Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]Cl.[Cl:3][C:4]1[C:5]([C:12]([Cl:15])([Cl:14])[Cl:13])=[N:6][CH:7]=[C:8]([Cl:11])[C:9]=1[Cl:10]>>[Cl:3][C:4]1[C:5]([C:12]([Cl:15])([Cl:13])[Cl:14])=[N:6][C:7]([Cl:1])=[C:8]([Cl:11])[C:9]=1[Cl:10]
Reactant: ClCl
Reactant: Clc1cnc(C(Cl)(Cl)Cl)c(Cl)c1Cl
Product: Clc1nc(C(Cl)(Cl)Cl)c(Cl)c(Cl)c1Cl
Yield: 65 %

Procedure:
Summarizing Example 1, starting with fifty grams of a mixture rich in 3,4,5-trichloro-2-trichloromethyl pyridine, the analysis of which is set forth in Table One, and which contained 3% by weight ferric chloride, its chlorination with 70 grams per hour of chlorine, sparged into a 250 ml glass reactor at 200° C. for 5 hours, resulted in a product the analysis of which is set forth in Table One. As will be noted, a molar yield in excess of 65% of 3,4,5,6-tetrachloro-2-trichloromethyl pyridine based on 3,4,5-trichloro-2-trichloromethyl pyridine conversion was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]([CH3:29])([CH2:16][N:17]1[CH:25]=[C:24]2[C:19]([C:20]([Cl:28])=[C:21]([Cl:27])[CH:22]=[C:23]2[Cl:26])=[N:18]1)[C:14]#[N:15]>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:12][C:13]([C:14]#[N:15])([CH3:29])[CH2:16][N:17]1[CH:25]=[C:24]2[C:19]([C:20]([Cl:28])=[C:21]([Cl:27])[CH:22]=[C:23]2[Cl:26])=[N:18]1)=[O:5]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(Cl)cc1Cl

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 2,4-dichlorobenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (0.075 mmole, described in Example 147) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (4.2 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=475, RT=0.74 min.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.Cl.[F:17][C:18]1[CH:19]=[C:20]([CH:24]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]([OH:27])=[O:26])[CH:21]=[CH:22][CH:23]=1.C1C=CC2N(O)N=NC=2C=1.[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47](O)[CH2:46]2>C1COCC1>[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47]([O:26][C:25](=[O:27])[CH:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=1)[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:46]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(Nc1ccccc1)c1cccc(F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
PS-DCC (982 mg, 1.31 mmol, loading: 1.33 mmol/g) is suspended in dry THF (15 mL). (3-fluoro-phenyl)-phenylamino-acetic acid hydrochloride (I98) (184 mg, 0.65 mmol), HOBT (200 mg, 1.31 mmol), and (R)-quinuclidin-3-ol (249 mg, 1.96 mmol) are added and the mixture is shaken at RT overnight. PS-DCC is filtered off and the filtrate is evaporated. The residue is dissolved in EtOAc and washed with NaHCO3, water and brine. The organic layer is dried over Na2SO4, filtered and evaporated to dryness. The crude compound is purified by filtration through a pad of silica-gel using DCM/MeOH=9/1 as the eluent. The title compound is obtained as a colorless oil (129 mg, 56% yield, mixture of diastereoisomers).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10](O)[C:9]2[C:4](=[C:5]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.P(Cl)(Cl)([Cl:23])=O.[OH-].[Na+]>>[CH3:1][C:2]1[CH:11]=[C:10]([Cl:23])[C:9]2[C:4](=[C:5]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)c2cccc(-c3ccc(Cl)cc3Cl)c2n1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(Cl)c2cccc(-c3ccc(Cl)cc3Cl)c2n1

Procedure:
A mixture of intermediate (9) (1.32 g) and phosphorous oxychloride (5 ml) was refluxed for 2 hours, cooled, poured onto ice and neutralized by 1N NaOH. The aqueous layer was extracted by ethyl acetate. The organic layer was washed with brine, dried, concentrated, yielding 2-methyl-4-chloro-8-(2′,4′-dichlorophenyl)quinoline (intermediate 1) (1.31 mg. 300 MHz 1H NMR (CDCl3): δ 2.58 (s,3H), 7.34 (s,2H), 7.39 (s,1H), 7.53 (s,1H), 7.63-7.65 (m,2H), 8.26 (dd, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=[N:3]1>[C].[Pd].C(O)C>[CH3:1][N:2]1[C:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1C=Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Cn1nccc1CCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 102.2 %

