Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.C(Cl)(Cl)Cl.[C:12]([O:16][C:17]([NH:19][C@H:20]([C:33](O)=[O:34])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:24][CH:23]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].N#N.Cl.[CH3:39][NH:40][C@@H:41]([C:46]([NH:48][CH2:49][CH2:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:47])[CH2:42][CH2:43][S:44][CH3:45]>O1CCCC1>[NH:19]([C:17]([O:16][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:18])[C@H:20]([C:33]([N:40]([CH3:39])[C@@H:41]([C:46]([NH:48][CH2:49][CH2:50][CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)=[O:47])[CH2:42][CH2:43][S:44][CH3:45])=[O:34])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)O
Reactant: CN[C@H](CCSC)C(=O)NCCCc1ccccc1
Agent: Cl
Agent: N#N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSCC[C@H](C(=O)NCCCc1ccccc1)N(C)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OC(C)(C)C

Procedure:
By the method of part A of Example 5 and using triethylamine instead of diisopropylethylamine and chloroform as a cosolvent with tetrahydrofuran, N-(tert-butyloxycarbonyl)-O-(tert-butyl)-L-tyrosine (2.13 g.) was condensed with N2 -methyl-N-(3-phenylpropyl)-D-methioninamide hydrochloride (2.0 g.). The product, [N-(tert-butyloxycarbonyl)-O-(tert-butyl-L-tyrosyl]-N2 -methyl-N-(3-phenylpropyl)-D-methioninamide, was purified by crystallization, the first crop (1.51 g., m.r. 129°-130° C.) from ethyl acetate, the second crop (0.53 g.) from ethyl acetate-hexane.
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH2:4][CH2:5][CH2:6][N:7]=1.[Br:8][C:9]1[CH:42]=[CH:41][C:12]2[N:13]=[C:14]([NH:16][C@H:17]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][C:29](OCC)=[O:30])=[CH:21][CH:20]=3)[S:15][C:11]=2[CH:10]=1.NN1C=CCNC1>C1COCC1>[Br:8][C:9]1[CH:42]=[CH:41][C:12]2[N:13]=[C:14]([NH:16][C@H:17]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][CH2:28][C:29](=[O:30])[NH:1][C:2]4[NH:7][CH2:6][CH2:5][CH2:4][N:3]=4)=[CH:23][CH:24]=3)[S:15][C:11]=2[CH:10]=1
Reactant: CCOC(=O)CCCOc1ccc(C[C@H](Nc2nc3ccc(Br)cc3s2)C(=O)OC(C)(C)C)cc1
Reactant: NC1=NCCCN1
Agent: NN1C=CCNC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)Nc1nc2ccc(Br)cc2s1
Reaction time: 20 h

Procedure:
80 mg of 2-amino-1,4,5,6-tetrahydropyrimidine is added to a solution of the ester 8-2 (123 mg) in 3 ml of THF, agitation is carried out for 20 hours at ambient temperature, 48 mg of tetrahydroaminopyrimidine is also added and agitation is carried out for 5 hours. After evaporating under reduced pressure, the mixture is chromatographed eluting with a CH2Cl2/AcOEt 80/20 then CH2Cl2/MeOH 90/10 mixture. 68 mg of the expected 8-3 is obtained.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]=1[C:7]#[N:8].[C:13](O)(=[O:15])[CH3:14].C(OC(=O)C)(=O)C>>[C:13]([NH:1][C:2]1[O:3][CH:4]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]=1[C:7]#[N:8])(=[O:15])[CH3:14]
Reactant: CC(C)(C)c1coc(N)c1C#N
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1occ(C(C)(C)C)c1C#N
Yield: 83.4 %

