Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([OH:10])(=O)=[O:8])[CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12].P(Cl)(Cl)(Cl)=O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([Cl:12])(=[O:10])=[O:8])[CH:2]=1
Reactant: O=S(=O)(O)c1cccnc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=S(=O)(Cl)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Pyridine-3-sulfonic acid (125 g, 0.78 m) was placed in a 1 L, 3-necked flask equipped with mechanical stirrer, reflux condenser, thermometer and nitrogen inlet. Next, the phosphorus pentachloride (250 g, 1.19 m, 1.5 eq) was added, followed immediately by the phosphorus oxychloride (330 ml, 3.8 m, 4.5 eq). The contents of flask were initially stirred at ambient temperature for 30 min, then brought slowly to gentle reflux (internal temp. approx. 110° C.) over the next hour, kept at this temperature for approx. 3.5 hr then allowed over the next 12 hr to cool back to ambient temperature. Gas evolution was observed during this time. The volatiles were stripped under reduced pressure (at 12 mmHg/40° C.) and yellow semi-solid residue was diluted with DCM (1 L). The slurry was poured slowly into the stirred, ice-cold sat. aq. bicarbonate, maintaining pH=7. Gas evolution was observed. The organic layer was separated and aqueous layer was back-extracted with DCM. The combined extracts were washed with cold sat. aq. bicarbonate, brine and dried with magnesium sulfate. The solids were filtered off and filtrate evaporated, leaving pyridine-3-sulfonyl chloride as a pale yellow, oily liquid, 123 g (93% pure; 88% theory). 1H-NMR, CDCl3, (δ): 9.26 (d, 1H), 8.98 (dd, 1H), 8.34 (m, 1H), 7.62 (m, 1H). 13C-NMR, CDCl3, (δ): 155.3, 147.4, 140.9, 134.6, 124.2.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][N:16]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:17])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>>[CH2:18]([N:16]([CH2:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)[C:6]=1[C:4]([OH:5])=[O:3])[CH3:17])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: BrCc1cccc2ccccc12
Reactant: CCOC(=O)c1[nH]c2ccccc2c1CN(C)Cc1ccccc1
Product: CN(Cc1ccccc1)Cc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccccc12

Procedure:
Using general procedure B, 3-[(benzyl-methyl-amino)-methyl]-1H-indole-2-carboxylic acid ethyl ester (Lit. 4) was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a pale yellow solid. MS: 433.4 ([M−H]−).
Reaction SMILES: [NH2:1][N:2]1[C:11]([OH:19])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:20]([F:23])([F:22])[F:21])[CH:9]=2)[N:4]=[CH:3]1.[C:24]1(=[O:38])[N:28]([CH2:29][C:30](Cl)=[O:31])[C:27](=[O:33])[C:26]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:25]12>N1C=CC=CC=1>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]([C:10]1[CH:9]=[C:8]([C:20]([F:23])([F:22])[F:21])[CH:7]=[CH:6][C:5]=1[N:4]([CH:3]=[N:2][NH:1][C:30](=[O:31])[CH2:29][N:28]1[C:24](=[O:38])[C:25]2[C:26](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:27]1=[O:33])[C:30](=[O:31])[CH2:29][N:28]1[C:27](=[O:33])[C:26]2[C:25](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:24]1=[O:38])=[O:19]
Reactant: NN1C=Nc2ccc(C(F)(F)F)cc2C1(O)c1ccccc1Cl
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Solvent: c1ccncc1
Product: O=C(CN1C(=O)c2ccccc2C1=O)NN=CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(C(F)(F)F)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 1, 3-amino-6-trifluoromethyl-3,4-dihydro-4-hydroxy-4-(o-chlorophenyl)quinazoline with pyridine is reacted with α-phthalimidoacetyl chloride to give 1,3-dioxo-2-isoindolineacetic acid, [[N-[2-(o-chlorobenzoyl)-4-(trifluoromethyl)phenyl]-1,3-dioxo-2-isoindolineacetamido]methylene]hydrazide.
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([O:16][CH3:17])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[F:18][C:19]1[CH:33]=[CH:32][C:22]([CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:21]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][S:39](=[O:43])(=[O:42])[NH:40][CH3:41])[CH:20]=1.N1C=CC=CC=1C1C=CC=CN=1>CN1C(=O)CCC1.ClCCl.[Cu-]=O>[C:27]([O:26][C:25]([NH:24][CH2:23][C:22]1[CH:32]=[CH:33][C:19]([F:18])=[CH:20][C:21]=1[O:34][CH2:35][CH2:36][CH2:37][CH2:38][S:39]([N:40]([C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([O:16][CH3:17])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)[CH3:41])(=[O:43])=[O:42])=[O:31])([CH3:30])([CH3:28])[CH3:29]
Reactant: COC(=O)c1nc(Br)c2cccnc2c1OC
Reactant: CNS(=O)(=O)CCCCOc1cc(F)ccc1CNC(=O)OC(C)(C)C
Agent: O=[Cu-]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: COC(=O)c1nc(N(C)S(=O)(=O)CCCCOc2cc(F)ccc2CNC(=O)OC(C)(C)C)c2cccnc2c1OC
Temperature: 120 °C
Reaction time: 10 h

