Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=1.[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:27]1[CH:32]=[C:31]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]3[S:16][C:15]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=4[C:13]=3[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:24])([F:25])[F:26])[CH:3]=2)[CH:30]=[N:29][CH:28]=1
Reactant: OB(O)c1cncnc1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)sc2ccc(F)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3cncnc3)cc2C(F)(F)F)sc2ccc(F)cc12
Yield: 45.1 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-trifluoromethyl-phenyl)-amide (0.10 g) and pyrimidine-5-boronic acid (0.053 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.32 ml) and 2 M aqueous sodium carbonate solution (0.8 ml) with tetrakis(triphenylphosphine)palladium (0.012 g) to obtain the title compound (0.045 g) as a colorless solid. MS (ISN): 466.1 (M−H)−
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[CH3:18])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:26](=[O:27])[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:7]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[CH3:18])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)c(C)c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)c(C)c1
Reaction time: 8 h
Yield: 44.8 %

Procedure:
To a solution of 3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-amine (700 mg, 2.9 mmol) in DCM (20 mL) was added K2CO3 (4.32 mmol) and phenyl chloroformate (6.48 mmol) and the reaction stirred overnight. The solvent was decanted and the solids washed with DCM. The combined organics were concentrated and purified using silica gel chromatography eluting with an EtOAC/hexane gradient (5-20%) gave phenyl 3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-ylcarbamate (472 mg, 45% yield). 1H NMR (300 MHz, DMSO d6) δ 1.09 (s, 9H), 1.98 (s, 3H), 2.36 (s, 3H), 6.26 (s, 1H), 7.00 (s, 2H), 7.14 (m, 4H), 7.37 (m, 2H), 9.80 (bs, 1H); LC-MS (ESI) m/z 364 (M+H)+
Reaction SMILES: CN(C)C=O.Br[CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].[NH2:27][C:28]1[CH:47]=[CH:46][C:31]([O:32][C:33]2[C:42]3[C:37](=[CH:38][C:39]([OH:45])=[C:40]([C:43]#[N:44])[CH:41]=3)[N:36]=[CH:35][CH:34]=2)=[CH:30][C:29]=1[F:48]>C(OCC)(=O)C.O>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][CH:8]([CH2:7][O:45][C:39]2[CH:38]=[C:37]3[C:42]([C:33]([O:32][C:31]4[CH:46]=[CH:47][C:28]([NH2:27])=[C:29]([F:48])[CH:30]=4)=[CH:34][CH:35]=[N:36]3)=[CH:41][C:40]=2[C:43]#[N:44])[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: N#Cc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COc2cc3nccc(Oc4ccc(N)c(F)c4)c3cc2C#N)CC1
Temperature: 50 °C
Yield: 47.7 %

Procedure:
After adding dimethylformamide (4 ml), tert-butyl 4-(bromomethyl)-1-piperidine carboxylate (708 mg) and potassium carbonate (467 mg) to 4-(4-amino-3-fluorophenoxy)-6-cyano-7-hydroxyquinoline (500 mg), the mixture was heated at 50° C. for 4 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate and the organic layer was washed with water and saturated brine in that order and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (n-hexane:ethyl acetate) to obtain the title compound (398 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[NH:15][C:14](=O)[C:13]3=[C:17]([CH3:21])[N:18]=[C:19]([CH3:20])[N:12]3[N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[NH2:27]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:15]=[C:14]([NH:27][C:26]3[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:24]([O:23][CH3:22])[CH:25]=3)[C:13]3=[C:17]([CH3:21])[N:18]=[C:19]([CH3:20])[N:12]3[N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2nn3c(C)nc(C)c3c(=O)[nH]2)cc1Cl
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc(Nc3cc(OC)c(OC)c(OC)c3)c3c(C)nc(C)n3n2)cc1Cl
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A mixture of 30 mg (0.08 mmol) of the compound of Example 33A with 100 mg (0.55 mmol) of 3,4,5-trimethoxyaniline is stirred in the form of a melt for 16 hours at a bath temperature of 120° C. It is taken up in ethyl acetate, washed with water, dried and concentrated. After purification on a silica gel column using dichloromethane/ethyl acetate [lacuna] to 2:1 and filtering off with suction using ether/heptane, 28.6 mg (43.31% of theory) of almost colourless crystals are obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:10]2=[O:19])=[CH:5][CH:4]=1)[CH3:2].O=C(Cl)[O:22][C:23](Cl)(Cl)Cl.[F:28][C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1>>[F:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:23]([N:16]2[CH2:17][CH2:18][C:11]3([C:10](=[O:19])[N:9]([C:6]4[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=4)[CH2:13][CH2:12]3)[CH2:14][CH2:15]2)=[O:22])=[CH:31][CH:30]=1
Reactant: CCc1ccc(N2CCC3(CCNCC3)C2=O)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(F)cc1
Product: CCc1ccc(N2CCC3(CCN(C(=O)Nc4ccc(F)cc4)CC3)C2=O)cc1

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-Ethyl-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and 4-Fluoro-phenylamine. MS (ESI): 396.3 (MH+).
