Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)=[CH:7][CH:6]=1.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([NH:25][CH2:20][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)=[CH:7][CH:6]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: FC(F)(F)c1c[nH]c(-c2ccc(OCC3CO3)cc2)n1
Reactant: CC(C)(C)N
Product: CC(C)(C)NCC(O)COc1ccc(-c2nc(C(F)(F)F)c[nH]2)cc1

Procedure:
A solution of 2-[4-(2,3-epoxypropoxy)phenyl]trifluoromethylimidazole (2.5 g.) in tert. butylamine (20 ml.) is heated 6 hours at reflux. The excess tert. butylamine is removed by distillation at atmospheric pressure over steam. The residue is triturated with nitromethane (5 ml.) and the resulting solid removed by filtration. After recrystallization from acetonitrile, (1.2 g.) of 2-[4-(3-tert. butylamino-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole is obtained, m.p. 185.5°-186.5° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[NH2:12][C:13]1[O:17][N:16]=[C:15]([CH3:18])[C:14]=1Br.[OH-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[NH2:12][C:13]1[O:17][N:16]=[C:15]([CH3:18])[C:14]=1[O:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=1
Reactant: Cc1noc(N)c1Br
Reactant: COc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2c(C)noc2N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.7 %

Procedure:
To a mixture of sodium hydride (60% dispersion in mineral oil, 52 mg, 1.3 mmol) in dry dimethylformamide (2.0 ml) was added 4-methoxyphenol (0.15 g, 1.2 mmol). After stirring the solution at room temperature of 10 min, 5-amino-4-bromo-3-methylisoxazole (0.20 g, 1.1 mmol) was added, followed by bis(triphenylphosphine)palladium(11) chloride (79 mg, 0.11 mmol). The mixture was heated to 50° C. for 2.5 h and then cooled to room temperature. The dark brown reaction mixture was worked up with ethyl acetate and 5% NaOH. The organic layer was dried with magnesium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel using 20% ethyl acetate in hexanes as eluent to give 0.13 g (51% yield) of 5-amino-4-(4-methoxyphenoxy)-3-methylisoxazole.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.C1(OCC)C=CC=CC=1.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOc1ccccc1
Solvent: CO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 76.2 %

Procedure:
To a mixture of 306 mg (purity: 98.0%; 1.82 mmol) of 4-hydroxy-3,6-dichloropyridazine and 821 mg (5.49 mmol) of 2-cyclopropyl-6-methylphenol were added ethyl phenyl ether (2.76 g) and 324 mg (5.50 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 384 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 77%) and 2.0 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.4%) were obtained.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:6]2[NH:7][C:8]([CH2:10][C:11]([O:13]CC)=[O:12])=[N:9][C:5]=2[CH:4]=1.C1COCC1.O.[OH-].[Li+:31]>C1COCC1>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:6]2[NH:7][C:8]([CH2:10][C:11]([O-:13])=[O:12])=[N:9][C:5]=2[CH:4]=1.[Li+:31]
Reactant: CCOC(=O)Cc1nc2cc(C(F)(F)F)cc(C(F)(F)F)c2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])Cc1nc2cc(C(F)(F)F)cc(C(F)(F)F)c2[nH]1
Reaction time: 8 h
Yield: 114.7 %

Procedure:
A solution of ethyl 2-(5,7-bis(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)acetate (250 mg, 0.74 mmol) in 4:1 THF/water (4 mL) was treated with lithium hydroxide (21 mg, 0.88 mmol), and the mixture was stirred overnight. Analysis by LC/MS indicated that the reaction was not complete, so additional lithium hydroxide (5 mg, 0.21 mmol) was added, and the mixture was stirred for 6 h. Analysis by LC/MS indicated that the reaction was still not complete, so additional lithium hydroxide (15 mg, 0.63 mmol) was added, and the mixture was stirred overnight. Analysis by LC/MS indicated that the reaction was complete. The THF was stripped in-vacuo at room temperature, and the aqueous was freeze-dried to yield 270 mg of yellow powder. This material was used as-is in the next step. 1H NMR (500 MHz, CD3OD) δ ppm 3.72 (s, 2 H) 7.54 (s, 1 H) 7.96 (s, 1 H).
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][CH2:13][O:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([N:30]1C=C[N:32]=[CH:31]1)([N:25]1C=CN=C1)=[O:24].C(N(CC)CC)C.CN(C=[O:46])C>O>[C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][CH2:13][O:14][C:15]3[CH:22]=[CH:21][C:18]([CH2:19][N:32]4[C:31](=[O:46])[NH:30][C:23](=[O:24])[NH:25]4)=[CH:17][CH:16]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(OCCc2coc(-c3ccccc3)n2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=c1[nH]c(=O)n(Cc2ccc(OCCc3coc(-c4ccccc4)n3)cc2)[nH]1
Temperature: 25 °C
Reaction time: 96 h
Yield: 27 %

