Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[Br:15]N1C(=O)CCC1=O.CCCCCCC>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:1][O:2][C:3](=[O:14])[CH:4]([Br:15])[C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc([N+](=O)[O-])cc1
Temperature: 74 °C
Yield: 78 %

Procedure:
(4-Nitro-phenyl)-acetic acid methyl ester (500 mg, 2.56 mmol) was dissolved in carbon tetrachloride (6.00 mL) and N-bromosuccinimide (502 mg, 2.82 mmol) was added followed by 2,2′-azo-bis-isobutyronitrile (12.6 mg, 0.0768 mmol). The reaction was heated at 74° C. overnight. The reaction was then cooled to room temperature and poured into heptane (25 mL). The resulting suspension was filtered and the filter cake washed with heptane (15 mL). The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography using a gradient of 0-25% EtOAc/hex as the eluting solvent to obtain bromo-(4-nitro-phenyl)-acetic acid methyl ester as a clear-colorless oil (547 mg, 78%). LCMS (m/e) 274 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.23 (d, 2H, J=8.6 Hz), 7.73 (d, 2H, J=8.6 Hz), 5.40 (s, 1H), 3.82 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[N:19]=[CH:20][CH:21]=[CH:22][N:23]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1
Reactant: C[C@@H]1CCCN(C(=O)c2ccccc2-c2ncccn2)[C@@H]1CN
Reactant: FC(F)(F)c1cnc(Cl)nc1
Product: C[C@@H]1CCCN(C(=O)c2ccccc2-c2ncccn2)[C@@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A316 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(2-(pyrimidin-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 457 [M+1]+. 1H NMR (500 MHz, CD3OD) δ 9.05-6.85 (m, 9H), 5.15-3.00 (m, 5H), 2.10-0.75 (m, 8H).
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)=[O:13])[C:9]([OH:24])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:25]1([OH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C([O-])([O-])=O.[Na+].[Na+]>CN1C(=O)N(C)CCC1>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([Cl:22])[CH:19]=1)[CH2:15][NH:14][C:12]([C:10]1[C:9]([OH:24])=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([O:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:11]=1)=[O:13]
Reactant: Oc1ccccc1
Reactant: O=C(NCc1cc(Cl)cc(Cl)c1)c1nc(Br)c2cccnc2c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Product: O=C(NCc1cc(Cl)cc(Cl)c1)c1nc(Oc2ccccc2)c2cccnc2c1O

Procedure:
To a solution of 5-bromo-N-(3,5-dichlorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide from Example 50 (26 mg, 0.068 mmol), phenol (28 mg, 0.304 mmol) and cesium carbonate (198 mg, 0.608 mmol) in DMPU (0.25 ml) was heated at 140C for 8 hrs. The reaction was poured into sat aq. Na2CO3 and extracted with CHCl3. The organic phase was washed with water and dried (Na2SO4). The solvent was evaporated in vacuo and the residue dissolved in DMF (0.7 ml) and purified by preparative HPLC. (Gilson semi preparative HPLC system and a YMC Combiprep Pro Column (50×20 mm I.D., C18, S-5 um, 120A) eluting with 5-95% acetonitrile/water (0.1% TFA) at 15 ml/min) to afford the title compound after lyophilization.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:10]([C:11]3[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH:18][CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH2:31][NH2:32]>C(O)C.C(OCC)(=O)C>[CH:19]1([NH:18][C:13]2[N:12]=[C:11]([C:10]3[C:9]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[N:8][N:7]4[C:2]([NH:31][NH2:32])=[CH:3][CH:4]=[CH:5][C:6]=34)[CH:16]=[C:15]([CH3:17])[N:14]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NN
Reactant: Cc1cc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)nc(NC2CCCC2)n1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(-c2c(-c3ccc(F)cc3)nn3c(NN)cccc23)nc(NC2CCCC2)n1
Temperature: 90 °C
Yield: 45.5 %

