Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.CN1CCOCC1.[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH2:45][NH2:46].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:46][CH2:45][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=1)=[O:5]
Reactant: NCc1ccccn1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCc1ccccn1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 41.3 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.031 mL, 0.278 mmol), pyridin-2-ylmethanamine (9.03 mg, 0.083 mmol), and BOP (36.9 mg, 0.083 mmol). This was stirred overnight and was then purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow rate=20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(pyridin-2-ylmethyl)acetamide (9.9 mg, 0.019 mmol, 40.5% yield): LCMS=522.0 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.47 (1H, dd, J=5.40, 1.88 Hz), 8.11-8.23 (2 H, m), 7.62-7.77 (5 H, m), 7.48-7.61 (3 H, m), 7.21-7.32 (2 H, m), 5.20 (1 H, s), 4.44-4.62 (2 H, m); Analytical LCMS: column: Mac-mod Halo C18, 4.6×50 mm, 2.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 90:10 acetonitrile:water with 0.05% TFA; Temperature: 45° C.; Gradient: 0-100% B over 4 minutes, flow rate=4 mL/min, product retention=2.1 min.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=3)=[C:8]([CH:15]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]([O:18]C)=[O:17])[N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1)#[N:2].[Li+].[OH-:34]>O1CCCC1.CO>[NH2:2][C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=3)=[C:8]([CH:15]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])[C:16]([OH:18])=[O:17])[N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1)=[O:34]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(C#N)cc2c(=O)n1C
Reactant: [OH-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3cc(C(N)=O)ccc23)cc1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
A solution of methyl [7-cyano-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl][(1,1-dimethylethyl)oxy]acetate (17 mg, 0.039 mmol) in tetrahydrofuran (THF) (0.600 mL) and methanol (0.6 mL) was treated with LiOH (0.118 mL, 0.236 mmol) and stirred at 50° C. for 2 hours. Additional LiOH (300 uL) was added and the reaction was stirred at 50° C. for 4 h, and then cooled to rt overnight. The mixture was concentrated and purified with reverse phase chromatography (20-100% MeCN/H2O-0.1% TFA, 12 min) to afford [7-(aminocarbonyl)-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl][(1,1-dimethylethyl)oxy]acetic acid (9.6 mg, 0.022 mmol, 56.0% yield) as white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.02 (s, 1 H), 8.22-8.10 (m, 1 H), 7.39-7.28 (m, 4 H), 7.25-7.15 (m, 1 H), 7.09-6.99 (m, 1 H), 5.39 (d, J=1.2 Hz, 1 H), 3.76 (s, 3 H), 2.38 (s, 3 H), 2.33 (s, 3 H), 1.08 (s, 4.5 H), 1.06 (s, 4.5 H); LCMS (m/z) ES+=437 (M+1).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:10]([CH2:13][C:14]1[CH:29]=[CH:28][C:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:16][CH:15]=1)(=[O:12])=[O:11].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH2:1]([NH:8][S:10]([CH2:13][C:14]1[CH:29]=[CH:28][C:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:16][CH:15]=1)(=[O:11])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(CS(=O)(=O)Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cc2ccc(CS(=O)(=O)NCc3ccccc3)cc2)cc1
Reaction time: 2 h

Procedure:
Benzylamine (0.3 mL) was added to a solution of 4-(4-chlorosulfonylmethyl-benzyl)-nitrobenzene (100 mg) in tetrahydrofuran (4 mL). The mixture was stirred for 2 hours, poured into dilute aqueous potassium carbonate, and extracted with dichloromethane (3×15 mL). Solvents were evaporated and the residue was chromatographed on silica gel, eluting with 2% acetone in dichloromethane, to give 4-(4-benzylaminosulfonylmethylbenzyl)-nitrobenzene (44 mg) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:16]1[O:17][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][N:20]=1)[CH3:15]>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:16]2[O:17][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][N:20]=2)[CH3:15])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CCOC(=O)C1CN=C([C@H](C)N)O1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)C1CN=C([C@H](C)NC(=O)Cc2cc(F)cc(F)c2)O1

Procedure:
Following General Procedure A and using 3,5-difluorophenylacetic acid (Aldrich) and (S)-2-(1-aminoethyl)-5(R,S)-ethoxycarbonyl-2-oxazoline (Example F), the title compound was prepared as a semisolid. The reaction was monitored by tlc (Rf=0.3 in 5% MeOH/CHCl3) and the product was purified by silica gel chromatography using 5% MeOH/CHCl3 as the eluent.
