Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([O:36][C:37]([N:39]1[CH2:42][CH:41]([C:43](O)=[O:44])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C(N(CC)CC)C>CN(C=O)C>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=[C:19]([CH:27]3[CH2:31][CH2:30][N:29]([C:43]([CH:41]4[CH2:42][N:39]([C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH2:40]4)=[O:44])[CH2:28]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: Nc1ncnn2c(C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(C(=O)N2CCC(c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)C2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
To a solution of (5-(2-benzyl-2H-indazol-6-yl)-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.244 mmol) in DMF (1.5 mL) was added 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (50.6 mg, 0.252 mmol), triethylamine (102 μl, 0.733 mmol), and (BOP) benzoltriazolyloxytris(dimethylamino)phosphomium-hexafluorophosphate (140 mg, 0.317 mmol). The reaction was stirred at rt overnight. The mixture was partitioned between ethyl acetate (25 mL) and H2O (25 mL). The layers were separated and the organic was washed with H2O (20 mL). The combined aqueous layers were extracted with ethyl acetate (20 mL). The combined organics were washed with water (5×20 mL) to remove DMF, dried (Na2SO4), and evaporated. The crude material was purified by trituration with ether to yield 50 mg (35%) of the desired product. 1H NMR (300 MHz, Methanol-d6) δ 8.36 (s, 1 H), 7.85-7.81 (m, 2 H), 7.65 (s, 1 H), 7.40-7.20 (m, 4 H), 7.23 (d, 1 H), 6.67 (d, 1 H), 5.85 (s, 2 H), 4.20-3.90 (m, 3 H), 3.80-3.40 (m, 2 H), 3.30-3.10 (m, 4 H), 2.60-2.10 (m, 2 H), 1.33 (d, 9H); ES-MS m/z 579.0 [M+H]+, HPLC RT (min) 2.46.
Reaction SMILES: [CH:1](=[C:7]1[CH2:11][CH2:10][CH2:9][C:8]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Na].C(OC)(=O)[CH2:15][C:16]([CH3:18])=[O:17]>CO>[CH2:2]([CH:1]1[CH:7]2[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:18][C:16](=[O:17])[CH2:15]1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COC(=O)CC(C)=O
Reactant: CCCCCC=C1CCCC1=O
Agent: [Na]
Solvent: CO
Product: CCCCCC1CC(=O)C=C2CCCC21
Yield: 57.5 %

Procedure:
The procedure of Example 1 is repeated with 98.5 g (0.59 mol) of hexylidene cyclopentanone, 1.61 g (0.072 g-atom) of sodium, 82 g (0.71 mol) of methyl acetoacetate, and 300 ml of methanol. The crude product is fractionated giving 70 g (bp 117°-123° C. at 0.5 mm) of 5-pentylbicyclo [4.3.0] non-1en-3-one having the structure: ##STR9##
Reaction SMILES: [CH3:1][CH:2]1[O:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH:9](N1C(=O)COC1=O)=[CH2:10]>>[CH:9]([N:4]1[C:3](=[O:8])[CH:2]([CH3:1])[O:6][C:5]1=[O:7])=[CH2:10]
Reactant: C=CN1C(=O)COC1=O
Reactant: CC1OC(=O)NC1=O
Product: C=CN1C(=O)OC(C)C1=O

Procedure:
3-Vinyl-5-methyl-2,4-oxazolidinedione was prepared from 5-methyl-2,4-oxazolidinedione by the procedure for making 3-vinyl-2,4-oxazolidinedione in Example 9 hereinafter.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:7]=2[O:6][CH:5]=1.CC(C)([O-])C.[K+].[C:21]1([C:27]2[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(=O)C>CN(C=O)C.O>[C:21]1([C:27]2[CH:28]=[CH:29][C:30]([CH2:31][O:1][CH2:2][CH2:3][C:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:7]=4[O:6][CH:5]=3)=[CH:33][CH:34]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Reactant: COc1cccc2c(CCO)coc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c(CCOCc3ccc(-c4ccccc4)cc3)coc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.1 %

