Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH:5]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][NH2:4].[H-].[Na+].Cl[CH2:24][CH2:25]I.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C.O>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][CH:5]([CH:2]1[O:1][CH2:25][CH2:24][NH:4][CH2:3]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccccc1OC(c1ccccc1)C(O)CN
Reactant: ClCCI
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1OC(c1ccccc1)C1CNCCO1
Temperature: 50 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a solution of 2-hydroxy-3-(2-methoxy-phenoxy)-3-phenyl-propylamine (10 g) in anhydrous dimethylformamide (150 ml), 55% NaH (1.75 g) was added at room temperature. After stirring for 1 hours, a solution of 2-chloro-1-iodo-ethane (7 g) in dimethylformamide (50 ml) was added all at one time. The temperature was maintained at 50° C. for 1 hour then Na2CO3 (5.82 g) was added and the whole was maintained at 50° C. for a further 3 hours. The whole was poured into water and extraction made with ethyl acetate. After a standard working up, procedure, 2-[α-(2-methoxy-phenoxy)-benzyl]-morpholine (6.24 g; 57%) was obtained as a transparent oil .HCl m.p. 140°-170° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:25][CH3:26])=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH2:8][CH2:9][C:10]2([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[O:15][C:14](=[O:16])[CH2:13][C:12](=[O:17])[CH2:11]2)[CH:7]=1.[CH3:27][C:28]1[CH:33]=[C:32]([CH3:34])[N:31]2[N:35]=[C:36]([CH:38]=O)[N:37]=[C:30]2[N:29]=1.B.CNC.Cl>CO.O>[Cl:1][C:2]1[C:3]([O:25][CH3:26])=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH2:8][CH2:9][C:10]2([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[O:15][C:14](=[O:16])[CH:13]([CH2:38][C:36]3[N:37]=[C:30]4[N:29]=[C:28]([CH3:27])[CH:33]=[C:32]([CH3:34])[N:31]4[N:35]=3)[C:12](=[O:17])[CH2:11]2)[CH:7]=1
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Reactant: COc1cc(OC)c(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: B
Agent: CNC
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1cc(OC)c(CCC2(C3CCCC3)CC(=O)C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The title compound was prepared by treating a suspension of 6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione (350 mg, 0.917 mmol) and 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxaldehyde (described in Step 3 of example B(75))(242 mg, 1.375 mmol, 1.5 equiv, from Step 3 of Example B(75)) in MeOH (10 mL) with dimethylamine borane (65 mg, 1.1 mmol, 1.2 equiv). The resulting mixture was stirred at room temperature for 18 h. A 1 M solution of HCl (3 mL) was added to the reaction mixture to acidify to a pH of 3. The mixture diluted with water and extracted with dichloromethane containing 10% methanol (3×10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated to a white amorphous foam. The foam was chromatographed on silica gel, eluting with 2% methanol in dichloromethane affording a white solid. This solid was recrystallized from ethyl acetate/hexanes to give 100 mg (19%) of the product as a fine white powder. Isolated as a monohydrate.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]1)[CH2:5][NH:6]2.C([Li])(C)(C)C.B(OC)(OC)[O:29]C.OO.[OH2:37]>O1CCCC1>[OH:37][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]1)[C:5](=[O:29])[NH:6]2
Reactant: Brc1cccc2c1C1(CN2)COc2cc3c(cc21)OCCO3
Reactant: O
Reactant: COB(OC)OC
Agent: OO
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: O=C1Nc2cccc(O)c2C12COc1cc3c(cc12)OCCO3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 1.6 %

