Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:15][N:16]=1)=[CH:8]2.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>O.CN(C)C=O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)=[O:21])=[CH:15][N:16]=1)=[CH:8]2)[S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:23])=[O:24]
Reactant: C1COCCN1
Reactant: CN(c1cccc2cc(-c3ncc(CCC(=O)O)s3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cccc2cc(-c3ncc(CCC(=O)N4CCOCC4)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
To a mixture of 3-(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-5-yl)propanoic acid (0.30 g), 1H-1,2,3-benzotriazol-1-ol (0.11 g) and N,N-dimethylformamide (8 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.15 g) at room temperature. The mixture was stirred at room temperature for 2 hr, and morpholine (0.30 g) was added. The reaction mixture was stirred at room temperature overnight, and water was added. The resulting crystals were collected by filtration and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (0.24 g, yield 69%) was obtained as yellow crystals from a fraction eluted with tetrahydrofuran-hexane (2:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 160-161° C.
Reaction SMILES: [C:1]1([C:7]([C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)([C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]4[N:30]5[N:31]=[C:32]([CH2:34][CH3:35])[N:33]=[C:29]5[C:28](CC5C=CC(C6C=CC=CC=6C6N(C(C7C=CC=CC=7)(C7C=CC=CC=7)C7C=CC=CC=7)N=NN=6)=CC=5)=[C:27]4[CH2:73][CH2:74][CH2:75][CH3:76])=[CH:21][CH:20]=3)=[N:11][N:10]=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:89]([C:93]1[CH:100]=[C:99]2[N:95]([N:96]=[C:97]([CH2:138][CH3:139])[N:98]2CC2C=CC(C3C=CC=CC=3C3N(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=NN=3)=CC=2)[N:94]=1)[CH2:90][CH2:91][CH3:92].C(C1C(CC2C=CC(C3C=CC=CC=3C3N(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=NN=3)=CC=2)=C2N(N=C(CC)N2)N=1)CCC>>[CH2:73]([C:27]1[N:26]([CH2:25][C:22]2[CH:21]=[CH:20][C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[N:8]([C:7]([C:77]4[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=4)([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:83]4[CH:84]=[CH:85][CH:86]=[CH:87][CH:88]=4)[N:9]=[N:10][N:11]=3)=[CH:24][CH:23]=2)[N:30]2[C:29]([CH:28]=1)=[N:33][C:32]([CH2:34][CH3:35])=[N:31]2)[CH2:74][CH2:75][CH3:76].[CH2:89]([C:93]1[CH:100]=[C:99]2[N:95]([N:96]=[C:97]([CH2:138][CH3:139])[NH:98]2)[N:94]=1)[CH2:90][CH2:91][CH3:92]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c2nc(CC)nn2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCc1cc2n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c(CC)nn2n1
Agent: CCCCc1nn2nc(CC)[nH]c2c1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCCc1cc2[nH]c(CC)nn2n1
Product: CCCCc1cc2nc(CC)nn2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 2285.4 %

Procedure:
In the same manner as described in Example 38, 0.61 g of 5,7-bis[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-6-butyl-2-ethyl-5H-pyrazolo[1,5-b][1,2,4]triazole (compound 50a), 2.52 g of 6-butyl-2-ethyl-1-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-pyrazolo[1,5-b][1,2,4]triazole (compound 50b), and 2.31 g of a mixture consisting (about 1:8) of 6-butyl-2-ethyl-7-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-pyrazolo[1,5-b][1,2,4]triazole (compound 50c) and 6-butyl-2-ethyl-5-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole (compound 50d) were obtained from 2.34 g of 6-butyl-2-ethyl-1H-pyrazolo[1,5-b][1,2,4]triazole.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]1[N:13]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[N:17][C:18]([CH3:24])=[CH:19][CH:20]=3)[N:15]=2)[C:12](=[O:25])[C:11]2[S:26][CH2:27][CH:28]([O:31][CH3:32])[CH2:29][S:30][C:10]1=2.Cl.Cl[C:35]([N:37]1[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]1)=[O:36].N1C=CC=CC=1>C(Cl)Cl>[CH3:32][O:31][CH:28]1[CH2:29][S:30][C:10]2[C:9](=[O:8])[N:13]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[N:17][C:18]([CH3:24])=[CH:19][CH:20]=4)[N:15]=3)[CH:12]([O:25][C:35]([N:37]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)=[O:36])[C:11]=2[S:26][CH2:27]1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: COC1CSC2=C(SC1)C(O)N(c1ccc3ccc(C)nc3n1)C2=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1CSC2=C(SC1)C(OC(=O)N1CCN(C)CC1)N(c1ccc3ccc(C)nc3n1)C2=O
Temperature: 45 °C
Yield: 43.1 %

