Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Oc1ccc(F)c(Br)c1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(F)c(Br)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-bromo-4-fluorophenol (2.18 g, 11.4 mmol) in DMF (15 mL) was added potassium carbonate (3.15 g, 22.8 mmol) portion wise at room temperature. The mixture was stirred at room temperature for 10 minutes then 4-methoxybenzyl chloride (1.55 mL, 11.4 mmol) was added drop wise. On completion of the addition the reaction was heated at 60° C. under nitrogen for 15 hours. The cooled reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3×50 mL). The combined extracts were washed with 1M aqueous NaOH solution (50 mL) and brine (50 mL), then dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford the crude title compound as an off-white solid in quantitative yield, 3.62 g.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[C:10]([CH:12]=[O:13])[N:11]=1)=[O:5].S([CH2:39][N+:40]#[C-:41])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[F:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)=[C:10]([C:12]2[O:13][CH:41]=[N:40][CH:39]=2)[N:11]=1)=[O:5]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(Nc1nc(-c2cnco2)c(-c2cccc(C(F)(F)F)c2)s1)c1c(F)cccc1F
Temperature: 65 °C
Yield: 72.4 %

Procedure:
Into a solution of Compound 67 (62 mg, 0.15 mmol) in 5 mL of dry methanol was added tosylmethyl isocyanide (35 mg, 0.18 mmol), followed by dry potassium carbonate (25 mg, 0.18 mmol). The reaction mixture was heated to 65° C. for 2 hours. The reaction mixture was dissolved in ethyl acetate, washed each with water and brine, dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel (eluted with 10-50% ethyl acetate in hexanes) to give Compound 76 (49 mg, 72%) as a white solid.
Reaction SMILES: N#N.[Cl:3][CH2:4][C:5]1[N:6]=[C:7]([CH:10]([OH:12])[CH3:11])[S:8][CH:9]=1>CC#N.O=[Mn]=O>[Cl:3][CH2:4][C:5]1[N:6]=[C:7]([C:10](=[O:12])[CH3:11])[S:8][CH:9]=1
Reactant: CC(O)c1nc(CCl)cs1
Agent: O=[Mn]=O
Agent: N#N
Solvent: CC#N
Product: CC(=O)c1nc(CCl)cs1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(4-chloromethyl-thiazol-2-yl)-ethanol (2.19 g, 12.31 mmol) in CH3CN (122 mL) was treated at rt with MnO2 (5.94 g, 61.52 mmol). The reaction mixture was stirred at rt until completion of the reaction, and then filtered through Celite. The solvent was removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 02: tR=0.84 min.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7]([CH3:12])=[C:8]([C:10]#[N:11])[O:9][C:5]=2[CH:4]=1.C([O-])(O)=O.[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:2]([C:3]1[CH:14]=[CH:13][C:6]2[C:7]([CH3:12])=[C:8]([C:10]#[N:11])[O:9][C:5]=2[CH:4]=1)=[O:1]
Reactant: Cc1c(C#N)oc2cc(CO)ccc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(C#N)oc2cc(C=O)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
To a solution of 6-(hydroxymethyl)-3-methylbenzofuran-2-carbonitrile (116 mg, 0.62 mmol) in 6 mL of DCM was added NaHCO3 (125 mg, 1.49 mmol), followed by Dess-Martin periodinane (315 mg, 0.74 mmol). The reaction was stirred at room temperature for 1 hr. The reaction was quenched by addition of 2 mL of sat. NaHCO3 and 2 mL of sat. Na2S2O3 and stirred for 30 min. The reaction mixture was extracted with DCM (3×50 mL), the organic layer was washed with H2O, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography 100% Heptane-50% Ethyl Acetate/50% Heptane) to give 6-formyl-3-methylbenzofuran-2-carbonitrile (96 mg). 1H NMR (400 MHz, DMSO-d6) δ 2.51 (br. s., 3H), 7.97 (dd, J=8.1, 1.2 Hz, 1H), 8.04-8.09 (m, 1H), 8.27 (s, 1H), 10.14 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:28](C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.C(O)(=O)C(O)=O.N1C2(COC2)CC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[C:23]3([CH2:28][O:25][CH2:24]3)[CH2:26][CH2:27]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: C1CC2(COC2)N1
Agent: O=C(O)C(=O)O
Product: CC(C)(C)c1nc(N2CCC23COC3)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 6-oxa-1-azaspiro[3.3]heptane oxalate and isolated as light-yellow gum (12.5 mg, 65%). MS (m/e): 399.4 (MH+).
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[CH2:15]([CH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([C:32]2[N:33]=[CH:34][N:35](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:36]=2)(O)[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[CH2:15]([CH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([C:32]2[N:33]=[CH:34][NH:35][CH:36]=2)=[CH:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: OC1(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)CC(Cc2ccccc2)c2ccccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1=C(c2c[nH]cn2)c2ccccc2C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Triethylsilane (1 ml, 0.728 g, 6.26 mmol) and trifluoroacetic acid (1.9 ml, 2.81 g, 24.7 mmol) were added to the solution of 3-benzyl-1-(1-trityl-1H-imidazol-4-yl)indan-1-ol (0.387 g, 0.73 mmol) in dichloromethane (13 ml). The reaction was stirred at room temperature for 20 hr. Then the reaction was quenched with water and made basic with the 2 M sodium hydroxide solution. The dichloromethane layer was washed with water and dried over sodium sulfate. The solvent was removed under reduced pressure. Flash chromatography using a dichloromethane-methanol gradient afforded 4-(3-benzyl-3H-inden-1-yl)-1H-imidazole.
Reaction SMILES: [CH2:1]([C@H:5]1[C@@H:14]([NH2:15])[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6]1)[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C(Cl)Cl>[CH2:1]([C@@H:5]1[C@@H:14]([NH:15][C:23](=[O:24])[O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:13][CH2:12][C:7]2([O:8][CH2:9][CH2:10][O:11]2)[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCCC[C@@H]1CC2(CC[C@@H]1N)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCC[C@H]1CC2(CC[C@@H]1NC(=O)OCc1ccccc1)OCCO2
Reaction time: 0.5 h
Yield: 43.2 %

