Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=[O:15])[C:8](=[N:13]O)[C:9](=[O:12])[CH2:10][CH3:11])=[CH:3][CH:2]=1.CS(O)(=O)=O>C(O)=O.CO.[Zn]>[CH:9]([OH:12])([CH3:10])[CH3:8].[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:15])[CH:8]([NH2:13])[C:9](=[O:12])[CH2:10][CH3:11])=[CH:3][CH:2]=1
Reactant: CCC(=O)C(=NO)C(=O)c1ccncc1
Agent: CS(=O)(=O)O
Agent: [Zn]
Solvent: CO
Solvent: O=CO
Product: CC(C)O
Product: CCC(=O)C(N)C(O)c1ccncc1
Temperature: 55 °C
Reaction time: 2 h
Yield: 1006.6 %

Procedure:
In 37.8 kg of 88% formic acid was dissolved 7.5 kg (91% pure, 36.37 mole) of 1-(4-pyridyl)-1,3-diketo-2-oximinopentane and 7.0 kg of methanesulfonic acid. The resulting solution was slowly added to a slurry of 8.3 kg of zinc powder in 35.7 kg of formic acid. The reaction temperature was kept at about 60° C. by proper cooling and slow addition. The mixture was allowed to stir at 55° C. for 2 hours and then cooled to 20° C. The solid zinc formate was filtered off. To the formic acid filtrate was added 3.6 kg of methanesulfonic acid. The formic acid was removed at the reduced pressure (40 mm Hg) and 70° C. To the residue was added a solution of 5.9 kg of methanol and 53.3 kg of isopropanol and stirred at 20° C. for 4 hours. Solid material was collected by centrifugation, washed with 12.5 kg of 10% methanol in isopropanol giving 11.0 kg, 87% yield, of the title compound as dimethanesulfonate salt after drying.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][N:20]=2)[C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])=[CH:5][CH:4]=1.N1[CH:25]=[CH:24]N=C1.C[C:27]([Si:30](Cl)([CH3:32])[CH3:31])([CH3:29])C>ClCCl>[CH3:17][O:16][N:14]([CH3:15])[C:12](=[O:13])[C:11]1[CH:18]=[CH:19][N:20]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][O:1][Si:30]([CH2:27][CH2:29][CH2:24][CH3:25])([CH2:32][CH2:5][CH2:6][CH3:7])[CH2:31][CH2:2][CH2:3][CH3:4])=[CH:4][CH:5]=2)[CH:10]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: c1c[nH]cn1
Reactant: CON(C)C(=O)c1ccnc(-c2ccc(CO)cc2)c1
Solvent: ClCCl
Product: CCCC[Si](CCCC)(CCCC)OCc1ccc(-c2cc(C(=O)N(C)OC)ccn2)cc1
Reaction time: 5 h
Yield: 147.6 %

Procedure:
To a solution of 2-(4-hydroxymethyl-phenyl)-N-methoxy-N-methyl-isonicotinamide (206 mg, 0.76 mmol) in dichloromethane (1.5 mL) was added imidazole (57 mg, 0.83 mmol) and TBSCl (126 mg, 0.83 mmol). After stirring for 5 hours, the mixture was partitioned between dichloromethane and water. The organic layer was dried (MgSO4), evaporated and the residue purified by SiO2 chromatography (eluting with 30-60% EtOAc/hexanes) to give the title compound (264 mg).
Reaction SMILES: C[O:2][C:3](=[O:17])[C@:4]1([CH3:16])[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[OH-].[Na+]>C1COCC1.O>[C:12]([O:11][C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@@:4]1([CH3:16])[C:3]([OH:17])=[O:2])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)[C@]1(C)CCCN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@]1(C)C(=O)O
Reaction time: 24 h
Yield: 56.9 %

Procedure:
To a stirred solution of N-tert-butoxycarbonyl-2-methylproline methyl ester (3.20 g, 0.0131 mol) in THF (20mL) was added 1N NaOH (15.7 mL) at room temp. After the resulting mixture was stirred for 24 hr, the mixture was diluted with water and washed with EtOAc. The separated aqueous layer was acidified by the addition of 1N HCl, and extracted with EtOAc. The extract was dried over Na2SO4 and evaporated in vacuo to afford 1.71 g(57%) N-tert-butoxycarbonyl-2-methylproline as a yellow syrup. 1H-NMR (CDCl3) δ1.42 (s, 9H), 1.48 (s, 3H), 1.88-2.31 (m, 4H), 3.34-3.57 (m, 2H), 9.35 (br s, 1H)
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH3:14][O:13][CH:3]([O:2][CH3:1])[CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:8][CH:7]=1
Reactant: CCCCCCCCBr
Reactant: COC(CSc1ccc(O)cc1)OC
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCCOc1ccc(SCC(OC)OC)cc1
Yield: 87 %

