Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH2:2]([CH:10]([C:16]([O:18]CC)=O)[C:11]([O:13]CC)=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[NH2:21][C:22]([NH2:24])=[O:23]>C(O)C>[CH2:2]([CH:10]1[C:11](=[O:13])[NH:24][C:22](=[O:23])[NH:21][C:16]1=[O:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: NC(N)=O
Reactant: CCCCCCCCC(C(=O)OCC)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCC1C(=O)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
To a solution of sodium (5.32 g) in 400 ml of anhydrous ethanol is added a solution of diethyl 2-octylmalonate (31.5 g) in 50 ml of ethanol and successively 10.27 g of urea, then the mixture is refluxed for 2 hours 30 minutes. The mixture is rapidly cooled to room temperature and the solid which was formed is recovered by filtration and washed with diethyl ether. The solid is then dissolved in 200 ml. of water and acidified with 6 N hydrochloric acid until pH 1.5-2 is reached. A solid separates. The mixture is added with 200 ml of ethyl acetate and it is stirred for 2 hours, then it is added with additional 800 ml of warm ethyl acetate. The organic phase is separated and the aqueous phase is washed with 200 ml of ethyl acetate. The pooled organic phases are washed with 250 ml of saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated to dryness. 21.03 g of the product are obtained.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:25][N:24]=[C:23](/[C:26](=[N:32]/[OH:33])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:22]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][F:42].C(OCC)(=O)C>CS(C)=O>[C:1]([NH:20][C:21]1[S:25][N:24]=[C:23](/[C:26](=[N:32]/[O:33][CH2:41][F:42])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:22]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C(=N\O)c1nsc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: FCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)/C(=N\OCF)c1nsc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.17 h
Yield: 90.1 %

Procedure:
Ethyl 2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z)-2-hydroxyiminoacetate (60.4 g) was dissolved in dimethylsulfoxide (210 ml), followed by an addition of potassium carbonate (96.48 g) under ice-cooling. The resulting mixture was stirred for 10 minutes. Bromofluoromethane (19 g) was thereafter added, followed by stirring at room temperature for 3 hours. Ethyl acetate (1 l) was added to the reaction mixture. The resulting mixture was washed with water and then with saturated saline, and was added with anhydrous magnesium sulfate to dry the mixture. The solvent was distilled out and ethanol (120 ml) was added to the residue. Crystals thus precipitated were collected by filtration and then washed to obtain 58.2 g of the title compound.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH:12]([CH3:14])[CH2:11][N:10]=[C:9]1[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.NN>C(O)C.[Ni]>[C:1]([N:8]1[CH2:13][CH:12]([CH3:14])[CH2:11][N:10]=[C:9]1[C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=1)([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: CC1CN=C(c2ccc([N+](=O)[O-])cc2)N(C(=O)OC(C)(C)C)C1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CC1CN=C(c2ccc(N)cc2)N(C(=O)OC(C)(C)C)C1
Temperature: 75 °C
Yield: 98.4 %

Procedure:
Raney Ni (19.0 g) was added to a 500 mL 3-necked round bottom flask, followed by washing with anhydrous ethanol (30 mL×3) and then ethanol (50 mL) was added. To the suspension was added a solution of compound 4 (16.6 g, 52.0 mmol, 1.0 eq) in ethanol (230 mL). Hydrazine monohydrate (10.4 g 208 mmol, 4.0 eq) was added dropwise at 50° C., followed by heating to 75° C. for 5 min. Upon cooling to room temperature, the catalyst was removed by suction filtration through celite. The filtrate was evaporated to dryness, then co-evaporated with toluene twice and finally dried at 60-65° C. for 30 min under reduced pressure to give compound 1 (14.8 g) in 99% yield.
Reaction SMILES: [CH:1]1([PH:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:14]1(=[O:20])[CH2:19][CH2:18][CH2:17][CH:16]=[CH:15]1>>[CH:8]1([P:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:16]2[CH2:17][CH2:18][CH2:19][C:14](=[O:20])[CH2:15]2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: C1CCC(PC2CCCCC2)CC1
Reactant: O=C1C=CCCC1
Product: O=C1CCCC(P(C2CCCCC2)C2CCCCC2)C1
Temperature: 60 °C

Procedure:
A 250 ml round-bottomed flask fitted with a condenser, nitrogen purge, and addition funnel was charged with a solution of 89.7 g (0.45 mol) dicyclohexylphosphine and heated to 60° C. with stirring. To the flask was added 50.8 g (0.53 mol) 2-cyclohexen-1-one over a period of 0.5 hour. When addition was complete, the temperature of the contents of the flask was slowly raised to 90° C. and maintained at that temperature for 6 hours, then cooled. Unreacted starting materials were removed by evaporation under reduced pressure at 150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:22]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([F:22])=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(F)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 1 h