Procedure:
A solution of crude (7R,8S)-7-(butyl)-8-(amino)-1,4-dioxa-spiro[4.5]decane (4.2 g, 0.02 mol) in 100 mL of CH2Cl2 was treated with an aqueous solution of K2CO3 and cooled in a ice bath. The mixture is stirred vigorously while benzyl chloroformate (3.42 g, 0.02 mol) is added slowly. After the addition is complete the mixture is stirred an additional 30 min. The organic layer is separated and washed with water, brine and concentrated. The residue was chromatographed on silica gel to give 3 g of benzyl ((7S,8S)-7-(butyl)-1,4-dioxa-spiro[4.5]dec-8-yl)-carbamate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[C:15]3[C@@H:14]4[CH2:16][C@@H:13]4[CH2:12][C:11]=3[C:10]([C:17]([OH:19])=O)=[N:9]2)=[CH:4][CH:3]=1.COC1N=NC(N2C3[C@@H]4C[C@@H]4CC=3C(C(O)=O)=N2)=CC=1.[NH2:40][C:41]([CH3:45])([CH3:44])[CH2:42][OH:43].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:43][CH2:42][C:41]([NH:40][C:17]([C:10]1[C:11]2[CH2:12][C@H:13]3[CH2:16][C@H:14]3[C:15]=2[N:8]([C:5]2[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1)=[O:19])([CH3:45])[CH3:44]
Reactant: O=C(O)c1nn(-c2ccc(Cl)nn2)c2c1C[C@H]1C[C@@H]21
Reactant: CC(C)(N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COc1ccc(-n2nc(C(=O)O)c3c2[C@@H]2C[C@@H]2C3)nn1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(CO)NC(=O)c1nn(-c2ccc(Cl)nn2)c2c1C[C@H]1C[C@@H]21
Temperature: 23 °C
Reaction time: 3 h

Procedure:
To a solution of a 4:1 mixture of (1aR,5aR)-2-(6-chloropyridazin-3-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid and (1aR,5aR)-2-(6-methoxypyridazin-3-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (100 mg, 0.361 mmol), 2-amino-2-methylpropan-1-ol (32.2 mg, 0.361 mmol), and triethylamine (0.101 mL, 0.723 mmol) in DMF (2 mL) was added HATU (151 mg, 0.398 mmol). The reaction was stirred at 23° C. for 3 h then concentrated. The residue was purified by HPLC to provide the title compound (73 mg) as a white solid. LCMS m/z=348.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.47 (td, J=4.6, 3.3 Hz, 1H), 1.29 (td, J=7.9, 4.9 Hz, 1H), 1.41 (s, 3H), 1.42 (s, 3H), 2.30-2.36 (m, 1H), 2.88-2.94 (m, 2H), 3.01 (dd, J=16.4, 6.2 Hz, 1H), 3.72 (s, 2H), 3.84 (bs, 1H), 6.88 (s, 1H), 7.61 (d, J=9.1 Hz, 1H), 8.12 (d, J=9.2 Hz, 1H).
Reaction SMILES: [O-:1][P:2]1([O:19][P:17]([O-:20])(=[O:18])[O:16]P([O-])(=O)OP([O-])(=O)OP([O-])(=O)[O:7][P:5]([O-:24])(=[O:6])[O:4]1)=[O:3].[Na+:25].[Na+].[Na+].[Na+].[Na+].[Na+].[O-]P(OP(OP(OP([O-])([O-])=O)([O-])=O)([O-])=O)(=O)[O-].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+]>>[O-:20][P:17]([O:19][P:2]([O:4][P:5]([O-:24])([O-:7])=[O:6])([O-:3])=[O:1])([O-:18])=[O:16].[Na+:25].[Na+:25].[Na+:25].[Na+:25].[Na+:25]
Reactant: O=P1([O-])OP(=O)([O-])OP(=O)([O-])OP(=O)([O-])OP(=O)([O-])OP(=O)([O-])O1
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Agent: [Na+]
Product: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]

