Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[Br:39]N1C(=O)CCC1=O>O.C(Cl)(Cl)Cl>[Br:39][CH2:17][C:16]([C:13]1[CH:12]=[CH:11][C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:15][CH:14]=1)=[O:18]
Reactant: CC(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)CBr)cc1
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a chloroform (7.5 mL) solution of 1-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]ethanone (0.23 g), under ice cooling in a nitrogen atmosphere, 2,6-lutidine (0.17 mL) and trimethylsilyl trifluoromethanesulfonate (0.19 mL) were added, and the resultant was stirred for 30 minutes. Then, N-bromosuccinimide (0.17 g) was added thereto, and the resultant was stirred for 30 minutes under ice cooling. Water was added to the reaction solution, and the resultant was stirred for 10 minutes, followed by extraction with chloroform. An organic layer was separated using a phase separator, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (OH-type silica gel; hexane/ethyl acetate-gradient elution=100/0→75/25) to obtain the title compound (0.26 g) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])[CH:3]=1.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.[Li]CCCC>C1COCC1>[CH3:14][C:9]1[N:8]([C:4]2[CH:3]=[C:2]([B:15]([OH:20])[OH:16])[CH:7]=[CH:6][N:5]=2)[C:12]([CH3:13])=[CH:11][CH:10]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1ccc(C)n1-c1cc(Br)ccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cc(B(O)O)ccn1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Step 2) To a solution of the above prepared 4-bromo-2-(2,5-dimethyl-pyrrol-1-yl)-pyridine (1.95 g, 7.77 mmol) and triisopropyl borate (2.68 mL, 11.6 mmol) in THF (40 mL) at −78° C. was added n-BuLi (1.6 M in hexane, 4.85 mL, 7.77 mmol) keeping the internal temperature below −65° C. Stirring was continued at −78° C. for 1 h, then more triisopropyl borate (2.68 mL, 11.6 mmol) and n-BuLi (4.85 mL, 7.77 mmol) was added and stirring was continued at −78° C. for 1 h. The reaction mixture was quenched with 1 M NaH2PO4-sol., allowed to quickly (waterbath) warm to ca. 20° C. and stirred for 10 min. Diluted with EtOAc, layers were separated, washed organic layer with brine and dried over Na2SO4. Removal of the solvent in vacuum left the title compound as a yellow foam (2.1 g, 100%, 80% purity), which was used without further purification. MS (ISN) 215.3 [(M−H)−].
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].I[C:20]1[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=1[OH:30]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:22]1[CH:23]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:25]=[CH:20][C:21]=1[OH:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(O)c(I)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1cc(S(C)(=O)=O)ccc1O

Procedure:
Following the general method as outlined in Intermediate 79, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 2-iodo-4-(methylsulfonyl)phenol (Intermediate 78), the title compound was obtained after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[C:14]([OH:16])[C:13]([Cl:17])=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[CH:18]([N:21]1[CH2:26][CH2:25][CH:24](O)[CH2:23][CH2:22]1)([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[C:14]([O:16][CH:24]3[CH2:25][CH2:26][N:21]([CH:18]([CH3:20])[CH3:19])[CH2:22][CH2:23]3)[C:13]([Cl:17])=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CC(C)N1CCC(O)CC1
Reactant: CCOC(=O)c1oc2cc(O)c(Cl)cc2c1C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1oc2cc(OC3CCN(C(C)C)CC3)c(Cl)cc2c1C
Reaction time: 4 h
Yield: 94.8 %

Procedure:
The above prepared 5-chloro-6-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (0.700 g, 2.75 mmol) was dissolved in 12 mL of THF and treated successively at −10° C. with 1-isopropyl-piperidin-4-ol (0.551 g, 1.4 eq.), triphenylphosphine (1.001 g, 1.4 eq.) and DIAD (0.755 mL, 1.4 eq.), and the mixture then kept at ambient temperature for another 4 h. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, NEt3/AcOEt=2/98), produced 0.990 g of the title compound as light yellow gum.
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[N:14][C:15]([C:18]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:17]=3)[CH:10]=2)[N:5]([C:26](=[O:28])[CH3:27])[C@@H:4]([CH3:29])[CH2:3]1.Br[C:31]1[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][N:32]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:29][C@H:4]1[CH2:3][C@@H:2]([NH:1][C:31]2[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][N:32]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[N:14][C:15]([C:18]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:17]=3)[CH:10]=2)[N:5]1[C:26](=[O:28])[CH3:27]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)nc3)cc2[C@H](N)C[C@@H]1C
Reactant: Cc1cnc(Br)cn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)nc3)cc2[C@H](Nc2cnc(C)cn2)C[C@@H]1C
Temperature: 120 °C
Yield: 26 %

