Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[Si:7]([O:14][C@@H:15]([C@@H:17]1[C@@H:20]([C@@H:21]([CH3:40])[C:22]([C:24]2[S:28][C:27]3=[C:29]([C:32]([C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)=[O:33])[N:30]=[CH:31][N:26]3[CH:25]=2)=[O:23])[N:19]([CH:41]([C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=2)=[O:44])O)[C:18]1=[O:56])[CH3:16])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].S(Cl)([Cl:59])=O>O1CCCC1.C(OCC)(=O)C>[Si:7]([O:14][C@@H:15]([C@@H:17]1[C@@H:20]([C@@H:21]([CH3:40])[C:22]([C:24]2[S:28][C:27]3=[C:29]([C:32]([C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)=[O:33])[N:30]=[CH:31][N:26]3[CH:25]=2)=[O:23])[N:19]([CH:41]([C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=2)=[O:44])[Cl:59])[C:18]1=[O:56])[CH3:16])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: O=S(Cl)Cl
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(C(O)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1[C@@H](C)C(=O)c1cn2cnc(C(=O)c3cccnc3)c2s1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(C(Cl)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1[C@@H](C)C(=O)c1cn2cnc(C(=O)c3cccnc3)c2s1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Pyridine (0.1 ml) was added to a solution of 0.23 g of the crude product of (3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}-1-[[(4-nitrobenzyloxy)carbonyl]hydroxymethyl]azetidin-2-one in 2 ml of tetrahydrofuran under an argon atmosphere, and the mixture was cooled to −20° C. Thionyl chloride (0.09 ml) was added thereto, and the mixture was stirred at that temperature for one hr. The reaction mixture was diluted with ethyl acetate, and the diluted reaction mixture was washed with water and saturated brine and was then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation to give a crude product of (3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}-1-[[(4-nitrobenzyloxy)carbonyl]chloromethyl]azetidin-2-one. Triphenylphosphine (0.26 g) and 0.05 g of potassium iodide were added to a solution of this crude product in 2 ml of dimethylformamide, and the mixture was stirred at 60° C. for one hr. The reaction mixture was diluted with ethyl acetate, and the diluted reaction mixture was washed with water and saturated brine and was then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, and the residue was purified by thin layer chromatography (developed with 10% methanol/ethyl acetate) to give 0.19 g of (3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}-1-[4-nitrobenzyloxycarbonyl(triphenylphosphoranylidene)methyl]azetidin-2-one.
Reaction SMILES: C[O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][CH2:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[C:16]2[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:15]2=[N:14][C:13]=3[NH2:24])=[C:5]([CH3:27])[CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:24][C:13]1[C:12]2[N:11]=[CH:10][C:9]([CH2:8][CH2:7][C:6]3[CH:25]=[CH:26][C:3]([OH:2])=[CH:4][C:5]=3[CH3:27])=[CH:18][C:17]=2[C:16]2[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:15]=2[N:14]=1
Reactant: COc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3C)cc12

Procedure:
To a stirred solution of 2-(4-methoxy-2-methylphenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine (Example 49) in methylene chloride (0.2 M) in an ice-water bath was added 1 N solution of BBr3 (2 eq) in CH2Cl2 in a drop-wise fashion. In 30 minutes the reaction was quenched with methanol and was concentrated en vaccuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-20% methanol in dichloromethane to give 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenol as a white solid. 1H NMR (DMSO-d6): δ 8.99 (s, 1H), 8.75 (d, 1H), 8.60 (d, 1H), 8.27 (d, 1H), 7.28 (s, 1H), 7.09 (dd, 1H), 6.99 (bs, 2H), 6.88 (d, 1H), 6.49 (d, 1H), 6.42 (dd, 1H), 3.02-2.96 (dd, 2H), 2.86-2.81 (dd, 2H), 2.38 (s, 3H), 2.13 (s, 3H). LRMS [M+H]=344.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[Cl-].[NH4+]>C1COCC1.CO.[Zn]>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[N:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2ccnc(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 103 %

