Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:4]([C:19](=O)[CH3:20])[CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:4]([CH:19]([NH2:28])[CH3:20])[CH:3]=1
Reactant: CC(=O)c1cc(Cl)c2ccccc2c1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc(Cl)c2ccccc2c1-c1cccc(F)c1
Temperature: 65 °C

Procedure:
A mixture of 1-[4-chloro-1-(3-fluorophenyl)-2-naphthyl]ethanone (58 mg, 0.19 mmol) and ammonium acetate (150 mg, 1.94 mmol) in methanol (1.1 mL) and acetonitrile (1.1 mL) was heated at 65° C., in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (24.4 mg, 0.388 mmol) was added to the resulting mixture. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature and quenched with sat. sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude material was used directly in the next step (58 mg, 100%). LCMS calculated for C18H13ClF (M−NH2)+: m/z=283.1; Found: 283.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([NH2:23])=[CH:18][C:17]=1[CH3:24].[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:37](=[O:38])[C:36]([C:39](O)=[O:40])=[CH:35][N:34]([CH:42]([CH3:44])[CH3:43])[C:33]2=[O:45])=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([CH3:24])=[CH:18][C:19]([NH:23][C:39]([C:36]2[C:37](=[O:38])[N:32]([C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=3)[C:33](=[O:45])[N:34]([CH:42]([CH3:44])[CH3:43])[CH:35]=2)=[O:40])=[CH:20][C:21]=1[CH3:22]
Reactant: CC(C)n1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Reactant: COc1cc2nccc(Oc3c(C)cc(N)cc3C)c2cc1OC
Product: COc1cc2nccc(Oc3c(C)cc(NC(=O)c4cn(C(C)C)c(=O)n(-c5ccc(F)cc5)c4=O)cc3C)c2cc1OC

Procedure:
This compound was synthesized using 4-(6,7-dimethoxy-quinolin-4-yloxy)-3,5-dimethyl-phenylamine and 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid using the procedure for example 1. mp=180-182° C.; LCMS m/z=599 (M+1); 1H NMR (DMSO-d6) δ: 10.89 (s, 1H), 8.65 (s, 1H), 8.41 (d, 1H, J=5 Hz), 7.60 (s, 1H), 7.58 (s, 2H), 7.45-7.33 (m, 5H), 6.19 (d, 1H, J=7 Hz), 4.18 (p, 1H, J=7 Hz), 3.95 (d, 6H, J=6 Hz), 2.05 (s, 6H), 1.45 (d, 6H, J=7 Hz).
Reaction SMILES: CO[C:3](=[O:8])[CH2:4][C:5]([OH:7])=[O:6].Cl.NCC(OC)=O.[N:16]1([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]3[CH:41]=[CH:40][CH:39]=[C:38]4[C:33]=3[CH2:34][CH2:35][CH2:36][N:37]4[C:42](=[O:55])[CH2:43][CH2:44][CH2:45][O:46][C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[C:48]=3[CH3:54])[CH:27]=2)=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:54][C:48]1[C:49]([CH3:53])=[CH:50][CH:51]=[CH:52][C:47]=1[O:46][CH2:45][CH2:44][CH2:43][C:42]([N:37]1[C:38]2[C:33](=[C:32]([C:28]3[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=3)[CH2:25][O:24][C:22]([N:16]3[CH2:21][CH2:20][N:19]([C:3](=[O:8])[CH2:4][C:5]([OH:7])=[O:6])[CH2:18][CH2:17]3)=[O:23])[CH:41]=[CH:40][CH:39]=2)[CH2:34][CH2:35][CH2:36]1)=[O:55]
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cccc(COC(=O)N5CCNCC5)c4)cccc32)c1C
Reactant: COC(=O)CC(=O)O
Agent: COC(=O)CN
Agent: Cl
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cccc(COC(=O)N5CCN(C(=O)CC(=O)O)CC5)c4)cccc32)c1C

