Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C[O-].[Na+].Br[CH2:14][C:15]([OH:17])=[O:16].Cl>CO.C(OCC)(=O)C>[C:15]([CH2:14][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1)([OH:17])=[O:16]
Reactant: c1ccc2[nH]ncc2c1
Reactant: O=C(O)CBr
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)Cn1ncc2ccccc21
Temperature: 0 °C
Yield: 32.7 %

Procedure:
To a solution of indazole (1.0 g, 8.3 mM) in methanol (10 μl) are added 28% solution of sodium methoxide in methanol (3.53 ml, 18.26 mmole) and bromoacetic acid (1.41 g, 9.96 mmole), and the mixture is heated to reflux for 2 hr. After addition of the same amount of sodium methoxide and bromoacetic acid, the mixture is heated to reflux for another 1 hr. This procedures of-addition are repeated two more times and the mixture is cooled to 0° C. After addition of ethyl acetate, the mixture is adjusted to pH 5 with 1N HCl. The organic layer is taken and the aqueous layer extracted with ethyl acetate. Each organic solution is washed with a brine, dried over anhydrous magnesium sulfate and concentrated. The residue, when purified with column chromatography (SiO2, ethyl acetate→ethyl acetate/acetic acid/water, (40:1:1)→(30:1:1)→(8:1:1)), gives 1-carboxymethylindazole (487 mg, yield 33%). 1H NMR (DMSO) δppm: 5.27 (s, 2H), 7.16(dd, J=7.0 Hz, J=8.0 Hz, 1H), 7.39(dd, J=7.0 Hz, J=8.0 Hz, 1H), 7.64(d, J=8.0 Hz, 1H), 7.77(d, J=8.0 Hz, 1H), 8.09(s, 1H).
Reaction SMILES: [H-].[Na+].[Cl-].[CH3:4][S+](C)(C)=O.[CH2:9]([O:11][C:12](=[O:25])[CH:13]=[CH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[CH3:10]>CS(C)=O>[CH2:9]([O:11][C:12]([C@@H:13]1[CH2:4][C@H:14]1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)=[O:25])[CH3:10]
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)C=Cc1ccc2ncccc2c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
To a suspension of sodium hydride (71 mg, 1.76 mmol) in DMSO (3 mL) under nitrogen atmosphere was added trimethylsulfoxonium chloride (261 mg, 2.03 mmol). After stirring at room temperature for 30 minutes, a solution of 3-quinolin-6-yl-acrylic acid ethyl ester (200 mg, 0.881 mmol) in DMSO (2 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2.5 h and quenched with a saturated aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate (2×) and the combined organic layers were washed with brine (3×) and adsorbed on silica gel. Purification on silica gel with 0-80% gradient of ethyl acetate in hexane provided 126 mg of product as a white solid. NMR 500 MHz (DMSO) δ 1.22 (t, 3H), 1.55 (m, 2H), 2.10 (m, 1H), 2.64 (m, 1H), 4.13 (q, 2H), 7.50 (dd, 1H), 7.58 (dd, 1H), 7.80 (d, 1H), 7.93 (d, 1H), 8.26 (dd, 1H), 8.84 (dd, 1H); MS (m/z) 242 [M+H+]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24]O)=[O:18])([CH3:15])([CH3:14])[CH3:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[Cl:1])=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-chloro-5-nitrophenol (5.06 g, 29.17 mmol), (S)-(−)-1-(tert-butoxycarbonyl)-2-pyrrolidinemethanol (5.87 g, 29.17 mmol), and Ph3P (7.65 g, 29.17 mmol) in 50 mL THF, cooled to −15° C., was added dropwise, over 75 min, a solution of DIAD (6.02 g, 29.75 mmol). The reaction was warmed to RT and stirred for 18 h. The reaction was concentrated to dryness. The crude residue was treated with a small mix of Et2O and hexanes and sonicated so as to triturate out bulk of impurities, which were filtered off. The filtrate was concentrated to dryness. The resulting residue was purified by silica gel column chromatography using 7% EtOAc in hexanes to elute the title compound as a thick yellow oil.
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]([CH2:17][CH2:18][CH:19]2[S:23][CH2:22][CH2:21][S:20]2)[CH2:8][C:7]1=[O:24])(=O)[CH2:2][CH2:3][CH3:4].[Cl-].[CH2:26]([O:29][NH3+:30])[CH:27]=[CH2:28]>C(O)C.C([O-])(=O)C.[Na+]>[CH2:26]([O:29][NH:30][C:1](=[C:6]1[C:11](=[O:12])[CH:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]([CH2:17][CH2:18][CH:19]2[S:23][CH2:22][CH2:21][S:20]2)[CH2:8][C:7]1=[O:24])[CH2:2][CH2:3][CH3:4])[CH:27]=[CH2:28]
Reactant: CCCC(=O)C1C(=O)CC(CCC2SCCS2)C(C(=O)OC)C1=O
Reactant: C=CCO[NH3+]
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: C=CCONC(CCC)=C1C(=O)CC(CCC2SCCS2)C(C(=O)OC)C1=O
Temperature: 20 °C
Reaction time: 20 h

