Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([OH:17])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH2:43][C:44]([NH:46][C:47]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)=[O:21]>>[CH2:1]([NH:8][C:9](=[O:10])[NH:11][N:12]([CH2:14][C:15]([NH:18][C@@H:19]([CH2:43][C:44](=[O:45])[NH:46][C:47]([C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)=[O:21])=[O:17])[CH3:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CN(C)NC(=O)NCc1ccccc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-3) 55 mg (0.23 mmol) was coupled with (S)-2-amino-N1—((S)-1,1-diethoxypropan-2-yl)-N1-(quinolin-8-ylmethyl)-N4-tritylsuccinamide (Compound IV-20) 100 mg (0.16 mmol) to obtain the title compound.
Reaction SMILES: [N+]([C:4]1C=CC(CCN)=CC=1)([O-])=O.[CH3:13][O:14][C:15]1N=[C:19]([NH:21][C@@H:22]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:23]([OH:25])=[O:24])[CH:18]=[C:17]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=2)[N:16]=1>>[CH3:13][O:14][C:15]1[CH:4]=[C:19]([NH:21][C@@H:22]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[C:23]([OH:25])=[O:24])[CH:18]=[C:17]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=2)[N:16]=1
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(C[C@H](Nc2cc(-c3cccc(OC)c3)nc(OC)n2)C(=O)O)cc1
Product: COc1ccc(C[C@H](Nc2cc(OC)nc(-c3cccc(OC)c3)c2)C(=O)O)cc1

Procedure:
By proceeding in a similar manner to Example 43(b) but substituting L-O-methyl tyrosine for 2-(4-nitro-phenyl)-ethylamine in Step 3 there is prepared (2S)-2-[2-Methoxy-6-(3-methoxy-phenyl)-pyrimidin-4-ylamino]-3-(4-methoxy-phenyl)-propionic acid [40.2 mg, 45%, Example 43(n)] as a solid. LC/MS: RT=2.38 minutes, MS: 410 (M+H). 1H NMR [300 MHz, (CD3)2SO]: □12 (1H, br s), 7.62 (1H, m), 7.49 (1H, m), 7.38 (1H, m), 7.18 (2H, m), 7 (1H, m), 6.8 (2H, m), 6.73 (1H, s), 4.59 (1H, m), 3.8 (3H, s), 3.78 (3H, s), 3.68 (3H, s), 3.1 (1H, m), 2.94 (1H, m). IC50=548 nM
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].[C:10]([NH:14][C:15]([C:17]1[S:39][C:20]2[N:21]=[C:22]([S:37][CH3:38])[N:23]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:32]([CH:35]=[CH2:36])(=[O:34])=[O:33])[CH:26]=3)[C:19]=2[C:18]=1[NH2:40])=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([NH:14][C:15]([C:17]1[S:39][C:20]2[N:21]=[C:22]([S:37][CH3:38])[N:23]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:32]([CH2:35][CH2:36][N:5]([CH2:6][CH2:7][O:8][CH3:9])[CH2:4][CH2:3][O:2][CH3:1])(=[O:34])=[O:33])[CH:26]=3)[C:19]=2[C:18]=1[NH2:40])=[O:16])([CH3:12])([CH3:11])[CH3:13]
Reactant: C=CS(=O)(=O)Nc1cccc(-c2nc(SC)nc3sc(C(=O)NC(C)(C)C)c(N)c23)c1
Reactant: COCCNCCOC
Product: COCCN(CCOC)CCS(=O)(=O)Nc1cccc(-c2nc(SC)nc3sc(C(=O)NC(C)(C)C)c(N)c23)c1
Reaction time: 0.5 h