Procedure:
1-((2S,4R)-4-amino-2-methyl-6-(6-(morpholine-4-carbonyl)pyridin-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation, see Intermediate 56) (80 mg, 0.203 mmol), 2-bromo-5-methylpyrazine (70.2 mg, 0.406 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1-biphenyl]-2-amine (16.0 mg, 0.041 mmol), tris(dibenzylideneacetone)dipalladium(0) (18.6 mg, 0.020 mmol) and sodium tert-butoxide (27.3 mg, 0.284 mmol) were combined in 1,4-dioxane (2 mL). The mixture was degassed over a period of 15 mins before being heated under microwave irradiation to 120° C. for 25 mins. The mixture was partitioned between saturated aq. sodium bicarbonate (50 mL) and DCM (3×50 mL). The organic layers were combined, dried by passing through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by MDAP (HpH) followed by further purification by MDAP (Formate) to give 1-((2S,4R)-2-methyl-4-((5-methylpyrazin-2-yl)amino)-6-(6-(morpholine-4-carbonyl)pyridin-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone (26 mg, 0.053 mmol, 26% yield).
Reaction SMILES: C(O[CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)C.[C:20]([O:27][CH3:28])(=[O:26])[CH2:21][C:22]([O:24][CH3:25])=[O:23].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.C([O-])(=O)C.[K+].[Cl-].[NH4+]>ClCCl.C(OCC)C>[C:14]1([C@H:5]([CH:21]([C:20]([O:27][CH3:28])=[O:26])[C:22]([O:24][CH3:25])=[O:23])[CH:6]=[CH:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)OC(C=Cc1ccccc1)c1ccccc1
Reactant: COC(=O)CC(=O)OC
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C(C(=O)OC)[C@H](C=Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In 0.5 ml of dichloromethane were suspended 0.9 mg (2.5 μmol) of [PdCl(η3-C3H5)]2 and 1.8 mg (5.5 μmol) of (R,R)-t-Bu-QuinoxP* (1), followed by stirring at room temperature for 10 to 30 minutes. To the resulting solution were added a solution of 126 mg (0.50 mmol) of 1,3-diphenyl-2-propenyl acetate in 1.5 ml of dichloromethane, 171 μl (1.50 mmol) of dimethyl malonate, 367 μl (1.50 mmol) of N,O-bis(trimethylsilyl)acetamide (BSA), and a trace amount of potassium acetate. The reaction system was stirred at room temperature for 1 hour. The reaction mixture was diluted with diethyl ether, and a saturated aqueous solution of ammonium chloride was added to stop the reaction. The resulting mixture was extracted with diethyl ether, and the organic layer was washed with a sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate. Any volatile matter was evaporated off, and the residue was purified by silica gel column chromatography.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[NH:17][N:18]=[CH:19][CH:20]=2)=[N:13][C:12]=1[CH3:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:32]=[CH:31][C:26]([O:27][CH2:28][CH2:29]Br)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:20]=[CH:19][N:18]([CH2:29][CH2:28][O:27][C:26]3[CH:31]=[CH:32][C:23]([F:22])=[CH:24][CH:25]=3)[N:17]=2)=[N:13][C:12]=1[CH3:21])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1ccccc1
Reactant: Fc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1nc(-c2ccn(CCOc3ccc(F)cc3)n2)sc1C(=O)NCc1ccccc1
Temperature: 90 °C
Yield: 26.7 %

Procedure:
A solution of 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid benzylamide (0.2 g, 0.61 mmol) in dimethyl sulfoxide (5 mL) was treated with 4-fluorophenoxyethyl bromide (0.14 g, 0.67 mmol) and potassium carbonate (0.30 g, 2.0 mmol), and the reaction mixture was heated to 90° C. for 16 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with brine (2×50 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by preparative thin layer chromatography over silica gel (methylene chloride:methanol, 95:5) to provide 2-{1-[2-(4-fluoro-phenoxy)-ethyl]-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid benzylamide (0.071 g, 51% yield) as a white solid.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:17][C@@H:16]2[C@@H:11]([C@@H:12]([Cl:30])[CH2:13][CH2:14][C:15]2([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10]1)=O)(C)(C)C>O1CCOCC1>[ClH:30].[Cl:30][C@@H:12]1[C@@H:11]2[C@@H:16]([CH2:17][NH:9][CH2:10]2)[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2[C@@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@H]2Cl
Agent: Cl
Solvent: C1COCCO1
Product: Cl[C@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@@H]21
Temperature: 25 °C
Reaction time: 2 h
Yield: 192.9 %

