Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][NH2:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[C:14]1[C:15]([NH2:21])=[N:16][CH:17]=[C:18]([Br:20])[N:19]=1.C(N(C(C)C)CC)(C)C>ClCCl.C(O)C>[Br:20][C:18]1[N:19]=[C:14]([NH:12][CH2:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)[C:15]([NH2:21])=[N:16][CH:17]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: NCc1ccc2ncccc2c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1ncc(Br)nc1NCc1ccc2ncccc2c1
Temperature: 130 °C
Yield: 48 %

Procedure:
A mixture of quinolin-6-ylmethanamine (13 g, 82 mmol), 3,5-dibromopyrazin-2-amine (21 g, 82 mmol) and di-isopropylethylamine (16 mL, 89 mmol) was heated to 130° C. for five hours. The reaction was diluted with dichloromethane:ethanol (9:1) and the resulting suspension was filtered. The precipitate was washed sequentially with water and ether and air dried to afford 6-bromo-N2-(quinolin-6-ylmethyl)pyrazine-2,3-diamine (13 g, 49%).
Reaction SMILES: [C:1]([CH2:4][CH:5]([CH3:10])[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[NH2:2].[CH:11](N)=[O:12].C[O-].[Na+].S(=O)(=O)(O)O>>[CH3:10][CH:5]([CH2:4][C:1]([O:12][CH3:11])=[O:3])[C:6]([O:8][CH3:9])=[O:7].[CH:1]([NH2:2])=[O:3]
Reactant: COC(=O)C(C)CC(N)=O
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: NC=O
Product: COC(=O)CC(C)C(=O)OC

Procedure:
A one L stainless steel-made autoclave equipped with a stirrer was charged with 72.5 g of the methyl 3-carbamoylisobutyrate which had been obtained in the preceding item (2), 180 g of methyl formate, 96 g of methanol and 1.1 g of sodium methylate to proceed with heating reaction at 60° C. for 2 hours. The reaction product was cooled and then analyzed. As a result, the conversion of the methyl 3-carbamoylisobutyrate was 83.2% and, there were obtained dimethyl methylsuccinate at a selectivity of 99.8% based on the reacted methyl 3-carbamoylisobutyrate, and formamide at a selectivity of 98.4% based on the same. The sodium methylate in the reaction liquid was neutralized with sulfuric acid, and subsequently the reaction liquid was distilled by a conventional method. As a result, methyl formate and methanol were recovered and there were obtained 60 g of dimethyl methylsuccinate with at least 99% purity and 16 g of formamide with 99% purity. The recovery of these substances inclusive of an intermediate fraction was quantitative, respectively.
Reaction SMILES: C(OC(=O)[N:7]([C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1)[C:8]1[C:9]2[N:10]([CH:23]=[CH:24][N:25]=2)[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:12][N:13]=1)(C)(C)C.Br[C:40]1[CH:45]=[C:44]([CH3:46])[N:43]=[C:42]([O:47][Si](C(C)(C)C)(C)C)[CH:41]=1.CC([O-])=O.[K+]>O1CCOCC1>[CH3:46][C:44]1[NH:43][C:42](=[O:47])[CH:41]=[C:40]([C:11]2[N:10]3[CH:23]=[CH:24][N:25]=[C:9]3[C:8]([NH:7][C:26]3[CH:27]=[CH:28][C:29]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[CH:30][CH:31]=3)=[N:13][CH:12]=2)[CH:45]=1
Reactant: CC(C)(C)OC(=O)N(c1ccc(N2CCOCC2)cc1)c1ncc(B2OC(C)(C)C(C)(C)O2)n2ccnc12
Reactant: Cc1cc(Br)cc(O[Si](C)(C)C(C)(C)C)n1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc(-c2cnc(Nc3ccc(N4CCOCC4)cc3)c3nccn23)cc(=O)[nH]1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Half of the solution prepared in Step 3 and 4-bromo-2-(tert-butyldimethylsilyloxy)-6-methylpyridine (30 mg, 0.10 mmol) are mixed and diluted with dioxane (0.15 mL). KOAc (15 mg, 0.15 mmol) and Pd(dppf)Cl2DCM (2 mg, 0.0025 mmol) are added and the system is flushed with N2 and heated at 80° C. for 2.5 h. The mixture is cooled to rt, diluted with DCM (5 mL) and MeOH (1 mL) and filtered through celite. The solvents are evaporated, the residue is suspended in DCM (2 mL) and TFA (0.5 mL) is added, causing the solid to dissolve. The solution is stirred at rt overnight and the solvents are then evaporated. The residue is purified by preparative HPLC to afford the title compound as a yellow solid. LCMS: Rt=0.84 min (100%), m/z (ESI) 403 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[C@H:16]3[CH2:19][C@H:20]([F:22])[CH2:21][N:15]3[C:14]2=[O:23])[C:10]([F:24])=[CH:9][C:8]=1[Cl:25])(=[O:5])=[O:4].N1C=CC=CC=1.Cl[C:33]([O:35][CH3:36])=[O:34]>ClCCl>[Cl:25][C:8]1[CH:9]=[C:10]([F:24])[C:11]([N:13]2[C:17](=[O:18])[C@H:16]3[CH2:19][C@H:20]([F:22])[CH2:21][N:15]3[C:14]2=[O:23])=[CH:12][C:7]=1[N:6]([S:3]([CH2:2][Cl:1])(=[O:5])=[O:4])[C:33](=[O:34])[O:35][CH3:36]
Reactant: O=C1[C@H]2C[C@H](F)CN2C(=O)N1c1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)N(c1cc(N2C(=O)[C@H]3C[C@H](F)CN3C2=O)c(F)cc1Cl)S(=O)(=O)CCl