Procedure:
Reaction of bis-(2-methoxyethyl) amine (244 mg) with tert-butyl 5-amino-2-methylthio-4-(3-(vinylsulfonamido)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 10, 87 mg) was performed according to the method described in example 11. The title compound was first purified by chromatography on silica gel with hept/EtOAc=3/2 (v/v) as eluent and then by HPLC using a Luna C-18 column with the following gradient: CH3CN/0.1% aq. TFA=10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and 0.1% aq TFA.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6](Cl)(C)[CH:5](Cl)[CH2:4][C:3]=1/[CH:11]=[CH:12]/Cl.[CH:14]1C=C(CN)C=C(CN)C=1.CC(N=NC(C#N)(C)C)(C#N)C>>[CH:1]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:11]=[CH:12][CH:14]=1
Reactant: NCc1cccc(CN)c1
Reactant: CC1=C(/C=C/Cl)CC(Cl)C(C)(Cl)C1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: c1ccc2ccccc2c1
Reaction time: 1 h

Procedure:
A laminate-type organic electrophotographic photoreceptor was produced in the same manner and in the same ratios of starting materials as in Example 24 except that (PC-1) was replaced by (PC-2), MXDA by azobisisobutylonitrile (AIBN), and the conditions of the reaction after the drying were changed to 120° C., 1 hour.
Reaction SMILES: [OH-].[K+].C[O:4][C:5]([C:7]1[NH:8][C:9](=[S:29])[N:10]2[C:16]3[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=3[C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[N:13][CH2:12][C:11]=12)=[O:6]>CO>[Cl:21][C:19]1[CH:18]=[CH:17][C:16]2[N:10]3[C:9](=[S:29])[NH:8][C:7]([C:5]([OH:6])=[O:4])=[C:11]3[CH2:12][N:13]=[C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:15]=2[CH:20]=1
Reactant: COC(=O)c1[nH]c(=S)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1[nH]c(=S)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Reaction time: 0.25 h

Procedure:
A solution of 1.1 g (0.02 mole) of potassium hydroxide in 40 ml of methanol was treated with 2.1 g (0.005 mole) of 8-chloro-6-(2-chlorophenyl)-1,2-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-1-thione-3-carboxylic acid methyl ester in a beaker. The solution was boiled in a steambath for 15 min and then evaporated at reduced pressure at 50°-60°. An aqueous solution of the residue was acidified with cold 6N aqueous hydrochloric acid adding ice to keep the mixture cold. The solid was collected by filtration, washed with water and air dried on the funnel overnight to yield crude end product. Recrystallization from ethanol gave light tan crystals with mp 277°-280° (dec).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.ClC1[N+]([O-])=NC([O:14][C:15]2[C:20]([CH:21]=[CH2:22])=[C:19](C)[CH:18]=[C:17](C)[C:16]=2C)=CC=1.[Cl:26][C:27]1N=[N+]([O-])C(OC2C(C=C)=C(C)C=C(C)C=2C)=[CH:31][CH:32]=1>>[Cl:26][CH2:27][CH2:32][CH2:31][CH:22]1[CH2:21][C:20]2[C:19]1=[CH:18][CH:17]=[CH:16][C:15]=2[OH:14]
Reactant: C=Cc1c(C)cc(C)c(C)c1Oc1ccc(Cl)[n+]([O-])n1
Reactant: C=Cc1c(C)cc(C)c(C)c1Oc1ccc(Cl)n[n+]1[O-]
Solvent: O=P(Cl)(Cl)Cl
Product: Oc1cccc2c1CC2CCCCl

