Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:6]=[N:7][C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[CH:14]=1.ClC1C=CC=C(C(OO)=[O:25])C=1.C(=O)(O)[O-].[Na+]>ClCCl>[F:16][C:2]([F:1])([F:15])[CH2:3][O:4][C:5]1[CH:6]=[N+:7]([O-:25])[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)COc1cnc2c(c1)CCCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1cc(OCC(F)(F)F)cc2c1CCCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 142.5 %

Procedure:
A mixture of 3-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydroquinoline (495 mg, 2.1 mmol) and 3-chloroperbenzoic acid (ca 75%, 739 mg, 3.2 mmol) in dichloromethane (10 mL) was stirred at room temperature for 1.5 hour. Then, the mixture was poured into saturated sodium bicarbonate aqueous solution (50 mL), and the aqueous phase was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give 740 mg of the crude title compound. This was used for the next step without further purification:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([NH:12][C:13]([C:15]2[C:24]3[O:23][CH2:22][CH2:21][O:20][C:19]=3[C:18]([O:25][CH3:26])=[CH:17][CH:16]=2)=[O:14])[CH:9]=[CH:10][CH:11]=1)=[O:5])C.[OH-].[Na+].O.O.Cl>C(O)C>[C:4]([C:6]1[CH:7]=[C:8]([NH:12][C:13]([C:15]2[C:24]3[O:23][CH2:22][CH2:21][O:20][C:19]=3[C:18]([O:25][CH3:26])=[CH:17][CH:16]=2)=[O:14])[CH:9]=[CH:10][CH:11]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1cccc(NC(=O)c2ccc(OC)c3c2OCCO3)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=O)Nc2cccc(C(=O)O)c2)c2c1OCCO2
Yield: 80 %

Procedure:
Compound 185 (0.19 g) obtained in Example 185 was suspended in ethanol (1 ml), mixed with a 24% aqueous sodium hydroxide solution (1.3 ml), and heat-refluxed for 2 hours. The resultant was allowed to stand for cooling, mixed with water, and adjusted to PH 2 by adding 2N hydrochloric acid water. The precipitated solid was collected by filtration to give Compound 186 (0.14 g, 80%) as colorless crystals.
Reaction SMILES: [H-].[Na+].[CH2:3](P(=O)(O)O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:30]=1[CH:31]=O.O>O1CCCC1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:30]=1/[CH:31]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=P(O)(O)Cc1ccccc1
Reactant: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(/C=C/c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
Sodium hydride (60 wt % oil, 52 mg) was dissolved in anhydrous tetrahydrofuran (1 ml), and a solution (0.5 ml) of benzylphosphonic acid (114 mg) in tetrahydrofuran was added dropwise to the solution at 0° C. under an argon atmosphere. The mixture was stirred at 0° C. for 30 min, and a solution (0.5 ml) of 2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methoxybenzaldehyde (100 mg) in tetrahydrofuran was then added dropwise thereto. The reaction mixture was stirred at room temperature for one hr, and water (1 ml) was then added dropwise thereto to stop the reaction. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give the title compound (100 mg, yield 80%).
Reaction SMILES: CN(/[CH:4]=[C:5]1\[C:6](=O)[C:7]2[C:12]([C@H:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[CH2:14]\1)=[CH:11][CH:10]=[CH:9][CH:8]=2)C.[OH:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:41]([NH2:43])=[NH:42])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1>>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C@H:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[N:43]=[C:41]([NH:40][C:37]3[CH:38]=[CH:39][C:34]([N:31]4[CH2:30][CH2:29][N:28]([CH2:27][CH2:26][CH2:25][CH2:24][OH:23])[CH2:33][CH2:32]4)=[CH:35][CH:36]=3)[N:42]=[CH:4][C:5]=2[CH2:14]1
Reactant: CN(C)/C=C1/C[C@@H](c2ccccc2F)c2ccccc2C1=O
Reactant: N=C(N)Nc1ccc(N2CCN(CCCCO)CC2)cc1
Product: OCCCCN1CCN(c2ccc(Nc3ncc4c(n3)-c3ccccc3[C@H](c3ccccc3F)C4)cc2)CC1

