Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10](N(OC)C)=[O:11])=[CH:4][CH:3]=1.Br[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)C[C@@H](c1ccc(Br)cc1)c1ccccc1C
Reactant: Cc1cc(Br)ccn1
Product: Cc1cc(C(=O)C[C@@H](c2ccc(Br)cc2)c2ccccc2C)ccn1

Procedure:
In analogy to example 74, step 5, from (S)-3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 142, step 1) and 4-bromo-2-methylpyridine was prepared the title compound as white solid, MS (ESI+): m/z=394.0 ([M+H]+, 1Br).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH:26]([CH2:30][CH2:31][OH:32])[CH2:27][CH2:28][OH:29]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([N:26]([CH2:30][CH2:31][OH:32])[CH2:27][CH2:28][OH:29])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: OCCNCCO
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N(CCO)CCO)c2c1

Procedure:
The title compound was prepared in analogy to Example 11-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2,2′-iminodiethanol. MS obsd. (ESI+) [(M+H)+] 442, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (dd, J=7.83, 1.26 Hz, 1 H), 7.81 (s, 1 H), 7.83 (s, 1 H), 7.63 (td, J=7.58, 1.26 Hz, 1 H), 7.56-7.39 (m, 2 H), 7.30 (dd, J=8.46, 1.89 Hz, 1 H), 6.78 (s, 1 H), 5.18 (s, 2 H), 4.57 (brs, 2 H), 3.73-3.56 (m, 6 H), 3.56-3.43 (m, 4 H), 2.42 (s, 3 H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[N:12]=[CH:13][S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:15]([O:17]C)=[O:16])=[CH:5][C:4]=2[NH:3]1.[Li+].[OH-].C1COCC1.[OH-].[Na+]>O.CO>[O:1]=[C:2]1[C:11]2[N:12]=[CH:13][S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:15]([OH:17])=[O:16])=[CH:5][C:4]=2[NH:3]1
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)c1ncsc12
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(c1)[nH]c(=O)c1ncsc12
Yield: 2.7 %

Procedure:
Methyl 4-oxo-4,5-dihydrothiazolo[4,5-c]quinoline-7-carboxylate (35 mg, 0.12 mmol) and LiOH (60 mg, 0.83 mmol) were stirred in a (1:1:1, v:v:v) mixture of THF, MeOH and water (0.6 ml) for 2 hours. 6N aqueous NaOH was added and the solution filtered through celite. The solution was acidified and the resulting solid filtered. Preparative HPLC purification and genevac evaporation provided 4-oxo-4,5-dihydrothiazolo[4,5-c]quinoline-7-carboxylic acid as a white solid (0.8 mg). LCMS (ES): 95% pure, m/z 247 [M+1]+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:32][OH:33])=[N:30][CH:31]=1.CC([O-])(C)C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:33][CH2:32][C:29]1[N:30]=[CH:31][C:26]([NH:25][C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]3=[N:6][CH:7]=2)=[CH:27][CH:28]=1
Reactant: Nc1ccc(CO)nc1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(CO)nc3)nc12
Temperature: 110 °C
Yield: 36.2 %

Procedure:
To a 35 ml seal tube, 1-(2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl)-2,2-dimethylpropane-1-one (0.25 g, 0.000606 mole) and (5-aminopyridin-2-yl)methanol (0.09 g, 0.00728 mole) was taken in toluene (3.0 ml). The reaction mixture was purged with argon for 15 min at RT and NaOtBu (0.11 g, 0.00121 mole) was added and the reaction mixture was further purged for 30 min with argon. BINAP (0.037 g, 0.000060 mole) and Pd2(dba)3 (0.027 g, 0.000030 mole) were added and the reaction mixture was heated to 110° C. for 3 hrs. After completion of the reaction, the reaction mixture was filtered through celite bed and washed with ethyl acetate. Filtrate was collected and concentrated to afford crude product which was purified using column purification by eluting with 40-50% ethyl acetate in hexanes to yield 0.1 g of 1-(2-(6-(hydroxymethyl)pyridin-3-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethylpropan-1-one.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Br[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:25])([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[F:18][C:17]([F:19])([F:20])[C:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:6]2[CH2:5][CH2:4][NH:3][C@H:2]([CH3:1])[CH2:7]2)=[CH:11][CH:12]=1)([OH:25])[C:21]([F:22])([F:24])[F:23]
Reactant: C[C@@H]1CNCCN1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@@H]1CN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CCN1
Yield: 30.1 %