Procedure:
This phenol is alkylated again by the same method, but using sodium hydride and 1-bromooctane, to provide 1-((2,2-dimethoxyethyl)thio)-4-(octyloxy)benzene as a colorless oil after chromatography (87% yield). By the method of example 2, this is converted into the title compound, obtained as a pale yellow solid, mp 70°-72° after recrystallization from hexane-dichloromethane.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1)=[C:2]=[S:3].Cl.[CH3:13][C:14]1[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=1[O:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:11][O:10][C:7]1[N:8]=[CH:9][C:4]([NH:1][C:2]([N:20]2[CH2:21][CH2:22][CH:17]([O:16][C:15]3[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=3[CH3:13])[CH2:18][CH2:19]2)=[S:3])=[CH:5][CH:6]=1
Reactant: Cc1ccccc1OC1CCNCC1
Reactant: COc1ccc(N=C=S)cn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=S)N2CCC(Oc3ccccc3C)CC2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
5-Isothiocyanato-2-methoxypyridine [(829 mg, 4.99 mmol), J. Org. Chem. (1980), 45, 4219] was added to a solution of 4-(2-methylphenoxy)-piperidine hydrochloride [(990 mg, 4.3 mmol), J. Med. Chem. (1978), 21, 309] and N,N-diisopropylethylamine (0.79 mL, 4.7 mmol) in dichloromethane (10 mL) and the mixture was stirred for 3 hours at room temperature. The organic solution was then diluted with dichloromethane and washed with sodium hydrogen carbonate solution and brine. The organic solution was dried over magnesium sulfate and concentrated in vacuo. Trituration of the residue with diethyl ether afforded the title compound as a solid in 85% yield, 1.3 g. LRMS APCI m/z 358 [M+H]+
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[NH:14][C:13](=[O:19])[CH2:12][CH2:11]2.CI.O>CN(C=O)C>[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]([CH3:1])[C:13](=[O:19])[CH2:12][CH2:11]2
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCc2cc(Br)c(Cl)cc2N1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CN1C(=O)CCc2cc(Br)c(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
Potassium tert-butoxide (0.45 g, 4.0 mmol) was added at 0° C. to a solution of 6-bromo-7-chloro-3,4-dihydro-1H-quinolin-2-one (0.52 g, 2.0 mmol) in DMF (5 mL). Then, the reaction mixture was stirred at 0° C. for 30 min and methyl iodide (0.18 g, 1.29 mmol) was added. The resulting mixture was then stirred for 2 h before water was added. After extraction of the reaction mixture with EtOAc, the organic layer was washed with water and brine in sequence. Then, the organic layer was dried over anhy. Na2SO4 and the solvent was removed under reduced pressure to give a crude product (0.49 g, 90% yield) as a white solid. MS: 274.0 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[C:11]3[CH2:26][CH2:25][CH2:24][C:12]=3[N:13]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH:17]3[C:21]([OH:23])=[O:22])[N:15]=2)[CH:5]=1)([CH3:3])[CH3:2].[CH:27]1C=CC2N(O)N=NC=2C=1.O.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>CO>[CH:1]([C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[C:11]3[CH2:26][CH2:25][CH2:24][C:12]=3[N:13]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH:17]3[C:21]([O:23][CH3:27])=[O:22])[N:15]=2)[CH:5]=1)([CH3:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(C)c1cc(Nc2nc(N3CCCC3C(=O)O)nc3c2CCC3)n[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: CO
Product: COC(=O)C1CCCN1c1nc2c(c(Nc3cc(C(C)C)[nH]n3)n1)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylic acid (5 g, 14 mmol) in MeOH (120 mL) was added HOBt.H2O (143 mg, 0.94 mmol), N-methylmorpholine (1.42 g, 14 mmol) and EDC.HCl (3.64 g, 19 mmol). The reaction mixture was stirred at RT overnight. The MeOH was removed under reduced pressure and the residue was dissolved in EtOAc (100 mL). The solution was washed with water (2×40 mL) followed by brine (40 mL) and dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure afforded methyl 1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate, Compound (iv) (5 g, 96% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 1.30 (d, 6H), 1.98-2.20 (m, 4H), 2.06-2.37 (m, 1H), 2.60-2.66 (m, 2H), 2.67-2.2.88 (m, 2H), 2.90-3.07 (m, 1H), 3.65-3.79 (m, 1H), 3.70 (s, 3H), 3.80-3.91 (m, 2H), 4.61-4.70 (m, 1H), 6.18 (s, 1H), 6.59 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.CN(C)P(N(C)C)(N(C)C)=O.[C:24]1([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]Cl)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[I-].[Na+]>C(O)C.O>[C:24]1([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: ClCCCCCCCCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(NCCCCCCCCc2ccccc2)cc1
Temperature: 110 °C

