Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[N:18]([C:21]1[C:22]([CH3:29])=[CH:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=1)=[C:19]=[S:20]>O1CCCC1>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:2]=1[NH:1][C:19](=[S:20])[NH:18][C:21]1[CH:26]=[N:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[CH3:29]
Reactant: COc1cc(C)c(N=C=S)cn1
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2cnc(OC)cc2C)c1NCCCO
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (4.00 g, 15.5 mmol) and 5-isothiocyanato-2-methoxy-4-methylpyridine (8.36 g, 46.4 mmol) in tetrahydrofuran (30 mL) was stirred at 70° C. for 8 hr. The mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give methyl 4-chloro-2-[(3-hydroxypropyl)amino]-3-{[(6-methoxy-4-methylpyridin-3-yl)carbamothioyl]amino}benzoate as a brown amorphous (3.90 g).
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[OH:12][CH:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:1][CH2:2][CH2:3][CH2:4]1
Reactant: O=C1CCCOc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCCOc2ccccc21

Procedure:
121.9 g (0.752 mole) of 2,3-dihydro-1-benzoxepin-5(4H)-one are dissolved in 1,400 ml of methanol and, while stirring vigorously, 18.5 g (0.489 mole) of sodium borohydride are introduced in portions so that the temperature remains below 20° C. The mixture is subsequently stirred for 2 hours, most of the solvent is distilled off in vacuo, and the residue is taken up in ethyl acetate. The organic phase is washed with water, 1N potassium bisulfate solution, water and saturated sodium chloride solution and dried over sodium sulfate. The mixture is filtered, and the solvent is evaporated off in vacuo. The oil crystallizes after some time.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:36]=[CH:35][C:17]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[NH:27]C(=O)OC(C)(C)C)=[O:19])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[C:4]([CH3:37])=[N:3]1.Cl.[OH-].[Na+]>O1CCOCC1.O.C(OCC)C>[NH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[NH:20][C:18](=[O:19])[C:17]1[CH:35]=[CH:36][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:5]3[C:4]([CH3:37])=[N:3][N:2]([CH3:1])[CH:6]=3)[CH2:13][CH2:12]2)=[CH:15][CH:16]=1
Reactant: Cc1nn(C)cc1CN1CCC(c2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: Cc1nn(C)cc1CN1CCC(c2ccc(C(=O)Nc3ccccc3N)cc2)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 93.3 %

Procedure:
tert-Butyl (2-{[4-(1-{1,3-dimethyl-1H-pyrazol-4-ylmethyl}piperidin-4-yl)benzoyl]amino}phenyl)carbamate (prepared as described in Method 6 below; 7.61 g, 15.11 mmol) was dissolved in 1,4 dioxane (70 ml) and cooled to 0° C., using an ice—water bath. A 4M solution of hydrogen chloride in 1,4 dioxane (150 ml, 600 mmol) was then added slowly. The resultant suspension was allowed to warm to room temperature and lumps broken up by agitation with a glass rod. The reaction mixture was stirred at room temperature for 18 hours. The mixture was filtered, under suction. The solid obtained was dissolved in water (200 ml), and the solution adjusted to pH 12 by slow addition of a 2M aqueous solution of sodium hydroxide. The mixture obtained was extracted with dichloromethane (300 ml) and the organics separated. The aqueous phase was further extracted with dichloromethane (200 ml) and the combined extracts washed with brine, dried over magnesium sulphate, filtered and evaporated to give a clear gum. The gum was taken up in diethyl ether and re-evaporated to dryness to afford the title compound (5.69 g, 93%); NMR Spectrum (CDCl3) δ 1.81 (m, 4H), 2.07 (m, 2H), 2.25 (s, 3H), 2.56 (m, 1H), 3.04 (m, 2H), 3.39 (s, 2H), 3.81 (s, 3H), 3.85 (s, 2H), 6.84 (m, 2H), 7.08 (m, 1H), 7.24 (s, 1H), 7.33 (m, 3H), 7.82 (m, 3H). Mass Spectrum: M+H+ 404.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:30]([OH:42])(=[O:41])/[CH:31]=[CH:32]/[C:33]1[CH:40]=[CH:39][C:37]([OH:38])=[C:35]([OH:36])[CH:34]=1>CO>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:30]([O-:42])(=[O:41])/[CH:31]=[CH:32]/[C:33]1[CH:40]=[CH:39][C:37]([OH:38])=[C:35]([OH:36])[CH:34]=1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CO
Product: O=C([O-])/C=C/c1ccc(O)c(O)c1
Temperature: 30 °C