Procedure:
0.02 mL (0.22 mmol) of phosphorus oxychloride was added to 27.6 mg (0.0949 mmol) of a mixture of 6-chloro-3-(2,3,5-trimethyl-6-vinylphenoxy)pyridazine 1-oxide and 3-chloro-6-(2,3,5-trimethyl-6-vinylphenoxy)pyridazine 1-oxide obtained in (6), and the resulting mixture was stirred at room temperature for 2 hours. To the mixture was added 0.4 mL of chloroform, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated, 0.2 mL (2.2 mmol) of phosphorus oxychloride was added to the residue and the resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated, the residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 1 plate was used, developed by hexane:ethyl acetate=5:1) to obtain 5.0 mg (0.016 mmol, Yield: 17%) of 4,6-dichloro-3-(2,3,5-trimethyl-6-vinylphenoxy)pyridazine.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.C(N(CC)CC)C.Cl[C:22]1[N:27]([CH3:28])[C:26](=[O:29])[C:25]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[C:24]([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)[N:23]=1>ClCCl>[OH:13][CH:3]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH2:2][NH:1][C:22]1[N:27]([CH3:28])[C:26](=[O:29])[C:25]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[C:24]([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)[N:23]=1
Reactant: COc1ccc(CC(O)CN)cc1
Reactant: Cn1c(Cl)nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CC(O)CNc2nc(-c3ccncc3)c(-c3ccc4ccccc4c3)c(=O)n2C)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirring solution of 1-amino-3-(4-methoxy-phenyl)-propan-2-ol (1.1 g, 6.1 mmol) and triethylamine in 25 mL dichloromethane was added 2-chloro-3-methyl-5-naphthalen-2-yl-6-pyridin-4-yl-3H-pyrimidin-4-one. The solution was stirred at room temperature for 72 h. The organic layer was washed twice with 5% sodium bicarbonate, once with brine, then dried over magnesium sulfate. The product was purified on 90 g of silica eluting with 1 to 5% methanol/dichloromethane to give a yellow foam. M+1=493.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH2:41][CH2:42][N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1)[CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=2[CH2:17]1
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Reactant: O=C(CCl)N1CCCC1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCCC3)c(F)c2)C(C)C)c1
Yield: 44.8 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-chloro-1-pyrrolidin-1-ylethanone (10 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.5 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][B-](F)(F)F)[C@H:10]([CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[K+].Cl[C:22]1[CH:23]=[C:24]([C:37]2[N:42]=[C:41]([CH3:43])[N:40]=[C:39]([N:44]([CH2:54][C:55]3[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=3)[CH2:45][C:46]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=3)[N:38]=2)[C:25]([NH:28][C:29]2[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)=[N:26][CH:27]=1>>[CH3:53][O:52][C:49]1[CH:48]=[CH:47][C:46]([CH2:45][N:44]([CH2:54][C:55]2[CH:56]=[CH:57][C:58]([O:61][CH3:62])=[CH:59][CH:60]=2)[C:39]2[N:40]=[C:41]([CH3:43])[N:42]=[C:37]([C:24]3[CH:23]=[C:22]([CH2:14][N:11]4[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C@H:10]4[CH3:19])[CH:27]=[N:26][C:25]=3[NH:28][C:29]3[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[N:38]=2)=[CH:51][CH:50]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C[B-](F)(F)F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: [K+]
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)C[C@H]4C)cnc3Nc3ccc(OC)nc3)n2)cc1
Yield: 74.3 %

Procedure:
The title compound was prepared in an analogous manner to that described above in Example 157, Step 1, using potassium (R)-((4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)methyl)trifluoroborate and 4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine to give (R)-tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)-3-methylpiperazine-1-carboxylate (188 mg, 0.247 mmol, 74.3% yield) as a yellow syrup. m/z (ESI, +ve ion) 761.7 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)C1C=CC=CC=1.[S:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1>>[OH:8][C:9]1[CH:14]=[C:13]([C:26]2[CH:27]=[CH:28][S:24][CH:25]=2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:21])(=[O:22])[NH:19][C:18](=[O:23])[CH2:17]1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: OB(O)c1ccsc1
Product: O=C1CN(c2ccc(-c3ccsc3)cc2O)S(=O)(=O)N1

Procedure:
The title compound is prepared using 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one and thiophene-3-boronic acid analogous to Example 272: 1H NMR (DMSO-d6δ9.68 (br s, 1H), 7.75 (m, 1H), 7.61 (m, 1H), 7.43 (m, 1H), 7.38 (m, 1H), 7.15 (m, 2H), 4.32 (s, 2H); (M−1)−=309.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: Nc1ccccc1
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3ccccc3)nc21
Temperature: 184 °C