Reaction SMILES: [N:1]#[N:2].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([S:15]([NH:18][C@H:19]([C:27]([OH:29])=O)[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:26])[NH2:25])(=[O:17])=[O:16])[CH:9]=[CH:8]2.C(OCC)C.S(Cl)([Cl:37])=O>>[N:1]#[N:2].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([S:15]([NH:18][C@H:19]([C:27]([Cl:37])=[O:29])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:26])[NH2:25])(=[O:17])=[O:16])[CH:9]=[CH:8]2
Reactant: COc1ccc2cc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)ccc2c1
Reactant: O=S(Cl)Cl
Agent: N#N
Solvent: CCOCC
Product: COc1ccc2cc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)Cl)ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 2.5 g of N2 -(6-methoxy-2-naphthylsulfonyl)-L-arginine in 20 ml of thionyl chloride was stirred for 2 hours at room temperature. Addition of cold dry ethyl ether resulted in a precipitate which was collected by filtration and washed several times with dry ethyl ether to give N2 -(6-methoxy-2-naphthylsulfonyl)-L-arginyl chloride.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:16])[C@@H:6]([NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH2:7][CH3:8].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1>ClCCl>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[S:27])[NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:16])[C@H:6]([NH:9][C:10](=[O:15])[C:11]([F:14])([F:12])[F:13])[CH2:7][CH3:8])=[CH:21][CH:20]=1
Reactant: CC[C@H](NC(=O)C(F)(F)F)C(=O)NCCN
Reactant: COc1ccc(N=C=S)cc1
Solvent: ClCCl
Product: CC[C@@H](NC(=O)C(F)(F)F)C(=O)NCCNC(=S)Nc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (S)—N-(2-aminoethyl)-2-(2,2,2-trifluoroacetamido)butanamide (276.6 mg, ca, 1.10 mmol) in dichloromethane (10 mL) was added 4-methoxyphenyl isothiocyanate (120 μL, 0.868 mmol). and the resulting mixture was stirred for 72 h at room temperature. The resulting mixture was then concentrated to an oil, which was purified by column chromatography, eluting with 6% methanol in chloroform to yield (R)—N-(2-(3-(4-methoxyphenyl)thioureido)ethyl)-2-(2,2,2-trifluoroacetamido)butanamide as a solid.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[C:13]([C:14]2[CH:19]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:28])=[CH:23][N:22]=3)[C:17](=[O:35])[N:16]([CH3:36])[CH:15]=2)=[CH:12][CH:11]=[CH:10][C:9]=1[N:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42]([CH:47]3[CH2:49][CH2:48]3)[CH:43]=2)[C:38]1=[O:50])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH:47]1([C:42]2[CH:43]=[C:44]3[C:39](=[CH:40][CH:41]=2)[C:38](=[O:50])[N:37]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]4[CH:19]=[C:18]([NH:20][C:21]5[CH:26]=[CH:25][C:24]([C:27]([N:29]6[CH2:34][CH2:33][O:32][CH2:31][CH2:30]6)=[O:28])=[CH:23][N:22]=5)[C:17](=[O:35])[N:16]([CH3:36])[CH:15]=4)[C:8]=2[CH2:7][OH:6])[CH:46]=[CH:45]3)[CH2:48][CH2:49]1
Reactant: Cn1cc(-c2cccc(-n3ccc4cc(C5CC5)ccc4c3=O)c2C(C)(C)O[SiH2]C(C)(C)C)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cn1cc(-c2cccc(-n3ccc4cc(C5CC5)ccc4c3=O)c2CO)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(2-(tert-Butyl-dimethyl-silanyloxymethyl)-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-6-cyclopropyl-2H-isoquinolin-1-one (56 mg, 0.078 mmol) was dissolved in 3 mL anhydrous THF. Added a 1.0 M solution of tetrabutylammonium fluoride (466 μL, 466 mmol) in THF and stirred at room temperature for 15 min. Partitioned the reaction mixture between 8 mL of water and 10 mL of CH2Cl2 and separated phases. Washed the organic phase with 8 mL of 1.0 M KHSO4 and 8 mL of saturated aqueous NaHCO3. Dried over Na2SO4 and concentrated in vacuo. Purified by C18 reverse phase flash chromatography (gradient elution, 10 to 95% acetonitrile +0.1% TFA/water +0.1% TFA). Added 1 mL of saturated NaHCO3 to the pooled product fractions and concentrated in vacuo. Extracted the remaining aqueous mixture with 2×10 mL CH2Cl2, dried over Na2SO4, and concentrated in vacuo to obtain 6-Cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one as an off-white solid. (29 mg, 0.048 mmol). MS (ESI) 604 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2[O:13][CH:14]=[N:15][N:16]=2)=[C:10]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[I-].[Li+]>N1C=CC=CC=1>[Cl:1][C:2]1[C:11]([C:12]2[O:13][CH:14]=[N:15][N:16]=2)=[C:10]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(-c2nnco2)c1Cl