Procedure:
Triethylamine (24.5 cc) is added, at about 15° C., to a suspension of 6-hydroxy-3-methoxy-7-(7-methyl-1,8-naphthyridin-2-yl)-8-oxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (7.3 g) and 1-chlorocarbonyl-4-methylpiperazine hydrochloride (11.7 g) in anhydrous methylene chloride (300 cc), and anhydrous pyridine (130 cc) is then added to the resulting mixture. The mixture is heated at 45° C. for 3 hours. 1-Chlorocarbonyl-4-methylpiperazine hydrochloride (6.0 g) is then added and the mixture is heated for a further 1/2 hour at 45° C. After cooling, the mixture is diluted by adding methylene chloride (300 cc). The organic phase is washed three times with distilled water (total 600 cc), dried over sodium sulphate and evaporated. The resulting residue (25.0 g) is dissolved in boiling acetonitrile (70 cc). After cooling the solution for 48 hours at 2° C., the resulting crystals are filtered off, washed twice with ice-cooled acetonitrile (total 20 cc) and dried under reduced pressure (20 mm Hg) at 20° C. The resulting product (5.25 g; m.p. 220° C.) is dissolved in methylene chloride (100 cc) and the solution is filtered through silica (0.2-0.5 mm; 200 g) contained in a column of diameter 2.1 cm. Elution is carried out with methylene chloride (400 cc); the eluate is discarded. Elution is continued with a mixture of methylene chloride (784 cc) and methanol (16 cc); this eluate is evaporated under reduced pressure (20 mm Hg) at a temperature below 60° C. The residue is dried under reduced pressure (0.2 mm Hg) at 50° C. 3-Methoxy-7-(7-methyl-1,8-naphthyridin-2-yl)-6-(4-methylpiperazin-1-yl)carbonyloxy-8-oxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (4.2 g), melting at 225° C., is obtained.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][Cl:20])[CH:15]=2)[O:10][C:9]([C:21]2[N:26]=[CH:25][N:24]3[CH:27]=[CH:28][CH:29]=[C:23]3[CH:22]=2)=[CH:8]1)(C)(C)C.[CH3:30][O:31][CH2:32][C@H:33]1[CH2:37][CH2:36][CH2:35][NH:34]1>>[ClH:20].[CH3:30][O:31][CH2:32][C@H:33]1[CH2:37][CH2:36][CH2:35][N:34]1[CH2:19][CH2:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([C:21]1[N:26]=[CH:25][N:24]3[CH:27]=[CH:28][CH:29]=[C:23]3[CH:22]=1)=[CH:8][C:7]2=[N:6][OH:5]
Reactant: COC[C@H]1CCCN1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCl)cc12
Product: COC[C@H]1CCCN1CCOc1ccc2oc(-c3cc4cccn4cn3)cc(=NO)c2c1
Product: Cl

Procedure:
6-[2-((R)-2-methoxymethylpyrrolidin-1-yl)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime, hydrochloride was prepared in 33% overall yield using the method described in example 87, starting from 6-(2-chloro-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 87B) and 2-((R)-2-methoxymethylpyrrolidine.
Reaction SMILES: [C:1]([C:3]1[S:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=2[F:22])[CH:4]=1)#[CH:2].Cl[Sn]Cl.[C:26]1([CH2:32][C:33]([N:35]=[C:36]=[S:37])=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO.CCO.C1(C)C=CC=CC=1>[C:1]([C:3]1[S:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:36]([NH:35][C:33](=[O:34])[CH2:32][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[S:37])=[CH:15][C:14]=2[F:22])[CH:4]=1)#[CH:2]
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: C#Cc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: Cl[Sn]Cl
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCO
Product: C#Cc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.5 %

