Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12](Cl)(=[O:14])=[O:13].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][C:24]=2[C:32]([NH2:34])=[O:33])=[CH:19][CH:18]=1>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([NH:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][C:24]=2[C:32]([NH2:34])=[O:33])=[CH:21][CH:22]=1)(=[O:14])=[O:13]
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)ccc1F
Reactant: NC(=O)c1[nH]c2ccccc2c1-c1ccc(N)cc1
Solvent: c1ccncc1
Product: NC(=O)c1[nH]c2ccccc2c1-c1ccc(NS(=O)(=O)c2cc(C(F)(F)F)ccc2F)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
162 mg of 2-fluoro-5-trifluoromethylphenylsulfonyl chloride in 6 ml of pyridine are added dropwise to a solution of 100 mg of 3-(4-aminophenyl)-1H-indole-2-carboxamide (example 1) in 12 ml of pyridine at 0° C. The mixture is stirred at ambient temperature for 6 hours and then poured into 50 ml of ice-cold water, and the precipitate formed is filtered off. After purification by flash chromatography on a silica column, elution being carried out with a mixture of cyclohexane and ethyl acetate (20/80 by volume), 50 mg of 3-[4-(2-fluoro-5-trifluoromethylbenzenesulfonylamino)phenyl]-1H-indole-2-carboxamide are obtained, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])[C:11](=[O:19])[CH:10]([CH3:20])[CH2:9]2)[CH:2]([CH3:4])[CH3:3].CC([O-])=O.[Na+].ClCCl.[Br:29]Br.[O-]S([O-])=O.[Na+].[Na+]>[I-].C([N+](CC)(CC)CC)C.O>[Br:29][C:7]1[C:6]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[C:14]([C:15]([CH3:17])([CH3:16])[CH3:18])[CH:13]=[C:12]2[C:8]=1[CH2:9][CH:10]([CH3:20])[C:11]2=[O:19]
Reactant: CC(C)COc1cc2c(cc1C(C)(C)C)C(=O)C(C)C2
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)CC
Agent: O=S([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: CC(C)COc1c(C(C)(C)C)cc2c(c1Br)CC(C)C2=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a mixture of 91.9 g (335 mmol) of 5-isobutoxy-6-tert-butyl-2-methylindanone, 82.5 g (1.0 mol) of NaOAc, 1.70 g (7.0 mmol) of tetraethylammonium iodide, 500 ml of water, and 170 ml of dichloromethane 17.2 ml (335 mmol) of bromine was added by vigorous stirring for 1 h at 0° C. The resulting mixture was stirred for 1 h at this temperature, and then 41.3 g (0.5 mol) of NaOAc was added. To the obtained mixture 9.0 ml (175 mmol) of bromine was added dropwise for 0.5 h at 0° C. The formed mixture was stirred for 2 h at 0° C., then Na2SO3 was added to remove an excess of bromine. The organic layer was separated, dried over Na2SO4, and then evaporated to dryness. This procedure gave 116 g (98%) of the title product which was further used without an additional purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([CH:8](C(OCC)=O)C(OCC)=O)=[N:6][CH:7]=1>Cl>[Br:1][C:2]1[CH:3]=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl
Product: Cc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 77.2 %

Procedure:
A stirred mixture of diethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate (12.5 g, 34.6 mmol) in HCl (7 N in water, 200 mL) is heated at reflux for 18 hours. The mixture is cooled to room temperature and extracted with CH2Cl2 (3×200 mL). Organic layer is collected, dried over Na2SO4, filtered and concentrated to dryness. The crude product is purified via chromatography using CH2Cl2 to afford the title compound (5.8 g, 84%) as a yellow solid: Rf 0.67 (CH2Cl2); LCMS (m/z)=217.1, 219.2 [M+H]+, tR=2.01 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:13][C:12]([CH3:15])([CH3:14])[O:11][CH:10]2[C:16]([O:18]C)=[O:17])=[CH:5][CH:4]=1.Cl>[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[O:13][C:12]([CH3:15])([CH3:14])[O:11][C@@H:10]2[C:16]([OH:18])=[O:17])=[CH:7][CH:8]=1
Reactant: COC(=O)C1OC(C)(C)OC1c1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc([C@H]2OC(C)(C)O[C@@H]2C(=O)O)cc1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
Methyl 5-(4-methoxyphenyl)-2,2-dimethyl-1,3-dioxolane 4-carboxylate (2.0 g, 7.5 mmol) and aqueous sodium hydroxide solution (0.36 g in 20 ml) and industrial methylated spirits (20 ml) were stirred at 80° C. for 3 hours. The mixture was cooled to room temperature, neutralised with dilute hydrochloric acid and concentrated in vacuo. The product was extracted with DCM, dried over NaSO4 and evaporated to dryness to leave (5R,4S)-5-(4-methoxyphenyl)2,2-dimethyl-1,3-dioxolane-4-carboxylic acid as a colourless oil (1.7 g, 90%). 1H-NMR was in accordance with expected signals. I.R. showed expected peaks.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:31])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=N)[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][CH2:5]2.C(O)(=[O:34])C.Cl>O>[OH:1][C:2]1[C:3]([CH3:31])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:34])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][CH2:5]2
Reactant: CC(=O)O
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC3SC(=N)NC3=O)cc1)O2
Agent: Cl
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2