Procedure:
10% Palladium carbon (30 mg) was added to an ethanol (3.0 mL) solution of 1-methyl-5-(2-phenylethenyl)-1H-pyrazole (300 mg), and the obtained solution was then stirred under a hydrogen atmosphere at a room temperature for 14 hours. Thereafter, the reaction solution was filtrated with Celite, and the filtrate was then concentrated under a reduced pressure, so as to obtain the title compound (310 mg) in the form of a colorless oily substance.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:5][C:6]1[C:7]2[CH:30]=[CH:29][N:28](S(C3C=CC(C)=CC=3)(=O)=O)[C:8]=2[N:9]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:27])[CH3:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:11]=1)[CH3:4].[OH-].[K+]>CO.O1CCOCC1>[OH:1][CH2:2][C@H:3]([NH:5][C:6]1[C:7]2[CH:30]=[CH:29][NH:28][C:8]=2[N:9]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:20][CH2:21][N:22]([C:25](=[O:27])[CH3:26])[CH2:23][CH2:24]3)=[CH:15][CH:14]=2)[N:11]=1)[CH3:4]
Reactant: CC(=O)N1CCN(c2ccc(Nc3nc(N[C@H](C)CO)c4ccn(S(=O)(=O)c5ccc(C)cc5)c4n3)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2ccc(Nc3nc(N[C@H](C)CO)c4cc[nH]c4n3)cc2)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 38.9 %

Procedure:
To a solution of (R)-1-(4-(4-(4-(1-hydroxypropan-2-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (25 mg, 0.044 mmol) in MeOH (1 mL) and dioxane (1 mL), aq. 1N KOH (1.0 mL, 1.0 mmol) was added. After being stirred at 60° C. for 3 h, it was concentrated in vacuo. The residue was acidified with HOAc (1 mL), then was purified by HPLC to give (R)-1-(4-(4-(4-(1-hydroxypropan-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (7 mg), MS 410.5 (M+H); UV 202.6, 267.5, 303.1 nm; and (R)-2-(2-(4-(piperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)propan-1-ol (3 mg), MS 368.5 (M+H); UV 229.6, 271.0, 301.9 nm.
Reaction SMILES: [Na].[C:2]([O:9][CH3:10])(=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1>CO>[CH3:7][O:6][C:4](=[O:5])[CH:3]([CH2:16][C:15]1[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=1)[C:2]([O:9][CH3:10])=[O:8]
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)CC(=O)OC
Agent: [Na]
Solvent: CO
Product: COC(=O)C(Cc1ccc(F)cc1)C(=O)OC
Reaction time: 0.5 h