Procedure:
To a mixture of the title compound of Example 1, Step H (0.32 g, 0.7 mmol) and pyridine (0.5 mL) in dichloromethane (5 mL) was added a solution of methyl chloroformate (0.09 g, 0.95 mmol) in dichloromethane (1 mL) at room temperature. After completion of the reaction (2 h), the solvents were removed in vacuo and the title compound of Step A, a compound of this invention, was isolated by flash chromatography (0.31 g, 95%) as a white solid melting at 108-115° C. 1H NMR (CDCl3) δ 7.40 (m, 2H), 5.42 (m, 1H), 5.36 (dd, 1H), 4.92 (dd, 1H), 4.60 (m, 1H), 4.04 (m, 1H), 3.82 (s, 3H), 3.60 (dd, 1H), 2.64 (m, 1H), 2.02 (m, 1H).
Reaction SMILES: [CH2:1]=[C:2]1[C@@H:7]([CH2:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([Br:17])=[CH:11][C:10]=2[OH:18])[C:6]([CH3:20])([CH3:19])[CH2:5][CH2:4][C:3]1=[O:21].[CH3:22][Li]>C1COCC1.CCOCC>[OH:21][C@@:3]1([CH3:22])[CH2:4][CH2:5][C:6]([CH3:19])([CH3:20])[C@H:7]([CH2:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([Br:17])=[CH:11][C:10]=2[OH:18])[C:2]1=[CH2:1]
Reactant: C=C1C(=O)CCC(C)(C)[C@@H]1Cc1cc(OC)c(Br)cc1O
Reactant: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C1[C@@H](Cc2cc(OC)c(Br)cc2O)C(C)(C)CC[C@]1(C)O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a flame-dried 50 mL round-bottomed flask containing a solution of (3S)-2-methylidene-3-(2-hydroxy-4'-bromo-5'-methoxyphenyl)methyl-4,4-dimethylcyclohexan-1-one (61) (150.0 mg, 0.322 mmol) in 15 mL THF at -70° C. under nitrogen atmosphere was added methyllithium (0.60 mL of a 1.40M solution in ether, 0.840 mmol, 2.61 equiv), and the mixture was allowed to stir for 5 min before quenching with saturated aqueous NH4C1. Upon warming to room temperature, the reaction mixture was extracted with ethyl acetate, and the organic phase was washed with brine, dried over Na2SO4, and concentrated under diminished pressure gave a 3:1 (1R,3S: 1S,3S) mixture of the diastereomeric tertiary hydroxyls. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, gradient elution) afforded 28 mg (18%) of the less polar, minor 1S,3S isomer (63), along with 88 mg (57%) of the more polar, major 1R,3S isomer (62), as well as 30.2 mg (20%) recovered starting material. The diastereomeric alcohols were then independently converted to the corresponding free phenols in the usual manner, providing the trans, 1R,3S isomer (62) 1H NMR (400MHz, CDCl3) δ0.84 and 1.04 (2s, 2×3 H, geminal-CH3 's), 1.39 (s, 3H, 5-CH3), 2.43 (br dd, 1H, J-- 11.3, 2.9 Hz, 3-H), 2.72 and 2.85 (d of ABq, 2H, JAB =16.1 Hz, JA =3.1 Hz, JB =11.5 Hz, benzylic-CH2) 3.77 (s, 3H, OCH3), 4.57 and 5.16 (2s, 2×1H, methylidene-CH2), 6.63 (s, 1H, 6'-H), 6.93 ppm (s, 1H, 3'-H); and the cis, 1S,3S isomer (63) 1H NMR (400MHz, CDCl3) δ0.77 and 1.08 (2s, 2×3H, geminal-CH3 's), 1.36 (s, 3H, 5-CH3), 2.65 and 2.82 (d of ABq, 2H, JAB =16.0 Hz, JA =3.0 Hz, JB =11.8 Hz, benzylic-CH2), 2.97 (br dd, 1H, J=11.7, 2.5 Hz, 3-H), 3.79 (s, 3H, OCH3), 4.64 and 4.96 (2s, 2×1H, methylidene-CH2), 6.73 (s, 1H, 6'-H), 6.92 ppm (s, 1H, 3'-H). [Compound 63 is hereinafter also referred to as COMPOUND "J" or 120286, and Compound 62 is hereinafter also referred to as COMPOUND "P" or 120273] ##STR12##
Reaction SMILES: Cl[C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([Cl:8])=[CH:6][N:7]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[Cl:8][C:5]1[N:4]=[C:3]([C:9]#[N:10])[C:2]([O:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[N:7][CH:6]=1
Reactant: N#Cc1nc(Cl)cnc1Cl
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2ncc(Cl)nc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
In 15 ml of dimethylformamide was dissolved 1.5 g of 3,6-dichloro-2-pyrazinecarbonitrile. After adding 1.2 g of 4-methoxyphenol and 1.8 g of potassium carbonate, the mixture thus obtained was stirred at room temperature for 30 minutes. A mixture of 20 mL of ethyl acetate and 60 mL of water was added to the reaction mixture, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent: n-hexane:ethyl acetate=5:1] to obtain 2.1 g of 6-chloro-3-(4-methoxyphenoxy)-2-pyrazinecarbonitrile as a yellow-colored solid product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1O>>[C:15]1([NH:14][C:4](=[O:5])[C:3]2[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=2[F:1])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Product: O=C(Nc1ccccc1)c1cc([N+](=O)[O-])ccc1F

