Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@@H:13]([O:19][C@H:20]2[O:37][C@H:36]([CH2:38][O:39][C:40](=[O:42])[CH3:41])[C@H:31]([O:32][C:33](=[O:35])[CH3:34])[C@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:21]2[O:22][C:23](=[O:25])[CH3:24])[C@@H:12]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[O:11][C@H:6]1[O:7][CH2:8][CH2:9]Br)(=[O:3])[CH3:2].[CH2:48]([SH:56])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55].C(=O)([O-])[O-].[Cs+].[Cs+].C(O[C@@H]1[C@@H](OC(=O)C)[C@@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1OCCSCCCCCCCC)(=O)C>[Cl-].C[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC.C1C=CC=CC=1.O>[C:1]([O:4][C@@H:5]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@@H:13]([O:19][C@H:20]2[O:37][C@H:36]([CH2:38][O:39][C:40](=[O:42])[CH3:41])[C@H:31]([O:32][C:33](=[O:35])[CH3:34])[C@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:21]2[O:22][C:23](=[O:25])[CH3:24])[C@@H:12]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[O:11][C@H:6]1[O:7][CH2:8][CH2:9][S:56][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@H](O[C@@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OCCBr)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CCCCCCCCS
Agent: CCCCCCCCSCCO[C@@H]1O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCSCCO[C@@H]1O[C@H](COC(C)=O)[C@H](O[C@H]2O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 47.5 %

Procedure:
Compound 15 (484 mg; 0.65 mmol), octanethiol (110 mg; 0.75 mmol; 130 μl), methyltrioctylammonium chloride (ca 10 mg) and cesium carbonate (245 mg; 0.75 mmol) were dissolved in benzene (1 ml) and water (1 ml). The reaction mixture was treated as for compound 21. Chromatography gave the title compound (23) (250 mg) and starting compound 15 (160 mg). Yield (based on consumed 15): 71%; [α]D21 +65.3° (c 1.4; CHCl3); 1H-NMR (CDCl3, TMS) δ 5.57 (dd, 1H, J4',5' =1 Hz, H4'), 5.39 (dd, 1H, J2', 3'=11 Hz, J3',4' =3.5 Hz, H3'), 5.20 (dd, H1, J1', 2' =3.5 Hz, H2'), 5.19 (dd, 1H, J2,3 =11 Hz, J1,2 =7.5 Hz, H2), 5.01 (d, 1H, J1',2' =3.5 Hz, H1'), 4.81 (dd, 1H, J3,4 =3 Hz, H3), 4.51 (d, 1H, J1,2 =7.5 Hz, H1), 2.73, 2.53 (t, 2H each, J=7 Hz, CH2 --S), 2.13, 2.11, 2.08, 2.08, 2.07, 2.04, 1.99 (s, 3H each, CH3 --CO) ppm. 13C-NMR (CDCl3, TMS) 170.7, 170.6, 170.5, 170.4, 170.1, 169.8, 169.1 (CO), 101.2 (Cl), 99.4 (Cl'), 77.1, 72.7, 71.9, 68.6, 68.6, 67.8, 67.4, 67.1 (C2-C5, C2'-C5'), 69.6 (O--CH2 --CH2 --S), 62.0, 60.5 (C6, C6'), 32.6, 31.8, 31.3, 29.8, 29.2, 28.8, 22.7 (aglycon-CH2), 21.0, 20.8, 20.7 (CH3 --CO), 14.1 (CH3 --CH2) ppm.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[F:22][C:23]([F:37])([F:36])[C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:28][CH:29]=1.CCN(C(C)C)C(C)C>CN(C)C=O>[C:16]1([C:3]2[C:2]([N:33]3[CH2:34][CH2:35][N:30]([C:27]4[CH:26]=[CH:25][C:24]([C:23]([F:37])([F:22])[F:36])=[CH:29][N:28]=4)[CH2:31][CH2:32]3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccc(C(F)(F)F)cn4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), 1-(5-(trifluoromethyl)pyridin-2-yl)piperazine (203.28 mg, 0.88 mmol, 2.00 equiv), DIEA (170.3 mg, 1.32 mmol, 3.00 equiv), N,N-dimethylformamide (3 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with 4×30 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50). This resulted in 210.8 mg (97%) of methyl 2-phenyl-3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][C:22]1[N:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:28]([C:25]3[CH:26]=[N:27][C:22]([CH3:21])=[CH:23][CH:24]=3)=[O:29])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: Cc1ccc(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 6-methyl-3-pyridinecarboxylic acid as starting materials, MS (LC/MS): 420.4 (M−H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([O:21][CH2:22][CH3:23])[CH:18]=[C:17]([CH:24]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=3)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:16]=2[F:39])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH2:28]([O:27][C:25](=[O:26])[CH:24]([NH:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]#[N:38])=[CH:35][CH:36]=1)[C:17]1[CH:18]=[C:19]([O:21][CH2:22][CH3:23])[CH:20]=[C:15]([O:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:16]=1[F:39])[CH3:29]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(OC2CCNCC2)c1F
Temperature: 25 °C
Yield: 82.7 %

