Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH2:12]Cl)[N:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:7]2=[O:21].O.[SH:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH2:12][S:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)[N:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:7]2=[O:21]
Reactant: O=c1c2cccc(Cl)c2nc(CCl)n1-c1ccccc1Cl
Reactant: Sc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cccc(Cl)c2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1Cl
Yield: 75.3 %

Procedure:
Prepared according to Procedure C using Intermediate 2h (200 mg, 0.589 mmol), 6-mercaptopurine monohydrate (124 mg, 0.726 mmol), K2CO3 (100 mg, 0.726 mmol), and DMF (4 mL). The crude product was recrystallized from EtOH to provide 202 mg of a white solid (75%), mp 211.9-212.7© (decomposes). 1H NMR (DMSO-d6) δ: 13.54 (br s, 1H); 8.47 (s, 1H); 8.44 (s, 1H); 8.12 (d, J=7.9 Hz, 1H); 8.07 (d, J=7.6 Hz, 1H); 7.78 (d, J=7.5 Hz, 1H); 7.67 (d, J=7.1 Hz, 1H); 7.58 (t, J=7.9 Hz, 1H); 7.42-7.54 (m, 2H); 4.52 (s, 2H). 13C NMR (DMSO-d6) ppm: 160.3, 156.9, 153.9, 151.5, 149.7, 143.5, 135.7, 134.0, 132.1, 131.8, 131.4, 131.1, 130.5, 130.3, 128.9, 128.3, 126.1, 122.4, 32.5. MS (ES): m/z 455.0 (M+). Anal. calcd. for C20H12Cl2N6OS: C, 52.76; H, 2.66; Cl, 15.57; N, 18.46; S, 7.04. Found: C, 52.65; H, 2.79; Cl, 15.32; N, 18.47; S, 7.18.
Reaction SMILES: [F:1]C1C=CC(C)=CC=1C(O)=O.F[C:13]1[CH:14]=[C:15]([C:22]([OH:24])=[O:23])[CH:16]=[C:17]([CH:21]=1)[C:18]([OH:20])=[O:19]>>[F:1][C:14]1[CH:13]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1[C:22]([OH:24])=[O:23]
Reactant: O=C(O)c1cc(F)cc(C(=O)O)c1
Reactant: Cc1ccc(F)c(C(=O)O)c1
Product: O=C(O)c1ccc(F)c(C(=O)O)c1

Procedure:
4-fluoro-isophthalic acid was synthesized from 2-fluoro-5-methylbenzoic acid following the procedure described for 5-fluoro-isophthalic acid.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:60][C:61]1[S:62][CH:63]=[CH:64][N:65]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[C:18][CH2:19][N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[CH:15][CH:16]=2)[C:8]([NH:60][C:61]2[S:62][CH:63]=[CH:64][N:65]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(C#CCN2CCOCC2)cc1
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(C#CCN2CCOCC2)cc1
Yield: 71.3 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-propionic acid (171 mg, 0.50 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (332 mg, 0.75 mmol), triethylamine (0.21 mL, 1.50 mmol) and 2-aminothiazole (86 mg, 0.86 mmol) in methylene chloride (5 mL) was stirred at 25° C. for 2 h. At this time, the reaction was diluted with methylene chloride (10 mL). This solution was washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), and a half-saturated aqueous sodium chloride solution (1×10 mL). The aqueous layers were back extracted with methylene chloride (1×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 98/2 ethyl acetate/methanol) afforded 3-cyclopentyl-2-[4-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide (151 mg, 71.2%) as a white foam: EI-HRMS m/e calcd for C24H29N3O2S (M+) 423.1980, found 423.1980.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:12])[CH3:3].[Mg].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.[Cl-].[NH4+]>C(OCC)C.O>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][C:6]2([OH:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:5]2[CH2:4][N:2]([CH3:1])[CH3:3])=[CH:17][CH:16]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CN(C)CC1CCCCCC1=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CN(C)CC1CCCCCC1(O)Cc1ccc(Cl)cc1
Reaction time: 2 h
Yield: 71 %