Procedure:
Example 128 was prepared using a procedure analogous to Example 126 except that Example 1 was replaced with 3-methoxy-3-oxopropanoic acid and methyl 2-aminoacetate hydrochloride was replaced with 3-(1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)benzyl piperazine-1-carboxylate. LCMS, [M+H]+=628.3. 1H NMR (400 MHz, MeOD) δ 7.54-7.42 (m, 2H), 7.41-7.31 (m, 2H), 7.30-7.14 (m, 3H), 7.06 (t, J=7.9 Hz, 1H), 6.79 (d, J=7.5 Hz, 1H), 6.75 (d, J=8.1 Hz, 1H), 5.25 (s, 2H), 3.97 (br, s, 2H), 3.83 (t, J=7.0 Hz, 2H), 3.74-3.55 (m, 8H), 2.90 (t, J=6.9 Hz, 2H), 2.46 (br. s, 2H), 2.31-2.16 (m, 5H), 1.91 (s, 3H), 1.85 (dt, J=13.3, 6.8 Hz, 2H), 1.37 (s, 2H). HPLC-1: Rt=10.8 min, purity=95.0%; HPLC-2: Rt=10.9 min, purity=93.1%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[C:12]([O-])(=[O:14])[CH3:13].[Na+].O>C(O)(=O)C>[C:12]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)[O-]
Reactant: NCc1ccc(C(=O)O)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)NCc1ccc(C(=O)O)cc1
Yield: 72.5 %

Procedure:
A mixture of 4-aminomethylbenzoic acid (Aldrich, 1.51 g, 0.01 mol) and anhydrous sodium acetate (1.5 g, 0.018 mol) in glacial acetic acid (5 mL) was heated at reflux for 18 h. On cooling, the mixture was poured into cold water (50 mL). The precipitate was separated by filtration and washed several times with cold water. The cake was recrystallized from water to give 1.4 g (72.5%) of the title compound as a white powder, mp 195° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[C:10]([C:24]#[N:25])[C:9]2=[O:26])=[CH:5][CH:4]=1.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31].C(NC(C)C)(C)C>ClCCl>[C:29]([N:21]1[CH2:20][CH2:19][N:18]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([F:2])=[CH:28][CH:27]=3)[C:9](=[O:26])[C:10]=2[C:24]#[N:25])[CH2:23][CH2:22]1)(=[O:32])[CH:30]=[CH2:31]
Reactant: C=CC(=O)Cl
Reactant: N#Cc1c(N2CCNCC2)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: C=CC(=O)N1CCN(c2c(C#N)c(=O)n(Cc3ccc(F)cc3)c3ccccc23)CC1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To a suspension of 1-(4-Fluoro-benzyl)-2-oxo-4-piperazin-1-yl-1,2-dihydro-quinoline-3-carbonitrile hydrochloride salt (1 eq, 0.150 g, 0.41 mmole) in dichloromethane at −10° C. was added acryloyl chloride (1.1 eq, 0.054 g, 0.45 mmole) followed by the addition of diisopropylamine (1.5 eq, 0.083 g, 0.62 mmole, 0.103 mL). The resulting solution stirred at 10° C. for 1 hour then warmed to RT and stirred for an additional 2 hours. The reaction was quenched into ice cooled water and extracted with ethyl acetate (25 mL×3). Combined organic phase was washed consecutively with water, brine before drying over sodium sulfate. Organic phase was evaporated and the residue was purified by flash chromatography to afford 4-(4-Acryloyl-piperazin-1-yl)-1-(4-fluoro-benzyl)-2-oxo-1,2-dihydro-quinoline-3-carbonitrile as a yellow solid (0.043 g, 25% calc M+H 417, obs M+H 417).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.[F:13][C:14]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17].C(N(CC)CC)C>CO>[CH3:11][O:10][C:8]([C:6]1[CH:5]=[C:4]([NH:17][CH2:16][C:15]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:14]=2[F:13])[N:3]=[C:2]([Cl:1])[N:7]=1)=[O:9]
Reactant: NCc1ccc(F)cc1F
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(NCc2ccc(F)cc2F)nc(Cl)n1
Reaction time: 1 h
Yield: 45.93 %

Procedure:
A suspension of methyl 2,6-dichloropyrimidine-4-carboxylate (1 g, 4.87 mmol) in methanol (20 ml) was cooled to −20° C., to this 2,4-difluoro benzylamine (0.627 mg, 4.39 mmol) and triethylamine (0.98 mg, 9.74 mmol) were added. The reaction mixture was stirred at same temperature for 1 hr then at room temperature for 4 hrs. Methanol was removed under vacuum. The residue was purified by column chromatography to get the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])[C:5]([N+:23]([O-:25])=[O:24])=[CH:4][N:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:36])[CH3:35])=[CH:29][CH:28]=1.Cl.C(OCC)C>CC(O)C>[ClH:1].[C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:6]1[C:5]([N+:23]([O-:25])=[O:24])=[CH:4][N:3]=[C:2]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([NH:33][C:34](=[O:36])[CH3:35])=[CH:31][CH:32]=2)[N:7]=1)(=[O:16])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)Nc1ccc(N)cc1
Reactant: O=C(c1ccccc1)c1ccccc1Nc1nc(Cl)ncc1[N+](=O)[O-]
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: CC(=O)Nc1ccc(Nc2ncc([N+](=O)[O-])c(Nc3ccccc3C(=O)c3ccccc3)n2)cc1
Temperature: 90 °C
Yield: 13.4 %