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH:9]2[CH2:14][CH:13]3[CH2:15][CH2:16][N:10]2[CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]1[CH2:28]CCC[CH2:24]1.C([Li])CCC.BrCC=C>CCCCCC>[C:17]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:28][CH:23]=[CH2:24])[CH2:8][CH:9]2[CH2:14][CH:13]3[CH2:15][CH2:16][N:10]2[CH2:11][CH2:12]3)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C1CCCCC1
Reactant: c1ccc(C(CC2CC3CCN2CC3)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C=CCBr
Product: C=CCC(CC1CC2CCN1CC2)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2.91 parts of 2-(2,2-diphenylethyl)-1-azabicyclo[2.2.2]octane in 40 parts by volume of cyclohexane are added under a nitrogen atmosphere 4.6 parts by volume of a 2.5 M solution of butyl lithium in hexane and 1.5 parts by volume of N,N,N'N'-tetramethylethylenediamine. The mixture is heated to reflux, with stirring, for 12/3 hour and then cooled to room temperature. 1.45 Parts of 3-bromopropene is then added during a 5-second period. Stirring is continued for about 6 minutes during which time the internal temperature reaches a maximum of 43° C. and then subsides. The resulting yellow mixture is washed with seven portions of water and then extracted with dilute hydrochloride acid. The acidic, aqueous extract is washed with ethyl ether and then basefied with aqueous sodium hydroxide resulting in the liberation of an oil. This oil is then extracted with ethyl ether. The ethereal extract is dried over anhydrous sodium sulfate and stripped in vacuo to give a light brown oil. This oil is crystallized from methanol and water to afford as a white solid, 2-(2,2-diphenyl-4-pentenyl)-1-azabicyclo[2.2.2]octane melting at about 95.5°-98° C. This compound is represented by the following structural formula: ##STR7##
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.C[Mg]Br.[CH3:11][CH2:12]OCC.[CH3:16][C:17](O)=O>O>[CH2:11]([C:1]1([CH2:16][CH3:17])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1)[CH3:12]
Reactant: CC(=O)O
Reactant: O=C1CCC(=O)O1
Reactant: CCOCC
Agent: C[Mg]Br
Solvent: O
Product: CCC1(CC)CCC(=O)O1
Temperature: 0 °C
Reaction time: 12 h
Yield: 46 %

Procedure:
Succinic anhydride (15.0 g, 150 mmol, 1.0 eq) was added into a round bottomed flask, and the flask was flushed with nitrogen. THF (500 mL) was then added via a syringe. The solution was cooled to 0° C. Methyl magnesium bromide in ether (3.0 M, 100 mL, 300 mmol, 2.0 eq) was added via syringe slowly. The reaction mixture was warmed to room temperature gradually, and then heated to 50° C. for 12 hours. A yellow solution was formed. After cooling the reaction mixture to room temperature, AcOH was added until pH=4, and stirring was continued for an additional 12 hours. Water (75 mL) was added, and THF and ether were removed under reduced pressure. The green suspension was extracted with CH2Cl2 (60 mL×5), and the organic phase was dried over anhydrous Na2SO4 and concentrated. Purification by vacuum distillation gave the product as brown oil (9.7 g, 46%). This compound has been synthesized using several different methods in the literature.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](/[CH3:17])\[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:16])/[CH2:9][CH2:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13].[SH:18][CH2:19][CH2:20][OH:21].C(N(CC)CC)C>CO>[OH:1][CH2:2]/[CH:3]=[C:4](/[CH3:17])\[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:16])/[CH2:9][CH2:10][C:11](=[O:15])[CH:12]([CH3:14])[CH2:13][S:18][CH2:19][CH2:20][OH:21]
