Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][C:11]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)=[CH:12][CH:13]=3)[C:8]2=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[CH2:32][CH:33]=O)=[CH:27][CH:26]=1>>[CH:1]1([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][C:11]([N:16]4[CH2:17][CH2:18][N:19]([CH2:33][CH2:32][CH:31]([C:28]5[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=5)[C:35]5[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=5)[CH2:20][CH2:21]4)=[CH:12][CH:13]=3)[C:8]2=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(C(CC=O)c2ccc(OC)cc2)cc1
Reactant: O=C1c2cc(N3CCNCC3)ccc2CN1C1CCCCC1
Product: COc1ccc(C(CCN2CCN(c3ccc4c(c3)C(=O)N(C3CCCCC3)C4)CC2)c2ccc(OC)cc2)cc1
Yield: 59.8 %

Procedure:
In the same manner as in Example 38, the title compound (52 mg) was prepared from the compound (47 mg) obtained in step (e) of Example 1 and the compound (110 mg) obtained in step (b).
Reaction SMILES: [C:1]([O:7][C:8]1[CH:42]=[CH:41][C:11]([C:12]([O:14][C:15]2[CH:16]=[C:17]([CH:37]([OH:40])[CH2:38]Br)[CH:18]=[C:19]([O:21][C:22](=[O:36])[C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:25][CH:24]=3)[CH:20]=2)=[O:13])=[CH:10][CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:43]([NH2:47])([CH3:46])([CH3:45])[CH3:44].C(Cl)[Cl:49]>>[ClH:49].[C:1]([O:7][C:8]1[CH:42]=[CH:41][C:11]([C:12]([O:14][C:15]2[CH:16]=[C:17]([CH:37]([OH:40])[CH2:38][NH:47][C:43]([CH3:46])([CH3:45])[CH3:44])[CH:18]=[C:19]([O:21][C:22](=[O:36])[C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:25][CH:24]=3)[CH:20]=2)=[O:13])=[CH:10][CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Oc1ccc(C(=O)Oc2cc(OC(=O)c3ccc(OC(=O)C(C)(C)C)cc3)cc(C(O)CBr)c2)cc1
Reactant: CC(C)(C)N
Reactant: ClCCl
Product: CC(C)(C)NCC(O)c1cc(OC(=O)c2ccc(OC(=O)C(C)(C)C)cc2)cc(OC(=O)c2ccc(OC(=O)C(C)(C)C)cc2)c1
Product: Cl

Procedure:
A solution of 3.2 g (0.005 moles) of 1-[3',5'-bis-(4-pivaloyloxybenzoyloxy)phenyl]-2-bromoethanol and 1.1 g (0.015 moles) of t-butylamine in 100 ml of methylene chloride was boiled under reflux for 18 hrs. After evaporation to dryness, diethyl ether was added to the residue. The precipitated t-butylamino hydrobromide (0.2 g) was filtered off and the filtrate was then acidified with ethanolic hydrochloric acid. HPLC analysis of this solution showed the presence of the title compound as compared with an authentic sample. ##STR63## The 1-[3',5'-bis-(4-pivaloyloxybenzoyloxy)phenyl]-2-bromoethanol which was used as starting material was prepared as follows.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([CH3:26])[S:17]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)(=[O:19])=[O:18])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.C(N[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].CC(C)=O.[CH3:50][C:51]([N:53](C)[CH3:54])=[O:52].O>C(OCC)(=O)C.O>[ClH:1].[CH3:26][N:16]([S:17]([C:20]1[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=1)(=[O:19])=[O:18])[CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][N:8]([C:3]2[C:2]([C:31]3[CH:32]=[CH:33][C:34]([CH2:54][NH:53][C:51](=[O:52])[CH3:50])=[CH:35][CH:36]=3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:9][CH2:10]1
Reactant: CC(=O)N(C)C
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Reactant: CN(CCN1CCN(c2nccnc2Cl)CC1)S(=O)(=O)c1cnn(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)NCc1ccc(-c2nccnc2N2CCN(CCN(C)S(=O)(=O)c3cnn(C)c3)CC2)cc1
Product: Cl
Temperature: 110 °C
Yield: 50 %

