Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[NH:3]([C:10]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]2[N:17]=[C:16]([S:26][CH2:27][C:28]([O:30]CC)=[O:29])[CH:15]=[C:14]([C:33]([F:36])([F:35])[F:34])[C:13]=2[C:12](=[O:37])[CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CCO>[NH:3]([C:10]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]2[N:17]=[C:16]([S:26][CH2:27][C:28]([OH:30])=[O:29])[CH:15]=[C:14]([C:33]([F:36])([F:35])[F:34])[C:13]=2[C:12](=[O:37])[CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CSc1cc(C(F)(F)F)c2c(=O)cc(Nc3ccccc3)n(-c3ccccc3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CSc1cc(C(F)(F)F)c2c(=O)cc(Nc3ccccc3)n(-c3ccccc3)c2n1
Reaction time: 4 h
Yield: 67.2 %

Procedure:
NaOH (160 mg, 4.0 mmol) was added to a stirred solution of ethyl {[7-anilino-5-oxo-8-phenyl-4-(trifluoromethyl)-5,8-dihydro-1,8-naphthyridin-2-yl]sulfanyl }acetate (30.0 mg, 0.060 mmol) in aqueous EtOH (10 mL EtOH in 4 mL H2O). The mixture was allowed to stir for 4 h and was then concentrated in vacuo. The reaction was acidified with 1N HCl and extracted with CH2Cl2. The organic layer was dried over MgSO4, and concentrated in vacuo. Purification by preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) provided {[7-anilino-5-oxo-8-phenyl-4-(trifluoromethyl)-5,8-dihydro-1,8-naphthyridin-2-yl]sulfanyl }acetic acid (19.0 mg, 66%): LCMS RT: 2.50 min, MH+: 472.1
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.C([Sn](CCCC)(CCCC)[C:18]([O:20][CH2:21][CH3:22])=[CH2:19])CCC.[F-].[K+].CC(OC)(C)C>CN(C=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([C:18]([O:20][CH2:21][CH3:22])=[CH2:19])[N:3]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: C=C(OCC)c1cc(C(=O)OC)nc(Cl)n1
Temperature: 94 °C
Reaction time: 0.17 h
Yield: 74.8 %

Procedure:
Methyl 2,6-dichloropyrimidine-4-carboxylate (8.44 g, 40.77 mmol) and bis(triphenylphosphine)-palladium(II) chloride (0.572 g, 0.82 mmol) in DMF (80 mL) was degased. Tributyl(1-ethoxy-vinyl)tin (14.46 mL, 42.81 mmol) was added under argon. The mixture was heated at 94° C. for 1 h. The mixture was poured into a solution of potassium fluoride (30 g) in water (400 mL). MTBE (300 mL) was added and the mixture was stirred for 10 min. The mixture was filtered and the filter was washed with 200 mL of MTBE. The filtrate was washed with brine (100 mL), dried over sodium sulfate and the solvents were evaporated. The residue purified by column chromatography on silica eluting with DCM to give the title compound as a solid (7.40 g, 75%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:4]=[C:5]([C:8](=[NH:10])[NH2:9])[S:6][CH:7]=1.CC[O-].[Na+].O=[C:18]([C:25]1[S:26][CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:29]=1)[CH2:19][C:20](OCC)=[O:21]>C(O)C>[F:12][C:2]([F:1])([F:11])[C:3]1[N:4]=[C:5]([C:8]2[N:9]=[C:20]([OH:21])[CH:19]=[C:18]([C:25]3[S:26][CH:27]=[C:28]([C:30]([F:32])([F:33])[F:31])[N:29]=3)[N:10]=2)[S:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1nc(C(F)(F)F)cs1
Reactant: N=C(N)c1nc(C(F)(F)F)cs1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Oc1cc(-c2nc(C(F)(F)F)cs2)nc(-c2nc(C(F)(F)F)cs2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