Procedure:
A mixture of 11.9 g of semicarbazide from Example 17 Part C, 8.10 g of carbonyldiimidazole, 0.5 mL of triethylamine and 400 mL of anhydrous DMF was stirred at 25° C. for 4 days, diluted with 1 L of H2O and filtered. The filtrate was evaporated. The residue was treated with 100 mL of MeOH and the solid was filtered and dried to give 3.43 g of 1-[(4-(2-(2-phenyl-4-oxazolyl)ethoxy)phenyl)methyl]1,2,4-triazolidin-3,5-dione (27%. mp 223.5°-230° C.).
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].O.C(=O)([O-])[O-:7].[K+].[K+].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH3:2][O:3][N:4]([C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:7]
Reactant: CON
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CON(O)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 0.312 mole methoxyamine hydrochloride in cooled (to about 0° C.) water, 0.312 mole potassium carbonate was added in portions; the temperature of the reaction mixture was maintained at about 0° C. during the addition. To that cool mixture, 0.25 mole benzoyl chloride dissolved in methylene chloride (about 300 ml) was added dropwise over about 0.5 hours. The temperature of the reaction mixture was kept at about 0 to 10° C. for the first hour; the reaction mixture was then allowed to come to room temperature and was stirred overnight. The layers were phase separated. The methylene chloride layer was dried over magnesium sulfate and then stripped. The residue was washed with cold ethyl ether/hexane to give the above-identified product as an off-white solid, melting point 58-60° C.
Reaction SMILES: O[CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:5]=[CH:4][C:3]1=2.O=S(Cl)[Cl:24]>>[Cl:24][CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: O=S(Cl)Cl
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCC3O)nc1
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCC3Cl)nc1
Temperature: 50 °C
Reaction time: 3.5 h

Procedure:
Charge flask with 6-(5-Hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide (288 mg, 1.01 mmol) and SOCl2 (5 ml) and heat at 50° C. under nitrogen atmosphere with stirring. After 3.5 hours, concentrate on rotary evaporator to give the title compound as a yellow oil. Due to instability, use this material without purification.
Reaction SMILES: [F:1][C:2]1[C:11](I)=[C:10]([CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[CH3:39][C:40]1([CH3:47])[C:44]([CH3:46])([CH3:45])[O:43][BH:42][O:41]1>C(O[Pd]OC(=O)C)(=O)C.O1CCOCC1>[F:1][C:2]1[C:11]([B:42]2[O:43][C:44]([CH3:46])([CH3:45])[C:40]([CH3:47])([CH3:39])[O:41]2)=[C:10]([CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC1(C)OBOC1(C)C
Reactant: COC(=O)c1ccc(C)c(I)c1F
Agent: CC(=O)O[Pd]OC(C)=O
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1F
Temperature: 60 °C
Reaction time: 8 h

