Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:8]1[S:9][CH:10]=[C:11]([CH3:13])[N:12]=1)([CH3:7])[C:3]([NH:5][NH2:6])=O.[F:14][C:15]1[C:16]([CH2:22][N:23]2[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[S:30])=[N:24]2)=[N:17][CH:18]=[CH:19][C:20]=1[CH3:21].S(=O)(=O)(O)O.N>C(O)C.O.C(OCC)(=O)C>[F:14][C:15]1[C:16]([CH2:22][N:23]2[CH:27]=[CH:26][C:25]([NH:28][C:29]3[S:30][C:3]([C:2]([C:8]4[S:9][CH:10]=[C:11]([CH3:13])[N:12]=4)([OH:1])[CH3:7])=[N:5][N:6]=3)=[N:24]2)=[N:17][CH:18]=[CH:19][C:20]=1[CH3:21]
Reactant: Cc1ccnc(Cn2ccc(N=C=S)n2)c1F
Reactant: Cc1csc(C(C)(O)C(=O)NN)n1
Agent: N
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1csc(C(C)(O)c2nnc(Nc3ccn(Cc4nccc(C)c4F)n3)s2)n1
Reaction time: 8 h
Yield: 68.2 %

Procedure:
A mixture of Intermediate 107, 2-hydroxy-2-(4-methyl-1,3-thiazol-2-yl)propanohydrazide (82 mg, 0.407 mmol), and Intermediate 79, 3-fluoro-2-[(3-isothiocyanato-1H-pyrazol-1-yl)methyl]-4-methylpyridine (84 mg, 0.340 mmol) in ethanol (6 mL) was heated under reflux for 3 h. Reaction mixture was concentrated and residue was treated with sulfuric acid (2 mL, 37.5 mmol) at 0° C., and the resulting mixture was allowed to reach room temperature overnight. Reaction mixture was placed in an ice-bath and treated slowly and dropwise with 37% aq. NH3 (10 mL) until pH was basic. Mixture was diluted with water and ethyl acetate (60 mL). Organic phase was separated, washed with brine, dried over sodium sulfate and concentrated. Crude was loaded on a silica cartridge and eluted with a linear gradient, 0-5% MeOH-DCM, affording 100 mg (68.3% yield) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.81 (s, 1H), 8.19 (d, 1H), 7.71 (s, 1H), 7.33-7.31 (m, 1H), 7.27 (s, 1H), 7.19 (s, 1H), 5.93 (s, 1H), 5.33 (s, 2H), 2.28 (br s, 6H), 1.96 (s, 3H). [ES+MS] m/z 432 (MH+).
Reaction SMILES: [OH2:1].ON1[C:7](=O)[CH2:6][CH2:5][C:4]1=[O:9].[C:10]([OH:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CC1C=CC(C)=CC=1>[CH3:4][C:14]1[CH:13]=[CH:12][C:11]([C:10]([OH:18])=[O:17])=[CH:16][CH:15]=1.[C:10]([OH:18])(=[O:17])[C:11]1[CH:12]=[CH:13][C:5]([C:4]([OH:9])=[O:1])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)c1ccccc1
Reactant: O
Solvent: Cc1ccc(C)cc1
Product: Cc1ccc(C(=O)O)cc1
Product: O=C(O)c1ccc(C(=O)O)cc1
Yield: 0.22 %
Yield: 1.31 %

