Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(S([C:6]1[N:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[CH:9]=[C:8]([O:23][C:24]2[CH:25]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:28][CH:29]=2)[N:7]=1)(=O)=O)C.C(Cl)(Cl)Cl.C(O)C.[BH4-].[Na+]>C(OCC)(=O)C>[F:22][C:19]([F:20])([F:21])[C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][C:10]1[CH:9]=[C:8]([O:23][C:24]2[CH:25]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:27]=[CH:28][CH:29]=2)[N:7]=[CH:6][N:11]=1
Reactant: CCS(=O)(=O)c1nc(Cc2cccc(C(F)(F)F)c2)cc(Oc2cccc(C(F)(F)F)c2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: FC(F)(F)c1cccc(Cc2cc(Oc3cccc(C(F)(F)F)c3)ncn2)c1
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 93.1 %

Procedure:
2-(Ethylsulfonyl)-4-[m-(trifluoromethyl)benzyl] -6-[(α,α,α-trifluoro-m-tolyl)oxy]pyrimidine (1.17 g, 2.4 mmol) is added to chloroform (10 ml) and ethanol (10 ml). sodium borohydride (0.3 g, 7.9 mmol) is added portionwise over 15 minutes and the reaction is stirred at room temperature for 80 mins. The mixture is taken up in ethyl acetate and is washed with water, brine and dried over magnesium sulfate. The solvent is evaporated to give 1.05 g of a cloudy oil which is chromatographed to yield 0.89 g 4-[m-(trifluoromethyl)benzyl]-6-[(α,α,α-trifluoro-m-tolyl)oxy]pyrimidine as a water white oil. 1H NMR CDCl3 4.17 (2H, s) 6.75 (1H,s) 7.3-7.6 (8H, m) 8.71 (1H, s)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:31][CH:30]=3)=[CH:25][N:24]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:43]1[CH2:46][CH:45]([C:47]([O:49][C:50]([CH3:53])(C)C)=[O:48])[CH2:44]1.[CH3:54][CH2:55]N(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:31][CH:30]=3)=[CH:25][N:24]=2)=[CH:19][CH:18]=1)[C:13]([N:43]1[CH2:44][CH:45]([C:47]([O:49][CH2:50][CH2:53][CH2:54][CH3:55])=[O:48])[CH2:46]1)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)C1CNC1
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)OCc4ccccc4)C(=O)O)cc3)nc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)OCc4ccccc4)C(=O)N4CC(C(=O)OCCCC)C4)cc3)nc2)cc1
Reaction time: 0.17 h

Procedure:
Prepared using General Procedure 7: A stirred solution of (S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl) propanoic acid INT-22 (1 g, 1.76 mmol), tert-butyl azetidine-3-carboxylate (0.554 g, 1.76 mmol) and DIEA (1.30 mL, 7.05 mmol) in DMF (20 mL) at 0° C. was treated with HATU (0.703 g, 1.85 mmol), added portionwise. After 10 min, the cooling bath was removed. After a further 1 h the mixture was poured onto 0.2 M HCl (100 mL) and extracted with EA (3×30 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO4 and evaporated. Column chromatography (EA/DCM/iso-hexanes) gave 708 mg (58%) often-butyl (S)-1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate as an off-white solid. LCMS-ESI (m/z) calculated for C42H50N4O6: 706.4. found 707.1 [M+H]+, tR=3.60 min (Method 6).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([Cl:24])=[CH:5][C:6]2[C:7](=[O:23])[N:8]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:9](=[O:16])[C:10]3[C:15]=2[C:14]=1[CH:13]=[CH:12][CH:11]=3.[CH:25](=O)[CH3:26].C([BH3-])#N.[Na+]>CO.O>[NH2:2][C:3]1[C:4]([Cl:24])=[CH:5][C:6]2[C:7](=[O:23])[N:8]([CH:17]3[CH2:18][CH2:19][N:20]([CH2:25][CH3:26])[CH2:21][CH2:22]3)[C:9](=[O:16])[C:10]3[C:15]=2[C:14]=1[CH:13]=[CH:12][CH:11]=3
Reactant: CC=O
Reactant: Nc1c(Cl)cc2c3c(cccc13)C(=O)N(C1CCNCC1)C2=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCN1CCC(N2C(=O)c3cccc4c(N)c(Cl)cc(c34)C2=O)CC1
Reaction time: 2 h