Procedure:
Sunitinib (1.0 g) was suspended in methanol (152 mL), followed by addition of caffeic acid (0.45 g) at 25-35° C. over a period of 15 minutes. After the stipulated time period, methanol was completely distilled off under vacuum below 45° C. The residue was treated with acetonitrile (38 mL) and refluxed. The reaction mass was maintained at reflux temperature for 60 minutes. The reaction mass was cooled to 25-35° C. for crystallization. The solid obtained was filtered, washed with acetonitrile, suck dried and dried under vacuum at 60° C. over 4-5 hr period to obtain sunitinib caffeate. (1.3 g; yield:89%)
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]([C:12]1[CH:29]=[CH:28][C:15]([O:16][C:17]2[CH:18]=[C:19]([C:24](I)=[CH:25][N:26]=2)[C:20]([O:22][CH3:23])=[O:21])=[C:14]([CH2:30][CH2:31][CH3:32])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]>CO.[C].[Pd]>[F:34][C:2]([F:1])([F:33])[C:3]([C:12]1[CH:29]=[CH:28][C:15]([O:16][C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][N:26]=2)[C:20]([O:22][CH3:23])=[O:21])=[C:14]([CH2:30][CH2:31][CH3:32])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1cc(C(=O)OC)c(I)cn1
Agent: [Pd]
Solvent: CO
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1cc(C(=O)OC)ccn1
Yield: 74 %

Procedure:
To a solution of methyl 2-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy)-5-iodoisonicotinate (88 mg, 146 μmol) in methanol (2 mL), 20 wt % palladium carbon (10 mg) was added and the resultant mixture was stirred at room temperature under an hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered using celite, and the filtrate was concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate) and the title compound (52 mg, yield 75%) was obtained as a colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]1[S:13][C:12]([C:14]2[CH:19]=[C:18]([NH:20][CH:21]3[CH2:23][CH2:22]3)[N:17]3[N:24]=[CH:25][C:26]([CH:27]=[O:28])=[C:16]3[N:15]=2)=[CH:11][CH:10]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.O>CN(C=O)C>[CH:21]1([NH:20][C:18]2[N:17]3[N:24]=[CH:25][C:26]([CH:27]=[O:28])=[C:16]3[N:15]=[C:14]([C:12]3[S:13][C:9]([CH2:8][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:10][CH:11]=3)[CH:19]=2)[CH2:23][CH2:22]1
Reactant: O=Cc1cnn2c(NC3CC3)cc(-c3ccc(CBr)s3)nc12
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cnn2c(NC3CC3)cc(-c3ccc(CN4CCCC4)s3)nc12
Temperature: 60 °C
Yield: 50.5 %

Procedure:
Potassium carbonate (30 mg, 0.20 mmol) was added to 5-(5-(bromomethyl)thiophen-2-yl)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (25 mg, 0.07 mmol) dissolved in DMF (0.7 mL). Pyrrolidine (6 μL, 0.07 mmol) was added and the reaction was heated to 60° C. for 4 h. Water (3 mL) was added and the orange precipitate was filtered and dried in vacuo to give 7-(cyclopropylamino)-5-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (13 mg, 54%) which was used without further purification. LCMS (ES): >85% pure, m/z 368 [M+1]+.
Reaction SMILES: [C:1]1([P:7]([Cl:10])(Cl)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1(C)C=CC=CC=1>[C:1]1([P:7]([Cl:10])([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCCCO
Reactant: O=P(Cl)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCP(=O)(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.5 %