Procedure:
3.1 g of 5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2-iminothiazolidin-4-one [prepared as described in Example 1(a)] were added to a mixture of 45 ml of acetic acid, 15 ml of concentrated hydrochloric acid and 8 ml of water, and the mixture was reacted for 12 hours at 85°-90° C. It was then processed and purified in a similar manner to Example 1(a), giving 2.5 g of 5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione, whose melting point and nuclear magnetic resonance spectrum were consistent with those of the product of Example 1(b).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21]([OH:23])=O)=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]=[CH:20][C:21]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:23])=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1CCNCC1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C=CC(=O)O)cc2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2ccc(C=CC(=O)N3CCCCC3)cc2)=C(C)C1=O
Yield: 55.2 %

Procedure:
3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acrylic acid (200 mg, 0.58 mmol) obtained in Example 2 and piperidine (65 mg, 0.76 mmol) were used, and a method similar to that described in Example 3 was employed to obtain the title compound (129 mg, 0.32 mmol, yield 54%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8](Br)=[CH:9]3)=[CH:4][C:3]1=2.[Mg].Br[C:22]1[S:23][CH:24]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:26]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].Cl[Ni]Cl.CCN(CCOC1C=CC(CC2C=CC=CC=2)=CC=1)CC.Cl>[CH3:1][C:2]1([CH3:19])[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8]([C:22]4[S:23][CH:24]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:26]=4)=[CH:9]3)=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1csc(Br)c1
Reactant: CC1(C)CCC(C)(C)c2cc3cc(Br)ccc3cc21
Agent: Cl[Ni]Cl
Agent: CCN(CC)CCOc1ccc(Cc2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1csc(-c2ccc3cc4c(cc3c2)C(C)(C)CCC4(C)C)c1
Reaction time: 1 h

Procedure:
A solution of 9.5 g (30 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-bromoanthracene was added dropwise to a suspension of 724 mg (30 mmol) of magnesium in 10 ml of THF. Once the addition was completed, the mixture was heated at reflux for one hour. At room temperature 4.1 g (30 mmol) of anhydrous zinc chloride were added and the mixture was stirred for one hour. 5.2 g (22 mmol) of ethyl 2-bromo-4-thiophenecarboxylate and 120 mg (0.22 mmol) of the complex NiCl2 /DPPE were then added successively and the mixture was maintained under stirring at room temperature for 12 hours. The reaction medium was poured into ice-cold water, extracted with ethyl ether, the organic phase decanted off, dried over magnesium sulfate and evaporated. The residue obtained was chromatographed on a silica column eluted with a mixture of hexane and dichloromethane (60/40). After evaporation of the solvents, 6.35 g (74%) of the expected ester of melting point 107°-108° C. were recovered.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[CH3:14])[C:10](=[O:15])[CH:9]([CH3:16])[CH2:8]2.CC([O-])=O.[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>[Br:1][C:6]1[C:5]([O:4][CH3:3])=[C:13]([CH3:14])[CH:12]=[C:11]2[C:7]=1[CH2:8][CH:9]([CH3:16])[C:10]2=[O:15]
Reactant: COc1cc2c(cc1C)C(=O)C(C)C2
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: COc1c(C)cc2c(c1Br)CC(C)C2=O
Reaction time: 16 h