Procedure:
A mixture of methyl 5-bromo-8-methoxy-1,6-naphthyridine-7-carboxylate (2.4 mmol), tert-butyl 4-fluoro-2-(4-(N-methylsulfamoyl)butoxy)benzylcarbamate (Example 19; 2.6 mmol), 2,2′-bipyridine (3.1 mmol) and copper (I) oxide (3.1 mmol) in NMP (30 ml) was stirred at 120° C. under nitrogen atmosphere for 10 hours. The reaction mixture was diluted with dichloromethane and filtered off. The filtrate was washed with 10% 2-[2-(bis(carboxylatomethyl)amino)ethyl-(carboxylatomethyl)amino]acetate (EDTA) disodium salt solution, saturated NaHCO3 solution and brine.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:19])[NH2:18])=O)C1C=CC=CC=1.[CH:23]1([S:26]([Cl:29])(=[O:28])=[O:27])[CH2:25][CH2:24]1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[ClH:29].[NH:19]=[C:17]([NH:18][S:26]([CH:23]1[CH2:25][CH2:24]1)(=[O:28])=[O:27])[NH:16][CH2:15][CH2:14][CH2:13][C@@H:12]([C:20]([N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:22])[NH2:11]
Reactant: O=S(=O)(Cl)C1CC1
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C1CCNC1
Product: Cl
Product: N=C(NCCC[C@H](N)C(=O)N1CCCC1)NS(=O)(=O)C1CC1

Procedure:
Starting from (S)-N2-(benzyloxycarbonyl)-arginine, cyclopropanesulphonyl chloride and pyrrolidine, the expected product is obtained according to the procedure described in Example 1.
Reaction SMILES: OCCC1N[C:6]2[C:11](C=1)=[CH:10][C:9](CC(OC)=O)=[CH:8][CH:7]=2.[O:18]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27](CCC)[CH:26]=1)[C:19]1C=CC=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.N1C2C(=CC=CC=2)C=C1>C1COCC1>[CH2:19]([O:18][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:27][CH:26]=1)[CH:20]=[CH2:21]
Reactant: CCCc1cc(Oc2ccccc2)ccc1O
Reactant: COC(=O)Cc1ccc2[nH]c(CCO)cc2c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc2[nH]ccc2c1
Solvent: C1CCOC1
Product: C=CCOc1ccc(Oc2ccccc2)cc1
Yield: 122.1 %