To a solution of compound 27 (0.43 mmol) and NaOEt (2.15 mmol) in ethanol (2 mL) was added compound 28 (0.43 mmol). The reaction mixture was stirred at 100° C. overnight. The solvent was evaporated and water and AcOEt were added. The aqueous layer was acidified to pH˜4-5 by addition of 2.5M HCl. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: DCM/MeOH 0 to 5%) to give compound 29 as a beige solid in 11% yield. MS (ESI, EI−): m/z=396.91 (MH−).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2O.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: Oc1ncnc2ccc(C(F)(F)F)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Temperature: 25 °C

Procedure:
A suspension of 6-(trifluoromethyl)quinazolin-4-ol (10.41 g, 48.4 mmol) in phosphorous oxychloride (100 mL) was heated at reflux for 3 h, during which time a clear, amber solution was observed. The solution was cooled to room temperature, concentrated in-vacuo, and stripped 3× from 150 mL methylene chloride to remove any remaining phosphorous oxychloride. The residue was partitioned between EtOAc and saturated sodium bicarbonate (1:1, 300 mL), and the mixture was stirred until gas evolution ceased. The layers were separated, the organic phase was washed successively with saturated sodium bicarbonate and brine, the combined aqueous phases were extracted with EtOAc (50 mL), and the combined organic phases were dried over sodium sulfate then concentrated in-vacuo. The residue was purified over silica gel, eluting with 25% EtOAc/Heptane, to yield 8.14 g of 4-chloro-6-(trifluoromethyl)quinazoline as a white solid. MS (ES+)=233, 235 (M+H+).
Reaction SMILES: O.[C:2]([O:5][C:6]1[CH:7]=[C:8]([O:16][C:17](=[O:19])[CH3:18])[CH:9]=[C:10]([O:12][C:13](=O)[CH3:14])[CH:11]=1)(=[O:4])[CH3:3].[H-].[Na+].C(Cl)[C:23]1[CH:28]=[CH:27]C=[CH:25][CH:24]=1.Cl>CN(C=O)C>[C:17]([O:16][C:8]1[CH:7]=[C:6]([O:5][C:2](=[O:4])[CH3:3])[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=2)[CH:9]=1)(=[O:19])[CH3:18]
Reactant: ClCc1ccccc1
Reactant: CC(=O)Oc1cc(OC(C)=O)cc(OC(C)=O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Oc1cc(OCc2ccccc2)cc(OC(C)=O)c1
Reaction time: 16 h

Procedure:
Water (4.3 ml, 236 mmol) in DMF (20 ml) was added drop wise at room temperature with stirring to a mixture of acetic acid 3,5-diacetoxy-phenyl ester (refer Kawamoto. H. et. al. Synth. Commun. 26, 531, 1996) (35 g, 139 mmol), NaH (5.66 g, 236 mmol) and benzyl chloride (19.16 ml, 166 mmol) in dry DMF (300 ml). The reaction mixture was stirred overnight (˜16 h), poured into chilled dil. aqueous HCl and extracted with CH2Cl2 to obtain the crude title compound which was purified using flash chromatography (silica gel, 20-50% CH2Cl2 in PE 60-80° C.). Yield, 12.5 g (30%), white solid; mp: 129-30° C.; MS (EI): 300 (M+), 258, 216, 91 (100%); analysis: C17H16O5 requires: C, 67.99; H, 5.37 found: C, 67.50; H, 5.40%.
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]([CH3:13])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23]Br)=[CH:17][CH:16]=1.C(N(CC)CC)C>CN(C=O)C>[ClH:1].[ClH:1].[CH3:13][N:4]([CH3:3])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:23][CH2:22][O:21][C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)[CH2:9][CH2:8]1
Reactant: CN(C)CCC1CCNCC1
Reactant: Fc1ccc(OCCBr)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CCC1CCN(CCOc2ccc(F)cc2)CC1

Procedure:
In a similar manner to Example 16, a mixture of 4-(2-dimethylaminoethyl)piperidine dihydrochloride (5.5 g), 2-bromoethyl 4-fluorophenyl ether (5.26 g), triethylamine (13.4 ml) and DMF (50 ml) was heated on a steam bath for 16 hours to give 4-(2-dimethylaminoethyl)-1-[2-(4-fluorophenoxy)ethyl]piperidine dihydrochloride, m.p. 260°-262° C.