Procedure:
This was synthesized by using (R,Z)-2-((dimethylamino)methylene)-4-(2-fluorophenyl)-3,4-dihydronaphthalen-1(2H)-one and 1-(4-(4-(4-hydroxybutyl)piperazin-1-yl)phenyl)guanidine as described in general procedure 1. LCMS m/e 524 (M+H).
Reaction SMILES: [C:1](=[N:4][NH:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[CH3:15])([CH3:3])[CH3:2].Cl[O:18][N:19]=[CH:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=1.C(Cl)(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>O>[CH3:28][C:23]1[CH:22]=[C:21]([C:20]2[N:4]([NH:5][C:6](=[O:16])[C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=3[CH3:15])[C:1]([CH3:3])([CH3:2])[O:18][N:19]=2)[CH:26]=[C:25]([CH3:27])[CH:24]=1
Reactant: Cc1cc(C)cc(C=NOCl)c1
Reactant: COc1cccc(C(=O)NN=C(C)C)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cccc(C(=O)NN2C(c3cc(C)cc(C)c3)=NOC2(C)C)c1C
Reaction time: 24 h
Yield: 37.5 %

Procedure:
3-Methoxy-2-methyl-benzoic acid isopropylidene-hydrazide (1.71 g, 7.77 mmol) and 3,5-dimethyl-benzaldehyde chlorooxime (2.29 g, 12.4 mmol), both as CHCl3 solutions (total volume 40 mL), were added to a 250 mL round bottom flask equipped with a magnetic stirrer. An aqueous K2CO3 solution (5 g in 30 mL) was added, the vessel was placed in a 50° C. water bath, and the reaction was stirred vigorously for 24 hours. The reaction was monitored by 1H NMR. Chloroform (100 μl) and water (50 mL) were added, and the mixture was shaken in a separatory funnel. The organic phase was separated, dried, and the solvent was removed in vacuo. Column chromatography on silica gel using a gradient of 10-30% ethyl acetate in hexane yielded 1.07 g of N-[3-(3,5-dimethyl-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-3-methoxy-2-methyl-benzamide (32%). An analytical sample was obtained by crystallization from CH2Cl2/hexane under refrigeration. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.4 (s, 2H), 7.1 (t, 1H), 7.07 (s, 1H), 6.85 (d, 1H), 6.65 (d, 1H), 3.78 (s, 3H), 2.30 (s, 6H), 2.07 (s, 3H), 1.65 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:16][CH3:17])=[CH:5][C:6]2[S:11](=[O:13])(=[O:12])[NH:10][C:9](=[O:14])[NH:8][C:7]=2[CH:15]=1.[H-].[Na+].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35]Cl)[CH2:30][CH2:29]1.O>CN(C)C=O>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][N:10]2[C:9](=[O:14])[NH:8][C:7]3[CH:15]=[C:3]([O:2][CH3:1])[C:4]([O:16][CH3:17])=[CH:5][C:6]=3[S:11]2(=[O:13])=[O:12])[CH2:32][CH2:33]1
Reactant: COc1cc2c(cc1OC)S(=O)(=O)NC(=O)N2
Reactant: COc1ccccc1N1CCN(CCCl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1OC)S(=O)(=O)N(CCN1CCN(c3ccccc3OC)CC1)C(=O)N2
Temperature: 80 °C
Reaction time: 5 h
Yield: 36 %

