Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[C:5]([N+:11]([O-:13])=[O:12])[C:3]=1N.C(ON=O)(C)(C)C.[ClH:21]>C(#N)C>[Br:1][C:2]1[C:3]([Cl:21])=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=[C:7]([F:10])[C:8]=1[F:9]
Reactant: Cl
Reactant: Nc1c([N+](=O)[O-])cc(F)c(F)c1Br
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: O=[N+]([O-])c1cc(F)c(F)c(Br)c1Cl
Reaction time: 0.13 h

Procedure:
To a mixture of anhydrous cupric chloride (3.1 g) and 2-bromo-3,4-difluoro-6-nitroaniline (4.6 g) in anhydrous acetonitrile (30 ml) was added t-butylnitrite (2.8 g) dropwise at 51° to 56° C. during 5 minutes. After stirring for 8 minutes at the same temperature, the reaction mixture was poured into chilled 10% diluted hydrochloric acid (30 ml) and extracted with benzene. The organic layer was washed with diluted hydrochloric acid and with water successively, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel chromatography eluting with dichloromethane-n-hexane (1:5) to give the title compound (4.0 g).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH3:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][NH2:25].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][NH:25][C:15]([CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1)=[O:17]
Reactant: CC(C)(C)CCN
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)NCCC(C)(C)C)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 3,3-dimethyl-butylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C18H27NO5 [M−H]−: 338.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:31][CH2:32][CH:33]4[CH2:35][CH2:34]4)[C:15]=3[NH:14][C:13]=2[CH3:36])=[O:11])[CH2:5][CH2:4]1.C([O:40][CH2:41][C:42](Cl)=[O:43])(=O)C>>[CH:33]1([CH2:32][O:31][C:22]2[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:36])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:41](=[O:40])[CH2:42][OH:43])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:35]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)CO)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f32) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[C:11](O)=[N:12][C:13]([S:16][CH3:17])=[N:14][CH:15]=1)=[O:9].N1C=CC=CC=1C.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:11]1[C:10]([C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[O:9])=[CH:15][N:14]=[C:13]([S:16][CH3:17])[N:12]=1
Reactant: CSc1ncc(C(=O)c2ccccc2Cl)c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccn1
Product: CSc1ncc(C(=O)c2ccccc2Cl)c(Cl)n1
Temperature: 80 °C

Procedure:
To a cooled (ice bath) mixture of (2-chlorophenyl)-(4-hydroxy-2-methylsulfanylpyrimidin-5-yl)methanone (18.72 g, 66 mmol) and picoline (3.95 mL, 39.6 mmol) was added dropwise phosphoryl chloride (37.3 mL, 396 mmol) via an addition funnel. The resulting mixture was removed from the ice bath and heated to 80° C. for 2 hours. The reaction was cooled to ambient temperature and poured onto ice (250 mL). Ethyl acetate was added and the layers were partitioned and separated. The organic layer was further washed with two consecutive solutions of saturated sodium bicarbonate (150 mL) followed by brine (150 mL). The aqueous layers were back extracted with ethyl acetate (2×150 mL). The combined ethyl acetate layers were dried over magnesium sulfate, filtered and concentrated to give the product as a yellow solid (17.36 g, (M+H)+=299.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[C:8]([CH3:13])=[N:7]2.CC[N:17]([CH:21]([CH3:23])[CH3:22])C(C)C.C1(N)CC1>CS(C)=O>[Br:1][C:2]1[C:3]([F:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:17][CH:21]1[CH2:23][CH2:22]1)[C:8]([CH3:13])=[N:7]2
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nc2ccc(F)c(Br)c2[nH]c1=O
Agent: NC1CC1
Solvent: CS(C)=O
Product: Cc1nc2ccc(F)c(Br)c2nc1NC1CC1
Temperature: 85 °C
Yield: 72.1 %