Procedure:
To a solution of 4′-bromo-1,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole] (0.30 g, 0.80 mmol) in anhydrous tetrahydrofuran (20 mL) at −98° C. was added tert-butyllithium (1.90 mL, 1.7 M solution in pentane, 3.2 mmol) and stirred for 15 min. Trimethyl borate (0.36 mL, 3.2 mmol) was added and the reaction mixture was allowed to warm to ambient temperature and stirred for 16 h. A solution of hydrogen peroxide in water (0.28 mL, 35% w/w, 3.2 mmol) was added to the reaction mixture at 0° C., and the mixture was allowed to warm to ambient temperature, stirred for 0.5 h and concentrated in vacuo. The residue was triturated with water and filtered. The resultant solid was purified by column chromatography and eluted with a 0% to 50% gradient of ethyl acetate in dichloromethane to afford 4′-hydroxy-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.004 g, 2%) as a colorless solid: mp>250° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.37 (s, 1H), 9.50 (s, 1H), 7.00 (dd, J=8.0, 8.0 Hz, 1H), 6.39-6.34 (m, 3H), 6.08 (s, 1H), 4.64 (ABq, 2H), 4.09 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 179.3, 155.5, 154.1, 144.0, 143.6, 137.7, 130.1, 121.0, 116.1, 111.1, 110.5, 101.8, 98.7, 76.8, 64.6, 64.0, 57.2; MS (ES+) m/z 311.7 (M+1).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:33]=[CH:32][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=3[O:30][CH3:31])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.[C:34]([Si:38]([O:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH:60]2[CH2:62][O:61]2)=[CH:54][CH:53]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([CH3:37])([CH3:36])[CH3:35]>C(Cl)(Cl)Cl.CO>[Si:38]([O:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][C@@H:60]([OH:61])[CH2:62][NH:4][CH2:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=4[O:30][CH3:31])=[O:19])[CH2:14][CH2:13]3)=[CH:32][CH:33]=2)=[CH:54][CH:53]=1)([C:34]([CH3:35])([CH3:37])[CH3:36])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: COc1cccc(CNC(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)c1OC
Solvent: O=CO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cccc(CNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)cc4)cc3)CC2)c1OC
Yield: 34 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(2,3-dimethoxybenzyl)-1-piperidine-carboxamide formate (0.30 g, 0.64 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.238 g, 0.588 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.163 g, 0.20 mmol).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21]N=1.O.[CH3:29]C(N(C)C)=O>>[CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:29]=2)=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)N(C)C
Reactant: Oc1ccc(CCNCc2ccccc2)cc1
Reactant: NC(=O)c1ccc(Cl)nc1
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc(CCNCc3ccccc3)cc2)cc1
Reaction time: 2 h

Procedure:
N-benzyl-4-hydroxyphenethylamine (J. Het. Chem., p. 839, 1971; 7.26 g, 0.032 mol) and 6-chloronicotinamide (5.0 g, 0.032 mol)were dissolved in 180 ml of dimethylacetamide and heated to reflux while water was collected in a Dean-Stark trap prefilled with isooctane. The reaction was refluxed under nitrogen for 17 hrs and additional 6-chloronicotinamide (1 g) added. After 2 hours, the solvent was removed in vacuo and the residue dissolved in 125 ml of ethyl acetate. The solution was shaken with dilute HCl and the solids collected by filteration (8.2 g). NMR.
Reaction SMILES: [NH2:1][CH:2]([CH3:36])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:17]3[CH2:23][CH2:22][N:21]([C:24]4[N:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:20][C:18]=3[N:19]=2)=[CH:10][CH:9]=1)=S.C(O)C>[Hg]=O>[CH3:36][CH:2]1[NH:1][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)[C:17]4[CH2:23][CH2:22][N:21]([C:24]5[N:29]=[CH:28][CH:27]=[CH:26][N:25]=5)[CH2:20][C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[N:4][CH2:3]1
Reactant: CC(N)CNC(=S)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2ncccn2)C3)cc1
Agent: O=[Hg]
Solvent: CCO
Product: CC1CN=C(Nc2ccc(-c3nc4c(c(N5CCOCC5)n3)CCN(c3ncccn3)C4)cc2)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Step 2—Synthesis of compound xk: 1-(2-aminopropyl)-3-(4-(4-morpholino-7-(pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)thiourea (0.293 g, 0.000579 mol) in dry Ethanol (12.0 mL, 0.206 mol) was added Mercury(II) oxide (0.260 g, 0.00120 mol). The reaction mixture was stirred at room temperature for 8 hours. The reaction mixture was heated at 40° C. and stirred overnight. The reaction mixture was heated at 50° C. and stirred overnight. The reaction mixture was heated at 78° C. for 8 hours. The reaction mixture was cooled to room temperature and stirred for 6 days. The reaction mixture was heated at 78° C. for 8 hours. The reaction mixture was cooled to room temperature, filtered through celite, filtered through a disc filter, concentrated, and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.43 (d, J=4.7, 2H), 8.17 (d, J=8.5, 2H), 7.01 (s, 2H), 6.69 (t, J=4.7, 1H), 6.32 (s, 2H), 4.80 (s, 2H), 3.98 (s, 2H), 3.82-3.70 (m, 5H), 3.46 (s, 5H), 2.92 (s, 1H), 2.75 (s, 2H), 1.15 (d, J=6.1, 3H). LC/MS-m/z+472.2 (M+H)+
Reaction SMILES: [Cl:1]NC(=O)CCC(N)=O.CSC.[CH2:13]([O:20][C:21]1[C:26]([CH2:27]O)=[C:25]([CH2:29][CH3:30])[CH:24]=[C:23]([CH3:31])[N:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl.[Cl-].[Na+].O>[CH2:13]([O:20][C:21]1[C:26]([CH2:27][Cl:1])=[C:25]([CH2:29][CH3:30])[CH:24]=[C:23]([CH3:31])[N:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(=O)CCC(=O)NCl
Reactant: CCc1cc(C)nc(OCc2ccccc2)c1CO
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CSC
Product: CCc1cc(C)nc(OCc2ccccc2)c1CCl
Temperature: -20 °C
Yield: 22.9 %

