Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][CH2:12][OH:13].[OH-].[Na+].C(O)(=[O:18])C>O>[OH:13][CH2:12][CH2:11][N:6]1[CH:5]=[N:4][C:3]2[C:2](=[O:18])[NH:10][CH:9]=[N:8][C:7]1=2
Reactant: OCCn1cnc2c(Cl)ncnc21
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]cnc2c1ncn2CCO

Procedure:
6-Chloro-9-hydroxyethyl purine, III (4 g), was added slowly to warm N NaOH (30 ml) and refluxed for 2 hr. The reaction is cooled in ice and neutralized with glacial acetic acid. After filtration, portions of unreacted III are removed. The product is recrystallized from methanol and washed with acetone. Colorless crystals. Yield, 1 g. (28%) mp. 274°; uv (H2O, pH 5.5), λmax 250 nm.
Reaction SMILES: [Cl:1]/[C:2](/[C:11]([O:13][CH2:14][CH2:15][CH3:16])=[O:12])=[C:3](\Cl)/[C:4]([O:6][CH2:7][CH2:8][CH3:9])=[O:5].C([O-])(=O)C.[NH4+:21]>CN(C)C=O>[NH2:21]/[C:3](/[C:4]([O:6][CH2:7][CH2:8][CH3:9])=[O:5])=[C:2](\[Cl:1])/[C:11]([O:13][CH2:14][CH2:15][CH3:16])=[O:12]
Reactant: CCCOC(=O)/C(Cl)=C(/Cl)C(=O)OCCC
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCCOC(=O)/C(N)=C(/Cl)C(=O)OCCC
Yield: 96.5 %

Procedure:
26.9 g (0.1 mol) of dipropyl dichloromaleate, 19.27 g (0.25 mol) of ammonium acetate and 40 ml of dimethylformamide were reacted under the same conditions as described in Example 1. 24.1 g (87.4% yield) of dipropyl aminochloromaleate were obtained as a reddish, viscous liquid (purity according to GC analysis 90.5%)
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[C:4]([CH2:11][NH2:12])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:19][N:16]1[CH2:15][CH2:14][N:13]([C:3]2[C:4]([CH2:11][N:12]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[CH3:1])[CH2:18][CH2:17]1
Reactant: Cc1cc([N+](=O)[O-])cc(CN)c1N1CCN(C)CC1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc([N+](=O)[O-])cc(CN2CCCC2)c1N1CCN(C)CC1
Yield: 53 %

Procedure:
A mixture of [3-methyl-2-(4-methylpiperazin-1-yl)-5-nitrophenyl]methanamine (188 mg, 0.71 mmol), 1,4-dibromobutane (93 μL, 1.1 eq) and K2CO3 (490 mg, 5 eq) in 15 mL of acetonitrile was refluxed for 48 h. After filtration and evaporation of the filtrate, the residue was purified by flash chromatography (DCM/MeOH/NH4OH//9/1/0.1) to yield expected compound as a pale yellow oil (120 mg, 53% yield).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:12][C@@H:13]([CH:21]([CH3:23])[CH3:22])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CS(C)=O>[CH3:22][CH:21]([CH3:23])[C@H:13]([NH:12][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)[C@H](Nc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 1-fluoro-4-nitrobenzene (3.0 g, 21 mmol) and tert-butyl (2S)-2-amino-3-methylbutanoate hydrochloride (5.4 g, 26 mmol) in DMSO (20 mL) was added K2CO3 (8.8 g, 64 mmol). The reaction mixture was stirred at 100° C. for 8 h. EtOAc (200 mL) was added. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1:10 v/v)) to obtain compound 55a as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C15H22N2O4: 295.2 (M+H). Found 295.2.
Reaction SMILES: C[Sn](C)C.C[Sn](C)C.[F:9][C:10]1[CH:11]=[CH:12][C:13](Br)=[N:14][CH:15]=1.Br[C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=2)[C:26]#[N:27])=[CH:20][CH:19]=1>ClCCl.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>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C:18]2[O:22][C:21]([C:23]3[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=3)[C:26]#[N:27])=[CH:20][CH:19]=2)=[N:14][CH:15]=1
Reactant: Fc1ccc(Br)nc1
Reactant: N#Cc1cccc(-c2ccc(Br)o2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)C
Solvent: ClCCl
Product: N#Cc1cccc(-c2ccc(-c3ccc(F)cn3)o2)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 43.6 %