Procedure:
A mixture of 5-bromo-3-chloro-6-fluoro-2-methylquinoxaline (600) (4.0 g, 14.52 mmol), DIEA (5.07 mL, 29.0 mmol) and cyclopropanamine (2.01 mL, 29.0 mmol) in DMSO (10 mL) in a sealed glass tube was heated in an oil bath at 85° C. for 3 h. The reaction mixture was poured onto 50 g of ice; the insoluble yellow solid was filtered, washed with 2×25 mL of water followed by 2×15 mL of hexanes. The yellow solid was collected and dried in a vacuum oven at 45° C. for 1 h to afford 3.1 g of the title compound. The filtrate was extracted with 2×50 mL of EtOAc. The combined organic extract was dried over MgSO4, filtered and concentrated. The crude residue was purified on a silica gel column (20-50% EtOAc in hexanes) affording 0.9 g of the title compound as a light orange crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.77 (1H, dd, J=9.0, 6.1 Hz), 7.47 (1H, br.), 7.33 (1H, t, J=8.8 Hz), 3.06 (1H, m), 2.47 (3H, s), 0.81 (2H, m), 0.67 (2H, m). 19F NMR (377 MHz, DMSO-d6) δ ppm −104.62. m/z (ESI, +ve) 296/298 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([Cl:17])[N:3]=1.[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25](OC)(OC)[CH2:26]Br)[CH:20]=1.CCOCC>ClC1C=CC=CC=1>[Br:18][C:19]1[CH:20]=[C:21]([C:25]2[N:1]=[C:2]3[C:14]([CH3:15])=[C:13]([CH3:16])[C:5]([C:6]([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7])=[C:4]([Cl:17])[N:3]3[CH:26]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: COC(CBr)(OC)c1cccc(Br)c1
Reactant: Cc1c(N)nc(Cl)c(C(=O)OC(C)(C)C)c1C
Solvent: Clc1ccccc1
Solvent: CCOCC
Product: Cc1c(C(=O)OC(C)(C)C)c(Cl)n2cc(-c3cccc(Br)c3)nc2c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.8 %

Procedure:
A slurry of tert-butyl 6-amino-2-chloro-4,5-dimethylnicotinate (1.2 g, 4.7 mmol, 1 equiv) and 1-bromo-3-(2-bromo-1,1-dimethoxyethyl)benzene (2.3 g, 7.0 mmol, 1.5 equiv) in chlorobenzene (23 mL) was heated at reflux for 1.5 h. Upon cooling to ambient temperature, the reaction was added slowly to ether. The slurry was stirred for 15 min and the filtered to provide the product as a HBr salt (1.86 g, 85%). 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.32 (s, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.47-7.40 (m, 1H), 2.56 (s, 3H), 2.30 (s, 3H), 1.60 (s, 9H); LCMS (ESI, M+1): 435.05.
Reaction SMILES: [CH:1]1([C@:4]2([OH:21])[CH2:8][CH2:7][N:6](C(OCC3C=CC=CC=3)=O)[C@H:5]2[CH2:19][CH3:20])[CH2:3][CH2:2]1>[Pd].O>[CH:1]1([C@:4]2([OH:21])[CH2:8][CH2:7][NH:6][C@H:5]2[CH2:19][CH3:20])[CH2:3][CH2:2]1
Reactant: CC[C@@H]1N(C(=O)OCc2ccccc2)CC[C@@]1(O)C1CC1
Agent: [Pd]
Solvent: O
Product: CC[C@@H]1NCC[C@@]1(O)C1CC1