Procedure:
To a solution of 6-amino-5-chloro-2,3-dihydro-2-(piperidin-4-yl)-1H-benz[de]isoquinoline-1,3-dione hydrochloride (0.9 g; 2.46 mmol), prepared as in Example 10, in methanol (30 mL) and water (5 mL), was added acetaldehyde (2 mL) and sodium cyanoborohydride (approximately 0.5 g) and the reaction mixture stirred for two hours. Additional sodium cyanoborohydride (0.4 g) was added and the mixture stirred for an additional 2 hours. The solution was concentrated to a small volume, acidified with concentrated hydrochloric acid, and then digested for 16 hours. Solid potassium carbonate was added and the solution was extracted twice with methylene chloride. The extracts were combined, dried over potassium carbonate, and concentrated. Purification by column chromatography (silica gel; 3% methanol in CH2Cl2 and approximately 1% NH4OH) gave 6-amino-5-chloro-2-(1-ethylpiperidin-4-yl)-2,3-dihydro-1H-benz[de]isoquinoline-1,3-dione (0.6 g; 1.68 mmol).
Reaction SMILES: [CH2:1]([N:8]([CH3:12])[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21].C(Cl)Cl>CN(C)C1C=CN=CC=1.CC(OC)(C)C>[C:20]([O:11][CH2:10][CH2:9][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:12])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CN(CCO)Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: COC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCN(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
To a 500 mL dry round bottom flask were added 2-(benzyl(methyl)amino)ethanol (46.3 g, 280.2 mmol), triethylamine (150 mL, 1.08 mol), acetic anhydride (31.8 mL, 336.2 mmol), anhydrous CH2Cl2 (100 mL) and a crystal piece of DMAP (4-Dimethylaminopyridine). The mixture was stirred at room temperature for 3 hours. MTBE (700 mL) was added into the reaction mixture, and this mixture was washed, respectively, with cold 2N NaOH (150 mL), water (100 mL), brine (150 mL). The MTBE layer was concentrated, and the residue was poured onto a silica gel pad (200.0 g). The pad was eluted with a co-solvents of ethyl acetate: heptane=3:1 to give 2-(benzyl(methyl)amino)ethyl acetate (50.8 g) as a yellow oil. Yield: 87%. 1H NMR (CDCl3, 300 MHz): δ=7.41-7.25 (m, 5H), 4.29 (t, J=6.3 Hz, 2H), 3.65 (s, 2H), 2.74 (t, J=6.0 Hz, 2H), 2.38 (s, 3H), 2.14 (s, 3H). 13C NMR (CDCl3, 75.5 MHz): δ=170.9, 138.7, 128.9, 128.2, 127.1, 62.5, 62.2, 55.3, 42.6, 21.0.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][CH2:11]2.CS(C)=O.[Br:26]N1C(=O)CCC1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:1]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[C:10]([Br:26])[CH2:11]2
Reactant: C1=Cc2c(cccc2-c2ccccc2-c2ccccc2)C1
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Solvent: O
Product: BrC1=Cc2c(cccc2-c2ccccc2-c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
A cold solution (5° C.) of compound 5 (40 g, 149 mmol, 1 equiv), dimethyl sulfoxide (400 mL) and water (5 mL) was treated in one portion with N-bromosuccinimide (39.8 g, 224 mmol, 1.5 equiv). The bath was removed and the reaction allowed to stir at room temperature overnight. The reaction was poured into water (1 L) and extracted with ethyl acetate (2×500 mL). The combined organic layers were washed with saturated brine (1 L), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in 500 mL of toluene and p-toluenesulfonic acid (5.6 g, 29.4 mmol, 0.2 equiv) was added. This mixture was refluxed for 20 hours while removing water with a Dean-Stark trap. The reaction was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified over silica gel (1 Kg), eluting with heptanes to give compound 6 (39 g, 75% yield) as a light yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:20][CH2:19]3)[C:9]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=3[CH2:11][CH2:12][C:3]=12.[Na].[SH:34][C:35]1[N:39](C)[N:38]=[N:37][N:36]=1.[CH3:41]N(C=O)C>>[Cl:17][C:14]1[CH:15]=[CH:16][C:9]2[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:20][CH2:19]3)[C:4]3=[N:5][CH:6]=[CH:7][C:2]([S:34][C:35]4[N:39]=[N:38][N:37]([CH3:41])[N:36]=4)=[C:3]3[CH2:12][CH2:11][C:10]=2[CH:13]=1
Reactant: O=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c(Cl)ccnc32)CC1
Reactant: Cn1nnnc1S
Reactant: CN(C)C=O
Agent: [Na]
Product: Cn1nnc(Sc2ccnc3c2CCc2cc(Cl)ccc2C3=C2CCN(C(=O)Cc3cccnc3)CC2)n1
Yield: 68 %