Procedure:
Prepared by the method of Example 15b), from 2-fluoro-5-nitrobenzoylchloride (2.23 g, 11.0 mmol) and 2-aminophenol (1.20 g, 11.0 mmol) the subtitle compound was obtained (2.89 g, 91%). 1H NMR (DMSO) δ 10.00(s, 1H), 9.75(d, 1H), 8.62(m, 1H), 8.46(m, 1H), 7.96(d, 1H), 7.67(t, 1H), 7.03(t, 1H), 6.94(d, 1H), 6.85(t, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:13]=1)[C:7](N(OC)C)=[O:8].[CH3:14][Mg+].[Br-]>C1COCC1>[Br:1][C:2]1[CH:13]=[C:6]([C:7](=[O:8])[CH3:14])[CH:5]=[N:4][CH:3]=1
Reactant: C[Mg+]
Reactant: CON(C)C(=O)c1cncc(Br)c1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To a solution of 5-bromo-N-methoxy-N-methyl-nicotinamide (2.08 g, 8.5 mmol) in THF (20 mL) was added MeMgBr (1.52 g, 12.75 mmol) at −78° C. After the addition, the reaction mixture was stirred at room temperature for 2 hours before quenching with water. After extraction with EtOAC, the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was then purified by flash column chromatography to afford the title compound (1.5 g, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7](=[O:14])[CH2:6]2.[C:15]([O:18][C:19](=O)C)(=O)C.COC(OC)OC>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15][O:18][CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)CC(=O)NC2=O
Solvent: CN(C)C=O
Solvent: COC(OC)OC
Product: COC=C1C(=O)NC(=O)c2ccc(OC)cc21