Procedure:
By an operation in the same manner as in Reference Example 4 and using benzyl (2S,3R)-3-cyclopropyl-2-ethyl-3-hydroxypyrrolidine-1-carboxylate (2.01 g) and 50% water containing-10% Pd/C (0.20 g), the title compound was obtained as a colorless solid (yield: 1.35 g, yield: 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[Br:12][CH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24].C(Cl)CCl>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH:9][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([CH2:13][Br:12])=[C:15]([N+:23]([O-:25])=[O:24])[CH:16]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(CBr)c([N+](=O)[O-])c1
Reactant: NNC(=O)c1ccc(Cl)cc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NNC(=O)c1ccc(CBr)c([N+](=O)[O-])c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 100 mL round-bottom flask was added 2.1 g (12.3 mmol) of 4-chlorobenzoic acid hydrazide, 3.20 g (12.3 mmol) of 4-bromomethyl-3-nitro benzoic acid, 3.54 g (18.5 mmol) of EDC, and 200 mL of DCM. Allowed to stir at room temperature for 18 h. Removed ⅔ of DCM, added water and filtered off white solid and washed with Et2O to give 3-nitro-4-bromomethyl-benzoic acid N′-(4-chloro-benzoyl)-hydrazide as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.99 (s, 1 H) 5.12 (s, 1 H) 7.59-7.64 (m, 2 H) 7.91-7.95 (m, 2 H) 7.96 (d, J=8.21 Hz, 1 H) 8.22-8.29 (m,1 H) 8.57 (dd, J=6.57, 1.77 Hz, 1 H) 10.76 (s, 1 H) 10.94 (dd, J=5.18, 0.88 Hz, 1 H). MS (m/z) 413.9 M (+1), tR=1.28, Meth 10. To a 500 mL round-bottom flask was added 4.95 g (12.0 mmol) of 3-nitro-4-bromomethyl-benzoic acid N′-(4-chloro-benzoyl)-hydrazide, 6.09 g (36.0 mmol) DMC, and 100 mL of DCE. To this pale yellow solution was added 6.70 mL (48.0 mmol) of Et3N, slowly over 5 min. The dark green solution was allowed to stir at 40° C. for 30 min. then cooled to room temperature stirred for 18 h. Removed solvent and purified over a silica plug 10-30% EtOAc/Hep to give the title compound as yellow solid. MS (m/z) 350.0 M (+1), retention time=1.51, Method 10.
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([C:16]3[C:35]([N:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)=[CH:34][C:19]4[NH:20][C:21]([NH:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:33])([F:32])[F:31])=[N:22][C:18]=4[CH:17]=3)=[O:15])[CH:11]=2)[CH:6]=[N:5]1.[C:42]([OH:46])(=[O:45])[CH:43]=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([C:16]3[C:35]([N:36]4[CH2:37][CH2:38][N:39]([CH2:43][C:42]([OH:46])=[O:45])[CH2:40][CH2:41]4)=[CH:34][C:19]4[NH:20][C:21]([NH:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:31])([F:32])[F:33])=[N:22][C:18]=4[CH:17]=3)=[O:15])[CH:11]=2)[CH:6]=[N:5]1
Reactant: O=CC(=O)O
Reactant: O=C(Nc1ccc2cn[nH]c2c1)c1cc2nc(Nc3ccccc3C(F)(F)F)[nH]c2cc1N1CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)CN1CCN(c2cc3[nH]c(Nc4ccccc4C(F)(F)F)nc3cc2C(=O)Nc2ccc3cn[nH]c3c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-piperazin-1-yl-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide trihydrochloride (0.25 mmol; see Example 88) in methanol (1 mL) was added glyoxylic acid (0.5 mmol), and the resulting mixture was stirred at RT for 60 min. The reaction mixture was then charged with solid sodium cyanoborohydride (0.6 mmol), and the stirring was continued at RT for 10 h. To the reaction mixture was then added a few drops of glacial acetic acid, and the mixture was stirred for 30 min. The volatiles were then removed in vacuo, and the residue was suspended in water (10 mL) with vigorous stirring. After 30 min, the solid was filtered, washed with water, and dried under vacuum to afford {4-[6-(1H-indazol-6-ylcarbamoyl)-2-(2-trifluoromethyl-phenylamino)-3H-benzoimidazol-5-yl]-piperazin-1-yl}acetic acid as a white solid. MS: m/z 579 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]1[O:15][CH:16]=[C:17]([CH2:19][O:20][C:21]2[CH:35]=[CH:34][C:24]([CH2:25][S:26][CH2:27][CH2:28][N:29]3[CH:33]=[CH:32][N:31]=[N:30]3)=[CH:23][CH:22]=2)[N:18]=1.ClC1C=C(C(OO)=[O:44])C=CC=1>ClCCl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]1[O:15][CH:16]=[C:17]([CH2:19][O:20][C:21]2[CH:35]=[CH:34][C:24]([CH2:25][S:26]([CH2:27][CH2:28][N:29]3[CH:33]=[CH:32][N:31]=[N:30]3)=[O:44])=[CH:23][CH:22]=2)[N:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1cc(C(F)(F)F)ccc1/C=C/c1nc(COc2ccc(CSCCn3ccnn3)cc2)co1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=S(CCn1ccnn1)Cc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3F)n2)cc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
To a solution of 101 mg (0.20 mmol) 1-[2-(4-{2-[2-(E)-(2-fluoro-4-trifluoromethylphenyl)-vinyl]-oxazol-4-ylmethoxy}-benzylsulfanyl)-ethyl]-1H-[1,2,3]triazole in 8 ml dichloromethane at −30° C. were added drop by drop during 20 min 54 mg (0.24 mmol) 3-chloro-benzenecarboperoxoic acid dissolved in 2 ml ethyl acetate. After 1 hour stirring at 30° C. the mixture was allowed to warm up over night, diluted with dichloromethane, washed with sodium bicarbonate solution, then with water, dried and evaporated. Elution from silica with ethyl acetate/methanol 9:1 furnished 73 mg (71%) title compound as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:4]=1[C:5](O)=O.[OH-:23].[NH4+]>>[CH3:1][O:2][C:3]1([OH:23])[C:4]2[C:8](=[CH:12][C:13]3[C:18]([CH:5]=2)=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[CH:9]=[CH:10][CH2:11]1
Reactant: [OH-]
Reactant: COc1cccc(Cc2cccc(C(F)(F)F)c2)c1C(=O)O
Agent: [NH4+]
Product: COC1(O)CC=Cc2cc3cc(C(F)(F)F)ccc3cc21
Reaction time: 0.5 h