Procedure:
12.0 parts by weight of 2-butyryl-4-methoxycarbonyl-5-[2-(1,3-dithiolan-2-yl)-ethyl]-cyclohexane-1,3-dione were dissolved in 150 parts by volume of ethanol, and 3.29 parts by weight of allyloxyammonium chloride and 3.28 parts by weight of anhydrous sodium acetate were added. The mixture was stirred at 20° C. for 20 hours, poured onto ice-water and extracted with methylene chloride. The organic phase was concentrated to give 13.1 parts by weight of 2-(1-allyloxyaminobutylidene)-4-methoxycarbonyl-5-[2-(1,3-dithiolan-2-yl)-ethyl]-cyclohexane-1,3-dione (compound No. 3) as a viscous oil having the following structure: ##STR9## C20H29O5NS2, molecular weight=427. Calculated: C 56.2, H 6.8, N 2.3, S 15.0. Found: C 57.0, H 6.7, N 2.8, S 14.7.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Br[C:11]1[N:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH:18][C:19]2[S:20][C:21]([C:24]([NH:26][C:27]3[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:34])=[O:25])=[CH:22][N:23]=2)[CH:12]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[CH3:33][C:32]1[C:27]([NH:26][C:24]([C:21]2[S:20][C:19]([NH:18][C:13]3[CH:12]=[C:11]([N:7]4[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]4)[N:16]=[C:15]([CH3:17])[N:14]=3)=[N:23][CH:22]=2)=[O:25])=[C:28]([Cl:34])[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1nc(Br)cc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)n1
Reactant: OCCN1CCNCC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)cc(N2CCN(CCO)CC2)n1

Procedure:
1-(2-hydroxyethyl)piperazine (Compound 3) (65 g, 0.5 mol), 2-(6-bromo-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-formamide (Compound 14) (43.9 g, 0.1 mol), isopropanol (650 mL) and DIPEA (28.3 g, 0.2 mol) were mixed in reaction flask and reacted by refluxing for 5 h. It was condensed by vacuum to dry to give crude Dasatinib (Compound 1) (purity: 95.4%).
Reaction SMILES: [C:1]1([CH:13]2[CH2:18][CH2:17][N:16](C(OCC3C=CC=CC=3)=O)[CH2:15][CH2:14]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2>CO.[C].[Pd]>[NH:16]1[CH2:15][CH2:14][CH:13]([C:1]2[N:2]=[N:3][N:4]3[C:9]=2[C:8]2[CH:10]=[CH:11][NH:12][C:7]=2[N:6]=[CH:5]3)[CH2:18][CH2:17]1
Reactant: O=C(OCc1ccccc1)N1CCC(c2nnn3cnc4[nH]ccc4c23)CC1
Agent: [Pd]
Solvent: CO
Product: c1cc2c(ncn3nnc(C4CCNCC4)c23)[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 25.8 %