Procedure:
In a 100 ml 3-neck round bottom flask equipped with a condenser, magnetic stirrer and nitrogen outlet was placed methyl 2-fluoro-3-iodo-4-methylbenzoate (2.0 g, 6.80 mmol), 10.0 ml of anhydrous 1,4-dioxane, diacetoxypalladium (0.076 g, 0.340 mmol) and [1,1′-biphenyl]-2-yldicyclohexylphosphine (0.477 g, 1.360 mmol) under nitrogen. 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.96 ml, 20.40 mmol) was added drop wise via syringe. The reaction mixture was heated at 60° C. for 2 hours and stirred at room temperature overnight. LCMS showed almost 100% conversion. The dioxane was removed and the residue was purified on 80 g ISCO silica column using ethyl acetate/hexane gradient and then switched to methanol/DCM gradient to give 1.25 g (62.5%) of IXS-5-48-1, 1.25 g (62.5%). 1H NMR (DMSO-d6, 400 MHz) δ 7.81 (t, 1H), 7.16 (d, 1H), 3.83 (s, 3H), 2.42 (s, 3H), 1.33 (s, 12H), and MS: [MH+]=295).
Reaction SMILES: [N:1]1([C:6]2[S:7][CH:8]=[C:9]([C:11](OCC)=[O:12])[N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CO>C(Cl)(Cl)Cl>[N:1]1([C:6]2[S:7][CH:8]=[C:9]([CH2:11][OH:12])[N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1csc(N2CCCC2)n1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: OCc1csc(N2CCCC2)n1
Yield: 4 %

Procedure:
Using the procedure of Example 11C but replacing ethyl 2-(4-morpholinyl)thiazole-4-carboxylate with ethyl 2-(1-pyrrolidinyl)thiazole-4-carboxylate provided, after silica gel chromatography using 2-4% methanol in chloroform, the desired compound (Rf 0.26, 4% methanol in chloroform) in 53% yield. 1H NMR (CDCl3) δ2.04 (m, 4H), 2.75 (br, 1H), 3.45 (m, 4H), 4.56 (s, 2H), 6.32 (s, 1H). Mass spectrum: (M+H)+ =185.
Reaction SMILES: [Br-:1].[F:2][C:3]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:4]([O:6][C@@H:7]1[CH:12]2[CH2:13][CH2:14][N+:9]([CH2:15][C:16](OC3C=CC=CC=3)=[O:17])([CH2:10][CH2:11]2)[CH2:8]1)=[O:5].[C:37]1([O:43]C(=O)C[Br:46])C=CC=C[CH:38]=1>>[Br-:46].[F:2][C:3]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:4]([O:6][C@@H:7]1[CH:12]2[CH2:13][CH2:14][N+:9]([CH2:15][C:16]#[CH:37])([CH2:10][CH2:11]2)[CH2:8]1)=[O:5].[Br-:1].[C:37]([O:17][CH2:16][CH2:15][N+:9]12[CH2:10][CH2:11][CH:12]([CH2:13][CH2:14]1)[C@@H:7]([O:6][C:4](=[O:5])[C:3]([F:2])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:8]2)(=[O:43])[CH3:38]
Reactant: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(F)(c1ccccc1)c1ccccc1)C2)Oc1ccccc1
Reactant: O=C(CBr)Oc1ccccc1
Agent: [Br-]
Product: C#CC[N+]12CCC(CC1)[C@@H](OC(=O)C(F)(c1ccccc1)c1ccccc1)C2
Product: CC(=O)OCC[N+]12CCC(CC1)[C@@H](OC(=O)C(F)(c1ccccc1)c1ccccc1)C2

Procedure:
These compounds, namely (R)-3-(2-Fluoro-2,2-diphenyl-acetoxy)-1-prop-2-ynyl-1-azonia-bicyclo[2.2.2]octane bromide and (R)-1-(2-Acetoxy-ethyl)-3-(2-fluoro-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide are prepared by an analogous method to (R)-3-(2-fluoro-2,2-diphenyl-acetoxy)-1-phenoxycarbonylmethyl-1-azonia-bicyclo[2.2.2]octane bromide (Example 109) by replacing bromo-acetic acid phenyl ester with the appropriate alkyl halide.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[OH-].[Na+].CO.Cl[CH2:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[CH2:15]>COC1C=CC(O)=CC=1.O>[CH:14]([C:13]1[CH:12]=[C:11]([CH:18]=[CH:17][CH:16]=1)[CH2:10][S:1][CH2:2][CH2:3][OH:4])=[CH2:15]
Reactant: OCCS
Reactant: C=Cc1cccc(CCl)c1
Agent: COc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=Cc1cccc(CSCCO)c1
Reaction time: 3 h
Yield: 54 %