Procedure:
A mixture of 6-methoxy-4H-isoquinoline-1,3-dione (400 mg, 2.1 mmole), 8 mL of a 4:1 mixture of acetic anhydride and N,N-dimethylformamide and trimethylorthoformate (1.7 mL, 15.5 mmole) is stirred and heated to reflux. After 30 minutes the solvents are removed, the residue treated with hexane-ethyl acetate, the solid collected by filtration, washed with fresh hexane-ethyl acetate and dried to give a yellow solid, 317 mg, (65%), mp 245-7° C., MS (ESI): m/z 234.1 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([SH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.F[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.Cl>O.CN(C=O)C>[CH2:7]([S:14][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: SCc1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(SCc2ccccc2)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a stirred mixture of cesium carbonate (12.81 g, 39.33 mmol), benzyl mercaptan (4.7 mL, 39 mmol), and N,N,-dimethylformamide (80 mL) was added 4-fluorobenzaldehyde, slowly over several minutes. The reaction mixture was stirred at 40° C. overnight. The reaction mixture was cooled to room temperature, then diluted with water (500 mL). The resulting mixture was acidified to pH 4 using 1 N aqueous HCl, then extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and concentrated. A solution of the crude product and dichloromethane was concentrated over silica gel, and the resulting silica gel supported crude product was loaded onto an Analogix SuperFlash™ column. Flash chromatography (100% hexanes -15% ethyl acetate in hexanes) afforded 7.70 g (90%) of 4-(benzylsulfanyl)-benzaldehyde as a slightly pink solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[C:14]3[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:29](OCC)(=[O:31])C.CCCCCC>C(Cl)(Cl)Cl>[CH:29]([C:18]1[C:13]2[O:12][CH2:11][C@H:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]=1[CH3:19])=[O:31]
Reactant: CCOC(C)=O
Reactant: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Yield: 83 %

Procedure:
Using (+)-N-((3R)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 37, the title compound was synthesized in the same manner as in Example 20. Yield: 83%. Melting point: 179-180° C. (ethyl acetate-hexane). [α]D20=−25.8° (c=0.48, chloroform).
Reaction SMILES: C(Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.ICCCCC.[CH3:15][C:16]1[N:17]=[C:18]([N:26]2[CH2:30][CH2:29][NH:28][C:27]2=[O:31])[S:19][C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH3:15][C:16]1[N:17]=[C:18]([N:26]2[CH2:30][CH2:29][N:28]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:2])[C:27]2=[O:31])[S:19][C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: BrCc1ccccc1
Solvent: CCCCCI
Product: CCCCCN1CCN(c2nc(C)c(C(=O)OCC)s2)C1=O
Yield: 69 %