Procedure:
A solution of 5-chloro-1H-indole-2-carboxylic acid (10.0 g, 51.1 mmol) and pyridine (33.1 mmol) in acetonitrile was added to a solution of cyanuric fluoride (2.76 g, 20.4 mmol) in acetonitrile (total 340 mL) at 25° C. The reaction was followed by TLC on aliquots quenched with butylamine and appeared nearly complete at 1 hour. The mixture was poured onto ice, extracted with ether, dried (Na2SO4), and concentrated giving a solid which was used without purification (10.0 g, 99%). TLC of a butylamine-quenched aliquot showed some 5-chloroindole-2-carboxylic acid and the less polar N-butylamide. A sample was purified by chromatography on silica gel eluting with ethyl acetate-hexanes (50-100%) for characterization (16368-130-1).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]1[CH:17]=[C:18]([C:22]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:19]=[CH:20][CH:21]=1)([CH3:3])[CH3:2].[C:30]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH2:12][CH2:13][N:14]([CH2:15][C:16]1[CH:17]=[C:18]([C:22]([N:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:23])[CH:19]=[CH:20][CH:21]=1)[CH3:30])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)Oc1ccccc1NCCNCc1cccc(C(=O)N2CCCCC2)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)Oc1ccccc1NCCN(C)Cc1cccc(C(=O)N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 45.2 %

Procedure:
To a solution of (3-{[2-(2-isopropoxy-phenylamino)-ethylamino]-methyl}-phenyl)-piperidin-1-yl-methanone (Example 1; 0.032 g, 0.081 mmol) in DMF (0.8 mL) was added K2CO3 (0.022 g, 0.16 mmol) and iodomethane (0.03 g, 0.2 mmol), and the resulting suspension was stirred at 25° C. for 45 min. The suspension was partitioned with EtOAc (20 mL) and H2O (20 mL), and the organic layer was washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by preparative TLC (2% CH3OH/CH2Cl2) to provide a colorless oil (0.015 g, 47%). MS (ESI): mass calculated for C26H35N3O2, 409.27. m/z found, 410.5 [M+H]+, 432.4 [M+Na]+. 1H NMR (CDCl3, 400 MHz): 7.46 (d, J=7.6 Hz, 1H), 7.36-7.31 (m, 2H), 7.27-7.25 (m, 1H), 6.84 (dt, J=7.8, 1.3 Hz, 1H), 6.78 (dt, J=7.8, 1.3 Hz, 1H), 6.63 (dt, J=7.8, 1.6 Hz, 1H), 6.58 (dt, J=7.8, 1.6 Hz, 1H), 4.53 (hept, J=6.1 Hz, 1H), 3.70 (br s, 2H), 3.60 (br s, 2H), 3.31 (br s, 2H), 3.20 (t, J=6.1 Hz, 2H), 2.73 (t, J=6.1 Hz, 2H), 2.20 (s, 3H), 1.62-1.46 (m, 6H), 1.37 (d, J=6.1 Hz, 6H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Cl:8].[SH:9][CH2:10][CH2:11][CH2:12][Si:13]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].CC[O-].[Na+]>>[Si:13]([CH2:12][CH2:11][CH2:10][S:9][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Cl:8])([O:17][CH2:18][CH3:19])([O:20][CH2:21][CH3:22])[O:14][CH2:15][CH3:16]
Reactant: CCO[Si](CCCS)(OCC)OCC
Reactant: ClCCCCCCCl
Agent: CC[O-]
Agent: [Na+]
Product: CCO[Si](CCCSCCCCCCCl)(OCC)OCC
Temperature: 80 °C

Procedure:
A 1-liter separable flask equipped with a nitrogen gas inlet, thermometer, Dimroth condenser and dropping funnel was charged with 310.0 g (2.0 mol) of 1,6-dichlorohexane and heated at 80° C. With stirring, the reaction product of 3-mercaptopropyltriethoxysilane with sodium ethylate was slowly added dropwise. After the completion of dropwise addition, the solution was continuously stirred at 80° C. for 5 hours, and then cooled. From the solution, the salt was filtered off and the ethanol and excess 1,6-dichlorohexane were distilled off in vacuum. The residual solution was subjected to vacuum distillation, collecting 64.2 g of a colorless clear liquid at a boiling point of 148–150° C./0.005 Torr. On analysis by IR, 1H-NMR and MS, the liquid was identified to be a compound of the following formula. (CH3CH2O)3Si(CH2)3S(CH2)6Cl Analysis by gas chromatography gave a purity of 98.7%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:12](Cl)(=[O:22])[C:13]1[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:15](Cl)=[O:16].Cl>N1C=CC=CC=1>[O:16]=[C:15]1[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[C:12](=[O:22])[N:1]1[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccc(N2C(=O)c3ccccc3C2=O)cc1
Temperature: 60 °C
Yield: 90.1 %