Procedure:
3-(2-hydroxyethyl)-7-methoxybenzofuran (373 mg) was dissolved in DMF (7 ml) and potassium t-butoxide (261 mg) was added to the obtained solution, followed by stirring the resulting solution at room temperature for 20 minutes. To this reaction solution, 4-phenylbenzyl chloride (511 mg) was added and the solution was stirred at room temperature for 1 hour. Acetic acid was added to the reaction solution and the resultant was poured into water layer (50 ml), followed by extraction twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=5/1) using silica gel to obtain the desired compound (613 mg, yield: 88%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([NH:16][C:17]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N+:25]([O-])=[CH:24][CH:23]=[CH:22]3)=[O:18])=[C:11]([CH3:30])[CH:10]=1)([F:8])[C:4]([F:7])([F:6])[F:5].P(Cl)(Cl)([Cl:35])=O.C(=O)([O-])[O-].[K+].[K+]>>[Cl:35][C:22]1[C:21]2[C:26](=[CH:27][CH:28]=[C:19]([C:17]([NH:16][C:12]3[C:13]([CH3:15])=[CH:14][C:9]([C:3]([F:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:32])([F:31])[F:1])=[CH:10][C:11]=3[CH3:30])=[O:18])[CH:20]=2)[N:25]=[CH:24][CH:23]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc2c(ccc[n+]2[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc2nccc(Cl)c2c1
Temperature: 100 °C
Yield: 22.8 %

Procedure:
To crude product of N-[4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-2,6-dimethylpheyl]quinoline-6-carboxamide-1-oxide (97 mg), phosphorus oxychloride (3.0 g) was added and the mixture was stirred under heating at 100° C. for 1 hour. The reaction solution was poured into ice water, neutralized with potassium carbonate and extracted twice with ethyl acetate. The organic phases were combined and washed with water, and dried over anhydrous magnesium sulfate. The drying agent (anhydrous magnesium sulfate) was removed by filtration and the solvent was distilled off under the reduced pressure. The residue was purified by column chromatography to obtain 2-chloro-N-[4-(,1,1,2,3,3,3-heptafluoropropan-2-yl)-2,6-dimethylphenyl]quinoline-6-carboxamide (35 mg, yield 35%) and 4-chloro-N-[4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-2,6-dimethylphenyl]quinoline-6-carboxamide (23 mg, yield 23%).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:29][CH2:30][CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(OCC)(=O)C>CN(C=O)C>[CH:32]1([CH2:31][CH2:30][CH2:29][N:2]2[CH2:3][CH2:4][CH2:5][C:6]3[CH:11]=[C:10]([O:12][C:13]4[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=4)[CH:9]=[CH:8][C:7]=3[CH2:1]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Reactant: ClCCCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCN(CCCC2CCCCC2)C3)nc1
Temperature: 50 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and (3-chloropropyl)cyclohexane (0.179 g, 1.11 mmol) in DMF (5.3 mL). Heat at 50° C. overnight, then increase the temperature to 80° C. for 3.5 hours. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1× 30 mL), brine (1× 30 mL), dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 408.3 (M+H)+, HRMS calcd for C25H34N3O2 408.2651 (M+H)+, found 408.2652, time 0.46 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=13.3 min, 100% purity.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[C:13]([CH3:14])=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[CH3:15])(=[O:5])[CH3:4].C(OCC)C.[Cl-].[NH4+]>O1CCOCC1>[CH3:14][C:13]1[CH:12]=[C:9]([CH:8]=[C:7]([CH3:15])[C:6]=1[C:3](=[O:5])[CH2:4][Br:1])[C:10]#[N:11]
Reactant: BrBr
Reactant: CC(=O)c1c(C)cc(C#N)cc1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1cc(C#N)cc(C)c1C(=O)CBr
Yield: 82.4 %

Procedure:
4.6 g of bromine are introduced slowly at about -5° C. into a solution of 4 g of 4-acetyl 3,5-dimethyl benzonitrile, prepared according to the method described in J. Chem. Soc. Perkin Trans. II, p. 943-949 (1988),in 10 ml of diethyl ether and 5 ml of dioxane. The mixture is allowed to attain room temperature, and after it has been stirred for 1 hour 15 ml of a saturated solution of ammonium chloride are added to it. The organic phase is separated and the solvent is removed under reduced pressure to give 4.8 g of the desired product. M.p.=76° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([NH2:22])=[C:12](Br)[CH:11]=1)[CH2:5][CH:6]1[CH2:9][CH2:8][CH2:7]1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.[F-].[Cs+].O>COCCOC.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.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:24])[CH:4]([C:10]1[CH:11]=[C:12]([C:30]2[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=2)[C:13]([NH2:22])=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH:15]=1)[CH2:5][CH:6]1[CH2:9][CH2:8][CH2:7]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C(CC1CCC1)c1cc(Br)c(N)c(OCC(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)C(CC1CCC1)c1cc(OCC(F)(F)F)c(N)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 100 °C
Yield: 104.5 %