Procedure:
A solution of 32.00 g of 2-dimethylaminomethylcycloheptanone in 190 ml of absolute diethyl ether was added dropwise at 20° C., with stirring, to a freshly prepared solution of the Grignard reagent comprising 6.17 g of magnesium turnings and 40.50 g of 4-chlorobenzyl chloride in 500 ml of absolute diethyl ether. When the addition was complete, stirring was continued for a further 2 hours at 20° C. Decomposition was then effected, while cooling with ice, by the dropwise addition of 100 ml of a saturated ammonium chloride solution followed by 200 ml of distilled water. The organic phase was separated off, and the aqueous phase was extracted twice using 200 ml of ethyl acetate each time. The combined organic extracts were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation in vacuo. The oily residue was purified by column chromatography with ethyl acetate as eluant, 39.69 g of the title compound being obtained in the form of the free base. This was dissolved in 270 ml of 2-butanone and converted into the hydrochloride by addition of 2.8 ml of water and 17.4 ml of trimethylchlorosilane. 37.30 g (59.4% of theory) of the title compound as a diastereoisomeric mixture were obtained in the form of colorless crystals.
Reaction SMILES: C1C=CN=C(NS(C2C=CC(N=N[C:19]3[CH:20]=[CH:21][C:22]([OH:28])=[C:23]([C:25]([OH:27])=[O:26])[CH:24]=3)=CC=2)(=O)=O)C=1.C1C([NH2:35])=CC(C(O)=O)=C(O)C=1.C1C(N=NC2C=CC(O)=C(C(O)=O)C=2)=CC(C(O)=O)=C(O)C=1.C1C(C(NCCC(O)=O)=O)=CC=C(N=NC2C=CC(O)=C(C(O)=O)C=2)C=1>>[NH2:35][O:28][C:22]1[C:23](=[CH:24][CH:19]=[CH:20][CH:21]=1)[C:25]([OH:27])=[O:26]
Reactant: O=C(O)c1cc(N=Nc2ccc(S(=O)(=O)Nc3ccccn3)cc2)ccc1O
Reactant: Nc1ccc(O)c(C(=O)O)c1
Agent: O=C(O)CCNC(=O)c1ccc(N=Nc2ccc(O)c(C(=O)O)c2)cc1
Agent: O=C(O)c1cc(N=Nc2ccc(O)c(C(=O)O)c2)ccc1O
Product: NOc1ccccc1C(=O)O

Procedure:
sulfasalazine, mesalamine, olsalazine, balsalazide.
Reaction SMILES: [N+](C1C=C(C=CC=1)C(C(C)CC#N)=O)([O-])=O.Cl.[N+:18]([C:21]1[CH:22]=[C:23]([CH:32]=[CH:33][CH:34]=1)[C:24]([CH:26]([CH3:31])[CH2:27][C:28](O)=[O:29])=O)([O-:20])=[O:19].O.[NH2:36][NH2:37]>C(O)C>[CH3:31][CH:26]1[C:24]([C:23]2[CH:32]=[CH:33][CH:34]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=2)=[N:37][NH:36][C:28](=[O:29])[CH2:27]1
Reactant: NN
Reactant: CC(CC(=O)O)C(=O)c1cccc([N+](=O)[O-])c1
Agent: CC(CC#N)C(=O)c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC1CC(=O)NN=C1c1cccc([N+](=O)[O-])c1

Procedure:
A 28 g. portion of 3-(m-nitrobenzoyl)butyronitrile [prepared as described in J. Org. Chem., Vol. 38, No. 23, 4044-4048 (1973)] is added to one liter of 6N hydrochloric acid and is stirred at reflux for one hour using a magnetic stirrer and a heating mantle. The reaction mixture is cooled and extracted with methylene chloride. The organic layer is separated and extracted with saturated sodium bicarbonate. The bicarbonate layer is added dropwise to a stirred cold hydrochloric acid solution and the resulting solid is kept cold in ice then is filtered and air dried to afford 27.24 g. of 3-m-nitrobenzoyl butyric acid as a white solid. The entire amount of the preceding compound is mixed with 12.8 ml. of 99% hydrazine hydrate in 140 ml. of ethyl alcohol and is stirred at reflux for 3 hours. A solid begins to appear after about half an hour. The reaction mixture is cooled in an ice bath and the resulting solid is filtered and air dried to afford the compound 4,5-dihydro-5 -methyl-6-(m-nitrophenyl)-3(2H)-pyridazinone as white to light yellow crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[O:10][N:9]=2)[CH:5]=[N:6][CH:7]=1.B1([C:25]2[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=2)OCCCO1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]1[O:10][N:9]=[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[CH:3]=2)[N:12]=1
Reactant: Brc1cncc(-c2noc(-c3ccccn3)n2)c1
Reactant: c1cncc(B2OCCCO2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: c1ccc(-c2nc(-c3cncc(-c4cccnc4)c3)no2)nc1
Yield: 43.1 %