Procedure:
A solution of 0.113 g (0.29 mmol) of 6-(2,6-dichlorophenyl)-2-methanesulfonyl-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 39 in 1.00 g (10.70 mmol) of aniline was maintained at reflux (184° C.) for 3 minutes. Most of the excess aniline was evaporated at reduced pressure. The remaining gum was dissolved in 1.0 mL of ethyl acetate. Crystals developed on inducement; wt 0.088 g. Further purification to remove dark colors was effected by silica gel chromatography, eluting with chloroform and then 50% hexane-ethyl acetate to obtain pure crystalline product; wt 0.046 g; mp 247°-249° C.
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][CH:6]=1)=[O:4].[O:22]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23]1>>[O:22]1[CH2:26][CH2:25][CH:24]([NH:27][C:3]([C:5]2[S:9][C:8]([CH2:10][CH2:11][C:12]3[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=3[CH3:17])=[N:7][CH:6]=2)=[O:4])[CH2:23]1
Reactant: NC1CCOC1
Reactant: CCCCc1noc(C)c1CCc1ncc(C(=O)OC)s1
Product: CCCCc1noc(C)c1CCc1ncc(C(=O)NC2CCOC2)s1
Yield: 71 %

Procedure:
As described for example 57b, 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid methyl ester (90 mg, 0.29 mmol) was converted, using tetrahydrofuran-3-amine instead of isopropylamine, to the title compound (45 mg, 71%) which was obtained as a light yellow oil. MS: m/e=364.3 [M+H]+.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[C:10]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:9]3[N:19]=[C:20]([C:22](=[O:26])[C:23](=[O:25])[CH3:24])[CH:21]=[C:8]3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:33]=1[NH2:34].[CH3:35]O>O>[CH2:2]([NH:1][CH2:5][CH3:4])[CH3:3].[CH3:23][C:22]1([C:20]2[CH:21]=[C:8]3[N:7]=[C:6]([N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:11]=[C:10]([NH:12][CH:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)[N:9]3[N:19]=2)[N:27]=[C:28]2[CH:29]=[N:30][CH:31]=[CH:32][C:33]2=[N:34][CH2:35]1.[N:1]1([C:6]2[CH:11]=[C:10]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:9]3[N:19]=[C:20]([C:22](=[O:26])[C:23](=[O:25])[CH3:24])[CH:21]=[C:8]3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccncc1N
Reactant: CO
Agent: CC(=O)C(=O)c1cc2nc(N3CCCC3)cc(NC3CCOCC3)n2n1
Solvent: O
Product: CC1(c2cc3nc(N4CCCC4)cc(NC4CCOCC4)n3n2)CN=c2ccncc2=N1
Product: CCNCC
Reaction time: 24 h