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1-c1nnco1
Yield: 84.3 %

Procedure:
At reflux temperature, 1.5 g (4.7 mmol) of methyl 2-chloro-4-methylsulfonyl-3-(1,3,4-oxadiazol-2-yl)benzoate in 50 ml of pyridine were added dropwise to 2.5 g (18.9 mmol) of lithium iodide in 50 ml of pyridine, and the mixture was heated under reflux until the reaction had gone to completion. The mixture was cooled, the solvent was removed, the residue was taken up in water, insoluble components were filtered off and the mixture was acidified using hydrochloric acid and extracted with methylene chloride or ethyl acetate. The combined organic phases were dried and concentrated. 1.2 g (86% of theory) of 2-chloro-4-methylsulfonyl-3-(1,3,4-oxadiazol-2-yl)benzoic acid were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:19]([OH:20])=[CH:18][C:5]2[C@H:6]([C:12]3[CH2:16][CH2:15][CH2:14][C:13]=3[CH3:17])[CH2:7][N:8]([CH3:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl>>[Cl:1][C:2]1[C:19]([OH:20])=[CH:18][C:5]2[C@H:6]([C:12]3[CH2:16][CH2:15][CH2:14][CH2:17][CH:13]=3)[CH2:7][N:8]([CH3:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: CC1=C([C@@H]2CN(C)CCc3cc(Cl)c(O)cc32)CCC1
Agent: Cl
Product: CN1CCc2cc(Cl)c(O)cc2[C@H](C2=CCCCC2)C1

Procedure:
(S)-7-chloro-8-hydroxy-3-methyl-(2-methyl-1-cyclopentenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. of hydrochloride 249-251° C. (dec.);
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:25]=[CH:24][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=1[OH:23])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN>CO.C1COCC1.[Ni]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11](=[O:12])[C:10]2[CH:24]=[CH:25][C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:27][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:15]([OH:23])[CH:16]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(NC(=O)c2ccc(OCc3ccccc3)cc2OCc2ccccc2)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
Compound 39 (470 mg, 1 mmol) was dissolved in MeOH (15 mL) and THF (15 mL). Raney Nickel (50% slurry in water) (2 mL) was added to the reaction mixture followed by anhydrous hydrazine (1 mL). The reaction mixture was stirred at room temperature for 30 minutes until the bubbling was stopped. The solid was filtered off through Celite under reduced pressure and washed with MeOH. The solvent was removed under reduced pressure. Liquid-liquid extraction was performed using CHCl3 (15 mL) and H2O (8 mL×2). The organic layer was dried over MgSO4, filtered and concentrated to give the compound 40 (263.8 mg, 59.9% crude yield) LC-MS (ESI): m/e=441.1 [M+1]+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:21]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: Cc1ccccc1C(=O)Cl
Product: Cc1ccccc1C(=O)Nc1cccc(C(=O)C2CCN(C)CC2)c1
Yield: 94.9 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and 2-methylbenzoyl chloride (90 μl, 0.687 mmol), 73.1 mg (95%) of the title compound were recovered.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.[Cl:15]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:15][C:3]1[CH:4]=[CH:5][C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[N:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)C(=O)Nc1cccc(Cl)n1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)Nc1ccc(Cl)c(Cl)n1
Temperature: 25 °C
Yield: 66 %

Procedure:
