Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[NH4+].[F:3][C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([F:13])[C:5]=1[N:14]1[CH2:18][CH:17]=[CH:16][CH2:15]1>CCO.O.[Fe]>[N:14]1([C:5]2[C:4]([F:3])=[CH:9][C:8]([NH2:10])=[CH:7][C:6]=2[F:13])[CH2:18][CH:17]=[CH:16][CH2:15]1
Reactant: O=[N+]([O-])c1cc(F)c(N2CC=CC2)c(F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc(F)c(N2CC=CC2)c(F)c1
Yield: 99.2 %

Procedure:
Ammonium chloride (1.18 g, 22.1 mmol) is added to a mixture of 1-(2,6-difluoro-4-nitrophenyl)-2,5-dihydro-1H-pyrrole (Step 1, 0.5 g, 2.21 mmol) dissolved in EtOH/water (2:1, 18.0 mL) and heated to reflux. Iron powder (0.37 g, 6.63 mmol) is added in portions over one hour. After refluxing for another 45 min, the reaction mixture is cooled, filtered, and extracted three times with dichloromethane. The organic layers are washed with saline, dried (MgSO4) and concentrated to provide the title compound (0.43 g, >95%), MS (m/z): [M+H]+=197; 1H NMR (300 MHz, CDCl3): δ 3.63 (bs, 2H), 4.10 (s, 4H), 5.84 (s, 2H), 6.17 (d, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[NH:7][C:8](=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=1)([O-])=O.[N:25]1[O:29][N:28]=[C:27]2[CH:30]=[C:31]([CH:34]=O)[CH:32]=[CH:33][C:26]=12>>[N:25]1[O:29][N:28]=[C:27]2[CH:30]=[C:31]([C:34]3[NH:22][C:21]4[CH:20]=[CH:19][C:6]([NH:7][C:8](=[O:18])[C:9]5[CH:10]=[CH:11][C:12]([N:15]([CH3:16])[CH3:17])=[CH:13][CH:14]=5)=[CH:5][C:4]=4[N:1]=3)[CH:32]=[CH:33][C:26]=12
Reactant: O=Cc1ccc2nonc2c1
Reactant: CN(C)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Product: CN(C)c1ccc(C(=O)Nc2ccc3[nH]c(-c4ccc5nonc5c4)nc3c2)cc1

Procedure:
Compound 186 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-dimethylaminobenzoyl)aniline and benzofurazan-5-carboxaldehyde. [M+H]+ calcd for C22H18N6O2: 399.15; found: 399.47.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([C:13]#[N:14])=[N:7][C:8]([CH2:11][CH3:12])=[CH:9][CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[CH2:11]([C:8]1[N:7]=[C:6]2[C:13]([NH2:14])=[N:1][CH2:4][C:5]2=[CH:10][CH:9]=1)[CH3:12]
Reactant: CCc1ccc(CN=[N+]=[N-])c(C#N)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccc2c(n1)C(N)=NC2
Yield: 89.3 %