Procedure:
A mixture of the title compound from Example 250 (0.24 grams), 5-mercapto-1-methyltetrazole sodium salt (0.6 grams) and anhydrous DMF (10 mL) was stirred while being irradiated with a 200 W lamp for 10 days. Isolation and purification as in Example 257 provided the title compound (0.2 grams, 68%, MH+ 544).
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].[H-].[Na+].Br[CH2:16][C@:17]1([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[CH2:19][CH:18]1[CH2:20]Br.C(OCC)(=O)C.CCCCCC>CN(C)C=O>[C:7]1([S:4]([C:3]2([S:2][CH3:1])[CH2:20][C@@H:18]3[C@@:17]([C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24][CH:23]=4)([CH2:19]3)[CH2:16]2)(=[O:5])=[O:6])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CSCS(=O)(=O)c1ccccc1
Reactant: BrCC1C[C@]1(CBr)c1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CSC1(S(=O)(=O)c2ccccc2)C[C@H]2C[C@@]2(c2cccc3ccccc23)C1
Temperature: 40 °C
Yield: 69.5 %

Procedure:
1-((Methylthio)methylsulfonyl)benzene (2.85 g, 14.1 mmole) was dissolved in dry dimethylforamide (DMF, 15 mL). Sodium hydride (1.69 g, 35.3 mmol) was added portion wise under nitrogen atmosphere at 0° C. The reaction mass was gradually heated to 40° C. and maintained for 30 min at 40° C. A solution of (1R)-1,2-bis(bromomethyl)-1-(1-naphthyl)cyclopropane (2.5 g, 7.0 mmol) in DMF (5 mL) was added dropwise for 30 min at 0° C. The temperature of the reaction mass was slowly brought to room temperature and maintained for 7 hours. The reaction was monitored by TLC (ethyl acetate/hexane (10:90)). The reaction mass was quenched with water. The aqueous layer was extracted with diethyl ether (2×150 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 10.0 g of crude oil that was purified by column chromatography (silica gel, ethyl acetate/hexane (4:96) to yield 1.92 g (69%) of product. 1H NMR δ(300 MHz,CDCl3): 1.93 (2H,m), 2.01 (1H,m), 2.07 (3H,s), 2.28 (2H,m), 2.44 (2H,m), 2.88 (1H,dd, J=15 Hz), 7.36 (1H,m), 7.47-7.68 (7H,m), 7.74 (1H,m), 7.91-7.97 (3H,m).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9].Cl[C:11]1[C:20]([C:21]#[N:22])=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:29])[CH:17]=2)[N:12]=1>C1(C)C=CC=CC=1.O>[Cl:29][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9])[C:20]([C:21]#[N:22])=[C:19]2[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C1CCCCN1
Reactant: N#Cc1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1c(N2CCCCC2=O)nc2ccc(Cl)cc2c1-c1ccccc1
Temperature: 100 °C
Yield: 64.9 %