Procedure:
16.4 g (0.1 mole) of 2-amino-3-cyano-4-tert.-butylfuran were heated to 100° C. with 24 ml (0.4 mole) of acetic acid and 10.4 ml (0.11 mole) of acetic anhydride for one hour. Thereafter, the reaction mixture was evaporated under reduced pressure and the residue was recrystallized from a mixture of toluene/cyclohexane (1:2). 17.2 g of 2-acetylamino-3-cyano-4-tert.-butyl-furan of melting point 135° C. were obtained in this manner.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([Cl:14])[CH:13]=1)[C:7](OC)=[O:8])=[O:3].C(O)C.[BH4-].[Li+]>O1CCCC1>[Cl:14][C:12]1[CH:13]=[C:4]([CH:5]=[C:6]([CH2:7][OH:8])[CH:11]=1)[C:2]([NH2:1])=[O:3]
Reactant: COC(=O)c1cc(Cl)cc(C(N)=O)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: NC(=O)c1cc(Cl)cc(CO)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
(Step 1) To a mixed solution of methyl 3-(aminocarbonyl)-5-chlorobenzoate (2.2 g) in tetrahydrofuran:ethanol=10:1 (33 ml) was added lithium tetrahydroborate (0.34 g) at room temperature. After stirring at 60° C. for 2 hr, the reaction solution was quenched with ice and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was treated by silica gel chromatography (ethyl acetate:hexane=5:1) to give 3-chloro-5-(hydroxymethyl)benzamide (0.95 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[CH:22]1([CH2:25][NH:26][C:27]2[C:28]([CH3:33])=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:24][CH2:23]1>>[CH:22]1([CH2:25][NH:26][C:27]2[CH:32]=[CH:31][C:30]([NH:1][C:2]3[S:3][C:4]([C:10]4[C:11]([F:21])=[CH:12][C:13]([C:17]([OH:20])([CH3:18])[CH3:19])=[CH:14][C:15]=4[F:16])=[CH:5][C:6]=3[C:7]([NH2:9])=[O:8])=[N:29][C:28]=2[CH3:33])[CH2:23][CH2:24]1
Reactant: Cc1ncccc1NCC1CC1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1NCC1CC1

Procedure:
The title compound was prepared in the same manner described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and N-(cyclopropylmethyl)-2-methylpyridin-3-amine (94 mg, 0.48 mmol) as starting materials.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([O:12][CH3:13])=[N:9]2)=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.O=P(Cl)(Cl)[Cl:28]>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:28])=[N:7][C:8]([O:12][CH3:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1nc2cc(Br)ccc2c(=O)[nH]1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COc1nc(Cl)c2ccc(Br)cc2n1
Reaction time: 0.33 h

Procedure:
A solution of 7-bromo-2-methoxyquinazolin-4(3H)-one (1.900 g, 7.45 mmol) in 30 mL DCM was treated with DBU (1.123 ml, 7.45 mmol) and was allowed to stir for 20 minutes. The cloudy purple solution was then treated with POCl3 (0.833 ml, 8.94 mmol) and was allowed to stir for one hour at room temperature. LC/MS showed mostly product, so the reaction mixture was concentrated. The crude residue was carried on to step 3 without purification. (M+H)+=271.2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:13][C:12](=[O:22])[CH:11]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[NH:13][C:12](=[O:22])[CH:11]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)cc1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)n1[nH]c(=O)cc1-c1ccc(N)cc1

Procedure:
A solution of 2.2 g (7.1 mmol) of tert-butyl 5-(4-nitrophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate in 100 ml of ethanol was hydrogenated in the presence of 253 mg of palladium (10% on activated carbon) at RT and standard pressure. The reaction mixture was then filtered through Celite and the filtrate was concentrated under reduced pressure and dried. Yield: 1.99 g (purity 90%, 92% of theory)
Reaction SMILES: [CH3:1][C:2]1C(C2C=C3C(=CC=2)C=C(CCOS(C)(=O)=O)C=C3)=CC=C(C)[N:3]=1.[CH3:26][C:27]1[C:32]([C:33]2[CH:34]=[C:35]3[C:40](=[CH:41][CH:42]=2)[CH:39]=[C:38]([CH2:43][CH2:44][OH:45])[CH:37]=[CH:36]3)=[CH:31][CH:30]=C(C)N=1>>[OH:45][CH2:44][CH2:43][C:38]1[CH:37]=[C:36]2[C:41](=[CH:40][CH:39]=1)[CH:42]=[C:33]([C:32]1[CH:31]=[CH:30][C:1]([C:2]#[N:3])=[CH:26][CH:27]=1)[CH:34]=[CH:35]2
Reactant: Cc1ccc(-c2ccc3cc(CCOS(C)(=O)=O)ccc3c2)c(C)n1
Reactant: Cc1ccc(-c2ccc3cc(CCO)ccc3c2)c(C)n1
Product: N#Cc1ccc(-c2ccc3cc(CCO)ccc3c2)cc1
Yield: 97 %

