Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:4]([F:12])=[C:5]([C:8]([F:11])=[CH:9][CH:10]=1)[C:6]#[N:7])=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[F:12][C:4]1[C:3]([CH:1]2[CH2:2][O:21]2)=[CH:10][CH:9]=[C:8]([F:11])[C:5]=1[C:6]#[N:7]
Reactant: C=Cc1ccc(F)c(C#N)c1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: N#Cc1c(F)ccc(C2CO2)c1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-Ethenyl-2,6-difluorobenzonitrile (1.70 g, 10.3 mmol) was added to DCM (10 mL) at 0° C. Then mCPBA (5.33 g, 30.9 mmol) was added and the mixture was stirred at RT for 48 h. The reaction mixture was washed with saturated aqueous Na2S2O3, then with 1N NaOH, and brine. The organic layer was separated and dried over Na2SO4, filtered, and evaporated to dryness. The crude product was purified by MPLC chromatography through a 120 g Redi-sep column, eluting with a 0-100% EtOAc/hexane solvent system. 2,6-Difluoro-3-(oxiran-2-yl)benzonitrile was isolated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[N:9]\[S:10]([C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.[F:17][CH2:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[C:22]1([S:19]([CH:18]([F:17])/[C:8](=[N:9]\[S:10]([C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:12])=[O:11])/[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)(=[O:21])=[O:20])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)S(=O)(=O)/N=C\c1cccc(Br)c1
Reactant: O=S(=O)(CF)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)(=O)/N=C(/c1cccc(Br)c1)C(F)S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a mixture of 2-methyl-propane-2-sulfonic acid 1-(3-bromo-phenyl)-meth-(Z)-ylideneamide (2.16 g, 7.49 mmol) and (fluoromethylsulfonyl)benzene (1.31 g, 7.49 mmol) in THF (50 mL), cooled to −78° C., was added LiHMDS (1M in THF; 7.87 mL, 7.87 mmol). The reaction mixture was stirred for 40 min at −78° C., followed by quenching saturated aqueous NH4Cl (10 mL) at −78° C. The mixture was extracted with EtOAc (3×), dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash column chromatography on silica gel (c-hexane/EtOAc 3:1) afforded the title compound. MS (LC/MS): 462/464 [M+H]+; tR (HPLC conditions f): 2.20 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]([Br:12])=[CH:10][N:9]=[C:8]([NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[CH:17]=[CH:18][CH:19]=2)[N:7]=1.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>N1C=CC=CC=1>[CH2:32]([O:31][C:29](=[O:30])[NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]([Br:12])=[CH:10][N:9]=[C:8]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[CH:15]=2)[N:7]=1)[CH3:33]
Reactant: NCCCNc1nc(Nc2cccc(NC(=O)N3CCCC3)c2)ncc1Br
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)NCCCNc1nc(Nc2cccc(NC(=O)N3CCCC3)c2)ncc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 6.6 %

Procedure:
To a solution of N-(3-((4-((3-aminopropyl)amino)-5-bromo-2-pyrimidinyl)amino)phenyl)-1-pyrrolidinecarboxamide (150 mg, 0.30 mmol) in pyridine (5 mL) was added ethyl chloroformate (38.5 mg, 0.35 mmol) at 0° C. under N2. The resulting reaction mixture was stirred at 0° C. for 1 h and then was stirred at room temperature overnight. The mixture was washed with water (3×50 mL). Then the reaction mixture was concentrated. Purification by HPLC chromatography using acetonitrile/water gave the title compound (10 mg).
Reaction SMILES: C(O[C:4](=O)[C:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:9])[CH2:6][O:7][NH2:8])C.[BH4-].[Li+].C1C[O:23]CC1>>[C:10]([C:5]([CH3:9])([CH3:4])[CH:6]([O:7][NH2:8])[OH:23])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: C1CCOC1
Reactant: CCOC(=O)C(C)(CON)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Product: CC(C)(C)OC(=O)C(C)(C)C(O)ON
Temperature: 0 °C
Reaction time: 17 h
Yield: 71 %