Procedure:
A solution of 2.30 g (RS)-4-{3-[(4-cyano-phenylamino)-ethoxycarbonyl-methyl]-5-ethoxy-2-fluoro-phenoxy}-piperidine-1-carboxylic acid tert-butyl ester in 40 ml dichloromethane was cooled to 0° C. and treated dropwise with 3.25 ml trifluoroacetic acid. The reaction mixture was warmed to r.t. within 3 hrs, then again cooled to 0° C. and treated with 20 ml of 10% Na2CO3 solution. The product was extracted with dichloromethane. The organic layer was dried over MgSO4, filtrated and evaporated to give 1.55 g (RS)-(4-cyano-phenylamino)-[5-ethoxy-2-fluoro-3-(piperidin-4-yloxy)-phenyl]-acetic acid ethyl ester as an off-white solid foam which was used for the next step without further purification. MS: 442.3 ([M+H]+).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[S:7][CH:8]=1.[O:12]([C:19]([NH:21][C@H:22]([C:26]([OH:28])=[O:27])[CH:23]([CH3:25])[CH3:24])=O)C1C=CC=CC=1.CCCCCCC>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][N:2]([C:19]([NH:21][C@H:22]([C:26]([OH:28])=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:12])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[S:7][CH:8]=1
Reactant: CNCc1csc(C(C)C)n1
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Temperature: 20 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
To a suspension of LiOH monohydrate (3.2 kg, 76.54 mol) in THF (66 kg) at 0° C. to 6° C. was added 11.3 kg (66.4 mol) of N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amine, followed by a 15 kg THF rinse. To this solution was added a cooled (0° C. to 6° C.) solution of N-phenoxycarbonyl-L-Valine (15 kg, 63.22 mol) dissolved in 41 kg of THF. Following a 25 kg THF rinse, 3.5 kg of water was added, and the reaction mixture was allowed to warm to 20° C. After 3 hours, the reaction was cooled to 10° C. and quenched with water (180 kg). The THF was removed under reduced pressure, MTBE (111 kg) was added, and the biphasic solution was adjusted to pH 9.0 with 4 N HCl. The layers were separated and the aqueous layer was washed with an additional 111 kg of MTBE. The aqueous layer was stirred with 130 kg of toluene and adjusted to pH 3 with 4 N HCl, and the phases were separated. The aqueous layer was back-extracted once more with 130 kg of toluene. The combined organic extracts were filtered and the material removed by filtration washed with toluene (50 kg). The combined filtrates were concentrated in vacuo. The residue obtained was redissolved in 100 kg of toluene and re-concentrated in vacuo. The residue obtained was cystallized using toluene and heptane to afford 16.6 kg (83.8%) of the title compound.
Reaction SMILES: C(OC(NC(C)(CC1C=CC=CC=1)COCC1C=C(C=C(N(S(C)(=O)=O)CCC)C=1)C(O)=O)=O)(C)(C)C.C(NCCC)CC.[NH2:45][C:46]([CH3:84])([CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)[CH2:47][O:48][CH2:49][C:50]1[CH:51]=[C:52]([N:69]([CH2:74][CH2:75][CH3:76])[S:70]([CH3:73])(=[O:72])=[O:71])[CH:53]=[C:54]([C:56]([N:58]2[CH2:62][CH2:61][CH2:60][CH:59]2[C:63]2C=CC=C[CH:64]=2)=[O:57])[CH:55]=1>>[NH2:45][C:46]([CH3:84])([CH2:77][C:78]1[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=1)[CH2:47][O:48][CH2:49][C:50]1[CH:55]=[C:54]([CH:53]=[C:52]([N:69]([S:70]([CH3:73])(=[O:72])=[O:71])[CH2:74][CH2:75][CH3:76])[CH:51]=1)[C:56]([N:58]([CH2:59][CH2:63][CH3:64])[CH2:62][CH2:61][CH3:60])=[O:57]
Reactant: CCCN(c1cc(COCC(C)(N)Cc2ccccc2)cc(C(=O)N2CCCC2c2ccccc2)c1)S(C)(=O)=O
Agent: CCCN(c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(C(=O)O)c1)S(C)(=O)=O
Solvent: CCCNCCC
Product: CCCN(CCC)C(=O)c1cc(COCC(C)(N)Cc2ccccc2)cc(N(CCC)S(C)(=O)=O)c1