Procedure:
In a similar fashion, Pd(PPh3)4 (25 mg, 0.022 mmol) was added to a solution of hexamethylditin (163 mg, 0.50 mmol) and 5-fluoro-2-bromopyridine (87 mg, 0.49 mmol) in toulene (4 mL) under argon. The resulting solution was stirred at 80° C. for 15 h. After cooling to room temperature, a second portion of Pd(PPh3)4 (25 mg, 0.022 mmol) and 3-(5-bromofuran-2-yl)-benzonitrile (105 mg, 0.42 mmol) were added and the resulting solution was stirred at 110° C. for 48 h. After cooling to room temperature, the mixture was diluted with dichloromethane and passed through a 1 g silica gel SPE tube using dichloromethane to elute the product. Flash chromatography (silica gel, 50–100% dichloromethane in hexane) afforded 48.4 mg (43%) of 3-(5-(5-fluoro-2-pyridyl)-2-furyl)-benzonitrile (pure by GC/MS). 1H-NMR (CDCl3), δ (ppm): 8.48 (d, 1H), 8.03 (s, 1H), 7.95 (m, 1H), 7.81 (m, 1H), 7.51 (m, 3H), 7.11 (d, 1H), 6.87 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:40])=[C:14]([C:35](OCC)=[O:36])[C:15](=[O:34])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]([CH3:33])[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:41][CH:42]([CH3:45])[CH2:43][OH:44]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:40])=[C:14]([C:35]([NH:41][CH:42]([CH3:45])[CH2:43][OH:44])=[O:36])[C:15](=[O:34])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]([CH3:33])[C:23](=[O:24])[O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CC(N)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN(C)C(=O)OCc2ccccc2)c1=O
Product: CC(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN(C)C(=O)OCc2ccccc2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)propyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-amino-1-propanol using conditions similar to Step 5 from Example 497 and obtained as a white solid: ES+ MS: 577 (M+H+).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:33])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17](O)=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2].C1N=[CH:37][N:36](C(N2C=NC=C2)=O)[CH:35]=1.CNC>C1COCC1>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:33])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:28])[F:29])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17]([N:36]([CH3:37])[CH3:35])=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2]
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)N(C)C)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Yield: 65 %

Procedure:
3-(4-Acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-N,N-dimethyl-propionamide was prepared by the procedure of example 13 from 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (0.5 g, 1.1 mmol), CDI (0.2 g, 0.1.3 mmol) and dimethylamine (2N in THF, 0.7 ml, 1.4 mmol) in THF (10 ml) to give 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-N,N-dimethyl-propionamide (0.35 g, 67% yield): mp, 163-165° C.; 1H NMR (CDCl3): δ 1.44 (t, J=7.0 Hz, 3H, OCH2CH3), 2.25 (s, 3H, CH3CO), 2.90 (s, 3H, NCH3), 2.98 (dd, J=5, 15 Hz, 1H, CH2), 3.05 (s, 4H, NCH3+CH2), 3.91 (dd, J=10, 15 Hz, 1H, CH2), 4.09 (q, J=7.0 Hz, 2H, OCH2CH3), 5.81-5.87 (m, 1H, CHN), 6.53 (t, JH-F=75 Hz, 1H, CF2H), 7.11-7.17 (m, 3H, Ar), 7.45 (d, J=7.0 Hz, 1H, Ar), 7.62 (t, J=8.0 Hz, 1H, Ar), 8.73 (d, J=8.8 Hz, 1H, Ar), 9.53 (s, 1H, NHCO). 13C NMR (DMSO-d6): δ 14.5, 24.8, 34.8, 35.5, 37.1, 51.3, 64.7, 111.9, 113.8, 115.4, 116.1, 117.9, 120.1, 120.2, 122.7, 124.7, 131.3, 135.8, 137.5, 138.1, 150.6, 168.1, 169.2, 169.3, 170.0; Anal Calcd for C24H25F2N3O6: C, 58.89; H, 5.15; N, 8.58. Found: C, 58.53; H, 4.78; N, 8.51.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH:11]=O)=[C:9]([CH3:13])[C:8]([O:14][C:15](=[O:17])[CH3:16])=[C:7]([O:18][CH3:19])[C:6]=1[O:20][CH3:21])(=[O:3])[CH3:2].O=[C:23](C)C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O[CH:49]1[CH2:54][CH2:53][CH2:52][CH2:51][O:50]1)C#C>O1CCOCC1>[C:1]([O:4][C:5]1[C:10]([CH2:11][CH2:23][CH:54]([CH3:49])[CH2:53][CH2:52][CH2:51][OH:50])=[C:9]([CH3:13])[C:8]([O:14][C:15](=[O:17])[CH3:16])=[C:7]([O:18][CH3:19])[C:6]=1[O:20][CH3:21])(=[O:3])[CH3:2]
Reactant: C#CCOC1CCCCO1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1c(OC(C)=O)c(C)c(C=O)c(OC(C)=O)c1OC
Solvent: C1COCCO1
Product: COc1c(OC(C)=O)c(C)c(CCC(C)CCCO)c(OC(C)=O)c1OC