Procedure:
After dissolving 3-(azidomethyl)-6-ethyl-2-pyridinecarbonitrile (1.0 g, 5.34 mmol) in tetrahydrofuran (16 ml)-water (0.8 ml), triphenylphosphine (2.1 g, 8.01 mmol) was added while stirring on ice, and the mixture was further stirred at room temperature for 2.0 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (solvent: ethyl acetate, ethyl acetate:methanol=4:1, ethyl acetate:methanol:aqueous ammonia=2:1:0.1 in this order). The title compound (0.769 g) was obtained as a light green substance. (89.3% yield)
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[F:17][C:18]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][C:19]=1/[CH:28]=[CH:29]/[C:30](O)=[O:31]>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH:16][C:30](=[O:31])/[CH:29]=[CH:28]/[C:19]3[CH:20]=[CH:21][CH:22]=[C:23]([C:24]([F:26])([F:25])[F:27])[C:18]=3[F:17])=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Reactant: O=C(O)/C=C/c1cccc(C(F)(F)F)c1F
Product: CC(F)(F)c1ccc(Cn2ccc(NC(=O)/C=C/c3cccc(C(F)(F)F)c3F)n2)o1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2-fluoro-3-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.16 min; [M+H]+=443.98.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[CH2:32][OH:33])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:27][CH3:28])=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:23])[CH2:21][CH3:22])=[CH:16][C:15]=2[CH:24]([CH3:26])[CH3:25])[CH:13]=1.[CH2:34]([Mg]Br)[CH3:35]>>[CH2:27]([C:11]1[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH2:34][CH3:35])([OH:23])[CH2:21][CH3:22])=[CH:16][C:15]=2[CH:24]([CH3:26])[CH3:25])=[CH:13][C:8]([O:7][CH2:6][C:5]2[CH:29]=[CH:30][C:31]([CH2:32][OH:33])=[C:3]([CH2:2][OH:1])[CH:4]=2)=[CH:9][CH:10]=1)[CH3:28]
Reactant: CC[Mg]Br
Reactant: CCC(=O)c1ccc(-c2cc(OCc3ccc(CO)c(CO)c3)ccc2CC)c(C(C)C)c1
Product: CCc1ccc(OCc2ccc(CO)c(CO)c2)cc1-c1ccc(C(O)(CC)CC)cc1C(C)C

Procedure:
In a manner similar to that of Example 1(q), by reacting 810 mg (1.8 mmol) of 1-{5′-[3,4-bis(hydroxymethyl)benzyloxy]-2′-ethyl-2-isopropylbiphenyl-4-yl}-1-propanone with 4.8 ml (15 mmol) of ethylmagnesium bromide (3M/ether), and after purification by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (35/65), 600 mg (70%) of {4-[6-Ethyl-4′-(1-ethyl-1-hydroxypropyl)-2′-isopropylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol are obtained in the form of white crystals with a melting point of 109° C.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:25]([O:27]C)=[O:26])[CH:19]=3)[NH:14]2)=[CH:9][CH:8]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+]>CO.O>[C:1]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]2[C:22]([CH3:23])([CH3:24])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:25]([OH:27])=[O:26])[CH:19]=3)[NH:14]2)=[CH:11][CH:12]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)C(C)C)cc1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)C(=O)Nc1ccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)cc1
Yield: 92 %

Procedure:
To a mixture of methyl 2-(4-isobutyramidophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (46 mg, 0.12 mmol) in methanol (3 mL) and water (1.5 mL) was added a solution of sodium hydroxide (82 mg, 2.06 mmol.) in water (1.5 mL). The resultant mixture was heated to reflux until the completion of the reaction (monitored by thin layer chromatography). Methanol was removed under vacuum. The residue was acidified with 2 M hydrochloric acid to pH=1. The precipitates were collected by filtration to afford 2-(4-isobutyramidophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a yellow solid, 40 mg, 92% yield; MS (ESI+APCI) M+1=367.6.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH:25]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[NH:24][C:23]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH:40]([CH3:42])[CH3:41])=[N:22]2)=[CH:17][CH:16]=1>C(Cl)Cl>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]2[CH:25]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[N:24]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[C:23]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH:40]([CH3:42])[CH3:41])=[N:22]2)=[CH:19][CH:20]=1
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)Oc1ccccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Oc1ccccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Isobutyryl chloride (8.1 μL, 0.077 mmol) was added to a solution of triethylamine (10.8 μL, 0.077 mmol) and 4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-1H-imidazole (30 mg, 0.071 mmol) in methylene chloride (3 mL). The reaction mixture was stirred at room temperature for 3 h. It was then diluted with methylene chloride and washed with water and brine, and dried over sodium sulfate. The solvents were remove under reduced pressure and chromotagraphy of the residue over silica gel using 25% ethyl acetate in hexanes gave 1-[4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-2-methyl-propan-1-one. HR-MS (ES, m/z) calculated for C28H29N2O2Cl2[(M+H)+]495.1601, observed 495.1606.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:20](O)=[O:21])=[CH:10][C:11]([CH:18]=[CH2:19])=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:24][NH:25][O:26][CH3:27].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:20]([N:25]([O:26][CH3:27])[CH3:24])=[O:21])=[CH:10][C:11]([CH:18]=[CH2:19])=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1
Reactant: C=Cc1cc(C(=O)O)c(-c2cccc(F)c2)c2ncccc12
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=Cc1cc(C(=O)N(C)OC)c(-c2cccc(F)c2)c2ncccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.2 %

