Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([F:21])([F:20])[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=2)[N:3]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[CH3:64][C:65]1[S:69][C:68]([NH2:70])=[N:67][CH:66]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[F:20][C:12]([F:21])([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[C:4]1[N:3]=[C:2]([NH:70][C:68]2[S:69][C:65]([CH3:64])=[CH:66][N:67]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1cnc(N)s1
Reactant: Fc1ccc(C(F)(F)c2nc(Cl)c3ccccc3n2)nc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cnc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3ccccc23)s1
Temperature: 110 °C
Yield: 4.8 %

Procedure:
To a mixture of 4-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazoline from Example 4 Step A (100 mg, 0.32 mmol), Pd2(dibenzylideneacetone)3 (12 mg, 0.013 mmol), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (23 mg, 0.04 mmol), 5-methylthiazol-2-amine (51 mg, 0.45 mmol), and Na2CO3 (48 mg, 0.45 mmol) was added toluene (3 mL). The mixture was evacuated and flushed with argon three times and then heated at 110° C. for 2 h. The mixture was diluted with MeOH, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Varian diphenyl reverse phase column, eluted with gradient of solvent B=0.05% HOAC/ACN and solvent A=0.05% HOAc/H2O) to afford N-(2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazolin-4-yl)-5-methylthiazol-2-amine (6 mg, 5%). 1H NMR (300 MHz, DMSO-d6) δ 12.45 (br s, 1H), 8.64 (d, J=2.4 Hz, 2H), 7.88-8.15 (m, 4H), 7.66-7.76 (m, 1H), 7.19 (s, 1H), 2.28 (s, 3H). LCMS (ESI) m/z 388 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[B]1OC2C(=CC=CC=2)O1>>[C:4]1([C@@H:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Agent: [B]1Oc2ccccc2O1
Product: C[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.6 %

Procedure:
(R)-3,3'-bis(2",4"-dihexyloxyphenyl)-1,1'-bi-2naphthol (42 mg, 0.05 mmol) and diethylzinc (0.01 mL, 0.1 mmol) were added to a Schlenk flask containing 10 mL of toluene (dried with Na and degassed with N2), under N2 at room temperature, to form the organozinc species. The resulting mixture was stirred at r.t. for 20 minutes. Acetophenone (0.12 mL, 1 mmol) was then added. The resulting mixture was cooled to -30° C. and 1.5 mL of catecholborane (1.5 mmol, 1M in THF) was added. Stirring was continued at this temperature for 48 h. The reaction was then quenched with 1N HCl and the aqueous layer was extracted with ether. The combined organic extracts were washed with brine until pH=7 and then dried over anhydrous Na2SO4. Purification by column chromatography on silica gel with EtOAc/hexanes (1:5) gave (S)-1-phenylethanol as a colorless liquid (107 mg, 88%). GC analysis on a β-Dex capillary column (Supelco Company), with helium as the carrier gas, a flow rate of 1 mL/min, and an increase in oven temperature from 100° C. at a rate of 1° C./min, showed an ee of 81.3%. The retention time of the (R)-isomer was 20.02 min and the retention time of the (S)-isomer was 20.68 min. 1H NMR (270 MHz, CDCl3): 1.49 (d, J=6.5, 3H), 1.79 (br, 1H), 4.90 (q, J=6.5, 1H), 7.25-7.40 (m, 5H).
Reaction SMILES: Cl.O1CCOCC1.[C:8]1([CH3:43])[C:9]([C:14]([CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]([C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:20][CH:19]([NH:34]C(OC(C)(C)C)=O)[C:18]2=[O:42])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=1>C(O)C>[C:8]1([CH3:43])[C:9]([C:14]([CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]([C:28](=[O:33])[C:29]([CH3:31])([CH3:32])[CH3:30])[CH2:20][CH:19]([NH2:34])[C:18]2=[O:42])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1ccccc1C(=O)CN1C(=O)C(NC(=O)OC(C)(C)C)CN(C(=O)C(C)(C)C)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1ccccc1C(=O)CN1C(=O)C(N)CN(C(=O)C(C)(C)C)c2ccccc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
4N HCl-dioxane solution (5 ml) was added to 1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (540 mg) in ethanol (5 ml), and the mixture was stirred at 50° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with methylene chloride. The extract was dried over anhydrous sodium sulfate, to thereby obtain 411 mg of the titled compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:11]([O:23][CH3:24])=[C:10]([O:25][CH3:26])[CH:9]=1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:26][O:25][C:10]1[CH:9]=[C:8]([NH2:7])[CH:13]=[C:12]([O:14][CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[C:11]=1[O:23][CH3:24]
Reactant: COc1cc(NC(=O)OC(C)(C)C)cc(OCCN2CCOCC2)c1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(N)cc(OCCN2CCOCC2)c1OC
Reaction time: 1 h