Procedure:
To a solution of 2-[4-amino-3-bromo-5-(2,2,2-trifluoro-ethoxy)-phenyl]-3-cyclobutyl-propionic acid methyl ester (13.8 g, 29.6 mmol) in DME (anhydrous, 100 mL) under argon atmosphere were added 4-trifluoromethylphenylboronic acid (6.8 g, 35.8 mmol), CsF (11 g, 72.3 mmol), and Pd(PPh3)4 (3.4 g, 2.94 mmol). The reaction mixture was refluxed for 18 h (oil bath, 100° C.). On the next day, a mixture water and EtOAc (100 mL/100 mL) was added and the layers were separated. The organic phase was dried over MgSO4 and evaporated to give a crude yellow oil, which was purified by a short silica gel column chromatography by use of Heptane-EtOAc (4:1) to give the product (14.7 g, 94%) as a yellowish oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.70 (d, J=8.2 Hz, 2H), 7.59 (d, J=8.0 Hz, 2H), 6.78 (dd, J=9.6, 1.4 Hz, 2H), 4.43 (q, J=8.0 Hz, 2H), 3.95 (br s, 2H), 3.66 (s, 3H), 3.39 (t, J=7.7 Hz, 1H), 2.25-2.07 (m, 2H), 2.03-1.91 (m, 2H), 1.88-1.75 (m, 3H), 1.69-1.52 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 174.6, 144.8, 133.1, 129.2, 128.6, 126.3, 125.7 (q, 3JCF=3.6 Hz), 123.8, 123.3 (q, 1JCF=277.6 Hz), 111.4, 66.5 (q, 1JCF=35.4 Hz), 52.0, 49.0, 40.9, 34.1, 28.3, 28.1, 18.5.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH:9]=[CH:10][CH2:11][CH2:12]Cl>C1C=CC=CC=1>[CH:1]1([N:7]2[CH2:12][CH:11]=[CH:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClC=CCCCl
Reactant: NC1CCCCC1
Solvent: c1ccccc1
Product: C1=CCN(C2CCCCC2)C1
Temperature: 92 °C
Yield: 76 %

Procedure:
A solution of 5.19 kg (52.3 moles) of cyclohexylamine in 4.0 liters of benzene was heated to mild reflux (92° C.) and then the heating discontinued. To the solution was added, dropwise, 1,635 g (13.1 moles) of 1,4-dichlorobutene at a rate sufficient to maintain gentle reflux, 3 hours time being required. Heat was reapplied and the reactants were heated at reflux temperature for 18 hours. The mixture was cooled to about 50° C. and filtered to remove the hydrochloride. Carbon dioxide was bubbled into the filtrate to precipitate excess amine carbonate which was removed by filtration. Solvent was removed from the filtrate by distillation under reduced pressure and the reddish fluid residue slightly contaminated with benzene weighed 1,506 g (76% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([OH:21])=[O:20]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([C:16]3[CH:24]=[CH:23][CH:22]=[C:18]([C:19]([OH:21])=[O:20])[CH:17]=3)[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: Nc1cccc(C(=O)O)c1
Product: O=C(O)c1cccc(N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)c1
Yield: 73.9 %