Procedure:
2-Boc-aminooxy-2-methyl-propionic acid ethyl ester (2.54 g, 10.27 mmol) was dissolved in freshly distilled THF (100 mL), cooled to 0° C. and charged with 2.0 M lithium borohydride solution (10.3 mL, 20.54 mmol) in THF. The ice bath was removed and reaction was heated to reflux. After 17 hours, the reaction was cooled to 0° C. and quenched with methanol and concentrated in vacuo. The afforded residue was partitioned between ethyl acetate and 1M sodium hydroxide solution. The organic layers were washed twice with 1M sodium hydroxide solution, twice with saturated sodium chloride solution, collected and dried over Na2SO4, filtered and concentrated in vacuo, affording 2-Boc-aminooxy-2-methyl-propan-1-ol (1.50 g, 71%) as a white solid: 1H NMR (400 MHz; CDCl3) δ 6.84 (bs, 1H), 3.37 (s, 2H), 1.45 (s, 9H), 1.18 (s, 6H); MS (APCI−)=204.0.
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:5](O)=[CH:4][C:3]=1[OH:9].[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=O)OC(=O)[C:14]2=[CH:20][C:21]=1[Cl:22].O>CS(O)(=O)=O>[Cl:22][C:21]1[C:11]([Cl:10])=[C:12]([C:2]2[CH:8]=[CH:7][CH:5]=[CH:4][CH:3]=2)[C:13]2[CH2:18][C:4]3[C:3]([O:9][C:14]=2[CH:20]=1)=[CH:2][CH:8]=[CH:7][CH:5]=3
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Agent: CS(=O)(=O)O
Solvent: O
Product: Clc1cc2c(c(-c3ccccc3)c1Cl)Cc1ccccc1O2
Temperature: 180 °C
Reaction time: 24 h

Procedure:
4-Chlororesorcinol (33 g) was mixed with 4,5-dichlorophthalic anhydride in methane sulfonic acid (100 mL) according to the procedure of Menchen, et. al, (U.S. Pat. No. 5,654,442). Briefly, with magnetic stirring, the solution was heated to 180° C. over 30 min and maintained for an additional 30 minutes. The mixture was allowed to cool to ˜100° C. and was cautiously poured into water (1 L). The solid was collected by filtration and air dried for several days, followed by 24 h of high vacuum and was characterized as having the structure above.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[NH:19][CH:20]=[C:21]([CH2:25][CH3:26])[C:22](=[O:24])[N:23]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[CH3:27].[CH3:28]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][C:18]3[N:19]([CH3:28])[CH:20]=[C:21]([CH2:25][CH3:26])[C:22](=[O:24])[N:23]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[CH3:27]
Reactant: CCc1c[nH]c(OCCc2ccc(Oc3ccc(Cl)c(C)c3)cc2)nc1=O
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CI
Product: CCc1cn(C)c(OCCc2ccc(Oc3ccc(Cl)c(C)c3)cc2)nc1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.7 %

Procedure:
A mixture solution of 2-[(2-{4-[(4-chloro-3-methylphenyl)oxy]phenyl}ethyl)oxy]-5-ethyl-4(1H)-pyrimidinone (30 mg, 0.078 mmol) and DIPEA (0.027 mL, 0.156 mmol) in DCM (2 mL) was added MeI (9.75 μL, 0.156 mmol). The mixture was stirred at room temperature for 3 h, and quenched with water. The aqueous layer was extracted with DCM. The combined organic layers was dried with anhydrous Na2SO4, filtered, concentrated, and purified via MDAP to afford the title compound (8 mg, 25.7% yield) as oil. LCMS: rt=3.56 min, [M+H+]=399
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Mg]Cl)=[CH:30][C:29]=1[CH3:36]>>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][N:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:31]3[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[C:29]([CH3:36])[CH:30]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ncccc2c1=O
Reactant: COc1ccc([Mg]Cl)cc1C
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ncccc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60, from 55 mg (0.136 mmol) of 1-(6-Bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid methoxy-methyl-amide, and 0.5 ml (0.285 mmol) of 4-methoxy-3-methylphenyl magnesium chloride, to give desired compound as a white solid. LCMS (M+H)+: 464.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-:12].[Na+:13].Cl>O1CCOCC1.O>[Na+:13].[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([O-:10])(=[O:12])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)([O-])c1ccc(Cl)nc1

