Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([C:23]#[C:24][Si](C)(C)C)[CH:22]=2)[O:19][C:18]([CH3:30])([CH3:29])[CH2:17][C:16]3([CH3:32])[CH3:31])=[CH:7][C:6]=1[F:33].CO.O1CCCC1.O.[OH-].[Li+]>O>[C:23]([C:21]1[CH:22]=[C:13]([C:12]#[C:11][C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:34])=[O:2])=[C:6]([F:33])[CH:7]=2)[CH:14]=[C:15]2[C:20]=1[O:19][C:18]([CH3:29])([CH3:30])[CH2:17][C:16]2([CH3:32])[CH3:31])#[CH:24]
Reactant: COC(=O)Cc1ccc(C#Cc2cc(C#C[Si](C)(C)C)c3c(c2)C(C)(C)CC(C)(C)O3)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cc(C#Cc2ccc(CC(=O)O)c(F)c2)cc2c1OC(C)(C)CC2(C)C

Procedure:
Following general procedure K and using [2-fluoro-4-(2,2,4,4-tetramethyl-8-trimethylsilanylethynyl-chroman-6-ylethynyl)-phenyl]-acetic acid methyl ester (Compound 39, 0.11 g, 0.23 mmol), methanol, tetrahydrofuran, water and lithium hydroxide monohydrate followed by recrystallization from hot acetonitrile, the title compound was obtained as a pale yellow solid (0.045 g, 50%).
Reaction SMILES: [C:1]1([N:7]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8]([C:10]2[CH:31]=[CH:30][C:13]3[N:14]([CH3:29])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=4[CH2:27][CH3:28])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:39].C(=O)([O-])[O-].[NH4+:44].[NH4+]>C(O)C>[ClH:39].[C:1]1([N:7]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8]([C:10]2[CH:31]=[CH:30][C:13]3[N:14]([CH3:29])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:44])[NH2:26])=[CH:21][C:20]=4[CH2:27][CH3:28])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1CC)n2C)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1CC)n2C)c1ccccc1

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyano-2-ethylphenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15](COCCO)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH3:32][O:33][CH2:34][C:35](=[O:37])[CH3:36]>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([C:35]([OH:37])([CH3:36])[CH2:34][O:33][CH3:32])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COCC(C)=O
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(COCCO)nc3N21
Agent: [Li]CCCC
Product: COCC(C)(O)c1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C

Procedure:
This compound was prepared in analogy to Example 51, intermediate, from (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 5, intermediate b), n-butyllithium and methoxy-2-propanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][O:8][C:9]([C:11]2C(C3C=CC=C([N+]([O-])=O)C=3)C(C(OC)=O)=C(C)[NH:15][C:16]=2[CH3:17])=[O:10])=[CH:5][CH:4]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9](=[O:10])/[CH:11]=[C:16](\[NH2:15])/[CH3:17])=[CH:32][CH:33]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCc2ccc(OC)cc2)C1c1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: COc1ccc(COC(=O)/C=C(/C)N)cc1
Yield: 75 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 3'-nitrobenzylideneacetoacetic acid methyl ester and 75 mmols of β-aminocrotonic acid 4-methoxybenzyl ester in 120 ml of ethanol gave 2,6-dimethyl-3-methoxycarbonyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 4-methoxybenzyl ester of melting point 136° C (from ethanol).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][O:5][C:4]([C:14]([O:16]CC)=[O:15])=[CH:3]1.Cl>>[O:1]=[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][O:5][C:4]([C:14]([OH:16])=[O:15])=[CH:3]1
Reactant: CCOC(=O)c1cc(=O)c(-c2ccccc2)co1
Agent: Cl
Product: O=C(O)c1cc(=O)c(-c2ccccc2)co1