Procedure:
One gram and a half of 6,7-dimethoxy-3,4-dihydro-1,2,4-benzothiadiazine-3-one 1,1-dioxide was dissolved in 10 ml of dimethylformamide. After adding 280 mg of sodium hydride in 50% oil, the mixture was heated to 80° C. Then, a solution of 1.5 g of 2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl chloride in 5 ml of dimethylformamide was added dropwise to the resultant reaction liquid. After the addition was finished, the stirring was continued for 5 hours while heating at 80° C. to react. The resultant reaction mixture was poured into water to precipitate crystals. The produced crystals were filtered off followed by recrystallizing from methanol to obtain 1.0 g of the titled compound (yield: 36%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[NH:6][CH:5]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[N:14]1([CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=3)[NH:6][CH:5]=2)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: c1c[nH]cn1
Reactant: Fc1ccc2[nH]cc(CCBr)c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Fc1ccc2[nH]cc(CCn3ccnc3)c2c1

Procedure:
A solution of 3-(2-bromo-ethyl)-5-fluoro-1H-indole (4.84 g, 20 mmol), imidazole (1.36 g, 20 mmol) and ethyl-diisopropylamine (3.4 ml, 20 mmol) in abs. dioxane (50 ml) was stirred at 90° C. for 8 h until according to TLC educt was no longer present. The solvent was then removed i. vac., CHCl3 (100 ml) was added to the residue and the organic phase was washed twice with water. The organic phase was dried over Na2SO4 and concentrated i. vac. and the residue which remained was purified by flash chromatography with CHCl3/MeOH (9:1).
Reaction SMILES: [CH:1]([C:3]1[C:8]2[C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][C:10]=3[O:20][C:7]=2[C:6]([O:21][CH3:22])=[CH:5][CH:4]=1)=[O:2].S(=O)(=O)([OH:25])N.Cl([O-])=O.[Na+]>O.CC(C)=O>[CH2:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][C:9]2[C:8]3[C:7](=[C:6]([O:21][CH3:22])[CH:5]=[CH:4][C:3]=3[C:1]([OH:25])=[O:2])[O:20][C:10]=2[CH2:11]1)=[O:16])[CH3:19]
Reactant: CCOC(=O)N1CCc2c(oc3c(OC)ccc(C=O)c23)C1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)N1CCc2c(oc3c(OC)ccc(C(=O)O)c23)C1
Yield: 41 %

Procedure:
Ethyl 5-formyl-8-methoxy-3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate (from step 6) (0.310 g, 1.02 mmol) was taken in acetone water mixture. To this was added sulphamic acid (0.148 g, 1.53 mmol) and sodium chlorite (0.157 g, 1.73 mmol) and stirred for half an hour. After removing acetone under diminished pressure and dilution with water, it yielded 2-(ethoxycarbonyl)-8-methoxy-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine-5-carboxylic acid (41%) which was filtered out, washed with water and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[NH:15][C:16]([NH2:18])=[S:17].Br.CS(C)=O>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:4]2[N:15]=[C:16]([NH2:18])[S:17][C:5]=2[C:6]([CH:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2CCOCC2)cc1NC(N)=S
Agent: Br
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: COc1ccc(C2CCOCC2)c2sc(N)nc12
Reaction time: 0.5 h

Procedure:
To a solution of 1 [2-methoxy-5-(tetrahydro-pyran-4-yl)-phenyl]-thiourea (XI) in acetic acid is added hydrobromic acid, and stirring continued for about 30 min at 80° C. DMSO is then added dropwise and the reaction mixture stirred for a further 30 min at 80° C. The product (XII) 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-ylamine is isolated by conventional means.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.C[O:14][CH:15](OC)[CH2:16][CH2:17][CH2:18][CH:19]=O>CCOC(C)=O.CCCCCC>[N+:10](/[C:9](/[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[CH:19]/[CH2:18][CH2:17][CH2:16][CH:15]=[O:14])([O-:12])=[O:11]
Reactant: Cc1ccc(CC[N+](=O)[O-])cc1
Reactant: COC(CCCC=O)OC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(C/C(=C\CCCC=O)[N+](=O)[O-])cc1
Yield: 34.9 %