Procedure:
To a solution of anhydrous methanol (250 mL) is added sodium metal (2.875 g, 0.125 mol) piecewise until the evolution of gas has deceased. Dimethyl malonate (16.5 g, 0.125 mol) is added dropwise and the mixture is stirred for 30 minutes. 4-Fluoro benzyl bromide (23.8 g, 0.126 mol) is added dropwise, and the reaction is refluxed for 2 hour. The majority of the solvent is removed under vacuum, and aqueous HCl is added. The solution is extracted with CHCl3, dried, and the solvent removed in vacuo. Distillation of the crude material under reduced pressure provides the desired compound which is used without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[Al](C)C.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([C:21](=[NH:22])[NH:9][C:8]2[CH:10]=[CH:11][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:19][CH:18]=1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline (7 g, 41 mmol) in toluene (400 mL), trimethylaluminum (2M solution in toluene, 30.5 mL, 61 mmol) was added over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 2.5 hours. A solution of 4-chlorobenzonitrile (11.3 g, 82 mmol) in toluene (200 mL) was added over 10 minutes and the reaction mixture was heated to 80-85° C. After 16 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride/methanol. The combined filtrates were concentrated in vacuo and the resulting yellowish solid was stirred with a mixture of hexane/ether (2/1, 1000 mL). The intermediate was filtered and washed with more of hexane/ether (2/1). The pale yellow solid 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (10.93 g, 86%) was used in the next reaction without further purification: mp (DSC) 191° C. Anal. Calc'd. for C14H13N2SO2Cl: C, 54.46, H, 4.24, N. 9.07. Found: C, 54.42, H, 4.30, N, 9.07.
Reaction SMILES: [F:1][C:2]([F:19])([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=1)[CH:3]([F:9])[O:4][C:5]([F:8])([F:7])[F:6].[C:20]([N:24]1[C:29](=[O:30])[C:28]([Cl:31])=[C:27](Cl)[CH:26]=[N:25]1)([CH3:23])([CH3:22])[CH3:21].[H-].[Na+]>CN(C)C=O.CCOCC>[C:20]([N:24]1[C:29](=[O:30])[C:28]([Cl:31])=[C:27]([O:16][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][C:2]([F:19])([F:1])[CH:3]([F:9])[O:4][C:5]([F:6])([F:7])[F:8])=[CH:12][CH:13]=2)[CH:26]=[N:25]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: OCc1ccc(OC(F)(F)C(F)OC(F)(F)F)cc1
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc(OCc2ccc(OC(F)(F)C(F)OC(F)(F)F)cc2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
1.16 g of 4-(1,1,2-trifluoro-2-trifluoromethoxy-ethoxy)-benzyl alcohol (Example 3) and, 15 minutes later, 0.95 g of 2-tert.-butyl-4,5-dichloro-3(2H)-pyridazinone are added to a suspension of 0.2 g of sodium hydride at 50% in 10 cc of dimethylformamide. The resulting reaction mixture is stirred for 1 hour at room temperature, is diluted with ether, is washed with diluted HCl and brine; the washed solution is thoroughly dehydrated, the solvent is evaporated off and the so obtained raw reaction product is chromatographed on silica gel with 9/1 hexane/ethyl acetate. 1.3 g of pure product is obtained. Melting point 68°-69° C.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:26])=O>>[CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([Cl:26])=[O:23])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: O=S(Cl)Cl
Product: CCCCCCCCc1ccc(-c2ccc(C(=O)Cl)cc2)cc1

Procedure:
After 4'-n-octylbiphenyl-4-carboxylic acid (3.2 g) and an excessive amount of thionyl chloride were heated under refluxing for 6 hours, unaltered thionyl chloride was distilled off to obtain 4'-n-octylbiphenyl-4-carboxylic acid chloride.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[C:5]([NH2:18])=[N:4][CH:3]=1.[C:19](N1C=CN=C1)(N1C=CN=C1)=[O:20]>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[NH:14][CH:13]=[CH:12]4)[C:19](=[O:20])[NH:18][C:5]2=[N:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ncc(Br)nc1Nc1ccc2[nH]ccc2c1
Solvent: C1CCOC1
Product: O=c1[nH]c2ncc(Br)nc2n1-c1ccc2[nH]ccc2c1
Temperature: 65 °C
Yield: 40.9 %

Procedure:
To a solution of 6-bromo-N2-(1H-indol-5-yl)pyrazine-2,3-diamine (0.450 g, 1.48 mmol) in THF (5 mL) was added carbonyldiimidazole (1.20 g, 7.40 mmol). The resulting mixture was heated at 65° C. for 48 hr, after which it was concentrated in vacuo and partitioned between EtOAc and H2O. The organic layer was separated, dried over MgSO4, filtered, and concentrated in vacuo to yield a residue that was purified via silica gel chromatography eluting with EtOAc to yield the title compound (0.20 g, 41%). HPLC retention time: 2.07 minutes; MS ESI (m/z): 330.2/332.2 (M+1)+, calc. 329.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][C:8]1[CH:9]=[C:10]([CH:14]2[CH2:23][C:22]([CH3:25])([CH3:24])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]#[N:27])[CH:20]=3)[NH:15]2)[CH:11]=[CH:12][CH:13]=1.N1C=CC=CC=1>ClCCl>[C:26]([C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]([C:10]1[CH:9]=[C:8]([NH:7][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:13]=[CH:12][CH:11]=1)[CH2:23][C:22]2([CH3:25])[CH3:24])#[N:27]
Reactant: CCS(=O)(=O)Cl
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C#N)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cccc(C2CC(C)(C)c3cc(C#N)ccc3N2)c1
Reaction time: 8 h
Yield: 60.1 %