Procedure:
The reaction was conducted in the same manner as in Example 1 except that 2 g of water was used instead of the mixture of N-hydroxysuccinimide and water. The conversion of the substrate and the amount and yield of the product were determined. Incidentally, it was assumed that the reaction was started at the time the addition of the water was started, and that the reaction was completed at the time the addition of the water was completed. As the results of the reaction, the conversion of p-xylene was 1.68%, and 5 g of p-toluic acid (yield 1.31%), 1 g of terephthalic acid (yield 0.22%), and 0.03 g of benzoic acid as a by-product (yield 0.0088%) were obtained.
Reaction SMILES: Cl.[CH:2]1([N:5]2[CH2:10][C:9]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[O:8][CH2:7][C:6]2=[O:16])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30](Br)[CH3:31])=[CH:26][CH:25]=1>CN(C)C=O.O>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([N:13]2[CH2:12][CH2:11][C:9]3([O:8][CH2:7][C:6](=[O:16])[N:5]([CH:2]4[CH2:4][CH2:3]4)[CH2:10]3)[CH2:15][CH2:14]2)[CH3:31])=[CH:26][CH:25]=1
Reactant: CC(Br)c1ccc(Br)cc1
Reactant: O=C1COC2(CCNCC2)CN1C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(c1ccc(Br)cc1)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (0.341 mmol) in N,N-dimethylformamide (1.5 mL) was treated with potassium carbonate (0.682 mmol) and 1-bromo-4-(1-bromoethyl)benzene (0.341 mmol). The reaction mixture was stirred at room temperature overnight. The solution was diluted with water (50 mL) and was extracted three times with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound as a brown residue (117 mg, 87%). MS(ES)+ m/e 392.9/394.7 [M+H]+ (bromide isotope pattern).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([C:8]([NH2:10])=[O:9])=[CH:5][CH:4]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>>[Cl:11][CH2:12][C:13]1[N:10]=[C:8]([C:6]2[S:7][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[O:9][CH:15]=1
Reactant: O=C(CCl)CCl
Reactant: COc1ccc(C(N)=O)s1
Product: COc1ccc(-c2nc(CCl)co2)s1
Yield: 1.2 %

Procedure:
In substantially the same manner as in Reference Example 47, 5-methoxy-2-thiophenecarboxamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(5-methoxy-2-thienyl)oxazole. The yield was 1.2%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 64-65° C.
Reaction SMILES: F[C:2]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:3]=1[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:20]=[C:21]([N:25]5[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]5)[CH:22]=[CH:23][CH:24]=4)[CH:17]=3)[NH:12][CH:11]=2)[CH:7]=[N:6]1.[ClH:43].CCOCC>CO.O1CCOCC1>[ClH:43].[F:42][C:39]1[CH:38]=[C:3]([CH:2]=[CH:41][CH:40]=1)[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[CH:20]=4)[CH:17]=3)[NH:12][CH:11]=2)[CH:7]=[N:6]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3cnc4[nH]cc(-c5cnn(Cc6cc(F)ccc6F)c5)c4c3)c2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOCC
Product: Fc1cccc(Cn2cc(-c3c[nH]c4ncc(-c5cccc(N6CCNCC6)c5)cc34)cn2)c1
Reaction time: 4 h
Yield: 29.8 %

Procedure:
To a stirred solution of tert-butyl 4-(3-(3-(1-(2,5-difluorobenzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (76 mg, 0.137 mmol) in methanol (5 ml) added saturated HCl in dioxane at 0° C. This gradually brought to RT and stirred for four hours. Reaction mass was cooled and added ether to get solids. Solvents decanted and solids washed by ethyl acetate and dried. This afforded 20 mg (29.8% yield) titled compound. 1H NMR (CD3OD, 400 MHz): δ 9.071-9.067 (d, 1H), 8.778-8.774 (d, 1H), 8.605 (s, 1H), 8.215 (s, 1H), 8.009 (s, 1H), 7.618-7.614 (m, 1H), 7.535-7.496 (t, 1H), 7.460-7.441 (m, 1H), 7.405-7.351 (m, 1H), 7.272-7.248 (m, 1H), 7.174-7.155 (m, 1H), 7.086-7.030 (m, 2H), 5.530 (s, 2H), 3.682-3.656 (m, 4H), 3.497-3.471 (m, 4H), 3.339 (s, 3H). MS: m/z=453.4 (M+1); HPLC: 89.28% in method A.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[H-].[Na+].I[CH3:20].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH3:20])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Nc2cc(Br)cn(C)c2=O)n[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Nc2cc(Br)cn(C)c2=O)nn1C
Yield: 33.7 %