Procedure:
A solution of 6-chloro-3-pyridinesulfonyl chloride (5.0 g, 24 mmol) (C. Rath. Annalen. 1931, 487, 105-119) in dioxane (10 ml) and the solution cooled to 0° C. A solution of sodium hydroxide (1.88 g, 47 mmol) in water (20 ml) was added drop-wise to the stirred solution over 10 mins. After another 10 mins 0.5 pellet of NaOH was added and after a further 15 minutes the pH was adjusted to pH 7 with 2M hydrochloric acid and the solvent was vacuumed down. The material was dried on a Dean and Stark trap to give the title compound. MS (ES−) 192/194 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].[N+:11]([O-])([OH:13])=[O:12]>OS(O)(=O)=O>[Br:1][C:2]1[C:9]([F:10])=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[C:4]([CH:3]=1)[CH:5]=[O:6]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: O=S(=O)(O)O
Product: O=Cc1cc(Br)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of 3-bromo-4-fluorobenzaldehyde (5.0 g, 24.6 mmol) in H2SO4 (25 mL) at 0° C. was added nitric acid (3 mL) in H2SO4 (30 mL), dropwise. The resulting mixture was warmed to room temperature overnight. The resulting solution was then poured slowly over ice and filtered to collect the yellow precipitate. The precipitate was washed with H2O and dried, then purified by silica gel chromatography eluted with a solvent mixture of ethyl acetate and heptanes from 0:100 to 25:75 to yield a light yellow solid.
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:12]=1[O:25][CH3:26])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[CH2:27](Br)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>CN(C)C=O>[C:3]([C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:12]=1[O:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4]
Reactant: CCCCCCCBr
Reactant: CCOC(=O)C(C#N)c1cccc(Oc2ccccc2C)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCC(C#N)(C(=O)OCC)c1cccc(Oc2ccccc2C)c1OC
Yield: 104.5 %

Procedure:
A suspension of sodium hydride (65%, 600 mg) in dimethylformamide (30 ml), a solution of ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]acetate (5 g) in dimethylformamide (10 ml) and n-heptyl bromide (4.1 g) were treated in a similar manner to that of Example 25-(1) to give oily ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]-n-nonanate (6.8 g).
Reaction SMILES: S(=O)(=O)(O)O.O.[OH:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[O:7]=[C:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1
Reactant: O=C(O)C1CCCC(O)C1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCCC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
The Jones oxidation reagent was prepared from sulfuric acid (30 mL), CrO3 (8.1 g) and H2O (30 mL) in an ice/water bath. A solution of 3-hydroxycyclohexane-1-carboxylic acid (11 g, 76.3 mmol, 1.00 equiv) in acetone (150 mL) was added slowly the prepared Jones reagent at 0° C. in 30 min. After addition, the resulting solution was stirred for 2 h at room temperature and the solids were filtered out. The resulting solution was extracted with DCM (3×100 mL). The combined organic layers were washed with brine and dried over sodium sulfate and concentrated under vacuum to give the desired 3-oxocyclohexane-1-carboxylic acid (8.7 g, crude) as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([O:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[C:29]([OH:36])[C:28]=2[CH2:37][CH2:38][CH3:39])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].Cl>C(O)C.O>[C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([O:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[C:29]([OH:36])[C:28]=2[CH2:37][CH2:38][CH3:39])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCOc2ccc(C(C)=O)c(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCc1c(OCCCOc2ccc(C(C)=O)c(OCCCC(=O)O)c2CCC)ccc(C(C)=O)c1O
Temperature: 0 °C
Yield: 61.4 %

Procedure:
To a solution of ethyl 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]butanoate (example 1, 1.7 g) in ethanol (5 ml) was added a solution of sodium hydroxide (0.38 g) in water (5 ml). The mixture was heated on water-bath for 10 minutes, poured into ice water, made acidic with concentrated hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography, eluting with dichloromethane-methanol (10:1). Recrystallization from benzene-n-hexane afforded the title compound (0.99 g, 61.4%) as colorless crystals, mp 50°-53° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][S:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][NH:11]2)=[CH:5][CH:4]=1.C=O.[C:19]([BH3-])#N.[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:19])=[CH:15][CH:16]=1
Reactant: [BH3-]C#N
Reactant: COc1ccc(CSC[C@@H]2CCCN2)cc1
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CSC[C@@H]2CCCN2C)cc1
Yield: 41.7 %

