Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[C:11]([CH3:16])=[N:12][CH:13]=[CH:14][CH:15]=1.[CH2:17]([N:22]1[C:30]2[C:25](=[CH:26][C:27]([CH3:31])=[CH:28][CH:29]=2)[C:24](=[O:32])[C:23]1=[O:33])[CH2:18][CH:19]([CH3:21])[CH3:20]>>[Br:9][C:10]1[C:11]([CH2:16][C:24]2([OH:32])[C:25]3[C:30](=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=3)[N:22]([CH2:17][CH2:18][CH:19]([CH3:20])[CH3:21])[C:23]2=[O:33])=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1ncccc1Br
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2CCC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: Cc1ccc2c(c1)C(O)(Cc1ncccc1Br)C(=O)N2CCC(C)C
Temperature: -78 °C
Yield: 8 %

Procedure:
To a flame dried flask cooled under argon was added freshly prepared LDA (0.82 mL, 0.48 mmol, 0.38M in anhydrous THF). While stirring at −78° C., 3-bromo-2-methylpyridine (50 μL, 0.48 mmol, purchased from Aldrich) was added. The solution stirred at this temperature for two hours at which point a 1-isopentyl-5-methylindoline-2,3-dione (0.045 grams, 0.19 mmol, 0.4 M in THF) was added. The solution was then warmed to room temperature slowly. Once all of the starting material had been consumed, the reaction was quenched with ammonium chloride (saturated), diluted with ethyl acetate, and the organic layer removed. The aqueous layer was salted out using sodium chloride and washed two more times with ethyl acetate. The combined organic material was dried with sodium sulfate, filtered, and concentrated. Purification was done on preparative thin layer chromatography using hexanes/ethyl acetate (2:1) to afford the desired material. (8% Yield). 1H NMR δ 8.53 (dd, 1H), 7.89 (dd, 1H), 7.17-7.09 (m, 3H), 7.03 (d, 1H), 6.73 (d, 1H), 3.83-57 (m, 2H), 3.52 (d, 1H), 3.34 (d, 1H), 2.30 (s, 3H), 1.65 (m, 1H), 1.54 (m, 2H), 0.96 (dd, 6H). Calculated mass for C20H23BrN2O2 402.09, observed, 425.1 (M+Na).
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH3:5][O:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([CH3:14])[CH:8]=1>O.C(O)(=O)C>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:10](=[CH:12][CH:13]=1)[NH:11][N:1]=[CH:14]2
Reactant: O=N[O-]
Reactant: COc1ccc(N)c(C)c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
A solution of sodium nitrite (3.38 g, 49.0 mmol) in water (8.1 ml) was added to a solution of 4-methoxy-2-methylaniline (6.69 g, 48.8 mmol) in acetic acid (350 ml) in an ice-water bath while maintaining the temperature at 25° C. or lower, and stirred overnight at room temperature. Then, the reaction solution was poured into water and extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=9/1) to obtain 5-methoxy-1H-indazole (1.30 g, 18%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:14](=O)[CH2:15]Br>>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:14]2[N:1]=[C:2]3[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]3[CH:15]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(C(=O)CBr)cc1OC
Reactant: Cc1ccnc(N)c1
Product: COc1ccc(-c2cn3ccc(C)cc3n2)cc1OC

Procedure:
The title compound, pale yellow solid, m.p. 163° C. and MS: m/e=268.1 (M+), was prepared in accordance with the general method of example 1 from 2-amino-4-methyl-pyridine and 3,4-dimethoxy-phenacylbromide.
Reaction SMILES: [OH:1][C@H:2]([C:10]1[CH:19]=[CH:18][C:13]2[C:14](=[O:17])[O:15][CH2:16][C:12]=2[C:11]=1[CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH3:21][C:22]1[C:27]([C:28]#[N:29])=[CH:26][CH:25]=[C:24]([CH:30]2[CH2:32][O:31]2)[N:23]=1>>[OH:31][CH:30]([C:24]1[N:23]=[C:22]([CH3:21])[C:27]([C:28]#[N:29])=[CH:26][CH:25]=1)[CH2:32][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][C@H:2]([OH:1])[C:10]2[C:11]([CH3:20])=[C:12]3[C:13](=[CH:18][CH:19]=2)[C:14](=[O:17])[O:15][CH2:16]3)[CH2:5][CH2:6]1
Reactant: Cc1c([C@@H](O)CN2CCNCC2)ccc2c1COC2=O
Reactant: Cc1nc(C2CO2)ccc1C#N
Product: Cc1nc(C(O)CN2CCN(C[C@H](O)c3ccc4c(c3C)COC4=O)CC2)ccc1C#N