Reaction SMILES: C(Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH2:12].C(N(C)C)C1C=CC=CC=1>CC1C=CC(C)=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][C:11](=[CH:10][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=C(C)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)Cc1ccccc1
Solvent: Cc1ccc(C)cc1
Product: CC(=Cc1ccccc1)c1ccccc1
Yield: 3.3 %

Procedure:
0.448 g (2 millimols) of palladium acetate, 28.11 g (0.2 mol) of benzoyl chloride, 23.64 g (0.2 mol) of α-methylstyrene and 27.04 g (0.2 mol) of N-benzyldimethylamine in 400 ml of p-xylene are stirred for 11 hours at 130° C. The mixture is extracted by shaking with 400 ml of 2 NHCl and 400 ml of 2 N NaOH and is then dried over magnesium sulfate. The crude product is chromatographed on silica gel in methylene chloride and subsequently recrystallised from n-pentane. 1.3 g (3% of theory) of α-methylstilbene are obtained as colourless crystals of melting point 79.0° C.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH3:22])[C:14]4=[O:23])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:37]=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[CH2:40][CH2:39]3)=[CH:34][CH:33]=2)O1.[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53]>C(Cl)Cl>[F:55][C:54]([F:57])([F:56])[C:52]([OH:58])=[O:53].[CH3:22][N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@:13]2([CH2:12][C@H:11]2[C:7]2[CH:6]=[C:5]3[C:10]([C:2]([C:32]4[CH:33]=[CH:34][C:35]([N:38]5[CH2:39][CH2:40][NH:41][CH2:42][CH2:43]5)=[CH:36][CH:37]=4)=[N:3][NH:4]3)=[CH:9][CH:8]=2)[C:14]1=[O:23]
Reactant: CN1C(=O)[C@@]2(C[C@H]2c2ccc3c(I)n[nH]c3c2)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)[C@@]2(C[C@H]2c2ccc3c(-c4ccc(N5CCNCC5)cc4)n[nH]c3c2)c2ccccc21
Reaction time: 2 h
Yield: 11 %

Procedure:
The title compound was synthesized according to the method of Example A45, except substituting (1R*,2S*)-2-(3-iodo-1H-indazol-6-yl)-1′-methylspiro[cyclopropane-1,3′-indolin]-2′-one (35 mg, 0.084 mmol) and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (42 mg, 0.109 mmol). The solvent was removed and the Boc-protected amine purified by column chromatography (silica gel, CH2Cl2/MeOH, 95:5) to give an impure product which dissolved into CH2Cl2 (1.0 mL) and TFA (50 uL) was added. The reaction was stirred for 2 h, the solvent removed and the residue purified by prep-HPLC to give the title compound as a white powder (4.0 mg, 11%); 1H NMR (400 MHz, CD3OD) δ 7.88-7.85 (m, 3H), 7.46 (s, 1H), 7.18-7.12 (m, 3H), 7.03-6.97 (m, 2H), 6.65 (t, J=7.7 Hz, 1H), 6.04 (d, J=7.5 Hz, 1H), 3.51-3.48 (m, 4H), 3.42-3.39 (m, 4H), 3.35 (s, 3H), 2.29-2.25 (m, 1H), 2.22-2.18 (m, 1H); MS ESI [M+H]+ 450.2, calcd for [C28H27N5O+H]+ 450.23.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13](=[O:14])[NH:12][C:11]([C:15]2[CH:20]=[CH:19][C:18](I)=[C:17]([O:22][CH3:23])[CH:16]=2)=[N:10]1.[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[C:35]#[CH:36].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[CH:27][C:26]=1[C:35]#[C:36][C:18]1[CH:19]=[CH:20][C:15]([C:11]2[NH:12][C:13](=[O:14])[N:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[N:10]=2)=[CH:16][C:17]=1[O:22][CH3:23]
Reactant: C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: COc1cc(-c2nn(-c3c(Cl)cccc3Cl)c(=O)[nH]2)ccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: COc1cc(-c2nn(-c3c(Cl)cccc3Cl)c(=O)[nH]2)ccc1C#Cc1ccc(C(F)(F)F)cc1Cl