Procedure:
To a mixture of 8-(3-fluorophenyl)-5-vinylquinoline-7-carboxylic acid (66 mg, 0.22 mmol), N,O-dimethylhydroxylamine hydrochloride (32.9 mg, 0.338 mmol) in N,N-dimethylformamide (0.4 mL) was added benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate (0.149 g, 0.338 mmol). After stirring at room temperature for 30 minutes, N,N-diisopropylethylamine (0.118 mL, 0.675 mmol) was added to the resulting mixture. The reaction was stirred at room temperature overnight, quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to dryness under reduced pressure. The resdiue was purified on silica gel, eluting 0 to 50% ethyl acetate in hexane, to give the desired product (32 mg, 42%). LCMS calculated for C20H18FN2O2 (M+H)+: m/z=337.1; Found: 337.1.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[N:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Cl.[F:19][C:20]([F:30])([F:29])[C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[NH2:22]>>[F:30][C:20]([F:19])([F:29])[C@H:21]([NH:22][C:13]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=2)[N:12]=1)=[O:15])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: N[C@H](c1ccccn1)C(F)(F)F
Reactant: O=C(O)c1cccc(Cc2ccc(F)cc2)n1
Agent: Cl
Product: O=C(N[C@H](c1ccccn1)C(F)(F)F)c1cccc(Cc2ccc(F)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(4-fluorobenzyl)picolinic acid (Example 277 a) and (R)-2,2,2-trifluoro-1-(pyridin-2-yl)ethanamine hydrochloride (CAN 1228565-87-4) as starting materials. MS (EI): m/e=390.1 [M+H]+.
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.C.[H][H]>C(O)(=O)C.[Pd]>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[NH2:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=C(C=Cc1cccc([N+](=O)[O-])c1)c1ccccc1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Nc1cccc(CCCc2ccccc2)c1
Yield: 71.1 %

Procedure:
253 g of 1-phenyl-3-(3'-nitrophenyl)-prop-2-en-1-one are suspended in 2.5 liters of glacial acetic acid. 196 g of concentrated sulfuric acid and 10 g of 10% strength Pd on animal charcoal are added and the mixture is hydrogenated under 1.1 bar hydrogen pressure at 65°-70° C., until no further hydrogen is absorbed. When the mixture has cooled, some of the acetic acid is distilled off, the residue is rendered alkaline with sodium hydroxide solution and extracted by shaking with ether, the organic phase is dried over sodium sulfate and filtered, the solvent is stripped off and the residue is distilled. 150 g of 3-(3-phenylpropyl)-aniline of boiling point 148° C./0.2 mbar are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[C:18](O)(=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22]>>[C:18]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)(=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CCCCC(=O)O
Product: CCCCC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 81.7 %