Procedure:
6-[1-Hydroxy-2-[4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-2-methyl-pyridine-3-carbonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLE 58 starting from 5-[(1R)-1-hydroxy-2-(piperazin-1-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one and 2-methyl-6-(oxiran-2-yl)pyridine-3-carbonitrile.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([CH2:14][CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[N:3]=1.[NH2:20][NH2:21]>O1CCOCC1>[NH:20]([C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([CH2:14][CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[N:3]=1)[NH2:21]
Reactant: NN
Reactant: CC(C)(O)CCc1nc(Cl)cc(N2CCOCC2)n1
Solvent: C1COCCO1
Product: CC(C)(O)CCc1nc(NN)cc(N2CCOCC2)n1
Yield: 80 %

Procedure:
4-(4-chloro-6-morpholin-4-yl-pyrimidin-2-yl)-2-methyl-butan-2-ol (3.3 g, 11.5 mmol) was dissolved in dioxane (30 mL). To the reaction mixture was added anhydrous hydrazine (7.5 mL, 220 mmol). The reaction was then heated at reflux for five hours. The solvent was removed under reduced pressure, and the crude solid was dissolved in a mixture of dichloromethane (800 mL) and 10% potassium carbonate (40 mL). The organic layer was isolated, dried with sodium sulfate, and evaporated to give 4-(4-hydrazino-6-morpholin-4-yl-pyrimidin-2-yl)-2-methyl-butan-2-ol (2.61 g, 9.2 mmol).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([OH:32])[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:45].S(Cl)(C1C=CC(C)=CC=1)(=O)=O>ClCCl.O>[NH2:45][C:9]1[C:8]2[N:17]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:18][C:19]3([OH:32])[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 15 %

Procedure:
To a solution of tert-butyl 4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-hydroxypiperidine-1-carboxylate (96%, 10.0 g, 22.7 mmol) in dichloromethane (150 mL) at rt was added m-CPBA (55%, 7.12 g, 22.7 mmol). After 1.5 h, the mixture was cooled to 0° C. and concentrated ammonium hydroxide (150 mL) was added, followed by TsCl (4.54 g, 23.8 mmol). The reaction was stirred rapidly overnight. More TsCl (1.00 g and 0.47 g) was added as the mixture was stirred an additional 6 h. Water (200 mL) was added and the mixture was extracted with dichloromethane (3×200 mL). The combined organic phases were washed with brine (3×250 mL) and dried over MgSO4, filtered, and concentrated to a foam, which was crystallized from acetonitrile twice. The fine yellow crystals were dried under vacuum to yield 1.60 g (15%) of tert-butyl 4-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-hydroxypiperidine-1-carboxylate, mp 195-197° C. 1H NMR (CDCl3, 300 MHz) δ 8.04 (dm, J=8.3 Hz, 1H), 7.82 (dm, J=8.3 Hz, 1H), 7.53 (m, 1H), 7.31 (m, 1H), 5.40 (br s, 2H), 4.85 (s, 2H), 4.75 (br s, 2H), 3.93 (br s, 3H), 3.72 (q, J=7.0 Hz, 2H), 3.03 (m, 2H), 1.76 (m, 2H), 1.49-1.40 (m, 2H), 1.42 (s, 9H), 1.27 (t, J=7.0 Hz, 3H); MS (APCI) m/z 456 (M+H+); Anal. calcd for C24H33N5O4: C, 63.28; H, 7.30; N, 15.37. Found: C, 63.32; H, 7.53; N, 15.39.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=1)=[O:21]
Reactant: COc1ccccc1NS(C)(=O)=O
Reactant: O=C(Cl)CCCCCBr
Product: COc1ccc(C(=O)CCCCCBr)cc1NS(C)(=O)=O

Procedure:
Using N-(2-methoxyphenyl)methanesulfonamide (10.0 g) and 6-bromohexanoyl chloride (8.37 ml) according to the same method as that of Reference Example 1, the title compound (9.80 g) was obtained as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[O:14]=[C:11]1[NH:12][N:13]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:15](=[O:17])[CH3:16])[CH:7]=[CH:6][CH:5]=2)[CH:9]=[CH:10]1
Reactant: Nc1cccc(-c2ccc(=O)[nH]n2)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc(-c2ccc(=O)[nH]n2)c1