Procedure:
To a solution of 4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-6-methyl-2-pyrimidinamine (100 mg, 0.237 mmol) in ethanol (1 mL) was added hydrazine (500 uL, 15.9 mmol). The reaction mixture was heated in a sealed tube at 90° C. for 72 hours. The mixture was cooled and diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, water and brine. The combined organics were dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (38:2 dichloromethane-methanol) provided N-cyclopentyl-4-[2-(4-fluorophenyl)-7-hydrazinopyrazolo[1,5-α]pyridin-3-yl]-6-methyl-2-pyrimidinamine (45 mg, 46%) as a yellow solid. Rf 0.43 (38:2 CH2Cl2-MeOH); 1H NMR (CDCl3) δ 7.78 (1H), 7.62 (2H), 7.35 (1H), 7.20 (1H), 7.12 (2H), 6.45 (1H), 6.24 (1H), 5.03 (1H), 4.35 (1H), 3.85 (2H), 2.18 (3H), 2.02 (2H), 1.62 (6H); MS m/z 418 (M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=O.[N:15]1([CH2:21][CH2:22][NH2:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([NH:23][CH2:22][CH2:21][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:13]
Reactant: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Reactant: NCCN1CCCCC1
Product: Cc1[nH]c2c(c1C(=O)NCCN1CCCCC1)CCCC2=O
Yield: 85.7 %

Procedure:
Similar procedure as Example 2, 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) 0.2 g (1.0 mmol) and 2-(piperidin-1-yl)ethanamine 0.27 g (2.1 mmol) was reacted to give 0.26 g (86%) of the titled compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH:21]=O)[CH:19]=2)[CH:14]=[N:13]1>>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18](/[CH:21]=[C:5]3/[C:6](=[O:11])[NH:7][C:8]4[C:4]/3=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=4)[CH:19]=2)[CH:14]=[N:13]1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: O=Cc1ccc2cn[nH]c2c1
Product: O=C1Nc2ccc(Br)cc2/C1=C\c1ccc2cn[nH]c2c1

Procedure:
The title compound was synthesized according to the method described for Example A11B except substituting 5-bromooxindole (40 mg, 0.189 mmol) and 1H-indazole-6-carbaldehyde (30 mg, 0.208 mmol) to obtain 1.0 mg (1.6%) of a yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.16 (s, 1H), 7.98-7.92 (m, 2H), 7.87 (s, 1H), 7.73 (s, 1H), 7.44 (d, J=8.34 Hz, 1H), 7.39 (d, J=8.59 Hz, 1H), 6.87 (d, J=8.34 Hz, 1H); MS ESI 340.1 [M+H]+, calcd for [C16H10BrN3O+H]+ 340.01.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[NH:5][O:6][CH2:7][C:8]([OH:10])=O)[CH3:2].[NH2:12][C@H:13]([C:26]([N:28]([C@@H:40]([CH3:48])[CH:41]([O:45][CH2:46][CH3:47])[O:42][CH2:43][CH3:44])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:39]=1[N:38]=[CH:37][CH:36]=[CH:35]2)=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>>[CH2:46]([O:45][CH:41]([O:42][CH2:43][CH3:44])[C@@H:40]([N:28]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:39]=1[N:38]=[CH:37][CH:36]=[CH:35]2)[C:26]([C@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])[NH:12][C:8](=[O:10])[CH2:7][O:6][NH:5][C:4](=[O:11])[NH:3][CH2:1][CH3:2])=[O:27])[CH3:48])[CH3:47]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Reactant: CCNC(=O)NOCC(=O)O
Product: CCNC(=O)NOCC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N(Cc1cccc2cccnc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-ethylureidooxy)acetic acid (Compound VI-13) 47 mg (0.29 mmol) was coupled with tert-butyl (S)-5-amino-6-(((S)-1,1-diethoxypropan-2-yl)(quinolin-8-ylmethyl)amino)-6-oxohexylcarbamate (Compound IV-14) 100 mg (0.19 mmol) to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH2:25])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:34][CH2:35][CH2:36]N.C([O-])(=O)C.[Na+].C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH:25][CH2:36][CH2:35][F:34])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NCCF
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(N)=O)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(=O)NCCF)C1
Yield: 95 %

Procedure:
Following general method 7, employing (S)-3-{[1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester and 2-fluoroethylamine hydrochloride, afforded the crude desired product (Note: 0.34 mmol of anhydrous sodium acetate was added to the reaction mixture to neutralise the amine). Column chromatography (silica, 12 g column, ISCO, 0-100% ethyl acetate in DCM) afforded the title compound as a glass (80 mg, 95%). LCMS (method B): RT=3.68 min, M+H+=492.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH:26]1([O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[NH2:34])[CH2:30][CH2:29][CH2:28][CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)(=O)C>ClC(Cl)C>[CH:26]1([O:31][C:32](=[O:37])[C:33]([NH:34][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)([CH3:35])[CH3:36])[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CC(C)(N)C(=O)OC1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(NC(C)(C)C(=O)OC2CCCC2)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 100.3 %