Yield: 24.7 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using 1-(2,6-dichlorophenyl)-3-(4-iodo-3-methoxyphenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-45, 0.070 g, 0.15 mmol), 2-chloro-1-ethynyl-4-(trifluoromethyl)benzene (Intermediate-25, 0.046 g, 0.22 mmol), TBAF (0.080 g, 0.30 mmol), bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.022 mmol) and DMSO (3.0 mL) at 80° C. to afford 0.020 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 3.95 (s, 3H), 7.50-7.53 (m, 2H), 7.56-7.79 (m, 5H), 7.88 (d, J=8.4 Hz, 1H), 8.05 (s, 1H), 12.04 (s, 1H); MS (m/z): 538.07 (M+).
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9](C)C)CC1.F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1.[C:26](=O)([O-])[O-].[Li+].[Li+]>>[OH:12][C@@:4]1([CH3:1])[CH2:8][C@@H:7]([CH3:26])[N:6]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=2)[C@H:5]1[CH3:9]
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: O=C([O-])[O-]
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Agent: [Li+]
Product: C[C@@H]1C[C@](C)(O)[C@H](C)N1c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
By an operation in the same manner as in Example 53 and using (2S,3S,5R)-2,3,5-trimethylpyrrolidin-3-ol 0.5 oxalate (83 mg), 4-fluoro-2-(trifluoromethyl)benzonitrile (203 mg) and lithium carbonate (93 mg), the title compound was obtained as a colorless solid (yield: 61.9 mg, yield: 44%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].CC(O)=O.C1C(=O)N([Br:27])C(=O)C1>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([Br:27])[S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2ccsc2CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCc2cc(Br)sc2CC1
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
The product of Example 1, step (d) (80 mg, 0.35 mmol) was dissolved in 2 mL of 1:1 CHCl3:HOAc and treated with NBS (62 mg, 0.35 mmol). After 15 minutes, the reaction was concentrated to dryness, dissolved in a minimal amount of EtOAc and filtered through a pad of silica gel. The filtrate was evaporated to give 105 mg of the sub-title compound.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:32][CH2:33][CH3:34])[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[C:7](=[O:16])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH3:2].I[CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[CH3:36][C:37]([CH3:40])([CH3:39])[CH2:38][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:8]2[C:7](=[O:16])[N:6]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)[C:5]([CH2:32][CH2:33][CH3:34])=[N:4][C:3]=2[CH2:1][CH3:2])=[CH:14][CH:13]=1
Reactant: CCCc1nc(CC)c(-c2ccc(O)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(-c2ccc(OCC(C)(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 61.6 %

Procedure:
A mixture of 4′-{[4-ethyl-5-(4-hydroxyphenyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.52 g), 1-iodo-2,2-dimethylpropane (0.29 g), cesium carbonate (0.45 g) and dimethylformamide (10 mL) were stirred at 80° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.37 g, 62%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]([CH3:14])[S:12][C:11](=[O:15])[NH:10][N:9]=2)=[CH:4][CH:3]=1.O1[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1.C(O)(=O)C>O>[O:22]=[C:19]1[CH:20]=[CH:21][N:1]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]([CH3:14])[S:12][C:11](=[O:15])[NH:10][N:9]=3)=[CH:6][CH:7]=2)[CH:17]=[CH:18]1
Reactant: O=c1ccocc1
Reactant: CC1SC(=O)NN=C1c1ccc(N)cc1
Solvent: CC(=O)O
Solvent: O