Procedure:
Following the procedure as described in Example 5, making variations to replace benzyl bromide with 1-iodopentane to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 69% yield: NMR (300 MHZ, CDCl3) δ 4.23 (q, J=7.2 Hz, 2H), 4.11-3.87 (m, 2H), 3.64-3.43 (m, 2H), 3.26 (t, J=7.5 Hz, 2H), 2.63 (s, 3H), 1.61-1.18 (m, 9H), 0.74 (t, J=7.2 Hz, 3H); MS (ES+) m/z 326.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]2[CH2:17][CH2:16][C:15](Br)([Br:18])[C@@H:14]2[C:20]2[CH:25]=[CH:24][C:23]([CH:26]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=2)=[CH:8][CH:9]=1)=[O:4].C(N=C(N(C)C)N(C)C)(C)(C)C.Cl>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]2[CH2:17][CH2:16][C:15]([Br:18])=[C:14]2[C:20]2[CH:21]=[CH:22][C:23]([CH:26]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:24][CH:25]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: CCCCCC(OCc1ccc(OC)cc1)c1ccc([C@@H]2[C@@H](CCCc3ccc(C(=O)OC)s3)CCC2(Br)Br)cc1
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Agent: Cl
Solvent: ClCCCl
Product: CCCCCC(OCc1ccc(OC)cc1)c1ccc(C2=C(Br)CC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Reaction time: 72 h

Procedure:
A solution of dibromide 3 (52 mg, 0.074 mmol) and 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG, 0.8 mL) in 1,2-dichloroethane (2 mL) was stirred at room temperature. After 3 days, 1 M HCl was added and the mixture was extracted with CH2Cl2 (3×25 mL). The combined dichloromethane solution was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (0%→20% ethyl acetate/hexanes) gave compound 5a contaminated with 15% of the alkene regioisomer 5b as an inseparable mixture (45 mg, 97%).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14](Cl)([Cl:16])=[O:15]>>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([Cl:16])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(Cl)Cl
Product: O=C(Cl)N1CCC(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
4-Benzylpiperidine (0.5 g, 2.86 mmol) was added to a mixture of phosgene (3.8 ml of 20% phosgene in toluene solution, 7.13 mmol). The mixture was stirred at 0° C. for 1 hour. The reaction mixture was partitioned between water (25 ml) and ethyl acetate (2×25 ml). The organic phase was washed with 1N HCl (1×40 ml), saturated sodium chloride (1×50 ml), dried over sodium sulfate and concentrated to give a yellow oil. Purification by flash column chromatography (silica gel, 0-10% ethyl acetate/hexane) gave 0.47 g of title product. IR (film) 1733.1 cm−1.
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]2)[C:9]=1[C:42]([O:44]CC)=[CH2:43].[ClH:57]>O1CCOCC1.O>[NH2:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]2)[C:9]=1[C:42](=[O:44])[CH3:43].[ClH:57]
Reactant: C=C(OCC)c1c(C2CCN(C(=O)OC(C)(C)C)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)c1c(C2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(1-ethoxyvinyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (11.5 g, 14.4 mmol) in dioxane (60 mL) was added 4M HCl in water (14.4 mL) at 0° C. After stirring for 30 min at 0° C., the reaction mixture was allowed to warm to rt in 1.5 hours. 4M HCl in dioxane (10 mL) was added. The reaction mixture was stirred at rt overnight. Solvent was removed in vacuo to get the desired product as an HCl salt (6.97 g).
Reaction SMILES: F[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].O.[NH2:22][NH2:23]>C(O)C>[NH:22]([C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])[NH2:23]
Reactant: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.1 %