Procedure:
To a solution of N-Boc-piperidinone (2.00 g, 10.0 mmol) in dichloroethane (25 mL) was added α,α-dimethylglycine cyclopentyl ester tosylate (3.97 g, 11.6 mmol) and sodium triacetoxyborohydride (4.248 g, 20.0 mmol). The mixture was stirred at room temperature for 22 hours then poured into ethyl acetate (300 mL). The organic layer was washed with water (3 times 100 mL), dried (MgSO4) and concentrated to yield the desired product (3.556 g, 84% yield) which was carried forward without further purification. LC/MS: m/z 355.25 [M+H]+
Reaction SMILES: [O:1]=[C:2]1[C@@:6]([N:12]2[CH:16]=[CH:15][CH:14]=[CH:13]2)([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][C:4](=[O:17])[NH:3]1.[Cl:18][C:19]([Cl:24])([Cl:23])[C:20](Cl)=[O:21].O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[O:1]=[C:2]1[C@@:6]([N:12]2[CH:13]=[CH:14][CH:15]=[C:16]2[C:20](=[O:21])[C:19]([Cl:24])([Cl:23])[Cl:18])([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][C:4](=[O:17])[NH:3]1
Reactant: CCOC(=O)[C@@]1(n2cccc2)CC(=O)NC1=O
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)[C@@]1(n2cccc2C(=O)C(Cl)(Cl)Cl)CC(=O)NC1=O
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of ethyl (R)-2,5-dioxo-3-(pyrrol-1-yl)pyrrolidine-3-carboxylate (767 mg) in ethyl acetate (10 ml) was added trichloroacetyl chloride (1.1 ml) and this solution was heated under reflux overnight. This reaction mixture was allowed to cool to room temperature, and thereto was added trichloroacetyl chloride (1.1 ml) and this mixture was heated under reflux for 3 hours. This reaction mixture was allowed to water-cooling to room temperature and the residual trichloroacetyl chloride was decomposed carefully with saturated aqueous sodium bicarbonate solution. After the aqueous layer was confirmed to be alkali, this mixture was extracted with ethyl acetate (5 ml) three times and the combined extract was washed sequentially with water and saturated brine, dried over magnesium sulfate, filtered and then concentrated to give a crude product as oil. This was purified by a flash column chromatography (n-hexane:ethyl acetate=1:1) to give ethyl (R)-2,5-dioxo-3-(2-trichloroacetylpyrrol-1-yl)pyrrolidine-3-carboxylate (1.17 g, 94%).
Reaction SMILES: [O:1]=[C:2]1[N:8]2[C@H:4]([O:5][C:6]([CH:9]=[CH2:10])=[CH:7]2)[CH2:3]1.[SH:11][CH2:12][CH2:13][OH:14].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[OH:14][CH2:13][CH2:12][S:11][CH2:10]/[CH:9]=[C:6]1/[CH2:7][N:8]2[C@H:4]([O:5]/1)[CH2:3][C:2]2=[O:1]
Reactant: C=CC1=CN2C(=O)C[C@H]2O1
Reactant: OCCS
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1C[C@H]2O/C(=C\CSCCO)CN12