Procedure:
[3,4-Dimethoxy-5-(2-morpholin-4-yl-ethoxy)-phenyl]-carbamic acid tert-butyl ester, (97 mg, 0.24 mmol, was stirred in 1 mL DCM and 1 mL TFA. After ˜1 h, the TFA and DCM were evaporated and 2 mL sat. sodium bicarbonate solution was added. The aqueous layer was extracted with DCM which was evaporated affording 60 mg 3,4-Dimethoxy-5-(2-morpholin-4-yl-ethoxy)-phenylamine. MS ES+ 283.1
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.Cl[S:15](O)(=[O:17])=[O:16]>>[O:16]=[S:15]1(=[O:17])[O:1][CH2:2][CH2:3][C:4]2[C:12]1=[CH:11][CH:10]=[C:9]1[NH:8][C:7](=[O:13])[CH2:6][C:5]1=2
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: O=S(=O)(O)Cl
Product: O=C1Cc2c(ccc3c2CCOS3(=O)=O)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
4-Hydroxyethyl-2-oxindole (5 g, 28.2 mmol) was dissolved in 20 mL of chlorosulfonic acid with stirring at room temperature. After 30 min, the reaction mixture was slowly added to ice water (300 mL) with stirring. The solid was filtered and dried to afford 1.9 g (28%) of 6,6-dioxo-3,6,8,9-tetrahydro-1H-7-oxa-6λ6-thia-3-aza-cyclopenta[α]naphthalen-2-one as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O>CC(C)=O>[Br:10][CH2:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1].[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH3:9]
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1ccc(I)cc1F
Solvent: CC(C)=O
Product: Fc1cc(I)ccc1CBr
Yield: 73 %

Procedure:
To a solution of 2-fluoro-4-iodo-1-methylbenzene (50 g, 210 mmol) in anhydrous acetone (490 mL) was added N-bromosuccinimide (42 g, 230 mmol) and 2,21-azobisiso-butyronitrile (100 mg, 0.60 mmol). The resulting solution was heated to reflux and maintained under reflux conditions for 5 h. The reaction was then cooled, concentrated, and filtered. The filtrate was concentrated, and the resulting dark red residue was purified by flash column chromatography (10% ethyl acetate in hexanes) to afford a 4:1 mixture (58 g) of 1-(bromomethyl)-2-fluoro-4-iodobenzene (49 g, 73%) and 2-fluoro-4-iodo-1-methylbenzene (9 g, 17%) as a red solid. 1H NMR (product) (CDCl3) δ 7.40-7.49 (m, 2H), 7.13 (t, 1H), 4.45 (s, 2H).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.S[CH2:18][CH2:19][C:20]([OH:22])=O>>[OH:16][C:6]1[CH:7]=[CH:12][C:13]([C:13]2([C:1]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:3][CH:2]=3)[C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6](=[O:16])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]2=3)=[CH:14][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Reactant: O=C(O)CCS
Product: O=C1c2ccccc2C(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Temperature: 65 °C

