Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1.O[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[C@H:20]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:19][CH2:18]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[C@H:20]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:19][CH2:18]3)=[N:7][CH:8]=1)#[N:11]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Reactant: N#Cc1ccc(OCCCO)nc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C#N)cn3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.8 %

Procedure:
To a solution of 6-(3-hydroxypropoxy)nicotinonitrile (Example 257) (0.86 g, 4.83 mmol) and ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6, 0.89 g, 4.02 mmol) in THF (20 mL) was added triphenylphosphine (1.49 g, 5.63 mmol) and 1,1′-(azodicarbonyl)-dipiperidine (1.44 g, 5.63 mmol) under argon. The golden yellow mixture was stirred at rt for 18 h and concentrated under reduced pressure. The product (1.22 g, 80%) was isolated after purification by silica gel flash chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD2Cl2) δ 8.47 (dd, 1H), 7.79 (dd, 1H), 7.05 (d, 1H), 6.82 (d, 1H), 6.77 (d, 1H), 6.69 (dd, 1H), 4.56 (t, 2H), 4.16 (q, 2H), 4.11 (t, 2H), 3.51 (qt, 1H), 2.95-2.78 (m, 2H), 2.70 (dd, 1H), 2.44-2.32 (m, 2H), 2.30-2.20 (m, 2H), 1.80-1.70 (m, 1H), 1.28 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:18]#[N:19].[C:20](OCC)(=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].Cl>CCO.CC[O-].[Na+]>[CH2:24]([O:23][C:21](=[O:22])[C:20](=[O:26])[CH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:18]#[N:19])[CH3:25]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1nc(-c2ncccc2C(F)(F)F)ccc1C#N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)Cc1nc(-c2ncccc2C(F)(F)F)ccc1C#N
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Dissolve 6-methyl-3′-trifluoromethyl-[2,2′]bipyridinyl-5-carbonitrile (150 mg, 0.570 mmol) and diethyl oxalate (150 mg, 1.03 mmol) in a solution of EtOH (2 mL) and 17% NaOEt in EtOH (0.6 mL, 1.71 mmol). Warm the mixture to 50° C. and stir overnight. Pour the mixture onto ice water (50 mL) and acidify with 3 N HCl. Extract with EtOAc (3×50 mL). Dry the combined organic extracts over Na2SO4 and remove the solvent under reduced pressure. Purify the crude product using silica gel chromatography eluting with EtOAc/hexane (1:1) to yield the title compound. MS 364.11 (M+1).
Reaction SMILES: [CH:1]([CH:3]([NH:8][C:9](=[O:19])[C@H:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[NH:11][C:12](=[O:14])[CH3:13])[CH2:4][CH2:5][CH2:6][CH3:7])=O.[CH2:20]([SH:23])[CH2:21][SH:22].B(F)(F)F.CCOCC>C(Cl)Cl>[S:22]1[CH2:21][CH2:20][S:23][CH:1]1[CH:3]([NH:8][C:9](=[O:19])[C@H:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[NH:11][C:12](=[O:14])[CH3:13])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCC(C=O)NC(=O)[C@H](CC(C)C)NC(C)=O
Reactant: SCCS
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCC(NC(=O)[C@H](CC(C)C)NC(C)=O)C1SCCS1
Yield: 73.7 %

Procedure:
In 20 ml of methylene chloride was dissolved 1.8 g of N-acetyl-L-leucine-(1-formyl)pentylamide obtained in the same manner as in Example 16-(c), and 700 mg of 1,2-ethanedithiol and 1.5 ml of boron trifluoride ethyl etherate were added thereto. The mixture was allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was purified by medium-pressure column chromatography on silica gel to obtain 1.7 g of the titled compound as a colorless crystal.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]([O:11][C:12]([N:14]1[CH2:21][CH:20]2[CH:16]([CH2:17][NH:18][CH2:19]2)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>C(O)CCC>[C:7]([O:11][C:12]([N:14]1[CH2:15][CH:16]2[CH:20]([CH2:19][N:18]([C:2]3[S:3][CH:4]=[CH:5][N:6]=3)[CH2:17]2)[CH2:21]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: Brc1nccs1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CC2CN(c3nccs3)CC2C1
Yield: 25.5 %