Procedure:
(R)-2-Methylpiperazine (37.9 mmol, 3.8 g), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (37.9 mmol, 12.79 g) and potassium carbonate (76 mmol, 10.49 g) were stirred at room temperature in acetonitrile (50 mL) overnight. The reaction mixture was diluted with ethyl acetate and filtered through dicalite. The filtrate was concentrated under vacuum. The resulting residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 85/15/1.5 dichloromethane/methanol/ammonia) to afford the title compound (4.06 g).
Reaction SMILES: C(OC(=O)C1C=CC([C:11]#[C:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17]([CH3:26])([CH3:25])[CH2:18][C:19]([CH3:24])([CH3:23])[S:20]3)=[CH:15][CH:14]=2)=NC=1)C.[OH-].[K+]>>[CH3:23][C:19]1([CH3:24])[CH2:18][C:17]([CH3:25])([CH3:26])[C:16]2[C:21](=[CH:22][C:13]([C:12]#[CH:11])=[CH:14][CH:15]=2)[S:20]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)SC(C)(C)CC3(C)C)nc1
Agent: [K+]
Agent: [OH-]
Product: C#Cc1ccc2c(c1)SC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 167 mg (0.4756 mmol) of ethyl-6-(2,2,4,4-tetramethyl-7-thiochromanyl)ethynyl-nicotinate (Compound 3) was added 5 ml of ethanolic KOH solution. The reaction mixture was stirred at room temperature for 48 hours. The ethanol was then removed in vacuo and the residue was taken up in water and ether. The layers were separated and the aqueous layer was acidified to Ph=2 with 1N HCl and then extracted with ether. The organic extracts were combined and washed successively with water and saturated sodium chloride solution and then dried (MgSO4). The solvent was removed in vacuo to give the title compound as a yellow solid.
Reaction SMILES: [C:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2].I[C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1.C(N(CC)CC)C>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.CN(C)C=O>[CH2:20]([O:19][C:17]([C:16]1[CH:22]=[CH:23][C:13]([C:2]#[C:1][C:3]2([OH:11])[CH:8]3[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]3)[CH2:4]2)=[CH:14][CH:15]=1)=[O:18])[CH3:21]
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#CC2(O)CN3CCC2CC3)cc1
Temperature: 65 °C
Yield: 46.4 %

Procedure:
A mixture of 3-ethynyl-3-hydroxyquinuclidine (604 mg), ethyl 4-iodobenzoate (1.1 g), bis(triphenylphosphine)-palladium (II) chloride (140 mg), copper (I) iodide (70 mg) and anhydrous triethylamine (4 ml) and anhydrous dimethylformamide (8 ml) was stirred under an atmosphere of argon. The reaction mixture was heated at 65° C. for 18 hours. The reaction mixture was cooled and the triethylamine and dimethylformamide removed by evaporation. To the residue was added 2M sodium hydroxide (25 ml) and the mixture extracted with dichloromethane. The organic phase was washed with water, saturated brine and dried (MgSO4). Evaporation gave a solid which was crystallised from acetonitrile to give 3-[2-(4-ethoxycarbonylphenyl)ethynyl]-3-hydroxyquinuclidine (553 mg) as a colourless solid, m.p. 176°-177° C.; microanalysis, found: C, 72.2; H, 7.3; N, 4.8%; C18H21NO3 requires: C, 72.2; H, 7.07; N, 4.68%; NMR (DMSO-d6): 1.32(3H, t), 1.49-2.01(5H, m), 2.68(4H, t), 2.78-3.14(2H, d of d), 4.32(2H, q), 5.66(1H, br.s), 7.49-7.58(2H, d) and 7.90-7.98(2H, d); m/Z 300 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:6][C:5]2=[C:7]([C:14]([O-:16])=[O:15])[CH:8]=[CH:9][C:10]([N+:11]([O-])=O)=[C:4]2[O:3]1.[C:18](=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.[Fe]>[NH2:11][C:10]1[CH:9]=[CH:8][C:7]([C:14]([O:16][CH3:18])=[O:15])=[C:5]2[C:4]=1[O:3][C:2]([CH3:17])([CH3:1])[CH2:6]2
Reactant: O=C([O-])[O-]
Reactant: CC1(C)Cc2c(C(=O)[O-])ccc([N+](=O)[O-])c2O1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(N)c2c1CC(C)(C)O2
Reaction time: 12 h
Yield: 74.6 %