Procedure:
Methanesulfonic acid 2-[6-(2,6-dimethyl-pyridin-3-yl)-naphthalen-2-yl]-ethyl ester The compound was prepared by the method in Example 3B substituting 2-[6-(2,6-dimethyl-pyridin-3-yl)-naphthalen-2-yl]-ethanol in place of 4-[6-(2-hydroxy-ethyl)-naphthalen-2-yl]-benzonitrile (0.9763 g, 97% yield). 1H NMR (CD3OD, 300 MHz), δ 8.09–8.05 (m, 1H), 7.99–7.87 (m, 2H), 7.82–7.79 (m, 1H), 7.66–7.62 (m, 1H), 7.53–7.44 (m, 2H), 7.22–7.13 (m, 1H), 4.57–4.52 (t, J=7.5 Hz, 2H), 4.08 (s, 3H), 3.27–3.19 (t, J=7.5 Hz, 2H). MS (DCI-NH3) [M+H]+ at 356.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].[H-].[Na+].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH:22][C:21]=1[Cl:31].[I-].[Na+]>CN(C=O)C>[Cl:31][C:21]1[CH:22]=[C:23]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])[CH:24]=[CH:25][C:20]=1[CH2:19][N:7]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:13]2[C:5]([CH2:4][C:3]([OH:2])=[O:15])=[C:6]1[CH3:14]
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Reactant: CCS(=O)(=O)c1ccc(CBr)c(Cl)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(Cn2c(C)c(CC(=O)O)c3cccnc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To an ice cooled (0° C.) stirred solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((2.68 g, 13.1 mmol) in dry DMF (95 ml) is added sodium hydride (577 mg of a 60% dispersion in mineral oil, 14.41 mmol). After stirring at room temperature for 1.5 hours, the reaction mixture is re-cooled to 0° C. and treated with 1-bromomethyl-2-chloro-4-ethanesulfonyl-benzene (6.6 g, 22.2 mmol) and sodium iodide (3.3 g, 22.2 mmol). The resulting mixture is stirred and allowed to warm to room temperature overnight. The reaction mixture is poured onto water (600 ml) and extracted with 1:1 ethyl acetate/diethyl ether (4×300 ml). The organic portions are washed with brine, dried (MgSO4) and concentrated in vacuo and the resulting crude is purified by chromatography on silica eluting with ethyl acetate/iso-hexane (1:8 increasing to 1:2) to yield the titled product. (MH+ 421)
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[CH:21]([NH:26][CH2:27][CH2:28][C@H:29]([N:32]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]1=[O:42])[CH2:30][F:31])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:52]([O:55][C@@H:56]([CH3:60])[C:57](Cl)=[O:58])(=[O:54])[CH3:53]>ClCCl>[C:52]([O:55][C@H:56]([CH3:60])[C:57]([N:26]([C@@H:21]([C:9]1[N:10]=[C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])[S:12][C:8]=1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:22]([CH3:24])([CH3:25])[CH3:23])[CH2:27][CH2:28][C@H:29]([N:32]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]1=[O:42])[CH2:30][F:31])=[O:58])(=[O:54])[CH3:53]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: CC(C)(C)C(NCC[C@@H](CF)N1C(=O)c2ccccc2C1=O)c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)O[C@H](C)C(=O)N(CC[C@@H](CF)N1C(=O)c2ccccc2C1=O)[C@@H](c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-((2S)-4-(1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropylamino)-1-fluorobutan-2-yl)isoindoline-1,3-dione (65 mg, 0.125 mmol) in dichloromethane (1 mL, 0.1 M solution) at room temperature was added DIEA (65.3 μL, 0.375 mmol). (S)-1-Chloro-1-oxopropan-2-yl acetate (35 μL, 0.276 mmol) was then added dropwise over 2 min. The resulting solution was stirred at room temperature for 1.5 h. