Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:10]=[CH:9][NH:8][N:7]=1.[H-].[Na+].[CH2:13](I)[CH2:14][CH3:15].C(N1C=CC(C2SC=CC=2)=N1)CC>CN(C)C=O.CC(OC)(C)C.O>[CH2:13]([N:7]1[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:9]=[N:8]1)[CH2:14][CH3:15]
Reactant: c1csc(-c2cc[nH]n2)c1
Reactant: CCCI
Agent: CCCn1ccc(-c2cccs2)n1
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1nccc1-c1cccs1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
3-(2-thienyl)-1H-pyrazole (33.3 mmol) was dissolved in 100 mL dry N,N-dimethylformamide and cooled to 0° C. under argon atmosphere. Sodium hydride (39.9 mmol, 60% dispersion in mineral oil) was added in portions at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred at room temperature for 15 min. After cooling to 0° C. again, propyl iodide (49.9 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 14 h. Water and MTBE were added to the reaction mixture. The phases were separated and the aqueous phase was extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated. 6.50 g of a mixture of 1-propyl-3-(2-thienyl)-1H-pyrazole and 1-propyl-5-(2-thienyl)-1H-pyrazole (81:19; 99% yield) were obtained. 1.0 g of this mixture was used as such in the next step. 5.50 g of the mixture were purified again by chromatography on silica gel (toluene:ethyl acetate 100:0 to 0:100) to afford 4.35 g of 1-propyl-3-(2-thienyl)-1H-pyrazole and 1-propyl-5-(2-thienyl)-1H-pyrazole (67% yield) and 0.40 g of 1-propyl-5-(2-thienyl)-1H-pyrazole (6% yield).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C([Li])CCC.[Cl:24][C:25]1[CH:36]=[CH:35][C:28]([C:29](N(OC)C)=[O:30])=[CH:27][C:26]=1[S:37](=[O:40])(=[O:39])[NH2:38]>O1CCCC1>[C:13]([Si:10]([CH3:12])([CH3:11])[O:9][CH2:8][CH2:7][O:6][C:5]1[CH:17]=[CH:18][C:2]([C:29]([C:28]2[CH:35]=[CH:36][C:25]([Cl:24])=[C:26]([S:37]([NH2:38])(=[O:39])=[O:40])[CH:27]=2)=[O:30])=[CH:3][CH:4]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CON(C)C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Temperature: -78 °C
Reaction time: 18 h
Yield: 53.1 %

Procedure:
[2-(4-Bromo-phenoxy)-ethoxy]-tert-butyl-dimethyl-silane (7.3 g, 22.12 mmol) is dissolved in tetrahydrofuran (120 mL) and cooled to −78° C. The solution is treated with a solution of n-butyllithium (1.6 M in hexanes, 13.8 mL, 22.12 mmol) and stirred 30 minutes after which a solution of 4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide (2.05 g, 7.37 mmol) in tetrahydrofuran (20 mL) is added. The reaction is allowed to stir for 18 hours while warming to ambient temperature. The reaction is quenched with a saturated solution of ammonium chloride and extracted twice with ether. The organic phase is separated and concentrated in vacuo. The residue is purified by column chromatography (gradient of ethyl acetate in hexanes 10-50%) affording 1.84 g (53% yield) of the title compound. MS (m/z): 470.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].Cl.Cl[CH2:21][C:22]1[C:23]([NH:33][CH3:34])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([CH3:32])=[CH:27][CH:26]=2>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[C:6]2[CH2:21][C:22]1[C:23]([NH:33][CH3:34])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([CH3:32])=[CH:27][CH:26]=2