Reactant: C=C(C)C(=O)CC/C(C)=C/CC/C(C)=C\CO
Reactant: OCCS
Solvent: CCN(CC)CC
Solvent: CO
Product: C/C(=C/CO)CC/C=C(\C)CCC(=O)C(C)CSCCO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 300 mg (0.0013 mol) of (6E,10Z)-12-hydroxy-2,6,10-trimethyl-1,6,10-dodecatrien-3-one in 10 ml of methanol is treated with 0.27 ml of 2-mercapto-ethanol and 0.53 ml of triethylamine. The solution is stirred at room temperature for 18 hours under argon. After removing the solvent on a rotary evaporator the residue is treated with water and methylene chloride. After extraction the organic phase is dried and freed from solvent on a rotary evaporator. The residue is chromatographed on silica gel with ether-methanol 50:1. There is obtained (6E,10Z)-12-hydroxy-1-[(2-hydroxyethyl)thio]-2,6,10-trimethyl-6,10-dodecadien-3-one which has the following absorption bands in the IR spectrum: 3369 cm-1, 1708 cm-1, 1667 cm-1, 1450 cm-1, 1044 cm-1, 1055 cm-1.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.Cl.[CH3:18][NH:19][CH:20]1[CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>CS(C)=O>[CH:20]1([N:19]([CH3:18])[C:2]2[C:3](=[O:16])[NH:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:22][CH2:21]1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: CNC1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N(C)C3CC3)nc2c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (300 mg, 1.26 mmol) in DMSO (2 mL), was added N-methylcyclopropanamine hydrochloride (175 mg, 1.63 mmol) and DIEA (325 mg, 2.52 mmol) with stirring for 2 h at 75° C. in an oil bath. Then the reaction was quenched by the addition of water (10 mL) to give the precipitate, which was collected by filtration to afford methyl 3-[cyclopropyl(methyl)amino]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as an off-white solid (297 mg, 86%).
Reaction SMILES: [NH2:1][C:2]([CH2:7][CH3:8])([CH2:5][OH:6])[CH2:3][OH:4].[C:9](O)(=O)[CH2:10][CH3:11].[C:14]([OH:19])(=O)[C:15]([CH3:17])=[CH2:16]>>[CH2:10]([C:11]1[O:4][CH2:3][C:2]([CH2:7][CH3:8])([CH2:5][O:6][C:14](=[O:19])[C:15]([CH3:17])=[CH2:16])[N:1]=1)[CH3:9]
Reactant: CCC(N)(CO)CO
Reactant: C=C(C)C(=O)O
Reactant: CCC(=O)O
Product: C=C(C)C(=O)OCC1(CC)COC(CC)=N1

Procedure:
2,4-Diethyl-4-methacryloyloxymethyl-2-oxazoline is prepared from 2-amino-2-ethyl-1,3-propanediol, propionic acid and methacrylic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[S:5][C:6]=1[CH2:7][CH3:8].C(=O)([O-])[O-].[K+].[K+].[CH3:19][N:20]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=[N:21]1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:7]([C:6]1[S:5][C:4]([C:9]([O:11][CH3:12])=[O:10])=[CH:3][C:2]=1[C:24]1[N:20]([CH3:19])[N:21]=[CH:22][CH:23]=1)[CH3:8]
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: CCc1sc(C(=O)OC)cc1Br
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1sc(C(=O)OC)cc1-c1ccnn1C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A solution of methyl 4-bromo-5-ethyl-2-thiophenecarboxylate (300 mg, 1.204 mmol), potassium carbonate (832 mg, 6.02 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (326 mg, 1.565 mmol) [prepared according to Preparation 7] and bis(tri-t-butylphosphine)palladium(0) (30.8 mg, 0.060 mmol) were combined in a sealed tube and stirred at 80° C. for 1 h. The reaction contents were then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated affording methyl 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (301 mg, 1.204 mmol, 100° A yield) as a brown oil: LCMS (ES) m/e 251 (M+H)+.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[N:10]=[C:9](Cl)[C:8]([Cl:12])=[CH:7][N:6]=1>CO>[Cl:4][C:5]1[N:10]=[C:9]([O:2][CH3:1])[C:8]([Cl:12])=[CH:7][N:6]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