Procedure:
A mixture of 14.9 g. of ethyl p-aminobenzoate, 50 ml. of hexamethylphosphoramide, 10.1 g. of 8-phenyloctyl chloride and 6.75 g. of sodium iodide is stirred and heated in an oil bath at 110° C. for 24 hours. The mixture is chilled, diluted with 50 ml. of water and 25 ml. of ethanol, chilled and filtered. The solid is washed with ethanol-water (1:1) and with water to give crystals, m.p. 61°-68° C. Recrystallization from ethanol gives white crystals, m.p. 75°-76° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1C#N.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[CH:19]1[O:23][CH2:22][CH2:21][O:20]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.O.C[N:38]([CH3:41])C=O>>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:3]2[CH:6]=[CH:7][C:8]([C:41]#[N:38])=[CH:9][C:2]=2[Cl:1])=[CH:14][C:13]=1[CH:19]1[O:20][CH2:21][CH2:22][O:23]1
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: CN(C)C=O
Reactant: Oc1ccc(Br)c(C2OCCO2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(Oc2ccc(Br)c(C3OCCO3)c2)c(Cl)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-4-fluorobenzonitrile (4.43 g, 28.4 mmol), 4-bromo-3-(1,3-dioxolan-2-yl)phenol (6.96 g, 28.4 mmol), and potassium carbonate (4.70 g, 34.1 mmol) in N,N-dimethylformamide (60 mL) was stirred at 100° C. under nitrogen atmosphere overnight. The mixture was poured into ethyl acetate/water. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to give crude 4-(4-bromo-3-(1,3-dioxolan-2-yl)phenoxy)-3-chlorobenzonitrile (10.8 g), which was used for the next step without purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10]C(=O)C)[CH:7]=[CH:6][C:5]=1[O:14]C)([O-:3])=[O:2]>Br>[N+:1]([C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:14])([O-:3])=[O:2]
Reactant: COc1ccc(OC(C)=O)cc1[N+](=O)[O-]
Agent: Br
Product: O=[N+]([O-])c1cc(O)ccc1O

Procedure:
The 2-nitro-4-acetyloxyanisole (160 g, 0.757 mole) in 47% aqueous hydrobromic acid (1,200 ml) was refluxed for 1 hour. The resulting solution was evaporated under vacuum to 200 ml. The 2-nitrohydroquinone (115 g, 78%) separated on cooling as orange prisms.
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]([C:21]#[N:22])=[C:7]([N:9]2[CH2:14][CH:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[N:8]=1.[CH2:23]([CH2:25][NH2:26])[OH:24]>O1CCOCC1>[OH:24][CH2:23][CH2:25][NH:26][C:3]1[N:4]=[N:5][C:6]([C:21]#[N:22])=[C:7]([N:9]2[CH2:14][CH:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[N:8]=1
Reactant: NCCO
Reactant: CSc1nnc(C#N)c(N2CC=C(c3ccccc3)CC2)n1
Solvent: C1COCCO1
Product: N#Cc1nnc(NCCO)nc1N1CC=C(c2ccccc2)CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
A mixture of 68 mg (0.21 mmol) of 3-methylsulfanyl-5-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-[1,2,4]triazine-6-carbonitrile and 14.5 mg (0.23 mmol) ethanolamine in 1 ml of dioxane was stirred at 120° C. overnight. For the working-up, the solution was evaporated under reduced pressure and the residue was chromatographed on silica gel with a 90:10:0.1 mixture of dichloromethane, methanol, and ammonium hydroxide as the eluent. There were obtained 35 mg (0.10 mmol, 50% of theory) of 3-(2-hydroxy-ethylamino)-5-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-[1,2,4]triazine-6-carbonitrile as an amorphous, white solid; MS: 323 (M+H)+;
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[C:10]1(C)C=CC=C[CH:11]=1.Cl[C:18]1[O:19][C:20]([C:27]([O-:29])=[O:28])=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=1>>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:18]1[O:19][C:20]([C:27]([O:29][CH2:10][CH3:11])=[O:28])=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=1
Reactant: Cc1ccccc1
Reactant: Cc1cccc(C)c1N
Reactant: O=C([O-])c1oc(Cl)nc1C(F)(F)F
Product: CCOC(=O)c1oc(Nc2c(C)cccc2C)nc1C(F)(F)F