Procedure:
A mixture of 3-(5-bromo-pyrid-3-yl)-5-(2-pyridyl)-1,2,4-oxadiazole 30.3 mg, 0.1 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (32.5 mg, 0.2 mmol), and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 15 mg, 0.013 mmol), in a solution of ethylene glycol dimethyl ether (1 mL) and 2M sodium carbonate (1 mL) was heated in a sealed vial at 100° C. for 1 hour. The reaction was cooled, diluted with dichloromethane, washed with water and saturated brine, filtered, and concentrated. Silica gel chromatography using 50% ethyl acetate in hexane and 100% ethyl acetate afforded 13 mg (43.2%) 5-(2-pyridyl)-3-[5-(3-pyridyl)-pyrid-3-yl]-1,2,4-oxadiazole. 1H-NMR (CDCl3), δ (ppm): 9.49 (d, 1H), 9.01 (d, 1H), 8.93 (dd, 2H), 8.72 (t, 2H), 8.35 (d, 2H), 8.00 (dt, 1H), 7.59 (m, 1H), 7.47 (dd, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]3)[C:6]=2[CH:28]=1.NC1CCN(CCN2C3C(=CC=C(C#N)C=3)C=CC2=O)CC1>>[NH2:20][CH:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][N:7]2[C:6]3[CH:28]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:9][C:8]2=[O:11])[CH2:15][CH2:16]1
Reactant: Cc1ccc2c(c1)N(CCN1CCC(NC(=O)OC(C)(C)C)CC1)C(=O)CO2
Agent: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Product: Cc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2

Procedure:
tert-Butyl {1-[2-(6-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 92) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was obtained as a colorless solid and used without further purification for the next step (quantitative yield).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Br:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:39]([C:36]4[CH:37]=[CH:38][C:33]([Br:32])=[CH:34][CH:35]=4)(=[O:41])=[O:40])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(Br)cc4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 4-bromo-benzenesulfonyl chloride. Purity (ELSD, based on MW=640.5)=100%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH3:21])[CH:15]=1.N>C(O)(C)C>[CH3:21][C:16]1[CH:15]=[C:14]([NH:13][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[F:12])[N:5]=[CH:4][N:3]=2)[CH:19]=[CH:18][C:17]=1[OH:20]
Reactant: Cc1cc(N)ccc1O
Reactant: Fc1cccc2ncnc(Cl)c12
Agent: N
Solvent: CC(C)O
Product: Cc1cc(Nc2ncnc3cccc(F)c23)ccc1O
Temperature: 25 °C
Yield: 82 %

Procedure:
4-Chloro-5-fluoroquinazoline (6.76 g) was dissolved in iso-propanol (200 ml) and 4-amino-2-methylphenol (5.00 g) was added. The mixture was heated under reflux for 2 hours, causing a yellow solid to precipitate. The mixture was cooled to ambient temperature and the solid was collected by filtration. The solid was dissolved in a boiling mixture of methanol (500 ml) and water (100 ml) to give a brown solution. With vigorous stirring, the solution was basified with aqueous ammonia (0.880, 10 ml), causing a light brown solid to precipitate. The mixture was concentrated in vacuo to such a volume that all of the methanol had been removed, leaving the product as a suspension in aqueous solution. The suspension was cooled; the solid was collected by filtration, triturated with ethyl acetate and dried over P2O5 in a vacuum oven to give 2-methyl-4-[(5-fluoroquinazolin-4-yl)amino]phenol as a light brown solid (8.18 g, 82%); NMR spectrum (DMSO-d6) 3.30 (s, 3H), 6.78 (d, 1H), 7.28 (m, 2H), 7.38 (dd, 1H), 7.57 (d, 1H), 7.78 (m, 1H), 8.43 (s, 1H), 8.88 (d, 1H), 9.22 (s, 1H); Mass spectrum MH+ 270.
Reaction SMILES: C([O:3][C:4]([C:6]12C[CH:10]1[CH2:9][N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:7]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O)C.C(OC(C1[C@H](C2C=CC=CC=2)N(S(C2C=CC(C)=CC=2)(=O)=O)CC=1)=O)C.CC(C[AlH]CC(C)C)C.CO>C(Cl)Cl>[C:22]1([CH:7]2[C:6]([CH2:4][OH:3])=[CH:10][CH2:9][N:8]2[S:12]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:14])=[O:13])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)C12CC1CN(S(=O)(=O)c1ccc(C)cc1)C2c1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Agent: CCOC(=O)C1=CCN(S(=O)(=O)c2ccc(C)cc2)[C@H]1c1ccccc1
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2CC=C(CO)C2c2ccccc2)cc1
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To racemic intermediate 1, one enantiomer being (S)-2-phenyl-1-(toluene-4-sulfonyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid ethyl ester (1.8 g, 5.0 mmol), was dissolved in methylene chloride (60 mL) in a three necked flask equipped with an addition funnel and an internal thermometer. The mixture was cooled to −25° C., DIBAL (1M/toluene, 12.5 mL, 12.5 mmol) was added dropwise and the reaction stirred for an additional 0.5 hours. Methanol was added to the cold solution until gas evolution ceased and the solvents were then removed at reduced pressure. The residue was partitioned between a saturated solution of Rochelle's salt and methylene chloride. The organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was chromatographed on silica gel using a gradient of 20% to 60% ETOAc/Hexanes to yield the title compound as a sticky foam (1.6 g, 98% yield).
Reaction SMILES: [CH2:1]([PH:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH:2]([CH3:4])[CH3:3].CN([CH2:13][C-:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19]N(C)C)C.[CH-:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1.[Fe+2:28]>C(O)(=O)C>[CH2:1]([P:5]([CH2:13][C-:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][P:5]([CH2:6][CH:27]([CH3:26])[CH3:23])[CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][CH:7]([CH3:9])[CH3:8])[CH:2]([CH3:4])[CH3:3].[CH-:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1.[Fe+2:28]
Reactant: CN(C)Cc1ccc[c-]1CN(C)C
Reactant: CC(C)CPCC(C)C
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: CC(=O)O
Product: CC(C)CP(Cc1ccc[c-]1CP(CC(C)C)CC(C)C)CC(C)C