Sodium methoxide (295 mg, 5.45 mmol) was taken up in methanol (13.6 mL) and 2,4,5-trichloropyrimidine (500 mg, 2.73 mmol) was added. The mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The resulting residue was diluted with diethyl ether, washed with 1:1 water:saturated aqueous ammonium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by Chromatography on silica gel (0-10% diethyl ether/hexanes) afforded 2,5-dichloro-4-methoxypyrimidine (280 mg, 1.56 mmol, 57%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.C(N(CC)CC)C.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[CH2:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: CCOC(=O)CBr
Reactant: Nc1ccc2c(c1)CCC2
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-aminoindan (15.0 g, 0.1128 mol) and triethylamine (11.92 g, 0.1184 mol) in 200 ml ethanol was added dropwise ethyl bromoacetate (18.83 g, 0.1128 mol). After the addition was complete the mixture was stirred at room temperature for 24 h and concentrated in vacuo. The residue was dissolved in ether, washed with H2O (4×300 ml), brine and dried (MgSO4). Concentration of the volatiles in vacuo provided a crystalline material which was recrystallized from petroleum ether; b.p. 30°-60° C., m.p. 49° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([NH:14][CH2:15][CH2:16][NH:17][C:18]2[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([O:25][C:26]3[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=3[CH3:34])[C:19]=2[CH3:35])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>C1COCC1.CO.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:14][CH2:15][CH2:16][NH:17][C:18]2[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([O:25][C:26]3[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=3[CH3:34])[C:19]=2[CH3:35])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC(=O)NCCNc2cc(C)nc(Oc3c(C)cc(C)cc3C)c2C)cc1OC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(CCNCCNc2cc(C)nc(Oc3c(C)cc(C)cc3C)c2C)cc1OC

Procedure:
Add BH3 in THF (1 M solution, 0.3 mmol, 0.3 mL) to a solution of the crude 2-(3,4-dimethoxyphenyl)-N-(2-{[3,6-dimethyl-2-(2,4,6-trimethylphenoxy)(4-pyridyl)]amino}ethyl) acetamide in THF (2.0 mL) at ambient temperature. Heat the reaction mixture under reflux for 15 h, dilute with a solution of 10% aq HCV/MeOH (1:1, 2 mL) and heat again under reflux (1 h). Dilute the reaction mixture with CHCl3 (10 mL), wash with saturated aq NaHCO3 (1×5 mL), dry and concentrate in vacuo. Chromatograph the crude residue on SiO2-gel using a gradient of 100% EtOAc to 10% Et2NH/EtOAc to obtain the title compound as a colorless oil. Immediately dissolve the product in Et2O (1 mL), treat with excess 4 M HCl/dioxane and concentrate in vacuo to obtain the hydrochloride salt of the title compound as a colorless solid. 1H NMR (d4-MeOH, Unity 400): d 6.99–6.77 (6H, m), 3.81 (3H, s), 3.78 (3H, s), 3.62 (2H, m), 2.98 (2H, t), 2.39 (3H, s), 2.29 (3H, s), 2.16 (3H, s), 2.07 (6H, s). M+1: 464.