Procedure:
Prepared according to the general procedure B from 1-methyl-4-(2-nitroethyl)benzene 112f (24 mmol) and 5,5-dimethoxypentanal 131 (16 mmol) to provide the title compound as yellow oil (1.38 g, 35% yield) after silica gel chromatography (EtOAc/Hexane).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:15](Br)[C:16]#[CH:17]>CN(C)C=O.O>[CH2:17]([O:12][CH2:11][C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1)[C:16]#[CH:15]
Reactant: OCc1ccc2c(c1)OCCO2
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOCc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 16.6 g of 1,4-benzodioxan-6-methanol in 20 ml of dimethylformamide is added dropwise with stirring to a suspension of 12.5 g of sodium hydride in 75 ml of dimethylformamide. 11.8 g of propargyl bromide are then added dropwise. The mixture is stirred for 3 hours at room temperature, cooled in an ice-bath, decomposed with 20 ml of ice-water, diluted with 150 ml of water and extracted three times with 150 ml of diethyl ether each time. The ether extract is washed with water, dried over sodium sulphate and evaporated. The oily residue is chromatographed on silica gel using benzene as the elution agent. There is obtained 6-[(2-propynyloxy)methyl]-1,4-benzodioxan; nD24 = 1.5487.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1/[CH:9]=[CH:10]/[CH2:11]O.[ClH:13]>O1CCOCC1>[Cl:13][CH2:11]/[CH:10]=[CH:9]/[C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Cl
Reactant: OC/C=C/c1cc(F)ccc1F
Solvent: C1COCCO1
Product: Fc1ccc(F)c(/C=C/CCl)c1
Temperature: 100 °C
Yield: 89 %

Procedure:
A mixture of (2E)-3-(2,5-difluorophenyl)prop-2-en-1-ol (Intermediate 70, 700 mg, 4.12 mmol), 1,4-dioxane (5 mL), and hydrochloric acid (12.1 M, 1 mL) was heated in the microwave at 100° C. for 3 hours. It was concentrated to dryness under reduced pressure, the residue taken up in ethyl acetate (10 mL), washed with water (1×10 mL), saturated sodium bicarbonate solution, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give 688 mg (89% yield) of product as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[S:3]([O:6][C:7]1[C:12]2[CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[O:15][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:5])=[O:4].[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>C(Cl)Cl>[F:20][C:2]([F:1])([F:19])[S:3]([O:6][C:7]1[C:12]2[CH:13]=[C:14]([CH2:16][CH2:17][O:18][S:22]([CH3:21])(=[O:24])=[O:23])[O:15][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:4])=[O:5]
Reactant: O=S(=O)(Oc1cccc2oc(CCO)cc12)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1cc2c(OS(=O)(=O)C(F)(F)F)cccc2o1