Procedure:
A polymerization inhibitor, p-methoxyphenol (1.24 g; 0.01 mole), was added to a mixture of 78 g (1.0 mole) of 2-mercaptoethanol, 133 g (1.0 mole) of a 30 % aqueous solution of sodium hydroxide and 0.15 liter of methanol. While the mixture was cooled to below 10° C., 152 g (1.0 mole) of m-(chloromethyl)styrene was added dropwise over 3 hours. Then, the reaction mixture was continuously stirred for an additional 3 hours to complete the reaction. Water (1 liter) was added to the reaction mixture to separate it into an oil layer and an aqueous layer. The oil layer was washed with water and distilled under reduced pressure (140°-150 ° C./1-2 mmHg) to give 105 g of 2-(3-vinylbenzylthio)ethanol as a colorless transparent liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][OH:16])O[CH:14]=2)=[CH:5][CH:4]=1.Cl.[NH2:21][OH:22]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][OH:16])[N:21]([OH:22])[CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(COc2coc(CO)cc2=O)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(COc2cn(O)c(CO)cc2=O)cc1
Reaction time: 0.5 h

Procedure:
39.3 g of 5-p-methoxybenzyloxy-2-hydroxymethyl-4-pyrone is dissolved in 600 ml of pyridine, then 52.2 g of hydroxylamine hydrochloride is added thereto, and reacted at 70°-75° C. for 2.5 hours. After the reaction, the reaction mixture is concentrated to about 100 ml and, after adding 100 ml of water thereto, added to a mixed solution of 75 ml of hydrochloric acid and 225 ml of water with ice cooling. The pH is adjusted to 2-2.5, and stirring is conducted at the same temperature for 30 minutes. The formed crystals are filtered off, washed with water and then dried to obtain 16.6 f of the title compound.
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].[H-].[Na+].CS(C)=O.C[O:13][C:14](=O)[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][C:24](=[O:26])[CH3:25])=[C:17]([O:27][CH3:28])[CH:16]=1>O>[CH3:22][O:21][C:19]1[CH:20]=[C:15]([C:14](=[O:13])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3])[CH:16]=[C:17]([O:27][CH3:28])[C:18]=1[NH:23][C:24](=[O:26])[CH3:25]
Reactant: COC(=O)c1cc(OC)c(NC(C)=O)c(OC)c1
Reactant: CS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(C(=O)CS(C)(=O)=O)cc(OC)c1NC(C)=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A suspension of 30.1 g. of dimethylsulfone and 11.5 g. of sodium hydride (50% dispersion in oil) in 80 ml. of dimethylsulfoxide was stirred at 50° C. for 3 hours with the exclusion of moisture. Then, 20.3 g. of 4-acetamido-3,5-dimethoxybenzoic acid methyl ester were added and the mixture was stirred at room temperature for an additional 20 hours. Thereafter, the solution was diluted with 1 liter of water and extracted with three 1 liter portions of ethyl acetate. The ethyl acetate extracts were washed with two 300 ml. portions of water, combined, dried over magnesium sulfate and evaporated to dryness under vacuum. Recrystallization of the residue from ethyl acetate gave 2',6'-dimethoxy-4'-[(methylsulfonyl-acetyl)]acetanilide having a melting point of 206°-207° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1B(O)O.Br[C:15]1[CH:16]=[C:17]([O:21][CH2:22][C@@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[CH3:28])[CH:18]=[N:19][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:15]1[CH:16]=[C:17]([O:21][CH2:22][C@@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[CH3:28])[CH:18]=[N:19][CH:20]=1
Reactant: Cn1c(B(O)O)cc2ccccc21
Reactant: CN1CCC[C@H]1COc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN1CCC[C@H]1COc1cncc(-c2cc3ccccc3n2C)c1