Procedure:
To a solution of 1-[5-pyrrolidin-1-yl-7-(tetrahydro-2H-pyran-4-ylamino)-pyrazolo[1,5-a]pyrimidin-2-yl]propane-1,2-dione (87 mg, 0.243 mmol) in methanol (3 mL) and water (0.3 mL) was added 3,4-diaminopyridine (29 mg, 0.268 mmol) at room temperature. After being stirred for 24 h at same temperature, the reaction mixture was concentrated in vacuo. The crude was purified by silica gel column chromatography (chloroform:methanol=99:1 to 19:1) and HPLC(CHIRALPAK IC, 20Φ×250 mm, hexane:etanol:diethylamine=30:70:0.1, frow rate 5.0 mL/min) to give 2-(3-methylpyrido[3,4-b]pyrazin-3-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (the compound of Example 5.001 listed in the Table of Examples as described hereinafter) as a more polar compound and 2-(2-methylpyrido[3,4-b]pyrazin-2-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (the compound of Example 5.002 listed in the Table of Examples as described hereinafter) as a less polar compound. The absolute configuration was determined by X-ray analysis of 2-(2-methylpyrido[3,4-b]pyrazin-2-yl)-5-pyrrolidin-1-yl-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine.
Reaction SMILES: [CH3:1][C:2]([OH:8])([CH2:5][CH2:6][CH3:7])[C:3]#[CH:4].[Na+].[CH3:10][O:11][C:12]1[CH:16]=[CH:15][NH:14][C:13]=1/[CH:17]=[C:18]1\[C:19](=[O:34])[NH:20][C:21]2[C:26]\1=[C:25](C#CCCC([O-])=O)[CH:24]=[CH:23][CH:22]=2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:8][C:2]([CH3:1])([CH2:5][CH2:6][CH3:7])[C:3]#[C:4][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1/[C:18](=[CH:17]/[C:13]1[NH:14][CH:15]=[CH:16][C:12]=1[O:11][CH3:10])/[C:19](=[O:34])[NH:20]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCC(=O)[O-])c21
Reactant: C#CC(C)(O)CCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC(C)(O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, 3-methyl-1-hexyn-3-ol (98 mg, 0.87 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material I supra) (127 mg, 0.4 mmol) using (Ph3P)2PdCl2 (46 mg) and CuI (22 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 22 h yielding rac-(Z)-1,3-dihydro-4-(3-hydroxy-3-methyl-1-hexynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 92 mg, 66%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[SH:34][C:35]1[CH:53]=[CH:52][C:51]([N+:54]([O-:56])=[O:55])=[CH:50][C:36]=1[CH2:37][N:38]([CH3:49])[C:39](=[O:48])[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.[CH3:57][O:58][CH2:59][C@H:60](O)[CH3:61]>C1COCC1>[CH3:57][O:58][CH2:59][C@@H:60]([S:34][C:35]1[CH:53]=[CH:52][C:51]([N+:54]([O-:56])=[O:55])=[CH:50][C:36]=1[CH2:37][N:38]([CH3:49])[C:39](=[O:48])[O:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[CH3:61]
Reactant: CN(Cc1cc([N+](=O)[O-])ccc1S)C(=O)OCc1ccccc1
Reactant: COC[C@@H](C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC[C@H](C)Sc1ccc([N+](=O)[O-])cc1CN(C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 108.4 %

Procedure:
To a solution of triphenylphosphine (355 mg, 1.354 mmol) in THF (4 mL) at 0° C., was added DIAD (0.263 mL, 1.354 mmol) dropwise. The mixture was stirred at 0° C. for 10 min affording a colorless suspension. A solution of 6B (300 mg, 0.903 mmol) and (R)-1-methoxypropan-2-ol (0.133 mL, 1.354 mmol) in THF (2 mL) was added dropwise. The resultant dark red solution was stirred at 0° C. for 0.5 h, then was allowed to slowly warm to rt over night. The reaction mixture was concentrated. The crude product was purified by flash chromatography (loaded in chloroform onto a 40 g column and eluted with a gradient from 0 to 40% ethyl acetate/hexanes) to afford 6C (396 mg, 108% yield) as yellow oil/semi-solid. MS (ESI) m/z: 405.2 [M+1]+; 1H NMR (400 MHz, chloroform-d) δ ppm 8.07 (d, J=8.53 Hz, 1H) 7.96 (d, J=18.57 Hz, 1H) 7.32-7.51 (m, 6H) 5.11-5.26 (m, 2H) 4.59 (d, J=18.07 Hz, 2H) 3.58-3.68 (m, 1H) 3.47 (d, J=6.53 Hz, 2H) 3.37 (s, 3H) 2.99 (br. s., 3H) 1.40 (br. s., 3H).
Reaction SMILES: Cl.[CH2:2]([NH:5][C:6](=[O:26])[C@@H:7]([CH3:25])[NH:8][C:9](=[O:24])[C@H:10]([CH2:20][C:21](=[O:23])[OH:22])[NH:11][C:12](=[O:19])[C@H:13]([CH2:15][CH2:16][S:17][CH3:18])[NH2:14])[CH2:3][CH3:4].[C:27]([O:31][C:32]([NH:34][C@H:35]([C:46](N[C@H](C(N[C@H](C(N[C@@H](C(N)=O)C)=O)CC(=O)O)=O)CCSC)=[O:47])[CH2:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[NH:39][CH:38]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[CH2:2]([NH:5][C:6](=[O:26])[C@@H:7]([CH3:25])[NH:8][C:9](=[O:24])[C@H:10]([CH2:20][C:21](=[O:22])[OH:23])[NH:11][C:12](=[O:19])[C@H:13]([CH2:15][CH2:16][S:17][CH3:18])[NH:14][C:46](=[O:47])[C@H:35]([CH2:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[NH:39][CH:38]=1)[NH:34][C:32]([O:31][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:33])[CH2:3][CH3:4]
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](C)C(N)=O
Reactant: CCCNC(=O)[C@@H](C)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](N)CCSC
Agent: Cl
Product: CCCNC(=O)[C@@H](C)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C

