mixture was stirred at room temperature overnight and then partitioned between methylene chloride and saturated sodium bicarbonate solution. The resulting solid was collected, washed with water and dried over P2O5 at 70° C. In this way, 39 mg of the analytical product was obtained, m.p.: 315°-317° (d).
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.F[C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:21])[NH:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1>CN(C=O)C.O>[N:7]1[CH:8]=[CH:9][C:4]([S:3][C:11]2[CH:20]=[C:19]3[C:14]([C:15](=[O:21])[NH:16][CH:17]=[N:18]3)=[CH:13][CH:12]=2)=[CH:5][CH:6]=1
Reactant: Sc1ccncc1
Reactant: O=c1[nH]cnc2cc(F)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]cnc2cc(Sc3ccncc3)ccc12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 21.8 %

Procedure:
Sodium hydride (3.3 g of a 50% suspension in mineral oil, 69 mmol) was added to a solution of 4-mercaptopyridine (8.12 g, 73 mmol) in DMF (100 ml) and the mixture stirred for 30 minutes. 7-Fluoro-3,4-dihydroquinazolin-4-one (1.5 g, 9 mmol) was added and the reaction heated at 100° C. for 4 hours. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The organic extracts were washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (97/3) to give 7-(4-pyridylthio)-3,4-dihydroquinazolin-4-one (500 mg, 6%).