Procedure:
2,2-Dimethyl-7-nitro-3H-benzofuran-4-carboxylate 4c (1.20 g, 4.77 mmol) and iron powder (0.80 g, 14.32 mmol) were dissolved in 25 mL of acetic acid. The reaction mixture was stirred for 12 hours. The resulting mixture was added with sodium carbonate and solid sodium bicarbonate to adjust pH to 7 to 8, extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with water (30 mL) and saturated sodium chloride solution (20 mL) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound methyl 7-amino-2,2-dimethyl-3H-benzofuran-4-carboxylate 4d (789 mg, yield: 74.6%) as a white solid.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]([O:8]CC)=O)[C:2]#[CH:3].[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[N:19]=[C:20]=[S:21].C(N(CC)CC)C>C(Cl)Cl>[CH3:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH3:11])[C:13]=1[N:19]1[C:6](=[O:8])[CH2:5][N:4]([CH2:1][C:2]#[CH:3])[C:20]1=[S:21]
Reactant: C#CCNCC(=O)OCC
Reactant: Cc1cccc(C)c1N=C=S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCN1CC(=O)N(c2c(C)cccc2C)C1=S
Temperature: 25 °C
Yield: 48.5 %

Procedure:
A mixture of ethyl N-propargylaminoacetate (14.1 g), 2,6-dimethylphenylisothiocyanate (16.3 g), triethylamine (10.1 g), and methylene chloride (150 mL) was heated at reflux for 3 hours. The reaction mixture was cooled to ambient temperature, washed with 1N HCl (100 mL), then with water. The organic layer was separated, dried over anhydrous magnesium sulfate, then evaporated to dryness. The residual oil was triturated with hexane. The solid was collected by filtration. Recrystallization from hexane-EtOAc afforded the title compound (12.5 g) as yellow solid, m.p. 117°-121° C. Anal. Calcd. for. C14H14N2S2O: C, 65.09; H, 5.46; N, 10.84. Found: C, 65.23; H, 5.43; N, 10.88. Mass spectrum (EI, M.+) m/z 258.
Reaction SMILES: [CH3:1][CH:2]([C:15](=O)[CH2:16][CH2:17][CH3:18])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=O.[NH2:20][C:21]([NH2:23])=[O:22].Cl>C(O)C>[CH3:1][C:2]1[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=2)=[N:20][C:21](=[O:22])[NH:23][C:15]=1[CH2:16][CH2:17][CH3:18]
Reactant: NC(N)=O
Reactant: CCCC(=O)C(C)C(=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCO
Product: CCCc1[nH]c(=O)nc(-c2cccc(C(F)(F)F)c2)c1C
Yield: 57.7 %

Procedure:
A stirred mixture of 2-methyl-1-(3-trifluoromethylphenyl)-hexane-1,3-dione (102 mg), urea (45 mg), HCl (0.10 mL, 5M) and ethanol (4 mL) was heated at reflux for 16 h. Further urea (30 mg) and HCl (0.10 mL, 5M) were added and heating continued at reflux for 24 h. The mixture was allowed to cool and the solvent was evaporated at reduced pressure. The residue was dissolved in a mixture of ethyl acetate (10 mL) and water (10 mL), the organic layer was separated and further washed with a solution of saturated sodium carbonate (10 mL) followed by water (10 mL). The ethyl acetate extract was then dried over sodium sulphate and evaporated at reduced pressure to afford 5-methyl-6-propyl-4-(3-trifluoromethylphenyl)-1H-pyrimidin-2-one as a yellow oil (64 mg).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CN1CCCC1.[Cl:18][CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>C1C=CC=CC=1>[C:1]1([O:11][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([CH2:19][Cl:18])=[CH:21][CH:22]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2ccccc12
Reactant: O=C(Cl)c1ccc(CCl)cc1
Agent: CN1CCCC1
Solvent: c1ccccc1
Product: O=C(Oc1cccc2ccccc12)c1ccc(CCl)cc1