Procedure:
To a solution of the alkyne 410 (200 mg, 0.64 mmol) in MeOH (10 ml) was added SnCl2×2H2O (574 mg, 4 eq, 2.54 mmol) and the reaction mixture was heated to reflux for 3 hours. It was then cooled to RT, concentrated and crude amine 411 was used directly in the next step with no additional purification (182 mg, 100%). To a solution of 411 (182 mg, 0.64 mmol) in EtOH (2 ml) and toluene (6 ml) was added 2-phenylacetyl isothiocyanate (227 mg, 2 eq, 1.28 mmol) and the reaction mixture was stirred at RT for 2 hrs, concentrated under reduced pressure and the residue was purified by column chromatography (1:3 EtOAc:hexane) to afford 406 as a white solid (25 mg, 9% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.49 (s, 1H), 11.82 (s, 1H), 8.58 (d, J=5.48 Hz, 1H), 8.01 (m, 1H), 7.88 (s, 1H), 7.50 (m, 2H), 7.25 (m, 5H), 6.73 (d, J=5.48 Hz, 1H), 5.01 (s, 1H), 3.81 (s, 2H). LCMS: 462.2 (M+H).
Reaction SMILES: Cl.Br[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=1.[O:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]2[S:34][C:33](B(OC(C)C)OC(C)C)=[CH:32][CH:31]=2)[CH2:24][CH2:23]1>>[Cl:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[F:20])[NH:13][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:33]3[S:34][C:30]([CH2:29][CH2:28][N:25]4[CH2:26][CH2:27][O:22][CH2:23][CH2:24]4)=[CH:31][CH:32]=3)[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: CC(C)OB(OC(C)C)c1ccc(CCN2CCOCC2)s1
Reactant: Fc1ccc(Nc2ncnc3ccc(Br)cc23)cc1Cl
Agent: Cl
Product: Fc1ccc(Nc2ncnc3ccc(-c4ccc(CCN5CCOCC5)s4)cc23)cc1Cl
Temperature: 25 °C
Yield: 27 %

Procedure:
Using an analogous procedure to that described in Example 5 except that the reaction mixture was heated to reflux for 4 hours, 6-bromo-4-(3-chloro-4-fluoroanilino)quinazoline hydrochloride salt was reacted with di-isopropyl 5-(2-morpholinoethyl)thien-2-ylboronate. The reaction mixture was cooled to ambient temperature and partitioned between methylene chloride and water. The organic phase was washed with brine, dried (MgSO4) and evaporated. The residue was triturated under a mixture of hexane and ethyl acetate to give 4-(3-chloro-4-fluoroanilino)-6-[5-(2-morpholinoethyl)thien-2-yl]quinazoline in 27% yield;
Reaction SMILES: [Li+].C[Si]([N-:6][Si](C)(C)C)(C)C.[CH3:11][O:12][C:13]1[N:18]=[C:17]([CH:19]=O)[CH:16]=[CH:15][CH:14]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH:22]=1>C1COCC1>[CH3:11][O:12][C:13]1[N:18]=[C:17]([CH:19]([NH2:6])[CH:27]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(C=O)n1
Reactant: c1cncc(Cc2cccnc2)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(C(N)C(c2cccnc2)c2cccnc2)n1
Temperature: 0 °C
Yield: 46.5 %