Procedure:
A solution of methyl 2-(2-hydroxyethyl)indole-5-acetate from Example 1, Step E (7.6 g), 4-phenoxy-2-propylphenol (8.28 g), triphenylphosphine (11.2 g), DIAD (8.5 mL) and THF (125 mL) was stirred under nitrogen at room temperature. After stirring overnight none of the starting indole remained as determined by TLC and the reaction was concentrated to a yellow oil. The oil was purified by silca gel chromatography (10%-20% ethyl acetate in hexanes) to give the desired product (9.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](S(C)(=O)=O)[N:28]=3)=[CH:23][C:22]2=[O:37])[C@@H:9]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)=[CH:4][C:3]=1[F:38].[O:39]1[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]1>CC(N(C)C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C@@H:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)[N:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH:45][CH:42]4[CH2:43][CH2:44][O:39][CH2:40][CH2:41]4)[N:28]=3)=[CH:23][C:22]2=[O:37])=[CH:4][C:3]=1[F:38]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]([C@H](c2ccc(Cl)c(F)c2)n2ccc(-c3ccnc(S(C)(=O)=O)n3)cc2=O)C1
Reactant: NC1CCOCC1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=c1cc(-c2ccnc(NC3CCOCC3)n2)ccn1[C@@H](c1ccc(Cl)c(F)c1)[C@@H]1CCNC1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
(R)-tert-Butyl 3-((R)-(4-chloro-3-fluorophenyl)(4-(2-(methylsulfonyl)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)pyrrolidine-1-carboxylate (45.1 mg, 0.0801 mmol) was dissolved in DMA (1.0 mL, 0.1M) at room temperature under nitrogen and treated with tetrahydro-2H-pyran-4-amine (40.5 mg, 0.401 mmol). The solution was heated to 120° C. for 1 hour in the microwave. The reaction was then diluted with EtOAc (15 mL) and washed with water (3×15 mL) and brine (15 mL). The organics were isolated, dried over sodium sulfate, filtered and concentrated. The crude product was loaded onto an SP1 samplet and purified by silica gel chromatography using a 10% to 80% gradient of acetone in hexanes. Product containing fractions were pooled, concentrated and then redissolved in dichloromethane (2 mL) and treated with 1:1 TFA/DCM (1.0 mL) and stirred at room temperature for 1 hour. The reaction was diluted to 15 mL with additional DCM and washed with NaHCO3 (2×15 mL). The organics were isolated, dried over sodium sulfate, filtered and concentrated to afford 1-((R)-(4-chloro-3-fluorophenyl)((R)-pyrrolidin-3-yl)methyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one as an oil. 1H NMR (400 MHz, ((CD3)2SO) δ 8.40 (d, 1H), 8.04 (d, 1H), 7.62 (m, 2H), 7.37 (d, 1H), 7.34 (br s, 1H), 7.13 (d, 1H), 7.08 (s, 1H), 6.86 (d, 1H), 5.84 (br s, 1H), 3.97 (m, 1H), 3.87 (m, 2H), 3.38 (m, 2H), 2.86 (m, 1H), 2.79 (m, 2H), 2.34 (m, 1H), 1.84 (br d, 2H), 1.74 (m, 1H), 1.52 (m, 3H), 1.27 (m, 2H); LCMS (ESI) m/z 484.1 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([OH:15])=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][S:32]([C:29]3[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=3)(=[O:34])=[O:33])=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2O)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3cccc(Cl)c3)c2=O)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79 %

Procedure:
To a 0° C. solution of 2-(3-chlorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 332, (6.79 g, 16 mmol) in pyridine (160 mL) was added p-toluenesulfonyl chloride (3.06 g, 16 mmol). The solution was left to warm slowly to room temperature with stirring under nitrogen. After 2.5 hours, the mixture was poured into H2O with constant stirring. The resulting off-white solid was filtered, rinsed with H2O and dried to provide the desired product (yield: 6.26 g, 79%). mp 198-200° C. 1H NMR (300 MHz, DMSO d6) δ 2.35 (s, 3H), 3.28 (s, 3H), 7.20 (m, 2H), 7.52-7.64 (M, 5H), 7.70 (m, 3H), 7.89 (m, 2H), 8.32 (s, 1H). MS APCI+531 (M+H)+, 548 (M+H2O)+, APCI−493 (M+35)−. Anal. calc. for C24H19ClN2O6S2: C, 54.29; H, 3.61; N, 5.28. Found: C, 54.55; H, 3.46; N, 5.57.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[OH-].[Na+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>CN(C)C=O>[CH3:27][O:26][C:24]([CH2:23][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:25]
Reactant: COC(=O)CBr
Reactant: O=C(OCc1ccccc1)c1cc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C(=O)OCc2ccccc2)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 12 h
Yield: 87 %