Procedure:
By the procedure of Example 15, 4.84 g (0.04 mol) of 2,6-dimethyl aniline was added to a stirred solution of 75 ml toluene containing 4.87 g (0.02 mol) of 2-chloro-4-trifluoromethyl-5-oxazolecarboxylate. The reaction mixture was stirred at reflux for 24 hours. The product was separated, distilled and then recrystallized from petroleum ether to yield 1.99 g of crystal product (m.p.=79°-81° C.) identified in Table I.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([Cl:11])[CH:7]=[C:4]([CH:5]=O)[C:3]=1[OH:12].[F:13][C:14]([F:23])([F:22])/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[Cl:11][C:8]1[C:9]([CH3:10])=[C:2]([Cl:1])[C:3]2[O:12][CH:15]([C:14]([F:13])([F:23])[F:22])[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5][C:4]=2[CH:7]=1
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: Cc1c(Cl)cc(C=O)c(O)c1Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(C)c(Cl)c2OC1C(F)(F)F
Temperature: 85 °C
Reaction time: 49 h
Yield: 83.8 %

Procedure:
A mixture of 3,5-dichloro-4-methylsalicylaldehyde (Step 1)(5.94 g, 29.0 mmol) and ethyl 4,4,4-trifluorocrotonate (7.67 g, 45.6 mmol) dissolved in anhydrous DMSO (10 mL) was treated with triethylamine (5.88 g, 58.1 mmol). The reaction was stirred at 85° C. for 49 hours then cooled in ice and filtered to give an orange solid. The solid was dissolved in ethyl acetate (100 mL), washed with 3 N HCl (2×50 mL), saturated NaHCO3, washed with brine, dried over MgSO4, and concentrated in vacuo to give a yellow solid (8.63 g, 84%): mp 117.1–119.5° C. 1H NMR (CDCl3/300 MHz) 7.63 (s, 1H), 7.17 (s, 1H), 5.80 (q, 1H, J=6.6 Hz), 4.33 (m, 2H), 2.48 (s, 3H), 1.35 (t, 3H, J=7.1 Hz).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:18]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=2[O:16][C:15](=[O:24])[CH:14]=1.CCN(C(C)C)C(C)C.Cl.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:23][C:20]1[CH:21]=[CH:22][C:17]2[O:16][C:15](=[O:24])[CH:14]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][NH:8][C:35](=[O:42])[C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)[C:18]=2[CH:19]=1
Reactant: NCCCOc1cc(=O)oc2ccc(Cl)cc12
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCCOc1cc(=O)oc2ccc(Cl)cc12)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
The trifluoroacetic acid salt of 4-(3-amino-propoxy)-6-chloro-1-benzopyran-2-one (0.272 mmol, 0.10 g) is dissolved in 3 mL of DCM and is added enough DIEA to bring the pH to ˜9 as measured by wet pH paper. Isonicotinoyl chloride hydrochloride is added (0.50 mmol, 0.089 g) and the reaction is stirred at ambient temperature overnight. The reaction mixture is evaporated under reduced pressure and the crude material is purified by HPLC to obtain the title compound as the trifluoroacetic acid salt (39 mg, 30%). 1H NMR (DMSO-d6, 300 MHz) δ 8.93 (1H, br t), 8.73 (2H, br d), 7.80 (2H, m), 7.76 (1H, d, J=2.5 Hz), 7.69 (1H, dd, J=2.5, 8.75 Hz), 7.45 (1H, d, J=8.75 Hz), 5.97 (1H, s), 4.31 (2H, t, J=5.75 Hz), 3.51 (2H, q, J=6.5 Hz), 2.11 (2H, m); MS (ESI, Pos.) calcd for C18H15ClN2O4 m/z [M+H]=359.1, found 359.1.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([CH3:17])[N:3]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>CN1C(=O)CCC1>[CH2:18]([NH:25][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([CH3:17])[N:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cc2scc(-c3ccccc3)c2c(Cl)n1
Reactant: NCc1ccccc1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1cc2scc(-c3ccccc3)c2c(NCc2ccccc2)n1
Temperature: 220 °C
Yield: 61.8 %