Procedure:
To a solution of the compound from step 36a and 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (270 mg, 1.0 mmol) in toluene (5.0 mL) was added Pd(0) (25 mg) and Na2CO3 (1 mL of a 2 M solution), and the mixture was heated at reflux for 60 hours. The solvent was removed under vacuum, and the residue was purified by chromatography on silica gel to afford 105 mg of the title compound. MS (CI/NH3) m/z 322 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.80 (m, 3H), 2.05 (m, 1H), 2.32 (m, 1H), 2.50 (s, 3H), 2.70 (m, 1H), 3.13 (m, 1H), 3.78 (s, 3H), 4.04 (m, 2H), 6.62 (s, 1H), 7.18 (m, 2H), 7.35 (m, 2H), 7.66 (m, 1H), 8.38 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12](C)=[C:11]2[C:6]([C:7]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1.[CH3:30]CCCCC.CCOC(C)=O>C1COCC1>[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([N:17]2[CH2:16][CH2:15][N:14]([C:7]3[C:6]4[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:10]=[C:9]([CH3:30])[CH:8]=3)[CH2:19][CH2:18]2)=[O:29])=[CH:23][CH:22]=1
Reactant: COc1ccc2c(N3CCNCC3)ccnc2c1C
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2c(N3CCN(C(=O)Nc4ccc(F)cc4)CC3)cc(C)nc2c1

Procedure:
7-Methoxy-8-methyl-4-(piperazin-1-yl)quinoline (0.20 g, 0.8 mmol) and 4-fluorophenyl isocyanate (102 μL, 0.9 mmol) in THF (10 mL) are reacted according to method C yielding the product as a yellow solid after column chromatography with hexane-EtOAc.
Reaction SMILES: C(N(CC)CC)C.[C:8](=[S:10])=S.[CH:11]([C:14]1[C:19]([NH2:20])=[C:18]([CH:21]([CH3:23])[CH3:22])[CH:17]=[C:16]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[N:15]=1)([CH3:13])[CH3:12].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[CH:11]([C:14]1[C:19]([N:20]=[C:8]=[S:10])=[C:18]([CH:21]([CH3:23])[CH3:22])[CH:17]=[C:16]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[N:15]=1)([CH3:12])[CH3:13]
Reactant: S=C=S
Reactant: CC(C)c1cc(Oc2ccc(Cl)cc2)nc(C(C)C)c1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(C)c1cc(Oc2ccc(Cl)cc2)nc(C(C)C)c1N=C=S
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 5.0 g of triethylamine in 10 ml of pyridine is cooled to from -5° C. to -10° C., and 20 ml of carbon disulfide are added dropwise. At -10° C., a solution of 15.0 g of 2,4-diisopropyl-6-(4-chlorophenoxy)-3-aminopyridine in 27 ml of pyridine is slowly added dropwise. The mixture is further stirred at -10° C. for 1 hour. A solution of 10.0 g of N,N'-dicyclohexylcarbodiimide in 10 ml of pyridine is then added. After a further 3 hours at -10° C., the mixture is stirred for 18 hours at room temperature. The reaction mixture is concentrated by evaporation and hexane is added to the residue. Thehhexane solution is filtered off and concentrated by evaporation. 2,4-Diisopropyl-6-(4-chlorophenoxy)-pyrid-3-yl isothiocyanate is obtained in the form of a yellow oil, which is used for the next reaction without being further purified; IR (CCl 4): 2090, 1490, 1220 cm-1.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:14])[CH2:9]2)=[C:4]2[CH:15]=[N:16][CH:17]=[CH:18][C:3]=12.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C(OCC)(=O)C.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>[CH3:14][C@@H:10]1[NH:11][CH2:12][CH2:13][N:8]([C:5]2[N:6]=[N:7][C:2]([C:24]3[CH:25]=[CH:26][C:21]([C:20]([F:31])([F:30])[F:19])=[CH:22][CH:23]=3)=[C:3]3[CH:18]=[CH:17][N:16]=[CH:15][C:4]=23)[CH2:9]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: C[C@H]1CN(c2nnc(Cl)c3ccncc23)CCN1
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: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@H]1CN(c2nnc(-c3ccc(C(F)(F)F)cc3)c3ccncc23)CCN1
Temperature: 100 °C
Reaction time: 16 h
Yield: 70.1 %