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Reactant: CNc1nc2ccc(C)cc2cc1CCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CNc1nc2ccc(C)cc2cc1Cc1c(O)nc(C)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (40 mg, 182 μmol) in toluene (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 2 N aq. KOH solution (0.17 mL, 0.34 mmol) at RT followed by 3-(chloromethyl)-N,6-dimethylquinolin-2-amine hydrochloride MDE 32062 (39 mg, 152 μmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (10 mL) before to be extracted with EtOAc (50 mL). The organic phase was isolated and the aqueous phase was further extracted with CH2Cl2 (50 mL). Both organic phases were washed with brine (10 mL), combined, dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 94:6 to 90:10) gave 12 mg of 6,7-dimethoxy-1-methyl-4-((6-methyl-2-(methylamino)quinolin-3-yl)methyl)isoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.09 M HCl solution in MeOH (1.0 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-1-methyl-4-((6-methyl-2-(methylamino)quinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 33 as a brown solid (14 mg, 19% yield).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][Cl:7])=[O:3].[Cl:8][C:9]1[C:14]([OH:15])=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[C:11]([NH2:19])[CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1>[Cl:8][C:9]1[C:14]([OH:15])=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[C:11]([NH:19][C:2](=[O:3])[O:4][CH2:5][CH2:6][Cl:7])[CH:10]=1
Reactant: O=C(Cl)OCCCl
Reactant: Nc1cc(Cl)c(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1cc(Cl)c(O)cc1[N+](=O)[O-])OCCCl
Temperature: 90 °C
Yield: 95 %

Procedure:
21 ml of β-chloroethyl chloroformate are added dropwise to 37.7 g (0.2 mole) of 6-chloro-3-nitro-4-aminophenol and 12 g of sodium carbonate in 130 ml of dioxane at 70° C. and the mixture is then heated at 90° C. for a further hour. After addition of 500 ml of water and stirring until cold, the mixture is extracted 3 times with methylene chloride and the extracts are dried and concentrated completely, after which 56 g (95%) of the product are obtained as a dark red oil, which crystallises completely, after some time, by trituration with toluene.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([O:16][CH3:17])[N:15]=2)[C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]=[C:27]([CH3:30])[C:28]=1[OH:29])[C:22]([NH:24]O)=[NH:23].Cl[CH2:32][C@@H:33]([OH:36])[CH2:34][OH:35]>>[Cl:18][C:19]1[CH:20]=[C:21]([C:22]2[N:24]=[C:10]([C:9]3[CH:13]=[C:14]([O:16][CH3:17])[N:15]=[C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH:8]=3)[O:12][N:23]=2)[CH:26]=[C:27]([CH3:30])[C:28]=1[O:29][CH2:32][C@@H:33]([OH:36])[CH2:34][OH:35]
Reactant: Cc1cc(C(=N)NO)cc(Cl)c1O
Reactant: OC[C@H](O)CCl
Reactant: COc1cc(C(=O)O)cc(C2CCCCC2)n1
Product: COc1cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CO)c(Cl)c3)no2)cc(C2CCCCC2)n1

Procedure:
The title compound is prepared in analogy to Example 3 starting from 2-cyclohexyl-6-methoxy-isonicotinic acid, 3-chloro-4,N-dihydroxy-5-methyl-benzamidine and (S)-3-chloro-1,2-propanediol; LC-MS**: tR=1.01 min, [M+H]+=473.95; 1H NMR (CDCl3): δ: 8.08 (s, 1H), 7.94 (s, 1H), 7.48 (s, 1H), 7.30 (s, 1H), 4.18 (m, 1H), 4.10-4.14 (m, 2H), 4.03 (s, 3H), 3.84-3.95 (m, 2H), 2.84 (s br, 1H), 2.69-2.80 (m, 1H), 2.45 (s, 3H), 1.99-2.13 (m, 2H), 1.86-1.96 (m, 2H), 1.76-1.84 (m, 1H), 1.15-1.68 (m, 6H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:48][CH:49]1[C@H:53]2[C@H:54](OC3CCCCO3)[N:55](C(OC(C)(C)C)=O)[C:56]3[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][C:57]=3[C:58](=[O:59])[N:52]2[CH2:51][CH2:50]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH:17]1[C@H:21]2[C@H:22](OC3CCCCO3)[N:23](C(OC(C)(C)C)=O)[C:24]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:25]=3[C:26](=[O:27])[N:20]2[CH2:19][CH2:18]1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:8]([O:48][CH:49]1[C@@H:53]2[CH:54]=[N:55][C:56]3[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][C:57]=3[C:58](=[O:59])[N:52]2[CH2:51][CH2:50]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH:17]1[C@@H:21]2[CH:22]=[N:23][C:24]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:25]=3[C:26](=[O:27])[N:20]2[CH2:19][CH2:18]1