Procedure:
5% Palladium-carbon (10.0 mg) was added to benzyl 4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)piperidine-1-carboxylate (30.0 mg, 0.0800 mmol) in methanol (2 mL) under an argon atmosphere, and after the reaction system was flushed with hydrogen, the reaction mixture was stirred at room temperature for 6 hours and then filtered. The filtrate was concentrated under reduced pressure. The resulting yellow solid was washed with methanol and collected by filtration to give the title compound as a pale yellow solid (5.0 mg, yield 26%).
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([O:27][CH2:28][CH:29]([OH:32])[CH:30]=[CH2:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>CN(C)C=O>[CH2:11]([O:27][CH2:28][CH:29]([O:32][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:30]=[CH2:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: BrCc1ccccc1
Reactant: C=CC(O)COCCCCCCCCCCCCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CC(COCCCCCCCCCCCCCCCC)OCc1ccccc1
Yield: 49 %

Procedure:
To stirred suspension of 3.35 g of 50% sodium hydride and 10.92 g of benzyl bromide in 75 ml of dimethylformamide was added a solution of 19 g of 1-(hexadecyloxy)-3-buten-2-ol in 75 ml of dimethylformamide. The mixture was stirred overnight, then water was added and the mixture was extracted with ether. The ether extract was dried over magnesium sulfate and activated charcoal and the solvent removed giving an oil. This oil was purified by HPLC [hexane: chloroform (8:1)] and the solvent removed giving 12 g of the desired compound as an oil.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([N:16]2[C:20]([NH2:21])=[CH:19][C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])=[N:17]2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.[F:29][C:30]1[C:35]([F:36])=[C:34]([F:37])[CH:33]=[CH:32][C:31]=1[N:38]=[C:39]=[O:40]>>[F:29][C:30]1[C:35]([F:36])=[C:34]([F:37])[CH:33]=[CH:32][C:31]=1[NH:38][C:39]([NH:21][C:20]1[N:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][OH:8])[CH:11]=2)[N:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[CH:19]=1)=[O:40]
Reactant: O=C=Nc1ccc(F)c(F)c1F
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(-n2nc(-c3ccccc3F)cc2N)c1
Product: O=C(Nc1ccc(F)c(F)c1F)Nc1cc(-c2ccccc2F)nn1-c1cccc(CO)c1
Yield: 72.3 %

Procedure:
Using general method A, 1-(3-((t-butyldimethylsilyloxy)methyl)phenyl)-3-(2-fluorophenyl)-1H-pyrazol-5-amine (available from ethyl 3-(5-amino-3-(2-fluorophenyl)-1H-pyrazol-1-yl)benzoate using general method followed by protection with TBSCl) (0.4 g, 1.0 mmol) was combined with 2,3,4-trifluorophenyl isocyanate (0.32 g, 1.2 mmol) to yield 1-(2,3,4-trifluorophenyl)-3-(3-(2-fluorophenyl)-1-(3-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)urea (330 mg, 72% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.14 (brs, 1H), 9.01 (s, 1H), 7.98 (dt, J=1.6, and 8.0 Hz, 1H), 7.86 (m, 1H), 7.2-7.6 (m, 8H), 6.96 (d, J=4.0 Hz, 1H), 5.39 (t, J=6.0 Hz, 1H), 4.62 (d, J=6.0 Hz, 2H); MS (EI) m/z: 457.0 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11](O)=[O:12])#[N:2].C(Cl)(=O)C(Cl)=O.[BH4-].[Na+]>C(Cl)Cl>[OH:12][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1ccccc1CCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccccc1CCCO
Temperature: 20 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
A solution of 3-(2-cyanophenyl)propanoic acid (Example 323b, 4.36 g) in DCM (40 mL) was treated with oxalyl chloride (3.26 mL) under nitrogen. The resulting solution was stirred at 20° C. for 1 h. The reaction mixture was evaporated to dryness, azeotroped with toluene. The solid was dissolved in THF (30 mL) and sodium borohydride (1.883 g) was added. The mixture was stirred at 20° C. for 16 h. Further Sodium borohydride (1.883 g) added and stirred for 4 h. The reaction required a further 3 days and a further sodium borohydride (18.83 g). The reaction mixture was evaporated, diluted with water (200 mL), and extracted with ethyl acetate (200 mL). The organic was dried (MgSO4), filtered and evaporated to give the subtitle compound as an oil (3.83 g).
Reaction SMILES: [CH:1]1(/[C:6](/[N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)=[CH:7]/[C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(Cl)Cl>[CH:1]1([C@@H:6]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(/C(=C\C#N)C4CCCC4)c3)ncnc21
Reactant: [H][H]
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@@H](CC#N)C4CCCC4)c3)ncnc21
Temperature: 75 °C
Reaction time: 19 h