Procedure:
higher condensed sodium polyphosphates, e.g., sodium hexametaphosphate, hexasodium tetraphosphate (Graham's Salt);
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH:9]([F:11])[F:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH4+:12].[OH-]>COCCO>[F:10][CH:9]([F:11])[O:8][C:7]1[C:2]([NH2:12])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)Oc1cccnc1Br
Reactant: [NH4+]
Agent: [OH-]
Solvent: COCCO
Product: Nc1ncccc1OC(F)F
Temperature: 100 °C
Yield: 80.4 %

Procedure:
To a steel bomb were charged with 2-methoxyethanol (20 ml), 2-bromo-3-(difluoromethoxy)pyridine (1.95 g, 8.7 mmol), conc. aqueous NH4OH (28-30%, 5 ml, 79 mmol) and Cu2O (0.25 g, 1.7 mmol). The reaction mixture was heated at 100° C. for 23 h, then cooled to 0° C., and partitioned between mixture of EtOAc/aq. 3 N NaOH/H2O (40 ml/10 ml/30 ml). The organic phase layer was collected, washed with saturated aqueous NaHCO3 solution (30 ml), brine (40 ml), dried (Na2SO4), and concentrated to produce 1.12 g of 3-(difluoromethoxy)pyridin-2-amine which was carried forward without further purification:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9](=[N:16][O:17][CH2:18][C:19]2[N:20]=[C:21]([NH2:24])[S:22][CH:23]=2)[C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[C:25]1([CH2:31][CH2:32][CH:33]=O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl.C([O-])(O)=O.[Na+]>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9](=[N:16][O:17][CH2:18][C:19]2[N:20]=[C:21]([NH:24][CH2:33][CH2:32][CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[S:22][CH:23]=2)[C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=CCCc1ccccc1
Reactant: CSc1cccc(C(=NOCc2csc(N)n2)c2nnnn2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CSc1cccc(C(=NOCc2csc(NCCCc3ccccc3)n2)c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
To a stirred solution of 4-{[({[3-(methylsulfanyl)phenyl](1-methyl-1H-tetrazol-5-yl)methylene}amino)oxy]methyl}-1,3-thiazol-2-amine (90.0 mg, 0.25 mmol) in dry 1,2-dichloroethane (5 mL), under argon atmosphere, were added 3-phenylpropionaldehyde (63.5 mg, 0.47 mmol), acetic acid (89.7 mg, 1.49 mmol) and sodium triacetoxyborohydride (156 mg, 0.70 mmol) at room temperature. After stirring at room temperature for 18 h, 3-phenylpropionaldehyde (63.5 mg, 0.47 mmol), acetic acid (89.7 mg, 1.49 mmol) and sodium triacetoxyborohydride (156 mg, 0.70 mmol) were added again and the reaction mixture was further stirred at room temperature for 20 h. The reaction mixture was diluted with dichloromethane (10 mL) and sat. aq. NaHCO3 (10 mL) was added. After phase separation, the aqueous layer was washed with ethyl acetate (3×10 mL), the combined organic layers were washed with water (10 mL), dried over MgSO4 and concentrated in vacuo. Purification on silica gel afforded 4-{[({[3-(methylsulfanyl)phenyl](1-methyl-1H-tetrazol-5-yl)methylene}amino)oxy]methyl}-N-(3-phenylpropyl)-1,3-thiazol-2-amine as a pale yellow oil [69 mg, yield 58%; HPLC/MS m/z=481 (M+H); logP(HCOOH)=3.71].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[NH2:21][OH:22]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[N:21][OH:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: NO
Reactant: COc1ccc(C(=O)Cc2ccc(SC)cc2)cc1Cl
Product: COc1ccc(C(Cc2ccc(SC)cc2)=NO)cc1Cl
Yield: 41 %

