Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:23][CH2:24][CH2:25][C@H:26]([OH:30])[C:27]([OH:29])=[O:28].CO.Cl>C[O-].[Na+].O>[OH:30][C@@H:26]([CH2:25][CH2:24][NH:23][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH:9]=2)=[O:4])[C:27]([OH:29])=[O:28]
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Reactant: NCC[C@H](O)C(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(NCC[C@H](O)C(=O)O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Yield: 91.2 %

Procedure:
A mixture of 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.34 mmol) and (S)-(−)-4-amino-2-hydroxybutyric acid (122 mg, 1.02 mmol) in 0.5 N NaOMe in MeOH solution (1.4 mL, 0.7 mmol) was microwaved at 120° C. for 1 h. Reaction mixture was diluted with water (100 mL), acidified by 1 N HCl aqueous solution to pH=3-4 and extracted with EtOAc. Organic layer was washed with brine, dried over Mg2SO4, filtered and concentrated to provide the title compound (120 mg, 0.31 mmol) in 92.4% yield. LC-MS ESI−: 381.05 (M−1)−.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]2[CH:10]([CH:11]=1)[NH:9][C:8](=[O:12])[CH2:7][CH2:6]2.C1C(=O)N([Br:20])C(=O)C1>>[Br:20][C:3]1[C:2]([OH:1])=[CH:11][CH:10]2[CH:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)[CH:4]=1
Reactant: O=C1CCC2C=CC(O)=CC2N1
Reactant: O=C1CCC(=O)N1Br
Product: O=C1CCC2C=C(Br)C(O)=CC2N1

Procedure:
This intermediate was obtained according to general procedure I from 7-hydroxy-3,4,4a,8a-tetrahydro-1H-quinolin-2-one (370 mg, 2.27 mmol) and NBS (424 mg, 2.38 mmol) after flash chromatography on silica gel (hexanes/ethyl acetate, 1/1, Rf=0.15) as white solid (500 mg, 2.07 mmol, 91%).
Reaction SMILES: CC1C=CN=C(NC2N=C(C3OC(NCC4C=CN=CC=4)=NC=3)C=CC=2)C=1.Cl[C:29]1[O:30][C:31]([C:34]2[N:39]=[C:38]([NH:40][C:41]3[S:42][C:43]([CH3:46])=[CH:44][N:45]=3)[CH:37]=[CH:36][CH:35]=2)=[CH:32][N:33]=1.[O:47]=[C:48]1[CH2:53][NH:52][CH2:51][CH2:50][NH:49]1>CC(O)C>[CH3:46][C:43]1[S:42][C:41]([NH:40][C:38]2[N:39]=[C:34]([C:31]3[O:30][C:29]([N:52]4[CH2:51][CH2:50][NH:49][C:48](=[O:47])[CH2:53]4)=[N:33][CH:32]=3)[CH:35]=[CH:36][CH:37]=2)=[N:45][CH:44]=1
Reactant: O=C1CNCCN1
Reactant: Cc1cnc(Nc2cccc(-c3cnc(Cl)o3)n2)s1
Agent: Cc1ccnc(Nc2cccc(-c3cnc(NCc4ccncc4)o3)n2)c1
Solvent: CC(C)O
Product: Cc1cnc(Nc2cccc(-c3cnc(N4CCNC(=O)C4)o3)n2)s1