Procedure:
A solution of (Z)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acrylonitrile (19, 116 mg) in methylene chloride (CH2Cl2, 4.0 mL) in a pressure glass tube was treated with the catalyst [Ru(p-cymene)(S—C3-TunePhos)Cl]Cl (8.5 mg) under nitrogen before the reaction mixture was pressurized with hydrogen gas to 60 bar pressure. The reaction mixture was stirred at 75° C. under this hydrogen pressure for 19 h. When HPLC analysis showed that the substrate was completely consumed, the reaction mixture was cooled down to room temperature. The enantiomeric excess of the reaction mixture was determined to be 34.1% ee (67.05% of the first peak, (S)-20; 32.95% of the second peak, (R)-20) by chiral HPLC analysis. The reaction mixture was then filtered through a thin silica gel pad and the pad was washed with methylene chloride (CH2Cl2, 5 mL). The filtrate was then concentrated under reduced pressure to dryness. The resultant foamy solid (107 mg) was analyzed by chiral HPLC analysis and result showed a 34.1% of enantiomeric excess favoring the first peak (67.05% of the first peak, (S)-20; 32.95% of the second peak, (R)-20).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:17][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:14][CH:13]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: NCc1ccc(Cl)cc1
Product: O=C(O)c1cccnc1NCc1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
A mixture of 2-chloronicotinic acid (30.0 g) and 4-chlorobenzylamine (45 ml) was heated at 120° C. for 3.5 hours. The mixture was cooled to ambient temperature and the solid obtained was washed with water and collected by filtration. The solid was boiled in methanol and filtered to give 2-(4-chlorobenzylamino)-nicotinic acid, m.p. 240°-242° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:19][C:18]3[C:13](=[C:14]([N+:20]([O-])=O)[CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:23])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CCOC(C)=O>[NH2:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[C:12](=[O:23])[N:11]([C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=1)[CH2:19]2
Reactant: CC(C)(C)c1ccc(N2Cc3cccc([N+](=O)[O-])c3C2=O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(N2Cc3cccc(N)c3C2=O)cc1
Reaction time: 2.5 h