Procedure:
A solution of 1.0 g (5.8 mmol) of p-aminophenylsulfonamide in 3.6 mL of pyridine was added 878 μL (6.1 mmol) of phthalic dichoride. After heating to 60° C. for 18 h, the solution was poured into 1N HCl, cooled to 0° C., the precipitate was collected by filtration, and dried under vacuum to give 1.58 g (90%) of the titled compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH:12]1[C:24](O)=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH:12]1[CH:24]=[O:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1c2[nH]c3ccccc3c2CCN1C(=O)OCc1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=CC1c2[nH]c3ccccc3c2CCN1C(=O)OCc1ccccc1
Reaction time: 4 h

Procedure:
A solution of 1,3,4,9-tetrahydro-beta-carboline-1,2-dicarboxylic acid 2-benzyl ester (3.7 mg, 9.4 mmol) in THF (100 ml) under N2 was cooled to −78° C. 1.5M DIBAL in toluene solution (31.2 ml, 47 mmol) was added over 2 hours. After stirring for 4 hours the reaction mixture was quenched with methanol and water, extracted into EtOAc and washed with dilute aqueous HCl. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. LCMS purity 50%, m/z 335 [M++H]+ The material was used in the next stage without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]3[CH:13]=[C:14]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH:20]([OH:24])[CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[C:4]([F:25])[N:3]=1.[O:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1>>[F:25][C:4]1[CH:5]=[C:6]([C:8]2[N:12]3[CH:13]=[C:14]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH:20]([OH:24])[CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:7]=[C:2]([C:28]2[CH:29]=[CH:30][O:26][CH:27]=2)[N:3]=1
Reactant: OC1CCCC(Nc2ccc3ncc(-c4cc(F)nc(Cl)c4)n3c2)C1
Reactant: OB(O)c1ccoc1
Product: OC1CCCC(Nc2ccc3ncc(-c4cc(F)nc(-c5ccoc5)c4)n3c2)C1

Procedure:
The title compound is prepared from (1SR,3RS)-3-[3-(2-Chloro-6-fluoro-pyridin-4-yl)-imidazo[1,2-a]pyridin-6-ylamino)-cyclohexanol (Intermediate T) and 3-furyl boronic acid using a procedure analogous to that described in Example 2.3.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38]([NH2:40])=[O:39].C(N(CC)CC)C.[CH2:51](O)[CH2:52][CH2:53][CH2:54]/[CH:55]=[CH:56]\[CH2:57][CH2:58][CH2:59][CH3:60]>C1COCC1>[CH2:51]([O:34][C:35]1[CH:36]=[C:37]([C:38]([NH2:40])=[O:39])[CH:41]=[CH:42][CH:43]=1)[CH2:52][CH2:53][CH2:54]/[CH:55]=[CH:56]\[CH2:57][CH2:58][CH2:59][CH3:60]
Reactant: NC(=O)c1cccc(O)c1
Reactant: CCCC/C=C\CCCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC/C=C\CCCCOc1cccc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.8 %