Procedure:
A mixture of 37 g of 6-(3-aminophenyl)-3(2H)-pyridazinone and 500 ml of acetic anhydride was heated at 85°-90° C. for 8 hours. The solvent was removed in vacuo and the residue dissolved in 500 ml of methanol. To this solution was added portionwise 40 g of potassium hydroxide. The solution was refluxed for 3 hours and the solvent removed in vacuo. The residue was dissolved in water and the solution neutralized with hydrochloric acid. The resulting solid was collected and recrystallized from dichloromethane-methanol, giving 10.8 g of the desired compound as crystals, mp 250°-252° C. (dec.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[CH3:17][S:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>C(O)C>[CH3:17][S:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:23]=[CH:24][CH:25]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Reactant: CSc1cccc(N)c1
Solvent: CCO
Product: CSc1cccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)c1
Reaction time: 2 h
Yield: 67 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-3-quinolinecarbonitrile, 200 ml ethanol, and 3.18 ml (25.8 mmol) 3-methylsulfanylaniline was heated to reflux under N2. At 2 hours, removed heat and made basic with saturated sodium bicarbonate. Stripped solvents and air dried. Washed residue with hexane, collected solids and washed with water. Dissolved in ethyl acetate, stirred with Darco, stripped solvent and dried in vacuo, giving 4.848 g of yellow solid: mass spectrum (electrospray m/e): M+H=337.1.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6](=[O:26])[C:7](=[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4]>>[CH2:3]([O:5][C:6](=[O:26])[CH:7]([CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:17][CH2:18]1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4]
Reactant: CCOC(=O)C(C(=O)OCC)=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Na+]
Product: CCOC(=O)C(C(=O)OCC)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To IMS (200 mL) at 0° C., NaBH4 (1.87 g, 0.047 mol) and a solution of 2-(1-(tert-butoxycarbonyl)piperidin-4-ylidene)malonic acid diethyl ester (17 g, 0.050 mol) in IMS (200 mL) were added. The resulting mixture was allowed to warm to ambient temperature and stirred for 1 h, then quenched with water and concentrated in vacuo. The resulting oil was then partitioned between EtOAc and water. The organic layer was separated and washed with brine, then dried (MgSO4) and concentrated in vacuo to afford the title compound as a yellow oil (14.6 g, 85%). LCMS (Method H): RT=3.90 min, [M+Na]+ 366.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:8]([C:9](=[O:18])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:7]1[C:19](=[O:40])[NH:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35](O)=[O:36])=[CH:29][C:28]2=[O:38])=[CH:23][C:22]=1[F:39])=[O:5])[CH3:2].Cl.[CH3:42][NH:43][CH3:44].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH:7]([C:19](=[O:40])[NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35](=[O:36])[N:43]([CH3:44])[CH3:42])=[CH:29][C:28]3=[O:38])=[CH:23][C:22]=2[F:39])[CH:8]1[C:9](=[O:18])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(C(=O)Nc2ccc(Cl)cc2)C1C(=O)Nc1ccc(-n2ccc(OCC(=O)O)cc2=O)cc1F
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)C1C(C(=O)Nc2ccc(Cl)cc2)C1C(=O)Nc1ccc(-n2ccc(OCC(=O)N(C)C)cc2=O)cc1F
Temperature: 25 °C
Reaction time: 10 h
Yield: 91.8 %

Procedure:
A mixture of 23 mg (0.04 mmol) of (1SR,2RS,3SR) 2-[4-(4-carboxymethoxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenylcarbamoyl]-3-(4-chloro-phenylcarbamoyl) cyclopropanecarboxylic acid ethyl ester (example 155), 5 mg (0.06 mmol) of dimethylamine hydrochloride, 1 mg of 1-hydroxybenzotriazole, and 25 ul (0.23 mmol) of N-methylmorpholine in 2.5 ml of DMF was treated with 11 mg (0.06 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and stirred at RT during 10 hrs. The mixture was poured into a 2M aqueous solution of HCl and extracted with AcOEt. Drying of the combined organic phases over Na2SO4, filtration, evaporation of the solvent and chromatography on silica gel with AcOEt/MeOH 10:1 gave 22 mg (95%) of (1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[4-(4-dimethylcarbamoylmethoxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenylcarbamoyl]-cyclopropanecarboxylic acid ethyl ester. Light brown solid. MS: 600 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[C:8]([CH:10]2[C:19]3[C:18](=[O:20])[CH2:17][CH:16]([CH2:21][CH2:22][CH3:23])[CH2:15][C:14]=3[NH:13][C:12]([CH3:24])=[C:11]2[C:25]#[N:26])[CH:7]=[C:6]([Br:27])[C:5]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1.C(O)(=O)C>O1CCOCC1.[OH-].[Na+]>[Br:27][C:6]1[C:5]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=2)=[C:4]([CH:9]=[C:8]([CH:10]2[C:19]3[C:18](=[O:20])[CH2:17][CH:16]([CH2:21][CH2:22][CH3:23])[CH2:15][C:14]=3[NH:13][C:12]([CH3:24])=[C:11]2[C:25]#[N:26])[CH:7]=1)[C:3]([OH:38])=[O:2]
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCc2cccc(OC)c2)c(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCc2cccc(OC)c2)c(C(=O)O)c1