Procedure:
LiHMDS (2.45 mL, 1.2 M in THF, 2.94 mmole) was added to a flame-dried round bottom flask. The mixture was cooled to 0° C. then 6-methoxypyridine-2-carbaldehyde (Comins, Daniel L.; Killpack, Michael O. J. Org. Chem. 1990, 55, 69-73, 161 mg, 1.18 mmole) was added. After 30 minutes di-3-pyridylmethane (200 mg, 1.18 mmole) in dry THF (2.0 mL) was added. After 2 hr the mixture was warmed to RT, quenched with saturated NH4Cl, and extracted with CH2Cl2(3×) and iBuOH (2×). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was taken up in MeOH (5 mL) and H2NOH (0.4 mL, 50% in H2O) was added. After 18 hr the mixture was concentrated. Flash column (gradient, 0-10% MeOH/CH2Cl2) gave 1-(6-methoxypyridin-2-yl)-2,2-dipyridin-3-ylethanamine as a pale yellow oil (168 mg, 47%): 1H-NMR (500 MHz, CDCl3) δ 8.64 (d, J=1.95 Hz, 1H), 8.51 (dd, J=1.46 and 3.17 Hz, 1H), 8.36 (d, J=1.95 Hz, 1H), 8.32 (dd, J=1.46 and 3.18 Hz, 1H), 7.76 (d, J=7.82 Hz, 1H), 7.49 (d, J=8.06 Hz, 1H), 7.37-7.27 (m, 2H), 7.09 (m, 1H), 6.56 (d, J=7.08 Hz, 1H), 6.52 (d, J=7.81 Hz, 1H), 4.59 (d, J=9.28 Hz, 1H), 4.42 (d, J=9.28 Hz, 1H), 3.91 (s, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([N+:24]([O-])=O)=[C:18]2[C:13]=1[C:14]([CH3:27])=[CH:15][CH:16]=[N:17]2.O(CCCC)CCCC.O>[Fe].CC(O)=O>[NH2:24][C:19]1[CH:20]=[C:21]([O:22][CH3:23])[C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[C:14]2[CH3:27]
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCCc1ccco1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCCCOCCCC
Solvent: O
Product: COc1cc(N)c2nccc(C)c2c1OCCCCCc1ccco1

Procedure:
A mechanically stirred mixture of 5-[5-(2-furyl)pentoxy]-6-methoxy-4-methyl-8-nitroquinoline (2.20 g, 0.0059 mol), Fe-filings (3.0 g), Bu2O (8 ml), H2O (30 ml) and HOAc (0.5 ml) was heated at 95°-100° C. for 2 h, allowed to cool and filtered. The residue was washed with Et2O (100 ml) and the filtrate and the washings were combined. The organic layer was separated and the aqueous layer was extracted with Et2O (2×50 ml). The combined organic layers were washed with saturated NaCl solution (1×50 ml), dried (Na2SO4), treated with Darco and concentrated to an oil which on trituration with cold hexane produced 8-amino-5-[5-(2-furyl) pentoxy]-6-methoxy-4-methylquinoline as a crude greenish-yellow solid 1.35 g (65%), mp 41°-42° C. This material was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.[NH2:37][C@H:38]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[CH:51]=2)=[CH:46][CH:45]=1)[CH2:39][C:40]([OH:42])=[O:41].CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([NH:37][C@H:38]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[CH:51]=2)=[CH:46][CH:45]=1)[CH2:39][C:40]([OH:42])=[O:41])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCC(=O)OCc1ccccc1
Reactant: N[C@@H](CC(=O)O)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)CCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
A solution of succinic acid mono-benzyl ester (71.1 mg, 0.342 mmol), EDCI (65.5 mg, 0.342 mmol) and HOAt (46.5 mg, 0.342 mmol) in DMF (1 ml), which is allowed to stir at room temperature for 1 hour, is added to a solution of (R)-3-amino-4-(3′-chlorobiphenyl-4-yl)butanoic acid (66 mg, 0.228 mmol) and DIPEA (0.080 ml, 0.456 mmol) in a mixed solvent DMF (2 ml) and water (2 ml). The reaction mixture is allowed to stir for 3 hours, and then diluted with H2O. The products are extracted twice with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated to give crude. The resulting residue is purified by preparative HPLC using a gradient of 20% MeCN/water (0.1% TFA) to 100% MeCN to give (R)-3-(4-(benzyloxy)-4-oxobutanamido)-4-(3′-chlorobiphenyl-4-yl)butanoic acid (42.4 mg) as a white solid; HPLC retention time=1.22 minutes (condition B); MS (m+1)=480.35; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.44-2.75 (m, 6 H) 2.86-2.99 (m, 2 H) 4.48-4.56 (m, 1 H) 5.11 (s, 2 H) 6.29 (br d, J=8.6 Hz, 1 H) 6.97-7.07 (m, 10 H) 7.25-7.36 (m, 2 H) 7.42-7.50 (m, 2 H) 7.54 (br t, J=1.6 Hz, 1 H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].Cl[CH2:7][CH2:8][C:9](Cl)=[O:10].C(=O)([O-])[O-].[Na+].[Na+].[ClH:18]>O.C(#N)C>[Cl:18][CH:8]([CH3:7])[C:9]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:10]
Reactant: Cl
Reactant: NCC(=O)O
Reactant: O=C(Cl)CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(Cl)C(=O)NCC(=O)O
Temperature: 0 °C