Procedure:
Bromine (6 mL, 11.7 mmol) was added at 0° C. to a mixture of 5-methoxy-2,6-dimethyl-1-indanone (22 g, 11.7 mmol), NaOAc (27 g) and tetrabutylammonium bromide (0.5 g) in CH2Cl2 (100 mL) and H2O (200 mL). After 16 h, 1 mL of Br2 and 6 g of NaOAc were added. After 24 h stirring, the organic phase was separated, washed with water, 10% aq. Na2SO3, aq. NaHCO3, dried over MgSO4 and evaporated. The residue was recrystallized from hexane. Yield=24.7 g (78.4%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[C:15]([O:21][CH2:22][CH2:23][CH3:24])(=[O:20])[CH2:16][C:17]([CH3:19])=[O:18].C(O)(=O)C.N1CCCCC1>ClCCl>[CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:16]([C:17](=[O:18])[CH3:19])[C:15]([O:21][CH2:22][CH2:23][CH3:24])=[O:20]
Reactant: CCCOC(=O)CC(C)=O
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CCCOC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O

Procedure:
2-Methyl-4-oxo-4H-chromene-8-carbaldehyde (2 g, 10.62 mmol) and propyl acetoacetate (1.53 g, 10.62 mmol) are dissolved in 500 ml of dichloromethane and, after addition of glacial acetic acid (0.76 ml, 13.28 mmol) and piperidine (0.1 ml, 1.06 mmol), heated under reflux with a water trap for 18 h. After cooling, the reaction mixture is diluted with 50 ml of dichloromethane and washed with 20 ml of sodium chloride solution, the organic phase is dried over sodium sulfate, and the solvent is removed in vacuo. 3.3 g (99% of theory) of the title compound are obtained as an E/Z isomer mixture.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22](I)[CH:23]=3)[N:18]=[CH:17][N:16]=2)=[CH:10][CH:9]=1.[CH:29]([O-])=[O:30].[Na+].C(N(CC)CC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH:29]=[O:30])[CH:23]=3)[N:18]=[CH:17][N:16]=2)=[CH:10][CH:9]=1
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4ccc(I)cc34)cc2)c1
Reactant: O=C[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)cc3)c2c1
Temperature: 80 °C
Yield: 77.8 %

Procedure:
In 100 ml of dimethylformamide was dissolved 4-(4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline hydrochloride (III-1, 5.0 g), and 1.25 g of sodium formate, dichlorobis(triphenylphosphine)palladium (324 mg), and triethylamine (3.2 ml) were added. The reaction mixture was degassed, and stirred under heating at 80° C. for 3 hours under the carbon monoxide atmosphere. Thereafter, the reaction mixture was poured into ice water, and extracted with ethyl acetate. The extract was washed with water and sodium chloride solution, and dried with magnesium sulfate. The dried solution was filtered with Celite, concentrated, and powdered with an ethyl acetate-hexane (1:2) to obtain 4-(4-(3-fluorobenzyloxy)phenylamino)-6-formylquinazoline (IV-1, 2.86 g) as a yellow solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.ClC1C=C([C:18]2[C:23]3[N:24]([CH2:36][C@H:37]4[CH2:42][CH2:41][C@H:40]([CH3:43])[CH2:39][CH2:38]4)[C:25](N4C[C@H](OC)C[C@H]4CO)=[N:26][C:22]=3[CH:21]=[C:20]([C:44]#[N:45])[N:19]=2)C=NC=1.C(N(CC)CC)C>ClCCl>[CH3:43][C@H:40]1[CH2:41][CH2:42][C@H:37]([CH2:36][N:24]2[C:23]3[CH:18]=[N:19][C:20]([C:44]#[N:45])=[CH:21][C:22]=3[N:26]=[CH:25]2)[CH2:38][CH2:39]1
Reactant: CO[C@@H]1C[C@@H](CO)N(c2nc3cc(C#N)nc(-c4cncc(Cl)c4)c3n2C[C@H]2CC[C@H](C)CC2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[C@H]1CC[C@H](Cn2cnc3cc(C#N)ncc32)CC1
Temperature: -60 °C
Reaction time: 0.17 h