Procedure:
To a suspension of sodium hydride (31.5 mg, 55% in mineral oil, 0.723 mmol) in toluene (4 ml) was added piperidin-2-one (133 mg, 1.34 mmol) followed by 2,6-dichloro-4-phenyl-quinoline-3-carbonitrile (prepared as described in example 27 step B) (200 mg, 0.669 mmol) and the mixture was heated to 100° C. for 6 h. The reaction mixture was cooled to room temperature, diluted with water and extracted twice with DCM and twice with EtOAc. The combined extracts were washed with brine, dried with Na2SO4 and evaporated. The remaining residue was triturated with cold diethyl ether to afford the title compound (157 mg, 62%) as light yellow solid. MS (ESI): 362.3 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([NH:20][C:21](=O)[CH3:22])[CH2:7][CH2:8][O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)(=O)C.[CH3:24]I>>[CH3:1][O:4][CH2:5][CH:6]([N:20]([CH2:21][CH3:22])[CH3:24])[CH2:7][CH2:8][O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)NC(CCOc1cccc2ccccc12)COC(C)=O
Reactant: CI
Product: CCN(C)C(CCOc1cccc2ccccc12)COC

Procedure:
2-(acetylamino)-4-(1-naphthyloxy)-1-butanol acetate, described in Example 5, with methyl iodide, followed by reduction, gives 1-methoxy-N-ethyl-N-methyl-4-(1-naphthyloxy)-2-butanamine, and
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C([N:12]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH2:20][CH2:21][CH2:22]3)[CH2:13]1)C1C=CC=CC=1>C1C=CC=CC=1>[CH2:22]1[C:23]2[C:19](=[C:18]([O:17][CH:14]3[CH2:15][CH2:16][N:12]([C:1]([Cl:4])=[O:2])[CH2:13]3)[CH:26]=[CH:25][CH:24]=2)[CH2:20][CH2:21]1
Reactant: c1ccc(CN2CCC(Oc3cccc4c3CCC4)C2)cc1
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)N1CCC(Oc2cccc3c2CCC3)C1
Reaction time: 18 h
Yield: 91 %

Procedure:
To a stirred solution of 6.9 g (0.07 mole) of phosgene in 100 ml of anhydrous benzene under nitrogen gas and cooled at 10° C. was added dropwise a solution of 18.13 g (0.062 mole) of 1-benzyl-3-(4-indanyloxy)pyrrolidine in 50 ml of dry benzene. After stirring for 18 hr, the slightly turbid reaction mixture was filtered through celite. The filtrate was washed with 50 ml of ice-water, dried over magnesium sulfate and concentrated on a rotary evaporator. The solid residue was triturated with boiling isopropyl ether. Fifteen grams of crude product was obtained by filtering the mixture. Recrystallization from a mixture of benzene and 30/60 petroleum ether gave 13.1 g of cream colored solid, m.p. 128°-129° C.
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([CH3:12])[N:9]=[C:10]([CH3:11])[N:6]2[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.Cl.Cl.[NH2:21][CH2:22][CH2:23][NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:12][C:8]1[N:9]=[C:10]([CH3:11])[N:6]2[C:7]=1[C:2]([NH:21][CH2:22][CH2:23][NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=1)=[N:3][C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[N:5]2
Reactant: Cc1nc(C)n2nc(-c3ccccc3)nc(Cl)c12
Reactant: N#Cc1ccc(NCCN)nc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C)n2nc(-c3ccccc3)nc(NCCNc3ccc(C#N)cn3)c12
Temperature: 150 °C