Procedure:
In a mixture composed of 80 g (2.0 mol) and 200 ml of water was dissolved with stirring 165 g (2.2 mol) of glycine and the mixture was cooled to 0° C. To the aqueous solution, there were simultaneously added dropwise 254 g (2.0 mol) of β-chloropropionyl chloride and an aqueous solution containing 127.2 g (1.2 mol) of sodium carbonate dissolved in 400 ml of water. After the completion of the reaction, 1 liter of acetonitrile was added to the reaction solution and the mixture was then acidified by adding 200 ml of concentrated hydrochloric acid. 1 liter of acetonitrile was further added to extract and the acetonitrile layer was separated. The acetonitrile solution was concentrated and the crystals thus deposited were collected and recrystallized from ethyl acetate to obtain 235.3 g of N-(β-chloropropanoyl)glycine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.C1COCC1.C1(C)C=CC=CC=1.[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C:34](=[O:39])N(OC)C)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C:34](=[O:39])[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.4 %

Procedure:
At 0° C. 4-chlorophenylmagnesiumbromide 0.9 molar in THF/toluene (66.7 ml, 60 mmol) was added over 15 minutes to a solution of (S)-2-(Methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester CAS 115186-37-3 (5.16 g, 20 mmol) in dry THF (50 ml). The reaction mixture was warmed to ambient temperature and stirred for another 4 hours. The reaction mixture was poured on 1N HCl/ice (150 ml) and then extracted with ethyl acetate (2×100 ml). The organic layers are washed with water (2×50 ml), saturated NaCl (50 ml) and then dried over Na2SO4. After evaporation of the solvent, the crude product (7.5 g in the form of a yellow oil) was purified by flash chromatography over silica gel 150 g, (eluent:cyclohexane/ethyl acetate 9:1) to afford 4.3 g (69.4% of theory) of (S)-2-(4-chloro-benzoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a as a white solid m.p. 117-122° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][C:11]1[CH:12]=[C:13]([CH:41]=[CH:42][CH:43]=1)[CH2:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24]2[C:25](=[O:40])[NH:26][C:27](=[O:39])[C:28]=2[C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]([CH3:38])[CH:30]=2)=[CH:16]1)(=O)=O>CN(C)C=O>[N:1]([CH2:10][C:11]1[CH:12]=[C:13]([CH:41]=[CH:42][CH:43]=1)[CH2:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24]2[C:25](=[O:40])[NH:26][C:27](=[O:39])[C:28]=2[C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]([CH3:38])[CH:30]=2)=[CH:16]1)=[N+:2]=[N-:3]
Reactant: Cn1cc(C2=C(c3cn(Cc4cccc(COS(C)(=O)=O)c4)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(C2=C(c3cn(Cc4cccc(CN=[N+]=[N-])c4)c4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium azide (0.144 g, 2.2 mmol) was added to a solution of the product of step b) (0.28 g, 0.5 mmol) in dry dimethylformamide (5 mL). The mixture was stirred at room temperature for 30 min and then partitioned between ethyl acetate and water. The organic phase was washed three times with water and evaporated (with ethanol), to give the crude sub-title product which was used without further purification.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23](Cl)=[N:24][C:17]=2[N:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])[C:15]1=[O:34])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:24][C:17]=2[N:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])[C:15]1=[O:34])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=c1c2cc(F)c(Cl)nc2n(-c2ccccc2F)c(=O)n1OCc1ccccc1
Reactant: C1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=c1c2cc(F)c(N3CCCC3)nc2n(-c2ccccc2F)c(=O)n1OCc1ccccc1
Yield: 84.6 %