Procedure:
5 g of benzyl indole-2-carboxlate in solution in 20 ml of dimethylformamide are introduced slowly into 30 ml of a suspension of 1 g of NaOH in 30 ml of dimethylformamide and 3.1 g of methyl bromoacetate are then introduced. After 12 hours at ambient temperature, with stirring, the mixture is poured into a volume of ice-water and then extracted with ethyl acetate. The dried organic phase is concentrated and the residue is recrystallised from aqueous ethanol (95%, V/V). m.p.=94° C.; yield 87%.
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:35])[NH:11][C:12]2[C:13]([CH3:34])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4([C:32]#[N:33])[CH2:31][CH2:30]4)=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)CCO.Cl.[N-:43]=[N+:44]=[N-:45].[Na+]>COCCOCCOC.C(Cl)Cl.O>[C:1]1([C@H:7]([O:9][C:10](=[O:35])[NH:11][C:12]2[C:13]([CH3:34])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[CH:25][C:26]([C:29]4([C:32]5[NH:45][N:44]=[N:43][N:33]=5)[CH2:30][CH2:31]4)=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C#N)CC4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: CN(C)CCO
Agent: Cl
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Solvent: ClCCl
Product: Cc1noc(-c2ccc(-c3ccc(C4(c5nnn[nH]5)CC4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
{5-[4′-(1-Cyano-cyclopropyl)-biphenyl-4-yl]-3-methyl-isoxazol-4-yl}-carbamic acid (R)-1-phenyl-ethyl ester (0.385 g, 0.83 mmol) and N,N-dimethylethanolamine (0.101 mL, 1.0 mmol) were combined in diglyme (diethylene glycol dimethyl ether; 2 mL). Hydrochloric acid (4M in 1,4-dioxane; 4.2 mL) was added, and the reaction was stirred for 15 minutes. Additional N,N-dimethylethanolamine (0.221 mL, 2.2 mmol) was added, followed by sodium azide (0.098 g, 1.5 mmol), and the reaction was stirred at 120° C. for 24 hours. After cooling to room temperature, the mixture was diluted with CH2Cl2 (20 mL) and H2O (10 mL). The organic layer was dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O)([OH:3])=[O:2].[H][H].[OH-].[Na+:22]>[Pd]>[Na+:22].[Na+:22].[NH2:11][C:10]1[CH:9]=[CH:8][C:7]([CH:14]([CH3:18])[C:15]([O-:17])=[O:16])=[CH:6][C:5]=1[CH2:4][C:1]([OH:3])=[O:2].[NH2:11][C:10]1[CH:9]=[CH:8][C:7]([CH:14]([CH3:18])[C:15]([O-:17])=[O:16])=[CH:6][C:5]=1[CH2:4][C:1]([OH:3])=[O:2]
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])c(CC(=O)O)c1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)[O-])c1ccc(N)c(CC(=O)O)c1
Yield: 91.7 %