Procedure:
To a solution of phenylphosphonic dichloride (3.0 g, 14.2 mmol) and triethylamine (2.4 mL, 17.1 mmol) in toluene (20 mL) at 0° C. is added dropwise a solution of 1-nonanol (2.05 g, 14.2 mmol) in toluene (5 mL). The mixture is allowed to warm slowly to room temperature and stirred for 2 hours. The mixture is filtered, and the filtrate is concentrated to afford 4.5 g of the title compound as a light yellow liquid; 1H NMR (200 MHz, CDCl3)δ7.40-7.15 (m, 5 H), 4.40-4.25 (m, 2 H), 1.90-1.65 (m, 2 H), 1.45-1.20 (m, 12 H), 0.89 (t, J=7 Hz, 3 H).
Reaction SMILES: C([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](=S)[NH2:23])C1C=CC=CC=1.CI.[F:27][C:28]1[CH:38]=[CH:37][C:31]([CH2:32][N:33]([CH:35]=O)[NH2:34])=[CH:30][CH:29]=1.C([O-])(O)=O.[Na+]>C(#N)C.CN(C=O)C>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH:35]=[N:23][C:22]([C:10]3[N:11]=[C:12]4[N:17]([C:18](=[O:19])[C:9]=3[OH:8])[CH2:16][CH2:15][O:14][C:13]4([CH3:20])[CH3:21])=[N:34]2)=[CH:37][CH:38]=1
Reactant: CC1(C)OCCn2c1nc(C(N)=S)c(OCc1ccccc1)c2=O
Reactant: NN(C=O)Cc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC1(C)OCCn2c1nc(-c1ncn(Cc3ccc(F)cc3)n1)c(O)c2=O
Temperature: 40 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carbothioamide (0.042 g, 0.122 mmol, 1.0 equiv) in acetonitrile (1.2 mL) under a nitrogen atmosphere, was added MeI (0.038 mL, 0.61 mmol, 5 equiv). The reaction was heated at 40° C. (oil bath) for 1 h. The reaction was then cooled to ambient temperature and concentrated in vacuo. N-(4-Fluorobenzyl)formohydrazide (0.045 g, 0.268 mmol, 2.2 equiv) was then added to the residue followed by DMF (1.5 mL) and the solution was heated at 140° C. (oil bath). After stirring 1 h, the reaction was cooled to ambient temperature stirred 17 h. The reaction was added to a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (×3). The combined CH2Cl2 extracts were dried (Na2SO4) and then concentrated in vacuo. The crude product was purified by reverse phase preparatory HPLC and trituration from ether to provide the title compound (0.024 g, 53% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.10 (s, 1H), 7.29-7.35 (m, 2H), 7.07-7.14 (m, 2H), 5.44 (s, 2H), 4.02-4.10 (m, 4H), 1.68 (s, 6H); LCMS (ES+, (M+H)+) m/z 372.20.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:35])=[C:5]([C:31]([O:33][CH3:34])=[O:32])[CH:6]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:7]=1[C:8]1[O:12][N:11]=[C:10]([CH2:13][S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:9]=1.ClC1C=C(C=CC=1)C(OO)=[O:41].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[NH:3][C:4]([CH3:35])=[C:5]([C:31]([O:33][CH3:34])=[O:32])[CH:6]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:7]=1[C:8]1[O:12][N:11]=[C:10]([CH2:13][S:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:41])[N:9]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)C1=C(C)NC(C)=C(c2nc(CSCc3ccccc3)no2)C1c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)C1=C(C)NC(C)=C(c2nc(CS(=O)Cc3ccccc3)no2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
To a solution of 1.00 g of methyl 1,4-dihydro-2,6-dimethyl-3-(3-benzylthiomethyl-1,2,4-oxadiazol-5-yl)-4-(3-nitrophenyl)pyridine-5-carboxylate in 50 ml of chloroform was added 0.47 g of m-chloroperoxybenzoic acid. After the mixture was stirred at room temperature for 3 hours, the aqueous sodium bicarbonate was added and the stirring was continued for a while. The chloroform layer was separated, washed, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel using chloroform-methanol (30:1) as eluent to give 980 mg of methyl 1,4-dihydro-2,6-dimethyl-3-(3-benzylsulfinylmethyl-1,2,4-oxadiazol-5-yl)-4-(3-nitrophenyl)pyridine-5-carboxylate, IR νmaxneat cm-1 : 3290, 3210, 1680, 1645, 1520, 1490, 1230.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.Br[C:10]1[C:15]([C:16]#[N:17])=[CH:14][CH:13]=[CH:12][C:11]=1[C:18]#[N:19]>C1COCC1.[Ni].C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Cl-].[Ni+2].[H-].C([Al+]CC(C)C)C(C)C>[C:18]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([C:16]#[N:17])[C:10]=1[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)#[N:19]
Reactant: N#Cc1cccc(C#N)c1Br
Reactant: Cc1ccc(Br)cc1
Agent: [Ni+2]
Agent: [Ni]
Agent: CC(C)C[Al+]CC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2c(C#N)cccc2C#N)cc1
Temperature: 18 °C
Reaction time: 0.25 h