Reaction SMILES: [N+:1]([C:4]1[C:5](=O)[NH:6][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].C1C=C[C:20]([N:23](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=[CH:19]C=1.C(N)C.C1COCC1>CN(C=O)C.O>[CH2:20]([NH:23][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[C:7]([C:10]([F:13])([F:12])[F:11])[N:6]=1)[CH3:19]
Reactant: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=c1[nH]c(C(F)(F)F)ccc1[N+](=O)[O-]
Agent: CCN
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CCNc1nc(C(F)(F)F)ccc1[N+](=O)[O-]
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
To a solution of 3-nitro-6-(trifluoromethyl)-2(1H)-pyridinone (2.4 g, 11.5 mmol) in DMF (69 mL) was added sodium hydride (350 mg, 13.8 mmol). The reaction was stirred for 30 min at 45° C., cooled to room temperature and N-phenyltrifluromethanesulfonimide (4.9 g, 13.8 mmol) was added. After 1 h, a 2 M solution of ethylamine in THF (13 mL, 25 mmol) was added. The reaction was stirred at room temperature overnight. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (3×). The combined organic layer was successively washed water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane:EtOAc, 9:1) to give the desired compound (1.1 g, 41% yield) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](F)[C:5]([CH2:9][OH:10])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]1.CN1CCOCC1.O>CN1CCCC1=O>[Br:1][C:2]1[N:7]=[C:6]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:12]2)[C:5]([CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: OCc1ccc(Br)nc1F
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2nc(Br)ccc2CO)C1
Temperature: 130 °C
Yield: 80.1 %

Procedure:
A mixture of (6-bromo-2-fluoro-3-pyridyl)methanol (1.766 mmol; 363.8 mg), tert-butyl N-[(3S)-3-piperidyl]carbamate (2.649 mmol; 530.5 mg), and N-Methylmorpholine (5.298 mmol; 541 mg; 0.588 mL) in 1-methyl-2-pyrrolidinone (10 mL) in a sealed pressure vial was heated at 130° C. for 4 hours. The mixture was poured into water, and extracted with EtOAc. The organic layer was concentrated. The residue was purified on silica eluted with 0 to 100% EtOAc in Heptane to afford tert-butyl N-[(3S)-1-[6-bromo-3-(hydroxymethyl)-2-pyridyl]-3-piperidyl]carbamate (546.3 mg, 80%).
Reaction SMILES: [CH3:1][NH:2][OH:3].Cl.[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1.[Cl-].[Na+]>C(N(CC)CC)C.O1CCCC1>[CH3:1][N:2]([S:11]([C:8]1[CH:9]=[CH:10][C:5]([CH3:15])=[CH:6][CH:7]=1)(=[O:13])=[O:12])[OH:3]
Reactant: CNO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N(C)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.02 Grams of N-methylhydroxylamine.HCl was suspended with 70 ml of tetrahydrofuran and 6.70 g of triethylamine was added to the solution. After stirring at room temperature for 0.5 hour, 5.73 g of p-toluenesulfonyl chloride was added to the reaction solution and stirred at room temperature over night. The saturated sodium chloride solution was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and N-methyl-N-(p-toluenesulfonyl)hydroxylamine was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-])=O)[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=2)[N:3]=1>CCO.[OH-].[OH-].[Pd+2]>[CH3:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=2)[N:3]=1
Reactant: Cc1cccc(Cn2nc(C)c3c([N+](=O)[O-])cccc32)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(Cn2nc(C)c3c(N)cccc32)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.1 %

Procedure:
A suspension of 3-methyl-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole (54 mg, 0.19 mmol) in absolute EtOH (1.5 mL) was treated at ambient temperature with 10% palladium hydroxide on carbon (27 mg, 0.019 mmol). The mixture was stirred at ambient temperature under a hydrogen atmosphere for 16 hours, and then filtered through a Celite® pad, washing with EtOH. The filtrate was concentrated under reduced pressure to afford the product (36 mg) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]3[CH2:14][CH2:13][CH2:12][C:11]=13)[N:8](C(OC(C)(C)C)=O)[C:7]([CH3:23])([CH3:22])[C:6](=[O:24])[C:5]2([CH3:26])[CH3:25].FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]3[CH2:14][CH2:13][CH2:12][C:11]=13)[NH:8][C:7]([CH3:22])([CH3:23])[C:6](=[O:24])[C:5]2([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1c2c(cc(Br)c3c2CCC3)C(C)(C)C(=O)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)Nc2c(cc(Br)c3c2CCC3)C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a solution of tert-butyl 6-bromo-2,2,4,4-tetramethyl-2,3,4,7,8,9-hexahydro-1H-cyclopenta[h]quinolin-3-one-1-carboxylate (1.0 g) obtained in Example 1, 8) in CH2Cl2 (10 ml) was added trifluoroacetic acid (10 ml), and the mixture was stirred at room temperature for 1 hr. The reaction solution was neutralized with 1N aqueous sodium hydroxide solution, and the mixture was extracted with CHCl3. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to normal phase chromatography (elution solvent hexane→hexane-ethyl acetate=7:3) to give the title compound (760 mg, 100%).