Procedure:
1-(3-Chloro-4-methoxyphenyl)-2-[4-(methylthio)phenyl]-ethan-1-one oxime was prepared in 41% yield from the reaction of 1-(3 chloro-4-methoxyphenyl)-2-[4-(methylthio)phenyl]-ethan-1-one from Step 4 with hydroxylamine by the method outlined in Example 1, Step 1: 1H NMR (CDCl3 /300 MHz) δ 7.69 (d, J=2.22 Hz, 1H), 7.47 (dd, J=8.66, 2.22 Hz, 1H), 7.21-7.16 (m, 4H), 6.86 (d, J=8.66 Hz, 1H), 4.11 (s, 2H), 3.89 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: S([O-])(O[O-])(=O)=[O:2].[K+].[K+].[CH3:9][S:10][C:11]1[C:21]2[O:20][CH2:19][CH2:18][C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][C:15]=2[CH:14]=[CH:13][CH:12]=1>O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH3:9][S:10]([C:11]1[C:21]2[O:20][CH2:19][CH2:18][C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][C:15]=2[CH:14]=[CH:13][CH:12]=1)=[O:2]
Reactant: O=S(=O)([O-])O[O-]
Reactant: CCOC(=O)C1=Cc2cccc(SC)c2OCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1=Cc2cccc(S(C)=O)c2OCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 23.6 %

Procedure:
A solution of potassium peroxymonosulfate (6.7 g) in water (33 ml) was added dropwise to a mixture of ethyl 2,3-dihydro-9-methylthio-1-benzoxepin-4-carboxylate (2.6 g) and tetrabutylammonium hydrogen sulfate (0.7 g) in ethyl acetate (26 ml) and water (13 ml) and the mixture was stirred at ambient temperature for 2.5 hours. The separated organic layer was washed with 10% aqueous sodium thiosulfate. The organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and toluene (1:1) as an eluent. The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl 2,3-dihydro-9-methanesulfinyl-1-benzoxepin-4-carboxylate (0.65 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].C([O-])([O-])=O.[K+].[K+].[Br:20][CH2:21][CH2:22]Br>CC(C)=O>[Br:20][CH2:21][CH2:22][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: BrCCBr
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCBr)c(OC)c1
Temperature: 25 °C

Procedure:
To a solution of methyl 4-hydroxy-3-methoxy-benzoate (2.0 g, 11 mmol) in acetone (330 mL) was added K2CO3 (6.1 g, 44 mmol) followed by 1,2-dibromoethane (6.2 g, 2.8 mL, 33 mmol). The mixture was stirred for 2d at 75° C. The mixture was cooled to ambient temperature and the solids were removed by filtration. The filtrate was concentrated and the residue was purified by column chromatography (10-25% ethyl acetate/hexanes) to give methyl 4-(2-bromoethoxy)-3-methoxybenzoate. ESI-MS m/z calc. 288.0, found 289.1 (M+1)+; Retention time: 1.47 minutes (3 min run).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]([CH:17]=[O:18])=[C:11]([Br:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([Mg]Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]([CH:17]([OH:18])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:11]([Br:19])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: Cn1c(C=O)c(Br)cc(OCc2ccccc2)c1=O
Solvent: C1CCOC1
Product: Cn1c(C(O)Cc2ccccc2)c(Br)cc(OCc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
To a 0° C. solution of 5-(benzyloxy)-3-bromo-1-methyl-6-oxo-1,6-dihydropyridine-2-carbaldehyde (1.09 g, 3.38 mmol) in 34 mL THF was added benzylmagnesium chloride (2.55 g, 3.38 mmol) dropwise. The mixture was allowed to stir at 0° C. for 1 h. After warming to room temperature, volatiles were removed under reduced pressure. The resulting residue was partitioned between dilute aqueous hydrochloric acid and ethyl acetate. The aqueous layer was removed and discarded, and the organic layer was collected, dried over anhydrous magnesium sulfate and purified by silica gel chromatography to afford 3-(benzyloxy)-5-bromo-6-(1-hydroxy-2-phenylethyl)-1-methylpyridin-2(1H)-one (1 g, 2.41 mmol, 71% yield). ES-MS (M+H)+=415.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl.Cl[CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH2:29][C:30]5[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=5)[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(Cc3ccncc3)C2=O)CC1
Yield: 74 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride (2.4 equivalents) and 4-(chloromethyl)pyridine hydrochloride, to give the desired product as a light yellow solid (74%).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:19]1[O:20][CH2:21][CH:22]([OH:31])[CH:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:24]=1>ClCCCl>[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:19]1[O:20][CH2:21][CH:22]([O:31][C:8](=[O:9])[NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:24]=1
Reactant: OC1COC(c2cc3ccccc3[nH]2)=NC1c1ccccc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCCl
Product: O=C(Nc1ccccc1)OC1COC(c2cc3ccccc3[nH]2)=NC1c1ccccc1
Reaction time: 7 h
Yield: 55.2 %