Procedure:
Anthraquinone (60 g) phenol (150 g) and 3-mercaptopropionic acid (8 g) were placed in a round-bottom flask. The mixture was heated at 65° C., and then dry hydrogen chloride was bubbled in for about 24 h. The phenol, hydrogen chloride, and cocatalyst were removed by steam distillation. This product was recrystallized from methanol as a slightly yellowish granular mass: MP 320°-322° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH2:8]2)[C:3]1=[O:23].[F:24][C:25]1[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[C:28]([F:35])=[CH:27][C:26]=1F.C([O-])([O-])=O.[Na+].[Na+].O>CS(C)=O>[F:24][C:25]1[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[C:28]([F:35])=[CH:27][C:26]=1[NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH2:8]2)[C:3]1=[O:23]
Reactant: CS(=O)(=O)c1cc(F)c(F)cc1F
Reactant: N[C@H]1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1cc(F)c(N[C@H]2CCN(C3CCN(C(=O)OCc4ccccc4)CC3)C2=O)cc1F
Temperature: 130 °C
Reaction time: 18 h
Yield: 64.6 %

Procedure:
A solution of (S)-benzyl 4-(3-amino-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (2.5, 7.9 mmol) (Preparation E, Step D), 1,2,4-trifluoro-5-(methylsulfonyl)benzene (3.3 g, 16 mmol), and Na2CO3 (2.5 g, 24 mmol) in DMSO (20 mL) was degassed using nitrogen and was stirred at 130° C. for 18 hours in a sealed tube. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine and dried over MgSO4, filtered then concentrated in vacuo. The material was purified over silica gel (100% EtOAc) to yield (S)-benzyl 4-(3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (2.6 g, 5.1 mmol, 65%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([N:16]2[CH2:21][CH2:20][O:19][C:18]([CH2:30][CH2:31][OH:32])([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([S:58](Cl)(=[O:60])=[O:59])=[CH:54][CH:53]=1.Cl>C(Cl)Cl.O>[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([S:58]([O:32][CH2:31][CH2:30][C:18]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[O:19][CH2:20][CH2:21][N:16]([C:14](=[O:15])[CH2:13][C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:4]=3)[CH2:17]2)(=[O:60])=[O:59])=[CH:54][CH:53]=1
Reactant: O=C(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCOC(CCO)(c2ccc(Cl)c(Cl)c2)C1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCOC(CCOS(=O)(=O)c2ccc(Cl)cc2)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 2.5 °C
Reaction time: 6 h
Yield: 47.6 %

Procedure:
To a solution of 2-[4-{[3,5-bis(trifluoromethyl)phenyl]acetyl}-2-(3,4-dichlorophenyl)morpholin-2-yl]ethanol obtained in Reference Example 2 (2.0 g, 3.8 mmol) in methylene chloride (20 ml) were added dimethylaminopyridine (0.05 g, 0.38 mmol) and triethylamine (0.8 ml, 5.7 mmol) under a nitrogen stream, the resulting mixture was cooled to 0-5° C., and then a solution of 4-chlorobenzenesulfonyl chloride (0.96 g, 4.5 mmol) in methylene chloride (6 ml) was further added dropwise at below 10° C. After stirring at 0-5° C. for 6 hours, water (20 ml) and concentrated hydrochloric acid (0.5 ml) were added to the reaction mixture, and the resulting mixture was partitioned. The separated organic layer was washed with water (20 ml) and evaporated to dryness. The residue obtained was purified by chromatography on a silica gel column and then crystallized from a mixed solvent of ethyl acetate (2.4 ml) and methylcyclohexane (24 ml) under ice-cooling to afford the title compound [1.3 g, yield: 47.6%] as a colorless crystalline solid.
Reaction SMILES: [C:1]([S:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9])([CH3:4])([CH3:3])[CH3:2].B.C1COCC1.CO.Cl>C1COCC1.CCOC(C)=O>[C:1]([S:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8][NH2:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Sc1ccccc1C#N
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)Sc1ccccc1CN
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 28.2 %