Procedure:
As shown in Scheme 15, 2-(2-Hydroxyethyl)-1-benzofuran-4-yl trifluoromethanesulfonate, prepared as described in Examples 85A-85C herein, is treated with methanesulfonyl chloride and triethylamine in CH2Cl2 at 0° C. to provide 2-{2-[(methylsulfonyl)oxy]ethyl}-1-benzofuran-4-yl trifluoromethanesulfonate. 2-{2-[(Methylsulfonyl)oxy]ethyl}-1-benzofuran-4-yl trifluoromethanesulfonate is treated with (2R)-methylpyrrolidine mono-(L)-tartaric acid salt and Cs2CO3 in MeCN at approximately 35° C. for 1 to 4 days to provide 2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-1-benzofuran-4-yl trifluoromethanesulfonate. 2-{2-[(2R)-2-Methyl-1-pyrrolidinyl]ethyl}-1-benzofuran-4-yl trifluoromethanesulfonate is processed as described in Murata, et al., Journal of Organic Chemistry (2000) 65, 164-168 to provide (2R)-2-methyl-1-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran-2-yl]ethyl}pyrrolidine. For example, one equivalent of 2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-1-benzofuran-4-yl trifluoromethanesulfonate is treated with palladium acetate or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (PdCl2dppf), 3 equivalents of triethylamine, and 1.5 equivalents of pinacolborane in 1,4-dioxane at 25° C. for several hours or until the reaction is complete as judged by TLC. (2R)-2-Methyl-1-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran-2-yl]ethyl}pyrrolidine is treated with a suitable starting material, for example, aryl halides, aryl triflates, or heterocyclic halides, a palladium catalyst, such as palladium (II) acetate, a trivalent phosphine such as biphen-2-yl-dicyclohexylphosphine, and aqueous sodium carbonate or potassium phosphate in an organic solvent such as ethanol or tetrahydrofuran at 25° C. to 120° C. to provide compounds of formula (51). Compounds of formula (51) can be isolated and purified by methods known to those skilled in the art. For example, compounds of formula (51) is partitioned between dichloromethane and water, the organic phase concentrated, and the residue purified by chromatography on silica gel.
Reaction SMILES: [CH2:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])[CH2:2][CH3:3].C([O-])(O)=O.[Na+].[I:16]I>CO.O>[I:16][C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:1][CH2:2][CH3:3])[CH:10]=1
Reactant: CCCc1ccccc1N
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCc1cc(I)ccc1N
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of 2-n-propylaniline in MeOH (25 mL) was added a solution of NaHCO3 (5.0 g, 59.5 mmol) in H2O (25 mL). Iodine (8.4 g, 33.3 mmol) was added portionwise over 70 min. while maintaining the temp. at 10° C., then the mixture was allowed to stir at 10° C. for 30 min. The resulting mixture was diluted with H2O (30 mL) and extracted with EtOAc (4×40 mL). The combined organic layers were sequentially washed with a 5% Na2S2O3 solution (30 mL) and a saturated NaHCO3 solution (30 mL), dried (Na2SO4), and concentrated under reduced pressure to give 4-iodo-2-n-propylaniline (9.4 g, 98%): TLC (20% EtOAc/hex) Rf0.43. This material was used in the next step without further purification.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:32][O:33][NH2:34]>CS(C)=O>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[N:34][O:33][CH3:32])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: CON
Solvent: CS(C)=O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=NOC)c4)cc23)CC1
Reaction time: 8 h
Yield: 55.8 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.114 mmol) in DMSO (3.0 mL) was added O-methylhydroxylamine (57 mg, 0.684 mmol). The reaction was stirred overnight. Additional O-methylhydroxylamine (0.342 mmol) was added to the reaction mixture and stirred for 48 h. The solvent was then concentrated and purified by Gilson Preparatory HPLC to give 29.8 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(methyloxy)imino]methyl}phenyl)-1H-indole-7-carboxamide (56%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>CS(C)=O>[N:20]1([CH2:19][CH2:18][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=Cc1cccc(O)c1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=Cc1cccc(OCCN2CCCC2)c1
Temperature: 90 °C

Procedure:
To a stirred solution of 3-hydroxybenzaldehyde (20 mmol) in DMSO (50 mL) at rt, solid Cs2CO3 (60 mmol) was added. 1-(2-chloroethyl)pyrrolidine hydrochloride (30 mmol) was added to the reaction mixture and heated to 90° C. for 9 h. After cooling to rt, the reaction was quenched by cold H2O (50 mL), and the resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with brine (3×50 mL) and dried (anhydrous Na2SO4). The solvent was removed in vacuo to afford crude 3-(2-pyrrolidin-1-yl-ethoxy)benzaldehyde.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:16]=[CH:15][C:14]3[C:10](=[C:11]([CH3:19])[N:12]([CH2:17][CH3:18])[N:13]=3)[CH:9]=2)[C:4](=[O:20])[CH:3]=1.[F:21][C:22]([F:31])([F:30])[C:23]1[N:24]=[C:25]([CH2:28][OH:29])[S:26][CH:27]=1.CC(C)([O-])C.[K+].O>C1(C)C=CC=CC=1>[CH2:17]([N:12]1[C:11]([CH3:19])=[C:10]2[C:14]([CH:15]=[CH:16][C:8]([N:5]3[CH:6]=[CH:7][C:2]([O:29][CH2:28][C:25]4[S:26][CH:27]=[C:23]([C:22]([F:31])([F:30])[F:21])[N:24]=4)=[CH:3][C:4]3=[O:20])=[CH:9]2)=[N:13]1)[CH3:18]
Reactant: OCc1nc(C(F)(F)F)cs1
Reactant: CCn1nc2ccc(-n3ccc(Br)cc3=O)cc2c1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCn1nc2ccc(-n3ccc(OCc4nc(C(F)(F)F)cs4)cc3=O)cc2c1C
Temperature: 100 °C
Reaction time: 2 h
Yield: 16.4 %