Procedure:
A solution of 2-(4-tert-butyl-phenyl)-7-nitro-2,3-dihydro-isoindol-1-one (110 mg, 0.35 mmol) and EtOAc (50 mL) was hydrogenated over 10% Pd/C (80 mg) at 1 atm and RT. After 2.5 h, the mixture was filtered through Celite® and concentrated in vacuo to afford the desired amine as a yellow solid.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:24].[NH2:25][C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1>C1COCC1>[OH:32][C:28]1[CH:27]=[C:26]([NH:25][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:24])[CH:31]=[CH:30][CH:29]=1
Reactant: Nc1cccc(O)c1
Reactant: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)cc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2cccc(O)c2)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
A small screw cap test tube was charged with N-[4-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-acetamide (as prepared in Example 29, 70 mg, 0.217 mmol) and THF (2 mL). To the resulting solution was added 3-aminophenol (28 mg, 0.257 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 mL of i-prOH affording the title compound in 76% yield (0.068 g, 0.1645 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1.OS(O)(=O)=O.C1C(=O)N([Br:23])C(=O)C1>O>[Br:23][C:5]1[C:6]([O:8][CH2:9][CH3:10])=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: CCOc1ccnc(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOc1cc(Cl)ncc1Br
Temperature: 60 °C
Reaction time: 10 h
Yield: 32.1 %

Procedure:
To a mixture of 2-chloro-4-ethoxypyridine (13 g, 82 mmol) and H2SO4 (40 mL, 750 mmol) was added NBS (17.62 g, 99 mmol). Then the mixture was stirred at 60° C. for 10 h. After cooling to rt, the mixture was poured into cold water (300 mL). The mixture was extracted with EA (200 mL×2). The combined organic layer was washed with saturated NaHCO3 solution (200 mL×2) and concentrated. The crude material was purified by silica column chromatography (PE/EA=15:1). All fractions found to contain product by TLC (PE/EA=5:1, Rf=0.6) were combined and concentrated to yield a yellow solid of 5-bromo-2-chloro-4-ethoxypyridine (8.5 g, 26.3 mmol, 32% yield): 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 6.79 (s, 1H), 4.16 (q, J=6.8 Hz, 2H), 1.50 (t, J=6.8 Hz, 3H); ES-LCMS m/z 238 (M+3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH:7]=[C:8]([C:10]([OH:12])=[O:11])[O:9][C:5]=2[C:4]=1[CH3:15]>[OH-].[Na+].[Na].[Hg]>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH:8]([C:10]([OH:12])=[O:11])[O:9][C:5]=2[C:4]=1[CH3:15]
Reactant: COc1ccc2cc(C(=O)O)oc2c1C
Agent: [Hg]
Agent: [Na+]
Agent: [Na]
Product: COc1ccc2c(c1C)OC(C(=O)O)C2
Reaction time: 5 h

Procedure:
To a solution of (16i) (29 g., 0.14 mole) dissolved in aqueous sodium hydroxide (15 g. NaOH is 750 ml. of water) was added 550 g. of 5% sodium amalgam portionwise over a period of 30 minutes. The mixture was stirred for 5 hours and then decanted from the mercury and filtered through Celite. The filtrate was acidified with hydrochloric acid and cooled in an ice bath. There was obtained 26 g. of crude acid after filtering. Recrystallization from methylene chloride/hexane gave pure 2,3-dihydro-6-methoxy-7-methylbenzofuran-2-carboxylic acid, m.p. 142°-143° C. Esterification of this material by the procedure described in Example 35 gave (5i) as an oil. Analysis (C13H16O4) C,H.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[N:18]1[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]1.S(Cl)([Cl:29])=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[N:18]1[CH2:23][CH2:22][CH:21]([C:24]([Cl:29])=[O:26])[CH2:20][CH2:19]1
Reactant: O=C(O)C1CCN(c2cc(-c3ccccc3)nc3ccc(F)cc23)CC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)C1CCN(c2cc(-c3ccccc3)nc3ccc(F)cc23)CC1