Procedure:
To a 0° C. solution of N-chloro succinamide (81.5 mg, 0.598 mmol) in dichloromethane (2.47 mL) was added dimethyl sulfide (48 ul, 0.653 mmol). The reaction mixture was then cooled to −20° C. and a solution of [2-(benzyloxy)-4-ethyl-6-methylpyridin-3-yl]methanol (Cpd DD, 140 mg, 0.554 mmol) in dichloromethane (1 mL) was added drop wise. After 2 hours the reaction mixture was poured into brine (5 mL) then extracted with dichloromethane (10 mL). The organic layer was dried over sodium sulfate, filtered, then concentrated under vacuum. The residue was purified by column chromatography (heptane/EtOAc) to give the title compound (Cpd EE, 35 mg, 23% yield) as a colorless oil. 1H NMR (chloroform-d) δ 7.52 (d, J=7.3 Hz, 2H), 7.29-7.44 (m, 3H), 6.65 (s, 1H), 5.46 (s, 2H), 4.74 (s, 2H), 2.72 (q, J=7.6 Hz, 2H), 2.44 (s, 3H), 1.28 (t, J=7.6 Hz, 3H).
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[NH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([Br:22])[C:13]=1[NH2:23]>>[Br:22][C:14]1[CH:15]=[C:16]([C:18]([F:19])([F:21])[F:20])[CH:17]=[C:12]2[C:13]=1[NH:23][C:2](=[O:4])[C:1](=[O:8])[NH:11]2
Reactant: Nc1cc(C(F)(F)F)cc(Br)c1N
Reactant: CCOC(=O)C(=O)OCC
Product: O=c1[nH]c2cc(C(F)(F)F)cc(Br)c2[nH]c1=O
Temperature: 25 °C

Procedure:
The title compound was prepared using an adaptation of the method of Cheeseman, G. W. H., J. Chem. Soc. 1171 (1962). A mixture of diethyl oxalate (1.15 g, 7.91 mmol) and 1,2-diamino-3-bromo-5-trifluoromethylbenzene (200 mg, 0.95 mmol) was heated to reflux under N2 for 2 h. The reaction was allowed to cool to room temperature and the solid collected by vacuum filtration and rinsed with EtOH (15 mL). This white solid was dried in a drying pistol (0.05 torr, 78° C.) to yield 148.3 mg (60.7%). mp 301-304 (dec). 1H NMR (d6 -DMSO) δ7.28 (s, 1H, ArH), 7.56 (s, 1H, ArH), 11.7 (br s, 2H, NH). 19F NMR (C6F6 external standard, δ-162.9) δ-57.97 (s). EIHRMS calc. for C9H4BrF3N2O2 307.9408, found 307.9411.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)=[O:4].O.[ClH:23]>C(OCC)(=O)C>[ClH:23].[ClH:23].[N:9]1([CH2:8][CH2:7][O:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1
Reactant: COC(=O)COCCN1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)COCCN1CCNCC1
Reaction time: 0.5 h
Yield: 92 %