Procedure:
To a solution of 4-bromo-1-(2-ethyl-3-methyl-2H-indazol-5-yl)pyridin-2(1H)-one (350 mg) and [4-(trifluoromethyl)-1,3-thiazol-2-yl]methanol (289 mg) in toluene (5 ml) was added potassium tert-butoxide (355 mg) at room temperature, and the mixture was stirred at 100° C. for 2 hr. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) and recrystallized from ethanol-water to give the title compound (75 mg).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[NH2:12][CH2:13][CH2:14][NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][N:22]=[CH:21]2>C(O)(C)C>[O:5]([CH2:1][CH:2]([OH:4])[CH2:3][NH:12][CH2:13][CH2:14][NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][N:22]=[CH:21]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: NCCNc1cccc2cn[nH]c12
Solvent: CC(C)O
Product: OC(CNCCNc1cccc2cn[nH]c12)COc1ccccc1
Yield: 67 %

Procedure:
3.0 g. Phenyl glycidyl ether and 7.0 g 7-(2-aminoethylamino)-indazole are stirred for 10 hours at 70° C. in 20 ml. isopropyl alcohol. The reaction mixture is then evaporated and purified chromatographically on a silica gel column in the manner described in Example 24. The residue of the pure fractions is digested with ethyl acetate and then recrystallized from ethyl acetate, with the use of active charcoal and fullers' earth. There are obtained 2.3 g. (35% of theory) of the desired product in the form of colorless crystals; m.p. 117°-119° C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][C:7]2([C:12]([O:14]C(C)(C)C)=[O:13])[CH2:9][C:8]2([F:11])[F:10])=[CH:4][C:3]=1[NH:21][C:22](=[O:37])[C@H:23]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26].C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][C:7]2([C:12]([OH:14])=[O:13])[CH2:9][C:8]2([F:11])[F:10])=[CH:4][C:3]=1[NH:21][C:22](=[O:37])[C@H:23]([C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)[C@@H:24]([CH3:29])[C:25]([F:26])([F:27])[F:28]
Reactant: C[C@H]([C@H](C(=O)Nc1cc(CC2(C(=O)OC(C)(C)C)CC2(F)F)ccc1Cl)c1ccc(Cl)cc1)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]([C@H](C(=O)Nc1cc(CC2(C(=O)O)CC2(F)F)ccc1Cl)c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.80 g (3.18 mmol) of tert-butyl 1-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}benzyl)-2,2-difluorocyclopropanecarboxylate (as diastereomer mixture) were dissolved in 5 ml of dichloromethane, and 4.9 ml of TFA were added at RT. The reaction mixture was stirred at RT for 1 h and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase first dichloromethane, then dichloromethane/ethyl acetate 10:1→5:1). This gave 1.25 g of the target compound (77.1% of theory).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[O:29][CH:28]=[N:27][C:26]=1[C:30](O)=[O:31]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=3)=[O:31])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccccn1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3ccccn3)cn2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-pyridin-2-yl-oxazole-4-carboxylic acid. LC-MS-conditions 05: tR=0.56 min; [M+H]+=378.14.