Procedure:
4-Bromotoluene (10.44 mL, 84.9 mmol, 1.2 eq.) was converted to the Grignard reagent (Mg: 3.10 g, 127 mmol, 1.9 eq.) in THF (50 mL) and then added to a stirred mixture of freshly fused zinc (II) chloride (9.34 g, 68.5 mmol, 1 eq.) in THF (50 mL) at such a rate as to maintain the temperature at 18° C. In another flash, bis(triphenylphosphine)nickel(II)-chloride (1.10 g, 1.7 mmol, 0.025 eq.) and THF (5 mL) were mixed and cooled to 0° C. Diisobutylaluminum hydride (1M in THF, 3.37 mL, 3.4 mmol, 0.049 eq.) was added to the black mixture of Ni catalyst and THF. After warming to 20° C., 1-bromo-2,6-dicyanobenzene (T. D. Krizan, J. C. Martin J. Org. Chem., (1982) 47, 2681) (0.95 g or 6.7% of the total amount to be coupled, 4.6 mmol, 0.067 eq.) in a minimum of THF was added to the Ni catalyst and stirred for 15 min. The Grignard solution was cooled to 6° C. and then to it the Ni catalyst mixture was transferred via cannula. The remaining 1-bromo-2,6-dicyanobenzene (13.16 g, 63.9 mmol, 0.933 eq.) in a minimum of THF was finally added to the Grignard+Ni catalyst mixture. After stirring overnight at 25° C., the mixture was diluted with ethyl acetate (400 mL) and washed with water (2×200 mL) and brine (1×200 mL). The ethyl acetate layer was dried (MgSO4) and the solvent removed in vacuo to yield a yellow solid. Chromatography in 75:25 hexane/ethyl acetate to 100% ethyl acetate followed by recrystallization from hexane/ethyl acetate yielded 8.46 g of a white solid; m.p. 184.0°-186.0° C. NMR (CDCl3): δ7.98 (d, 2H, J=9 Hz); 7.58 (t, 1H, J=9 Hz); 7.45 (d, 2H, J=9 Hz); 7.37 (d, 2H, J=9 Hz); 2.44 (s, 3H). Anal. calcd. for C15H10N2 : C, 82.55; H, 4.62; N, 12.84. Found: C, 82.34; H, 4.78; N, 12.87.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:17]3[C:12]([C:13]([NH2:18])=[N:14][CH:15]=[N:16]3)=[C:11]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:35]1(=O)[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH2:28]([N:24]1[CH:23]=[C:22]2[C:26]([CH:27]=[C:19]([C:11]3[CH:10]=[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][CH:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)[CH:4]=4)[N:17]4[C:12]=3[C:13]([NH2:18])=[N:14][CH:15]=[N:16]4)[CH:20]=[CH:21]2)=[N:25]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Reactant: O=C1CCCC1
Product: Nc1ncnn2c(-c3cccc(CNC4CCCC4)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 28 %