Procedure:
To a solution of 2-(tert-butylthio)benzonitrile (Guiu, E. et al., J. Organomet. Chem., 689:1911-1918 (2004)) (1.00 g, 5.23 mmol) in THF (10.5 mL) was added BH3.THF (10.5 mL, 10.5 mmol, 1.0M solution in THF) via syringe. The resulting clear, colorless solution was stirred at room temperature for 1.5 h and then at 50° C. for 2 h. The reaction mixture was cooled to room temperature, and MeOH (2.5 mL) was added carefully via syringe (gas evolution) followed by 1N aq. HCl solution (12.0 mL). The mixture was poured into EtOAc and the layers were separated. The aqueous layer was basified with 1N aq. NaOH solution (pH=12) and then extracted with CH2Cl2 (5×). The combined CH2Cl2 extracts were dried over MgSO4, filtered and concentrated in vacuo to give the title compound (288 mg, 28%) as a colorless oil. 1H NMR (CDCl3) δ 7.57-7.53 (m, 1H), 7.44-7.40 (m, 1H), 7.37-7.32 (m, 1H), 7.25-7.19 (m, 1H), 4.07 (s, 2H), 1.30 (s, 9H); MS(ESI+) m/z 196.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([OH:23])[C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].Br[CH2:27][C:28]#[N:29]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([O:23][CH2:27][C:28]#[N:29])[C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:11]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](O)c2cc(F)cc(Cl)c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCC#N)c2cc(F)cc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 150.7 %

Procedure:
A solution of (R)-tert-butyl 3-((R)-(3-chloro-5-fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (55 g, 0.156 mol) in acetonitrile (1.2 L) was cooled to 0° C., NaH (19.2 g, 0.48 mol, 60% in oil) was added in portions, then the mixture was stirred at rt for 1 hr. The mixture was cooled to −20° C. and bromoacetonitrile (57.7 g, 0.48 mol) was added dropwise. After 0.5 hr, additional NaH (19.2 g, 0.48 mol, 60% in oil) and bromoacetonitrile (57.7 g, 0.48 mol) was added. TLC showed 80% of the starting material was reacted. The reaction was quenched with saturated NH4Cl solution (200 mL), water (1 L) was added. Acetonitrile was removed by reduced pressure, CH2Cl2 (1 L) was added, the aqueous layer was back extracted with CH2Cl2 (3×500 mL), dried over Na2SO4 and concentrated in vacuo to give the crude (R)-tert-butyl 3-((R)-(3-chloro-5-fluorophenyl)(cyanomethoxy)methyl)piperidine-1-carboxylate (90 g), which was used for the next step without further purification.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:32]=[CH:31][C:22]([C:23]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[O:24])=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:41][CH2:42][CH2:43][OH:44]>C(O)C>[OH:44][CH2:43][CH2:42][CH2:41][N:28]1[CH2:27][CH2:26][N:25]([C:23](=[O:24])[C:22]2[CH:21]=[CH:20][C:19]([C:17]([N:14]3[CH2:15][CH2:16][N:11]([C:6]4[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][N:7]=4)[CH2:12][CH2:13]3)=[O:18])=[CH:32][CH:31]=2)[CH2:30][CH2:29]1
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N3CCNCC3)cc2)CC1
Reactant: OCCCBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N3CCN(CCCO)CC3)cc2)CC1
Reaction time: 1 h
Yield: 77.7 %