Procedure:
A solution of 541 μl (6.0 mmol) 2-bromothiazole and 1.27 g (6.0 mmol) hexahydro-pyrrolo[3,4-c]pyrrol-2-carboxylic acid tert-butyl-ester in n-butanol (10 ml) was heated for 2 h under reflux. Subsequently, the solvent was removed in vacuo and the residue taken up by chloroform. This solution was washed with water and brine in turn, dried over MgSO4, filtered and concentrated in vacuo. Column chromatography was carried out on the residue (SiO2, DCM/EtOH 10:1), yielding 450 mg (1.53 mmol, 25%) 5-thiazol-2-yl-hexahydro-pyrrolo[3,4-c]pyrrol-2-carboxylic acid tert-butyl-ester.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]1[N:14]=[C:13]2[N:15]=[CH:16][CH:17]=[C:18]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[C:22]([F:34])[CH:21]=3)[C:12]2=[N:11][CH:10]=1>>[F:34][C:22]1[CH:21]=[C:20]([O:19][C:18]2[C:12]3=[N:11][CH:10]=[C:9]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[N:14]=[C:13]3[N:15]=[CH:16][CH:17]=2)[CH:25]=[CH:24][C:23]=1[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc3nc(Cl)cnc23)cc1F
Reactant: CN1CCNCC1
Product: CN1CCN(c2cnc3c(Oc4ccc(NC(=O)OC(C)(C)C)c(F)c4)ccnc3n2)CC1

Procedure:
Method D6 was used with N-methylpiperazine and tert-butyl 4-(3-chloropyrido[2,3-b]pyrazin-8-yloxy)-2-fluorophenylcarbamate to give the title compound as a yellow solid. Yield: 142 mg (92%).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C@@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:12]([O:14]C)=[O:13])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[OH-].[Li+].Cl>O1CCOCC1.O>[CH2:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C@@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:12]([OH:14])=[O:13])=[CH:8][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C=CCc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Yield: 97.8 %

Procedure:
A solution of 2.03 g (6.36 mmol) of methyl(R)-3-(4-allylphenyl)-2-tert-butoxycarbonylaminopropionate (prepared as in Synlett, 2005, 12, 1877-1880) in 20 ml of dioxane/water (1:1, v/v) and 0.30 g (12.71 mmol) of lithium hydroxide was stirred at RT for 2 h and then neutralized with 1N hydrochloric acid. The reaction mixture was extracted with ethyl acetate, and the organic phase was dried over Na2SO4, filtered and concentrated. 1.90 g of the title compound were obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][N:38]3[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=4[N:40]=[CH:39]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][N:38]3[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=4[N:40]=[CH:39]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)ccc(OCCn3cnc4ccccc43)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(C)ccc(OCCn3cnc4ccccc43)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-butyl-7-[2-(benzimidazol-1-yl)-ethoxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])O.[Na+]>ClCCl>[CH:19]1([NH:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC1CCCCC1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc2c(NC3CCCCC3)nnc(Cc3ccncc3)c2c1
Temperature: 5 °C
Reaction time: 8 h
Yield: 0.56 %

Procedure:
A mixture of 0.3 g (1.173 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine and 0.523 g (5.278 mmol) cyclohexylamine is stirred for 8 h at 11 5° C. The cooled reaction mixture is then distributed between dichloromethane and saturated aqueous sodium hydrogencarbonate solution. The organic solution washed with brine and dried over anhydrous sodium sulfate is evaporated and the residue purified on silica gel by flash chromatography using acetate/methanol (19:1). Title compound (with water content of 0.56%) is obtained after crystallization of the product-containing fractions from acetonitrile and drying under HV; m.p. 137-139° C.; ESI-MS: (M+H)+=319.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]#[N:11])[C:4]=2[CH:3]=[N:2]1.Br[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:10]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[N:2][N:1]2[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:11]
Reactant: CCOC(=O)CCBr
Reactant: N#Cc1cccc2[nH]ncc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ncc2c(C#N)cccc21
Temperature: 90 °C
Yield: 78.1 %