Procedure:
Prepared as for 5-[6-(4-methylpyridin-2-ylamino)pyridin-2-yl]-N-(pyridin-4-ylmethyl)oxazol-2-amine above from [6-(2-Chloro-oxazol-5-yl)-pyridin-2-yl]-(5-methyl-thiazol-2-yl)-amine and 2-oxopiperazine in iPrOH. 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.14 (s, 1H), 7.68 (t, J=7.9 Hz, 1H), 7.59 (s, 1H), 7.16-6.97 (m, 2H), 6.83 (d, J=8.2 Hz, 1H), 4.11 (s, 2H), 3.86-3.63 (m, 2H), 3.43-3.32 (m, 2H), 2.37 (s, 3H). (ESI+) m/z 357 (M+H)+. Retention time=1.91 mins (method 1).
Reaction SMILES: C(OC1C(C(O)=O)=NC=CC=1OC)C1C=CC=CC=1.C([O:27][C:28]1[C:29]([C:38]([OH:40])=O)=[N:30][CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35])C1C=CC=CC=1.CO[C:43]1[CH:56]=[CH:55][C:46]([O:47][C:48]2[CH:54]=[CH:53][C:51]([NH2:52])=[CH:50][CH:49]=2)=[CH:45][CH:44]=1.O(C1C=CC(N)=CC=1)C1C=CC=CC=1>>[OH:27][C:28]1[C:29]([C:38]([NH:52][C:51]2[CH:50]=[CH:49][C:48]([O:47][C:46]3[CH:55]=[CH:56][CH:43]=[CH:44][CH:45]=3)=[CH:54][CH:53]=2)=[O:40])=[N:30][CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35]
Reactant: COc1ccc(Oc2ccc(N)cc2)cc1
Reactant: COc1cnc(C(=O)O)c(OCc2ccccc2)c1OC
Agent: COc1ccnc(C(=O)O)c1OCc1ccccc1
Agent: Nc1ccc(Oc2ccccc2)cc1
Product: COc1cnc(C(=O)Nc2ccc(Oc3ccccc3)cc2)c(O)c1OC

Procedure:
The procedure of Example 29 was repeated, except that 3-benzyloxy-4-methoxypicolinic acid was changed to 3-benzyloxy-4,5-dimethoxypicolinic acid and 4-(4′-methoxyphenoxy)aniline was changed to 4-phenoxyaniline. Thus, the title compound was prepared.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]([CH3:10])[CH2:7][CH:8]=[CH2:9])[CH:2]=[CH2:3].CN1CCOCC1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH2:1]([N:4]([CH2:5][CH:6]([CH3:10])[CH2:7][CH:8]=[CH2:9])[S:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=1)(=[O:26])=[O:25])[CH:2]=[CH2:3]
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: C=CCNCC(C)CC=C
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C=CCC(C)CN(CC=C)S(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.4 %

Procedure:
Allyl-(2-methyl-pent-4-enyl)-amine (1.0 g, 7.2 mmol) and NMM (1.7 g, 17.2 mmol) were mixed in 30 ml CH2Cl2.2-pyridinesulphonyl chloride (1.53 g, 8.6 mmol) was added slowly to the solution while it was cooled in an ice-water bath. After addition, the reaction mixture was stirred at RT overnight. The reaction mixture was washed with 10% NaHCO3 and the brine, then was purified by column chromatography to give the title compound as a colorless oil (1.2 g, 60% yield): MS (M+H+) 281.2; 1H-NMR (400 Hz, CDCl3): d=8.70(d, 1H), 8.0-7.75(m, 2H), 7.5 (m, 1H) 5.80-5.60(m, 2H), 5.15-4.92(m, 4H), 4.00-3.90(m, 2H), 3.20-3.06(m, 2H), 2.15(m, 1H), 1.85(m, 2H), 0.89(d, 3H)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][C:6]=2[CH:13]=1.[CH3:14][NH:15][CH2:16][CH:17]=[O:18]>C1C=CC=CC=1>[CH3:14][N:15]([CH2:16][CH:17]=[O:18])[C:11]([NH:10][C:8]1[S:9][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:13][C:6]=2[N:7]=1)=[O:12]
Reactant: Cc1ccc2sc(N=C=O)nc2c1
Reactant: CNCC=O
Solvent: c1ccccc1
Product: Cc1ccc2sc(NC(=O)N(C)CC=O)nc2c1
Reaction time: 1 h