Procedure:
3-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-5-[(methylsulfonyl)(propyl)amino]-N,N-dipropylbenzamide was prepared from 3-({2-[(tert-butoxycarbonyl)amino]-2-methyl-3-phenylpropoxy}methyl)-5-[(methylsulfonyl)(propyl)amino]benzoic acid (intermediate XI) and dipropylamine following a similar procedure as described for the preparation of N-{3-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-5-[(2-phenylpyrrolidin-1-yl)carbonyl]phenyl}-N-propylmethanesulfonamide. HRMS (ES, M+H) calculated for C28H43N3O4S: 518.3047, found: 518.3051.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:18](=[O:19])[CH2:17][O:16][CH2:15][C:14]2=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:21].[Na+:22]>>[N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[CH2:15][O:16][CH2:17][C:18]([O-:21])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1.[Na+:22]
Reactant: [OH-]
Reactant: O=C1COCC(=O)N1CCCCCCN1CCCCC1
Agent: [Na+]
Product: O=C([O-])COCC(=O)NCCCCCCN1CCCCC1
Yield: 90 %

Procedure:
To a mixture of 3.63 grams (9.84 millimoles) of 6-(3,5-dioxomorpholino)hexyl p-toluenesulfonate (prepared as described in Example IX) and 84.75 milligrams (10.7 millimoles) of lithium hydride in 10 milliliters of 1,2-dimethoxyethane was added 1.0 milliliter (10.0 millimoles) of piperidine in 10 milliliters of 1,2-dimethoxyethane. The mixture was heated under reflux for 22 hours, and the resulting heterogeneous mixture filtered to obtain a clear yellow filtrate. The filtrate was concentrated to an orange oil which after evaporative distillation (bath 120° C.; 0.05 torr.) produced 1.18 grams (42.5 percent yield) of 4-(6-piperidinohexyl)-3,5-dioxomorpholine base having infrared and nuclear magnetic resonance spectral characteristics appropriate for said compound. A 286.23 milligram (1.02 millimoles) sample of the free base, 4-(6-piperidinohexyl)-3,5-dioxomorpholine, was dissolved in 1.0 milliliter of 1 N sodium hydroxide (1.0 millimole) and the mixture concentrated to produce 289.63 grams (90 percent yield) of sodium [2-(6-piperidinohexyl)amino-2-oxoethoxy]acetate product with the following spectral characteristics:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:23](=[O:24])[C:22]3[CH:25]=[CH:26][C:27]([N+:28]([O-])=O)=[C:20]4[C:21]=3[C:16](=[CH:17][CH:18]=[CH:19]4)[C:15]2=[O:31])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+].C(Cl)Cl>C(O)(=O)C>[NH2:28][C:27]1[CH:26]=[CH:25][C:22]2[C:23](=[O:24])[N:14]([CH:11]3[CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:9][CH2:10]3)[C:15](=[O:31])[C:16]3[C:21]=2[C:20]=1[CH:19]=[CH:18][CH:17]=3
Reactant: O=C1c2cccc3c([N+](=O)[O-])ccc(c23)C(=O)N1C1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1ccc2c3c(cccc13)C(=O)N(C1CCN(Cc3ccccc3)CC1)C2=O
Reaction time: 2 h
Yield: 82.1 %