Procedure:
A solution of 5-bromo-1-methyl-3-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2(1H)-one (2.8 g, 9.9 mmol) in anhydrous DMF (10 mL) was treated with 60% dispersion of NaH in mineral oil (0.51 g, 13 mmol) while stirring under nitrogen. After effervescence the reaction was stirred for an additional 30 minutes. At this time the reaction was treated with iodomethane (0.98 g, 7.0 mmol) with continued stirring under nitrogen for 2 hours. Water (50 mL) was added slowly and the mixture was filtered. The filtrate was extracted with ethyl acetate (3×30 mL). The combined extract was concentrated under reduced pressure and the residue was purified by flush column chromatography eluting with 3:1 petroleum ether/ethyl acetate to afford 218a (0.70 g, 24%). MS: [M+H]+ 297.
Reaction SMILES: Cl.[CH:2]1([N:8]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:9]([NH:11][C:12]2[S:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:15][N:16]=2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:39][N:40]1[CH:44]=[C:43]([S:45](Cl)(=[O:47])=[O:46])[N:42]=[CH:41]1>>[CH:24]1([N:8]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[C:9]([NH:11][C:12]2[S:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([S:45]([C:43]4[N:42]=[CH:41][N:40]([CH3:39])[CH:44]=4)(=[O:47])=[O:46])[CH2:20][CH2:19]3)=[CH:15][N:16]=2)=[O:10])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(Nc1ncc(CN2CCNCC2)s1)N(C1CCCCC1)C1CCCCC1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cnc(S(=O)(=O)N2CCN(Cc3cnc(NC(=O)N(C4CCCCC4)C4CCCCC4)s3)CC2)c1
Yield: 66.1 %

Procedure:
Prepared as described in general procedure (Q) using 1,1-dicyclohexyl-3-(5-piperazin-1-ylmethyl-thiazol-2-yl)-urea hydrochloride (27 mg, 0.055 mmol), DIEA (29 μL, 0.17 mmol) and N-methylimidazole-4-sulfonyl chloride (20 mg, 0.11 mmol) to afford 20 mg (66%) of the desired product after purification.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[N:18]1[CH:23]=[CH:22][C:21]([C:13]2[N:12]=[C:11]([NH:10][C:8]3[CH:7]=[CH:6][C:5]4[S:1][CH:2]=[N:3][C:4]=4[CH:9]=3)[CH:16]=[N:15][CH:14]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccncc1
Reactant: Clc1cncc(Nc2ccc3scnc3c2)n1
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: COCCOC
Solvent: O
Product: c1cc(-c2cncc(Nc3ccc4scnc4c3)n2)ccn1
Yield: 50.3 %

Procedure:
A mixture of benzothiazol-5-yl-(6-chloro-pyrazin-2-yl)-amine (0.06 g, 0.228 mmol), pyridine-4-boronic acid (0.043 g, 0.342 mmol), sodium carbonate (0.124 g, 1.14 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.013 g, 0.0114 mmol) in DME:water (3:2, 5 mL) was heated at reflux for 22 h. The reaction mixture was concentrated under reduced pressure and the residue obtained was extracted with dichloromethane. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (5% methanol in CH2Cl2 as eluent) to yield N-(6-pyridin-4-ylpyrazin-2-yl)-1,3-benzothiazol-5-amine (0.035 g, 50%) as a yellow solid. 1H NMR (CD3OD) δ 9.31 (s, 1H), 8.98 (d, J=2.02 Hz, 1H), 8.75-8.74 (d, J=5.31 Hz, 2H), 8.64 (s, 1H), 8.31 (s, 1H), 8.24-8.22 (d, J=5.99 Hz, 2H), 8.06-8.04 (d, J=8.77 Hz, 1H), 7.74-7.71 (dd, J=10.73, 2.01 Hz, 1H); MS (API-ES/Positive); m/z: 306 (M+H)+.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([O-:4])=[O:3].[N:12]([O-])=O.[Na+].F[B-](F)(F)F.[Na+].[CH3:22][C:23]1([CH3:32])[CH2:28][CH:27]([OH:29])[CH2:26][C:25]([CH3:31])([CH3:30])[NH:24]1>O.C(#N)C>[CH3:22][C:23]1([CH3:32])[CH2:28][CH:27]([OH:29])[CH2:26][C:25]([CH3:31])([CH3:30])[N:24]1[N:12]=[N:9][C:8]1[CH:10]=[CH:11][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: O=N[O-]
Agent: Cl
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC1(C)CC(O)CC(C)(C)N1N=Nc1ccc([N+](=O)[O-])cc1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 4.6 %