Procedure:
To a mixture of {2-[(2-chloro-5-nitropyrimidin-4-yl)amino]phenyl}(phenyl)-methanone (63 mg, 0.178 mmol) and N-(4-aminophenyl)acetamide (28 mg, 0.185 mmol) in 2-propanol (2 mL) was added 1N HCl in diethyl ether (50 uL, 0.05 mmol). The reaction mixture was heated at 90° C. for approx. 18 hours. After the reaction was cooled to room temperature cold diethyl ether was added to precipitate out the product. The precipitate was filtered and washed with cold diethyl ether, then dried under vacuum to give N-[4-({4-[(2-benzoylphenyl)amino]-5-nitropyrimidin-2-yl}amino)phenyl]acetamide hydrochloride (12 mg, 13%) as a tan solid. 1H NMR (DMSO-d6/D2O): δ 8.98 (s, 1H), 8.12 (m, 1H), 7.69-7.43 (m, 12 H), 2.05 (s, 3 H). MS m/z 468 (M+1).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:16][CH2:17][OH:18].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:18][CH2:17][CH2:16][C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][C:11]=2[CH:1]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccc2c(c1)Cc1ccccc1CO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccc2c(c1)Cc1ccccc1CO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(6,11-Dihydrodibenz[b,e]oxepin-2-yl)ethanol (14 g) and triethylamine (6.7 g) in 200 ml of dry dichloromethane was treated with methanesulfonylchloride (5.2 ml) and stirred at room temperature for 2 hours. This solution was evaporated to a paste, taken up in ethyl acetate, washed dried, and evaporated to an oil. Passage through a short pad of silica gel with chloroform as eluent gave 13.5 g of 2-(6,11-dihydrodibenz[b,e]-oxepin-2-yl)ethanol methanesulfonate as an oil.
Reaction SMILES: [OH:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[CH:5][C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[N:3]1.[CH3:23][N:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25](Cl)=[O:26]>>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:4]2[CH:5]=[C:6]([C:7]3[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=3)[N:2]([O:1][C:25](=[O:26])[N:24]([CH3:23])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:3]=2)=[CH:16][CH:17]=1
Reactant: COc1ccc(-c2cc(-c3ccc(OC)cc3)n(O)n2)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: COc1ccc(-c2cc(-c3ccc(OC)cc3)n(OC(=O)N(C)c3ccccc3)n2)cc1

Procedure:
The title compound was prepared from 1-hydroxy-3,5-bis-(4-methoxyphenyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12,.EtOAc-heptane) (29%, beige crystals).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH3:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)=[O:4].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[NH2:46][C:47]1[CH:52]=[CH:51][C:50]([NH2:53])=[CH:49][N:48]=1>ClCCl>[NH2:46][C:47]1[N:48]=[CH:49][C:50]([NH:53][C:10]([C:9]2[CH:13]=[C:5]([CH:6]=[CH:7][C:8]=2[CH3:14])[C:3]([O:2][CH3:1])=[O:4])=[O:12])=[CH:51][CH:52]=1
Reactant: Nc1ccc(N)nc1
Reactant: COC(=O)c1ccc(C)c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(C(=O)Nc2ccc(N)nc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a round-bottomed flask was charged 5-(methoxycarbonyl)-2-methylbenzoic acid (0.2 g, 1.0 mmol), dicloromethane (3 ml), n,n-diisopropylethylamine (0.7 ml, 4.0 mmol), HOBt (0.16 g, 1.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.24 g, 1.2 mmol), and 2,5-diaminopyridine (0.11 g, 1.0 mmol) in that order. The reaction mixture was stirred at RT under N2 for 18 h. The reaction was partitioned between DCM (30 ml) and brine (20 mL). The aqueous layer was back extracted with DCM (3×15 mL) and the combined DCM layer was dried (Na2SO4) and concentrated. The crude product was dissolved in MeOH and absorbed on silica gel, purified by chromatography through a Redi-Sep 40 g column, eluting with a gradient of 0% to 10% MeOH in CH2Cl2, to provide methyl 3-((6-aminopyridin-3-yl)carbamoyl)-4-methylbenzoate as a tan solid. MS (ESI, pos. ion) m/z: 286.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=[O:4].[CH2:11]1[O:21][C:14]2([CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)[O:13][CH2:12]1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][CH:17]1[CH2:18][CH2:19][C:14]2([O:21][CH2:11][CH2:12][O:13]2)[CH2:15][CH2:16]1)=[O:4]
Reactant: COC(=O)c1sccc1N
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1sccc1NC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.5 %