Procedure:
To a solution of stannous chloride (5.0 g; 22.2 mmol) and 2-(1-benzylpiperidin-4-yl)-2,3-dihydro-6-nitro-1H-benz[de]isoquinoline-1,3-dione (1.9 g; 4.75 mmol), prepared as in Example 3, in glacial acetic acid (5 mL) was added 10% hydrochloric acid (7 mL). The reaction mixture was stirred for 2 hours and then a mixture of 10% sodium hydroxide and methylene chloride was added. The aqueous layer was extracted three additional times with methylene chloride and then the combined extracts were dried over potassium carbonate. Filtration and concentration of the methylene chloride extracts gave 6-amino-2-(1-benzylpiperidin-4-yl)-2,3-dihydro-1H-benz[de]isoquinoline-1,3-dione (1.5 g; 3.90 mmol), m.p. 226°-228° C. Anal.: Calcd. for C21H21N3O3Cl2 . 0.333 H2O: C, 57.30; H, 4.96; N, 9.54. Found: C, 57.39; H, 5.06; N, 9.52.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:12])=[CH:5][C:6](=[O:11])[C:7]=1[N+:8]([O-:10])=[O:9].C1C(=O)N([I:20])C(=O)C1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(O)(=O)C>[I:20][C:5]1[C:6](=[O:11])[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[NH:3][C:4]=1[CH3:12]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(=O)c([N+](=O)[O-])c(C)[nH]1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1[nH]c(C)c([N+](=O)[O-])c(=O)c1I
Temperature: 105 °C
Reaction time: 0.25 h
Yield: 69.6 %

Procedure:
To a suspension of 2,6-dimethyl-3-nitropyridin-4(1H)-one (0.44 g, 2.62 mmol) in acetic acid (13 mL) was added NIS (0.765 g, 3.40 mmol). The mixture was heated at 105° C. for 2 h, at which time it was poured into ice water (100 mL). The mixture was stirred for 15 min and cooled in a freezer for 15 min. To the cooled mixture was added 0.1M Na2S2O3 (1-2 mL) with swirling The solids were filtered, washed with water, air dried for 5 min, and further dried in a vacuum oven for 4 h to give 3-iodo-2,6-dimethyl-5-nitropyridin-4(1H)-one (596 mg, 1.824 mmol, 69.7% yield). 1H NMR (400 MHz, DMSO-d6) δ 2.28-2.31 (m, 3 H) 12.32 (br. s., 1 H). MS(ES) [M+H]+ 294.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[N:10]=[N:9]2)=[C:4]([CH:17]2[CH2:19][CH2:18]2)[CH:3]=1.[NH2:20][C:21]1[C:22](=[O:34])[N:23]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[N:24]([CH3:27])[C:25]=1[CH3:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:20][C:21]3[C:22](=[O:34])[N:23]([CH:28]4[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]4)[N:24]([CH3:27])[C:25]=3[CH3:26])=[O:16])[N:10]=[N:9]2)=[C:4]([CH:17]2[CH2:19][CH2:18]2)[CH:3]=1
Reactant: Cc1c(C(=O)O)nnn1-c1ccc(Cl)cc1C1CC1
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)nnn1-c1ccc(Cl)cc1C1CC1

Procedure:
The title compound was prepared from 1-(4-chloro-2-cyclopropylphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (Example 13, step 5) and 4-amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate A) analogously to Example 1, step 3.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:10]([N:12]1[CH2:16][C@@H:15]([CH2:17][O:18][CH3:19])[CH2:14][C@H:13]1[C:20]1[NH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4[NH:41][C:40]([C@@H:42]5[CH2:46][C@H:45]([S:47][CH3:48])[CH2:44][N:43]5[C:49](=[O:59])[C@@H:50]([NH:54][C:55](=[O:58])[O:56][CH3:57])[CH:51]([CH3:53])[CH3:52])=[N:39][CH:38]=4)=[CH:33][CH:32]=3)=[CH:27][CH:26]=2)=[CH:23][N:24]=1)=[O:11])=[O:7])(C)(C)C.Cl.[CH:67]1(C(O)=O)[CH2:69][CH2:68]1.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CO.CCOC(C)=O.CN(C=O)C.CO>[CH:67]1([C:6]([NH:8][C@H:9]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C:10]([N:12]2[CH2:16][C@@H:15]([CH2:17][O:18][CH3:19])[CH2:14][C@H:13]2[C:20]2[NH:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:32]=[CH:33][C:34]([C:37]5[NH:41][C:40]([C@@H:42]6[CH2:46][C@H:45]([S:47][CH3:48])[CH2:44][N:43]6[C:49](=[O:59])[C@@H:50]([NH:54][C:55](=[O:58])[O:56][CH3:57])[CH:51]([CH3:53])[CH3:52])=[N:39][CH:38]=5)=[CH:35][CH:36]=4)=[CH:27][CH:26]=3)=[CH:23][N:24]=2)=[O:11])=[O:7])[CH2:69][CH2:68]1
Reactant: O=C(O)C1CC1
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc(-c4ccc(-c5cnc([C@@H]6C[C@H](SC)CN6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]5)cc4)cc3)[nH]2)N(C(=O)[C@H](NC(=O)OC(C)(C)C)c2ccccc2)C1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc(-c4ccc(-c5cnc([C@@H]6C[C@H](SC)CN6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]5)cc4)cc3)[nH]2)N(C(=O)[C@H](NC(=O)C2CC2)c2ccccc2)C1
Reaction time: 20 h
Yield: 19.5 %