Procedure:
2-Chloro-4-(6-nitropyridin-3-yloxy)pyridine (0.540 g, 2.146 mmol) was dissolved in THF (54 ml) and MeOH (54 ml). Ammonium chloride (1.148 g, 21.46 mmol) was then added, followed by zinc dust (1.403 g, 21.46 mmol). The reaction was stirred at RT for 45 minutes, filtered over Celite® and concentrated under reduced pressure to yield 5-(2-chloropyridin-4-yloxy)pyridin-2-amine as a brown solid (0.49 g, 99%). It was used as is in the next reaction. 1H NMR (400 MHz, DMSO-d6): δ 8.46 (d, 1H), 7.81 (d, 1H), 7.30 (dd, 1H), 6.90 (m, 2H), 6.50 (d, 1H), 6.08 (s, 2H); MS (ESI) m/z: 222.0 (M+H+).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:35]3[CH:36]=[C:29]([F:28])[CH:30]=[CH:31][C:32]=3[C:33]#[N:34])[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: CC1(C)OB(c2cc(F)ccc2C#N)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Product: N#Cc1ccc(F)cc1-c1cc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cnc1N1CC[C@@H](O)C1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
(R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 171.1, 50 mg, 0.108 mmol), 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (32 mg, 0.130 mmol), PdCl2(dppf) (7.91 mg, 10.81 μmol) and K3PO4 (68.8 mg, 0.324 mmol) were added to a vial and flushed with argon. Dioxane (1 mL) was added and the mixture was stirred at 120° C. for 1.5 h. The solvent was evaporated off under reduced pressure and the crude product was purified by preparative SFC (Column 2-EP, from 17% to 22% in 6 min). The purified product was lyophilized in water/min. vol. MeCN to afford the title product as a slightly yellow powder. UPLC-MS (Condition 3), tR=1.09 min, m/z=503.1/505.2 [M+H]+.
Reaction SMILES: S1C2C=CC=CC=2N=C1S[S:11][C@H:12]1[N:15]([CH:16]([C:30]([CH3:32])=[CH2:31])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[C:14](=[O:33])[C@H:13]1[NH:34][C:35](=[O:44])[CH2:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.O.[C:46]1([CH3:55])[CH:51]=[CH:50][C:49]([S:52]([O-:54])=[O:53])=[CH:48][CH:47]=1.[Na+]>CC(C)=O.O.[N+]([O-])([O-])=O.[Ag+]>[C:46]1([CH3:55])[CH:51]=[CH:50][C:49]([S:52]([S:11][C@H:12]2[N:15]([CH:16]([C:30]([CH3:32])=[CH2:31])[C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)=[O:18])[C:14](=[O:33])[C@H:13]2[NH:34][C:35](=[O:44])[CH2:36][O:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)(=[O:54])=[O:53])=[CH:48][CH:47]=1
Reactant: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SSc1nc2ccccc2s1
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 4-nitrobenzyl 2-[(3R,4R)-4-[(benzothiazol-2-yl)dithio]-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-3-methyl-3-butenoate (XIIIc, 3.25 g, 0.005 mole) in acetone (90 mL) and water (10 mL) was treated at room temperature with silver nitrate (1.06 g, 0.00625 mole), followed by treatment with a solution of sodium p-toluenesulfinate hydrate (0.90 g, 0.050 mole) in acetone (70 mL) - water (10 mL). The slurry was stirred for 1 h at room temperature under darkness. It was then filtered through Celite, which was washed with acetone. The volume of the filterate was reduced in vacuo, and the product was extracted into ether (3×250 mL). The ether phase was dried over magnesium sulfate and concentrated. Flash chromatography (silica gel, 50% ethyl acetate in hexane) gave the pure title product, XIIId, as a solid (2.053 g, 62%).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]([CH3:31])([CH3:30])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[C:22](=[O:29])[NH:23][NH:24][C:25]=2[CH:26]([CH3:28])[CH3:27])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][C:33]([O:35][CH2:36][C@H:37]1[O:42][C@H:41](Br)[C@H:40]([O:44][C:45]([CH3:47])=[O:46])[C@@H:39]([O:48][C:49]([CH3:51])=[O:50])[C@@H:38]1[O:52][C:53]([CH3:55])=[O:54])=[O:34].[OH-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.ClCCl>[C:45]([O:44][C@@H:40]1[C@@H:39]([O:48][C:49](=[O:50])[CH3:51])[C@H:38]([O:52][C:53](=[O:54])[CH3:55])[C@@H:37]([CH2:36][O:35][C:33](=[O:34])[CH3:32])[O:42][C@H:41]1[O:29][C:22]1[C:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])([CH3:31])[CH3:30])=[CH:19][CH:18]=2)=[C:25]([CH:26]([CH3:27])[CH3:28])[NH:24][N:23]=1)(=[O:46])[CH3:47]
Reactant: CC(C)c1[nH][nH]c(=O)c1Cc1ccc(OCC(C)(C)C(=O)OCc2ccccc2)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCC(C)(C)C(=O)OCc3ccccc3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.9 %