Reactant: COc1ccc2c(c1)C(=O)N1CCC(OCCCCCCCCOC3CCN4C(=O)c5cc(OC)ccc5N(C(=O)OC(C)(C)C)[C@@H](OC5CCCCO5)[C@H]34)[C@H]1[C@H](OC1CCCCO1)N2C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)C(=O)N1CCC(OCCCCCCCCOC3CCN4C(=O)c5cc(OC)ccc5N=C[C@@H]34)[C@@H]1C=N2
Reaction time: 1 h
Yield: 94.4 %

Procedure:
95% TFA (3 mL) was added drop-wise to dimer compound 15f (190 mg, 0.18 mmol) at 0° C. This was then stirred for 1 hr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3×20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 16f (105 mg, 0.17 mmol, 96%) as a solid: [α]20D=+1330° (c=0.13, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.32-1.58 (m, 8H, 14-H, 14′-H, 15-H, 15′-H), 1.78-1.92 (m, 4H, 13-H, 13′-H), 1.93-2.10 (m, 4H, 2-H, 2′-H), 2.26-2.38 (m, 4H, 1-H, 1′-H), 3.55-3.64 (m, 2H, 3-H, 3′-H), 3.70-3.76 (m, 2H, 11a-H, 11a′-H), 3.77-3.89 (m, 2H, 3-H, 3′-H), 3.93 (s, 6H, 7-OMe, 7′-OMe), 3.98-4.15 (m, 4H, 12-H, 12′-H), 6.79 (s, 2H, 9-H, 9′-H), 7.51 (s, 2H, 6-H, 6′-H), 7.65 (d, 2H, J=4.4, 11-H, 11′-H); 13C NMR (CDCl3, 400 MHz): δ 24.1, 25.8, 28.8, 29.2; 29.6; 46.6; 53.7, 56.1, 69.0, 110.4, 111.6, 120.0, 140.6, 147.8, 150.9, 162.2, 164.67; IR (neat): 3326, 2934, 1599, 1505, 1455, 1431, 1382, 1261, 1216, 1092, 1019 cm−1; MS (FAB) m/z (relative intensity) 667 ([M+2×MeOH]+., 3), 635 ([M+MeOH]+., 8), 603 (M+., 100).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[P:38]([O:50][CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][N:56]([CH2:59][CH2:60][C@@H:61]([NH:70][C:71]2[CH:76]=[CH:75][C:74]([S:77](=[O:80])(=[O:79])[NH2:78])=[CH:73][C:72]=2[S:81]([C:84]([F:87])([F:86])[F:85])(=[O:83])=[O:82])[CH2:62][S:63][C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH2:55][CH2:54]1)([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[P:38]([O:50][CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][N:56]([CH2:59][CH2:60][C@@H:61]([NH:70][C:71]2[CH:76]=[CH:75][C:74]([S:77](=[O:79])(=[O:80])[NH:78][C:20](=[O:21])[C:19]3[CH:18]=[CH:17][C:16]([N:13]4[CH2:12][CH2:11][CH:10]([C@@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3])[C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[C:31]5[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=5)[CH2:15][CH2:14]4)=[CH:24][CH:23]=3)=[CH:73][C:72]=2[S:81]([C:84]([F:87])([F:86])[F:85])(=[O:83])=[O:82])[CH2:62][S:63][C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH2:55][CH2:54]1)([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CC(C)(C)OP(=O)(OCCN1CCN(CC[C@H](CSc2ccccc2)Nc2ccc(S(N)(=O)=O)cc2S(=O)(=O)C(F)(F)F)CC1)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OP(=O)(OCCN1CCN(CC[C@H](CSc2ccccc2)Nc2ccc(S(=O)(=O)NC(=O)c3ccc(N4CCC([C@@H](O[Si](C)(C)C(C)(C)C)c5ccccc5-c5ccc(Cl)cc5)CC4)cc3)cc2S(=O)(=O)C(F)(F)F)CC1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(R)-4-(4-((tert-butyldimethylsilyloxy)(4 ′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 13, 170 mg, 0.32 mmol), (R)-di-tert-butyl 2-(4-(4-(phenylthio)-3-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino)butyl)piperazin-1-yl)ethyl phosphate (INTERMEDIATE 61, 275 mg, 0.35 mmol), DMAP (116 mg, 0.95 mmol) and EDC (122 mg, 0.63 mmol) were dissolved in DCM (3.2 ml). The reaction mixture was stirred at r.t. for 72 hours. The mixture was diluted with DCM (10 ml) and washed with NaHCO3 solution (saturated, aq., 5 ml) and brine (5 ml). The collected organic layer was dried over Na2SO4 and concentrated to give the title compound (446 mg, yield: almost quantitative). The title compound was used in the preparation of EXAMPLE 10 without further purification.