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 10.0 mg (0.10 mMol) pentanoic acid, 12.8 mg (82%) of the title compound were recovered.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:27](Cl)([Cl:29])=[O:28]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:27]([Cl:29])=[O:28])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Reactant: O=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: O=C(Cl)OC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
1-Benzyloxycarbonyl-4-hydroxypiperidine (15 g., 0.0638 mole) and N,N-diisopropylethylamine (12.3 ml., 9.13 g., 0.0707 mole) were dissolved in toluene (150 ml.), and the solution was added over 30 min. to a solution of phosgene (12.63 g., 0.128 mole) in toluene (150 ml.). The reaction mixture was protected from atmospheric moisture (drying tube), stirred magnetically, and kept at ambient temperature in a water bath during the addition. When the addition was complete the mixture was filtered and the solid residue washed with toluene (ca. 50 ml.). The solvent in the combined filtrate and washings was evaporated in vacuo (1 mm. pressure, solid CO2 cold finger condenser) to give 1-benzyloxycarbonyl-4-chlorocarbonyloxypiperidine, I.R. λmax 1775 cm.-1 and 1700 cm.-1.
Reaction SMILES: [CH2:1]([OH:10])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11](OC(=O)C)(=[O:13])[CH3:12]>N1C=CC=CC=1>[C:11]([O:10][CH2:1]/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:13])[CH3:12]
Reactant: CCCCCC/C=C/CO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCCC/C=C/COC(C)=O

Procedure:
Pyridine (100 ml) and trans-2-nonen-1-ol (28.4 g, 0.2 mole) are heated to 110°C and acetic anhydride (30.6 g, 0.3 mole) is added dropwise. The reaction mixture is maintained at 110°-115° for 2 hours and 120°-125°C for 3 hours. The mixture is cooled and washed with water, 5% sulfuric acid, and finally water. The solution is dried over sodium sulfate. Trans-2-nonenyl acetate, 33.0 g is obtained by vacuum distillation, b.p. 70°-5°C/50-55 mm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: NCCN1CCOCC1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Product: O=S(=O)(NCCN1CCOCC1)c1cccc(Br)c1
Yield: 90.8 %

Procedure:
Prepared by general procedure III from 3-Bromobenzenesulfonyl chloride (5.0 g, 20 mmol) and 4-(2-Aminoethyl)-morpholine (2.80 mL, 22 mmol) to give the title compound (6.34 g, 93%) as a white solid. MS (ISN) 347.1[(M−H)−], 349.3[(M+2−H)−].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[OH:15]O>C(O)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[N:8]=[CH:7][C:6]([OH:15])=[CH:5]2
Reactant: O=[N+]([O-])c1cc(F)cc2cccnc12
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(F)cc2cc(O)cnc12
Temperature: 70 °C
Reaction time: 5 h

Procedure:
A solution of 6-fluoro-8-nitro-quinoline (900 mg, 4.7 mmol) in acetic acid (10 ml) was treated at room temperature with hydrogen peroxide (30% in water (1.6 ml), then it was stirred at 70° C. for 5 hours. For the workup, the reaction mixture was cooled and poured into ice-water. The precipitate was filtered, washed with water, collected and dried. 6-Fluoro-8-nitro-quinolin-3-ol was obtained as a brown solid (285 mg, 29%); (calculated) C9H5FN2O3 [208.2]; (found) [M−H]−=207.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:25][C@H:26]4[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]4)[C:15]([N:17]4[CH2:21][CH2:20][CH2:19][C@H:18]4[C:22]([OH:24])=O)=[N:16][C:12]=3[CH:11]=[C:10]([C:33]#[N:34])[N:9]=2)[CH:5]=[N:6][CH:7]=1.CCCP(=O)=O.[CH3:41][NH:42][CH2:43][CH3:44]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:25][C@H:26]4[CH2:27][CH2:28][C@H:29]([CH3:32])[CH2:30][CH2:31]4)[C:15]([N:17]4[CH2:21][CH2:20][CH2:19][C@H:18]4[C:22]([N:42]([CH2:43][CH3:44])[CH3:41])=[O:24])=[N:16][C:12]=3[CH:11]=[C:10]([C:33]#[N:34])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3C(=O)O)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: CCNC
Agent: CCCP(=O)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C)C(=O)[C@@H]1CCCN1c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a reaction vessel was added the crude residue of (S)-1-(4-(5-chloropyridin-3-yl)-6-cyano-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-2-yl)pyrrolidine-2-carboxylic acid (0.030 g, 0.063 mmol), propylphosphonic anhydride (0.10 mL, 50% w/w in DMF), and N-methylethanamine (0.0037 g, 0.063 mmol) suspended in DMF (0.5 mL). The reaction was stirred at ambient temperature for 6 hours. The reaction was diluted with H2O (2.0 mL) and was extracted with EtOAc (2×5 mL). The combined organics were concentrated in vacuo to afford (S)-1-(4-(5-chloropyridin-3-yl)-6-cyano-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-2-yl)-N-ethyl-N-methylpyrrolidine-2-carboxamide as a crude residue. MS ESI calc'd. for C28H34ClN7O [M+H]+ 520. found 520.
Reaction SMILES: [C:1]1([C:7]([NH:9][CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:26](OC3C=CC([N+]([O-])=O)=CC=3)=[O:27])[CH2:11]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:39][C@@H:40]1[CH2:45][CH2:44][C@H:43]([OH:46])[CH2:42][CH2:41]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:46][CH:43]1[CH2:44][CH2:45][CH:40]([NH:39][C:26]([N:12]2[CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][CH:17]=3)[CH2:15][CH:10]([NH:9][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:8])[CH2:11]2)=[O:27])[CH2:41][CH2:42]1
Reactant: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Reactant: N[C@H]1CC[C@@H](O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)NC2CCC(O)CC2)C1)c1ccccc1