Procedure:
5-Methylbenzothiazol-2-yl isocyanate dimer (0.1 mole), the dimethyl acetal of 2-methylaminoacetaldehyde (0.2 mole) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at ambient temperatures for a period of about one hour. After this time the reaction mixture is filtered, and the filtrate is stripped of solvent to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-methylbenzothiazol-2-yl)ureido]acetaldehyde as the residue.
Reaction SMILES: [CH2:1]([C:5]1[CH:22]=[CH:21][C:8]([NH:9][C:10]2[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)=[C:7]([F:23])[CH:6]=1)[CH2:2][CH2:3][CH3:4].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:36][O:37][CH2:38][CH2:39][OH:40]>>[CH2:1]([C:5]1[CH:22]=[CH:21][C:8]([NH:9][C:10]2[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:11]=2[C:12]([NH:36][O:37][CH2:38][CH2:39][OH:40])=[O:14])=[C:7]([F:23])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NOCCO
Reactant: CCCCc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCCCc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Yield: 68 %

Procedure:
The title compound was prepared from reaction of 2-(4-butyl-2-fluoroanilino)-3,4-difluorobenzoic acid with CDI and 2-(aminooxy)ethanol by the general procedure of Example 1, Step E, then purified by flash column chromatography on silica (50% EtOAc/Hexane as eluant) to give 2-(4-butyl-2-fluoroanilino)-3,4-difluoro-N-(2-hydroxyethoxy)benzamide as a white solid (68%); m.p. (EtOAc/Hexane) 163–165° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][C:11](=[O:13])[N:10]([CH:14]([CH3:24])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:23])[CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:26][C:27]([CH2:29]Br)=[O:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][C:11](=[O:13])[N:10]([CH:14]([CH3:24])[CH2:15][CH:16]3[CH2:21][CH2:20][C:19]4[O:22][CH2:26][C:27](=[O:28])[CH2:29][C:18]=4[O:23][CH2:17]3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(Cc1ccc(O)c(O)c1)N1CC(c2cccc(Cl)c2)OC1=O
Reactant: O=C(CBr)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(CC1CCC2=C(CC(=O)CO2)OC1)N1CC(c2cccc(Cl)c2)OC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
One equivalent of 5-(3-chlorophenyl)-3-(2-(3,4-dihydroxyphenyl)-1-methylethyl)-2-oxazolidinone, prepared by the procedure of U.S. Pat. No. 5,061,727 Example 1, is treated with one equivalent of 1,3-dibromoacetone and excess potassium carbonate in acetonitrile. The mixture is stirred at room temperature for 18 hours, filtered and evaporated in vacuo to give 7-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-1,5-dioxabenzocycloheptan-3-one. One equivalent of this ketone is reduced, at room temperature for one hour, with excess sodium borohydride in methyl alcohol. The reaction mixture is poured into water, made acidic with 1N hydrochloric acid and extracted with methylene chloride. The organic extracts are dried and evaporated in vacuo to give 7-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl-1,5-dioxabenzocycloheptan-3-ol. Hydrolysis with 2.5N sodium hydroxide gives the title compound.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:67][N:68]1[CH2:73][CH2:72][N:71]([CH2:74][C:75]2[CH:82]=[CH:81][C:78]([CH:79]=O)=[CH:77][CH:76]=2)[CH2:70][CH2:69]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:79]([C:78]3[CH:77]=[CH:76][C:75]([CH2:74][N:71]4[CH2:70][CH2:69][N:68]([CH3:67])[CH2:73][CH2:72]4)=[CH:82][CH:81]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: CN1CCN(Cc2ccc(C=O)cc2)CC1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccc(-c3nc4c(N5CCN(Cc6cccnc6)CC5)c(Br)cnc4[nH]3)cc2)CC1
Reaction time: 6 h
Yield: 20.5 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (50 mg, 0.13 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.38 mmol, 0.38 mL) and 4-[(4-methylpiperazin-1-yl)methyl]benzaldehyde (1.1 eq, 0.14 mmol, 31 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 9:1) gave the product (15 mg, 21%) as a pale yellow solid; δH (500 MHz, DMSO-d6) 2.16 (s, 3H, CH3), 2.34-2.38 (m, 8H, 2× piperazine N(CH2)2), 2.62 (t, J=4.7 Hz, 4H, piperazine N(CH2)2), 3.52 (s, 2H, NCH2), 3.62 (s, 2H, NCH2), 3.70 (t, J=4.6 Hz, 4H, piperazine N(CH2)2), 7.39 (dd, J=7.6, 4.6 Hz, 1H, pyridine H-5), 7.45 (d, J=8.4 Hz, 2H, phenyl H-3 & H-5), 7.79 (dt, J=7.7, 1.8 Hz, 1H, pyridine H-4), 8.13 (d, J=8.3 Hz, 2H, phenyl H-2 & H-6), 8.23 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.49 (dd, J=4.8, 1.7 Hz, 1H, pyridine H-6), 8.56 (d, J=1.6 Hz, 1H, pyridine H-2), 13.47 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:21][C:22]1[NH:26][C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[N:23]=1)[CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:39]1([S:45](Cl)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:21][C:22]1[N:26]([S:45]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:47])=[O:46])[C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[N:23]=1)[CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cccnc1CN(CCCCNC(=O)OC(C)(C)C)Cc1nc2ccccc2[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccnc1CN(CCCCNC(=O)OC(C)(C)C)Cc1nc2ccccc2n1S(=O)(=O)c1ccccc1
Yield: 70.3 %