Procedure:
A suspension of 3-amino-thiophene-2-carboxylic acid methyl ester (5.0 g, 31.85 mmol) in dry THF (9 mL) is treated with 1,4-cyclohexanedione monoethylene ketal (5.0 g, 32.05 mmol), followed by dibutyltin dichloride (482 mg, 1.59 mmol). After 5 min, phenyl silane (4.3 mL, 34.96 mmol) is added and the reaction mixture is stirred overnight at room temperature. After concentration, the residue is dissolved in EtOAc and washed with NaHCO3 followed by brine. The organic layer is separated, dried (Na2SO4), filtered and concentrated. The residue is purified by column chromatography using 30% ethyl acetate in hexane as eluent to give 3-(1,4-dioxa-spiro[4.5]dec-8-ylamino)-thiophene-2-carboxylic acid methyl ester (4.5 g, 47% yield).
Reaction SMILES: [Na].[CH2:2]([CH:10]([C:16]([O:18]CC)=O)[C:11]([O:13]CC)=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[NH2:21][C:22]([NH2:24])=[O:23]>C(O)C>[CH2:2]([CH:10]1[C:11](=[O:13])[NH:24][C:22](=[O:23])[NH:21][C:16]1=[O:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCC(C(=O)OCC)C(=O)OCC
Reactant: NC(N)=O
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCC1C(=O)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
To a solution of sodium (5.32 g) in 400 ml of anhydrous ethanol is added a solution of diethyl 2-octylmalonate (31.5 g) in 50 ml of ethanol and successively 10.27 g of urea, then the mixture is refluxed for 2 hours 30 minutes. The mixture is rapidly cooled to room temperature and the solid which was formed is recovered by filtration and washed with diethyl ether. The solid is then dissolved in 200 ml. of water and acidified with 6 N hydrochloric acid until pH 1.5-2 is reached. A solid separates. The mixture is added with 200 ml of ethyl acetate and it is stirred for 2 hours, then it is added with additional 800 ml of warm ethyl acetate. The organic phase is separated and the aqueous phase is washed with 200 ml of ethyl acetate. The pooled organic phases are washed with 250 ml of saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated to dryness. 21.03 g of the product are obtained.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].O>C(O)C>[C:1]1([C:7]2[N:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cnc(-c2ccccc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCc1cnc(-c2ccccc2)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
2-Phenylpyrimidine-5-carbaldehyde (2.0 g) was dissolved in ethanol (20 mL), sodium tetrahydroborate (411 mg) was added under ice-cooling, and the mixture was stirred at 0° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and then saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (1.75 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2SC(NCCF)=N[C:6]=2[CH:14]=1.[CH3:15][N:16](C1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1)[C:17](=[O:23])[O:18]C(C)(C)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:6]1([O:23][C:17](=[O:18])[NH:16][CH3:15])[CH:5]=[CH:4][CH:3]=[CH:2][CH:14]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: FCCNc1nc2cc(Br)ccc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CNC(=O)Oc1ccccc1
Temperature: 95 °C
Yield: 198.5 %

Procedure:
A mixture of 5-Bromo-N-(2-fluoroethyl)benzo[d]thiazol-2-amine (60 mg, 0.2 mmol), tert-butyl methyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (68 mg, 0.2 mmol), and tetrakis(triphenylphosphine)palladium (11 mg, 0.01 mmol) in 2 mL dioxane and 0.5 mL of a 1 M Na2CO3 aqueous solution was heated at 95° C. in a microwave reactor for 10 min. After cooling to rt, it was diluted with EtOAc (30 mL) and washed with brine (30 mL), dried over MgSO4 and concentrated. The crude product was purified with silica chromatography (5% to 50% EtOAc in hexane) to afford tert-butyl 44242-fluoroethylamino)benzo[d]thiazol-5-yl)phenyl(methyl)carbamate as a white solid (60 mg, 75%). MS (ESI) m/z 402 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:17]([CH2:29][CH2:30][CH3:31])=[N:18][C:19]3[C:24]([C:25]=2[C:26]([OH:28])=[O:27])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:11][CH:10]=1)#[N:2].C([Sn]([N:45]=[N+:46]=[N-:47])(CCCC)CCCC)CCC.CO>CC1C=CC=CC=1C>[CH2:29]([C:17]1[C:16]([O:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[N:45]=[N:46][NH:47][N:2]=3)=[CH:14][CH:13]=2)=[C:25]([C:26]([OH:28])=[O:27])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)[CH2:30][CH3:31]
Reactant: CCCc1nc2ccccc2c(C(=O)O)c1Oc1ccc(-c2ccccc2C#N)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Solvent: CO
Product: CCCc1nc2ccccc2c(C(=O)O)c1Oc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 253.3 %