Procedure:
1-[4-[1-[3-(Isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoyl]piperazine (0.5 g) was dissolved in anhydrous ethanol (25 ml) and then, triethylamine (0.3 ml) and 3-bromo-1-propanol (0.5 g) were added. The solution was heated to reflux for 12 hours. The solvent was concentrated under reduced pressure and then, the residue was dissolved in chloroform (50 ml), and the solution was washed with water twice. Water (40 ml), methanol (5 ml) and aqueous 10% sodium hydroxide (10 ml) were added to chloroform solution and the mixture was stirred for 1 hour. The separated organic layers were washed with water and the solvent was concentrated under reduced pressure. The concentrated residue was crystallized by treatment with ether, and further recrystallized using ethyl acetate and ether, filtered and dried to give 0.44 g (yield: 78%) of the desired compound as white crystal.
Reaction SMILES: C(OC(=O)C1C=CC(CN2C(=O)C3C=C(C#CCC4C=CC=CC=4)C=CC=3N(C)S2=O)=CC=1)(C)(C)C.C([O:41][C:42](=[O:72])[C:43]1[CH:48]=[CH:47][C:46]([CH2:49][N:50]2[C:55](=[O:56])[NH:54][C:53]3[CH:57]=[CH:58][C:59]([C:61]#[C:62][CH2:63][C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)=[CH:60][C:52]=3[S:51]2(=[O:71])=[O:70])=[CH:45][CH:44]=1)(C)(C)C>>[O:71]=[S:51]1(=[O:70])[C:52]2[CH:60]=[C:59]([C:61]#[C:62][CH2:63][C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)[CH:58]=[CH:57][C:53]=2[NH:54][C:55](=[O:56])[N:50]1[CH2:49][C:46]1[CH:45]=[CH:44][C:43]([C:42]([OH:72])=[O:41])=[CH:48][CH:47]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CN2C(=O)Nc3ccc(C#CCc4ccccc4)cc3S2(=O)=O)cc1
Agent: CN1c2ccc(C#CCc3ccccc3)cc2C(=O)N(Cc2ccc(C(=O)OC(C)(C)C)cc2)S1=O
Product: O=C(O)c1ccc(CN2C(=O)Nc3ccc(C#CCc4ccccc4)cc3S2(=O)=O)cc1
Yield: 839.9 %

Procedure:
When in the procedure of Example 4, Step (5) 4-[1-methyl-2,4-dioxo-6-(3-phenyl-prop-1-ynyl)-1,4-dihydro-2H-2λ4-benzo[1,2,6]thiadiazin-3-ylmethyl]benzoic acid tert-butyl ester was replaced with 4-[1,1,3-trioxo-7-(3-phenyl-prop-1-ynyl)-3,4-dihydro-1H-1λ6-benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic acid tert-butyl ester (0.12 g, 0.24 mmol) to give 0.9 g (84%) of 4-[1,1,3-trioxo-7-(3-phenyl-prop-1-ynyl)-3,4-dihydro-1H-1λ6-benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoic acid as a white solid. 1H-NMR (CDCl3); 11.00 (s, 1H), 7.85 (d, 2H), 7.74 (s, 1H), 7.43 (d, 1H), 7.35 (d, 2H), 7.16 (m, 6H), 4.94 (s, 2H), and 3.70 (s, 2H). MS: M++1=447.0 Da
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[C:12]([CH2:21][C:22]3[N:27]=[C:26]([C:28]([O:30]CC4C=CC=CC=4)=[O:29])[CH:25]=[CH:24][CH:23]=3)=[C:11]2[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C.[Pd]>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[C:12]([CH2:21][C:22]3[N:27]=[C:26]([C:28]([OH:30])=[O:29])[CH:25]=[CH:24][CH:23]=3)=[C:11]2[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc2c(Cc3cccc(C(=O)OCc4ccccc4)n3)c(-c3ccccc3)n(S(=O)(=O)c3ccccc3)c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc2c(Cc3cccc(C(=O)O)n3)c(-c3ccccc3)n(S(=O)(=O)c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 93.3 %

Procedure:
To a solution of benzyl 6-(1-benzenesulfonyl-6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxylate (1.10 g) in ethyl acetate (9.3 mL) was added 10% palladium on carbon (56.5% water included, 253 mg), and this mixture was stirred at room temperature for 100 minutes under a hydrogen atmosphere. The reaction mixture was filtrated through a Celite (registered trademark) pad. The filtrate was concentrated under reduced pressure to obtain the title compound (869 mg). 1H-NMR (DMSO-d6) δ ppm: 3.84 (3H, s), 3.97 (2H, s), 6.87 (1H, dd, J=2.3, 8.6 Hz), 6.95-7.02 (1H, m), 7.30 (1H, d, J=8.6 Hz), 7.40-7.51 (7H, m), 7.56-7.68 (4H, m), 7.70-7.85 (2H, m), 12.80-13.60 (1H, br).
Reaction SMILES: [I:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[I:1][C:2]1[C:7]([O:8][CH3:10])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(O)c(I)n1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(C)nc1I
Temperature: 45 °C
Reaction time: 20 h