Procedure:
Ethyl 4-oxo-5-phenyl-4H-pyran-2-carboxylate (4.9 g) was heated with concentrated hydrochloric acid (12 ml) on a steam bath for 11/2 hours. The mixture was cooled and the solid title product was recrystallised from ethyl acetate-dimethylformamide (mp 225°-227° C. with decomposition).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=[CH:11]/[C:12]1[NH:13][C:14]2[C:19]([C:20]=1[S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2.[H][H]>[Pd].CO.O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][C:12]1[NH:13][C:14]2[C:19]([C:20]=1[S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: [H][H]
Reactant: C(=C/c1[nH]c2ccccc2c1Sc1ccccc1)\c1nc2ccccc2o1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc(Sc2c(CCc3nc4ccccc4o3)[nH]c3ccccc23)cc1

Procedure:
A solution of trans-2-(2-benzoxazol-2-ylethenyl)-3-phenylthioindole (0.420 g, 1.14 mmol) in 1:1 methanol/tetrahydrofuran (250 mL) was stirred under 1 atmosphere of hydrogen in the presence of 10% palladium on charcoal (100 mg). Additional catalyst was added as needed to drive the reaction to completion. The catalyst was removed by filtration, and the filtrate concentrated in vacuo. The resulting solid was triturated with 10% ethyl acetate in hexane and collected by filtration to afford the title compound, mp 192°-193° C. Anal. calc. for C23H18N2OS: C, 72.80; H, 5.04; N, 7.38. Found: C, 72.78; H, 4.95; N, 7.45.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH2:7]O)([O-:3])=[O:2].[C:15]1([C:21]2[C:22]([NH:24][C:25](=[O:27])[CH:26]=2)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O.C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][N:24]2[C:25](=[O:27])[CH:26]=[C:21]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:22]2=[O:23])[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)([O-:3])=[O:2]
Reactant: O=C1C=C(c2ccccc2)C(=O)N1
Reactant: O=[N+]([O-])c1cc(CO)cc([N+](=O)[O-])c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1C=C(c2ccccc2)C(=O)N1Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reaction time: 24 h
Yield: 74 %

Procedure:
In a 500 ml three-necked flask equipped with a stirring means and a dropping funnel were placed 7.92 g of 3,5-dinitrobenzyl alcohol, 6.90 g of α-phenylmaleimide and 11.5 g of triphenylphosphine, and the mixture was dissolved in 200 ml of THF with stirring. To the solution was added dropwise 20.9 g of diethyl azodicarboxylate (as a 40% toluene solution) at 0° C. or lower. After the dropwise addition, the temperature was allowed to rise to room temperature and stirring was continued for 24 hours. The reaction solution was poured into water and extracted three times with ethyl acetate. The organic layer was washed three times with water and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration and the organic layer was concentrated under reduced pressure. The resulting pale yellow crystal was collected by filtration with n-heptane and recrystallized twice from ethyl acetate to afford 10.41 g of N-(3,5-dinitrophenyl)methyl-α-phenylmaleimide.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH:12]1([OH:16])[CH2:15][CH2:14][CH2:13]1.[OH-].[K+]>CS(C)=O.O>[Br:1][C:2]1[C:3]([O:16][CH:12]2[CH2:15][CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: OC1CCC1
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cnc(OC2CCC2)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
5-Bromo-6-chloronicotinic acid (CAN 29241-62-1, 2.0 g, 8.46 mmol) was dissolved in DMSO (20.0 mL). Cyclobutanol (793 mg, 857 μL, 11.0 mmol) and potassium hydroxide powder (1.42 g, 25.4 mmol) were added and the mixture was stirred at room temperature overnight. Water (20 mL) was added and the mixture was acidified (under ice-water bath cooling) with 37% HCL in water (pH=2). The suspension was filtered, washed with water and the solid was dried to yield 1.88 g (82%) of the title compound as a white solid; MS (ESI): 270.2 (M−H)−.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)=[O:10])[CH2:3][CH2:2]1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:17])=[O:10])[CH2:5][CH2:6]1
Reactant: O=C(CCN1CCOCC1)c1ccccc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1ccccc1C(=O)CCN1CCOCC1
Yield: 98 %