Procedure:
The procedure described in preparation 5-(4) was repeated, but using 2 g of (2S)-2-(4-methoxybenzylthio-methyl)pyrrolidine, 35% formalin and 848 mg of sodium cyanoborohydride in the presence of 44 ml of acetonitrile, to afford 883 mg of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([F:10])[C:3]=1[OH:11].[Br:12][CH2:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:12][CH2:13][CH2:14][CH2:15][O:11][C:3]1[C:2]([F:1])=[CH:7][C:6]([C:8]#[N:9])=[CH:5][C:4]=1[F:10]
Reactant: BrCCCBr
Reactant: N#Cc1cc(F)c(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(F)c(OCCCBr)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
A mixture of 2,6-difluoro-4-cyanophenol (6 g, 0.038 mol), 1,3-dibromopropane (46.9 g, 0.23 mol) and dry potassium carbonate (8 g, 0.058 mol) in dry DMF (50 ml) was stirred at RT overnight under nitrogen atmosphere. Solvent was removed under reduced pressure and the residue was purified by column chromatography over silica gel using 4% ethyl acetate in petroleum ether as eluent to yield (9.6 g) of the title compound as a liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:13][CH2:14][CH2:15][O:16][C:17]1[C:24]([CH3:25])=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=1[CH3:26].S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[Cl:12][C:7]1[CH:8]=[C:9]([Cl:11])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:21]([C:20]1[CH:23]=[C:24]([CH3:25])[C:17]([O:16][CH2:15][CH2:14][OH:13])=[C:18]([CH3:26])[CH:19]=1)=[N:1]2
Reactant: NC(=O)c1c(N)cc(Cl)cc1Cl
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3cc(Cl)cc(Cl)c3c(=O)[nH]2)cc(C)c1OCCO
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a solution of 2-amino-4,6-dichloro-benzamide (1.54 g, 7.50 mmol) and 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (1.46 g, 7.50 mmol) in N,N-dimethylacetamide (15 mL) were added sodium hydrogen sulfite (58.5 wt %, 1.51 g, 8.25 mmol) and p-toluenesulfonic acid monohydrate (0.28 g, 1.50 mmol). The reaction mixture was stirred at 120° C. for 16 hours under nitrogen, and then cooled to room temperature. Solvent was evaporated under reduced pressure. Water (100 mL) was added. The separated solid was filtered, washed with water (50 mL), and dried under vacuum. Crude compound was further washed with ether and dried under vacuum to give 5,7-dichloro-2-[4-(2-hydroxy-ethoxy)-3,5-dimethylphenyl]-3H-quinazolin-4-one as a white solid. Yield: 2.42 g (85%).
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[N:2].[N:10]([O-])=O.[Na+]>Cl>[NH:7]([C:6]1[CH:8]=[CH:9][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[NH2:10]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: N#Cc1ccc(NN)cc1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 71006.4 %

Procedure:
To a cold solution of 4-cyanoaniline (6.0 g, 0.050 mol) in conc. HCl was added aq. solution of sodium nitrite (3.85 g, 0.055 mmol) at −15° C. The reaction mass was stirred at 0-10° C. for 15 minutes and filtered off to remove insolubles. The filtrate was added to stannous chloride in conc. HCl (24.0 g, 0.166 mmol). The reaction mass was stirred at −15° C. for 30 minutes. The reaction mass was filtered to afford 5.2 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 7.04 (d, 2H), 7.70 (d, 2H), 9.17 (br s, 1H), 10.66 (br s, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=1>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:41])([F:42])[F:43])=[CH:36][CH:35]=2)=[O:9])=[CH:5][CH:4]=[N:3]1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Cn1nccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cn1nccc1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.1 %

Procedure:
A mixture of 1-methyl-1H-pyrazol-5-carboxylic acid (1.00 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.82 g), 1-hydroxybenzotriazole monohydrate (1.70 g) and chloroform (20 mL) was stirred at a room temperature for 15 minutes. Thereafter, 4-aminobenzotrifluoride (1.27 g) was added to the reaction solution, and the obtained mixture was then stirred for 24 hours. Thereafter, the reaction solution was concentrated under a reduced pressure, and the residue was then purified by column chromatography (chromatorex NH, hexane:ethyl acetate=4:1), so as to obtain the title compound (1.00 g) in the form of a colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-])=O>CO.[Pd]>[NH:9]1[C:10]2[C:6](=[CH:5][C:4]([NH2:1])=[CH:12][CH:11]=2)[CH:7]=[N:8]1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2[nH]ncc2c1
Yield: 97 %

Procedure:
A mixture of 5-nitro-1H-indazole (25 g, 0.153 mmol, commercially available) and 10% Pd/C (2.0 g) in MeOH was stirred under H2 (1 atm) overnight. After filtration, the filtrate was concentrated to yield 20 g (97%) of 1H-indazol-5-amine as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 12.50 (brs, 1H), 7.70 (s, 1H), 7.21 (d, J=8.7 Hz, 1H), 6.77 (d, J=8.7 Hz, 1H), 6.74 (s, 1H), 4.71 (brs, 1H), 3.15 (d, J=4.8 Hz, 2H); MS (ESI) m/z: 134 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[CH3:12][S:13]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([CH:25]=1)[C:21]([NH:23][NH2:24])=[O:22])(=[O:15])=[O:14]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](/[C:8](=[N:24]/[NH:23][C:21](=[O:22])[C:20]2[CH:25]=[C:16]([S:13]([CH3:12])(=[O:15])=[O:14])[CH:17]=[N:18][CH:19]=2)/[CH3:9])[CH:7]=1
Reactant: CS(=O)(=O)c1cncc(C(=O)NN)c1
Reactant: CC(=O)c1cc(Cl)ccc1O
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cncc(S(C)(=O)=O)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 65 %