Procedure:
A mixture of 6 parts of 1,4-diacetoxy-2,3-dimethoxy-6-formyl-5-methylbenzene, 12 parts of 2-oxo-1-propylidenetriphenylphosphoran and 500 volume parts of dioxane is stirred under reflux for 17 hours and the reaction mixture is evaporated to dryness. The residue is purified by chromatography on a column of silica gel, whereupon 1,4-diacetoxy-2,3-dimethoxy-5-methyl-6-(3'-oxo-1'-butenyl)-benzene (Formula (VII) wherein R=OCH3 ; OY, OY'=OCOCH3) is obtained as a brown oil. 2 Parts of this product is reacted with 2.77 parts of 2-propargyloxytetrahydropyran, reduced catalytically and hydrolyzed in the same manner as Reference Example 4. The described procedure gives 1,4-diacetoxy-2,3-dimethoxy-5-methyl-6-(6'-hydroxy-3'-methylhexyl)benzene (Formula (IX) wherein R=OCH3 ; OY, OY'=OCOCH3 ; OY"=OH) as a colourless oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1.[H-].[Na+].Br[C:12]1[S:13][CH:14]=[CH:15][N:16]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[S:13]1[CH:14]=[CH:15][N:16]=[C:12]1[O:1][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1
Reactant: Brc1nccs1
Reactant: OCC1(CO)CCC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCC1(COc2nccs2)CCC1
Reaction time: 0.25 h
Yield: 39.6 %