Procedure:
When an equivalent quantity of L-methionyl-L-aspartyl-D-alanine n-propylamide hydrochloride is substituted for the L-methionyl-L-aspartyl-D-alanine amide hydrochloride of Example 6, and the procedure detailed therein substantially repeated, there is obtained N-t-butoxycarbonyl-L-tryptophanyl-L-methionyl-L-aspartyl-D-alanine n-propylamide. This compound melts at about 143.5°-148° C. with decomposition and is represented by the following formula.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH2:8])=[CH:4][N:3]=[CH:2]1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(=O)C.C(OCC)(=O)C>[CH:13](=[N:8]/[C:7]1[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=1[C:5]1[NH:1][CH:2]=[N:3][CH:4]=1)\[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccccc1-c1cnc[nH]1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C(=N/c1ccccc1-c1cnc[nH]1)\c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.8 %

Procedure:
2-(1H-imidazol-5-yl)aniline 965 mg, 0.410 mmol) was dissolved in acetic acid (2 mL) and benzaldehyde (43 mg, 0.410 mmol) was added. The reaction was stirred for 1 h at room temperature, diluted with 30 mL ethyl acetate, and extracted with 5% HCl (56 mL from 50 mL water+6 mL 12N HCl). The aqueous layer was basified with K2CO3 (add solid portionwise until PH=7), then extracted with ethyl acetate (30 mL×2). The organic layer was evaporated under reduced pressure and the residue was separated by column chromatography to afford the desired product (9 mg, 0.036 mmol, 9%). 1H NMR (MeOH-d4): 7.11-7.25 (m, 3H), 7.41-7.48 (m, 2H), 7.61-7.67 (m, 2H), 7.78 (s, 1H), 8.32 (s, 1H), 8.39 (s, 1H), 8.83 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([S:5]([C:8]2[CH:9]=[C:10]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=2)[C:11]([N:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[O:28][CH3:29])[CH3:14])=[O:12])(=[O:7])=[O:6])[CH2:2]1.CCN(C(C)C)C(C)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48].[NH4+].[Cl-]>C(Cl)Cl>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[N:13]([CH3:14])[C:11](=[O:12])[C:10]2[CH:30]=[C:31]([C:33]([F:34])([F:36])[F:35])[CH:32]=[C:8]([S:5]([CH:3]3[CH2:4][N:1]([S:47]([CH3:46])(=[O:49])=[O:48])[CH2:2]3)(=[O:7])=[O:6])[CH:9]=2)=[C:22]([O:28][CH3:29])[CH:23]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)C2CNC2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)C2CN(S(C)(=O)=O)C2)c1
Temperature: 0 °C
Reaction time: 1.75 h

Procedure:
To an ice-cold solution of 3-(azetidin-3-ylsulfonyl)-N-(4-(4-fluoro-2-methoxyphenyl)-pyridin-3-yl)-N-methyl-5-(trifluoromethyl)benzamide (0.05 g, 95.5 μmol, example 280) and DIPEA (24.7 mg, 33.4 μL, 191 μmol) in CH2Cl2 (1 mL) was added methanesulfonyl chloride (16.4 mg, 11.2 μL, 143 μmol) and stirring was continued in an ice-bath for 1.75 hours. The reaction mixture was poured on saturated aqueous NH4Cl solution and CH2Cl2 and the layers were separated. The aqueous layer was extracted twice with CH2Cl2. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 5 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless solid (0.044 g; 76%). MS (ESI): m/z=602.10 [M+H]+.