Procedure:
80 mg (0.16 mmol) of 4-nitrophenyl 3-[(phenylcarbonyl)amino]-5-[4-(trifluoromethyl)phenyl]piperidine-1-carboxylate were initially charged in 1.7 ml of DMF, and 71 mg (0.47 mmol) of cis-4-aminocyclohexanol hydrochloride and 129 mg (0.94 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150° C. for 15 min. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 3 mg (4% of theory)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:36])[C@@H:15]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:27][CH:26]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:37][C:38]([F:51])([F:50])[C:39]1[CH:40]=[C:41]([CH:47]=[CH:48][CH:49]=1)/[CH:42]=[CH:43]/[C:44](O)=[O:45]>>[CH2:16]([C@H:15]([N:23]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:29][CH:30]=1)[C:44](=[O:45])[CH:43]=[CH:42][C:41]1[CH:47]=[CH:48][CH:49]=[C:39]([C:38]([F:50])([F:51])[F:37])[CH:40]=1)[C:14]([N:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]1)=[O:36])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCCCc1ccc(CN[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Reactant: O=C(O)/C=C/c1cccc(C(F)(F)F)c1
Product: CCCCCc1ccc(CN(C(=O)C=Cc2cccc(C(F)(F)F)c2)[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Yield: 69.9 %