Procedure:
4-nitrophthalic anhydride (0.25 g, 0.0013 mol) and m-aminobenzoic acid (0.18 g, 0.0013 mol) were refluxed as above overnight. The clear solution was purified as per 120 to yield 0.30 g (74%) 146 as a very pale dull yellow powder: mp=368–370° C.; Rf 0.83 (A): Rf 0.93 (C): Rf 0.53 (D): IR (cm−1): 2700–3280 (OH), 3122 (C═CH), 2687 (C—H), 1781 (C═O), 1727 (bs, C═O), 1622 (C═C), 1588 (C═C), 1546 (N═O), 1461 (C═C), 1420 (C═C), 1386 (C—O), 1350 (N═O), 1113 (C—O), 727 (C═CH); MS m/z (rel intensity) 311 (68), 285 (46), 267 (46), 191 (100).
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:25])=[C:6](SC2C=CC=CC=2)[C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:9]=1)(=[O:3])[CH3:2].Cl[C:27]1[CH:32]=[CH:31][CH:30]=[C:29](C(OO)=O)[CH:28]=1.[S:37]([O-:41])([O-])(=[O:39])=S.[Na+].[Na+]>ClCCCl>[C:1]([C:4]1[C:5]([CH3:25])=[C:6]([S:37]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:41])=[O:39])[C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1nn(-c2cccc(Cl)c2)c(=O)c(Sc2ccccc2)c1C
Agent: [Na+]
Solvent: ClCCCl
Product: CC(=O)c1nn(-c2cccc(Cl)c2)c(=O)c(S(=O)(=O)c2ccccc2)c1C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 6-acetyl-2-(3-chlorophenyl)-5-methyl-4-phenylthio-3(2H)-pyridazinone (0.37 g) in 1,2-dichloroethane (10 ml) was added m-chloroperbenzoic acid (0.65 g), followed by stirring at room temperature for 12 hours. An aqueous solution of sodium thiosulfate was added to the reaction mixture to decompose excess oxidizing agent, and then the mixture was extracted with chloroform. After washing with a saturated aqueous sodium hydrogen carbonate solution and a brine, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, and the resulting residue was allowed to stand at room temperature to obtain crystalline 6-acetyl-2-(3-chlorophenyl)-5-methyl-4-phenylsulfonyl-3(2H)-pyridazinone (0.38 g) (Compound No. 1-83).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1.[NH:28]1[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29]1.C(O)(C(F)(F)F)=O>C(O)(=O)C>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]([N:28]4[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29]4)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1
Reactant: CC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Reactant: OC1CCNC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(C)N4CCC(O)C4)cc3)cc12

Procedure:
1-(1-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2yl)ethyl)phenyl)ethyl)pyrrolidin-3-ol was prepared from 1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethanone (from Example 171) and pyrrolidin-3-ol following the procedures described for Example 187, except that in this case, acetic acid was used instead of triethylamine (20%). 1H NMR (Acetone-d6) TFA Salt: δ 8.83 (s, 1H), 8.76 (s, 1H), 8.72 (s, 1H), 8.29 (d, 1H), 7.57 (s, 1H), 7.42 (s, 1H), 7.33-7.38 (m, 3H), 4.41 (m, 2H), 3.77 (m, 2H), 3.33 (t, 2H), 3.21 (t, 2H), 3.19 (m, 2H), 3.10 (m, 2H), 2.10 (s, 3H), 1.75 (d, 3H). LRMS [M+H]=427.2
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[N:22]([C:24](Br)=[C:25]([CH3:27])[N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:36]([NH2:40])(=[O:39])[CH:37]=[CH2:38].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[N:22]([C:24](/[CH:38]=[CH:37]/[C:36](=[O:39])[NH2:40])=[C:25]([CH3:27])[N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(N)=O
Reactant: Cc1nc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nn2c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nn2c1/C=C/C(N)=O
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
200 mg (0.375 mmol) {1-[4-(3-Bromo-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, (intermediate example Int-2-3), 53.3 mg (0.75 mmol) acrylamide, 19.4 mg (0.064 mmol) tri-2-tolylphosphane, 16.8 mg (0.075 mmol) palladium(II) acetate and 0.06 mL (0.427 mmol) triethylamine in 2.6 mL degassed acetonitrile were heated in the microwave at 110° C. for three hours. The reaction mixture was poured on water/saturated ammonium chloride/dichloromethane and vigorously stirred for 30 minutes. The organic phase was separated, washed with brine, dried, and the solvent was removed. The crude product (247 mg) was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[CH:3]=1.[H-].[Na+].Cl.[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19]Cl.C(O)C>CN(C)C=O.O>[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][N:9]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=1)[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)Nc1cc(C)cc(C)n1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: CC(=O)N(CCN(C)C)c1cc(C)cc(C)n1
Reaction time: 0.25 h

Procedure:
One hundred and seventy seven grams (1.08 moles) of N-(4,6-dimethyl-2-pyridyl)acetamide is dissolved in 1.8 l of dry dimethylformamide in a 3 liter 3-neck flask equipped with a mechanical stirrer, thermometer, drying tube and slow nitrogen sweep. Sodium hydride in mineral oil (57%, 45.5 g) is added over a 30 minute period. After stirring for an additional 15 minutes, one hundred thirteen grams of 2-dimethylaminoethyl chloride hydrochloride is added in three portions over a 30 minute period. This is followed by 25.7 g of sodium hydride added in portions over a 60 minute period. Then 58.7 g of 2-dimethylaminoethyl chloride hydrochloride is added over a few minute period followed by 25.7 g of sodium hydride. A total of 96.9 g (2.3 mole) of 57% sodium hydride in mineral oil and 171.7 g (1.2 mole) of 2-dimethylaminoethyl chloride hydrochloride are used. The reaction mixture is stirred at 50° for 30 minutes then heated at 95° for 21/2 hours. After adding 75 ml of ethanol and 75 ml of water, the dimethylformamide is removed by distillation in vacuum.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1.[Si:17]([C:21]#[CH:22])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>O1CCOCC1.CCOC(C)=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.[Cu]I>[O:14]1[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][NH:8][C:5]2[CH:4]=[CH:3][C:2]([C:22]#[C:21][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:7][N:6]=2)[CH2:12][CH2:13]1
Reactant: Ic1ccc(NCCN2CCOCC2)nc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1ccc(NCCN2CCOCC2)nc1
Temperature: 80 °C