Procedure:
A microwave reaction vessel was charged with 4-chloro-6-methyl-3-phenyl-thieno[3,2-c]pyridine (254 mg, 0.982 mmol), benzylamine (642 μl, 5.886 mmol), triethylamine (137 μl, 0.982), solvated in NMP (3 ml), and set to stir in a Biotage microwave reactor. The reaction was heated at 220° C. for 6 h. The crude reaction was next partitioned between ethyl acetate (25 ml) and distilled water (25 ml). The organic phase was dried (MgSO4) and the solvent removed in vacuo. Purification by flash column chromatography (petroleum spirit 40-60° C.:ethyl acetate, 5:1, Rf 0.5) afforded the title compound as a yellow solid (200.4 mg, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH:10]2[C:16](OCC)=O)[CH:6]=[CH:7][CH:8]=1.[OH-:21].[Na+].CO>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[C:11](=[O:21])[C:10]2=[CH2:16])[CH:6]=[CH:7][CH:8]=1
Reactant: [OH-]
Reactant: CCOC(=O)C1CN(C)CCC1c1cccc(OC)c1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=C1C(=O)N(C)CCC1c1cccc(OC)c1
Yield: 93.1 %

Procedure:
The ester ethyl 4-(3'-methoxyphenyl)-1-methylpiperidine-3-carboxylate (23 (5.0 g, 17.5 mmol), NaOH (1.49 g, 35 mmol), CH3OH (50 mL), and H2O (25 mL) were refluxed for 5 h. After the thorough removal of solvents, the residue was mixed with acetic anhydride (50 mL) and refluxed for 1 h, then cooled and evaporated and the crude reaction product partitioned between CHCl3 (50 mL) and saturated NaHCO3 (50 mL, pH 8). The aqueous layer was extracted with CHCl3 (2×50 mL) and the combined organic phases dried and evaporated. Distillation gave 3.77 g (92%) of 4-(3'-methoxyphenyl)-1-methyl-3-methylene-2-piperidone (24). Recrystallization (CH3Cl2 /hexane) gave the analytical sample: mp 67°-70° C.: NMR δ 7.29 (m, 1 H), 6.82 (m, 3H), 6.40 (t,J=2 Hz, 1H), 5.07 (t,J=2 Hz, 1H), 3.75 (s, 3H), 3.34 (m, 2H), 3.04 (s, 3H), 2.17 (m, 2H); IR (KBr) 1645, 1600 cm-1 ; mass spectrum m/e (rel intensity) 231 (100), 216 (13). Anal. Calcd for C14H17NO2 : C, 72.7; H, 7.4; N, 6.1. Found: C, 72.6; H, 7.3; N, 6.0.
Reaction SMILES: C(O[C:4](=[O:22])[CH2:5][N:6]1[CH2:10][C@H:9]([O:11][CH3:12])[C@@H:8]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:7]1)C.[C:23]([O:27][C:28]([C:30]1[CH2:35][CH2:34][C:33]2[S:36][C:37]([NH2:39])=[N:38][C:32]=2[N:31]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([C:30]1[CH2:35][CH2:34][C:33]2[S:36][C:37]([NH:39][C:4](=[O:22])[CH2:5][N:6]3[CH2:10][C@H:9]([O:11][CH3:12])[C@@H:8]([NH:13][C:14]([C:16]4[S:17][C:18]([Cl:21])=[CH:19][CH:20]=4)=[O:15])[CH2:7]3)=[N:38][C:32]=2[N:31]=1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)CN1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](OC)C1
Reactant: CC(C)(C)OC(=O)C1=Nc2nc(N)sc2CC1
Product: CO[C@H]1CN(CC(=O)Nc2nc3c(s2)CCC(C(=O)OC(C)(C)C)=N3)C[C@@H]1NC(=O)c1ccc(Cl)s1