Procedure:
To a solution of 4-{[4-(2-benzyloxycarbonyl-2-methyl-propoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one (0.25 g), acetobromo-α-D-glucose (0.48 g) and benzyl-tri(n-butyl)ammonium chloride (0.18 g) in dichloromethane (5 mL) was added 5 mol/L aqueous sodium hydroxide solution (0.35 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by column chromatography on aminopropylated silica gel (eluent: n-hexane/ethyl acetate=1/1-1/3) to give the title compound (0.28 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[C:23]([F:24])=[CH:22][N:21]=[C:20]([O:25]CC4C=CC=CC=4)[N:19]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].[H][H]>CO.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][C:18]3[C:23]([F:24])=[CH:22][NH:21][C:20](=[O:25])[N:19]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:33]([F:35])([F:34])[F:36]
Reactant: [H][H]
Reactant: Fc1cnc(OCc2ccccc2)nc1OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: [Pd]
Solvent: CO
Product: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)c(F)c[nH]1
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
To a solution of 4-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-5-fluoro-2-[(phenylmethyl)oxy]pyrimidine (240 mg, 0,463 mmol) in methanol (10 mL) was added wet Pd/C (24.61 mg, 0.023 mmol), the suspension was charged with hydrogen and stirred for 30 min, then filtrated. The solvent was removed in vacuum afforded title product (150 mg). LC-MS (ESI): m/z 429[M+H]+; 4.22 min (ret time).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[C:16]([F:23])[CH:15]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:5][C:4]2[CH:6]=[C:7]([F:9])[CH:8]=[C:2]([Br:1])[C:3]=2[CH3:10])=[O:21])=[C:16]([F:23])[CH:15]=1
Reactant: COC(=O)c1ccc(C(=O)Cl)c(F)c1
Reactant: Cc1c(N)cc(F)cc1Br
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)Nc2cc(F)cc(Br)c2C)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Bromo-5-fluoro-2-methylaniline (515 mg, 2.53 mmol) was dissolved in pyridine (20 ml). Then Intermediate 33 (547 mg, 2.53 mmol) and DMAP (3.09 mg, 0.025 mmol) were added and the resulting mixture was stirred at r.t. for 2 hrs. The solvents were removed in vacuo and the residue was taken up with EtOAc and H2O. The organic layer was washed with sat. NaHCO3 solution and brine, and then dried over Na2SO4. The solvents were removed in vacuo and the resulting residue was recrystallized with MeOH to afford Intermediate 34 as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[OH:19][CH:20]1[CH2:25][CH2:24][CH:23]([CH2:26][C:27](O)=[O:28])[CH2:22][CH2:21]1.COC1C2N=C(NC(=O)CC3CCOCC3)SC=2C(C2CCOCC2)=CC=1>>[OH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([CH2:26][C:27]([NH:12][C:10]2[S:11][C:7]3[C:6]([CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:28])[CH2:22][CH2:21]1
Reactant: O=C(O)CC1CCC(O)CC1
Reactant: COc1ccc(C2CCOCC2)c2sc(N)nc12
Agent: COc1ccc(C2CCOCC2)c2sc(NC(=O)CC3CCOCC3)nc12
Product: COc1ccc(C2CCOCC2)c2sc(NC(=O)C[C@H]3CC[C@H](O)CC3)nc12