Procedure:
Phenyl isocyanate (2.3 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (4RS, 5RS)-2-(2-indolyl)-4-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (5.15 g) in 1,2-dichloroethane (50 cc). The solution obtained is stirred for 7 hours under reflux and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After two successive recrystallizations in diisopropyl ether, (4RS, 5RS)-2-(2-indolyl)-4-phenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (4 g), m.p. 166° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([N:12]([CH2:14][C:15]1[O:19][CH:18]=[C:17]([C:20](O)=[O:21])[CH:16]=1)[CH3:13])(=[O:11])=[O:10].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:35]1[CH2:39][CH2:38][N:37]=[C:36]1[C:40]1[CH:45]=[CH:44][C:43]([CH2:46][NH:47][CH3:48])=[CH:42][CH:41]=1.Cl>ClCCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([N:12]([CH2:14][C:15]1[O:19][CH:18]=[C:17]([C:20]([N:47]([CH2:46][C:43]2[CH:44]=[CH:45][C:40]([C:36]3[NH:37][CH2:38][CH2:39][N:35]=3)=[CH:41][CH:42]=2)[CH3:48])=[O:21])[CH:16]=1)[CH3:13])(=[O:10])=[O:11]
Reactant: CNCc1ccc(C2=NCCN2)cc1
Reactant: CN(Cc1cc(C(=O)O)co1)S(=O)(=O)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: CN(Cc1ccc(C2=NCCN2)cc1)C(=O)c1coc(CN(C)S(=O)(=O)c2ccc(Cl)cc2Cl)c1
Reaction time: 2 h

Procedure:
5-({[(2,4-dichlorophenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (34 mg, 0.08 mmol) was dissolved in DCE (1 mL) and CDI (26 mg, 0.16 mmol) was added. The reaction was stirred for 2 h. The activated acid solution in DCE was added to a vial containing 1-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylmethanamine.HCl (41 mg, 0.16 mmol) and TEA (0.022 mL, 0.16 mmol). The reaction was stirred at ambient temperature for 18 h, then partitioned between saturated aqueous NaHCO3 (1 mL) and DCE (3×1 mL)). The organic layer was dried over MgSO4 and solvents were removed in vacuo. A portion of the crude was product purified using prep method A.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:11]([C:13]1[C:14](=[O:26])[N:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:16]([CH3:19])[C:17]=1[CH3:18])=[O:12].CC([O-])(C)C.[K+].Cl[C:34]1[CH:39]=[CH:38][N:37]=[C:36]([C:40]([NH2:42])=[O:41])[CH:35]=1.O>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:10][C:11]([C:13]2[C:14](=[O:26])[N:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:16]([CH3:19])[C:17]=2[CH3:18])=[O:12])=[CH:4][C:5]([F:9])=[C:6]([CH:7]=1)[O:8][C:34]1[CH:39]=[CH:38][N:37]=[C:36]([C:40]([NH2:42])=[O:41])[CH:35]=1
Reactant: Cc1c(C(=O)Nc2cc(F)c(O)cc2Cl)c(=O)n(-c2ccccc2)n1C
Reactant: NC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)Nc2cc(F)c(Oc3ccnc(C(N)=O)c3)cc2Cl)c(=O)n(-c2ccccc2)n1C
Temperature: 120 °C
Reaction time: 15 h
Yield: 29.2 %

Procedure:
To a suspension of N-(2-chloro-5-fluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (751.6 mg, 2 mmol) and t-BuOK (224.4 mg, 2 mmol) in DMF (4 mL) and was added 4-chloropicolinamide (313.2 mg, 2 mmol). The reaction was warmed up to 120° C. and stirred for 15 hours. After the mixture cooling to rt, H2O (40 mL) was added and the resulted mixture was stirred at rt overnight. Filtered and the filter cake was purified by a silica gel column chromatography (DCM/CH3OH (v/v)=50/1) to give the title compound as a light yellow solid (290 mg, 60.5%).