Procedure:
A solution of oxalyl chloride (0.160 ml, 1.826 mmol) in dichloromethane (5 ml) was cooled to −78° C., and a solution of DMSO (0.259 ml, 3.65 mmol) in dichloromethane (2.5 ml) was slowly added. The reaction was warmed to −60° C. After 10 min of stirring, a solution of 4-(5-chloropyridin-3-yl)-2-((2S,4R)-2-(hydroxymethyl)-4-methoxypyrrolidin-1-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (452 mg, 0.913 mmol) in dichloromethane (5 ml) was slowly added. The reaction was stirred for 30 min at −40° C. Then triethylamine (0.764 ml, 5.48 mmol) was added, and the reaction was warmed to room temperature and stirred overnight. The reaction mixture was quenched with saturated aqueous NaHCO3 (30 mL). The dichloromethane layer was separated. The aqueous layer was extracted with dichloromethane (20 mL). The combined dichloromethane layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with EtOAc/isohexane to give 4-(5-chloropyridin-3-yl)-2-(2S,4R)-2-formyl-4-methoxypyrrolidin-1-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C26H29ClN6O2 [M+H]+ 493. found 493.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]([CH2:13][CH:14]=O)[C:4](=[O:16])[CH:3]=1.[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][N:39]([CH2:14][CH2:13][N:5]4[C:6]5[C:11](=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=5)[C:2]([Cl:1])=[CH:3][C:4]4=[O:16])[CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: O=CCn1c(=O)cc(Cl)c2ccc(F)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(Cl)c3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
To 20 mL of a chloroform solution containing 0.71 g of (4-chloro-7-fluoro-2-oxoquinolin-1(2H)-yl)acetaldehyde, 1.03 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 0.18 g of acetic acid were added, and stirred at room temperature for 1 hour. To the reaction mixture, 0.99 g of sodium triacetoxyborohydride was added, and stirred for 1 hour. Aqueous saturated sodium hydrogen carbonate solution was added, and the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; ethyl acetate:hexane=4:1], to give 0.76 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-chloro-7-fluoro-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow oil.
Reaction SMILES: C[Al](C)C.[CH:5]1([NH2:8])[CH2:7][CH2:6]1.C[O:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:21]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:22][O:23][C:24]=2[CH2:25][OH:26])=[N:14][CH:13]=1>O1CCOCC1>[CH:5]1([NH:8][C:11](=[O:10])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[C:21]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)=[N:22][O:23][C:24]=3[CH2:25][OH:26])=[N:14][CH:13]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Reactant: NC1CC1
Agent: C[Al](C)C
Solvent: C1COCCO1
Product: O=C(NC1CC1)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Reaction time: 8 h
Yield: 41.7 %

Procedure:
Trimethylaluminium solution (2M in toluene, 0.51 mL, 1.00 mmol) was added to a solution of cyclopropylamine (71.9 μL, 1.00 mmol) in dioxane (4.0 mL). After 45 min stirring at 50° C. a solution of 6-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (90 mg, 0.25 mmol) in dioxane (4.0 mL) was added and stirring was continued overnight at 85° C. The dioxane was removed by distillation. The remaining material was purified by chromatography (silica, ethyl acetate) to afford the title compound (40 mg, 42%) as light brown solid. MS: m/e=382.1 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[C:13]([C:14](=[O:20])[C:15]2[S:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][C:5]2[CH2:6][CH:7]([C:9](O)=[O:10])[O:8][C:4]=2[C:3]=1[Cl:21].S(Cl)([Cl:24])=O>C1C=CC=CC=1>[Cl:1][C:2]1[C:13]([C:14](=[O:20])[C:15]2[S:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][C:5]2[CH2:6][CH:7]([C:9]([Cl:24])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:21]
Reactant: O=C(c1cccs1)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(c1cccs1)c1cc2c(c(Cl)c1Cl)OC(C(=O)Cl)C2

Procedure:
6,7-Dichloro-2,3-dihydro-5-(2-thenoyl)-2-benzofuran carboxylic acid (3.4 g.; 0.01M.) is combined with 2 ml. thionyl chloride and 50 ml. benzene. After 2 hours at reflux the excess thionyl chloride and benzene are removed by distillation at 20 mmHg to give 6,7-dichloro-2,3-dihydro-5-(2-thenoyl)-2-benzofuran carboxylic acid chloride as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:13])[CH2:11][CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:13][C:22]3[N:30]=[CH:29][N:28]=[C:27]4[C:23]=3[NH:24][CH:25]=[N:26]4)[CH2:11][CH3:12])[N:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[CH:20]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1ncnc2nc[nH]c12)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 21 %

Procedure:
A mixture of (S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)propylamine from Example 28 (42 mg, 0.16 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (37 mg, 0.16 mmol) and DIPEA (0.14 mL, 0.8 mmol) in n-butanol (1 mL) was stirred in a sealed vial for 16 h at 90° C. After cooling to RT, the crude reaction mixture was loaded into an Isolute® SCX-2 which was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) affording 160 as a white solid (13 mg, 21%). LCMS: RT 3.61 min [M+H]+ 388.1. 1H NMR (DMSO, 400 MHz): δ 8.22-8.03 (2H, m), 7.80 (1H, s), 7.71-7.43 (6H, m), 7.09 (1H, t, J=9.42 Hz), 6.85 (1H, d, J=8.93 Hz), 5.38 (1H, s), 2.08-1.88 (2H, m), 0.83 (3H, t, J=7.34 Hz)
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH2:10])[N:5]=1.Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O>[NH2:10][C:6]1[N:5]=[C:4]([CH:3]=[O:2])[CH:9]=[CH:8][N:7]=1
Reactant: COC(OC)c1ccnc(N)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Nc1nccc(C=O)n1
Temperature: 25 °C
Yield: 37.3 %