Procedure:
72.1 g (0.5 mole) of α-naphthol was heated to 50° C. with 150 ml of benzene and 0.5 ml of N-methylpyrrolidine, whereupon a clear solution was obtained. Following the procedure of Method C, 95 g (0.5 mole) of p-chloromethylbenzoyl chloride dissolved in 80 ml of benzene was added drop by drop over a period of about 30 minutes, and then the mixture was refluxed for 5 hours under a weak current of nitrogen gas. The benzene was then distilled from the clear, orange-colored solution. The residue crystallized upon cooling to a yellow mass amounting to 148 g (100%), M.P. 93°-96° C. The entire amount of the raw product was recrystallized from 3 liters of cyclohexane with the addition of decolorizing carbon. About 80% of the material put in was obtained in light yellow needles of a melting point of 104°-106° C. For the analysis, 20 g was again recrystallized from 400 ml of cyclohexane. 16.5 g of very pale yellow needles was obtained, M.P. 105°-106.5° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9].[F:24]C1C=CC=CC=1S(Cl)(=O)=O>>[F:24][C:7]1[CH:2]=[C:3]([S:8]([NH:11][C@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])[CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: O=C(O)[C@@H](Cc1ccc(O)cc1)NS(=O)(=O)c1ccccc1F
Product: O=C(O)[C@@H](Cc1ccc(O)cc1)NS(=O)(=O)c1cccc(F)c1

Procedure:
Following 17a synthetic method, using 2-fluorobenzenesulfonyl chloride (145.62 μL, 1.1 mmol) instead of 2-fluorobenzenesulfonyl chloride gave the final compound 18a as a colorless oil; (77.34 mg, 45.6%). [α]D25: +21.3 (c=0.25, CHCl3); 1H-NMR (300 MHz, acetone-d6): δ 7.95-7.76 (m, 3H), 7.41-7.25 (m, 6H), 5.04-4.97 (m, 1H), 3.45-2.26 (m, 2H); 13C NMR (300 MHz, acetone-d6): δ 171.50, 163.90, 160.62, 139.15, 136.64, 133.50, 129.49, 128.40, 126.89, 124.94, 118.56, 115.15, 109.30, 54.04, 36.79; HRMS (ESI): calcd for: C15H14FNO5S [M+Na]+=362.0469, obsd [M+Na]+=362.0475.
Reaction SMILES: [C:1]([N:9]1[CH2:20][CH2:19][C:12]2[N:13]=[N:14][C:15](SC)=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][NH:22][NH2:23]>C(O)C>[C:1]([N:9]1[CH2:20][CH2:19][C:12]2[N:13]=[N:14][C:15]([N:22]([CH3:21])[NH2:23])=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNN
Reactant: CSc1cc2c(nn1)CCN(C(=O)c1ccccc1)C2
Solvent: CCO
Product: CN(N)c1cc2c(nn1)CCN(C(=O)c1ccccc1)C2