Procedure:
A mixture of concentrated HCl (15 ml, 32%) and water (15 ml) is charged into 100 ml three necked round bottomed flask followed by addition of 4-nitro-aniline (5 g, 0.04 mol). The mixture is cooled to 0 to 5° C. and solution of sodium nitrite (4.14 g, 0.06 mol) in water (5 ml) is added into it while maintaining temperature 0 to 5° C. This reaction mixture is then slowly added into a solution of sodium tetrafluoroborate (6.6 g, 0.06 mol) in water (60 ml) at 0 to 5° C. The resulting solution of diazonium tetrafluoroborate salt is then added to solution of 2,2,6,6-tetramethyl-4-hydroxypiperdine (25.1 g, 0.16 mol) in acetonitrile (1000 ml)) and the mixture is stirred at 0 to −5° C. for 1 h. This reaction mixture filtered and mother liquor is evaporated to dryness at 40° C. The residue is extracted with diethyl ether (200 ml) the extract is decolorized with charcoal (50 g), filtered through bed of celite and concentrated to dryness to afford 0.56 g of 2,2,6,6-Tetramethyl-1-(4-nitrophenyldiazenyl)-piperidin-4-ol as a yellow solid, m.p. 108-110° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([CH:20](OCC)OCC)[NH:15][C:16]3=[O:19])=[CH:11][CH:10]=2)[CH2:4]1.[CH2:27]([NH:29][C:30]1[C:31]([NH2:36])=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH3:28]>>[CH2:27]([N:29]1[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[N:36]=[C:20]1[C:14]1[NH:15][C:16](=[O:19])[C:17]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([N:5]1[CH2:4][C@H:3]([CH2:2][OH:1])[O:7][C:6]1=[O:8])[CH:18]=2)[CH3:28]
Reactant: CCOC(OCC)c1cc2ccc(N3C[C@H](CO)OC3=O)cc2c(=O)[nH]1
Reactant: CCNc1ccccc1N
Product: CCn1c(-c2cc3ccc(N4C[C@H](CO)OC4=O)cc3c(=O)[nH]2)nc2ccccc21
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
Purified water (0.01 ml) and TFA (0.01 ml) were added to a dichloromethane solution that contained the 7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-diethoxymethyl-2H-isoquinolin-1-one (3.3 mg, 0.009 mmol) prepared in step C. The obtained mixture was left at a room temperature for 30 minutes, and the reaction solution was concentrated. The obtained yellow solid and an ethanol solution that contained N-ethyl-1,2-benzenediamine (1.2 mg, 0.009 mmol), which was a known compound described in a publication (Leicester Polytech; Synthetic Communications, vol. 19(7-8), p. 1381, (1989)), were heated to reflux for 17 hours. Thereafter, the reaction solution was concentrated. The obtained residue was purified by preparative silica gel TLC (dichloromethane:methanol=20:1), so as to obtain 3-(1-ethyl-1H-benzoimidazol-2-yl)-7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-2H-isoquinolin-1-one (2.7 mg, yield: 74%) in the form of a yellow solid.
Reaction SMILES: ClCC(OC)=O.[CH2:7]([C:9]1[O:10][C:11]2[CH:31]=[CH:30][CH:29]=[CH:28][C:12]=2[C:13]=1[C:14]([C:16]1[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22](OC)=[O:23])=[CH:18][CH:17]=1)=[O:15])[CH3:8].O.[NH3:33]>>[CH2:7]([C:9]1[O:10][C:11]2[CH:31]=[CH:30][CH:29]=[CH:28][C:12]=2[C:13]=1[C:14]([C:16]1[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([NH2:33])=[O:23])=[CH:18][CH:17]=1)=[O:15])[CH3:8]
Reactant: N
Reactant: CCc1oc2ccccc2c1C(=O)c1ccc(OCC(=O)OC)cc1
Agent: COC(=O)CCl
Solvent: O
Product: CCc1oc2ccccc2c1C(=O)c1ccc(OCC(N)=O)cc1

Procedure:
According to the Procedure B of Example 1, the intermediate of the Example 3 was reacted with methyl chloroacetate. The resulting product methyl 4-(2-ethyl-benzofuroyl) phenoxyacetate (Compound 11) was treated with concentrated ammonia water 28%) 100 ml and was stirred under ice-cooled condition for three hours. The white powder thus obtained, after drying was recrystallized from methanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][CH:3]=1.[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C(C)=CC=CC=1>[Br-:1].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][P+:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: Brc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Br-]
Yield: 156.1 %