Procedure:
To a solution of 3-morpholino-1-(2′-nitrophenyl) propane-1-one(200 mg, 0.758 mmol) dissolved in 10 ml of 95% ethanol was added sodium dithionite(660 mg, 3.79 mmol) and the reaction mixture was stirred under reflux for 3 hrs. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with ethanol-dichloromethane-triethylamine to yield the desired product (174 mg, 89%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[C:13]([Cl:18])=[N:14][CH:15]=[CH:16][CH:17]=1>N1C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[C:13]([Cl:18])=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:5]
Reactant: O=C(Cl)c1ccccc1F
Reactant: Nc1cccnc1Cl
Solvent: c1ccncc1
Product: O=C(Nc1cccnc1Cl)c1ccccc1F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4.44 g (28 mmol) of 2-fluorobenzoyl chloride are added to 30 ml of anhydrous pyridine at 0° C. while the temperature is maintained below 5° C. 3 g of 3-amino-2-chloropyridine in 20 ml of pyridine are added with stirring using a pressure equalizing funnel. After being left overnight at room temperature, the reaction medium is poured into an ice/water mixture. The solid obtained is filtered off and washed several times with water.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:13]([NH:14][CH:15]([CH3:17])[CH3:16])[CH2:12][N:11]([C:18]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([C:28]4([CH3:31])[CH2:30][CH2:29]4)=[O:27])[CH2:22][CH2:21]3)=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)=[O:34]>>[F:42][C:39]1[CH:40]=[CH:41][C:36]([O:35][C:33](=[O:34])[N:14]([C@H:13]2[C@H:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][N:11]([C:18]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([C:28]4([CH3:31])[CH2:30][CH2:29]4)=[O:27])[CH2:22][CH2:21]3)=[O:19])[CH2:12]2)[CH:15]([CH3:16])[CH3:17])=[CH:37][CH:38]=1
Reactant: CC(C)N[C@@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)Oc1ccc(F)cc1
Product: CC(C)N(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 1 (step h), the title compound rac-{(3S,4R)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-isopropyl-carbamic acid 4-fluoro-phenyl ester was prepared from rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-isopropylamino-pyrrolidin-1-yl]-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone instead of rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 4-fluorophenyl chloroformate and was obtained as a colorless foam. MS m/e: 604.3 [M]+.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.O.[NH2:17][NH2:18]>C(O)COCCO>[NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4](=[N:17][NH2:18])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NN
Reactant: Nc1ccccc1C(=O)c1ccccc1
Solvent: O
Solvent: OCCOCCO
Product: NN=C(c1ccccc1)c1ccccc1N

Procedure:
In the manner given in Preparation 1, 2-aminobenzophenone is refluxed with hydrazine hydrate in diethylene glycol to give 2-aminobenzophenone hydrazone.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:30])[C:4]1([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:9][CH2:8][C:7](=[CH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:12])[CH2:6][CH2:5]1>[Pd].CO>[CH3:30][N:3]([CH3:2])[C:4]1([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:9][CH2:8][CH:7]([CH2:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:12])[CH2:6][CH2:5]1
Reactant: CN(C)C1(c2ccc(F)cc2)CCC(=CC(=O)NCCCc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C)C1(c2ccc(F)cc2)CCC(CC(=O)NCCCc2ccccc2)CC1
Reaction time: 17 h
Yield: 24 %