Procedure:
Using 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-ylamine and (4-hydroxy-cyclohexyl)-acetic acid, the title compound was prepared in the same manner as described for N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-2-(tetrahydro-pyran-4-yl)-acetamide and obtained as white crystals (25% yield). Mp 120-145° C., MS: m/e=405(M+H+).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]2[C:25]([N:26]=1)=[C:24]1[CH2:27][CH:28]([CH2:30][C@H:31]3[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33][CH2:32]3)[O:29][C:23]1=[CH:22][N:21]=2.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]2[C:25]([N:26]=1)=[C:24]1[CH2:27][CH:28]([CH2:30][C@H:31]3[CH2:36][CH2:35][C@H:34]([NH:37][C:12]([C:9]4[CH:10]=[CH:11][C:5]5[S:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)=[O:14])[CH2:33][CH2:32]3)[O:29][C:23]1=[CH:22][N:21]=2
Reactant: COc1ccc2ncc3c(c2n1)CC(C[C@H]1CC[C@H](N)CC1)O3
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2ncc3c(c2n1)CC(C[C@H]1CC[C@H](NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1)O3
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (31 mg, 0.14 mmol, 1.0 eq) is added at room temperature to a stirred solution of trans-4-(8-methoxy-1,2-dihydro-3-oxa-5,9-diaza-cyclopenta[a]naphthalen-2-ylmethyl)-cyclohexylamine (47 mg, 0.14 mmol, 1.0 eq) in N,N-dimethylformamide (4 mL), followed by 1-hydroxybenzotriazole (24 mg, 0.16 mmol, 1.1 eq), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (32 mg, 0.16 mmol, 1.15 eq) and N,N-diisopropylethylamine (56 μL, 0.32 mmol, 2.25 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid [trans-4-(8-methoxy-1,2-dihydro-3-oxa-5,9-diaza-cyclopenta[a]naphthalen-2-ylmethyl)-cyclohexyl]-amide as a white lyophilized powder (16 mg, 21% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:6][CH:5]([CH2:7][NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH2:4][O:3]1.[H-].[Na+].[Cl:16][C:17]1[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[C:19](Cl)[N:18]=1.O>CN(C=O)C>[Cl:16][C:17]1[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[C:19]([N:8]([CH2:7][CH:5]2[CH2:4][O:3][C:2]([CH3:13])([CH3:1])[O:6]2)[S:9]([CH3:12])(=[O:10])=[O:11])[N:18]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: CC1(C)OCC(CNS(C)(=O)=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N(CC2COC(C)(C)O2)S(C)(=O)=O)nc(Cl)n1
Reaction time: 0.17 h
Yield: 57.4 %

Procedure:
To a solution of N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)methane sulfonamide (0.875 g, 4.18 mmol) in DMF (25 mL) was added 60% NaH in mineral oil (0.193 g, 4.83 mmol). After 10 minutes, methyl 2,6-dichloropyrimidine-4-carboxylate (0.871 g, 4.21 mmol) was added. After stirring for 30 minutes, the reaction mixture was diluted into 100 mL water and extracted three times with 50 mL EtOAc. The combined organic layers were washed once with 25 mL brine, dried over MgSO4, filtered, and evaporated to a residue. The residue was chromatographed over silica gel with 30-60% EtOAc in hexanes. The product fractions were concentrated in vacuo. After sitting overnight a crystalline solid formed. The solid was decanted and dried under vacuum to give methyl 2-chloro-6-(N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)methylsulfonamido)pyrimidine-4-carboxylate as a cream-colored powder (0.911 g, 2.40 mmol, 57% yield). LC/MS: m/z=380.2 [M+H]+.
Reaction SMILES: N1CCC[C@H]1C(O)=O.[CH3:9][S:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)(=[O:12])=[O:11].[CH3:21][C:22]1([CH3:30])[O:29][C:27](=[O:28])[CH2:26][C:24](=[O:25])[O:23]1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>CCO>[CH3:9][S:10]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17][CH:26]2[C:27](=[O:28])[O:29][C:22]([CH3:30])([CH3:21])[O:23][C:24]2=[O:25])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CC1(C)OC(=O)C(Cc2ccc(S(C)(=O)=O)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Proline (0.126 g, 1.086 mmol) was added to a solution of 4-(methylsulfonyl)benzaldehyde (1.00 g, 5.428 mmol) and Meldrum's acid (1.38 g, 5.428 mmol) in EtOH (10 mL). The mixture was stirred at room temperature for 1 hour and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (1.38 g, 5.428 mmol) was added. Stirring was continued for 3 hours and EtOH removed under reduced pressure. The residue was diluted with i-PrOH and filtered to provide the title compound as a white solid.
Reaction SMILES: Br.[OH:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([OH:11])=[O:10])[CH:4]=1.[ClH:12].[CH2:13](O)[CH3:14]>>[ClH:12].[OH:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([O:11][CH2:13][CH3:14])=[O:10])[CH:4]=1
Reactant: O=C(O)c1cc(O)ccn1
Reactant: CCO
Agent: Br
Agent: Cl
Product: CCOC(=O)c1cc(O)ccn1
Temperature: 0 °C