Procedure:
To a solution of 0.5 g (4.31 mmol) of [1-(hydroxymethyl)cyclobutyl]methanol in 15 mL of N,N-dimethylformamide:tetrahydrofuran (1:1), was added a 60% dispersion of 0.165 g (4.31 mmol) sodium hydride in oil. After stirring for 15 min, 0.71 g (4.31 mmol) of 2-bromothiazole was added and the contents refluxed for 3 h. A saturated solution of sodium bicarbonate was added followed by ethyl acetate. The organic phase was isolated, dried with magnesium sulfate and concentrated under vacuum. The crude product was purified by silica gel chromatography eluting with ethyl acetate:hexane (4:6) to afford 0.340 g (40%) of {1-[(1,3-thiazol-2-yloxy)methyl]cyclobutyl}methanol as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.05 (d, J=4 Hz, 1H), 6.64 (d, J=4 Hz, 1H), 4.51 (s, 2H), 3.59 (s, 2H), 2.03-1.72 (m, 6H). GC-MS m/z 200 (M+H).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH:9]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[CH:21][CH:20]=[C:19]2[S:23](Cl)(=[O:25])=[O:24])=[CH:14][CH:13]=1)([CH3:11])[CH3:10].[CH:27]([C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37]2)=[CH:32][CH:31]=1)([CH3:29])[CH3:28]>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:23]([C:19]1[N:18]([C:15]2[CH:16]=[CH:17][C:12]([CH:9]([CH3:11])[CH3:10])=[CH:13][CH:14]=2)[CH:22]=[CH:21][CH:20]=1)(=[O:24])=[O:25].[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:41]([C:38]1[CH:39]=[CH:40][N:36]([C:33]2[CH:34]=[CH:35][C:30]([CH:27]([CH3:29])[CH3:28])=[CH:31][CH:32]=2)[CH:37]=1)(=[O:42])=[O:43]
Reactant: CC(C)c1ccc(-n2ccc(S(=O)(=O)Cl)c2)cc1
Reactant: Cc1noc(N)c1Br
Reactant: CC(C)c1ccc(-n2cccc2S(=O)(=O)Cl)cc1
Product: Cc1noc(NS(=O)(=O)c2cccn2-c2ccc(C(C)C)cc2)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccn(-c3ccc(C(C)C)cc3)c2)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl) 1-(4′-isopropylphenyl)pyrrole-2-sulfonamide and N-(4-bromo-3-methyl-5-isoxazolyl) 1-(4′-isopropylphenyl)pyrrole-3-sulfonamide were prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and a mixture of 1-(4′-isopropylphenyl)pyrrole-2-sulfonyl chloride and 1-(4′-isopropylphenyl)pyrrole-3-sulfonyl chloride in 65% combined yield. The mixture was subjected to preparative HPLC to give N-(4-bromo-3-methyl-5-isoxazolyl) 1-(4′-isopropylphenyl)pyrrole-2-sulfonamide (retention time 22.85 min, 5% to 95% acetonitrile in water with 0.1% TFA over 30 min period, C18 analytical column) and N-(4-bromo-3-methyl-5-isoxazolyl) 1-(4′-isopropylphenyl)pyrrole-3-sulfonamide (retention time 24.56 min, 5%, to 95% acetonitrile in water with 0.1% TFA over 30 min period, C18 analytical column) as oils.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13](=[O:19])OC(C)(C)C)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:29]=1)C(O)=O.O[CH2:37][CH2:38][N:39]1[CH2:43][CH2:42][CH2:41][C:40]1=O>>[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([N:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)[CH:29]=1)[C:13]([NH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O:1][CH2:43][C:42]2[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=2)=[CH:3][CH:4]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Reactant: O=C1CCCN1CCO
Reactant: O=C(O)c1cc(F)cc(N2CCCCC2)c1
Product: O=C(Nc1ccc(OCc2ccncc2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from tert-butyl (4-hydroxy-1-naphthyl)carbamate, 3-fluoro-5-piperidin-1-yl-benzoic acid and 1-(2-hydroxy-ethyl)-pyrrolidin-2-one according to conditions described in general procedure D. A pink solid is produced (38 mg). Mp: 69-71° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.58 (s, 6H), 3.28 (s, 4H), 5.42 (s, 2H), 6.95 (d, J=8.4 Hz, 1H), 7.06 (d, J=8.1Hz, 1H), 7.15 (d, J=6.9 Hz, 1H), 7.44 (s, 1H), 7.55-7.60 (m, 4H), 7.85-7.92 (m, 1H), 8.30-8.38 (m, 1H), 8.60-8.63 (m, 1H), 10.26 (s, 1H); MS 456 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:15])[C:10]#[C:11][CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:22][O:23][C:24](=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Br)[CH:26]=1>CN(C=O)C>[CH3:22][O:23][C:24](=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[I:1])[C:9](=[O:15])[C:10]#[C:11][CH:12]([CH3:13])[CH3:14])[CH:26]=1
Reactant: CC(C)C#CC(=O)Nc1ccccc1I
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN(C(=O)C#CC(C)C)c2ccccc2I)c1
Reaction time: 0.17 h
Yield: 51.4 %