Procedure:
To a solution of {4-[(1H-benzoimidazol-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester (0.215 g, 0.51 mmol) in CH2Cl2 (10 mL) was added Et3N (0.30 mL, 2.15 mmol) followed by benzenesulfonyl chloride (0.—ml, 1.02 mmol) and the resultant solution was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 (40 mL), washed with brine (3×10 mL), dried (Na2SO4), and concentrated. Purification of the crude material by column chromatography on silica gel (15:1 CH2Cl2-MeOH) provided 0.202 g (70%) of {4-[(1-Benzenesulfonyl-1H-benzoimidazol-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester as an orange-brown oil.
Reaction SMILES: Cl.[C:2]([C@H:5]1[CH2:14][C@H:13]([NH:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH2:26])=[CH:20][CH:19]=2)=[O:17])[C:12]2[C:7](=[CH:8][C:9]([Cl:28])=[CH:10][C:11]=2[Cl:27])[NH:6]1)([OH:4])=[O:3].Cl.[C:30]([C@H]1C[C@H](NC(C2C=CC=C(CN)C=2)=O)C2C(=CC(Cl)=CC=2Cl)N1)(O)=O>>[ClH:27].[CH3:30][O:3][C:2]([C@H:5]1[CH2:14][C@H:13]([NH:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH2:26])=[CH:20][CH:19]=2)=[O:17])[C:12]2[C:7](=[CH:8][C:9]([Cl:28])=[CH:10][C:11]=2[Cl:27])[NH:6]1)=[O:4]
Reactant: NCc1cccc(C(=O)N[C@H]2C[C@H](C(=O)O)Nc3cc(Cl)cc(Cl)c32)c1
Reactant: NCCc1ccc(C(=O)N[C@H]2C[C@H](C(=O)O)Nc3cc(Cl)cc(Cl)c32)cc1
Agent: Cl
Product: COC(=O)[C@H]1C[C@H](NC(=O)c2ccc(CCN)cc2)c2c(Cl)cc(Cl)cc2N1