Procedure:
Using the method of Example N-4, pyrrolidine (0.04 mL, 0.52 mmol), 3-benzyloxy-7-chloro-6-fluoro-1-(2-fluorophenyl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example R-2, 0.15 g, 0.42 mmol) and triethylamine (0.36 mL, 2.6 mmol) were combined in 20 mL of acetonitrile to give 0.16 g of the title compound as a solid, mp 221-222° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:4].C(N(CC)CC)C.C1C[O:34][CH2:33][CH2:32]1.C(Cl)(=O)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[C:10]([C:14]([F:16])([F:17])[F:15])=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[CH:18]1[CH2:23][CH2:22][N:21]([C:33](=[O:34])[CH3:32])[CH2:20][CH2:19]1)=[O:4]
Reactant: C1CCOC1
Reactant: COC(=O)c1sc2c(C(F)(F)F)cccc2c1C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1sc2c(C(F)(F)F)cccc2c1C1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a room temperature solution of 3-piperidin-4-yl-7-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid methyl ester (4.37 g, 12.7 mmol), triethylamine (2.70 mL.19.4 mmol), and anhydrous THF (80 mL) under nitrogen was added acetyl chloride (1.10 mL, 15.5 mmol) in one portion and the reaction stirred at room temperature overnight. The reaction was diluted with ethyl acetate (300 mL) and washed with water (150 mL) and brine (150 mL) successively. The organic layer was dried over magnesium sulfate, filtered, and the solvent removed. The residue was chromatographed on silica, eluting with 10% methanol/ethyl acetate, to afford 4.28 g (88%) of the desired product as a white solid, mp: 155.2° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:13]([F:16])([F:15])[F:14])[C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[N:6][CH:7]=1.[CH2:17]([O:19][C:20]1[C:25](=[O:26])[NH:24][CH:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[C:29]([F:37])[CH:28]=2)[CH:21]=1)[CH3:18].C1C=CC2N(O)N=NC=2C=1.C(Cl)C[Cl:50].CCN(CC)CC>CN(C=O)C>[ClH:50].[C:9]([C:8]([C:5]1[N:6]=[CH:7][C:2]([NH:1][C:34](=[O:35])[CH2:33][C:30]2[CH:31]=[CH:32][C:27]([C:22]3[CH:21]=[C:20]([O:19][CH2:17][CH3:18])[C:25](=[O:26])[NH:24][CH:23]=3)=[CH:28][C:29]=2[F:37])=[CH:3][C:4]=1[C:13]([F:16])([F:14])[F:15])([CH3:12])[CH3:11])#[N:10]
Reactant: CCOc1cc(-c2ccc(CC(=O)O)c(F)c2)c[nH]c1=O
Reactant: ClCCCl
Reactant: CC(C)(C#N)c1ncc(N)cc1C(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cnc(C(C)(C)C#N)c(C(F)(F)F)c3)c(F)c2)c[nH]c1=O
Product: Cl
Yield: 26.2 %

Procedure:
A suspension of 2-(5-amino-3-(trifluoromethyl)pyridin-2-yl)-2-methylpropanenitrile (13.91 mg, 0.061 mmol) in DMF (5 mL) was added to a solution of 2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid (52 mg, 0.061 mmol) in DMF (5 mL). HOBt (13.94 mg, 0.091 mmol), EDC (17.45 mg, 0.091 mmol) and Et3N (0.025 mL, 0.182 mmol) and the mixture was at 50° C. for 12 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by preparative HPLC (MeCN/H2O as eluants, acidic condition) to yield an off white solid of N-(6-(2-cyanopropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide, hydrochloride (8.62 mg, 0.016 mmol, 26.4% yield). TLC (DCM/MeOH=10:1, Rf=0.3): 1H NMR (400 MHz, CD3OD) δ: 8.95 (d, J=2.2 Hz, 1H), 8.56 (d, J=2.4 Hz, 1H), 7.26-7.47 (m, 5H), 4.14 (q, J=7.0 Hz, 2H), 3.81-3.90 (m, 2H), 1.77-1.91 (m, 6H), 1.47 (t, J=6.9 Hz, 3H); ES-LCMS m/z 503.1 (M+H).