Procedure:
Palladium-on-charcoal (5%, 24 mg) was added to a solution of 2-[4-dimethylamino-4-(4-fluorophenyl)-cyclohexylidene]-N-(3-phenylpropyl)-acetamide (base of Example 19; 390 mg, 0.99 mmol) in abs. methanol (25 ml). The reaction mixture was hydrogenated at RT under a pressure of 2 bar for 17 h. The catalyst was separated off over Celite and the filtrate was concentrated. After separation of the residue (402 mg) by chromatography on silica gel (80 g) with EA/methanol (2:1), the less polar diastereoisomer of 2-[4-dimethylamino-4-(4-fluorophenyl)cyclohexyl]-N-(3-phenylpropyl)acetamide was isolated as a beige-coloured oil in a yield of 24% (78 mg) and the more polar diastereoisomer of 2-[4-dimethylamino-4-(4-fluorophenyl)cyclohexyl]-N-(3-phenylpropyl)acetamide was isolated as a colourless oily solid in a yield of 76% (297 mg).
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1C(C2SC3C=CC=C(C(N)=O)C=3C=2)=NC(NCCC2CCN(C)CC2)=NC=1.[CH:32]1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44]([C:47]4[C:52]([CH3:53])=[CH:51][N:50]=[C:49]([NH:54][CH2:55][CH2:56][N:57]5[CH2:62][CH2:61][NH:60][CH2:59][C@H:58]5[CH3:63])[N:48]=4)[S:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:37])[CH2:34][CH2:33]1>>[ClH:3].[ClH:1].[ClH:3].[CH:32]1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44]([C:47]4[C:52]([CH3:53])=[CH:51][N:50]=[C:49]([NH:54][CH2:55][CH2:56][N:57]5[CH2:62][CH2:61][N:60]([CH3:4])[CH2:59][C@H:58]5[CH3:63])[N:48]=4)[S:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:37])[CH2:34][CH2:33]1
Reactant: CN1CCC(CCNc2ncc(Cl)c(-c3cc4c(C(N)=O)cccc4s3)n2)CC1
Reactant: Cc1cnc(NCCN2CCNC[C@H]2C)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1
Agent: Cl
Product: Cc1cnc(NCCN2CCN(C)C[C@H]2C)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1

Procedure:
Using the method of 2-{5-chloro-2-[2-(1-methylpiperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid amide di-hydrochloride, the title compound is synthesized from (R)-2-{5-methyl-2-[2-(2-methylpiperazin-1-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and isolated as a yellow solid. ES+(m/z) 465 [M(free base)+H].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH:15]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:23]=4)=[O:20])[CH2:16]3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl-].O.[CH2:34]1[CH2:38]O[CH2:36][CH2:35]1>>[C:28]([C:24]1[CH:23]=[C:22]([NH:21][C:19]([CH:15]2[CH2:14][CH2:13][C:12]3[C:17](=[CH:18][C:9]([O:8][C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:1][CH2:23][CH:22]([N:21]5[CH2:38][CH2:34][CH2:35][CH2:36]5)[CH3:27])[CH:7]=4)=[CH:10][CH:11]=3)[CH2:16]2)=[O:20])[CH:27]=[CH:26][CH:25]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(N)c4)cc3C2)c1
Reactant: C1CCOC1
Agent: [Cl-]
Solvent: O
Product: CC(CNc1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cccc(C(C)(C)C)c2)CC3)ccn1)N1CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 7-[(2-aminopyridin-4-yl)oxy]-N-(3-tert-butylphenyl)-1,2,3,4-tetrahydronaphthalene-2-carboxamide (1.50 g, 3.64 mmol) in THF (36 mL) at 0°, was added TEA (1.02 mL, 7.29 mmol) and then 2-chloropropanyoyl chloride (0.39 mL, 4.01 mmol) dropwise. The reaction was allowed to warm to rt and stir for 18 h. Water was added and the mixture was extracted with EtOAc (2×). The organic solutions were combined, washed with water, dried over Na2SO4 and concentrated. The residue was purified by column chromatography to give N-(3tert-butylphenyl)-7-({2-[(2-pyrrolidin-1-ylpropanyl)amino]pyridin-4yl}oxy)-1,2,3,4-tetrahydronaphthalene-2-carboxamide I-275 as a pale yellow solid (1.37 g, 74.9%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@@H:5]([NH2:13])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C[O:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[CH2:25]Br.C(N(CC)CC)C>C(#N)C.O>[CH3:2][O:3][C:4](=[O:14])[C@@H:5]([N:13]1[CH2:25][C:19]2[C:18](=[CH:23][CH:22]=[CH:21][C:20]=2[F:24])[C:17]1=[O:16])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: COC(=O)c1cccc(F)c1CBr
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)[C@H](CC1CCCCC1)N1Cc2c(F)cccc2C1=O
Temperature: 82 °C
Yield: 57.2 %