Procedure:
A solution of the title E compound of Example 1, 3-[(2'-cyano[1,1'-biphenyl]-4-yl)oxy]-2-propyl-4-quinolinecarboxylic acid (3.9 g, 9.6 mmol) and tri-n-butyltin azide (9.6 g, 28.9 mmol) in o-xylene (3.9 mL) was heated to 108° C. for 48 hours. After cooling to room temperature, methanol (15 mL) was added and the dark brown solution was stirred for 20 minutes. The methanol was removed under vacuum, more methanol was added (15 mL), the reaction mixture was stirred briefly and concentrated again. The residue was dissolved in ethyl acetate (500 mL), washed three times with 1.0M trisodium citrate solution, brine, dried over sodium sulfate, and concentrated to yield a brown, viscous oil (10.98 g). Flash chromatography on silica gel (659 g), eluting with 70:25:5 toluene:acetone:acetic acid yielded the title compound as a light yellow solid 2.14 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:19][CH:20]=O)([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.F[B-](F)(F)F.C([N+]1C2C=CC=CC=2OC=1Cl)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N+:19]#[C-:20])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: CCCCC(Cn1cncn1)(NC=O)c1ccc(Cl)cc1
Agent: CC[n+]1c(Cl)oc2ccccc21
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [C-]#[N+]C(CCCC)(Cn1cncn1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 0.40 g (1.3 mmols) of N-[2-(4-chlorophenyl)-1-(1,2,4-triazol-1-yl)-2-hexyl]formamide in 5 mL of methylene chloride under nitrogen was added 0.45 mL (3.26 mmols) of triethylamine. To this mixture was added a slurry of 0.439 g (1.63 mmols) of 3-ethyl-2-chlorobenzoxazolium tetrafluoroborate, which was weighed out under a nitrogen atmosphere, in 5 mL of methylene chloride. The reaction mixture was then allowed to stir at room temperature for 12 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed once with 10% hydrochloric acid, brine, and dried over magnesium sulfate. Removal of solvents gave a crude oil which was purified by column chromatography (Merck 60 silica gel, ethyl acetate/hexane) to give 0.20 g (52%) of a clear, colorless oil.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[C:21]12[CH2:28][NH:27][CH2:26][C:25]=1[CH2:24][NH:23][CH2:22]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:23]4[CH2:24][C:25]5[CH2:26][NH:27][CH2:28][C:21]=5[CH2:22]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C1NCC2=C1CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4=C(CNC4)C3)c(F)cc2c1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
0.28 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.16 g of 3,7-diazabicyclo-[3.3.0]oct-1(5)-ene and 0.3 ml of 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU) were suspended in 20 ml of acetonitrile and refluxed in 100° C. oil bath for 5 hours. The reaction mixture was kept overnight at room temperature. The produced precipitate was filtered and was washed with ethanol-ethylether (1:1) solvent. 0.3 g of the title compound was obtained (yield 80%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]#[C:10][CH3:11].[OH:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1>CC(=O)CC>[CH2:8]([O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=1)[C:9]#[C:10][CH3:11]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC#CCOc1ccc(C(=O)OC)cc1
Reaction time: 18 h
Yield: 99.9 %

Procedure:
13.6 g (98.5 mmol) of potassium carbonate then 9.6 g (65.7 mmol) of 1-bromobut-2-yne are added to a solution containing 10 g (65.7 mmol) of methyl 4-hydroxybenzoate diluted in 250 ml of 2-butanone. The reaction medium is stirred at reflux for 5 h then at ambient temperature for 18 h. After filtration of the salts, the filtrate is concentrated under vacuum. 13.4 g (100%) of methyl 4-but-2-ynyloxybenzoate are obtained in the form of a light-yellow solid.