Procedure:
To a 1 l. round bottom flask was added 45.5 g (0.21 mol) of 4-hydroxy-2-pyridinecarboxylic acid hydrobromide and 500 ml of ethanol saturated with hydrochloric acid. The mixture was heated to reflux overnight, cooled and concentrated under vacuum to 1/3 of its original volume. After cooling the mixture to about 0° C., the resultant crystals were collected by vacuum filtration, washed with ethanol and diethyl ether, and dried under vacuum to afford 29.5 g of ethyl 4-hydroxy-2-pyridinecarboxylate hydrochloride.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@H:12]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][C:23]([Sn](CCCC)(CCCC)CCCC)=[N:24][C:25]=3[NH:29][CH2:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[I:57]I.O1CCCC1>C(OCC)(=O)C>[Si:1]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@H:12]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][C:23]([I:57])=[N:24][C:25]=3[NH:29][CH2:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: II
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]4OC(C)(C)O[C@H]43)c2n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@H]2n1cnc2c(NCC(c3ccccc3)c3ccccc3)nc(I)nc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 128.8 %

Procedure:
A mixture of 9-[(3aR,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-N-(2,2-diphenylethyl)-2-(tributylstannyl)-9H-purin-6-amine (1.0 g, 1.12 mmol) (Preparation 4), iodine (0.43 g, 1.68 mmol) and tetrahydrofuran (30 ml) was stirred at 50° C. for 30 minutes. The mixture was cooled, dissolved in ethyl acetate and washed sequentially with saturated aqueous sodium thiosulphate solution followed by water. The organic phase was separated, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of hexane gradually changing to hexane:ethyl acetate (50:50, by volume) to afford the title compound (1.05 g).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1.Cl[C:13]1[S:14][C:15]([C:18]#[N:19])=[CH:16][N:17]=1.Cl>O.C1COCC1>[CH3:3][O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:13]2[S:14][C:15]([C:18]#[N:19])=[CH:16][N:17]=2)[CH:6]=1
Reactant: N#Cc1cnc(Cl)s1
Reactant: COc1cc(N)ncn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Nc2ncc(C#N)s2)ncn1
Reaction time: 1 h

Procedure:
A flame dried flask under argon gas was charged with sodium hydride (39 mg, 60% dispersion, 0.97 mmol) and 2 mL anhydrous THF. 6-Methoxy-pyrimidin-4-ylamine (55 mg, 0.44 mmol) was added slowly followed, after 10 minutes, by the addition of 2-chloro-thiazole-5-carbonitrile (76 mg, 0.53 mmol). After 1 hour, the reaction was diluted with water and adjusted to pH 7 with 1M HCl (aq). The resulting precipitate was filtered, washed with water and air dried. The resulting solid triturated with ether, sonucated, filtered and washed with ether. 1H-NMR (400 MHz, DMSO-d6) 12.40 (s, 1H), 8.68 (1H, s), 8.31 (1H, s), 6.42 (1H, s), 3.92 (s, 3H). M+1=234.2. mp 246–248.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>CC(C)=O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCCCCCBr
Agent: [K]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCCCBr

Procedure:
Potassium phthalimide (92.5 g) was added in six portions over 4 hours to a boiling solution of 1,5-dibromopentane (230 g) in acetone (670 ml). The mixture was boiled under reflux for 24 hours, then cooled and filtered. The filtrate was evaporated to dryness and the residue dissolved in petroleum ether, b.p. 60-80° C./ethyl acetate (1:1) and the solution filtered. The filtrate was evaporated to dryness and the residue washed with several portions of petroleum ether, b.p. 60-80° C. to remove excess dibromopentane. The remaining oil was dried under vacuum at 50° C. The petrol washings were evaporated to dryness and distilled under vacuum to give recovered dibromopentane and a second fraction b.p. 86-120° C. at 17 mbar. This fraction solidified on cooling and scratching. A little of this solid was used to seed the remaining oil and the combined solids were recrystallised from absolute ethanol (300 ml) to give N-(5-bromopentyl)phthalimide, m.p. 62-63° C.