Procedure:
2-Methoxy-6-(3'-trifluoromethylbenzyl)benzoic acid (3.1 g.) is added in small portions with stirring to polyphosphoric acid (60 ml.) at 90°-95°C., the reaction mixture is stirred for 30 minutes at this temperature and then allowed to cool. Excess 8N ammonium hydroxide solution is added and the solution is stirred for 15 minutes and then extracted with ether. The ether layer is washed with water and with brine, and evaporated to give 1-methoxy-6-trifluoromethylanthrol, m.p. 102°-110°C., which is used without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[N+:15]([O-])=O)(=[O:3])[CH3:2].[ClH:18].O.NN>C(O)C.[Pd]>[ClH:18].[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[NH2:15])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(NC(C)=O)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(NC(C)=O)c(N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
To a suspension of 15 (0.870 g, 3.65 mmol) in ethanol (30 mL) was added Pd-C (0.87 g) and 5% HCl (0.85 mL). Hydrazine hydrate (55% hydrazine, 0.85 mL, 0.47 g, 15 mmol) dissolved in ethanol (SmL) was then added dropwise to the above mixture. The reaction mixture was stirred at room temperature for 1/2 hour and the Pd-C was filtered. The filtrate was concentrated under vacuum to give 16 (0.500 g, 78.7% yield) as a white solid: mp 187°-190° C.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:44])[CH2:14][O:15][C:16]1[CH:21]=[C:20]([C:22]2[NH:26][C:25](=[O:27])[O:24][N:23]=2)[CH:19]=[C:18]([O:28][CH2:29][C:30]([N:32]2[CH2:36][CH2:35][CH2:34][C@@H:33]2[C:37]([O:39]C(C)(C)C)=[O:38])=[O:31])[CH:17]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:37]([C@H:33]1[CH2:34][CH2:35][CH2:36][N:32]1[C:30](=[O:31])[CH2:29][O:28][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([C:22]2[NH:26][C:25](=[O:27])[O:24][N:23]=2)[CH:19]=1)[O:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:44])([OH:39])=[O:38]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)COc1cc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)cc(-c2noc(=O)[nH]2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1CCCN1C(=O)COc1cc(OCC(=O)N2CCC[C@@H]2C(=O)O)cc(-c2noc(=O)[nH]2)c1
Reaction time: 8 h
Yield: 74.3 %