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:24]([O:25]C(=O)C)=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1.[CH3:31][NH2:32]>C(#N)C>[CH3:31][NH:32][C:2]1[O:3][C:4]2[C:24]([OH:25])=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Reactant: CN
Solvent: CC#N
Product: CNc1oc2c(O)c(OC)ccc2c1C(=O)c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
To a stirred solution of 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran (20 mg, 0.066 mmol) in acetonitrile (3 mL) was added the solution of methyamine (1 mL, excess as reactant and base), and the reaction mixture was stirred at room temperature for 1 hour when the precipitates appeared. The solvent was distilled under vacuo and the crude was dissolved in tetrahydrofuran (2 mL), 1M hydrochloric acid (1 mL) was added and the reaction mixture was stirred for 1 hour then diluted with dichloromethane (10 mL) and washed with water. The organic layer was dried over magnesium sulfate and solvent was distilled under vacuo. The crude was purified by PTLC (eluent=Hexane:ethylacetate:triethylamine; 2:8:1%) to gave the title compound as a yellow-green solid (5 mg, 29%); 1H NMR (300 MHz, CDCl3) δ 8.91 (broad, 1H, NH), 6.93 (s, 2H, benzoyl Hs), 6.59 (d, 1H, J=8.56 Hz), 6.46 (d, 1H, J=8.51 Hz), 5.61 (bs, 1H, OH), 3.91 (s, 3H, OMe), 3.86 (s, 3H, OMe), 3.84 (s, 6H, 2×OMe), 3.28 (d, 3H, J=5.28 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[OH-].[NH4+].CCN(C(C)C)C(C)C.[O:25](C(OC(C)(C)C)=O)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=O>CO.[Ni].C(Cl)Cl>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][NH:7][C:26](=[O:25])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[C:8]([C:10]([F:11])([F:13])[F:12])[CH:9]=1
Reactant: Cc1cc(C(F)(F)F)c(C#N)cn1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(F)(F)F)c(CNC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 90 %

Procedure:
6-Methyl-4-(trifluoromethyl)nicotinonitrile (1.0 equiv.) was dissolved in MeOH (0.1 M), wet Raney nickel was added, followed by ammonium hydroxide (32 equiv.). The reaction vessel was evacuated three times, refilled with hydrogen and then equipped with a hydrogen balloon and stirred at room temperature for 48 h. The mixture was filtered through a short pad of celite which was washed with MeOH. Ethanol was added to remove excess water upon concentration. The volatile solvents were removed to afford crude product which was dissolved in DCM. DIEA (1.8 equiv.) was added followed by BOC2O (0.95 equiv.). The reaction was stirred at room temperature for 1 h. The volatile solvent was removed and the residue was purified via Biotage chromatography (10-100% ethyl acetate in hexanes) to afford tert-butyl ((6-methyl-4-(trifluoromethyl)pyridin-3-yl)methyl)carbamate (90% yield); MS(ESI) m/z 290.3[M+1]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH:18]2[CH:23]3[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]3)[CH2:19]2)=[O:16])[C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[N:7]([CH3:13])[C:6]=2[CH:14]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:15]([NH+:17]([O-:34])[CH:18]2[CH:23]3[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]3)[CH2:19]2)=[O:16])[C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[N:7]([CH3:13])[C:6]=2[CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1Oc2c(C(=O)NC3CN4CCC3CC4)cc(Cl)cc2N(C)C1=O