Procedure:
A mixture of 1-bromo-4-(bromomethyl)benzene (5 g) and triphenylphosphine (5.24 g) in xylene (20 mL) were heated to reflux for 18 hours. The reaction mixture was cooled, filtered, washed with hexane and tried under vacuum to afford the title compound (8 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Si:7]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].O>CCOCC>[NH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCC#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCCCCCCCN
Reaction time: 2 h

Procedure:
To a solution of lithium aluminium hydride (600 mg, Aldrich) in ether (50 mL) was added dropwise the product (3.8 g) from Example 4 in ether (50 mL). After 1-3 h, the mixture was poured into water and stirred for 30 min. The insoluble aluminium hydroxide was filtered through a celite pad, and the aqueous layer was extracted with ether three times. The ether extracts were washed with brine solution, dried and concentrated. The crude product was distilled at 0.25 Torr and 82° C. High resolution mass spectrum for C13 H31 O N Si: calculated 245.2175, found 245.2159.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:21])=[C:15]([F:20])[CH:16]=2)[NH:11][C:10]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:26][CH:27]1[CH2:29][CH2:28]1>CN(C=O)C>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:21])=[C:15]([F:20])[CH:16]=2)[N:11]([CH2:26][CH:27]2[CH2:29][CH2:28]2)[C:10]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cc(F)c(F)cc2c(=O)n1OCc1ccccc1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2cc(F)c(F)cc2n(CC2CC2)c(=O)n1OCc1ccccc1
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
A solution of 3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example B, 1.22 g, 4 mmol) in 25 mL of DMF was added to a suspension of sodium hydride (0.19 g, 4.8 mmol) in 20 mL of DMF and stirred for 30 minutes. Bromomethylcyclopropane (0.6 mL, 6.0 mmol) was added, and the mixture was stirred at 25° C. for 18 hours. The reaction was quenched with 1 mL of water and concentrated to an oil. The residue was dissolved in chloroform, washed with water, brine, and dried over magnesium sulfate. The solution was concentrated to give 1.10 g of the title compound as a solid, mp 121-123° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([N:30]1[C:38]2[C:33](=[C:34]([OH:39])[CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31]1)(=[O:29])=[O:28].[C:40]([O:44][C:45](=[O:51])[N:46]([CH2:48][CH2:49]O)[CH3:47])([CH3:43])([CH3:42])[CH3:41].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:40]([O:44][C:45](=[O:51])[N:46]([CH2:48][CH2:49][O:39][C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:33]=1[CH:32]=[CH:31][N:30]2[S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[F:20])(=[O:28])=[O:29])[CH3:47])([CH3:43])([CH3:42])[CH3:41]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: O=S(=O)(c1ccccc1F)n1ccc2c(O)cccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(CCOc1cccc2c1ccn2S(=O)(=O)c1ccccc1F)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 72 h

Procedure:
A 100 mL flask equipped with a magnetic stirrer and a rubber septum was charged with triphenyl phosphine (0.506 g, 0.0019 mol) and 1-(2-fluorobenzenesulfonyl)-4-hydroxy-1H-indole (0.330 g, 0.0012 mol), and purged with N2. The mixture was cooled to 0° C. and freshly distilled THF was added (45 mL). A solution of 2-hydroxyethyl methylcarbamic acid tert-butyl ester (0.317 g, 0.0018 mol) and diethylazodicarboxylate (0.337 g, 0.0019 mol) in 5 mL of THF was added dropwise at 0° C. to give a yellow solution. The reaction mixture was warmed to ambient temperature and stirred for 72 hours, concentrated in vacuo and the resulting crude oil was purified by flash chromatography using a 25:75 of hexanes/ethyl acetate mixture to give 2-[1-(2-fluorobenzenesulfonyl)-1H-indol-4-yloxy]ethyl methylcarbamic acid tert-butyl ester as a clear oil (0.483 mg; 89%). 1H NMR (300 MHz, CDCl3) δ: 1.44 (bs, 9 H), 3.01 (s, 3 H), 3.65 (bs, 2 H), 4.19 (bs, 2 H), 6.65 (d, 1 H, J=8.03), 6.76 (d, 1 H, J=3.77), 7.09 (t, 1 H, J=8.67). 7.17 (t, 1 H, J=8.11), 7.28 (t, 1 H, J=7.73), 7.44 (d, 1 H, J=8.29), 7.55 (m, 2 H), 803 (t, 1 H, J=7.44).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6].[NH2:32][CH:33]([C:35]1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=N[CH:36]=1)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.N1C2C(=CC=CC=2C(O)=O)C=CC=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:28][O:27][C:19]1[CH:18]=[C:17]([NH:16][C:13]2[N:14]=[N:15][C:10]([CH:8]([NH:7][C:5]([C:4]3[CH:29]=[CH:30][CH:31]=[C:2]4[C:3]=3[N:32]=[CH:33][CH:35]=[CH:36]4)=[O:6])[CH3:9])=[CH:11][N:12]=2)[CH:22]=[C:21]([O:23][CH3:24])[C:20]=1[O:25][CH3:26]
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1cccc2cccnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc4cccnc34)nn2)cc(OC)c1OC