Procedure:
In 1N aqueous sodium hydroxide solution (6 mL) was dissolved 2-(3-carboxymethyl-4-nitrophenyl)propionic acid (obtained in Example 1, 760 mg, 3 mmol.). The solution was stirred for 18 hours at room temperature in a hydrogen gas atmosphere, after addition of 1006 palladium/carbon (15 mg). Insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure to give a brown crystalline product. The obtained crystalline product was washed successively with ethanol and hexane to give 734 mg (yield: 91.7%) of the desired compound as a white crystalline product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[S:11])=[CH:5][CH:4]=1.Cl.[O-:13][Mn](=O)(=O)=O.[K+].[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20]>>[CH2:19]([N:21]1[C:22](=[O:23])[N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:10](=[O:13])[S:11]1)[CH3:20]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCN=C=O
Reactant: COc1ccc(N=C=S)cc1
Agent: Cl
Agent: [K+]
Product: CCn1sc(=O)n(-c2ccc(OC)cc2)c1=O

Procedure:
Reagents: 4-Methoxyphenyl isothiocyanate (0.89 ml, 6.5 mmol), 35% HCl (3.1 ml), KMnO4 (0.5 g), ethyl isocyanate (0.51 ml, 6.5 mmol).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][C@@H:6]([C:15]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19](=[O:26])[NH:20]2)[O:7][Si](C(C)(C)C)(C)C.[ClH:27]>CO>[ClH:27].[NH2:4][CH2:5][C@@H:6]([C:15]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19](=[O:26])[NH:20]2)[OH:7]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Agent: Cl
Solvent: CO
Solvent: O=CO
Product: NC[C@H](O)c1ccc(O)c2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
(R)-5-(2-Amino-1-(tert-butyldimethylsilyloxy)ethyl)-8-hydroxyquinolin-2(1H)-one formate (0.23 g, 0.61 mmol) was dissolved in hydrochloric acid (5 mL, 4 M solution in dioxane) and methanol (5 mL). The reaction mixture was stirred at RT for 16 hours before concentrating in vacuo. The resultant residue was washed with ethyl acetate and dried in a vacuum oven for 18 hours to afford the title compound (0.15 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[OH:25])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:60][CH:61]([F:64])[CH2:62]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[O:25][CH2:62][CH:61]([F:64])[F:60])=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)C4CC4)c23)c(Cl)c1
Reactant: OCC(F)F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(OCC(F)F)C4CC4)c23)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.6 %

Procedure:
To a solution of [9-chloro-1-(2-chloro-4-methoxyphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](cyclopropyl)methanol (120 mg, 0.26 mmol), 1,1′-(azodicarbonyl)dipiperidine (131 mg, 0.52 mmol) in tetrahydrofuran (5.0 mL) was added tri(n-butyl)phosphine (0.130 mL, 0.52 mmol) at room temperature. After the mixture was stirred at room temperature for 10 min under nitrogen atmosphere, 2,2-difluoroethanol (0.165 mL, 2.61 mmol) was added to the reaction mixture. The mixture was stirred at 50° C. for 16 hr under nitrogen atmosphere. The mixture was concentrated in vacuo and diethyl ether was added to the residue. The solid was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture and recrystallization from ethyl acetate/n-hexane to give the title compound (72.8 mg, 0.155 mmol, 58%) as colorless crystals.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[C:13]1([OH:21])[C:14]([CH3:20])=[CH:15][CH:16]=[CH:17][C:18]=1[CH3:19].C1(C)C=CC=CC=1>O>[CH3:1][S:2]([O:21][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(C)c1O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(C)c1OS(C)(=O)=O