To a solution of N-(6-chloropyridin-2-yl)pivalamide, synthesized as in J. Org. Chem 2005, 70, 1771, (1.02 g, 4.80 mmol) in chloroform (25 mL) was added 1-chloropyrrolidine-2,5-dione (0.62 g, 4.67 mmol) and the mixture was refluxed in an oil bath for 3 hrs. It was allowed to cool to room temperature overnight. The reaction mixture was evaporated in vacuo and re-dissolved in DMF (15 mL). Another 480 mg 1-chloropyrrolidine-2,5-dione was added and the resulting solution was heated overnight in an oil bath at 95-100°, then cooled again to room temperature. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The aqueous phase was washed twice more with ethyl acetate and the combined organic phases were washed with brine, dried over magnesium sulfate, and evaporated in vacuo. TLC (10% ethyl acetate/hexane) showed a robust spot at Rf 0.6 with smaller spots at Rf 0.4 and 0.2. The material was subjected to the Biotage in 5-10% ethyl acetate/hexane, collecting the Rf 0.6 fraction to give 790 mg (66%) white solid, N-(5,6-dichloropyridin-2-yl)pivalamide. 1H NMR (500 MHz, CDCl3) δ ppm 8.17 (s, 1 H), 7.96 (s, 1 H), 7.72 (s, 1 H), 1.31 (s, 10 H). MS (LC/MS) R.T.=1.85; [M+H]+=248.8.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C:11]1[C:19]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[CH3:28])=[C:18]([F:29])[C:14]2[NH:15][CH:16]=[N:17][C:13]=2[CH:12]=1)=[O:10]>Cl.CO.C(O)C>[OH:7][NH:8][C:9]([C:11]1[C:19]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[CH3:28])=[C:18]([F:29])[C:14]2[NH:15][CH:16]=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: Cc1cc(I)ccc1Nc1c(C(=O)NOC2CCCCO2)cc2nc[nH]c2c1F
Agent: Cl
Solvent: CCO
Solvent: CO
Product: Cc1cc(I)ccc1Nc1c(C(=O)NO)cc2nc[nH]c2c1F

Procedure:
The compound 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid O-(tetrahydro-2H-pyran-2-yl)-oxyamide is dissolved in an appropriate hydrogen chloride-saturated solvent like methanol or ethanol. Once homogeneous, the solution is concentrated in vacuo to give the desired product. The product may be triturated with an appropriate solvent like chloroform or dichloromethane if further purification is necessary.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:20][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([NH2:19])=[CH:11][C:12]=3[C:13]3([O:18][CH2:17][CH2:16][CH2:15][O:14]3)[C:5]2=[N:4][CH2:3]1.CCN(CC)CC.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH3:1][C:2]1([CH3:21])[CH2:20][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([NH:19][S:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:37])=[O:36])=[CH:11][C:12]=3[C:13]3([O:18][CH2:17][CH2:16][CH2:15][O:14]3)[C:5]2=[N:4][CH2:3]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC1(C)CN=C2N(C1)c1ccc(N)cc1C21OCCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CN=C2N(C1)c1ccc(NS(=O)(=O)c3ccccc3)cc1C21OCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
To a solution of 3′,3′-dimethyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indol]-8′amine (0.060 g 0.21 mmol, 1 eq) in CH2Cl2 (2 mL) was added Et3N (0.060 mL, 0.43 mmol, 2.05 eq) and benzenesulfonyl chloride (0.030 mL, 0.23 mmol, 1.07 eq). The reaction was stirred at rt 1 hour and concentrated. The crude residue purified by column chromatography using acetone/hexanes (30/70) as an eluent to give the title compound as a white solid (0.064 g, 71%). NMR (400 Mz, DMSO-d6): consistent
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27](O)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.[N:32]1([C@H:37]2[CH2:41][CH2:40][NH:39][CH2:38]2)[CH:36]=[CH:35][N:34]=[CH:33]1>C(#N)C>[CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=3)=[O:15])[C@H:11]([C:27]([N:39]3[CH2:40][CH2:41][C@H:37]([N:32]4[CH:36]=[CH:35][N:34]=[CH:33]4)[CH2:38]3)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: c1cn([C@H]2CCNC2)cn1
Solvent: CC#N
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC[C@H](n4ccnc4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