Procedure:
Dissolve 1-methyl-1H-pyrazole-4-sulfonic acid [2-(3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-ethyl]-methyl-amide (200 mg, 0.483 mmol) in DMA-H2O (10 ml; 3:1 v/v, previously degassed with nitrogen). Add 4-acetamidophenyl boronic acid (112 mg, 0.580 mmol), potassium carbonate (160 mg, 1.16 mmol) and tetrakis(triphenyl-phosphine)palladium (28 mg, 0.024 mmol). Heat the reaction mixture at 110° C. for 18 hr. Cool and dilute with ethyl acetate and water. Extract the aqueous layer with ethyl acetate and combine the organic layers. Wash the combined organic layers with brine and concentrate. Purify by chromatography, eluting with 1:2 hexanes:acetone to afford the free base of the title compound (124 mg, 50% yield) as a white foam.
Reaction SMILES: Cl/[C:2](=[N:8]\[OH:9])/[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[CH:11].C(N(CC)CC)C>CCOCC>[C:12]1([C:10]2[O:9][N:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:11]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C#Cc1ccccc1
Reactant: CCOC(=O)/C(Cl)=N/O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)c1cc(-c2ccccc2)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a mixture of (Z)-ethyl 2-chloro-2-(hydroxyimino)acetate (3.03 g, 20 mmol) and ethynylbenzene (4.39 mL, 40 mmol) in ether (80 mL) at room temperature was added a solution of triethylamine (5.58 mL, 40.0 mmol) in ether (20 mL) dropwise over 60 minutes. The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was filtered, and the filtrate was concentrated to a yellow oil which was purified by flash silica gel chromatography using a mixture of ethyl acetate in hexane (0-12%) to afford ethyl 5-phenylisoxazole-3-carboxylate (3.06 g, 14.09 mmol, 70% yield) as a white solid. The compound had an HPLC retention time=2.99 minutes (YMC-Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS:(M+H)=218.12. 1H-NMR (400 MHz, CDCl3) δ ppm 1.45 (t, J=7.3Hz, 3H), 4.48 (q, J=7.3, 2H), 6.93 (s, 1H), 7.45-7.53 (m, 3H), and 7.77-7.85 (m, 2H).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[C:6]([OH:10])[C:5](Br)=[CH:4][C:3]=1[CH2:12][C:13]([CH3:21])([CH3:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C>C(O)C.[Pd]>[OH:10][C:6]1[CH:5]=[CH:4][C:3]([CH2:12][C:13]([CH3:20])([CH3:21])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:2][C:7]=1[O:8][CH3:9]
Reactant: CCOC(=O)CC(C)(C)Cc1cc(Br)c(O)c(OC)c1Br
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CC(C)(C)Cc1ccc(O)c(OC)c1
Reaction time: 1 h
Yield: 54.9 %

Procedure:
A mixture of the product of STEP 5 (0.525 g, 1.3 mmol), 20% Pd/C, triethylamine (0.39 g, 3.9 mmol) in ethanol was subjected to hydrogenation conditions at 40 psi and room temperature for 1 h. The reaction was filtered through a short column of Celite® and concentrated. The residue was purified by chromatography (on silica gel, ethyl acetate/hexane=1/3) to afford 0.19 g colorless oil. NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: [C:1]([C:9]1[O:10][C:11]2[CH:35]=[CH:34][CH:33]=[CH:32][C:12]=2[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:21]=2)=[CH:16][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:37]([C:40]1[CH:48]=[CH:47][C:43]([C:44]([OH:46])=[O:45])=[C:42]([OH:49])[CH:41]=1)(=[O:39])=[O:38]>>[C:1]([C:9]1[O:10][C:11]2[CH:35]=[CH:34][CH:33]=[CH:32][C:12]=2[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][S:37]([C:40]3[CH:48]=[CH:47][C:43]([C:44]([OH:46])=[O:45])=[C:42]([OH:49])[CH:41]=3)(=[O:39])=[O:38])=[C:22]([CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)[CH:21]=2)=[CH:18][CH:19]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: O=C(c1ccccc1)c1oc2ccccc2c1-c1ccc(-c2ccc(O)c(C3CCCC3)c2)cc1
Product: O=C(O)c1ccc(S(=O)(=O)Oc2ccc(-c3ccc(-c4c(C(=O)c5ccccc5)oc5ccccc45)cc3)cc2C2CCCC2)cc1O

Procedure:
The title compound was prepared from 4′-(2-benzoyl-benzofuran-3-yl)-3-cyclopentyl-biphenyl-4-ol and 4-chlorosulfonyl-2-hydroxy-benzoic acid, in substantially the same manner, as described in Example 1 step g, and was obtained as a yellow solid, mp 105-108° C.; MS m/e 694 (M-H)+;
Reaction SMILES: COC([N:5]1[CH2:9][CH:8]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH:7]2[N:20]([C:23](=[O:39])[CH:24]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:21][CH2:22][CH:6]12)=O.C([O-])([O-])=O.[K+].[K+].Br[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49]>C(#N)C.O>[CH2:51]([O:50][C:48](=[O:49])[CH2:47][N:5]1[CH2:9][CH:8]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH:7]2[N:20]([C:23](=[O:39])[CH:24]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:21][CH2:22][CH:6]12)[CH3:52]
Reactant: COC(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CN1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 82.9 %