Procedure:
1H-indazole-4-carbonitrile (0.716 g, 5 mmol), ethyl 3-bromopropanoate (1.276 ml, 10.00 mmol) and caesium carbonate (4.90 g, 15.00 mmol) were added to N,N-dimethylformamide (DMF) (20 ml) and the mixture was was heated to 90° C. for 80 minutes. The mixture was cooled before being extracted in a mixture of ethyl acetate and water. The organic fraction was washed with 3×30 ml portions of water, dried (MgSO4), filtered and evaporated. The crude product mixture was added to a Biotage column and was eluted with ethyl acetate/petrol 1:3 to give 0.95 g of the title compound. δH (CDCl3, 400 MHz) 1.17 (3H, t), 3.01 (2H, t), 4.08 (2H, q), 4.71 (2H, t), 7.46 (1H, dd), 7.54 (1H, dd), 7.81 (1H, d), 8.21 (1H, d).
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([C:22]3[N:23](CC4C=CC=CC=4)[N:24]=[N:25][C:26]=3[C:27]([F:30])([F:29])[F:28])=[O:21])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1)=[O:7]>CO.C(O)(=O)C.[Pd]>[CH3:1][CH:2]([CH3:38])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:15][CH2:16][N:17]([C:20]([C:22]3[NH:23][N:24]=[N:25][C:26]=3[C:27]([F:29])([F:28])[F:30])=[O:21])[CH2:18][CH2:19]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3c(C(F)(F)F)nnn3Cc3ccccc3)CC2)nn1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3[nH]nnc3C(F)(F)F)CC2)nn1
Reaction time: 8 h
Yield: 36.3 %

Procedure:
6-[4-(3-benzyl-5-trifluoromethyl-3H-[1,2,3]triazole-4-carbonyl)piperazin-1-yl]pyridazine-3-carboxylic acid (3-methylbutyl)amide (0.4 g, 0.75 mmol) was dissolved in 10 mL of MeOH with 3 drops of acetic acid and 0.2 g of 10% Pd/C was added. The reaction mixture was kept under normal pressure of H2 at ambient temperature overnight. After filtration the reaction mixture was evaporated under reduced pressure and the residue was recrystallized from 3 mL of EtOH to give 120 mg (36% yield) of 6-[4-(5-trifluoromethyl-3H-[1,2,3]triazole-4-carbonyl)-piperazin-1-yl]pyridazine-3-carboxylic acid (3-methylbutyl)amide as a white powder. 1H NMR (500 MHz, Acetone-d6) 88.18, 7.91, 7.32, 3.92-3.72, 3.45, 1.67, 1.52, 0.92.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[CH2:25][C:26]([NH:28][CH:29]1[C:34]([CH3:36])([CH3:35])[CH:33]2[CH2:37][C:30]1([CH3:38])[CH2:31][CH2:32]2)=[O:27].O>O1CCCC1>[CH:8]1([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:25][C:26]([NH:28][CH:29]2[C:34]([CH3:36])([CH3:35])[CH:33]3[CH2:37][C:30]2([CH3:38])[CH2:31][CH2:32]3)=[O:27])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: c1ccc(NC2CCCCC2)cc1
Reactant: CC12CCC(C1)C(C)(C)C2NC(=O)CCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC12CCC(C1)C(C)(C)C2NC(=O)CN(c1ccccc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of N-cyclohexylaniline (100 mg, 0.56 mmol) in tetrahydrofuran (4 ml) at −78° C. was added LiHMDS (1 ml of a 1M solution in tetrahydrofuran) dropwise. The solution was allowed to warm to 0° C., then recooled to −78° C., and a solution of 2-chloro-N-(1,3,3-trimethylbicyclo[2,2,1]hept-2-yl)acetamide (124 mg, 0.56 mmol) in tetrahydrofuran (1 ml) added dropwise. The mixture was allowed to warm to room temperature, and was stirred for 1 hour. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate. The ethyl acetate solution was absorbed onto silica gel, which was eluted with 3% methanol/methylene chloride, to yield 2-(cyclohexylphenylamino)-N-(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)acetamide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:5]2[CH2:6][CH2:7][N:8]([CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[C:9](=[O:12])[C:10]=2[CH:11]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[C:9]([C:10]1[CH:5]=[C:4]([C:2]2[CH:3]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:5]3[CH2:6][CH2:7][N:8]([CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[C:9](=[O:12])[C:10]=3[CH:11]=2)[CH:3]=[CH:2][CH:11]=1)#[N:8]
Reactant: CCCC(CCC)N1CCc2c(C(=O)OC)cc(Br)cc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCCC(CCC)N1CCc2c(C(=O)OC)cc(-c3cccc(C#N)c3)cc2C1=O
Temperature: 150 °C