Procedure:
12.5 Parts of methanesulphonyl chloride and 11.0 parts of triethylamine were added separately and simultaneously to a solution of 12.2 parts of 2,6-xylenol (the material available commercially from Synthetic Chemicals Limited and containing at least 92% 2,6-xylenol) in 65 parts of toluene over 40 minutes. The reaction mixture was mechanically agitated and the temperature was maintained at 40°-50° C. with external cooling. After agitating for a further 30 minutes, 24 parts of water were added, and the two phase mixture was separated. Evaporation of the organic phase gave 19.7 parts of 2,6-xylyl methanesulphonate. The product was purified by distillation at 188°-191° C. at 30 mm. On cooling the ester solidified, remelting at 26°-27° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:18][S:19][C@@H:20]([C:45](=[O:58])N4[C@@H](C5C=CC=CC=5)COC4=O)[C@@H:21]([C:30]4[CH:44]=[CH:43][C:33]([O:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:32][CH:31]=4)[NH:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][O:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:18][S:19][C@H:20]4[C:45](=[O:58])[N:22]([C:23]5[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=5)[C@@H:21]4[C:30]4[CH:44]=[CH:43][C:33]([O:34][CH2:35][C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])=[CH:32][CH:31]=4)[O:11][CH2:12][C:13]([CH3:17])([CH3:16])[CH2:14][O:15]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC1(C)COC(CS[C@@H](C(=O)N2C(=O)OC[C@@H]2c2ccccc2)[C@H](Nc2ccc(F)cc2)c2ccc(OCC(=O)OC(C)(C)C)cc2)(c2ccc3c(c2)OCO3)OC1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)COC(CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)OC(C)(C)C)cc2)(c2ccc3c(c2)OCO3)OC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
tert-Butyl (4-{(1R,2R)-2-({[2-(1,3-benzodioxol-5-yl)-5,5-dimethyl-1,3-dioxan-2-yl]methyl}thio)-1-[(4-fluorophenyl)amino]-3-oxo-3-[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]propyl}phenoxy)acetate (Method 15) (22.30 g, 27.4 mmol) was dissolved in dry toluene (800 mL) and heated to 90° C. under inert atmosphere. N,O-Bis(trimethylsilyl)acetamide (BSA, 20.1 mL, 82.1 mmol) was added and the mixture was stirred at 90° C. for one hour. The mixture was then given 45° C. and tetrabutylammonium fluoride trihydrate (TBAF, cat., 1 g) was added and the mixture was stirred at 45° C. for 1 hour. The mixture was then concentrated under reduced pressure and purified by flash-chromatography (heptane:EtOAc 5:1). This afforded 10.0 g (56%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].Cl[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[CH2:18][CH2:17]1.[OH-].[Na+]>C(O)CCC.O>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[CH2:20][CH2:21]1
Reactant: COc1ccccc1N1CCN(CCCl)CC1
Reactant: Nc1ccccc1OC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCO
Product: COc1ccccc1N1CCN(CCNc2ccccc2OC(F)(F)F)CC1

Procedure:
A solution of 2.09 g of 2-trifluoromethoxyaniline and 3.15 g of 1-(2-chloroethyl)-4-(2-methoxyphenyl)piperazine in 20 mL of n-butanol was stirred at 100° C. for 2 hrs. The mixture was then cooled, diluted with H2O alkalinized with 2 N NaOH and extracted with CHCl3. The organic phase was dried on anhydrous Na2SO4, evaporated until dry and the crude purified via flash chromatography (EtOAc-petrolium ether 3:7) and subsequently crystallized from EtOH giving 0.55 g (12%) of the title compound. Melting point: 69.5-71° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[N:26][C:5]2[O:6][C:7]([CH3:25])([CH3:24])[C:8](=[O:23])[N:9]([CH:10]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[C:4]=2[CH:3]=1.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>ClCCl>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[Cl:1][C:2]1[CH:27]=[N:26][C:5]2[O:6][C:7]([CH3:24])([CH3:25])[C:8](=[O:23])[N:9]([CH:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]3)[C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)C(C)(C)Oc3ncc(Cl)cc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)Oc2ncc(Cl)cc2N(C2CCNCC2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under ice cooling, to a dichloromethane solution (145 ml) of tert-butyl 4-(7-chloro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)piperidine-1-carboxylate (74.2 g) was added trifluoroacetic acid (145 ml), followed by stirring at room temperature for 3 hours. After the reaction solution was concentrated under reduced pressure, ether was added to the residue, and the slurry was stirred overnight. The insolubles were collected by filtration to afford 7-chloro-3,3-dimethyl-1-piperidin-4-yl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one trifluoroacetate (76.1 g).