Procedure:
2 g (0.0066 mol) of tert-butyl 4-(2-methoxycarbonylmethoxyethyl)piperazine-1-carboxylate prepared in Example I.4.3. are dissolved in 5 ml of ethyl acetate in a 50 ml three-necked round-bottomed flask fitted with a water-cooled condenser and a mechanical stirrer. 20 ml of a 3M solution of hydrochloric acid in ethyl acetate are added in a single portion with stirring. The mixture is stirred at room temperature for 30 minutes. 5 ml of a 3M solution of hydrochloric acid in ethyl acetate are then added and stirring is continued for 30 minutes. The precipitate is filtered off and is washed with 2×5 ml of ethyl acetate. 1.68 g (92%) of methyl 2-(1-piperazinyl)ethoxyacetate dihydrochloride are obtained in the form of a beige-colored solid.
Reaction SMILES: O.[OH-].[Li+].[O:4]=[C:5]([C:34]1[N:42]2[C:37]([CH:38]=[CH:39][CH:40]=[CH:41]2)=[CH:36][C:35]=1[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([O:27][CH2:28][CH2:29][O:30]C(=O)C)[CH:24]=[CH:23][N:22]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)=[O:7]>CO>[OH:30][CH2:29][CH2:28][O:27][C:25]1[CH:24]=[CH:23][N:22]=[C:21]([N:18]2[CH2:19][CH2:20][N:15]([C:12]3[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5](=[O:4])[C:34]4[N:42]5[C:37]([CH:38]=[CH:39][CH:40]=[CH:41]5)=[CH:36][C:35]=4[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[CH:14][CH:13]=3)[CH2:16][CH2:17]2)[CH:26]=1
Reactant: CC(=O)OCCOc1ccnc(N2CCN(c3ccc(NC(=O)C(=O)c4c(-c5ccccc5)cc5ccccn45)cc3)CC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(Nc1ccc(N2CCN(c3cc(OCCO)ccn3)CC2)cc1)C(=O)c1c(-c2ccccc2)cc2ccccn12
Reaction time: 3 h
Yield: 43.6 %

Procedure:
Lithium hydroxide monohydrate (0.048 g, 1.16 mmol) was added to a stirred solution of acetic acid 2-[2-(4-{4-[2-oxo-2-(2-phenyl-indolizin-3-yl)-acetylamino]-phenyl}-piperazin-1-yl)-pyridin-4-yloxy]-ethyl ester (0.35 g, 0.58 mmol) in methanol (15 mL) at r.t. under nitrogen and stirred for 3 h. The reaction mixture was evaporated to dryness, diluted with water and extracted with dichloromethane. The organic layer was washed with water and brine solution, dried over sodium sulfate and filtered. The filtrate was concentrated and purified by column chromatography over neutral alumina using 0-1% methanol in dichloromethane to afford N-(4-{4-[4-(2-hydroxy-ethoxy)-pyridin-2-yl]-piperazin-1-yl}-phenyl)-2-oxo-2-(2-phenyl-indolizin-3-yl)-acetamide (0.142 g, 44%) as a yellow solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([S:9][CH3:10])[C:6]2=[N:11][CH:12]=[CH:13][N:5]2[N:4]=1.[Br:14]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:14][C:13]1[N:5]2[C:6]([C:7]([S:9][CH3:10])=[N:8][C:3]([S:2][CH3:1])=[N:4]2)=[N:11][CH:12]=1
Reactant: CSc1nc(SC)c2nccn2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc(SC)c2ncc(Br)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
A mixture of 2,4-bis(methylthio)imidazo[2,1-f][1,2,4]triazine (5.27 g, 24.82 mmol) and 1-bromopyrrolidine-2,5-dione (6.19 g, 34.8 mmol) in DMF (15 mL) was stirred at room temperature for 2 hours. The reaction was diluted with water, and the product extracted with dichloromethane (3×50 mL). The organic layer was washed with brine, dried and concentrated. The crude product mixture was purified via ISCO (0-50% of ethyl acetate/dichloromethane in 10 minutes, 80 g silica column) to give the pure product 7-bromo-2,4-bis(methylthio)imidazo[2,1-f][1,2,4]triazine (4.61 g).
Reaction SMILES: [CH2:1]([Cl:4])[CH:2]=[CH2:3].CO[SiH](OC)OC.[CH2:12]([O:14][SiH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[CH3:13]>[Ru]>[Cl:4][CH2:1][CH2:2][CH2:3][Si:15]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])[O:14][CH2:12][CH3:13]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=CCCl
Agent: [Ru]
Agent: CO[SiH](OC)OC
Product: CCO[Si](CCCCl)(OCC)OCC
Yield: 41 %