Procedure:
183 mg (0.71 mmol) of the 4-chloro-5,7-dimethyl-2-phenylimidazo[5,1-f][1,2,4]triazine (Example 16A) were initially charged in 4 ml of DMSO, and 200 mg (0.85 mmol) of 6-[(2-aminoethyl)amino]nicotinonitrile (Example 2A) and 1.23 ml (7 mmol) of N,N-diisopropylethylamine were added and the mixture was heated at 150° C. for 12 h. Purification by chromatography on silica gel (mobile phase: dichloromethane/methanol 100:1) gave 10 mg (4% of theory) of the product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH:5]([C:7]1[C:12]([O:13][CH2:14][O:15][CH3:16])=[CH:11][CH:10]=[CH:9][N:8]=1)[OH:6].ClC1C=CC=C(C(OO)=[O:28])C=1.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH:5]([C:7]1[C:12]([O:13][CH2:14][O:15][CH3:16])=[CH:11][CH:10]=[CH:9][N+:8]=1[O-:28])[OH:6]
Reactant: COCOc1cccnc1C(O)c1cccc(Br)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1ccc[n+]([O-])c1C(O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
A mixture of 2-(3-bromo-α-hydroxybenzyl)-3-methoxymethoxy pyridine (4.65 g), 70% m-chloro-perbenzoic acid (7.10 g) and tetrahydrofuran (200 mL) was stirred overnight at room temperature, to which was poured an aqueous solution of sodium sulfite. The mixture was stirred for 30 minutes, and then subjected to extraction with ethyl acetate. The extract was washed with water and a saturated aqueous saline solution, successively, and dried (sodium sulfate) and then concentrated. The concentrate was purified by means of a silica gel column (ethyl acetate--hexane) to afford 2-(3-bromo-α-hydroxybenzyl)-3-methoxymethoxypyridine 1-oxide (4.58 g). Spectrum data of the product are shown below:
Reaction SMILES: [C:1]([O:4][C@@H:5]([C@H:9]([O:40][C:41](=[O:43])[CH3:42])[C@H:10]([O:36][C:37](=[O:39])[CH3:38])[C@@H:11]([NH:17][C:18](=[O:35])[C@H:19]([CH2:31][CH:32]([CH3:34])[CH3:33])[NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:12][O:13][C:14](=[O:16])[CH3:15])[C:6](O)=[O:7])(=[O:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:59][C@H:60]([C:67]1[CH:72]=[CH:71][C:70]([CH3:73])=[CH:69][CH:68]=1)[CH2:61][C:62]([O:64][CH2:65][CH3:66])=[O:63].C(N(CC)CC)C>C(#N)C>[C:1]([O:4][C@@H:5]([C@H:9]([O:40][C:41](=[O:43])[CH3:42])[C@H:10]([O:36][C:37](=[O:39])[CH3:38])[C@@H:11]([NH:17][C:18](=[O:35])[C@H:19]([CH2:31][CH:32]([CH3:34])[CH3:33])[NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:12][O:13][C:14](=[O:16])[CH3:15])[C:6]([NH:59][C@H:60]([C:67]1[CH:68]=[CH:69][C:70]([CH3:73])=[CH:71][CH:72]=1)[CH2:61][C:62]([O:64][CH2:65][CH3:66])=[O:63])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C[C@H](N)c1ccc(C)cc1
Reactant: CC(=O)OC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@H](NC(=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H](COC(C)=O)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
To a solution of [(2S,3R,4R,5S)-2,3,4,6-tetraacetoxy-5-(N-benzyloxycarbonyl-L-leucyl)aminohexanoic acid (250 mg) in acetonitrile (10 ml) were added N-hydroxy-5-norbornene-2,3-dicarboxyimide (110 mg) and N,N′-dicyclohexylcarbodimide (110 mg) and the mixture was stirred at room temperature for 1 hour. After addition of a solution of ethyl (S)-3-amino-3-(4-methylphenyl)propionate (150 mg) and triethylamine (0.13 ml) in acetonitrile (10 ml), the whole was stirred at room temperature for 18 hours. The formed insoluble solid was filtrated off and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 ml) and washed with saturated brine (50 ml×2), followed by drying over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was passed through silica gel column chromatography, followed by elution with ethyl acetate-hexane (2:1). The effective fractions were combined and concentrated under reduced pressure to afford the title compound (184 mg).
Reaction SMILES: O[C:2]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[C:8]([OH:16])[CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:17][O-:18].[Na+].Cl[CH2:21][CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25]>CO.ClC1C=CC=CC=1>[CH2:22]([N:23]([CH2:26][CH2:17][O:18][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[C:8]([O:16][CH2:21][CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:24][CH3:25])[CH3:21]
Reactant: C[O-]
Reactant: O=C1c2cccc(O)c2-c2cccc(O)c21
Reactant: CCN(CC)CCCl
Agent: [Na+]
Solvent: CO
Solvent: Clc1ccccc1
Product: CCN(CC)CCOc1cccc2c1C(=O)c1cccc(OCCN(CC)CC)c1-2