Product: CC1SC(=O)NN=C1c1ccc(-n2ccc(=O)cc2)cc1

Procedure:
A stirred mixture of 5-(4-aminophenyl)-6-methyl-3H,6H-1,3,4-thiadiazine-2-one (0.54 g), 4H-pyran-4-one (0.26 g), glacial acetic acid (0.15 g) and water (20 ml) was heated under reflux for 24 hours to give a solid, 0.54 g. Recrystallisation from aqueous ethanol gave the title compound, 0.28 g, which darkened at 265° C. and sublimed at 273°-275° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:11][CH3:12])=[N:9][CH:10]=2)[CH:7]=1.O.C(=O)(O)[O-].[Na+].[I:19]I>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:11][CH3:12])=[N:9][C:10]=2[I:19])[CH:7]=1
Reactant: II
Reactant: CSc1ncc2ccc(F)cn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CSc1nc(I)c2ccc(F)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
In a round-bottomed flask, 6-fluoro-3-methylsulfanyl-imidazo[1,5-a]pyridine (178 mg, 0.88 mmol) was dissolved in ethanol (1.6 ml). Water (0.8 ml), sodium bicarbonate (278 mg, 3.31 mmol) and iodine (312 mg, 1.23 mmol) were added. The dark brown suspension was stirred at room temperature overnight then quenched with 10% aqueous Na2S2O3 and extracted with EtOAc (2×). The combined organic layers were washed with 10% aqueous Na2S2O3, water, and brine then dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed with EtOAc/hexanes (gradient 0-10% EtOAc) to afford 110 mg (41%) of 6-fluoro-1-iodo-3-methylsulfanyl-imidazo[1,5-a]pyridine as a brown solid.
Reaction SMILES: [Cl-].[C:2]([O:6][C:7]([NH:9][NH:10][C:11]([CH2:13][C:14]1[CH:39]=[CH:38][C:17]([CH2:18][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:16][CH:15]=1)=[O:12])=[O:8])([CH3:5])([CH3:4])[CH3:3].C([Li])CCC.[CH:45]([C:47]1[S:51][C:50]([NH:52][C:53](=[O:55])[CH3:54])=[CH:49][CH:48]=1)=O.[Cl-].[NH4+]>O1CCCC1>[C:53]([NH:52][C:50]1[S:51][C:47]([CH:45]=[CH:18][C:17]2[CH:16]=[CH:15][C:14]([CH2:13][C:11]([NH:10][NH:9][C:7]([O:6][C:2]([CH3:3])([CH3:4])[CH3:5])=[O:8])=[O:12])=[CH:39][CH:38]=2)=[CH:48][CH:49]=1)(=[O:55])[CH3:54]
Reactant: CC(=O)Nc1ccc(C=O)s1
Reactant: CC(C)(C)OC(=O)NNC(=O)Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C=Cc2ccc(CC(=O)NNC(=O)OC(C)(C)C)cc2)s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
{4-[2-(tert-Butoxycarbonyl)hydrazinocarbonylmethyl]benzyl}(triphenyl)phosphonium chloride (2.97 g, 5.29 mmol) was suspended in anhydrous tetrahydrofuran (8 ml), and cooled to −78° C. n-Butyllithium (1.6M-hexane solution, 3.3 ml, 5.3 mmol) was added dropwise, and the mixture was stirred at −78° C. for 15 mins and at 0° C. for 2 hrs. A solution of N-(5-formylthiophen-2-yl)acetamide (280 mg, 1.65 mmol) in anhydrous tetrahydrofuran (2 ml) was added dropwise, and the mixture was warmed to room temperature. After stirring at room temperature overnight, saturated aqueous ammonium chloride solution was added. The mixture was extracted with dichloromethane and the combined organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=97:3→80:20) to give tert-butyl 2-({4-[2-(5-acetylaminothiophen-2-yl)vinyl]phenyl}acetyl)hydrazinecarboxylate (192 mg, yield 28%, E/Z mixture) as a yellow solid.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(O[C:6](C)(C)[CH3:7])=O.[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]=2[C:38]([O:40]C)=[O:39])(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(O)C.[Li+].[OH-]>C1COCC1>[CH2:6]([N:27]([S:24]([C:21]1[CH:20]=[CH:19][C:18]([F:17])=[CH:23][CH:22]=1)(=[O:25])=[O:26])[C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]=1[C:38]([OH:40])=[O:39])[CH3:7]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2)ccc2ccccc12