Procedure:
A solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester hydrochloride (Novabiochem, 500 mg, 2.25 mmol) in acetonitrile (20 mL) was placed in a flask and treated with 2-bromomethyl-3-fluoro-benzoic acid methyl ester (557 mg, 2.25 mmol) and triethylamine (660 μL, 4.74 mmol). The reaction mixture was then heated at reflux (82° C.) overnight for 16 h. After this time, the reaction mixture was diluted with water (5 mL) and concentrated in vacuo to remove the acetonitrile. The remaining material was then diluted with another portion of water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were then dried over magnesium sulfate, filtered to remove the drying agent and the filtrate concentrated in vacuo. The crude material was purified using an Analogix Intelliflash 280 chromatography system (RS-40 silica gel column, 10-25% ethyl acetate/hexanes) to afford (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester (411 mg, 57%) as a clear colorless oil: [α]30D=−17.3° (c=0.30, methylene chloride); HR-ES(+) m/e calcd for C18H22NO3F [M+H]+ 320.1657, observed 320.1656; 1H NMR (300 MHz, DMSO-d6) δ 7.54-7.63 (m, 2H), 7.42-7.54 (m, 1H), 4.96 (dd, J=4.53, 11.47 Hz, 1H), 4.49-4.65 (m, 2H), 3.63 (s, 3H), 1.48-1.99 (m, 7H), 0.74-1.23 (m, 6H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:15])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([O:13][CH3:14])[CH:7]=2.[C-:16]#[N:17].[Na+].[C-]#N.[K+]>>[CH3:14][O:13][C:8]1[CH:7]=[C:6]2[C:11]([CH:12]=[C:3]([CH2:2][C:16]#[N:17])[C:4]([CH3:15])=[N:5]2)=[CH:10][CH:9]=1
Reactant: COc1ccc2cc(CCl)c(C)nc2c1
Reactant: [C-]#N
Agent: [K+]
Agent: [Na+]
Product: COc1ccc2cc(CC#N)c(C)nc2c1