Procedure:
To a suspension of polymer-supported triphenyl phosphine (1.4 g, 3 mmol, based on a loading of 2.15 mmol/g [purchased from Argonaut], 1.5 equiv.) swollen in THF (20 ml) at room temperature was added diisopropylazodicarboxylate (0.47 ml, 2.4 mmol, 1.2 equiv.). The mixture was shaken for 5 min before 3-hydroxybenzamide (274 mg, 2 mmol, 1 equiv.), triethylamine (0.28 ml, 2 mmol, 1 equiv.) and cis-5-decenol (313 mg, 2 mmol, 1 equiv.) were added. The resulting suspension was shaken at room temperature for 16 h and then filtered. The resin was washed with additional THF (×3) and then the combined filtrate and washings were concentrated under reduced pressure, to give the crude product as a colourless semi-solid. It was purified by column chromatography on silica eluting with EtOAc/hexane (20%-40% gradient) to give the desired compound as a white solid (390 mg, 71%), mp 98-100° C. HPLC-MS (method 1): m/z 276 [M+H]+, Rt=5.00 min. 1H NMR (CDCl3) δ=7.35 (s, 1H), 7.32-7.28 (m, 2H), 7.08-7.02 (m, 1H), 6.18 (br, 2H), 5.41-5.32 (m, 2H), 3.98 (t, J=6.4 Hz, 2H), 2.12-2.05 (m, 2H), 2.05-1.98 (m, 2H), 1.79 (m, 2H), 1.51 (m, 2H), 1.34-1.28 (m, 4H), 0.88 (t, J=7.0 Hz, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[NH2:9][CH2:10][CH:11]1[CH2:14][N:13]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:27]3)(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[O:16])[CH2:12]1.C(N(CC)CC)C>O1CCOCC1>[F:8][C:4]1[N:3]=[C:2]([NH:9][CH2:10][CH:11]2[CH2:12][N:13]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([S:23]([N:26]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[C:28]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:27]4)(=[O:25])=[O:24])=[CH:21][CH:22]=3)=[O:16])[CH2:14]2)[CH:7]=[CH:6][CH:5]=1
Reactant: NCC1CN(C(=O)c2ccc(S(=O)(=O)n3cc(-c4ccccc4)c4ccccc43)cc2)C1
Reactant: Fc1cccc(F)n1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1)N1CC(CNc2cccc(F)n2)C1
Temperature: 80 °C

Procedure:
Add 2,6-difluoropyridine (55 μL, 70 mg, 0.61 mmol, 2.0 equiv) to a solution of (3-aminomethyl-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone (134 mg, 0.301 mmol, 1 equiv) and triethylamine (120 μL, 87 mg, 0.86 mmol, 2.9 equiv) in 1,4-dioxane (3 mL) and heat at 80° C. for 16 h. Mass spec shows no desired product. Add more triethylamine (120 μL) and 2,6-difluoropyridine (110 μL). After 32 h at 80° C., LC/MS shows a small amount of desired product. Add more triethylamine (200 μL) and 2,6-difluoropyridine (110 μL). After 38 h, add more triethylamine (200 μL) and 2,6-difluoropyridine (110 μL). After 100 h, transfer the reaction solution to a column of silica gel (80 mm×20 mm dia.) and elute (50-65% EtOAc/hex) to yield 65 mg (40%) of [3-[(6-fluoro-pyridin-2-ylamino)-methyl]-azetidin-1-yl]-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone as a white foam. MS (m/e): 541.02 (M+1); 539.17 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:39][CH2:40][CH2:41][C:42]([CH3:45])([OH:44])[CH3:43]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:39][CH2:40][CH2:41][C:42]([OH:44])([CH3:45])[CH3:43])=[CH:27][CH:28]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(C)(O)CCCBr
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCC(C)(C)O)cc2)c2ccccc21
Temperature: 80 °C
Yield: 78.8 %

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (0.1 g, 0.23 mmol) was dissolved in DMF (5 mL) at room temperature. K2CO3 (0.317 g, 2.3 mmol) was added. 5-Bromo-2-methyl-pentan-2-ol (0.092 g, 0.51 mmol) was added and the reaction was allowed to heat to 80° C. overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (70% EtOAc/30% Hexane) to afford the product (0.097 g, 79%).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([N+:12]([O-:14])=[O:13])=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1.C(O)(=[O:24])C.OO>C(Cl)(Cl)Cl>[CH3:1][S:2]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([N+:12]([O-:14])=[O:13])=[C:9]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]=2[CH:21]=1)=[O:24]
Reactant: CSCc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Reactant: CC(=O)O
Agent: OO
Solvent: ClC(Cl)Cl
Product: CS(=O)Cc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
A solution of 2.8 g. (0.009 mole) of 5-methylthiomethyl-2-nitro-3-phenylbenzofuran in 200 ml. of acetic acid is obtained by warming. The solution is cooled to 20° C., and 0.51 g. (0.0045 mole) of hydrogen peroxide in 15 ml. of acetic acid is added dropwise. After 20 hours, an additional 1.02 g. of 30 percent hydrogen peroxide in 20 ml. of acetic acid is added dropwise. After an additional 2.5 hours, the reaction is poured onto ice, the precipitate is collected by filtration and washed with water, then dissolved in a dichloromethane-diethyl ether mixture. This mixture is washed with water and saturated sodium chloride solution, then dried. Evaporation provides a solid which is dissolved in chloroform and eluted through a silica gel column with more chloroform. The desired product is eluted from the silica gel with ethyl acetate, recrystallized from a benzene-hexane mixture then from aqueous ethanol to provide yellow plates of 5-methylsulfinylmethyl-2-nitro-3-phenylbenzofuran, m.p. 162°-165° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:25]([C:28]1[CH:32]=[C:31]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[N:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:29]=1)([CH3:27])[CH3:26])#[N:24]>C1COCC1.CN(C1C=CN=CC=1)C>[C:23]([C:25]([C:28]1[CH:32]=[C:31]([NH:33][C:34]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:35])[N:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:29]=1)([CH3:27])[CH3:26])#[N:24]
Reactant: CC(C)(C#N)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C#N)nn4-c4ccccc4)c3)c2cc1OC
Yield: 47.1 %