Procedure:
Ethanesulfonyl chloride (104 mg, 0.81 mmol) was added dropwise to a mixture of 2-(3-amino-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (150 mg, 0.54 mmol) and pyridine (77 mg, 0.97 mmol) in dichloromethane (5 mL). The resultant mixture was allowed to stir overnight. The reaction mixture was washed by water, dried over magnesium sulfate. It was filtered and concentrated to provide the crude product. It was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=5:1) to afford ethanesulfonic acid [3-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide as off-white solid (120 mg, yield: 60.0%). MS (ESI+APCI) M+1=370.2.
Reaction SMILES: C[O:2][C:3](=[O:38])[C@@H:4]([N:11]1[C:15](=[O:16])[C:14]2([CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:18][CH2:17]2)[N:13]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Li+].CO>O>[CH2:25]([O:24][C:22]([N:19]1[CH2:18][CH2:17][C:14]2([N:13]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:12][N:11]([C@@H:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3]([OH:38])=[O:2])[C:15]2=[O:16])[CH2:21][CH2:20]1)=[O:23])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)[C@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(C(=O)OCc3ccccc3)CC2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)[C@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (S)-benzyl 3-(2-methoxy-2-oxo-1-phenylethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (2.16 g, 4.21 mmol, 1 equiv.) and lithium hydroxide (353 mg, 8.41 mmol, 2 equiv) in a 4:1 mixture of methanol and water (20 ml t/v) was stirred at ambient temperature for 16 hrs. The reaction was concentrated in vacuo and the mixture was partitioned between ethyl acetate and 10% citric acid. The organic layer was further washed with water and brine, dried over MgSO4, filtered and concentrated. The resulting residue was dried thoroughly to afford (S)-2-(8-(benzyloxycarbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetic acid as a white solid (2.05 g, quant); 1H NMR (400 MHz, DMSO-d6): δ 1.67 (t, 2H, J=12.4 and 10.4 Hz); 2.25-2.33 (m, 2H); 3.56 (m, 2H); 3.98-4.05 (m, 2H); 4.14 (d, 1H, J=4.4 Hz); 4.86 (d, 1H, J=5.2 Hz); 5.14 (m, 2H); 5.81 (s, 1H); 6.67 (d, 2H, J=7.6 Hz); 6.81 (t, 1H, J=6.8 and 7.6 Hz); 7.17 (dd, 2H, J=7.6 and 7.2 Hz); 7.32-7.45 (m, 10H); 13.5 (s, 1H); MS for C29H29N3O5 m/z 500.21 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([NH2:20])[CH:17]=[N:16][CH:15]=2)=[CH:10][N:9]=1.[CH3:23][N:24]1[C:32](=[O:33])[C:31]2[N:30]([C@@H:34]([CH3:38])[C:35](O)=[O:36])[CH:29]=[N:28][C:27]=2[N:26]([CH3:39])[C:25]1=[O:40].C1CCC(N=C=NC2CCCCC2)CC1.N1C=CC=CC=1>C(Cl)Cl>[CH3:23][N:24]1[C:32](=[O:33])[C:31]2[N:30]([C@@H:34]([CH3:38])[C:35]([NH:20][C:18]3[CH:17]=[N:16][CH:15]=[C:14]([C:11]4[CH:10]=[N:9][C:8]([N:4]5[CH2:5][CH2:6][CH2:7][C@H:3]5[C:2]([F:21])([F:1])[F:22])=[N:13][CH:12]=4)[N:19]=3)=[O:36])[CH:29]=[N:28][C:27]=2[N:26]([CH3:39])[C:25]1=[O:40]
Reactant: Nc1cncc(-c2cnc(N3CCC[C@H]3C(F)(F)F)nc2)n1
Reactant: C[C@@H](C(=O)O)n1cnc2c1c(=O)n(C)c(=O)n2C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H](C(=O)Nc1cncc(-c2cnc(N3CCC[C@H]3C(F)(F)F)nc2)n1)n1cnc2c1c(=O)n(C)c(=O)n2C
Reaction time: 0.08 h