Procedure:
(5R)-7-Oxo-3-vinyl-4-oxa-1-azabicyclo[3.2.0] hept-2-ene (2.5 mmole) in dry tetrahydrofuran (20 ml) was treated with 2-mercaptoethanol (0.4 ml) and benzoyl peroxide (10 mg). The resulting mixture was stirred under dry nitrogen while being irradiated using a 200 W bulb placed 1" from the reaction vessel for a total time of 14 hours. The mixture was diluted with ethyl acetate (100 ml) and was washed with saturated sodium bicarbonate solution and saturated brine. The solution was dried (magnesium sulphate) and the solvent was evaporated under reduced pressure to give a yellow oil. The oil was chromatographed on silica gel (20 g) using graded elution from 1:4 to 1:1 ethyl acetate/petroleum ether (b.p. 60°-80°). The title compound was thus obtained as a colourless gum (45 mg), [α]D22 =+66.8° (c 1.0, CHCl3). νmax (CHCl3): 3370, 1795, 1695 cm-1. δ(CDCl3): 2.40 (1H, br.s, OH), 2.65 (2H, t, J 6 Hz), 2.95 (1H, d, J 16 Hz), 3.15-3.80 (6H, complex), 4.25-4.55 (2H, complex), 5.47 (1H, d, J 2 Hz). m/e: 138 (67%), 96 (100).
Reaction SMILES: [CH3:1][C:2](=[O:6])[C:3](=[O:5])[CH3:4].CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24]>CCOCC>[C:23]([O:5][C:3](=[CH2:4])[C:2](=[O:6])[CH3:1])(=[O:25])[CH3:24]
Reactant: CC(=O)C(C)=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=C(OC(C)=O)C(C)=O
Reaction time: 3 h
Yield: 56 %

Procedure:
To a solution of 19.6 g. (228 mol) of 2,3-butanedione in 200 ml. of ether was added 3.34 g. (27 mmole) of dimethylamino pyridine, and 23 g. (228 mmole) of triethylamine. The solution was cooled to 0° and 23.24 g. (228 mmol) of acetic anhydride was added dropwise with vigorous stirring. The clear yellow solution was allowed to warm to 25° and was stirred 3 hours. The reaction mixture was transferred to a separatory funnel, washed with water (3×) and dried over MgSO4. Filtration and evaporation in vacuo afforded 17.6 g. of crude 3-acetoxy-3-buten-2-one (assayed by 1H-NMR with internal standard as 91% pure, 56% yield): 1H-NMR (CDCl3) delta 2.06 (s, 3), 2.25 (s, 3), 5.42, 5.49, 5.79, 5.82 (AB, 2).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[C:18]([CH:22]=1)[C:19](O)=[O:20])[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[NH2:32][C@@H:33]([CH2:41][CH2:42][S:43]([CH3:46])(=[O:45])=[O:44])[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[C:18]([CH:22]=1)[C:19]([NH:32][C@@H:33]([CH2:41][CH2:42][S:43]([CH3:46])(=[O:45])=[O:44])[C:34]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:35])=[O:20])[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: O=C(O)c1cc(OC(Cn2ccnc2)c2nccs2)ccc1CCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCS(C)(=O)=O
Product: CC(C)(C)OC(=O)[C@H](CCS(C)(=O)=O)NC(=O)c1cc(OC(Cn2ccnc2)c2nccs2)ccc1CCc1ccc(F)cc1
Yield: 75 %

Procedure:
The title compound was prepared in 75% yield from 5-[1-(thiazol-2-yl)-2-(imidazol-1-yl)ethoxy]-2-(4-fluorophenethyl)benzoic acid and L-methionine sulphone tert-butyl ester by similar methodology to that used for Example 40.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([OH:11])[C:8]([CH3:12])=[CH:7][C:6]=1[S:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH2:31]([NH:33][S:34](Cl)(=[O:36])=[O:35])[CH3:32]>CCOCC>[C:1]([C:5]1[CH:10]=[C:9]([O:11][S:34](=[O:36])(=[O:35])[NH:33][CH2:31][CH3:32])[C:8]([CH3:12])=[CH:7][C:6]=1[S:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:15])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNS(=O)(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(O)cc2C(C)(C)C)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCNS(=O)(=O)Oc1cc(C(C)(C)C)c(SS(=O)(=O)c2ccc(C)cc2)cc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask equipped with a magnetic stirrer and nitrogen were added toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxy-5-methyl-phenyl) ester (prepared in Example RRR; 6.86 g, 19.6 mmol), Et2O (100 mL), and NEt3 (3.25 mL, 23.4 mmol), respectively. The solution was cooled to 0° C. and treated rapidly with a solution of (ethyl amino)sulfonyl chloride (3.37 g, 23.4 mmol) in Et2O (10 mL). The reaction was stirred for 30 minutes and then filtered. The solids were washed with Et2O, and the filtrate was concentrated. The resulting residue was dried in a high vacuum oven at 40° C. overnight to yield the title compound. 1H NMR (CDCl3) δ 1.15 (s, 9 H), 1.23 (t, 3 H) 2.19 (s, 3 H), 2.35 (s, 3 H), 3.30 (m, 2 H), 4.75 (br t, 1 H), 7.16 (s, 1 H), 7.19 (s, 1 H), 7.32 (d, 2 H), 7.39 (d, 2 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([NH2:14])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)[CH3:2].C(O)(=O)C.CO[CH:25]1[CH2:29][CH2:28][CH:27](OC)O1>CCCCCCC>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([N:14]2[CH:25]=[CH:29][CH:28]=[CH:27]2)=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)[CH3:2]
Reactant: COC1CCC(OC)O1
Reactant: CCOC(=O)c1cc(OCC)c(N)c(OCC)c1
Solvent: CC(=O)O
Solvent: CCCCCCC
Product: CCOC(=O)c1cc(OCC)c(-n2cccc2)c(OCC)c1
Yield: 82 %