Procedure:
94.1 In analogy to example 25.3 {(3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-methoxy-pyrrolidin-1-yl}-acetic acid ethyl ester (example 25.2) was reacted with 2-amino-6,7-dihydro-thiazolo[5,4]pyridine-5-carboxylic acid tert-butyl ester (CAS 365996-05-0) to give 2-(2-{(3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-methoxy-pyrrolidin-1-yl}-acetylamino)-6,7-dihydro-thiazolo[5,4-]pyridine-5-carboxylic acid tert-butyl ester as off-white solid. MS 556.3 ([M+H]+)
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]2=[CH:3][C:2]=1[C:10]([OH:12])=O.[NH2:13][CH2:14][CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[CH:22]=2)=[N:17]1>>[Cl:29][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][CH2:14][NH:13][C:10]([C:2]3[CH:3]=[C:4]4[N:9]=[CH:8][CH:7]=[CH:6][N:5]4[N:1]=3)=[O:12])[N:17]=2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: N#Cc1ccc(-c2ccn(CCN)n2)cc1Cl
Reactant: O=C(O)c1cc2ncccn2n1
Product: N#Cc1ccc(-c2ccn(CCNC(=O)c3cc4ncccn4n3)n2)cc1Cl
Yield: 12 %

Procedure:
The title compound was prepared using the method of Example 34 (d) starting from pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (0.16 g; 0.97 mmol) and 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.20 g; 0.81 mmol). Yield 12%. 1H-NMR (400 MHz; d6-DMSO): δ 3.75 (q, 2H), 4.41 (t, 2H), 6.96 (d, 1H), 7.03 (s, 1H), 7.19 (m, 1H), 7.86 (d, 1H), 7.97 (m, 2H), 8.06 (s, 1H), 8.64 (m, 1H), 8.71 (m, 1H), 9.09 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[Br:22][C:23]1[CH:24]=[C:25]([C:29]2[C:33]3[CH:34]=[N:35][CH:36]=[CH:37][C:32]=3[N:31]([CH2:38][CH2:39][NH:40][CH3:41])[N:30]=2)[CH:26]=[CH:27][CH:28]=1>CN(C)C=O.C(O)C>[Br:22][C:23]1[CH:24]=[C:25]([C:29]2[C:33]3[CH:34]=[N:35][CH:36]=[CH:37][C:32]=3[N:31]([CH2:38][CH2:39][N:40]([CH3:41])[CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([C:6]4[C:5]5[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=5[O:8][N:7]=4)=[CH:14][CH:13]=3)[N:30]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: CNCCn1nc(-c2cccc(Br)c2)c2cnccc21
Solvent: CCO
Solvent: CN(C)C=O
Product: CN(CCn1nc(-c2cccc(Br)c2)c2cnccc21)C[C@@H](O)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and {2-[3-(3-bromo-phenyl)-pyrazolo[4,3-c]pyridin-1-yl]-ethyl}-methyl-amine (Table No. 1, SM 6) in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=616.
Reaction SMILES: [I-].[Na+].[CH3:3][C:4](=[CH2:18])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]([OH:17])=O)=[N:7]1.[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1>>[S:21]1[CH:22]=[CH:23][N:24]=[C:20]1[NH:19][C:15]([C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]([CH2:5][C:4]([CH3:3])=[CH2:18])[N:7]=1)=[O:17]
Reactant: Nc1nccs1
Reactant: C=C(C)Cn1nc(C(=O)O)c2ccccc21
Agent: [I-]
Agent: [Na+]
Product: C=C(C)Cn1nc(C(=O)Nc2nccs2)c2ccccc21
Yield: 23.2 %

Procedure:
1-(2-Methylallyl)-indazole-3-carboxylic acid (440 mg) was obtained from methyl indazole-3-carboxylate (0.5 g, 2.84 mmol) and 1-chloro-2-methylpropene (0.28 mL, 2.84 mmol, with a catalytic amount of sodium iodide) following the general procedures G and E. 1-(2-Methylallyl)indazole-3-carboxylic acid thiazol-2-ylamide (45 mg) was prepared from 1-(2-methylallyl)indazole-3-carboxylic acid (140 mg, 0.65 mmol) and 2-aminothiazole (65 mg, 0.65 mmol) following the general procedure H.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(Cl)([Cl:16])=O>>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:16])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Product: CC(=O)Oc1ccc(C(=O)Cl)cc1

Procedure:
100 Grams (0.555 mol) of 4-acetoxybenzoic acid was added to 400 g (3.36 mol) of thionyl chloride, and the mixture was refluxed under heat for 4 hours.