Procedure:
2.9 g of 6-benzoyl-5,6,7,8-tetrahydro-3-methylmercaptopyrido[4,3-c]pyridazine and 1.5 g of methylhydrazine are heated in 20 cc of 95% ethanol in an autoclave at a bath temperature of 150° for 18 hours, and the mixture is subsequently worked up as described in Example 47. The biscentisinate of the title compound has a M.P. of 166°-168° (decomp.).
Reaction SMILES: [H-].[Na+].[CH3:3][OH:4].C(OC1C=CC(O[C:18]2[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][C:19]=2[N+:26]([O-:28])=[O:27])=CC=1)C1C=CC=CC=1>O>[CH3:3][O:4][CH2:22][C:21]1[CH:24]=[CH:25][CH:18]=[C:19]([N+:26]([O-:28])=[O:27])[CH:20]=1
Reactant: CO
Reactant: O=[N+]([O-])c1cc(CCl)ccc1Oc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% Oily sodium hydride (0.22 g, 5.5 mmol) was added to methanol (50 ml) under ice-cooling, and after stirring at room temperature for 30 minutes, 4-[4-(benzyloxy)phenoxy]-3-nitrobenzyl chloride (1.00 g, 2.7 mmol) was added thereto, followed by stirring for 3 hours. The reaction solution was poured into water and extracted with ethyl acetate. After drying, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography [eluent; hexane - chloroform (1:1)] to give 1-[4-benzyloxy)phenoxy]-4-(methoxymethyl)-2-nitrobenzene (0.92 g).
Reaction SMILES: CN(C)CC(C)(C)CNC[CH2:8][CH2:9][O:10][C:11]1[CH:35]=[CH:34][C:14]([CH2:15][C:16]2[CH:17]=[C:18]([C@H:23]3[C@H:28]([OH:29])[C@@H:27]([OH:30])[C@H:26]([OH:31])[C@@H:25]([S:32][CH3:33])[O:24]3)[CH:19]=[CH:20][C:21]=2[CH3:22])=[CH:13][CH:12]=1.[NH2:39][C:40]1([C:45]([NH2:47])=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41]1>>[CH3:22][C:21]1[CH:20]=[CH:19][C:18]([C@H:23]2[C@H:28]([OH:29])[C@@H:27]([OH:30])[C@H:26]([OH:31])[C@@H:25]([S:32][CH3:33])[O:24]2)=[CH:17][C:16]=1[CH2:15][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][NH:39][C:40]2([C:45]([NH2:47])=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:35][CH:34]=1
Reactant: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(OCCCNCC(C)(C)CN(C)C)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: NC(=O)C1(N)CCCC1
Product: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(OCCNC4(C(N)=O)CCCC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The same procedure was employed as for amine 50, using 1-aminocyclopentanecarboxamide, to provide the product 52. 1H NMR (400 MHz, MeOH-d4) δ ppm 7.11-7.21 (m, 3 H), 7.06 (d, J=8.3 Hz, 2 H), 6.85 (m, J=8.6 Hz, 2 H), 4.39 (d, J=9.6 Hz, 1H), 4.12 (d, J=9.3 Hz, 1 H), 4.06 (t, J=4.9 Hz, 2 H), 3.94 (s, 2 H), 3.34-3.54 (m, 3 H), 2.92 (t, J=4.8 Hz, 2 H), 2.20 (s, 3 H), 2.14 (s, 3 H), 2.06-2.13 (m, 2 H), 1.75-1.83 (m, 6 H); MS (ES+) [M+H]+=531.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].Br[CH:12]1[CH2:16][CH2:15][O:14][CH:13]1[O:17][CH3:18].[I-].[Na+]>CN(C=O)C.O>[CH2:9]([O:8][C:6](=[O:7])[CH:5]([C:3]#[N:4])[CH:12]1[CH2:16][CH2:15][O:14][CH:13]1[O:17][CH3:18])[CH3:10]
Reactant: COC1OCCC1Br
Reactant: CCOC(=O)CC#N
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C#N)C1CCOC1OC
Reaction time: 1 h
Yield: 15.2 %