Procedure:
A solution of 220 mg (0.36 mmol) (R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 1.5 ml trifluoroacetic acid was stirred for 4 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 135 mg (74%) of the title compound as a light brown powder.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:25])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:24])([CH3:23])[CH2:21]O)=[CH:16][CH:15]=2)[CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.CO.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:25])=[CH:15][CH:16]=1)([CH3:21])([CH3:23])[CH3:24]
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)CO)cc3)cc(Cl)n2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)c1ccc(C(=O)Nc2cc(-c3ccc(F)cc3)n3nccc3n2)cc1
Temperature: 110 °C

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(1-hydroxy-2-methylpropan-2-yl)benzamide (4G, 44 mg, 1.0 equivalent), 4-fluorophenylboronic acid (1.2 equivalents), Pd(OAc)2 (0.05 equivalent), and K2CO3 (4.0 equivalents) in DME/H2O was warmed to 110° C. in a microwave reactor. The reaction mixture was cooled to room temperature, diluted with methanol, filtered, and purified via preparative HPLC to afford the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.37 (s, 9 H) 6.50 (d, J=2.26 Hz, 1 H) 7.23-7.32 (m, 1 H) 7.56 (d, J=8.29 Hz, 2 H) 7.89 (d, J=8.29 Hz, 2 H) 8.11 (d, J=2.26 Hz, 1 H) 8.12-8.18 (m, 2 H) 8.25 (s, 1 H) 8.67 (s, 1 H); ESI-MS: m/z 389 (M+H)+.
Reaction SMILES: C(O[C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16]([OH:18])=[O:17])=[O:10])C1C=CC=CC=1.[C:19]([C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:43])[C:31]2[CH:36]=[CH:35][C:34]([CH:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[CH:33][CH:32]=2)[CH:26]=[CH:27][CH:28]=1)([CH3:22])([CH3:21])[CH3:20].C(C1C=C(NC(C2C=CC(N3CCN(C([C@H]4CCC[C@@H]4C(O)=O)=O)CC3)=NC=2)=O)C=CC=1)(C)(C)C>>[C:19]([C:23]1[CH:24]=[C:25]([NH:29][C:30]([C:31]2[CH:32]=[CH:33][C:34]([CH:37]3[CH2:38][CH2:39][N:40]([C:9]([C@@H:11]4[CH2:15][CH2:14][CH2:13][C@H:12]4[C:16]([OH:18])=[O:17])=[O:10])[CH2:41][CH2:42]3)=[CH:35][CH:36]=2)=[O:43])[CH:26]=[CH:27][CH:28]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCNCC3)cc2)c1
Reactant: O=C(O)[C@H]1CCC[C@@H]1C(=O)OCc1ccccc1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(C(=O)[C@H]4CCC[C@@H]4C(=O)O)CC3)nc2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCN(C(=O)[C@@H]4CCC[C@H]4C(=O)O)CC3)cc2)c1

Procedure:
(1R,2R)-2-{4-[4-(3-tert-Butyl-phenylcarbamoyl)-phenyl]-piperidine-1-carbonyl}-cyclopentanecarboxylic acid was synthesized from (1S,2S)-cyclopentane-1,2-dicarboxylic acid monobenzyl ester and N-(3-tert-butyl-phenyl)-4-piperidin-4-yl-benzamide in a manner similar to the one described in the synthesis of (1S,2S)-2-{4-[5-(3-tert-butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carbonyl}-cyclopentane-carboxylic acid above. LCMS calcd for C29H36N2O4 (m/e) 476, obsd 477 (M+H).
Reaction SMILES: [CH:1]1([C:4]#[CH:5])[CH2:3][CH2:2]1.[N:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N+:7]=[N-:8]>C(#N)C.[Cu](I)I.C(N(CC)CC)C>[CH:1]1([C:4]2[N:8]=[N:7][N:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: C#CC1CC1
Agent: I[Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1cc(C2CC2)nn1
Yield: 95.4 %