Procedure:
This compound was prepared by the method given for Example 82 using trans-2-carboxy-5,7-dichloro-4-(4-aminoethylphenyl)carbonylamino-1,2,3,4-tetrahydroquinoline hydrochloride Example 85, in the place of trans-2-carboxy-5,7-dichloro-4(3-aminomethylphenyl)carbonylamino-1,2,3,4-tetrahydroquinoline hydrochloride to give the title compound as a colourless crystalline solid, m.p. 218° C. (dec). δ (DMSO, 360 MHz) 1.78 (1H, ddd, J=13.2, 12.8 and 4.1 Hz, CHACHBHCCHD), 2.25 (1H, dm, J=13.2 Hz, CHACHBHCCHD), 2.92 (2H, t, J=7.0 Hz, CHE2CHF2), 3.04 (2H, t, J=7.0 Hz, CHE2CHF2), 3.71 (3H, s, CH3), 4.06 (1H, dd, J=12.5 and 2.4 Hz, CHACHBHCCHD), 5.26 (1H, m, CHACHBHCCHD), 6.69 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.91 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.94 (1H, s, Ar NHCH), 7.33 (2H, d, J=8.1 Hz, Ar-H), 7.86 (2H, d, J=8.1 Hz, Ar-H), 7.96 (2H, br, s, NH2), 8.70 (1H, d, J=7.1 Hz, NHCO); m/e (CI+, NH3) 422 (M+1); Found C, 48.59; H, 4.55; N, 8.48.C20H21Cl2N3O3.2HCl requires C, 48.51; H, 4.68; N, 8.48%.
Reaction SMILES: CCN(C(C)C)C(C)C.[S:10]([N:20]1[CH2:25][CH2:24][N:23]2[CH:26]=[CH:27][CH:28]=[C:22]2[CH:21]1[CH2:29][C:30]([OH:32])=O)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[F:55][CH:56]1[CH2:61][CH2:60][N:59]([CH2:62][C:63]2[CH:64]=[C:65]3[C:70](=[CH:71][CH:72]=2)[CH:69]([NH2:73])[CH2:68][CH2:67][CH2:66]3)[CH2:58][CH2:57]1>C(Cl)Cl>[F:55][CH:56]1[CH2:61][CH2:60][N:59]([CH2:62][C:63]2[CH:64]=[C:65]3[C:70](=[CH:71][CH:72]=2)[C@H:69]([NH:73][C:30](=[O:32])[CH2:29][CH:21]2[N:20]([S:10]([C:13]4[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=4)(=[O:11])=[O:12])[CH2:25][CH2:24][N:23]4[CH:26]=[CH:27][CH:28]=[C:22]24)[CH2:68][CH2:67][CH2:66]3)[CH2:58][CH2:57]1
Reactant: Cc1ccc(S(=O)(=O)N2CCn3cccc3C2CC(=O)O)cc1
Reactant: NC1CCCc2cc(CN3CCC(F)CC3)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N2CCn3cccc3C2CC(=O)N[C@@H]2CCCc3cc(CN4CCC(F)CC4)ccc32)cc1
Reaction time: 0.5 h
Yield: 38 %

Procedure:
DIPEA (630 μl, 3.592 mmol, 4.0 eq.) was added to a stirred solution of 2-(2-tosyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid (S11) (300 mg, 0.898 mmol, 1.0 eq.) in DCM (15 ml), followed by EDCl (260 mg, 1.347 mmol, 1.5 eq.) and HOBT (183 mg, 1.347 mmol, 1.5 eq.) which were added at 0° C. The reaction mixture was allowed to stir for 30 min. A solution of R)-6-((4-fluoropiperidin-1-yl)methyl)-1,2,3,4-tetrahydronaphthalen-1-amine (A52) (0.898 mmol, 1.0 eq.) in DCM (5 ml) was added to the reaction mixture and it was stirred at RT for 16 h. The reaction mixture was diluted with DCM (50 ml) and washed with sat. NH4Cl solution (50 ml), sat. NaHCO3 solution (50 ml), water (50 ml) and brine (50 ml), and dried over Na2SO4. The solvent was evaporated under reduced pressure to give crude product which was purified by column chromatography (silica gel; 2% MeOH/DCM) to yield the desired compound as an off white solid. Yield: 38% (197 mg, 0.34 mmol); MS, Rt=3.2 min; m/z=579.1 [M H]+
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][S:11][C:5]=2[N:4]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:3]1=[O:21].[Cl:22][C:23]1[S:24][C:25]([CH:29]=[O:30])=[C:26]([Cl:28])[N:27]=1.CN1C(=O)N(C)CCC1.[Li+].CC([N-]C(C)C)C>C1COCC1.C(O)(=O)C>[Cl:22][C:23]1[S:24][C:25]([CH:29]([OH:30])[C:10]2[S:11][C:5]3[N:4]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:3](=[O:21])[N:2]([CH3:1])[C:7](=[O:8])[C:6]=3[C:9]=2[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:26]([Cl:28])[N:27]=1
Reactant: CCOC(=O)c1csc2c1c(=O)n(C)c(=O)n2CC(C)C
Reactant: O=Cc1sc(Cl)nc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)c1c(C(O)c2sc(Cl)nc2Cl)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Temperature: 25 °C
Yield: 18.9 %