Procedure:
A mixture of 4-methyl-pent-2-ynoic acid (2-iodo-phenyl)-amide (21 g, 67.1 mmol) and cesium carbonate (33.0 g, 100.7 mmol) in DMF (170 ml) was stirred for 10 minutes. 3-bromomethyl-benzoic acid methyl ester (16.9 g, 73.8 mmol) was added. Then the mixture was stirred for 12 hours at room temperature. After removal of the solids, the filtrate was treated with water and extracted with ether. The organic layer was dried over sodium sulfate and concentrated to give the residue which was purified by flash chromatography, eluting with ethyl acetate/hexane=1:4 to afford the product 3-{[(2-iodo-phenyl)-(4-methyl-pent-2-ynoyl)-amino]-methyl}-benzoic acid methyl ester as yellow solid (15.9 g, 51%). MS calcd. for C21H20ClNO3 461.3, obsd. (ESI+) [(M+H)+] 461.9.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:11]=[C:12]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[C:13]4[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][C:14]=4[N:15]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.O1CCOC[CH2:35]1>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:11]=[C:12]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][C@@H:28]4[CH3:35])[C:13]4[CH2:19][CH2:18][NH:17][CH2:16][C:14]=4[N:15]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1CCc2c(nc(-c3ccc4[nH]ccc4c3)nc2N2CCOCC2)C1
Agent: Cl
Product: C[C@H]1COCCN1c1nc(-c2ccc3[nH]ccc3c2)nc2c1CCNC2
Reaction time: 2 h

Procedure:
Tert-butyl 2-(1H-indol-5-yl)-4-morpholino-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (0.199 g, 0.000443 mol) and 4.0 M of Hydrogen chloride in 1,4-Dioxane (3.4 mL) were combined and shaken for 2 hours then concentrated, diluted 10% MeOH in dichloromethane and sat NaHCO3, extracted three times with 10% MeOH in dichloromethane, dried over Magnesium sulfate, filtered, concentrated, and vacuum pump dried overnight, and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 11.18 (s, 1H), 8.56 (s, 1H), 8.12 (dd, J=8.6, 1.4, 1H), 7.42 (d, J=8.6, 1H), 7.36 (t, J=2.7, 1H), 6.53 (s, 1H), 4.10 (d, J=6.7, 1H), 3.95-3.78 (m, 3H), 3.74 (dd, J=11.3, 2.8, 1H), 3.68-3.50 (m, 3H), 3.50-3.39 (m, 1H), 3.02-2.90 (m, 1H), 2.87-2.76 (m, 1H), 2.55 (d, J=11.2, 2H), 1.25 (t, J=10.2, 3H). LC/MS-m/z+350.2 (M+H)+
Reaction SMILES: C(O)(C)C.Cl[C:6]1[C:7]2[C:14]3[CH2:15][CH2:16][C:17]4([CH2:22][C:13]=3[S:12][C:8]=2[N:9]=[CH:10][N:11]=1)[O:21][CH2:20][CH2:19][O:18]4.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=1)[NH2:27].Cl>O1CCOCC1>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:6]2[C:7]3[C:14]4[CH2:15][CH2:16][C:17]5([CH2:22][C:13]=4[S:12][C:8]=3[N:9]=[CH:10][N:11]=2)[O:21][CH2:20][CH2:19][O:18]5)[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=1
Reactant: Clc1ncnc2sc3c(c12)CCC1(C3)OCCO1
Reactant: Cc1cccc(COc2ccc(N)cc2Cl)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Cc1cccc(COc2ccc(Nc3ncnc4sc5c(c34)CCC3(C5)OCCO3)cc2Cl)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To isopropanol (80 mL) was sequentially added 4-chloro-5,8-dihydro-6H-spiro[1-benzothieno[2,3-d]pyrimidine-7,2′-[1,3]dioxolane] (5.5 g, 19.4 mmol), 3-chloro-4-[(6-methylpyridin-2-yl)methoxy]aniline (4.61 g, 18.5 mmol), and 4N HCl in dioxane (0.8 mL). The suspension was stirred with heating to 80° C., upon which time the contents turn brown and homogeneous. After 8 h, the heterogeneous mixture was removed from heating, and allowed to cool to rt. The resultant precipitate was collected by filtration as a light-brown solid (5.67 g, 81%), which was used without further purification. 1H-NMR (DMSO-d6) δ 8.35 (s, 1H), 8.16 (s, 1H), 7.78 (d, 1H), 7.73 (d, 1H), 7.51 (dd, 1H), 7.34 (d, 1H), 7.21 (m, 1H), 7.19 (d, 1H), 5.21 (s, 2H), 3.97 (s, 4H), 3.26 (t, 2H), 3.01 (s, 2H), 2.48 (s, 3H), 1.95 (t, 2H); LCMS RT=2.78 min; [M+H]+=495.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][C:23]([C:25]4[CH:33]=[C:32]5[C:28]([CH:29]=[CH:30][NH:31]5)=[CH:27][CH:26]=4)=[N:22][C:21]=3[C:34](O)=[O:35])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.[N:44]1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.N.O1CCOCC1>CN(C=O)C>[C:34]([C:21]1[N:22]=[C:23]([C:25]2[CH:33]=[C:32]3[C:28]([CH:29]=[CH:30][NH:31]3)=[CH:27][CH:26]=2)[O:24][C:20]=1[C:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]2)=[CH:19][CH:18]=1)(=[O:35])[NH2:44]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3oc(-c4ccc5cc[nH]c5c4)nc3C(=O)O)cc2)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3oc(-c4ccc5cc[nH]c5c4)nc3C(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
To a solution of 5-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)-2-(1H-indol-6-yl)oxazole-4-carboxylic acid (0.038 g, 0.08 mmol) in DMF (1 ml) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.036 g, 0.09 mmol) and diisopropylethylamine (0.016 ml, 0.09 mmol). The solution was stirred at room temperature for 5 minutes and then 0.5M ammonia in dioxane (0.31 ml, 0.16 mmol) was added and the resultant mixture stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford tert-butyl 4-(4-(4-carbamoyl-2-(1H-indol-6-yl)oxazol-5-yl)phenyl)piperazine-1-carboxylate (0.018 g, 0.04 mmol, 46%). LCMS (2) Rt: 3.39 min; m/z (ES+) 488.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.C([Li])CCC.[CH2:12]([Sn:16]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])Cl)[CH2:13][CH2:14][CH3:15]>O1CCCC1.[Cl-].[Na+].O>[CH3:1][N:2]1[C:6]([Sn:16]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:5][N:4]=[N:3]1
Reactant: Cn1ccnn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnnn1C
Temperature: -78 °C
Yield: 65.7 %