Procedure:
5-Iodo-N-(2-morpholinoethyl)pyridin-2-amine (0.82 g, 2.46 mmol), TMS acetylene (1.70 mL, 12.3 mmol), and triethylamine (0.69 mL, 4.92 mmol) were dissolved in dioxane (20 mL) and with nitrogen for about 15 min. Tetrakis(triphenylphosphine)palladium (142 mg, 0.12 mmol) and copper (I) iodide (47 mg, 0.25 mmol) were added before the reaction mixture was heated to 80° C. for 3.5 h. The reaction mixture was diluted with 100 mL EtOAc, washed with 50 mL saturated, aqueous NaHCO3, and dried over anhydrous Na2SO4. After purification by chromatography, the title compound was obtained. MS (ES+): 304 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([OH:11])[CH:3]=1.[CH3:12][C@@H:13](O)[CH2:14][CH:15]=[CH2:16].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>C1COCC1.CCOCC>[F:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:11][C@H:15]([CH2:14][CH:13]=[CH2:12])[CH3:16])[CH:3]=1
Reactant: C=CC[C@@H](C)O
Reactant: O=Cc1cc(F)c(F)cc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC[C@H](C)Oc1cc(F)c(F)cc1C=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 9 %

Procedure:
To a solution of 4,5-difluoro-2-hydroxybenzaldehyde (1.0 g, 6.33 mmol) in THF (14 ml) were added (R)-(−)-pent-4-en-2-ol (1.090 g, 12.65 mmol) and triphenylphosphine (2.157 g, 8.22 mmol). DIAD (1.599 ml, 8.22 mmol) was added dropwise (exotherm) and the mixture was stirred at rt. After 1.5 h, the mixture was diluted with Et2O and washed with 1N NaOH followed by water (3×'s) then brine, dried (Na2SO4), filtered and concentrated. The yellow oil was purified by flash chromatography (Biotage; 0%-100% EtOAc/hexane; 20 CV) to give (S)-4,5-difluoro-2-(pent-4-en-2-yloxy)benzaldehyde (0.1295 g, 0.572 mmol, 9.05% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 10.36 (d, J=3.2 Hz, 1H), 7.76-7.55 (m, 1H), 6.83 (dd, J=11.9, 6.0 Hz, 1H), 6.04-5.67 (m, 1H), 5.23-5.06 (m, 2H), 4.48 (sxt, J=6.0 Hz, 1H), 2.71-2.35 (m, 2H), 1.41 (d, J=6.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]3[O:29][C:30]([CH3:33])=[N:31][N:32]=3)[CH:26]=2)[N:21]=[CH:20][N:19]=1>>[ClH:17].[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:14]=[CH:13][C:11]([NH:12][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]5[O:29][C:30]([CH3:33])=[N:31][N:32]=5)[CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1nnc(-c2ccc3ncnc(Cl)c3c2)o1
Reactant: Nc1ccc(OCc2ccc(F)cc2)cc1
Product: Cc1nnc(-c2ccc3ncnc(Nc4ccc(OCc5ccc(F)cc5)cc4)c3c2)o1
Product: Cl

Procedure:
The title compound was prepared according to Procedure A from 4-(4-fluoro-benzyloxy)aniline and 4-chloro-6-(5-methyl-1,3,4-oxadiazol-2-yl)-quinazoline; δH [2H6]DMSO 11.68(1H, bs), 9.39(1H, s), 8.89(1H, s), 8.56(1H, d), 8.07(1H, d), 7.64(2H, d), 7.54(2H, m), 7.24(2H, dd), 7.14(2H, d), 5.14(2H, s), 2.65(3H, s); m/z (M+1+) 428.