Procedure:
To a solution of ethyl 3-methyl-1-(2-methylpropyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-5-carboxylate (1.5 g), 2,4-dichlorothiazole-5-carboxaldehyde (1.75 g) and DMPU (1.2 ml) in THF (25 ml) at −78° C., was added LDA (10 mmol). Acetic acid (3 ml) was added and the mixture allowed to warm to ambient temperature. The mixture was then partitioned between ethyl acetate and water, the organics were collected, dried over magnesium sulphate and concentrated to dryness. The residue was purified by normal phase chromatography (3:1 i-hexane:ethyl acetate) to give the sub-title compound as a yellow foam (0.45 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:19])([CH3:18])[C:6](=[O:17])[CH:7](Br)[O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[CH3:2].[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.[C:26]1([S:40]([OH:43])(=[O:42])=[O:41])[C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([S:36]([OH:39])(=[O:38])=[O:37])[C:30]=2[CH:29]=[CH:28][CH:27]=1>C(#N)C.CC(C)=O>[C:26]1([S:40]([OH:43])(=[O:42])=[O:41])[C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([S:36]([OH:39])(=[O:38])=[O:37])[C:30]=2[CH:29]=[CH:28][CH:27]=1.[CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:19])([CH3:18])[C:6](=[O:17])[CH:7]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)[CH3:2]
Reactant: CCOC(=O)C(C)(C)C(=O)C(Br)Oc1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Agent: O=S(=O)(O)c1cccc2c(S(=O)(=O)O)cccc12
Solvent: CC#N
Solvent: CC(C)=O
Product: CCOC(=O)C(C)(C)C(=O)C(Oc1ccc(Cl)cc1)n1ccnc1
Yield: 54.8 %

Procedure:
145 g (0.4 mol) of 4-bromo-4-(4-chlorophenoxy)-2,2-dimethyl-3-keto-butanoic acid ethyl ester were dissolved in 800 ml of acetonitrile. 100 g (1.45 mol) of imidazole were added and the mixture was heated for 20 hours under reflux. The solvent was then distilled off in vacuo, the residue was taken up in 500 ml of methylene chloride and the solution was washed three times with 200 ml of water each time, dried over sodium sulphate and concentrated. The oil which remained was dissolved in 800 ml of acetone and 100 g (0.35 mol) of 1,5-naphthalenedisulphonic acid in 300 ml of acetone were added. The resulting crystalline precipitate was filtered off and dried. 122.5 g (62% of theory) of 4-(4-chlorophenoxy)-2,2-dimethyl-4-(imidazol-1-yl)-3-keto-butanoic acid ethyl ester 1,5-naphthalenedisulphonate of melting point 194° C. were obtained.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[NH:16][C:17]([C@@H:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][N:20]1[C:29](=[O:35])[C@@H:30]([NH2:34])[CH:31]([CH3:33])[CH3:32])=[O:18].[C:36]([O:40][C:41]([NH:43][C@@H:44]([CH3:48])[C:45]([OH:47])=O)=[O:42])([CH3:39])([CH3:38])[CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:36]([O:40][C:41](=[O:42])[N:43]([C@H:44]([C:45](=[O:47])[NH:34][C@H:30]([C:29]([N:20]1[CH2:21][CH2:22][C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:19]1[C:17](=[O:18])[NH:16][C:10]1[C:11]([F:15])=[CH:12][CH:13]=[CH:14][C:9]=1[Cl:8])=[O:35])[CH:31]([CH3:33])[CH3:32])[CH3:48])[CH3:2])([CH3:37])([CH3:38])[CH3:39]
Reactant: O=C(O)C(F)(F)F
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)[C@H](N)C(=O)N1CCc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
To a solution of (S)-2-((S)-2-amino-3-methyl-butyryl)-1,2,3,4-tetrahydro-isoquinoline-1-carboxylic acid (2-chloro-6-fluoro-phenyl)-amide trifluoroacetate (48 mg, 92.7 μmol, Eq: 1.00), (S)-2-(tert-butoxycarbonylamino)propanoic acid (17.5 mg, 92.7 μmol, Eq: 1.00), HATU (38.8 mg, 102 μmol, Eq: 1.1) in DMF (300 μL) at 0° C. was added DIEA (35.9 mg, 48.6 μL, 278 μmol, Eq: 3). The reaction was stirred at RT for 1 h, diluted with water and extracted with EtOAc. The combined organics were washed with water, brine, dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography to give ((S)-1-{(S)-1-[(S)-1-(2-chloro-6-fluoro-phenylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2-methyl-propylcarbamoyl}-ethyl)-methyl-carbamic acid tert-butyl ester (36 mg) as a white foam.
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10])[CH2:2][CH2:3][CH3:4].[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl.[OH-:21].[Na+]>O>[C:11]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:9][CH2:8][CH2:7][C:6]([OH:10])=[O:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [OH-]
Reactant: CCCCN1CCCC1=O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCCN(CCCC(=O)O)C(=O)c1ccccc1
Yield: 47.1 %