Procedure:
A mixture of 4 g of 1-[6-fluoro-2-phenyl-4-quinolinyl]-4-piperidinecarboxylic acid, 12 ml of thionyl chloride, and 100 ml of methylene chloride were stirred and heated under reflux for 1 hr. The reaction mixture was cooled and concentrated in vacuo to leave 4.2 g of product as a yellow solid, mp 243°-5°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[N:11][N:12]([CH:14]2[CH2:18][NH:17][CH:16]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[C:29]#[N:30])[CH2:23][CH2:22]3)=[O:20])[CH2:15]2)[N:13]=1.[F:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][C:43]=1[F:44])[CH:39]=O>>[F:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][C:43]=1[F:44])[CH2:39][N:17]1[CH2:18][C@@H:14]([N:12]2[N:11]=[N:10][C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[N:13]2)[CH2:15][C@H:16]1[C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=2[C:29]#[N:30])[CH2:25][CH2:26]1)=[O:20]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(n3nnc(-c4ccc(F)cc4F)n3)CN2)CC1
Product: N#Cc1ccccc1N1CCN(C(=O)[C@@H]2C[C@H](n3nnc(-c4ccc(F)cc4F)n3)CN2Cc2ccc(F)c(F)c2)CC1
Yield: 13.5 %

Procedure:
As described for Example 1e, 2-(4-{4-[5-(2,4-difluoro-phenyl)-tetrazol-2-yl]-pyrrolidine-2-carbonyl}-piperazin-1-yl)-benzonitrile (60 mg, 0.13 mmol) was converted, using 3,4-difluoro-benzaldehyde (20 mg, 0.14 mmol) instead of benzaldehyde, to the title compound (10.4 mg, 13.5%) as light yellow oil. MS m/e=591.2 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[CH3:10][C:11](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:12]>>[C:11]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)(=[O:12])[CH3:10]
Reactant: O=C(O)C1CCNCC1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Product: CC(=O)N1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of 100 g of isonipecotic acid and 40 ml of acetic anyhydride is refluxed for 2 hours and then allowed to stir at room temperature overnight. The reaction mixture is then evaporated under reduced pressure and the residue triturated with diethyl ether. The resulting solids are recrystallized from a mixture of isopropanol and diethyl ether to afford the N-acetyl isonipecotic acid, melting at 175°.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[N:12]=[CH:13][NH:14][C:15]=1[CH3:16])=S)#[N:2].Cl.P(Cl)(Cl)(Cl)(Cl)Cl.[C:24](N=C(Cl)NCCSCC1N=CNC=1C)#[N:25]>C(Cl)Cl>[C:1]([N:3]=[C:4]([NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[N:12]=[CH:13][NH:14][C:15]=1[CH3:16])[NH:25][CH3:24])#[N:2]
Reactant: Cc1[nH]cnc1CSCCNC(=S)NC#N
Reactant: Cc1[nH]cnc1CSCCNC(Cl)=NC#N
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CNC(=NC#N)NCCSCc1nc[nH]c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 1.5 %

Procedure:
To a suspension of N-cyano-N'-[2-(5-methylimidazol-4-ylmethylthio)ethyl]thiourea (monohydrate, 765 mg) in CH2Cl2 (7 ml) was introduced dry HCl gas for a few minutes under ice-cooling. PCl5 (1.25 g) was added to the mixture and stirred at room temperature for 3 hrs. The reaction mixture containing N'-cyano-N-[2-(5-methylimidazol-4-ylmethylthio)ethyl]chloroformamidine was concentrated to small volume, diluted with CH2Cl2 (5 ml) and cooled to -5° C. To the mixture was added a solution of CH3NH2 in C2H5OH (40%, 15 ml) below 30° C. After stirring for 20 hrs. at room temperature, the reaction mixture was filtered and the filtrate was concentrated to small volume, diluted with CH3CN and filtered agein. The filtrate was dried up and the residue was purified with column chromatography [SiO2, CH3CN-CH3OH (4:1)], preparative thin layer chromatography [SiO 2, CH3COOC2H5 --CH3OH-- 28% NH3 (aq) (10:1:1)] and then recrystallization from CH3CN to give N"-cyano-N-methyl-N'-[2-(5-methylimidazol-4-ylmethylthio)ethyl]guanidine (10.4 mg). Yield 1.5%, m.p. 136.5°-138° C.