Procedure:
Ruthenium has been reported to be a very efficient catalyst for the hydrosilation reaction of allyl chloride and trimethoxysilane. Japanese Patent No. 2,976,011 discloses the Ru-catalyzed hydrosilation reaction of triethoxysilane and allyl chloride to give chloropropyltriethoxysilane in about 41% yield. U.S. Pat. No. 5,559,264 describes the hydrosilation reaction of a methoxysilane and allyl chloride in the presence of a ruthenium catalyst and preferably in the substantial absence of solvent to provide a chloroalkylalkoxysilane. Tanaka et al., J. Mol. Catal. 1993, 81, 207-214 report the ruthenium carbonyl-catalyzed hydrosilation reaction of trimethoxysilane and allyl chloride and Japanese Patent Application No. 8[1996]-261232 describes the activation of ruthenium carbonyl for use as a hydrosilation catalyst for the same reaction.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[CH3:25][N:26]([CH3:28])[NH2:27]>>[CH3:25][N:26]([CH3:28])[NH:27][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4]
Reactant: CN(C)N
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)n[nH]1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NN(C)C)[nH]n1
Yield: 23 %

Procedure:
As described for example 8b, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.3 mmol) was converted, using N,N-dimethylhydrazine instead of 4-aminomorpholine, to the title compound (25 mg, 23%), which was obtained as a white solid after recrystallization from ethyl acetate. MS: m/e=360.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=3Br)[S:9][C:5]=2[CH:4]=1.[C:21](=O)([O-])[O-].[K+].[K+].CB(O)O>C1(C)C=CC=CC=1.C(OC(=O)C)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>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=3[CH3:21])[S:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2nc(-c3cccc(OC)c3Br)sc2c1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc2nc(-c3cccc(OC)c3C)sc2c1
Temperature: 100 °C
Yield: 63.2 %

Procedure:
To a solution of 6-methoxy-2-(2-bromo-3-methoxy-phenyl)-benzothiazole (0.128, 0.366 mmol) in dry toluene (4 mL) was added potassium carbonate (0.404 g, 2.92 mmol), methylboronic acid (88 mg, 1.47 mmol) and tetrakis(triphenylphosphine)palladium (42 mg, 0.036 mmol). The mixture was heated to 100° C. for 3 h, then cooled to room temperature. The mixture was diluted with ethylacetate and washed with water, saturated sodium carbonate and brine. After chromatographic purification gave 6-methoxy-2-(2-methyl-3-methoxy-phenyl)-benzothiazole (66 mg, 63% yield) as a white solid. Mass spec: MH+=286.
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][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26](O)=[O:27])=[CH:21][CH:20]=[CH:19]2.[NH2:29][CH2:30][C:31]1[CH:46]=[CH:45][C:34]([C:35]([NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[NH2:44])=[O:36])=[CH:33][CH:32]=1>>[NH2:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[NH:37][C:35]([C:34]1[CH:33]=[CH:32][C:31]([CH2:30][NH:29][C:26]([C:22]2[C:23]3[C:18](=[CH:17][C:16]([O:15][C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][CH:7]=4)=[CH:25][CH:24]=3)[CH:19]=[CH:20][CH:21]=2)=[O:27])=[CH:46][CH:45]=1)=[O:36]
Reactant: COc1cc2nccc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Reactant: NCc1ccc(C(=O)Nc2ccccc2N)cc1
Product: COc1cc2nccc(Oc3ccc4c(C(=O)NCc5ccc(C(=O)Nc6ccccc6N)cc5)cccc4c3)c2cc1OC
Yield: 81.9 %