Procedure:
Cyclopropylacetylene (15 g, 0.116 mol), ethyl azidoacetate (11.5 g, 0.174 mol), triethylamine (0.32 mL, 2.33 mmol) and copper iodide (442 mg, 2.33 mmol) in acetonitrile (100 mL) were stirred at 25° C. for 18 hours. The mixture was evaporated in vacuo and the residue was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic phase was dried over sodium sulfate, evaporated in vacuo and purified by silica gel column chromatography eluting with EtOAc: Hexane 40: 60 to afford the title compound as a colorless liquid (95%, 21.6 g).
Reaction SMILES: [CH:1]([NH:4][C:5]([C@H:7]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]([O:23][CH3:24])[CH:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]>CC(O)=O.CO.C(Cl)Cl.[Fe]>[NH2:20][C:19]1[C:14]([NH:13][C@@H:10]2[CH2:9][CH2:8][C@H:7]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:12][CH2:11]2)=[CH:15][C:16]([O:23][CH3:24])=[N:17][CH:18]=1
Reactant: COc1cc(N[C@H]2CC[C@@H](C(=O)NC(C)C)CC2)c([N+](=O)[O-])cn1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(N[C@H]2CC[C@@H](C(=O)NC(C)C)CC2)c(N)cn1
Temperature: 100 °C

Procedure:
To solution of cis-N-isopropyl-4-(2-methoxy-5-nitropyridin-4-ylamino)cyclohexanecarboxamide (264 mg, 0.785 mmol) in AcOH (1.5 μmL) was added iron powder (219 mg, 3.92 mmol), and the mixture was heated to 100° C. for 5 minutes. The mixture was allowed to cool to RT, was diluted with 10% MeOH/DCM, and was filtered through a pad of Celite® brand filter aid and concentrated. The mixture was purified via flash chromatography using a linear gradient of 0% to 10% of 1% NH4OH in MeOH in DCM. Cis-4-(5-amino-2-methoxypyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide was isolated as a red film (211 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[Mn]([O-])(=O)(=O)=[O:18].[K+].C(=O)=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:18])=[O:9])=[CH:6][CH:7]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=C(Cc1ccccc1)c1ccc(Cl)cc1
Agent: O=C=O
Agent: [K+]
Solvent: c1ccncc1
Product: O=C(C(=O)c1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 25.1 %

Procedure:
A benzene solution containing 51.2 g 4-chlorophenylacetic acid and 39.3 g thionyl chloride is refluxed for 6 hours and the solvent removed. The crude reaction product is added dropwise to a slurry of 40 g aluminum chloride in 200 ml benzene maintaining the temperature below 50° C. After addition the reaction is refluxed for 1.5 hours. After cooling, the mixture is poured into ice and the resulting white solid is separated yielding 61.3 g of crude product. The product is taken up in methylene chloride and washed with 5% sodium hydroxide solution followed by water, dried over sodium sulfate and stripped yielding 49.3 g (71%) of >95% pure 4'-chlorodeoxybenzoin. 15 g of 4-chlorodeoxybenzoin is dissolved in 105 ml pyridine. An aqueous solution containing 15 g potassium permanganate is added and the reaction stirred for 6 hours at room temperature using dry ice to buffer the pH near 7. The mixture is extracted with methylene chloride, the extract washed with water, dried over Na2SO4 and stripped. The residue is recrystallized from ethanol yielding 6.1 g of white plate-like crystals which is identified as starting material. Concentration of the mother liquor yields 4 g of 4-chlorobenzil.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][OH:10])[CH2:5][O:4]1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>N1C=CC=CC=1>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:5][O:4]1
Reactant: COC1CCC(CO)CO1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC1CCC(COC(C)=O)CO1
Temperature: 5 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
2-Methoxy-5-hydroxymethyltetrahydropyran (0.91 g) was dissolved in pyridine (10 ml), and the solution cooled to 5° C. Acetic anhydride (3.15 ml) was added thereto, and the mixture stirred at the same temperature For 1 hour, and then at room temperature overnight. After removing pyridine by evaporation under reduced pressure, the residue was purified on a silica gel column (eluent: n-hexane/ethyl acetate=1/2) to obtain the desired product (0.93 g, 80.0%) as pale yellow oil.