Procedure:
Compounds of formula (50), wherein R4 and R5 are as defined in formula (I) and R6 is aryl or heteroaryl, can be prepared as described in Scheme 6. Ethyl 7-methoxy-2-methyl-3-quinolinecarboxylate can be prepared using the procedures described in Synthetic Comm., 17(14):1647-1653 (1987). Ethyl 7-methoxy-2-methyl-3-quinolinecarboxylate can be treated with a reducing agent, such as, but not limited to, lithium aluminum hydride or sodium borohydride, to provide (7-methoxy-2-methyl-3-quinolinyl)methanol. (7-Methoxy-2-methyl-3-quinolinyl)methanol can be treated with a chlorinating reagent, such as, but not limited to, thionyl chloride to provide 3-(chloromethyl)-7-methoxy-2-methylquinoline. 3-(Chloromethyl)-7-methoxy-2-methylquinoline can be treated with sodium cyanide or potassium cyanide to provide (7-methoxy-2-methyl-3-quinolinyl)acetonitrile. (7-Methoxy-2-methyl-3-quinolinyl)acetonitrile can be treated with acid, such as, but not limited to, glacial acetic acid and concentrated sulfuric acid, in water and 1,4-dioxane with heat to provide (7-methoxy-2-methyl-3-quinolinyl)acetic acid. (7-Methoxy-2-methyl-3-quinolinyl)acetic acid can be treated with a reducing agent, such as, but not limited to, B2H6, borane-THF complex, or borane-pyridine complex, to provide 2-(7-methoxy-2-methyl-3-quinolinyl)ethanol. 2-(7-Methoxy-2-methyl-3-quinolinyl)ethanol can be treated with methanesulfonyl chloride and a base, such as, but not limited to, triethylamine or diisopropylamine to provide 2-(7-methoxy-2-methyl-3-quinolinyl)ethyl methanesulfonate. 2-(7-Methoxy-2-methyl-3-quinolinyl)ethyl methanesulfonate can be treated with an amine of formula (5) to provide amines of formula (47). Amines of formula (47) can be treated with BBr3 to provide hydroxy compounds of formula (48). Hydroxy compounds of formula (48) can be treated with trifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chloride to provide triflates of formula (49). Triflates of formula (49) can be treated with boronic acids of formula (7) as described in Scheme 1 to provide compounds of formula (50).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:19])=[C:6]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH:17]=[O:18])[CH:7]=1.[BH4-].[Na+].O>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:19])=[C:6]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][OH:18])[CH:7]=1
Reactant: O=Cc1c(-c2cc(Br)ccc2O)nc2ccccn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1c(-c2cc(Br)ccc2O)nc2ccccn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
2-(5-bromo-2-hydroxyphenyl)imidazo[1,2-a]pyridine-3-carbaldehyde (0.19 g, 0.63 mmol) was dissolved in MeOH (2 mL) at 0° C. NaBH4 (0.072 g, 1.9 mmol) was added portionwise. After addition, the mixture was stirred at 25° C. for 30 minutes, and then H2O (20 mL) was added by dropwise. Extracted with EtOAc (3*50 mL), washed by brine (50 mL). After concentrated, the resulting residue was purified using Prep-TLC (petroleum ether:EtOAc=3:1) to provide 4-bromo-2-(3-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)phenol (150 mg, yield: 85%). 1H-NMR (CDCl3, 400 MHz) δ 8.33˜8.35 (m, 1H), 7.72 (s, 1H), 7.62˜7.64 (m, 1H), 7.31˜7.37 (m, 2H), 6.92˜7.01 (m, 2H), 5.20 (s, 2H). MS (M+H)+: 319/321.
Reaction SMILES: [CH2:1]([C:3]([CH:12]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH2:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-])=O)([C:8]([O:10][CH3:11])=[O:9])[C:4]([O:6][CH3:7])=[O:5])[CH3:2].Cl.C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([C:3]([CH:12]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH2:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[NH2:21])([C:8]([O:10][CH3:11])=[O:9])[C:4]([O:6][CH3:7])=[O:5])[CH3:2]
Reactant: CCC(C(=O)OC)(C(=O)OC)C(Cc1cc(Cl)ccc1[N+](=O)[O-])c1ccc(OC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(C(=O)OC)(C(=O)OC)C(Cc1cc(Cl)ccc1N)c1ccc(OC)cc1
Reaction time: 2 h

Procedure:
α -Ethyl-[2-(5-chloro-2-nitrophenyl)-1-(4-methoxyphenyl) ethyl]propanedioic acid, dimethyl ester (12.64 g, 28.10 mmole) was dissolved in methanol (600 ml) under argon at room temperature. Powdered stannous chloride dihydrate (32.98 g, 146.2 mmole, 5.2 eq) was added followed by concentrated hydrochloric acid (36 ml) with stirring. The solution turned clear and homogeneous. After 2 hours, Celite, ethyl acetate and saturated potassium carbonate solution were added with stirring. (The potassium carbonate solution was added portionwise). The suspension was filtered though a pad of Celite and the Celite pad was rinsed with ethyl acetate (3 times). The filtrate was concentrated to remove most of the organic solvents, and the residue was collected by suction-filtration. The crude material was used without further purification.