Procedure:
Methyl (S)-1-((2S,4S)-2-(5-(4′-(2-((2S,4S)-1-((R)-(tert-butoxycarbonylamino)-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methylthio)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (179 mg, 0.20 mmol) was dissolved in DCM (5 mL), MeOH (1 mL) and HCl (4 M in dioxane, 1 mL) was added. The reaction mixture was stirred for 20 h and then concentrated under reduced pressure. The crude residue was treated with cyclopropanecarboxylic acid (16 μL, 0.20 mmol), COMU (96 mg, 0.20 mmol) and DMF (5 mL), then DIPEA (0.17 mL, 1.0 mmol) was added dropwise. After 30 min, the mixture was diluted with 10% MeOH/EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by HPLC to afford methyl (S)-1-((2S,4S)-2-(5-(4′-(2-((2S,4S)-1-((R)-2-(cyclopropanecarboxamido)-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methylthio)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (34 mg, 20%). LCMS-ESI+: calculated for C48H56N8O6S: 872.40; observed [M+1]+: 874.38.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:10][C:11]([OH:13])=O.[NH2:20][CH2:21][C:22]([NH:24][CH:25]1[CH:30]2[CH:26]1[CH2:27][N:28]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:29]2)=[O:23].C(OC(NCC(O)=O)=O)(C)(C)C.C(N1CC2C(C2N)C1)C1C=CC=CC=1.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.O>[CH2:31]([N:28]1[CH2:27][CH:26]2[CH:30]([CH:25]2[NH:24][C:22]([CH2:21][NH:20][C:11](=[O:13])[CH2:10][CH:9]([C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[OH:1])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:23])[CH2:29]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: NCC(=O)NC1C2CN(Cc3ccccc3)CC21
Reactant: Cc1ccc(O)c(C(CC(=O)O)c2ccccc2)c1
Agent: CC(C)(C)OC(=O)NCC(=O)O
Agent: NC1C2CN(Cc3ccccc3)CC12
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(O)c(C(CC(=O)NCC(=O)NC2C3CN(Cc4ccccc4)CC32)c2ccccc2)c1
Reaction time: 1 h

Procedure:
The compound, 3-(2-hydroxy-5-methylphenyl)-3-phenyl propionic acid (198 mg, 0.77 mmole, 1 eq) and 2-amino-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl)-acetamide, 200 mg, 0.179 mmole, 1 eq prepared by reacting t-butoxy carbonylamino-acetic acid with 3-benzyl-3-azabicylo[3.1.0]hex-6-yl amine, which in turn, was prepared following the procedure of T. F. Braish et al., Synlett, 1996, 1100) were dissolved in dimethylformamide (3 ml). The reaction mixture was cooled to 0° C. with subsequent addition of N-methyl morpholine (2.31 mmole, 3 eq) and HOBT (0.77 mmole, 1 eq). The resulting reaction mixture was stirred for 1 hour at the same temperature and then at room temperature. The reaction mixture was diluted with water and extracted the organic compound with ethyl acetate. The solvent was removed under reduced pressure and dried. The crude compound was purified by column chromatography using ethyl acetate, methanol and dichloromethane solvent system.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:16])[C:14](I)=[C:10]2[N:9]=[C:8]([CH3:17])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[Cl:26][C:27]1[S:28][CH:29]=[C:30]([Cl:32])[N:31]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.N#N>[Cu]I.CC(N(C)C)=O>[CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:16])[C:14]([C:29]3[S:28][C:27]([Cl:26])=[N:31][C:30]=3[Cl:32])=[C:10]2[N:9]=[C:8]([CH3:17])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: Clc1csc(Cl)n1
Reactant: CCC(CC)c1cc(C)nc2c(I)c(C)nn12
Agent: [Cu]I
Agent: N#N
Agent: O=P([O-])([O-])[O-]
Solvent: CC(=O)N(C)C
Product: CCC(CC)c1cc(C)nc2c(-c3sc(Cl)nc3Cl)c(C)nn12
Temperature: 120 °C
Reaction time: 6 h
Yield: 70 %