Procedure:
Sodium hydride (95%, 30.32 g, 1.2 mol) was suspended in anhydrous DMF (350 ml) in a 2 L, 3-necked flask and ethyl cyanoacetate (136 ml, 1.2 mol) was added dropwise with stirring under argon over 1 h. After a further 15 min, 3-bromo-2-methoxytetrahydrofuran (75 g, 0.41 mol) was added, followed by sodium iodide (2 g) and then the solution was heated with vigorous stirring at 140° C. for 20 h under argon. After cooling, water (200 ml) was added and the solution was concentrated on a rotary evaporator to about 300 ml. More water (200 ml) was added and the crude product was extracted into diethylether (4×500 ml). The combined extracts were dried (Na2SO4), filtered and evaporated. Distillation of the residue under reduced pressure through a Vigreaux column afforded a colourless liquid (13.28 g, 15%). The cut b. p. 90-110° C./0.4 mmHg was taken; Rf (in A), 0.45, 0.36; stains yellow with anisaldehyde/H+; δH(d6-DMSO) 5.00 (0.75 H, m, mixt. of trans-2-H), 4.89 (0.25 H, d J2.1, cis-2-H), 4.29-4.19 (2 H, 2 q, cis/trans-CH2), 4.06-3.83 (2 H, 2 m, cis/trans-5-H), 3.39 (0.75 H, s, MeO), 3.36 (0.75 H, s, MeO), 3.35 (0.75 H, s, MeO), 3.31 (0.75 H, s, MeO), 2.78-2.70 (1 H, m, cis/trans-3-H), 2.30-1.71 (2 H, 2 m, 2×cis/trans-4-H) ppm; m/z (EI) 213.1002 (M+; Calc. for C10H15NO4, 213.1023).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH:20]=[C:19]([NH:21][CH:22]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)[N:18]=[CH:17][N:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](Cl)(=O)[CH:29]=[CH2:30]>CN1C(=O)CCC1>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[N:16]=[CH:17][N:18]=[C:19]([NH:21][CH:22]3[CH2:27][CH2:26][CH2:25][N:24]([CH2:30][CH:29]=[CH2:28])[CH2:23]3)[CH:20]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Oc2ccc(Nc3cc(NC4CCCNC4)ncn3)cc2)cc1
Reactant: C=CC(=O)Cl
Solvent: CN1CCCC1=O
Product: C=CCN1CCCC(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of N4-(4-phenoxyphenyl)-N6-(piperidin-3-yl)pyrimidine-4,6-diamine (0.025 g, 0.069 mmol) in NMP (0.5 mL) at 0° C. was added acryloyl chloride (0.007 g, 0.083 mmol), and the reaction mixture was stirred at 0° C. for 5 min. The reaction mixture was quenched by adding 10% NaHCO3 solution and it was extracted with EtOAc (2×5 mL). The combined EtOAc extract was washed with water (3 mL) and brine (3 mL), was dried over Na2SO4 and was concentrated under reduced pressure. The residue obtained was purified by column chromatography (SiO2, 230-400, chloroform/methanol:98/2) to give 1-(3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)piperidin-1-yl)prop-2-en-lone (I-86) as an off white solid. 1H NMR (MeOD) δ ppm: 1.5-1.75 (m, 2H), 1.80-2.00 (m, 1H), 2.0-2.20 (m, 1H), 2.70-2.90 (m, 1H), 2.90-3.05 (m, 1H), 3.80-4.00 (m, 2H), 4.30-4.45 (m, 1H), 5.65 & 5.75 (d, J=10.8 Hz & d, J=10.8 Hz respectively, together 1H), 5.81 (d, J=10.8 Hz, 1H), 6.14 & 6.18 (d, J=17.2 Hz & d, J=19.2 Hz respectively, together 1H), 6.60-6.70 & 6.70-6.85 (m, together 1H), 6.97-7.00 (m, 4H), 7.04 (t, J=7.6 Hz, 1H), 7.32-7.38 (m, 4H), 8.04 & 8.07 (s, together 1H); LCMS: m/e 416.1 (M+1).
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[N:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)[C:7]=1[C:8]#[N:9]>ClCCl.C(OCC)(=O)C>[Cl:5][C:6]1[N:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:7]=1[C:8]#[N:9]
Reactant: COc1ccc(-c2ccnc(Cl)c2C#N)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1c(-c2ccc(O)cc2)ccnc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.7 %

Procedure:
A 1.0 M dichloromethane solution of boron tribromide (12.26 mL, 12.26 mmol) was added to a solution of 2-chloro-4-(4-methoxyphenyl)nicotinonitrile (300 mg, 1.226 mmol) in dichloromethane (10 mL). The mixture was stirred at room temperature for 2 h, diluted with ethyl acetate (50 mL), and carefully quenched with saturated sodium bicarbonate (20 mL). The aqueous layer was separated and extracted with ethyl acetate (2×50 mL). The combined extracts were washed with water (30 mL), brine (30 mL), dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 10-50% ethyl acetate in hexanes, gave 2-chloro-4-(4-hydroxyphenyl)nicotinonitrile as a brown solid (50 mg, 18% yield). 1H NMR (500 MHz, CDCl3) δ ppm 8.55 (1H, δ, J=5.22 Hz), 7.49-7.62 (2H, m), 7.38 (1H, δ, J=5.22 Hz), 6.94-7.05 (2H, m); MS (ES+) m/z: 231 (M+H); LC retention time: 2.841 min (analytical HPLC Method A).