Procedure:
A solution of 3-bromo-5-(3-cyano-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinolin-4-yl)-2-(3-methoxy-benzyloxy)-benzoic acid methyl ester (5.7 g) in dioxane (135 ml) and 1N NaOH (15 ml) was stirred for 17 h. The mixture was acidified with conc. acetic acid and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in ethanol and then concentrated until a solid precipitated. The solid was collected by filtration and washed with petroleum ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:23])[C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]2)[C:10]1=[O:22].[C:32]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.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>[Cl:1][C:2]1[CH:3]=[C:4]([C:44]2[CH:45]=[CH:46][C:41]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:42][CH:43]=2)[CH:5]=[C:6]([Cl:23])[C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]2)[C:10]1=[O:22]
Reactant: O=C1C(N2CCC(F)(F)CC2)CCN1Cc1c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc1Cl
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
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: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1C(N2CCC(F)(F)CC2)CCN1Cc1c(Cl)cc(-c2ccc(-c3ccccc3)cc2)cc1Cl
Temperature: 80 °C
Yield: 100.1 %

Procedure:
Purge with N2 a mixture of trifluoro-methanesulfonic acid 3,5-dichloro-4-[3-(4,4-difluoro-piperidin-1-yl)-2-oxo-pyrrolidin-1-ylmethyl]-phenyl ester (0.097 g, 0.19 mmol), 4-biphenylboronic acid (0.045 g, 0.23 mmol) in THF (5 mL), and 2M sodium carbonate (0.29 mL). Treat the reaction with Pd(PPh3)4 (0.011 g, 0.01 mmol) and heat to 80° C. for 1 hour under N2. Cool the reaction, dilute with ethyl acetate, and wash with water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product. Purify on silica with 100% ethyl acetate to afford 0.098 g (100%) of the titled product. Rf=0.44 (100% ethyl acetate). MS (m/z): 515 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:34]([N:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH2:45]O)[CH2:39][CH2:38]1)[CH:35]=[CH2:36].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH2:34]([N:37]1[CH2:38][CH2:39][N:40]([CH2:43][CH2:44][CH2:45][O:14][C:8]2[CH:7]=[C:6]3[C:11]([C:2]([Cl:1])=[N:3][CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])[CH2:41][CH2:42]1)[CH:35]=[CH2:36]
Reactant: C=CCN1CCN(CCCO)CC1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=CCN1CCN(CCCOc2cc3ncnc(Cl)c3cc2OC)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-chloro-7-hydroxy-6-methoxyquinazoline (300 mg, 1.43 mmol), (prepared as described for the starting material in Example 4), in methylene chloride (15 ml) was added triphenylphosphine (522 mg, 2.0 mmol), 3-(4-allylpiperazin-1-yl)propan-1-ol (288 mg, 1.57 mmol), (DE 2755707), and diisopropyl azodicarboxylate (336 μl, 1.71 mmol) and the mixture stirred at ambient temperature for 2 hours. The crude reaction mixture was loaded directly onto a silica chromatography column and eluted with methylene chloride/methanol (95/5). The volatile solvents were removed under vacuum to give 7-[3-(4-allylpiperazin-1-yl)propoxy]-4-chloro-6-methoxyquinazoline as an oil which crystallised on standing (480 mg, 89%).
Reaction SMILES: [CH2:1]([S:4]([N:7]1[CH2:10][C:9]([CH2:17][NH2:18])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:8]1)(=[O:6])=[O:5])[CH2:2][CH3:3].CCN(C(C)C)C(C)C.[Cl:28][C:29]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>C(Cl)Cl>[Cl:28][C:29]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:30]=1[C:31]([NH:18][CH2:17][C:9]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:10][N:7]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:5])=[O:6])[CH2:8]1)=[O:32]
Reactant: CCCS(=O)(=O)N1CC(CN)(c2ccccn2)C1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCS(=O)(=O)N1CC(CNC(=O)c2ccc(Cl)cc2Cl)(c2ccccn2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-[1-(propylsulfonyl)-3-pyridin-2-ylazetidin-3-yl]methanamine (II-2, 10 mg, 0.04 mmol) in CH2Cl2 (1 mL) was treated with i-Pr2NEt (0.1 mL, 0.58 mmol), 2,4-dichlorobenzoyl chloride (20 μL, 0.14 mmol), and stirred at room temperature. After 3 h, volatiles were removed under a stream of N2 and the residue purified by reverse phase HPLC to afford 2,4-dichloro-N-{[1-(propylsulfonyl)-3-pyridin-2-ylazetidin-3-yl]methyl}benzamide (II-3) as a white amorphous solid.
Reaction SMILES: CS[C:3]1[S:4][C:5](=[CH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20]#[N:21])=[C:13]3[C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[C:6](=[O:8])[N:7]=1.[NH3:28]>CO>[NH2:28][C:3]1[S:4][C:5](=[CH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20]#[N:21])=[C:13]3[C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[C:6](=[O:8])[N:7]=1
Reactant: CSC1=NC(=O)C(=Cc2ccc3ncc(C#N)c(-c4cccnc4)c3c2)S1
Reactant: N
Solvent: CO
Product: N#Cc1cnc2ccc(C=C3SC(N)=NC3=O)cc2c1-c1cccnc1