Solvent: ClC(Cl)Cl
Product: CC1Oc2c(C(=O)[NH+]([O-])C3CN4CCC3CC4)cc(Cl)cc2N(C)C1=O
Reaction time: 0.5 h

Procedure:
To a solution of 5.0 g of 6-chloro-3,4-dihydro-2,4-dimethyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide in 150 ml of chloroform is added portionwise 3.7 g of metachloroperbenzoic acid under cooling and stirring. After 0.5 hour, ammonia gas is bubbled through the reaction solution under stirring and the precipitate is filtered off. The mother liquor is distilled off under reduced pressure followed by recrystallizing the residue from ethanol-isopropyl ester to give 6-chloro-3,4-dihydro-2,4-dimethyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide N-oxide, melting at 188°-190° C. with decomposition.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([OH:15])[C:13]=3[N:12]=[CH:11]2)[C@H:7]([OH:20])[C@@H:6]1[OH:21])=[N+]=[N-].[H][H]>CO>[NH2:1][CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([OH:15])[C:13]=3[N:12]=[CH:11]2)[C@H:7]([OH:20])[C@@H:6]1[OH:21]
Reactant: [H][H]
Reactant: [N-]=[N+]=NC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Solvent: CO
Product: NC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Yield: 91 %

Procedure:
The thus-obtained 5′-azido-5′-deoxyinosine was then dissolved in methanol and reduced with hydrogen for 12 hours using palladium-on-carbon Pd/C (10%, 80 mg) as a catalyst, whereby 5′-amino-5′-deoxyinosine was obtained. Yield 91%.
Reaction SMILES: N(OCCC(C)C)=O.[F:9][C:10]([F:23])([F:22])[O:11][C:12]1[CH:21]=[CH:20][C:15]2[N:16]=[C:17](N)[S:18][C:14]=2[CH:13]=1.[ClH:24]>C(#N)C.[Cu](Cl)Cl>[Cl:24][C:17]1[S:18][C:14]2[CH:13]=[C:12]([O:11][C:10]([F:23])([F:22])[F:9])[CH:21]=[CH:20][C:15]=2[N:16]=1
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: FC(F)(F)Oc1ccc2nc(Cl)sc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution containing dry copper (II) chloride (3.44 g, 25.62 mmol) and tri(ethylene glycol) dimethyl ether (10 g) in acetonitrile (150 mL) was added isoamyl nitrite (4.5 mL, 32.02 mmol). The reaction mixture was stirred at rt under argon for 30 minutes. To this suspension was added dropwise, a solution containing 6-trifluoromethoxy-1,3-benzothiazol-2-ylamine (5 g, 21.35 mmol) and tri(ethylene glycol) dimethyl ether (10 g). The reaction mixture was stirred at rt for 10 minutes, and then heated at 50° C. for 3 h. The mixture was cooled to rt, poured cautiously into aqueous 6 N HCl, and extracted with ethyl acetate. The organic layer was washed with 1N aqueous HCl and brine, and concentrated under reduced pressure to give the desired compound in near-quantitative yield, which was used without further purification in the next step.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:19].C(N(C(C)C)CC)(C)C>C(#N)C.[Cl-].[Na+].O>[N:8]1([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([O:12][CH2:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1)=[O:19])=[O:11]
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)OCC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of BOC-L-Proline (0.485 g, 2.25 mmol) and 2-Bromo-4′-nitro acetophenone (0.500 g, 2.05 mmol) in acetonitrile (20 mL) was added diisopropylethylamine (0.39 mL, 2.25 mmol) dropwise at ambient temperature. After stirred for four hours, the solution was poured into brine and extracted into ethyl acetate, dried over sodium sulfate, filtered, and the filtrate was concentrated to give a crude material that was used without purification (100% yield).