1.09 g of N,N'-carbonyldiimidazole were added to a solution of 2.5 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid in 25 ml of dry acetonitrile, and the resulting mixture stirred at room temperature for 30 minutes. A solution of 850 mg of (3S)-3-(imidazol-1-yl)pyrrolidine in 5 ml of dry acetonitrile was then added, and the mixture was stirred at room temperature for 2 hours and then at 40° C. for a further 4 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was purified by reverse phase column chromatography through 200 ml of Cosmo Sil 75C18 -PREP (a trade mark for a product of Nacalai Tesque), using a gradient elution method, with mixtures of acetonitrile and water ranging from 50:50 to 55:45 by volume as the eluent. Those fractions containing the title compound were combined and concentrated by evaporation under reduced pressure, to give 2.54 g of the title compound, as a powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:25]3[CH2:30][CH2:29][C@H:28]([CH2:31]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:27][CH2:26]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[CH:5]=[CH:6][N:7]=1.[NH:43]1[CH2:46][CH2:45][CH2:44]1>C1COCC1>[N:43]1([CH2:31][C@H:28]2[CH2:29][CH2:30][C@H:25]([C:8]3[N:4]4[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]4=[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH:12]=4)[N:9]=3)[CH2:26][CH2:27]2)[CH2:46][CH2:45][CH2:44]1
Reactant: C1CNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](c3nc(-c4cccc(OCc5ccccc5)c4)c4c(N)nccn43)CC2)cc1
Solvent: C1CCOC1
Product: Nc1nccn2c1c(-c1cccc(OCc3ccccc3)c1)nc2[C@H]1CC[C@H](CN2CCC2)CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
General procedure to Examples 33 and 34: A THF solution (3 mL) of trans-toluene-4-sulfonic acid 4-[8-amino-1-(3-benzyloxy-phenyl)imidazo[1,5-a]pyrazin-3-yl]-cyclohexylmethyl ester (200 mg, 0.34 mmol) in a sealed tube was charged with azetidine (8.92 mmol, 510 mg) and stirred at 50° C. for 24 h. The reaction mixture concentrated in vacuo and partitioned b/w EtOAc and sat. NaHCO3. The organic layer was washed with sat. NaHCO3 (2×), water (1×), brine (1×), dried over Na2SO4, filtered, and concentrated to a yellow oil. The crude material was purified by silica gel column chromatography [Jones Flashmaster, 5 g/25 mL cartridge, eluting with CH2Cl2 to 2% ˜7 N NH3 in MeOH/CH2Cl2] to afford trans-3-(4-azetidin-1-ylmethyl-cyclohexyl)-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-8-ylamine as a white solid (130 mg, 82%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[CH3:8].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1/[CH:8]=[CH:16]/[N:17]([CH3:19])[CH3:18]
Reactant: COc1ncc([N+](=O)[O-])c(C)c1Br
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ncc([N+](=O)[O-])c(/C=C/N(C)C)c1Br
Temperature: 90 °C

Procedure:
To a solution of 3-Bromo-2-methoxy-4-methyl-5-nitro-pyridine (3.00 g, 12.1 mmol) in DMF (0.6M) was added via syringe N,N-dimethylformamide-dimethylacetal (3.0 mL, 22.4 mmol, 1.8 eq) in a fast dropwise manner. The solution was heated for 2 hr at 90° C., cooled to 23° C., then diluted with Ethyl Acetate (200 mL). The washed reaction mixture was washed with water, brine, dried (Na2SO4), and concentrated giving [(E)-2-(3-Bromo-2-methoxy-5-nitro-pyridin-4-yl)-vinyl]-dimethyl-amine as a red solid which was used without further purification (3.45 g, 10.9 mmol, 89%). MS ESI m/z 304.2 (M+2H)+. 1NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.03 (d, J=13.5 Hz, 1H), 5.30 (d, J=13.5 Hz, 1H), 4.05 (s, 3H), 2.97 (s, 3H).
Reaction SMILES: [CH2:1]([N:4]([C:14](=[O:25])[CH2:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=1[CH3:24])[C:5]1[N:6]=[CH:7][S:8][C:9]=1[C:10]([O:12]C)=O)[CH:2]=[CH2:3].[H-].[Na+].O>CN(C)C=O>[CH2:1]([N:4]1[C:14](=[O:25])[C:15]([C:16]2[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])=[C:10]([OH:12])[C:9]2[S:8][CH:7]=[N:6][C:5]1=2)[CH:2]=[CH2:3]
Reactant: C=CCN(C(=O)Cc1c(C)cc(C)cc1C)c1ncsc1C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(=O)c(-c2c(C)cc(C)cc2C)c(O)c2scnc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
1.8 g (5 mmol) of methyl 4-[allyl(mesitylacetyl)amino]-1,3-thiazole-5-carboxylate were initially charged in 5 ml of N,N-dimethylformamide and cooled to 0° C. 1.5 eq of sodium hydride (60%) were added and allowed to warm up gradually to room temperature (RT). After stirring at RT for one hour, 5 ml of water were added and the mixture was acidified to pH 1-2. The precipitate formed was filtered off with suction. 1.5 g of inventive compound I-a-2 were thus obtained.