Procedure:
Similar procedure as described in example 41c was used, starting from 6-(2-methylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-4-pyridin-3-yl-quinoline-3-carbonitrile (example 63e), and ammonia in methanol to give 6-(2-amino-4-oxo-4H-thiazol-5-ylidenemethyl)-4-pyridin-3-yl-quinoline-3-carbonitrile. Flash chromatography using a small amount of trifluoroacetic acid as a cosolvent gave 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-pyridin-3-yl-quinoline-3-carbonitrile; compound with trifluoro-acetic acid. LC-MS m/e 358 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][NH:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:13]([CH3:12])[CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNCCN1CCCC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: ClCCl
Product: CN(CCN1CCCC1)S(=O)(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
To a solution of 6-chloropyridine-3-sulfonylchloride (636 mg, 3 mmol; described in: Naegeli, C. et al. Helv. Chim. Actal. 1938, 21, 1746-1750) in methylene chloride (10 mL) was added methyl-(2-pyrrolidin-1-ylethyl)amine (384 mg, 3 mmol; described in: J. Amer. Chem. Soc. 1955, 77, 3632-3634) dissolved in methylene chloride (10 mL) dropwise. The reaction mixture was stirred over night at room temperature followed by the extraction with aqueous HCl (3%). The acidic water layer was alkalized with an aqueous saturated solution of NaHCO3 and extracted with methylene chloride. The organic phase was dried (Na2SO4) and evaporated in vacuo to give 0.75 gram (80% yield) of the title compound: MS (ES) m/z 304 (M++1).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:7][CH2:6][C:5]([C:8]2[C:9]([NH:14][C:15]([NH:17]C(OCC)=O)=S)=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH2:3]1.Cl.[NH2:25]O.CO>C(O)C>[CH3:23][C:2]1([CH3:1])[CH2:7][CH2:6][C:5]([C:8]2[C:9]3[N:10]([N:25]=[C:15]([NH2:17])[N:14]=3)[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH2:3]1
Reactant: NO
Reactant: CCOC(=O)NC(=S)Nc1ncccc1C1=CCC(C)(C)CC1
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CC1(C)CC=C(c2cccn3nc(N)nc23)CC1
Temperature: 70 °C
Yield: 62.4 %

Procedure:
To a solution of N-[3-(4,4-dimethyl-cyclohex-1-enyl)-pyridin-2-yl]-N′-carboethoxy-thiourea (1.42 g, 3.48 mmol) in ethanol (4.3 mL) was added at room temperature hydroxylamine hydrochloride (1.50 g, 21.4 mmol) and methanol (4.3 mL). The yellow suspension was heated to 70° C. over night. The solvent was evaporated under reduced pressure and the residue was partitionated between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate and the organic layers were combined, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude material was purified by column chromatography on silica gel first with ethyl acetate as the eluent and then once again with a mixture of heptane/ethyl acetate (1:1 v/v) as the eluent to yield the title compound as a yellow solid (526 mg, 51%).