Procedure:
A solution containing amine 50 (200 mg, 0.41 mmol) in ACN (5 mL) was cooled to 0° C. K2CO3 (63 mg, 0.46 mmol) was added followed by ethyl bromoacetate (75 mg, 0.45 mmol) and the reaction mixture was warmed to ambient temperature. After 16 h, the reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (1:1 hexanes/EtOAc) to afford 194 mg (82%) of 58 as an off-white-colored foam. 1H NMR (300 MHz, CDCl3), mixture of amide rotamers: δ8.50 (s, 0.8H), 8.29 (s, 0.2H), 7.55 (dd, J=5.4, 8.7 Hz, 1H), 7.11 (s, 1H), 6.99 (d, J=9.0 Hz, 0.2H), 6.82 (d, J=9.6 Hz, 0.8H), 5.30-5.24 (m, 1H), 4.85-4.82 (m, 1H), 4.34 (t, J=6.0 Hz, 1H), 4.23-4.07 (m, 2H), 3.93 (t, J=8.7 Hz, 1H), 3.68-3.64 (m, 2H), 3.59-3.54 (m, 2H), 3.44-3.40 (m, 2H), 2.82 (app t, J=9.0 Hz, 1H), 2.05-2.01 (m, 1H), 1.83-1.65 (m, 6H), 1.38 (s, 9H), 1.28 (t, J=6.9 Hz, 3H), 1.24-1.05 (m, 2H) ppm. Mass spectrum, m/z [571.4] (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[NH2:38][CH2:39][CH:40]([OH:43])[CH2:41][OH:42]>>[OH:43][CH:40]([CH2:41][OH:42])[CH2:39][NH:38][C:21]([N:11]1[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)([CH3:13])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)([CH3:37])[N:9]=[C:10]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:26][C:25]=1[O:34][CH2:35][CH3:36])=[O:22]
Reactant: NCC(O)CO
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)NCC(O)CO

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 3-amino-propane-1,2-diol (Aldrich) to give the title compound as a mixture of diastereomers. HR-MS (ES, m/z) calculated for C30H31N3O4F3Cl2 [(M+H)+] 624.1638, observed 624.1641.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)=[O:8])=[CH:5][NH:4][N:3]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17](S(O)(=O)=O)=[CH:16][CH:15]=1.[CH2:25](O)[CH3:26]>>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:7]([C:6]1[CH:5]=[N:4][N:3]2[C:24]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:26][CH:25]=[N:1][C:2]=12)=[O:8]
Reactant: Nc1n[nH]cc1C(=O)c1ccco1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCO
Product: O=C(c1ccco1)c1cnn2c(-c3ccccc3)ccnc12

Procedure:
A mixture of 0.86 g of (3-amino-1H-pyrazol-4-yl)-2-furanylmethanone and 0.63 g of 1-phenyl-1-propynone in 25 ml of ethanol with a catalytic amount of p-toluenesulfonic acid was heated on a steam bath for 1.5 hours. The mixture was chilled and then filtered giving 1.0 g of yellow solid. This solid was dissolved in a small amount of dichloromethane and placed on a silica gel column. The column was eluted with ethyl acetate:hexane (1:20) with a gradual change to ethyl acetate:hexane (2:5) as eluent. The column was then washed with ethyl acetate and the ethyl acetate wash was concentrated to a solid. This solid was cyrstallized from dichloromethane, giving 0.85 g of the desired product as cream crystals having a melting point of 188°-190° C. and a pmr spectrum identical to that of the product prepared as described in Example 22.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:20]=1[C:21](O)=O>>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:20]=1[C:21]1[O:14][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:15][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: COc1ccc(OC)c(C(=O)O)c1
Product: COc1ccc(OC)c(-c2nnc(-c3c(-c4ccccc4)noc3C)o2)c1
Yield: 53 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 2,5-dimethoxybenzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=75:5:20 to 60:20:20, 176 mg, 53%) which was obtained as a white solid. MS: m/e=364.2 [M+H]+.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:11])[C:7](C)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N)(C)(C)C.C(N(CC)CC)C.C(Cl)(=O)C(C)C>>[C:1]([NH:5][C:6](=[O:11])[CH:7]([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)C(C)(C)C
Agent: CC(C)C(=O)Cl
Solvent: CC(C)(C)N
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NC(C)(C)C
Yield: 96 %