Procedure:
A round bottom flask was charged with (S)-6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyrazin-2-amine (5.097 g, 16.43 mmol) and (S)-2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanoic acid (Intermediate 8) (4.97 g, 19.71 mmol). The reagents were suspended in DCM (Volume: 36.5 ml, Ratio: 4), sonicated and allowed to stir for 5 minutes. To the yellow heterogenous mixture was added DCC (5.76 g, 27.9 mmol) and finally pyridine (Volume: 18.25 ml, Ratio: 2) was added and the mixture was allowed to stir for 3 hours. The reaction mixture was diluted with CH2Cl2 and filtered over Celite®. The filtrate was then concentrated and redissolved in a minimal amount of and added dropwise to stirring hexanes to precipitate out crude 2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6-(2-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyrazin-2-yl)propanamide, which was dried overnight. The mixture of diasteromers was resolved using SFC purification to give the (S,S)-isomer in 2.58 g (retention time: 2.5 min, de: 98%); and the (R,S)-isomer in 0.208 g (retention time: 2.2 min, de: 99%); 1H NMR, (S,S)-isomer (300 MHz, DMSO-d6) δ 11.40 (s, 1H), 9.16 (d, J=3.5 Hz, 3H), 8.97 (s, 1H), 8.36 (s, 1H), 5.86 (d, J=7.3 Hz, 1H), 5.20-5.03 (m, 1H), 3.73 (t, J=6.5 Hz, 2H), 3.46 (s, 3H), 3.19 (s, 3H), 2.29-2.04 (m, 4H), 1.89 (d, J=7.3 Hz, 3H); m/z found [M+H]+=545.19
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=O.CN.CC(O)=O.[BH3-][C:19]#[N:20].[Na+]>CO>[CH3:19][NH:20][CH2:10][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: O=Cc1cc2ccccc2o1
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.2 %

Procedure:
To a stirred solution of 2-benzofurancarboxaldehyde (2.22 g, 15.2 mmole) in MeOH (5 mL) was added 2 M methylamine in MeOH (15 mL), HOAc (0.86 mL, 15 mmole), and NaBH3CN (1.0 g, 15.9 mmole). The reaction was stirred for 18 h at RT then concentrated under vacuum. The remaining residue was taken up in Et2O, and the solution was washed with 1 N NaOH then brine, dried (Na2SO4), and concentrated to dryness. Purification by flash chromatography on silica gel (5% (5% NH4OH in MeOH)/CHCl3) gave the title compound (1.23 g, 50%) as a pale yellow oil: MS (ES) m/e 162.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][CH:5]=2.[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[N:18]=[CH:17][CH:16]=1>CN1C(=O)CCC1.Cl.O1CCOCC1>[ClH:14].[Cl:25][C:21]1[CH:20]=[C:19]2[C:24]([C:15]([C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[CH:8]=4)[NH:3][C:2]=3[CH3:1])=[CH:16][CH:17]=[N:18]2)=[CH:23][CH:22]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1[nH]c2ccc([N+](=O)[O-])cc2c1-c1ccnc2cc(Cl)ccc12
Temperature: 160 °C
Yield: 95.6 %