Procedure:
Charge 7-(1-ethyl-propyl)-3-iodo-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (1.03 g, 3.00 mmoles), K3PO4 (1.95 g, 9.00 mmoles), 2,4-dichlorothiazole (0.58 g, 3.75 mmoles), 1,10 phenanthroline (0.05 g, 0.30 mmoles) and anhydrous DMAC (5 mL) to a round bottom flask equipped with a magnetic stir bar, thermal couple and N2 inlet. Degas the yellow heterogeneous reaction mixture with N2 (gas) for 30 min. and then add CuI (0.06 g, 0.30 mmoles) in one portion followed by additional 30 min. degassing with N2 (gas). Stir the reaction mixture at 120° C. for about 6 hr. Cool the reaction mixture to room temperature overnight, add toluene (10 mL) and stir for 1 hr. Purify the mixture through silica gel eluting with toluene (10 ml). Extract with 1 M HCl (10 mL), water (10 mL), brine (10 mL) and concentrate under reduced pressure to give a yellow solid. Recrystallize the solid from methanol (5 ml) to yield the title compound as a yellow crystalline solid. (0.78 g, 70% yield, >99% pure by LC) MS (ES)=369 (M+1). 1H NMR (CDCl3)=6.5 (1H, s); 3.6 (1H, m); 2.6 (3H, s); 2.5 (3H, s); 1.9 (4H, m); 0.9 (6H, t).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([O:4][C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([CH:19]=[C:20]([C:22]([O:24]CC)=[O:23])[N:21]=3)[CH:18]=2)[N:12]=1)=[O:6])[CH3:3].CC(C)(OC(NC1N=C(C2C=CC3N(C=C(C(O)=O)N=3)C=2)C=CC=1)=O)C>>[CH3:3][C:2]([CH3:27])([O:4][C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([CH:19]=[C:20]([C:22]([OH:24])=[O:23])[N:21]=3)[CH:18]=2)[N:12]=1)=[O:6])[CH3:1]
Reactant: CCOC(=O)c1cn2cc(-c3csc(NC(=O)OC(C)(C)C)n3)ccc2n1
Agent: CC(C)(C)OC(=O)Nc1cccc(-c2ccc3nc(C(=O)O)cn3c2)n1
Product: CC(C)(C)OC(=O)Nc1nc(-c2ccc3nc(C(=O)O)cn3c2)cs1
Yield: 77.6 %

Procedure:
125 mg of ethyl 6-(2-{[(1,1-dimethylethoxy)carbonyl]amino}thiazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylate are saponified under conditions similar to those described for the preparation of Intermediate 11 (step 11.3), to give 90 mg of 6-(2-{[(1,1-dimethylethoxy)carbonyl]amino}thiazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylic acid in the form of a brown solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:20]2[NH:21][CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[CH:24]=2)=[O:19])[CH2:13][CH2:12]1)([CH3:10])[CH3:9].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:35][C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][N:40]=1)=[O:37]>CN(C=O)C>[CH:8]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:20]2[N:21]([CH2:35][C:36](=[O:37])[NH:38][C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][N:40]=3)[CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[CH:24]=2)=[O:19])[CH2:13][CH2:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)N1CCC(NC(=O)c2cc([N+](=O)[O-])c[nH]2)CC1
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CCC(NC(=O)c2cc([N+](=O)[O-])cn2CC(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 20 h
Yield: 43.9 %

Procedure:
To a solution of 4-nitro-1H-pyrrole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide trifluoroacetate salt (30 mg) in DMF (4 mL) was added Cs2CO3 (70 mg). The mixture was stirred for 30 min at RT after which 2-bromo-N-(5-chloro-pyridin-2-yl)-acetamide (27 mg) was added. Stirring was continued for 20 h at RT. The mixture was filtered and directly subjected to preparative HPLC(CH3CN/H2O gradient+0.05% TFA) to give 1-[(5-chloro-pyridin-2-ylcarbamoyl)-methyl]-4-nitro-1H-pyrrole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide (15 mg) as its trifluoroacetate salt. MS (ESI+): m/e=449 [M+H]+, chloro pattern.