Procedure:
In a fashion similar to the preparation of LtBu,tBuH, treatment of tert-butylamine (11.3 mL, 105 mmol) and triethylamine (14.9 mL, 105 mmol) with isobutyryl chloride (10.8 mL, 100 mmol) afforded LiPr,tBuH as white crystalline solid (13.75 g, 96%) upon sublimation at 55° C./0.05 Torr: mp 117-119° C.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:14]=[C:15]([F:21])[C:16]([F:20])=[C:17]([F:19])[CH:18]=1)#[CH:12].N>>[F:19][C:17]1[CH:18]=[C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[CH:12]=2)[CH:14]=[C:15]([F:21])[C:16]=1[F:20]
Reactant: C#Cc1cc(F)c(F)c(F)c1
Reactant: ON=C(Cl)c1cccnc1
Agent: N
Product: Fc1cc(-c2cc(-c3cccnc3)no2)cc(F)c1F

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 5-ethynyl-1,2,3-trifluorobenzene (Apollo, 78 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.69 (dd, J=7.9, 4.8 Hz, 1H), 7.85 (s, 1H), 7.95 (dd, J=8.7, 6.7 Hz, 2H), 8.35 (dt, J=8.1, 1.7 Hz, 1H), 8.79 (d, J=3.6 Hz, 1H), 9.11 (s, 1H) ppm; MS (DCI/NH3) m/z 277 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@H:9]([C:12]#[CH:13])[CH2:10][OH:11].S=[C:15]1[CH2:19][S:18][C:17](=[O:20])[NH:16]1.C(N(C(C)C)C(C)C)C>C(O)C>[OH:11][CH2:10][C@H:9]([NH:8][C:15]1[CH2:19][S:18][C:17](=[O:20])[N:16]=1)[C:12]#[CH:13]
Reactant: C#C[C@@H](N)CO
Reactant: O=C1NC(=S)CS1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: C#C[C@H](CO)NC1=NC(=O)SC1
Yield: 20.1 %

Procedure:
To a solution of (R)-2-aminobut-3-yn-1-ol trifluoroacetate (601 mg) in ethanol (15 mL) were added 4-thioxo-1,3-thiazolidin-2-one (402 mg) and N-ethyl-N-(1-methylethyl)propan-2-amine (1.63 mL), and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate), and the obtained powder was washed with ethyl acetate to give the title compound (112 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[CH:21]=[CH2:22])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[C:15]([CH:21]=[CH2:22])[CH:16]=1
Reactant: C=Cc1cc(C)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: C=Cc1cc(C)ccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.7 %

Procedure:
A mixture of 4-bromo-3-chlorotoluene (2.1 g), Boc-piperazine (1.9 g), palladium acetate (112 mg), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (312 mg), sodium tert-butoxide (1.4 g) and toluene (20 mL) was refluxed for 5 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give 4-(2-chloro-4-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester (3.1 g). To a mixture of 4-(2-chloro-4-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester (932 mg), 2,4,6-trivinylcyclotriboroxane pyridine complex (1 g), palladium acetate (74 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (271 mg) and potassium fluoride (697 mg) was added tetrahydrofuran (4 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give 4-(4-methyl-2-vinylphenyl)piperazine-1-carboxylic acid tert-butyl ester (0.9 g). 4-(4-Methyl-2-vinylphenyl)piperazine-1-carboxylic acid tert-butyl ester (0.9 g) was dissolve in chloroform (2 mL), 4N hydrogen chloride/ethyl acetate (1 mL) was added, and the mixture was stirred at room temperature for 3 hr. 1N aqueous sodium hydroxide solution (8 mL) was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated to give 1-(4-methyl-2-vinylphenyl)piperazine (606 mg). 1-(4-Methyl-2-vinylphenyl)piperazine (606 mg) was dissolved in tetrahydrofuran (8 mL), 4-iodobenzoyl chloride (1.1 g) and 1N aqueous sodium hydroxide solution (4 mL) were added, and the mixture was stirred at room temperature overnight. The mixture was extracted with ethyl acetate, washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give the title compound (1 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][N:6]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2[NH:14][C:15]([CH:18]=O)=[C:16]([CH3:17])[C:8]=2[C:7]1=[O:20])[CH3:2].[Br:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27]2>>[Br:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])/[C:27]/2=[CH:18]\[C:15]1[NH:14][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][N:6]([CH2:5][CH2:4][N:3]([CH2:21][CH3:22])[CH2:1][CH3:2])[C:7](=[O:20])[C:8]=2[C:16]=1[CH3:17]
Reactant: CCN(CC)CCN1CCCCc2[nH]c(C=O)c(C)c2C1=O
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: CCN(CC)CCN1CCCCc2[nH]c(/C=C3\C(=O)Nc4ccc(Br)cc43)c(C)c2C1=O
Yield: 68 %