Procedure:
15.5 g of n-butylpyrrolidone is heated for 20 hours under reflux in a mixture of 15 g of sodium hydroxide in 100 ml of water. Into the solution (which is cooled to 0° and vigorously agitated) there is slowly introduced (drop by drop) 23.1 g of benzoyl chloride, which is then stirred for a further 5 hours; while further cooling, 5 N hydrochloric acid is added until the reaction mixture becomes acid. The precipitated deposit, which still contains benzoic acid, is separated and recrystallized several times from ligroin to obtain 13.6 g (47% of theory) of N-benzoyl-4-(n-butyl)aminobutyric acid (M.P. 62° to 64°).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10]O)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:13].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Cl:13][CH2:10][C:4]1[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: COc1cc(F)cc(CO)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(F)cc(CCl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.4 %

Procedure:
To a solution of (3-fluoro-5-methoxyphenyl)methanol (4.9 g, 30 mmol) in CCl4 (50 mL), PCl5 (13 g, 60 mmol) was added. The mixture was stirred at room temperature for 1 h. To this mixture, saturated Na2CO3 solution was slowly added until pH was adjusted to 7˜8. The mixture was extracted with DCM (3×15 mL), and the organic phase was concentrated to give a colorless oil, which was purified by silica-gel column chromatography (100% petroleum ether) to give 2.9 g of 1-(chloromethyl)-3-fluoro-5-methoxybenzene. 1H NMR (CDCl3): δ 6.68-6.72 (m, 2H), 6.54-6.59 (m, 1H), 4.51 (s, 2H), 3.81 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:12]([CH3:21])[C:11]([C:22](O)=O)=[N:10]1.[CH3:25][C:26]([NH:31][CH3:32])([CH3:30])[C:27]([NH2:29])=[O:28]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[C:12]([CH3:21])[C:11]([C:22]2[N:31]([CH3:32])[C:26]([CH3:30])([CH3:25])[C:27](=[O:28])[N:29]=2)=[N:10]1
Reactant: CNC(C)(C)C(N)=O
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(F)cc1
Product: Cc1c(C2=NC(=O)C(C)(C)N2C)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(F)cc1

Procedure:
Compound 19 was synthesized from 4g (248 mg, 0.68 mmol) and 5a (130 mg, 1.08 mmol) as a white solid (121 mg, 39%) in a manner similar to that described in Example 36. 1H NMR (400 MHz, CDCl3) δ 7.39 (d, 1H), 7.20 (dd, 1H), 7.13 (d, 1H), 7.06 (dd, 2H), 6.97 (dd, 2H), 3.43 (s, 3H), 2.33 (s, 3H), 1.36 (s, 6H); ESMS m/z: 445.0 (M+1).