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and filtered. After the volatile organic materials were removed in vacuo, the crude diastereomers were purified by preparative reverse phase HPLC. The combined fractions of each diastereomer were neutralized with saturated NaHCO3 solution, which was then extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The nonpolar diastereomer, (R)-1-(((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropyl)((S)-3-(1,3-dioxoisoindolin-2-yl)-4-fluorobutyl)amino)-1-oxopropan-2-yl acetate, was obtained in 23% (10 mg). LC/MS (uplc) MH+ 706.2, 1.37 min. The polar isomer, (R)-1-(((S)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropyl)((S)-3-(1,3-dioxoisoindolin-2-yl)-4-fluorobutyl)amino)-1-oxopropan-2-yl acetate, was obtained in 12% (5 mg). LC/MS (uplc) MH+ 706.2, 1.36 min.
Reaction SMILES: [CH:1]([C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)=O.C(O)(=O)C.[NH2:49][CH2:50][CH:51]1[CH2:55][CH2:54][CH2:53][N:52]1[CH2:56][CH3:57].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C([O-])(O)=O.[Na+]>[CH2:56]([N:52]1[CH2:53][CH2:54][CH2:55][CH:51]1[CH2:50][NH:49][CH2:1][C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:23])([CH3:24])[C:12]([C:25]2[CH:26]=[CH:27][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:36][CH:37]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)[CH3:57]
Reactant: CCN1CCCC1CN
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C=C(C)[C@@H]1CC[C@]2(CNCC3CCCN3CC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.1 g, 0.167 mmol) in DCE (2 ml) was added acetic acid (1M in DCM) (0.167 ml, 0.167 mmol) and 2-(aminomethyl)-1-ethylpyrrolidine (0.029 ml, 0.200 mmol). The mixture was stirred for 15 minutes at rt and sodium triacetoxyborohydride (0.071 g, 0.334 mmol) was added. The mixture was stirred at rt for 1.5 h then an additional 0.1 g of sodium triacetoxyborohydride was added and the mixture was stirred at rt overnight. After 24 h of stirring, some starting material still remained by TLC. To the mixture was added acetic acid (1M in DCM) (0.167 ml, 0.167 mmol), 2-(aminomethyl)-1-ethylpyrrolidine (0.029 ml, 0.200 mmol), and sodium triacetoxyborohydride (0.071 g, 0.334 mmol). The mixture was stirred at rt for an additional 19 h then was diluted with 7 ml of sat. NaHCO3. The mixture was extracted with dichloromethane (3×7 ml) and the combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The mixture was purified by flash chromatography using a 0-10% MeOH in dichloromethane gradient. Two products were isolated as white foams. LC/MS indicated the same mass for both, with different retention times. 1H NMR confirmed that two diastereomers were isolated. 44 mg of diastereomer 1 (less polar spot by TLC) was isolated while 55 mg of diastereomer 2 (more polar spot) was isolated. Diastereomer 1: LCMS: m/e 711.4 (M+H)+, 3.34 min (method 6). Diastereomer 2: LCMS: m/e 711.6 (M+H)+, 3.27 min (method 6).
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[CH2:11][C:12]([C:14]1[CH2:18][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][N:15]=1)=O>CN1CCCC1=O>[C:19]1([CH:17]2[O:16][N:15]=[C:14]([C:12]3[N:9]=[C:1]([C:2]4[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=4)[S:8][CH:11]=3)[CH2:18]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NC(=S)c1ccncc1
Reactant: O=C(CCl)C1=NOC(c2ccccc2)C1
Solvent: CN1CCCC1=O
Product: c1ccc(C2CC(c3csc(-c4ccncc4)n3)=NO2)cc1
Temperature: 100 °C
Yield: 63.3 %