Procedure:
To a round bottomed flask was added (S)-1-chloro-4-(3-methylpiperazin-1-yl)pyrido[3,4-d]pyridazine 4 (155 mg, 588 μmol), 4-trifluoromethylphenylboronic acid (167 mg, 882 μmol), tetrakis(triphenylphosphine)palladium (34 mg, 29 μmol), and 2 M aqueous sodium carbonate (588 μl, 1.18 mmol). Toluene (5.9 mL) was added and the reaction was heated to 100° C. After 16 h, the reaction was cooled to RT and diluted with ethyl acetate (70 mL). The organic layer was washed with 1×10 mL of sat. NaHCO3, 1×10 mL of brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by column chromatography (10:0.5:0.1) (CH2Cl2:MeOH:Et3N) afforded (S)-4-(3-methylpiperazin-1-yl)-1-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazine 47 (154 mg, 70% yield). 1H-NMR (400 MHz, CDCl3): δ 9.55 (d, J=0.8 Hz, 1H), 8.90 (d, J=5.5 Hz, 1H), 7.86 (m, 4H), 7.73 (dd, J=5.5, 0.8 Hz, 1H), 4.09 (m, 2H), 3.37 (ddd, J=12.5, 11.0, 3.5 Hz, 1H), 2.23 (m, 3H), 2.99 (dd, J=12.5, 10.2 Hz, 1H), 2.85 (br s, 1H), 1.17 (d, J=6.3 Hz, 1H). MS 373.1 (calc'd) 374.0 (M+H, found).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[CH:18]=2)[N:9]=1.[C:32]1(=O)[CH2:36][CH2:35][CH2:34][CH2:33]1.CO>C(Cl)(Cl)Cl.C(Cl)Cl>[CH:32]1([N:5]2[CH2:6][C@@H:1]3[CH2:7][C@H:4]2[CH2:3][N:2]3[C:8]2[N:13]3[CH:14]=[CH:15][N:16]=[C:12]3[CH:11]=[C:10]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@H:24]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH3:25])[CH:18]=3)[N:9]=2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CC(Nc1cc(-c2cc3nccn3c(N3CC4CC3CN4)n2)ccn1)c1ccccc1
Reactant: O=C1CCCC1
Solvent: CO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: C[C@H](Nc1cc(-c2cc3nccn3c(N3C[C@@H]4C[C@H]3CN4C3CCCC3)n2)ccn1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 120 mg (0.28 mmol) {4-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-imidazo[1,2-c]pyrimidin-7-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 3 mL chloroform was treated with 0.25 mL (2.8 mmol) cyclopentanone and 180 mg (0.84 mmol) NaBH3(CN), followed by addition of 5 mL methanol. The mixture was stirred at ambient temperature for 3 h when MS showed that all starting materials had converted to product. The reaction mixture was diluted with 50 mL DCM, washed with 50 mL satd. NaHCO3, and dried over anhydrous Na2SO4. After purification by HPLC, the title compound was obtained. MS (ES+): 480 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:18]1[C:19]2[CH:27]=[C:26]([Cl:28])[N:25]=[CH:24][C:20]=2[N:21]=[CH:22][N:23]=1>>[C:1]1([S:7]([C:10]2[CH:16]=[CH:15][C:13]([NH:14][C:18]3[C:19]4[CH:27]=[C:26]([Cl:28])[N:25]=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:12][CH:11]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Reactant: Clc1cc2c(Cl)ncnc2cn1
Product: O=S(=O)(c1ccccc1)c1ccc(Nc2ncnc3cnc(Cl)cc23)cc1

Procedure:
Prepared according to Procedure A from 4-benzenesulphonylaniline (Helv. Chim. Acta., 1983, 66 (4), 1046) and 4,6-dichloropyrido[3,4-d]pyrimidine; δH [2H6]-DMSO 9.09 (1H, s), 8.80-8.88 (2H, m), 8.19 (2H, d), 7.94-8.09 (4H, m), 7.53-7.20 (3H, m); m/z (M+1)+397.