Procedure:
Using a procedure similar to that of Example 111 with 7-(3-aminomethyl-phenyl)-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and cyclopentanone as starting materials, 66 mg (28%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.70 (s, 2 H), 3.00 (m, 1 H), 1.80-1.60 (m, 4 H), 1.30-1.20 (m, 4 H); ES-MS m/z 514.16 [M+H]+, HPLC RT (min) 2.45.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]2[NH:14][N:13]=[CH:12][CH:11]=2)[CH:7]=[C:6]([F:15])[C:3]=1[C:4]#[N:5].O[CH2:17][C@@H:18]([NH:20]C(=O)OC(C)(C)C)[CH3:19].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>>[NH2:20][C@@H:18]([CH3:19])[CH2:17][N:13]1[CH:12]=[CH:11][C:10]([C:8]2[CH:7]=[C:6]([F:15])[C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=2)=[N:14]1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: N#Cc1c(F)cc(-c2ccn[nH]2)cc1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(F)c2)n1
Yield: 39.4 %

Procedure:
The title compound was prepared from 2,6-difluoro-4-(1H-pyrazol-5-yl)-benzonitrile (1.39 g, 6.78 mmol) and (S)-tert-butyl 1-hydroxypropan-2-ylcarbamate (1.423 g, 8.12 mmol), triphenylphosphine (2.129 g, 8.12 mmol) and DIAD (1.578 ml, 8.12 mmol) using the method of Example 34(c) affording 0.70 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 0.95 (d, 3H), 3.22 (m, 1H), 4.01 (m, 2H), 7.02 (d, 1H), 7.78 (m, 1H), 7.81 (m, 1H), 7.88 (d, 1H).
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]([CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][OH:16])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:21]=[C:20]([Cl:30])[C:19]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:1]([O:5][N:6]=[C:7]([CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][C:19]1[C:20]([Cl:30])=[CH:21][C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:28])[Cl:29])=[CH:23][C:18]=1[Cl:17])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: CC(COCCOCCO)=NOC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(COCCOCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)=NOC(C)(C)C
Yield: 67.1 %

Procedure:
To a mixture of 0.51 g of 2-(2-hydroxyethoxy)ethoxyacetone O-tert-butyloxime, 0.58 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 0.58 g of triphenylphosphine, and 20 ml of tetrahydrofuran is slowly added dropwise 0.49 g of diisopropyl azodicarboxylate with stirring under ice cooling in a stream of nitrogen gas. After stirring at room temperature for 4 hours, the reaction mixture is concentrated to give a residue. This residue is subjected to silica gel chromatography, which affords 0.68 g (yield, 68%) of 2-(2-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)ethoxy)ethoxyacetone O-tert-butyloxime, nD23.0 1.5172.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][S:15]([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]([CH3:28])[NH:23][CH2:22][CH2:21]2)(=[O:17])=[O:16]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:23]3[CH2:22][CH2:21][C:20]4[C:25](=[CH:26][CH:27]=[C:18]([S:15]([CH3:14])(=[O:16])=[O:17])[CH:19]=4)[CH:24]3[CH3:28])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cc(S(C)(=O)=O)ccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2ccc(S(C)(=O)=O)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Methanesulfonyl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[C:29]([F:31])[C:28]([O:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[C:27]([F:38])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[F:38][C:27]1[CH:26]=[C:25]([C:23]2[N:24]=[C:20]([NH:19][C:17](=[O:18])[CH2:16][N:10]3[C:6]4[C:5](=[O:12])[N:4]([CH3:13])[C:3](=[O:14])[N:2]([CH3:1])[C:7]=4[CH:8]=[CH:9]3)[S:21][CH:22]=2)[CH:30]=[C:29]([F:31])[C:28]=1[O:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36]
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Reactant: CC(C)CCOc1c(F)cc(-c2csc(NC(=O)CBr)n2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CCOc1c(F)cc(-c2csc(NC(=O)Cn3ccc4c3c(=O)n(C)c(=O)n4C)n2)cc1F