Procedure:
To 2-iodo-6-methyl-pyridin-3-ol (1.0 g, 4.25 mmol) and K2CO3 (1.18 g, 8.51 mmol) in acetone (20 mL) was added MeI (0.91 g, 6.38 mmol). The reaction was stirred at 45° C. under N2 for 20 h. The reaction was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography using dichloromethane to afford 1.04 g (98%) of I-95 as light yellow solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH3:17].C(O)(=O)C(C)(C)C.F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:11][N:12]1[C:16]([C:2]2[N:7]=[C:6]([O:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=2)=[CH:15][N:14]=[C:13]1[CH3:17]
Reactant: Cc1nccn1C
Reactant: COc1nc(Br)ccc1N
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COc1nc(-c2cnc(C)n2C)ccc1N
Temperature: 120 °C
Yield: 33.5 %

Procedure:
Palladium acetate (5.5 mg, 0.025 mmol) was added to a solution of 6-bromo-2-methoxypyridin-3-amine (25 mg, 0.123 mmol), 1,2-dimethyl-1H-imidazole (35.5 mg, 0.369 mmol), pivalic acid (3.8 mg, 0.037 mmol), tricyclohexylphosphine tetrafluoroborate salt (18.1 mg, 0.049 mmol) and potassium carbonate (25.5 mg, 0.185 mmol) in DMA (410 μL). The reaction mixture was heated under microwave irradiation at 120° C. for 1 hour. The reaction was diluted with EtOAc and quenched with water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The crude mixture was purified by Biotage silica gel column chromatography eluting with 1 to 5% MeOH/aq. NH3 (10/1) in DCM to afford the title compound as a white solid (9 mg, 35%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([OH:9])=[C:4](I)[N:3]=1.C(N(CC)CC)C.[C:18]([C:20]12[CH2:27][CH2:26][CH2:25][N:24]1[CH2:23][CH2:22][CH2:21]2)#[CH:19].Cl>CN(C=O)C.[Cu]I.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:3]=[C:4]2[CH:19]=[C:18]([C:20]34[CH2:27][CH2:26][CH2:25][N:24]3[CH2:23][CH2:22][CH2:21]4)[O:9][C:5]2=[CH:6][C:7]=1[Cl:8]
Reactant: C#CC12CCCN1CCC2
Reactant: Oc1cc(Cl)c(Cl)nc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Clc1cc2oc(C34CCCN3CCC4)cc2nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
2,3-Dichloro-6-iodo-5-pyridinol (163 mg, 0.56 mmol) from example 25a, copper(I) iodide (20 mg, 0.10 mmol), bis(triphenylphosphine)palladium(II) chloride (20 mg, 0.030 mmol) and triethylamine (176 mL, 0.67 mmol) were combined and allowed to stir for 1 hour at ambient temperature. 7a-ethynyl-hexahydro-1H-pyrrolizine (91 mg, 0.67 mmol) in DMF (1.0 mL) was added to the reaction mixture which was then heated to 60° C. for 18 hours. After cooling to ambient temperature, 2 N aqueous HCl was added and the mixture was washed with Et2O (2×), basified with 15% NaOH solution and extracted with CH2Cl2 (2×). The CH2Cl2 phases were combined, dried (MgSO4), concentrated and the residue was chromatographed (silica gel; EtOAc/hexane, 1:3) to afford a white solid (116 mg, 70%): 1H NMR (CDCl3, 300 MHz) δ 1.83-1.97 (m, 6H), 2.20-2.31 (m, 2H), 2.67-2.77 (m, 2H), 3.18-3.25 (m, 2H), 6.71 (s, 1H), 7.78 (s, 1H); MS (CI/NH3) m/z: 297 (M+H)+.