Procedure:
Using the procedure described in Example 306B, to a solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.3 mmol), prepared as described in Example 113A, in THF (3.3 ml) was added DMAP (20 mg, 0.16 mmol) and phenyl 3-(2-cyanopropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate (104 mg, 0.3 mmol) described in the previous step to afford 1-(3-(2-cyanopropan-2-yl)-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (77.6 mg, 42%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.72 (s, 6H), 3.99 (s, 6H), 6.57 (s, 1H), 6.94 (d, J=6 Hz, 1H), 7.18 (d, J=6.6 Hz, 1H), 7.17-7.20 (m, 2H), 7.35-7.56 (m, 7H), 8.56 (s, 1H), 8.64 (s, 1H), 9.28 (s, 1H); LC-MS (ESI) m/z 550 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]([CH3:18])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:19])=[CH:4][CH:3]=1.Br.Br[CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:18][C:17]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:3][CH:4]=2)[C:9](=[O:19])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: Cc1cc2ccccc2c(=O)n1-c1ccc(O)cc1
Reactant: BrCCCN1CCCCC1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc2ccccc2c(=O)n1-c1ccc(OCCCN2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 39.8 %

Procedure:
2-(4-hydroxyphenyl)-3-methyl-1(2H)-isoquinolinone (30 mg, 0.12 mmol), 1-(3-bromopropyl)piperidine hydrobromide (51 mg, 0.18 mmol) and potassium carbonate (49 mg, 0.36 mmol) were mixed in dimethylformamide (3 mL) and stirred at 80° C. for 3 hours. The solvent was distilled off under reduced pressure, distilled water was added. and the mixture extracted with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate, and the product purified by silica gel column chromatography (chloroform/methanol=20/1) to obtain the title compound (18 mg, 40%) as a colorless solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[CH3:2].F[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:22]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:18][CH3:19])=[CH:17][CH:16]=2)[CH:12]=[CH:13]1
Reactant: Fc1ccccc1-c1ccccc1
Reactant: CCN(CC)CCCCOc1ccc2[nH]ccc2c1
Product: CCN(CC)CCCCOc1ccc2c(ccn2-c2ccccc2-c2ccccc2)c1

Procedure:
In analogy to example 4.6, Diethyl-[4-(1H-indol-5-yloxy)-butyl]-amine and 2-fluorobiphenyl were converted to yield [4-(1-Biphenyl-2-yl-1H-indol-5-yloxy)-butyl]-diethyl-amine as light yellow oil, MS: 412 (M).
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17][C:18]2[CH:19]=[CH:20][C:21]3[N:22]([C:24]([CH:27]([CH3:29])[CH3:28])=[N:25][N:26]=3)[CH:23]=2)C=CC=CC=1.[CH2:31]([NH:33][CH3:34])[CH3:32]>CS(C)=O>[CH2:31]([N:33]([CH3:34])[C:8]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:24]([CH:27]([CH3:28])[CH3:29])=[N:25][N:26]=2)[CH:23]=1)=[O:7])[CH3:32]
Reactant: CC(C)c1nnc2ccc(Sc3ccccc3CNC(=O)Oc3ccccc3)cn12
Reactant: CCNC
Solvent: CS(C)=O
Product: CCN(C)C(=O)NCc1ccccc1Sc1ccc2nnc(C(C)C)n2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a solution of [2-(3-Isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-ylsulfanyl)-benzyl]-carbamic acid phenyl ester (42 mg, 0.10 mmol) in DMSO (200 μL) was added ethylmethylamine (6.0 μL, 0.105 mmol). The reaction was stirred at ambient temperature for 30 minutes, then quenched with water. The reaction mixture was extracted with organics, the organics combined, dried over sodium sulfate, and concentrated in vacuo. The residue was triturated with 1:1 hexane:diethyl ether to give the title compound (37 mg, 96%). MS (M+1)=384.4.