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCN(c1ccc2ccccc2c1C(=O)O)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Macroporous polystyrene-bound triphenylphosphine resin (56 mg, 0.17 mmol) was treated with di-tert-butyl azodicarboxylate (29 mg, 0.13 mmol) in THF (0.5 mL), shaken at ambient temperature for 15 minutes, treated with a solution of Example 98A (30 mg, 0.08 mmol) in THF (1 mL), shaken at ambient temperature for 15 minutes, treated with ethanol (0.006 mL, 0.11 mmol), shaken for 16 hours at 60° C., filtered, and concentrated. The residue was dissolved in 2:1 dioxane/water (1 mL), treated with LiOH (25 mg, 0.6 mmol), and heated to 160° C. for 30 minutes in a microwave reactor. The reaction mixture was concentrated and purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product. MS (DCI) m/e 391 (M+NH4)+; 1H NMR (500 MHz, DMSO-d6) δ 7.99 (m, 2H), 7.92 (m, 1H), 7.81 (br s, 2H), 7.64 (br s, 2H), 7.46 (t, 2H), 7.02 (d, 1H), 3.60 (br s, 2H), 0.99 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH3:18])[CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:19].[H-].[Na+].[Cl:24][C:25]([Cl:29])=[CH:26][CH2:27]Cl>CN(C)C=O>[F:1][C:2]([F:20])([F:21])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH3:18])[CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:19][CH2:27][CH:26]=[C:25]([Cl:29])[Cl:24]
Reactant: ClCC=C(Cl)Cl
Reactant: CCOc1cccc(Oc2ccc(O)c(C(F)(F)F)c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cccc(Oc2ccc(OCC=C(Cl)Cl)c(C(F)(F)F)c2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 61.6 %

Procedure:
To a solution prepared by dissolving 0.44 g of 2-trifluoromethyl-4-(3-ethoxyphenoxy)phenol in 10 ml of N,N-dimethylformamide, 0.062 g of sodium hydride (60% oil-based) was added with stirring under ice cooling. After 10 minutes, a solution prepared by dissolving 0.24 g of 1,1,3-trichloro-1-propene in 5 ml of N,N-dimethylformamide was added dropwise under ice cooling. After stirring at room temperature for 10 hours, the reaction solution was poured into ice-water, and extracted twice with 50 ml of diethyl ether. Then, the ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and concentrated to give a crude product. This crude product was subjected to silica gel chromatography to give 0.37 g of 2-trifluoromethyl-4-(3-ethoxyphenoxy)-1-(3,3-dichloro-2-propenyloxy)benzene, yield 62%; nD23.6 1.5369.
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][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.Cl.[CH2:37]([NH2:40])[C:38]#[CH:39].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[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][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:28]([NH:40][CH2:37][C:38]#[CH:39])=[O:34])=[C:18]([F:23])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: C#CCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C#CCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoroaniline (50 mg) was dissolved in chloroform (3 ml) and triethylamine (0.3 ml), and a solution of triphosgene (47 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, propargylamine hydrochloride (29 mg) was added to the reaction solution, and the mixture was further stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with chloroform to give 21 mg (yield 33%) of the title compound.