Procedure:
To a solution of 4-amino-3,5-diethoxy-benzoic acid ethyl ester (3.0 g, 11.84 mmol, 1.0 equiv; prepared as described in I. Kompis and A. Wick Helv. Chim. Acta 1977, 60, 3025-3034) in heptane (10 mL) and conc. acetic acid (0.2 mL) was added 2,5-dimethoxy-tetrahydro-furan (1.88 g, 14.21 mmol, 1.2 equiv). After heating to reflux for 5 h, a Dean-Stark apparatus was attached and the reaction mixture heated for an additional time period of 5 h. Filtration of the crude reaction mixture and crystallization at 0° C. from heptane provided 2.94 g (82%) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.15 (t, J=7.0 Hz, 6H), 1.27 (t, J=7.1 Hz, 3H), 3.98 (q, J=7.0 Hz, 4H), 4.28 (q, J=7.1 Hz, 2H), 6.07-6.08 (m, 2H), 6.73-6.74 (m, 2H), 7.22 (s, 2H). 13C NMR (75 MHz, DMSO): δ 14.11, 14.35, 61.06, 64.57, 106.87, 107.64, 122.61, 123.33, 129.29, 153.75, 165.06. MS (ISP): 303.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15](O)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.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.[F:60][C:61]1[CH:62]=[C:63]([CH2:67][NH2:68])[CH:64]=[CH:65][CH:66]=1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:68][CH2:67][C:63]3[CH:64]=[CH:65][CH:66]=[C:61]([F:60])[CH:62]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NCc1cccc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CC[C@H](C(=O)NCc2cccc(F)c2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90.9 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the mixture was stirred at room temperature for 5 minutes. Then 1-(3-fluorophenyl)methanamine (60 mg, 0.48 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and the formed solid was filtered, washed by water and dried to give the title compound (201 mg) as a yellow solid. LC-MS (ES) m/z=463 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2
Reactant: [N-]=[N+]=NCc1ccc2ncccc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc2ncccc2c1
Yield: 25.5 %

Procedure:
6-(azidomethyl)quinoline (320 mg) and triphenylphosphine (880 mg) were dissolved in 7 mL THF. The reaction mixture was treated with 0.5 mL of H2O and refluxed for 7 hours. The reaction mixture was cooled and partitioned between Et2O and 1N HCl. The aqueous portion was then treated with 1N NaOH until basic and extracted into EtOAc. The organic portion was dried over Na2SO4 and concentrated under reduced pressure to give the title compound (70 mg) as a brown oil. MS(CI) m/e 159 (M+H)+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8](O)=O.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>>[CH:12]1([NH:15][CH2:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:11])[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: Cc1ccccc1CC(=O)O
Product: Cc1ccccc1CCNC1CC1

Procedure:
Synthesized according to typical procedures C and D from o-tolylacetic acid and cyclopropylamine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([NH2:15])([CH3:14])[CH3:13].[Cu](C#N)[C:17]#[N:18]>CN1CCCC1=O>[C:17]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([NH2:15])([CH3:14])[CH3:13])#[N:18]
Reactant: N#C[Cu]C#N
Reactant: CC(C)(N)Cc1c[nH]c2ccc(Br)cc12
Solvent: CN1CCCC1=O
Product: CC(C)(N)Cc1c[nH]c2ccc(C#N)cc12

Procedure:
A mixture of 6.45 g of 2-(5-bromo 3-indolyl)1,1-dimethyl ethylamine and 3.25 g of copper cyanide in 40 ml of N-methylpyrrolidone is heated to reflux for 5 hours.