Procedure:
To a solution of thioisonicotinamide (0.5 g, 3.6 mmol) in 1-methyl-2-pyrrolidinone (25 mL) was added 2-chloro-1-(4,5-dihydro-5-phenyl-3-isoxazolyl)ethanone (0.807 g, 3.6 mmol), at room temperature. The reaction mixture was then heated to 100° C. for 3 h. Then the reaction mixture was cooled to room temperature, quenched with water (100 mL) and extracted with ethyl acetate (50 mL×2). The reaction mixture was diluted with water (50 mL) and brine (50 mL), and the organic layer was concentrated under reduced pressure and purified by medium-pressure liquid chromatography using 2% of methanol in chloroform as eluant to give 0.7 g of the title compound as a brown solid.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH2:21][C:22]4(O)[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.COCCN(S(F)(F)[F:44])CCOC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH2:21][C:22]4([F:44])[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC(O)(COc2cccc3ccc(-c4nnc5ccccn45)nc23)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(F)(COc2cccc3ccc(-c4nnc5ccccn45)nc23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.2 %

Procedure:
(NOTE: the reaction was run in a 10 mL plastic bottle) To a 0° C. cloudy solution of tert-butyl 3-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-3-hydroxyazetidine-1-carboxylate (0.070 g, 0.156 mmol) in 2 mL DCM was added Deoxo-Fluor (0.0346 mL, 0.188 mmol). The reaction mixture was warmed to ambient temperature, and after 30 minutes, it was cooled back to 0° C., and another 2 equiv. of DeoxoFluor was added, and the reaction mixture continued to stir at 0° C. After a total of 3.5 hours, saturated NaHCO3 was carefully added dropwise until the excess Deoxofluor was quenched. The mixture was extracted with DCM, and the combined extracts were dried (Na2SO4), filtered, and concentrated. The residue was purified by preparative TLC (2 mm plate, 9:1 DCM:MeOH) to give the desired product (0.0156 g, 22.2% yield) as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([CH:11](P(OCC)(OCC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6][CH2:5]2.C=O.[C:27]([O-])([O-])=O.[K+].[K+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([C:11](=[CH2:27])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6][CH2:5]2
Reactant: CCOC(=O)C(C1CCc2cc(Br)ccc21)P(=O)(OCC)OCC
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C(=O)OCC)C1CCc2cc(Br)ccc21

Procedure:
The compound obtained in Step C (76.18 mmol), paraformaldehyde (4.60 g, 152.36 mmol, 2 eq.), and K2CO3 (20.98 g, 2 eq.) are refluxed in 350 ml of THF for 15 hours. The mixture is concentrated to three quarters, 100 ml of water are added and the mixture is extracted with ether. The organic phase is washed with water, with saturated NaCl, dried over Na2SO4 and then concentrated under reduced pressure to yield the title compound in the form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([O:20][C:19](=[O:21])[CH2:18][O:17][C:14]2[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=2)=[CH:25][CH:24]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)Oc1ccc(F)cc1
Yield: 79 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 4-fluorophenol (17 mg, 0.15 mmol) as the coupling partner. Concentration (no chromatography) yielded 52 mg (79%) of the titled compound. ESI-MS m/z 386 (MH+), 384 (M−H−).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:15]([O:17][CH3:18])=[O:16])[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:21]I.O>O1CCCC1.C(OCC)(=O)C>[CH3:21][C:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)([C:15]([O:17][CH3:18])=[O:16])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C)(C(=O)OC)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
640 mg of compound 229.1 were dissolved in 12 ml of dry tetrahydrofuran and admixed with 138 mg of sodium hydride (60% in mineral oil). The mixture was stirred at room temperature for one hour, then a solution of 393 μl of methyl iodide in 5 ml of dry tetrahydrofuran was added dropwise and the resulting mixture was stirred at room temperature overnight. For workup, the reaction mixture was admixed cautiously with water and ethyl acetate. The organic phase was removed, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel; n-heptane/0-10% ethyl acetate). Dimethyl 2-methyl-2-(4-nitrophenyl)malonate (231.1) was obtained; 1H NMR: 8.22, d, 2H, 7.61, d, 2H, 3.71, s, 6H, 1.82, s, 3H.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.[Cu][C:34]#[N:35]>[C-]#N.C([N+](CC)(CC)CC)C.O1CCOCC1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:34]#[N:35])=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(I)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: N#C[Cu]
Agent: [Fe+2]
Agent: [Pd]
Agent: CC[N+](CC)(CC)CC
Solvent: C1COCCO1
Product: COc1cc(-c2csc3c(C#N)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Yield: 12.2 %

Procedure:
N-[4-(4-amino-7-iodothieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide (A-796259.0, 100 mg, 0.36 mmol), copper(I) cyanide (65 mg, 0.72 mmol), tetraethylammonium cyanide (28 mg, 0.18 mmol), Tris(dibenzylideneacetone)-dipalladium(0) (7 mg, 0.007 mmol), and 1,1′-bis(diphenylphosphino)ferrocene (16 mg, 0.029 mmol) were purged and heated to 110° C. in 1,4-dioxane (2 mL) for 16 hours. The mixture was evaporated in vacuo, diluted with dichloromethane/methanol (95:5, 50 mL), and washed with ammonium hydroxide (8% aqueous, 8 mL). The aqueous layer was washed with dichloromethane/methanol (95:5, 10 mL), and the combined organics were evaporated in vacuo, diluted with dimethylformamide (2.5 mL), and filtered. The precipitate was triturated in acetic acid (3 mL) and filtered to yield the title compound (20 mg, 25% yield): 1H NMR (DMSO, 400 MHz) δ 9.49 (s, 1H), 8.44 (s, 1H), 8.03 (d, 1H), 7.76 (s, 1H), 7.70 (d, 1H), 7.56 (d, 1H), 7.05-7.33 (m, 5H), 4.01 (s, 3H), 3.89 (s, 3H); RP-HPLC (Conditions i) Rt 24.9 min. MS: 452.2 MH−.