Procedure:
1-(5-Chloro-2-hydroxyphenyl)ethanone (50 mg, 0.293 mmol) and 5-(methylsulfonyl)nicotinohydrazide (63.1 mg, 0.293 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. The reaction was monitored by TLC. Upon completion of the reaction and following cooling, the solvent was removed by vacuum, and the resulting crude material was purified by flash column chromatography (3% CH3OH/CH2Cl2) affording the title compound (70 mg, 63.0% yield) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 11.86 (s, 1H), 9.37 (s, 1H), 9.27 (s, 1H), 8.76 (s, 1H), 7.68 (s, 1H), 7.36 (d, 1H, J=8.8 Hz), 6.97 (d, 1H, J=8.8 Hz), 3.42 (s, 3H), 2.53 (s, 3H). ESI-MS: 368.8 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1F)[C:30]#[N:31].C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[O:8][C:6]1[CH:5]=[CH:4][C:3]([CH:9]([CH3:25])[C:10]([C:16]2[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=2)([OH:15])[C:11]([F:13])([F:14])[F:12])=[C:2]([Cl:1])[CH:7]=1)[C:30]#[N:31]
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn(C)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc(C(O)(C(C)c2ccc(Oc3ccc(C#N)cc3Cl)cc2Cl)C(F)(F)F)cn(C)c1=O

Procedure:
In analogy to Example 156, step 1, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1H-pyridin-2-one (Example 203, step 5) was reacted with 3-chloro-4-fluorobenzonitrile and cesium carbonate to give the title compound as a colorless solid. MS (m/e)=511.2 [M+H+].
Reaction SMILES: [CH3:1][NH:2][CH3:3].[NH:4]1[C:12]2[C:7](=[C:8]([C:13]3[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=O)[CH:16]=[CH:17][CH:18]=3)[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[NH:4]1[C:12]2[C:7](=[C:8]([C:13]3[CH:14]=[C:15]([CH2:19][C:20]([N:2]([CH3:3])[CH3:1])=[O:22])[CH:16]=[CH:17][CH:18]=3)[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1
Reactant: O=C(O)Cc1cccc(-c2cccc3[nH]ccc23)c1
Reactant: CNC
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)Cc1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dimethylamine (2M in THF, 5 mL) was added to a mixture of [3-(1H-indol-4-yl)-phenyl]-acetic acid (1.26 g, 5 mmol), EDC (1.19 g, 1.25 eq.) and HOBt (675 mg, 1 eq.) in THF (10 mL) was stirred at rt for 5 hours. The reaction was concentrated, diluted with ethyl acetate, washed with 10% Na2CO3 (3×), brine, dried and concentrated. The residue was purified on a silica gel column to give 658 mg of 2-[3-(1H-indol-4-yl)-phenyl]-N,N-dimethyl-acetamide as a solid.
Reaction SMILES: [CH2:1]([CH:3]1[NH:16][CH:15]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].[C:22](Cl)(=[O:32])[C:23]1[CH:31]=[CH:30][C:29]2[O:28][CH2:27][O:26][C:25]=2[CH:24]=1>>[CH2:1]([CH:3]1[N:16]([C:22](=[O:32])[C:23]2[CH:31]=[CH:30][C:29]3[O:28][CH2:27][O:26][C:25]=3[CH:24]=2)[CH:15]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: CCOC(=O)C1=CNC(CC)Cc2c1[nH]c1ccccc21
Product: CCOC(=O)C1=CN(C(=O)c2ccc3c(c2)OCO3)C(CC)Cc2c1[nH]c1ccccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using ethyl 2-ethyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate and piperonyloyl chloride. 1H-NMR (CDCl3): δ 10.38 (1H, br s), 8.15 (1H, s), 7.52 (1H, d), 7.37 (1H, d), 7.10 (4H, m), 6.88 (1H, d), 6.07 (1H, d), 6.06 (1H, d), 5.34 (1H, m), 4.16-4.33 (2H, m), 3.53 (1H, dd), 3.00 (1H, dd), 1.29-1.45 (2H, m), 1.24 (3H, t), 0.81 (3H, t); MS (ES): 433 (MH+).