Procedure:
A solution of 2.5 g (15 mmol, 1.0 eq.) of 2-aminopyrimidine-4-carboxaldehyde dimethylacetal (I-8) in 16 mL (48 mmol, 3.2 eq.) of 3M HCl was heated at 48° C. for 14 h. The mixture was allowed to cool to room temperature and diluted with 50 mL of EtOAc. The aqueous layer was neutralized with NaHCO3 and then extracted with EtOAc (5×50 mL). The combined organic extracts were dried (Na2SO4) and the solvent removed in vacuo to provide 0.69 g (5.6 mmol, 37%) of 2-aminopyrimidine-4-carboxaldehyde (I-9) as a yellow solid.
Reaction SMILES: C[N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH3:33])=[CH:8][C:9]=2[CH2:11][O:12][CH2:13][C:14]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:4]=[N:3]1.CN1C=C2C(C(COCC3(C4C=CC=CC=4)CCN(C(OC(C)(C)C)=O)CC3)=CC(C)=C2)=N1>>[CH3:33][C:7]1[CH:6]=[C:5]2[C:10](=[C:9]([CH2:11][O:12][CH2:13][C:14]3([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[CH2:16][CH2:15]3)[CH:8]=1)[NH:2][N:3]=[CH:4]2
Reactant: Cc1cc(COCC2(c3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)c2c(cnn2C)c1
Agent: Cc1cc(COCC2(c3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)c2nn(C)cc2c1
Product: Cc1cc(COCC2(c3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)c2[nH]ncc2c1

Procedure:
tert-Butyl 4-(((1,5-dimethyl-1H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate and tert-Butyl 4-(((2,5-dimethyl-2H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate. To a solution of tert-butyl 4-(((5-methyl-1H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (38 mg, 0.087 mmol) in dimethylformamide (1 mL) at 0° C. was added sodium hydride (60% in mineral oil, 7.0 mg, 0.174 mmol). After 5 min, the reaction was treated with iodomethane (11 μL, 0.174 mmol). After 30 min, the reaction was quenched by addition of saturated ammonium chloride and poured into diethyl ether. The organics were washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (25%→75% EtOAc/Hex) gave two fractions. The faster eluting fraction was concentrated to give tert-butyl 4-(((1,5-dimethyl-1H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (24 mg, 61%). Concentration of the second fraction gave tert-butyl 4-(((2,5-dimethyl-2H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (8 mg, 20%). tert-Butyl 4-(((1,5-dimethyl-1H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate: 1H-NMR (CDCl3, 500 MHz) δ 7.81 (s, 1H), 7.39 (s, 1H), 7.15-7.30 (m, 5H), 6.92 (s, 1H), 4.63 (s, 2H), 3.90 (s, 3H), 3.65 (bs, 2H), 3.41 (s, 2H), 3.00 (m, 2H), 2.39 (s, 3H), 2.10 (m, 2H), 1.79 (m, 2H), 1.41 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 155.1, 142.9, 137.3, 132.1, 130.8, 129.3, 128.5, 127.2, 126.4, 126.0, 120.6, 119.8, 79.4, 78.7, 71.3, 41.5, 40.1 (br), 38.0, 32.1, 28.6, 21.0. tert-Butyl 4-(((2,5-dimethyl-2H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate: 1H-NMR (CDCl3, 500 MHz) δ 7.72 (s, 1H), 7.30-7.43 (m, 4H), 7.22 (m, 2H), 6.84 (s, 1H), 4.81 (s, 2H), 4.15 (s, 3H), 3.71 (bs, 2H), 3.53 (s, 2H), 3.06 (m, 2H), 2.32 (s, 3H), 2.17 (m, 2H), 1.97 (m, 2H), 1.43 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 155.1, 146.3, 143.3, 131.0, 128.5, 127.4, 127.1, 126.3, 125.7, 122.9, 122.5, 117.0, 79.4, 79.3, 69.1, 41.9, 40.3, 40.2 (br), 32.0, 28.6, 21.9.