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (0.123 g, 0.40 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.152 g, 0.40 mmol), quinoline-8-carboxylic acid (0.070 g, 0.40 mmol), diisopropylethylamine (0.14 mL, 0.80 mmol) in DMF (2 mL) gave N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)quinoline-8-carboxamide (0.180 g) as an orange solid. 1H NMR (CDCl3): δ8.95 (dd, J=4.4, 1.8 Hz, 1H), 8.83 (dd, J=7.4, 1.6 Hz, 1H), 8.50 (s, 1H), 8.30 (dd, J=8.2, 1.8 Hz, 1H), 7.99 (dd, J=8.3, 1.6 Hz, 1H), 7.71-7.65 (m, 1H), 7.53-7.48 (m, 1H), 7.42 (bs, 1H), 6.95 (s, 2H), 5.60 (p, J=7.1 Hz, 1H), 3.88 (s, 6H), 3.82 (s, 3H), 1.87 (d, J=7.1 Hz, 3H). MS m/z 461 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=[C:5]([C:11]([F:14])([F:13])[F:12])[N:4]=1.C1N=CN([C:20](N2C=NC=C2)=[O:21])C=1.[NH2:27][C:28]1[C:33]2[O:34][CH2:35][C:36](=[O:38])[NH:37][C:32]=2[CH:31]=[CH:30][CH:29]=1>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[C:8]([CH2:9][NH:10][C:20]([NH:27][C:28]2[C:33]3[O:34][CH2:35][C:36](=[O:38])[NH:37][C:32]=3[CH:31]=[CH:30][CH:29]=2)=[O:21])=[CH:7][CH:6]=[C:5]([C:11]([F:14])([F:12])[F:13])[N:4]=1
Reactant: Nc1cccc2c1OCC(=O)N2
Reactant: COc1nc(C(F)(F)F)ccc1CN
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1nc(C(F)(F)F)ccc1CNC(=O)Nc1cccc2c1OCC(=O)N2
Temperature: 70 °C
Yield: 14 %

Procedure:
To a solution of 29c (0.38 g, 1.84 mmol) in THF (15 mL) was added CDI (2.1 mol eq, 0.63 g) and the mixture was heated at 70° C. overnight. The reaction mixture was evaporated, water was added and the aqueous phase was extracted with EtOAc (3×25 mL). The recombined organic phases were anhydrified over Na2SO4 and evaporated at reduced pressure (yellow oil, 0.62 g, quantitative yield). The oil obtained was dissolved in DMF (20 mL) and the bicyclic amine 1f was added (0.8 mol eq, 0.21 g), then the mixture obtained was heated at 100° C. overnight. The solvent was removed at reduced pressure and the residue was purified by chromatography (1:1 EtOAc:petroleum ether) to afford the product as a white solid (0.1 g, 14% Yield). 1HNMR (DMSO, 400 MHz) δ 3.96 (s, 3H), 4.29 (d, 2H, J=6), 4.62 (s, 2H), 6.46 (dd, 1H, J=2), 6.80 (t, 1H, J=8), 7.34 (bt, 1H), 7.51 (d, 1H, J=8), 7.72 (m, 2H), 8.24 (s, 1H), 10.66 (s, 1H). [M+1] 396.99 (C17H15F3N4O4 requires 396.32).