Procedure:
Acylation of 1-(4-benzyl-piperazin-1-yl)-(S)-2-(4-pentyl-benzylamino)-3-phenyl-propan-1-one (43.5 mg, 0.09 mmol) according to the procedure described for the preparation of Example 1 with trans-3-trifluoromethyl-cinnamic acid (21.4 mg, 0.099 mmol) gave 42.9 mg (69%) of N—[(S)-1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-N-(4-pentyl-benzyl)-3-(3-trifluoromethyl-phenyl)-acrylamide. LC-MS: tR=1.02 min; [M+H]+=682.48.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:17])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][C:15]#[CH:16])[C:5](O)=[O:6].C(N1C=CN=C1)([N:20]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:17])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][C:15]#[CH:16])[C:5]([NH2:20])=[O:6]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C#CCCCOc1c(C)cc(C(=O)O)cc1C
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C#CCCCOc1c(C)cc(C(N)=O)cc1C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
To a solution of 4.7 g 3,5-dimethyl-4-(3-ethynylpropoxy)benzoic acid in 100 ml dry tetrahydrofuran was added 3.7 g carbonyldiimidazole and the mixture was stirred 2 hrs. at room temperature. To the latter was added 10 ml concentrated ammonium hydroxide, and the mixture was stirred for 30 min., poured onto water and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated to give 4.7 g 3,5-dimethyl-4-(3-ethynylpropoxy)benzamide, m.p. 81°-84° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[C:11]([Cl:19])[CH:10]=2)=[N:6][CH:7]=1.[CH3:20][Si:21]([CH3:40])([CH3:39])[CH2:22][CH2:23][O:24][CH2:25][N:26]1[C:35]2[C:30](=[CH:31][C:32]([CH:36]=[CH2:37])=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]1=[O:38]>CN(C=O)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:19][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:4]=[CH:3][C:2](/[CH:37]=[CH:36]/[C:32]3[CH:31]=[C:30]4[C:35](=[CH:34][CH:33]=3)[N:26]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:20])([CH3:40])[CH3:39])[C:27](=[O:38])[CH:28]=[CH:29]4)=[CH:7][N:6]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH:16]([F:18])[F:17]
Reactant: FC(F)Oc1ccc(Nc2ncc(Br)cn2)cc1Cl
Reactant: C=Cc1ccc2c(ccc(=O)n2COCC[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(=O)ccc2cc(/C=C/c3cnc(Nc4ccc(OC(F)F)c(Cl)c4)nc3)ccc21
Temperature: 120 °C
Yield: 49.1 %

Procedure:
To a solution of 5-bromo-N-(3-chloro-4-(difluoromethoxy)phenyl)pyrimidin-2-amine (0.3 g, 0.856 mmol) in DMF (5 mL), were added 1-((2-(trimethylsilyl)ethoxy)methyl)-6-vinylquinolin-2(1H)-one (0.258 g, 0.856 mmol) triethylamine (0.358 mL, 2.57 mmol), tetrabutylammonium chloride, hydrate (0.380 g, 1.284 mmol) and PdOAc2 (0.019 g, 0.086 mmol). The reaction mixture was heated at 120° C. for 12 h. The reaction mixture was concentrated, dissolved in ethyl acetate, filtered through celite, and washed with water. The organic layer was dried over anhydrous sodium sulfate, concentrated and purified by flash chromatography on silica gel using 15% ethyl acetate in petroleum ether to give (E)-6-(2-(2-(3-chloro-4-(difluoromethoxy)phenylamino)pyrimidin-5-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)quinolin-2(1H)-one (0.24 g, 49%). LCMS (ES-API), RT: 2.56 m/z 571.2 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:13]=[CH:12][C:11]2[NH:10][C:9]3[N:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:8]=3[C:7]=2[CH:6]=1)=[O:4].[OH-].[Li+].Cl>O1CCCC1.O>[Cl:18][C:17]1[C:8]2[C:7]3[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[N:13]=[CH:12][C:11]=3[NH:10][C:9]=2[N:14]=[CH:15][CH:16]=1
Reactant: COC(=O)c1cc2c(cn1)[nH]c1nccc(Cl)c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2c(cn1)[nH]c1nccc(Cl)c12
Temperature: 50 °C
Yield: 0.1 %

Procedure:
A mixture of 4-chloro-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid methyl ester (0.73 g, 2.8 mol) and lithium hydroxide (0.38 g, 9.0 mmol) in tetrahydrofuran (15 mL) and water (3 mL) was heated at 50° C. for 1.5 hours. The mixture was allowed to cool to ambient temperature, treated with hydrochloric acid (1M, 9 mL) and evaporated in-vacuo to afford a grey solid (0.68 g, 98%). LCMS (Method B): RT=2.98 min, M+H+=248. 1H NMR (400 MHz, DMSO-d6): 12.98 (s, 1H), 9.05 (d, J=1.0 Hz, 1H), 8.95 (d, J=1.0 Hz, 1H), 8.63 (d, J=5.3 Hz, 1H), 7.54 (d, J=5.3 Hz, 1H).