Procedure:
A mixture of 2-methyl-5-nitroindole (1.34 g) and 4,7-dichloroquinoline (1.53 g) in NMP (1 ml) and 4M HCl in dioxane (0.1 ml) was heated at 145° C. for 2 hours and at 160° C. for 4 hours. After cooling the mixture triturated with ether and the solid collected to give the sub-title compound (2.72 g) as a green solid.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:11][CH2:12][CH2:13][CH3:14])[NH:7][C:8]=1[C:9]#[N:10])(=[O:3])[CH3:2].[CH2:15]([Mg]Br)[CH2:16]C>>[CH2:11]([C:6]1[NH:7][C:8]([C:9]#[N:10])=[C:4]([C:1](=[O:3])[CH2:2][CH2:15][CH3:16])[N:5]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCc1nc(C(C)=O)c(C#N)[nH]1
Reactant: CCC[Mg]Br
Product: CCCCc1nc(C(=O)CCC)c(C#N)[nH]1
Yield: 57.2 %

Procedure:
Following a procedure similar to that described in Preparation 24(i), but using propylmagnesium bromide instead of methylmagnesium bromide, the title compound, melting at 91°-92° C., was obtained in a 57.2% yield.
Reaction SMILES: C([O:5][C:6](=[O:12])[C@@H:7]([CH3:11])[C@@H:8]([NH2:10])[CH3:9])(C)(C)C.C[O:14][C:15]([C:17]1[N:18]=[C:19]([C:35]#[N:36])[C:20]2[C:25]([C:26]=1[OH:27])=[CH:24][CH:23]=[C:22]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:21]=2)=O.C(N(CC)CC)C>CCO>[C:35]([C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[C:22]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:21]=2)[C:26]([OH:27])=[C:17]([C:15]([NH:10][C@@H:8]([CH3:9])[C@H:7]([CH3:11])[C:6]([OH:5])=[O:12])=[O:14])[N:18]=1)#[N:36]
Reactant: C[C@H](N)[C@H](C)C(=O)OC(C)(C)C
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@H](NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)[C@H](C)C(=O)O
Temperature: 140 °C
Yield: 35.1 %

Procedure:
A mixture of (2S,3S)-3-amino-2-methyl-butyric acid tert-butyl ester (20 mg, 0.12 mmol), 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (25 mg, 0.078 mmol), and triethylamine (0.050 mL) in EtOH (2 mL) was heated in a microwave reactor at 140° C. for 6 h. The resulting mixture was concentrated to dryness, and the residue was re-dissolved in CH2Cl2 and passed through a plug of silica gel. After evaporating the solvent, the residue was dissolved in CH2Cl2 (3 mL) and treated with trifluoroacetic acid (2 mL) for 2 h. The mixture was concentrated in vacuo, and the resulting residue was taken up in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH ˜2 and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 11.1 mg of the title compound as a white solid. MS: (−) m/z 404.32 (M−1).
Reaction SMILES: [OH:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]=1[C:17]([NH:19][CH2:20][C:21]([O:23]CC)=[O:22])=[O:18].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br.C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)C=O>[OH:1][C:2]1[N:7]([CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:28]([O:27][CH3:26])[CH:29]=2)[C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]=1[C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18]
Reactant: COc1cccc(CBr)c1
Reactant: CCOC(=O)CNC(=O)c1c(O)[nH]c(=O)n(Cc2ccccc2)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(Cn2c(O)c(C(=O)NCC(=O)O)c(=O)n(Cc3ccccc3)c2=O)c1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 10.7 %

Procedure:
A mixture of ethyl N-{[6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycinate (example 11a, 369 mg, 1.06 mmoles), 3-methoxybenzyl bromide (163 uL, 1.17 mmoles) and sodium carbonate (330 mg, 3.1 mmoles) in dimethylformamide (6.0 mL) was stirred under argon at 100° C. for 2.5 hours. The mixture was cooled, poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The ester was hydrolysed by stirring in a mixture of ethanol (3 mL) and 1 molar sodium hydroxide solution (3 mL) for 3 hours. The mixture was acidified and extracted with ethyl acetate. Purification by preparative HPLC (acetonitrile-water-0.1% TFA, 20-100%) and crystallization from ethanol-water gave the title compound (50 mg, 11%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.10 (br. s., 1 H), 10.12 (t, 1 H), 7.14-7.47 (m, 6 H), 6.69-6.97 (m, 3 H), 5.00 (s, 2 H), 5.03 (s, 2 H), 4.13 (d, J=5.56 Hz, 2 H), 3.71 (s, 3 H).