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (50 mg, 0.279 mmol) with 2-bromo-N-{4-[3,5-difluoro-4-(3-methylbutoxy)phenyl]-1,3-thiazol-2-yl}acetamide (140 mg, 0.334 mmol) in the presence of NaH (16 mg, 0.666 mmol) in dry DMF (5.0 mL) to give 75 mg of the product as an off-white solid; 1H NMR (δ ppm, DMSO-d6, 300 MHz) 0.92 (d, J=6.6 Hz, 6H), 1.60 (d, J=6.3 Hz, 2H), 1.75-1.85 (m, 1H), 3.17 (s, 3H), 3.39 (s, 3H), 4.15 (d, J=6.3 Hz, 2H), 5.32 (s, 2H), 6.22 (s, 1H), 7.35 (s, 1H), 7.63 (s, 1H), 7.66 (s, 1H), 7.77 (s, 1H), 12.68 (br s, 1H); ESI-MS (m/z) 516.41 [M−H].
Reaction SMILES: [H][H].C([SiH](CC)CC)C.[OH:10][C:11]1[CH:12]=[CH:13][C:14]2[S:18][CH:17]=[CH:16][C:15]=2[CH:19]=1.FC(F)(F)C(O)=O>>[OH:10][C:11]1[CH:12]=[CH:13][C:14]2[S:18][CH2:17][CH2:16][C:15]=2[CH:19]=1
Reactant: Oc1ccc2sccc2c1
Reactant: [H][H]
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc2c(c1)CCS2

Procedure:
Scheme I depicts the preparation of the simplest member (2) of the invention, that is where R4 and R6 are both hydrogen. Triethylsilane is reacted with 5-hydroxybenzothiophene in a suitable solvent, e.g, trifluoroacetic acid (TFA) to yield the 5-hydroxy-2,3-dihydrobenzothiophene. ##STR4##
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:22]3[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]3)[CH:18]=2)[N:13]=[CH:12]1.S(Cl)(Cl)=O.[NH2:35][C:36]1[CH:40]=[CH:39][O:38][N:37]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[CH:28]([N:25]1[CH2:26][CH2:27][N:22]([C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][N:11]([C:3]2[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=2[CH3:1])[C:6]([NH:35][C:36]2[CH:40]=[CH:39][O:38][N:37]=2)=[O:7])[C:20]3=[O:21])[CH2:23][CH2:24]1)([CH3:30])[CH3:29]
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(N3CCN(C(C)C)CC3)cc2c1=O
Reactant: Nc1ccon1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2ccon2)cc1-n1cnc2ccc(N3CCN(C(C)C)CC3)cc2c1=O
Temperature: 40 °C
Reaction time: 18 h

Procedure:
To a stirred slurry of 4-methyl-3-[6-(4-isopropylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzoic acid (0.2 g) and DMF (0.05 ml) in methylene chloride (4 ml) at 35° C. was added thionyl chloride (0.20 ml). The resultant green solution was stirred at 40° C. for 18 hours. The reaction mixture was concentrated to give an orange/brown solid. The solid was stirred in methylene chloride (4 ml) at room temperature and 3-aminoisoxazole (0.15 ml) and N,N-diisopropylethylamine (0.26 ml) was added, stirred for 1.5 hours and concentrated. The resultant oil was partitioned between ethyl acetate and saturated NaHCO3 solution. The aqueous layer was separated and the organic layer washed with brine (5 ml). The organic phase was concentrated to give an orange/brown solid. The residue was purified by column chromatography on a silica column using a 9:1 mixture of ethyl acetate and methanol as eluent to give the title compound as a yellow solid (50 mg); NMR Spectrum: (DMSOd6) 1.04 (d, 6H), 2.18 (s, 3H), 2.62 (m, 4H), 2.68 (m, 1H), 3.28 (m, 4H), 7.05 (s, 1H), 7.49 (s, 1H), 7.66 (m, 3H), 8.08 (m, 2H), 8.12 (s, 1H), 8.86 (s, 1H), 11.47 (s, 1H); Mass Spectrum: M+H+ 473.