Procedure:
Added to a solution of 0.3 g of methyl 7-bromo-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate in 9.4 cm3 of dioxane and 1.8 cm3 of water, at a temperature close to 20° C., are 147 mg of sodium bicarbonate. The reaction medium is then degassed under an argon atmosphere, then 111 mg of 3-cyanophenylboronic acid and 72 mg of tetrakis(triphenylphosphine)palladium are added. The mixture is heated at 150° C. in a microwave oven for 4 minutes, cooled to a temperature close to 20° C. and filtered. The filtrate is dried over anhydrous magnesium sulfate then filtered; added to the filtrate is 1 g of silica and the absorbed residue is purified by flash chromatography over silica (column: 15 g; spherical silica of BP-SUP type, particle size: 20-40 μm, eluent: 80% heptane/20% ethyl acetate then 60% heptane/40% ethyl acetate). After concentrating the fractions under reduced pressure, 103 mg of methyl 7-(3-cyanophenyl)-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate are obtained in the form of an orange oil.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][C:8]1[C:9](=[O:20])[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([O:18]C)=[CH:13][CH:12]=2)[C:4]([OH:6])=[O:5].[BrH:21]>>[BrH:21].[NH2:2][CH:3]([CH2:7][C:8]1[C:9](=[O:20])[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([OH:18])=[CH:13][CH:12]=2)[C:4]([OH:6])=[O:5]
Reactant: COc1ccc2[nH]c(=O)c(CC(N)C(=O)O)cc2c1
Agent: Br
Agent: Cl
Product: NC(Cc1cc2cc(O)ccc2[nH]c1=O)C(=O)O

Procedure:
To 6 g of 2-amino-3-(6-methoxy-2-quinolon-3-yl)propionic acid hydrochloride was added 60 ml of 47%-hydrobromic acid, and the mixture was refluxed for 7 hours. After the reaction mixture was cooled, the crystals precipitated were collected by filtration, then recrystallized from water to obtain 1.8 g of 2-amino-3-(6-hydroxy-2-quinolon-3-yl)proprionic acid hydrobromide in the form of yellowish powdery product.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)=O)(C)(C)C.O1CCCC1.O.[OH-].[Na+].Cl>O>[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3ccccc3n2C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Reaction time: 18 h

Procedure:
Combine (1-(t-butoxycarbonyl)-1H-benzimidazol-2-yl)(1-(t-butoxycarbonyl)piperidin-4-yl)amine (3.2 g, 7.7 mmol), tetrahydrofuran/water (200 mL/200 mL). Add a 1 M aqueous solution of sodium hydroxide (8.4 mL, 8.4 mmol). Heat to reflux. After 18 hours, concentrate the reaction mixture in vacuo to form a solid. Dillute with water, adjust the pH to about 7 using a 1 M aqueous solution of hydrochloric acid, collect the solid by filtration, and dry to give (1H-benzimidazol-2-yl)(1-(t-butoxycarbonyl)piperidin-4-yl)amine: Rf=0.38 (silica gel, 20/1 ethyl acetate/methanol).
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][N:14]([CH3:21])[CH2:15][C:16]([CH3:20])([CH3:19])[CH2:17]O>>[C:1]([O:12][CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][N:14]([CH3:21])[CH3:13])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CN(C)CC(C)(C)CO
Product: CCCCCCC/C=C/C(=O)OCC(C)(C)CN(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 3-dimethylamino-2,2-dimethyl-1-propanol as starting materials to give the aimed compound.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]#[N:16].[F:17][C:18]([F:35])([F:34])[C:19]1[CH:20]=[CH:21][C:22]([O:25][C:26]2[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=2)=[N:23][CH:24]=1>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]#[N:16])=[C:2]([N:1]=[CH:30][C:29]3[CH:28]=[CH:27][C:26]([O:25][C:22]4[CH:21]=[CH:20][C:19]([C:18]([F:35])([F:17])[F:34])=[CH:24][N:23]=4)=[CH:33][CH:32]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1N
Solvent: CCO
Solvent: C1CCNCC1
Product: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1N=Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Yield: 52 %

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carbonitrile (100 mg) was then suspended in EtOH (4 mL) and 4-[{5-(Trifluoromethyl)pyridin-2-yl}oxy]benzaldehyde (230 mg, 1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 3-((3-chlorophenyl)amino)-5-((4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzylidene)amino)-1H-pyrazole-4-carbonitrile as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr (217 mg, 52% yield).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[C:24]([OH:25])=[CH:23][C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)=[C:21]([F:33])[CH:20]=1)[C:14](=[O:34])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:42][C:43]#[N:44].O>CN(C=O)C>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[CH:20]=[C:21]([F:33])[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)=[CH:23][C:24]=1[O:25][CH2:42][C:43]#[N:44])[C:14](=[O:34])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCBr
Reactant: O=c1ccc2cc(SCc3ccccc3)ccc2n1-c1cc(F)c(-c2cccc(F)c2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCOc1cc(-c2cccc(F)c2)c(F)cc1-n1c(=O)ccc2cc(SCc3ccccc3)ccc21
Yield: 107 %