Procedure:
The title compound was prepared under the same conditions as described in step 6 of Example 60 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7,8,9-hexahydro-1H-1,5-diaza-cyclopentacyclooctene-2-carbaldehyde 60e obtained from step 5 of Example 60 and 5-bromo-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-2-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-diethylamino-ethyl)-3-methyl-6,7,8,9-tetrahydro-1H,5H-1,5-diaza-cyclopentacycloocten-4-one 61 (16 mg, yield 68%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:14]([OH:16])=[O:15])=[C:6]2[C:10]=1[O:9][CH:8]([CH2:11][O:12][CH3:13])[CH2:7]2.Cl[C:18]1[N:27]=[CH:26][C:25]2[N:24]([CH3:28])[C:23](=[O:29])[C@@H:22]([CH2:30][CH3:31])[N:21]([CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[C:20]=2[N:19]=1.Cl>C(O)C.O>[CH:32]1([N:21]2[C:20]3[N:19]=[C:18]([NH:1][C:2]4[CH:3]=[CH:4][C:5]([C:14]([OH:16])=[O:15])=[C:6]5[C:10]=4[O:9][CH:8]([CH2:11][O:12][CH3:13])[CH2:7]5)[N:27]=[CH:26][C:25]=3[N:24]([CH3:28])[C:23](=[O:29])[C@H:22]2[CH2:30][CH3:31])[CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Reactant: COCC1Cc2c(C(=O)O)ccc(N)c2O1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OC(COC)C4)nc2N1C1CCCC1
Yield: 44.5 %

Procedure:
7-Amino-2-(methoxymethyl)-2,3-dihydrobenzofuran-4-carboxylic acid 40d (160 mg, 0.70 mmol) and (7R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydro-5H-pteridin-6-one 1o (232 mg, 0.80 mmol) were dissolved in 34 mL of the mixture solvent of ethanol and water (V:V=1:2.4) followed by the addition of 0.4 mL of concentrated hydrochloric acid. The reaction solution was heated to reflux for 16 hours with stirring, then cooled down resulting in the formation of precipitate. The precipitate was filtered to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2-(methoxymethyl)-2,3-dihydrobenzofuran-4-carboxylic acid 40e (0.15 g, yield: 43.0%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1.C(OCC)(=O)C>[NH2:13][CH2:12][C:11]1[C:2]([NH2:1])=[N:3][C:4]2[C:9]([C:10]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1ccc(-c2c(C#N)c(N)nc3ccccc23)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2c(CN)c(N)nc3ccccc23)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 10.7 %

Procedure:
A solution of 2-amino-4-p-tolyl-quinoline-3-carbonitrile (46 mg, 0.177 mmol) in THF (0.5 ml) was added slowly to a suspension of LiAlH4 (67.3 mg, 1.77 mmol) in THF (1 ml) under an atmosphere of argon. The mixture was stirred for 2 h at 40° C. Upon cooling to −20° C., 0.3 ml water added and stirring was continued for 15 min at r.t. The mixture was taken up in ethyl acetate and filtered through dicalite. The filtrate was washed with water and brine, dried (Na2SO4), and evaporated. Purification of the re-dissolved (DMF, 1 ml) residue by automated, preparative HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min) gave 5 mg (11%) of the title compound as a solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH3:9][C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13].[ClH:16]>CN(C)C=O>[ClH:16].[N:1]1[CH:2]=[CH:3][C:4]([CH:7]=[C:11]([C:10](=[O:15])[CH3:9])[C:12](=[O:14])[CH3:13])=[CH:5][CH:6]=1
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)C(=Cc1ccncc1)C(C)=O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution containing 1.1 g of pyridine-4-carboxaldehyde and 1.0 g of 2,4-pentanedione in 10 ml of N,N-dimethylformamide was saturated with hydrogen chloride gas at 20° C. The solution was stirred for 1 h at 20° C. and then for 2 h at 80° C. The solvent was evaporated in vacuo and the residue was crystallized from ethanol. Yield 0.17 g, mp 175°-186° C.