Procedure:
In a manner analogous to Example 3D1, prepare a solution of 1,5-dihydroxy-fluoren-9-one (0.5 g, 2.3 mmole) in 4 mL of methanol and 12 mL chlorobenzene, then add the sodium methoxide (0.28 g, 5.1 mmole). The free base 2-chloro-ethyl-diethyl amine is added (1.1 g, 6 mmole) in 20 mL chlorobenzene. Work-up the reaction in the usual manner to obtain the title compound. m.p. 180-184° C. (dec.). Yield 0.68 g, 61%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21](O)=[O:22])[N:9]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Br.[S:34]1[C:43]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38][C:37]=2[N:36]=[C:35]1[NH2:44].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[NH2:44][C:35]1[S:34][C:43]2[CH2:42][CH2:41][N:40]([C:21](=[O:22])[CH2:20][N:10]3[C:11]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)=[CH:12][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9]3)[CH2:39][CH2:38][C:37]=2[N:36]=1
Reactant: O=C(O)Cn1nc(-c2ccc(F)cc2)cc1-c1ccc(F)cc1
Reactant: Nc1nc2c(s1)CCNCC2
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1nc2c(s1)CCN(C(=O)Cn1nc(-c3ccc(F)cc3)cc1-c1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.7 %

Procedure:
100 mg (3,5-bis-(4-fluoro-phenyl)-pyrazol-1-yl)-acetic acid was dissolved in 2 mL DMF. 165 mg PFTU and 170 μL DIPEA were added to this solution and the mixture was stirred for 15 min at RT. Then, 160 mg 5,6,7,8-Tetrahydro-4H-thiazolo (4,5-d) azepin-2-ylamine hydrobromide was added and the reaction was stirred over night. Then, K2CO3 solution (5%) and CH2Cl2 were added, the organic phase was separated and washed two times with water. The solvent was removed and the residue was purified by HPLC (method 1) to give 78 mg of the desired compound. Rt: 0.80 min (method C), (M+H)+: 466
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[Cu](C#N)[C:19]#[N:20].O.Cl>CN(C)C=O.[Fe](Cl)Cl>[C:19]([C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:5]=[CH:6][CH:7]=1)#[N:20]
Reactant: N#C[Cu]C#N
Reactant: Brc1cccc(CCOCCc2ccsc2)c1
Agent: Cl[Fe]Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(CCOCCc2ccsc2)c1
Temperature: 150 °C
Reaction time: 8 h
Yield: 44.9 %

Procedure:
46 mg of the resulting ether compound was dissolved in 1 ml of dimethylformamide, and 17 mg of copper cyanide was added. The mixture was stirred overnight at 150° C. To this solution was added, a mixture of 39 mg of iron(II) chloride, 0.1 ml of water and 16 μl of hydrochloric acid, and the mixture was stirred at 60° C. for 30 minutes. The solution was extracted with ethyl ether, and the extract was worked up in a customary manner to give 17 mg of 3-[2-[2-(3cyanophenyl)ethoxy]ethyl]thiophene as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.N1C=CC=CC=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[CH2:11]([O:10][C:6]1[C:7](=[O:9])[CH:8]=[C:3]([CH2:2][NH:1][S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])[O:4][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1cc(=O)c(OCc2ccccc2)co1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=c1cc(CNS(=O)(=O)c2ccccc2)occ1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.5 %

Procedure:
To a stirred solution of 2-aminomethyl-5-benzyloxy-pyran-4-one (5) (4.4 gm, 19.05 mmol) in dichloromethane (100 mL) was added pyridine (6.15 mL, 76.19 mmol) under ice cold conditions, followed by addition of benzene sulfonyl chloride (6-01) (6.07 mL, 47.62 mmol) and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, it was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with saturated NaHCO3, water and brine, dried over Na2SO4 and concentrated under reduced pressure. It was then purified using normal column chromatography to get N-(5-benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-benzene sulfonamide (7-01) (2.3 gm, 32.51%) as an off white solid.