Procedure:
The title compound was prepared in accordance with the procedure of Example 2 employing di-iso-butylphosphine (Strem 486 mg, 3.33 mmol), 1,2-bis(dimethylaminomethyl)ferrocene (0.5 g, 1.66 mmol) and anhydrous acetic acid (100 ml). Yield 0.372 g.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:7]([OH:9])=O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.Cl.[Cl:43][C:44]1[C:45]([NH:72][C:73](=[O:93])[C:74]2[CH:79]=[CH:78][C:77]([N:80]3[CH2:85][CH2:84][N:83]([C:86](=[O:91])[C:87]([CH3:90])([CH3:89])[CH3:88])[CH2:82][C@H:81]3[CH3:92])=[N:76][CH:75]=2)=[CH:46][C:47]([O:67][C:68]([F:71])([F:70])[F:69])=[C:48]([C:50]2[CH:55]=[CH:54][C:53]([C:56]3[N:57]=[C:58]([C@@H:61]4[CH2:65][C@H:64]([CH3:66])[CH2:63][NH:62]4)[NH:59][CH:60]=3)=[CH:52][CH:51]=2)[CH:49]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@@H:6]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:7]([N:62]1[CH2:63][C@@H:64]([CH3:66])[CH2:65][C@H:61]1[C:58]1[NH:59][CH:60]=[C:56]([C:53]2[CH:54]=[CH:55][C:50]([C:48]3[CH:49]=[C:44]([Cl:43])[C:45]([NH:72][C:73]([C:74]4[CH:75]=[N:76][C:77]([N:80]5[CH2:85][CH2:84][N:83]([C:86](=[O:91])[C:87]([CH3:90])([CH3:89])[CH3:88])[CH2:82][C@H:81]5[CH3:92])=[CH:78][CH:79]=4)=[O:93])=[CH:46][C:47]=3[O:67][C:68]([F:70])([F:71])[F:69])=[CH:51][CH:52]=2)[N:57]=1)=[O:9]
Reactant: COC(=O)N[C@H](C(=O)O)C1CCOCC1
Reactant: C[C@@H]1CN[C@H](c2nc(-c3ccc(-c4cc(Cl)c(NC(=O)c5ccc(N6CCN(C(=O)C(C)(C)C)C[C@H]6C)nc5)cc4OC(F)(F)F)cc3)c[nH]2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCN(C(=O)C(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
To a solution of (S)-methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (9.4 mg, 0.046 mmol; Preparation 29) in DMA (5 mL) was added HATU (45.3 mg, 0.12 mmol). The reaction mixture was stirred at RT for 15 min, and N-{5-chloro-4′-[2-((2S,4S)-4-methyl-pyrrolidin-2-yl)-1H-imidazol-4-yl]-2-trifluoromethoxy-biphenyl-4-yl}-6-[(R)-4-(2,2-dimethyl-propionyl)-2-methyl-piperazin-1-yl]-nicotinamide tri-HCl (30.0 mg, 0.036 mmol; Preparation 31 was added followed by DIPEA (86.4 μL, 0.50 mmol). The reaction mixture was stirred at RT overnight, concentrated by rotary evaporation, dissolved in 1:1 acetic acid:water (1.5 mL) and purified by reverse phase HPLC to provide the di-TFA salt of the title compound (14 mg, 37% yield). (m/z): [M+H]+ calcd for C46H54ClF3N8O7 923.38. found 923.8.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH:10]([OH:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:23]([NH2:27])[CH:24]([CH3:26])[CH3:25].OS1C2C=CC=CC=2N=C1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH:10]([OH:14])[C:11]([NH:27][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(O)C(=O)O
Reactant: CC(C)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O[SH]1C=Nc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)CNC(=O)C(O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Yield: 125.8 %