Reaction SMILES: [N:1]1[N:10]2[C:4]([CH2:5][NH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:41])=[C:27]([CH:40]=1)[C:28]([NH:30][C:31]1[N:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[CH:33][CH:32]=1)=[O:29]>ClCCl>[N:1]1[N:10]2[C:4]([CH2:5][N:6]([C:37]([C:34]3[CH:33]=[CH:32][C:31]([NH:30][C:28](=[O:29])[C:27]4[CH:40]=[C:23]([F:22])[CH:24]=[CH:25][C:26]=4[CH3:41])=[N:36][CH:35]=3)=[O:38])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Reactant: c1ccc2c(c1)Cn1nccc1CN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.1 %

Procedure:
To a chilled (0° C.) solution of 0.37 g of 5,10-dihydro-4H-pyrazolo [5,1-c][1,4]benzodiazepine and 836 microliters of triethylamine in 5 ml of dichloromethane is added 0.761 g of 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride. The mixture is stirred at room temperature under argon for 5 hours. An additional 420 microliters of triethylamine and 0.38 g of 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride is added and the mixture stirred 16 hours. The mixture is diluted with 60 ml of dichloromethane and washed with 25 ml each of H2O, 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered (twice) through a thin pad of hydrous magnesium silicate and the pad washed with dichloromethane. The filtrate is concentrated to give a yellow glass (0.68 g) which is crystallized from ethyl acetate to give 0.38 g of white crystals, m.p. 250°-260° C.; mass spectrum (FABL) 442.4 (M+H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].[CH2:42]([Cl:44])[Cl:43]>C(O)(=O)C>[NH3:1].[CH2:42]([Cl:44])[Cl:43].[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH2:13][NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccccn1
Reactant: O=Cc1ccccc1OCCCN1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: N
Product: c1ccc(NCc2ccccc2OCCCN2CCCCC2)nc1
Reaction time: 16 h

Procedure:
A solution of 2-(3-piperidin-1-yl-propoxy)-benzaldehyde (269 mg), 2-aminopyridine (110 mg), and acetic acid (0.07 mL) in DCM (5 mL) was treated with sodium triacetoxyborohydride (410 mg). After 16 h, the resulting mixture was treated with 10% sodium hydroxide (6 mL) and extracted with DCM (3×10 mL). The combined organic phases were dried (sodium sulfate) and evaporated. Chromatography of the residue (1-5% 2 M methanolic ammonia/DCM) gave the title compound as a colorless oil (128 mg). 1H NMR (400 MHz, CDCl3): 8.07 (m, 1H), 7.37 (m, 1H), 7.29 (m, 1H), 7.22 (m, 1H), 6.91-6.84 (m, 2H), 6.54 (m, 1H), 6.37 (m, 1H), 5.00 (m, 1H), 4.48 (d, J=5.6, 2H), 4.04 (t, J=6.3 Hz, 2H), 2.52 (m, 2H), 2.41 (br, 4H), 2.02.(m, 2H), 1.64-1.57 (m, 4H), 1.47-1.40 (m, 2H).