Procedure:
The title compound (49.0 mg, 82% yield) was prepared as a brown solid from 6-(6,7-dimethoxyquinolin-4-yloxy)-1-naphthoic acid (37.5 mg, 0.1 mmol) and 4-(aminomethyl)-N-(2-aminophenyl)benzamide (28.9 mg, 0.12 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) δ 3.93 (s, 3H, —OCH3), 3.95 (s, 3H, —OCH3), 4.63 (d, J=5.6 Hz, 2H, —CH2), 4.90 (s, 2H, benzene-NH2), 6.56-6.59 (m, 2H, Ar—H), 6.78 (d, J=7.6 Hz, 1H, Ar—H), 6.96 (t, J=8.1 Hz, 1H, Ar—H), 7.17 (d, J=7.6 Hz, 1H, Ar—H), 7.42 (s, 1H, Ar—H), 7.53-7.55 (m, 4H, Ar—H), 7.62 (t, J=8.0 Hz, 1H, Ar—H), 7.71 (d, J=6.8 Hz, 1H, Ar—H), 7.87 (s, 1H, Ar—H), 7.98-8.06 (m, 3H, Ar—H), 8.39 (d, J=9.2 Hz, 1H, Ar—H), 8.49 (d, J=5.2 Hz, 1H, Ar—H), 9.26 (t, J=6.0 Hz, 1H, —CONH), 9.66 (s, 1H, benzene-NH). LC-MS (m/z) 599 (M+1).
Reaction SMILES: [C:1]([S:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].OC1[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]1.[NH2-].[Li+]>C1(C)C(C)=CC=CC=1>[C:1]([S:5]([CH2:8][C:9]([O:11][CH:12]1[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]1)=[O:10])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CS(=O)(=O)C(C)(C)C
Reactant: CC1(C)CC(O)CC(C)(C)N1
Agent: [Li+]
Agent: [NH2-]
Solvent: Cc1ccccc1C
Product: CC1(C)CC(OC(=O)CS(=O)(=O)C(C)(C)C)CC(C)(C)N1
Reaction time: 12 h

Procedure:
38.8 g (0.2 mol) of methyl t-butylsulphonyl-acetate, prepared according to the method of von Leusen and Strating, Rec. Trav, Chim. 84, 140 (1965), and 31.4 g (0.2 mol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine are dissolved in 50 ml of xylene. The mixture is warmed to 130°, 0.2 g of lithium amide in 50 ml of xylene is added and the mixture is stirred for 12 hours at 130°-140°. The xylene is removed in vacuo and the residue is distilled to give 2,2,6,6-tetramethyl-4-piperidinyl t-butyl-sulphonyl-acetate; yield: 33.7 grams, boiling point 153°-154°/10-3 mm Hg.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7](I)=[C:6]([F:12])[CH:5]=1)[CH2:2][CH3:3].[CH3:13][C:14]([OH:18])([C:16]#[CH:17])[CH3:15].[I-]>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.[Cu].C(N(CC)CC)C>[CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([C:17]#[C:16][C:14]([CH3:15])([OH:18])[CH3:13])=[C:6]([F:12])[CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1cc(F)c(I)c(F)c1
Reactant: C#CC(C)(C)O
Agent: [Cu]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Solvent: CCN(CC)CC
Product: CCCc1cc(F)c(C#CC(C)(C)O)c(F)c1
Reaction time: 2 h
Yield: 88.8 %

Procedure:
A mixture of 2 g of 1-propyl-3,5-difluoro-4-iodobenzene, 0.626 g of 2-methyl-3-butyn-2-ol, 0.164 g of tetrakis(triphenylphosphine)palladium(0), 10 ml of triethylamine and 0.054 g of copper(l) iodide was stirred at 90° for 2 hours. Then, the cooled reaction mixture was partitioned between water and ether, the ether phase was washed several times with water, dried over magnesium sulphate, filtered over Celite and evaporated on a rotary evaporator. The residue was then chromatographed on 75 g of silica gel (eluent: 10% ethyl acetate in hexane) and again evaporated. There were obtained 1.5 g of 4-(4-propyl-2,6-difluorophenyl)-2-methylbutyn-2-ol as a yellow liquid.