Procedure:
2-fluoroadenosine (4 g, 14 mmol) was dissolved in 100 mL ethanol in a 300 mL three-necked flask. Hydrazine hydrate (4.1 mL, 6 equivalents, 84 mmol) was added and the mixture was heated to reflux for 1 hour. The reaction mixture was allowed to cool to room temperature and stirred overnight (16 hours). The resulting white precipitate was isolated by filtration and dried in oven at 40° C. overnight to afford 2-hydrazinoadenosine (yield: 94%, 3.5 g, 96% purity).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][N:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17](=[O:24])[NH:16][C:15]1=[O:25].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N:16]2[C:17](=[O:24])[CH:18]=[C:19]([C:20]([F:22])([F:23])[F:21])[N:14]([CH3:13])[C:15]2=[O:25])[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Cn1c(C(F)(F)F)cc(=O)[nH]c1=O
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
Into 10 ml of dimethylsulfoxide was dissolved 1.77 g of 2,4,5-trifluoronitrobenzene and 1.94 g of 3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydro pyrimidine. After adding 1.52 g of anhydrous potassium carbonate at room temperature, the mixture was stirred at 80° C. for 1 hour. The reaction solution was cooled to room temperature, and then the solution was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica-gel column chromatography to give 1.51 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene.
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([OH:9])[CH2:2]1.C(N(CC)CC)C.[C:17](=O)([O:26]N1C(=O)CCC1=O)[O:18][N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25]>C(#N)C>[O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:17]([O:18][N:19]2[C:23](=[O:24])[CH2:22][CH2:21][C:20]2=[O:25])=[O:26])[CH2:2]1
Reactant: O[C@H]1CO[C@H]2OCC[C@H]21
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(O[C@H]1CO[C@H]2OCC[C@H]21)ON1C(=O)CCC1=O
Temperature: 20 °C
Reaction time: 3 h
Yield: 39.9 %

Procedure:
In a glass-lined reactor 17.7 kg (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol in acetonitrile (30%) was added, then 3.9 kg of triethylamine 9 kg of solid disuccinimidyl carbonate (DSC) was added in portions, while keeping the reaction temperature below 35° C. The reaction mixture was stirred at 20° C. for 3 hours. The temperature was lowered to 2° C. and 45 kg of ice-water was added to the reactor. Precipitation was observed and the precipitate was filtered off. The cake was dissolved in 41 kg of chloroform and the aqueous phase was separated. The solution was evaporated to dryness and 18.8 kg of petroleum ether was added to the reactor containing the residue. The mixture was stirred at 0-5° C. for 1 hour. The resulting white precipitation was filtered off and rinsed with about 2 kg of petroleum ether. 1-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy)-2,5-pyrrolidinedione was obtained as an off-white solid, weight 3.69 kg (yield 39.9%, purity 68.7% by HPLC area, mobile phase: CH3CN/15 mmol/L Na2HPO4, pH 3.0 by H3PO4(35/65); speed: 0.8 mL/min; retention time: 7.730 min.).
Reaction SMILES: FC(F)(F)C1C=CC(C=C)=CC=1.Br[C:14]1[CH2:18][CH2:17][O:16][N:15]=1.Br[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][N:21]=1>>[N:21]1[CH:20]=[CH:25][CH:24]=[C:23]([O:26][C:14]2[CH2:18][CH2:17][O:16][N:15]=2)[CH:22]=1
Reactant: Oc1ccc(Br)nc1
Reactant: BrC1=NOCC1
Agent: C=Cc1ccc(C(F)(F)F)cc1
Product: c1cncc(OC2=NOCC2)c1

Procedure:
3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-216a and I-216b were prepared in 2 steps from 1-(trifluoromethyl)-4-vinylbenzene using the cycloaddition conditions from Method 1. The resulting bromo-4,5-dihydroisoxazole was reacted with 2-bromo-5-hydroxypyridine using Method 5 to provide racemic compound I-216. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=389.1 m/z. Activity: B
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][O:11][C:5]=2[CH:4]=1)#[CH:2].I[C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=1>>[CH3:13][C:9]1([CH3:12])[CH2:8][O:7][C:6]2[CH:14]=[CH:15][C:3]([C:1]#[C:2][C:17]3[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=3)=[CH:4][C:5]=2[O:11][CH2:10]1
Reactant: C#Cc1ccc2c(c1)OCC(C)(C)CO2
Reactant: CC(=O)c1ccc(I)cc1
Product: CC(=O)c1ccc(C#Cc2ccc3c(c2)OCC(C)(C)CO3)cc1

Procedure:
The title compound is prepared in analogy to example 1 from 7-ethynyl-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine (6) (example 1d) and 1-(4-iodo-phenyl)-ethanone. MS (ESI) 320.2 (M•)+.