Procedure:
A solution of 1-methyl-1H-[1,2,3]triazole (350 mg) in dry tetrahydrofuran (5.0 ml) was added dropwise under nitrogen to a stirred, cooled (-78° C.) solution of n-butyl lithium (2.81 ml of 1.6M solution in hexanes) in dry tetrahydrofuran (10 ml). After 1 hour tributylchlorostannane (1.46 g) was added. The reaction was maintained at -78° C. for 30 min. and then allowed to warm to room temperature over 2 hours. The reaction mixture was diluted with brine (10 ml) and extracted into ethyl acetate (50 ml). The organic layer was separated, washed with brine (50 ml), dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue was purified by flash column chromatography (20% ethyl acetate/n-hexane), to give 1-methyl-5-tributylstannanyl-1H-[1,2,3]triazole as a yellow oil (1.03 g). 1H NMR (360 MHz,CDCl3) δ 0.87 (9H, m), 1.15 (6H, m), 1.28 (6H, m), 1.36 (6H, m), 4.02 (3H, s), 7.60 (1H, s); MS m/z CI+ 372 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.S1(CCCC1)(=O)=O.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O=S1(=O)CCCC1
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 35.4 %

Procedure:
To a mixture of 308 mg (purity: 99.0%; 1.85 mmol) of 4-hydroxy-3,6-dichloropyridazine and 824 mg (5.47 mmol) of 2-cyclopropyl-6-methylphenol were added sulfolane (2.76 g) and 332 mg (5.63 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 181 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 36%) and 7.1 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 1.4%) were obtained.