Procedure:
6-(Benzylthio)-1-(2,3′-difluoro-5-hydroxy-[1,1′-biphenyl]-4-yl)quinolin-2(1H)-one (528 mg, 1.120 mmol) was dissolved in DMF (2240 μl). Then potassium carbonate (155 mg, 1.120 mmol) was added followed by 2-bromoacetonitrile (86 μl, 1.232 mmol). The whole was stirred at rt for 1d. Water (1 mL) was added. White precipitate was collected with an aid of water, and dried to afford 2-((4-(6-(benzylthio)-2-oxoquinolin-1(2H)-yl)-3′,6-difluoro-[1,1′-biphenyl]-3-yl)oxy)acetonitrile (612 mg, 107% yield). m/z (ESI): [M+H]+=511.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.25 (s, 2 H) 5.14-5.31 (m, 2 H) 6.59 (d, J=8.80 Hz, 1 H) 6.71 (d, J=9.59 Hz, 1 H) 7.19-7.40 (m, 6 H) 7.44 (dd, J=8.80, 2.15 Hz, 1 H) 7.53-7.68 (m, 5 H) 7.81 (d, J=2.15 Hz, 1 H) 7.95 (br. s., 1 H) 7.99 (d, J=9.49 Hz, 1 H).
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[H-].[Na+].CN(C)C=[N:10][S:11]([C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=1)(=[O:13])=[O:12]>CN(C=O)C>[OH:4][CH2:3][CH2:2][S:1][C:17]1[CH:18]=[CH:19][C:14]([S:11]([NH2:10])(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: OCCS
Reactant: CN(C)C=NS(=O)(=O)c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(SCCO)cc1

Procedure:
A solution of 2-mercaptoethanol (58.6 g, 0.75 mol) in freshly degassed DMF (100 mL) was added dropwise under N2 to a stirred mixture of NaH (34.5 g, 50% oil suspension, 0.75 mol) and DMF (400 mL). When gas evolution was complete, N,N-dimethyl-N'-(4-bromobenzenesulfonyl)formamidine (146 g, 0.50 mol) was added and the mixture was heated on the steam bath for one hour. The DMF was removed in vacuo and methanol (500 mL) and 10% (w/v) aqueous NaOH solution (500 mL) was added to the residue. This solution was warmed on the steam bath for one hour and the methanol removed. The residue was diluted with water (2500 mL) and washed with petroleum ether. The separated aqueous layer was acidified with concentrated HCl. The white solid that separated was filtered, washed with water and dried. Extraction of the aqueous filtrate with ethyl acetate produced an additional quantity of product; total yield, 112.4 g; mp 103°-108° C. Recrystallization of a sample from water followed by recrystallization from dichloroethane gave material with mp 111°-112° C.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([NH:17][CH2:18][CH2:19][OH:20])[C:11]([CH3:21])=[C:10]([CH3:22])[N:9]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([NH:17][CH2:18][CH2:19][O:20][C:23](=[O:25])[CH3:24])[C:11]([CH3:21])=[C:10]([CH3:22])[N:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCO)c1C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCCNc1c(C)c(C)nc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.3 h
Yield: 95.6 %

Procedure:
Pyridine (1.0 mL, 12 mmol) and 4-dimethylaminopyridine (DMAP) (0.005 g, 0.04 mmol) was added to a solution of 2-(2-chloro-5,6-dimethyl-3-nitropyridin-4-ylamino)ethanol (0.50 g, 2.0 mmol) in anhydrous dichloromethane (4.5 mL). Under a nitrogen atmosphere, acetic anhydride (0.8 mL, 8 mmol) was added, and the yellow solution was stirred at room temperature for 1.3 hours. The volatiles were removed under reduced pressure, and the residual yellow oil was dissolved in dichloromethane. The solution was washed with aqueous sodium bicarbonate, water, and brine, and then dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 0.55 g of acetic acid 2-(2-chloro-5,6-dimethyl-3-nitropyridin-4-ylamino)ethyl ester as a yellow solid.