Procedure:
To a solution of 400 mg of the butyric acid compound, 175 mg of isobutylamine hydrochloride, 270 mg of 1-hydroxybenzotiazole and 0.22 ml of triethylamine in 20 ml of ethyl acetate was added 300 mg of dicyclohexylcarbodiimide with stirring under ice-cooling, and then the mixture was still stirred for 16 hours. The reaction mixture was cooled, and filtered to remove insoluble materials. The filtrate was washed successively with an aqueous citric acid solution, a 5% aqueous sodium bicarbonate solution and a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to obtain 595 mg of (2RS, 3S)-3-(tert-butoxycarbonyl)amino-4-cyclohexyl-2-hydroxy-N-isobutylbutyramide.
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.[CH:21]1([C:24]2[S:28][C:27]([NH2:29])=[N:26][N:25]=2)[CH2:23][CH2:22]1.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>>[CH:21]1([C:24]2[S:28][C:27]([NH:29][C:15]([CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)=[O:17])=[N:26][N:25]=2)[CH2:23][CH2:22]1
Reactant: Nc1nnc(C2CC2)s1
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: COC(Cc1ccc(OCC(=O)Nc2nnc(C3CC3)s2)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 5-cyclopropyl-[1,3,4]thiadiazol-2-ylamine 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 C17H19N3O5S [M−H]−: 376.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:14])[N:9]([CH2:11][O:12][CH3:13])[N:10]=[C:4]2[C:3]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:7]=[CH:6][N:5]3[C:8](=[O:14])[N:9]([CH2:11][O:12][CH3:13])[N:10]=[C:4]3[C:3]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COCn1nc2c(-c3ccncc3)c(Br)ccn2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COCn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 20 °C
Yield: 75.1 %

Procedure:
To a degassed mixture of crude 7-bromo-2-(methoxymethyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (620 mg, 1.85 mmol), 4-chlorophenylboronic acid (850 mg, 5.55 mmol) and K2CO3 (1.02 g, 7.4 mmol) in 1,4-dioxane (18 mL) and H2O (6.0 mL) under argon at 20° C. was added Pd(PPh3)4 (107 mg, 0.093 mmol). The reaction mixture was refluxed for 15 h under argon and then cooled to 20° C. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (3×50 mL). The combined organic extract was washed with saturated aqueous NaHCO3 solution (20 mL), then brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with a 0-60% gradient of EtOAc in hexanes to obtain the title compound as a yellow solid (510 mg, 1.39 mmol). MS: [M+H]+=367.1. 1H NMR (400 MHz, CDCl3) δ 3.46 (s, 3H), 5.32 (s, 2H), 6.62 (d, J=7.1 Hz 1H), 7.01-7.09 (m, 2H), 7.17-7.22 (m, 2H), 7.23-7.29 (m, 2H), 7.85 (d, J=7.1 Hz, 1H), 8.55 (d, J=4.40 Hz, 2H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].O1CCCCC1[N:34]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=[N:35]1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:36]3[NH:35][N:34]=[CH:38][CH:37]=3)[C:3]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1Br
Product: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1-c1ccn[nH]1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 26 using 5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(ethyl(2-hydroxyethyl)amino)nicotinamide (Stage 24.1) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to afford a yellow solid. UPLC-MS (Condition 3) tR=1.02 min, m/z=452.2 [M+H]+, m/z=450.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.09 Hz, 3H) 3.17-3.27 (m, 2H) 3.35-3.43 (m, 2H) 3.43-3.53 (m, 2H) 4.59 (br. s, 1H) 6.53 (d, J=1.96 Hz, 1H) 7.33 (d, J=9.05 Hz, 2H) 7.76 (br. s, 1H) 7.82-7.95 (m, 2H) 8.13 (d, J=2.45 Hz, 1H) 8.72 (d, J=2.45 Hz, 1H) 10.29 (s, 1H) 12.98 (br. s, 1H).