Procedure:
10 cm3 of a 6.3N solution of hydrochloric acid in dioxane are added to a solution of 1.03 g of (3aR, 7S, 7aR)-2-tert-butyloxycarbonyl-7-chloro-4,4-diphenylperhydroisoindole in 5 cm3 of dioxane. The reaction mixture is stirred at room temperature for 2 hours and then concentrated to dryness under reduced pressure (2.7 kPa). 0.84 g of (3aR, 7S, 7aR)-7-chloro-4,4-diphenylperhydroisoindole hydrochloride is obtained in the form of a solid which is used in the crude state in the following test.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C@H:6]([NH:13][CH2:14][C:15]#[N:16])[CH2:7]2.[CH:17](OCCCC)=[O:18]>>[C:15]([CH2:14][N:13]([C@H:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=2[F:1])[CH2:7]1)[CH:17]=[O:18])#[N:16]
Reactant: CCCCOC=O
Reactant: N#CCN[C@H]1CCc2c(F)cc(F)cc2C1
Product: N#CCN(C=O)[C@H]1CCc2c(F)cc(F)cc2C1
Reaction time: 19 h

Procedure:
A solution of the (S)-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamino)acetonitrile in butyl formate (8.7M, 240 mL, 2.10 mol) was heated to reflux and stirred under nitrogen for 19 hours. The solvents were removed under reduced pressure, toluene was added and then evaporated. Drying gave (S)-N-(cyanomethyl)-N-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)formamide as an oily residue (53.2 g). A stirring mixture of the formamide (53.2 g) and ethyl formate (12.4M, 48.7 mL, 0.604 mol) in 0.925 L of anhydrous THF was cooled to -15° C. A solution of potassium tert-butoxide in THF (1.0M, 302 mL, 0.302 mol) was added over 20 minutes and the mixture was stirred for 18 hours. Evaporation of the solvent gave potassium (S)-N-(1-cyano-2-oxyvinyl)-N-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)formamide as a residue.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([C:8]([CH2:15][OH:16])([CH2:11][CH2:12][CH2:13][CH3:14])[CH:9]=[O:10])[CH3:7]>>[CH2:6]([C:8]([CH2:15][O:16][S:2]([CH3:1])(=[O:4])=[O:3])([CH2:11][CH2:12][CH2:13][CH3:14])[CH:9]=[O:10])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCC(C=O)(CC)CO
Product: CCCCC(C=O)(CC)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 103.4 %

Procedure:
To a cold (10° C.) solution of 12.6 g (0.11 mole) of methanesulfonyl chloride and 10.3 g (0.13 mole) of triethylemine was added dropwise 15.8 g of 2-ethyl-2-(hydroxymethyl)hexanal, prepared according to the procedure described in Chem. Ber. 98, 728-734 (1965), while maintaining the reaction temperature below 30° C. The reaction mixture was stirred at room temperature for 18 h, quenched with dilute HCl and extracted with methlyene chloride. The methylene chloride extract was dried over MgSO4 and concentrated in vacuo to give 24.4 g of brown oil.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[CH3:9][C:10]1[CH:11]=[C:12]2[N:17]([C:18]=1[C:19]([C:21]1[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:24]3=[O:36])=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13]2.O>CN(C=O)C>[CH3:9][C:10]1[CH:11]=[C:12]2[N:17]([C:18]=1[C:19]([C:21]1[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=1)[N:27]([CH3:1])[CH:26]=[C:25]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:24]3=[O:36])=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13]2
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c[nH]c2ccc(C(=O)c3c(C)cc4ccccn34)cc2c1=O
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c2ccc(C(=O)c3c(C)cc4ccccn34)cc2c1=O
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 87.5 %

Procedure:
1.53 g (11.12 mmol) of potassium carbonate and 0.69 ml (11.12 mmol) of methyl iodide are added, at ambient temperature under an inter atmosphere, to 3.73 g (9.27 mmol) of ethyl 6-[(2-methylindolizin-3-yl)carbonyl]-4-oxo-1,4-dihydroquinoline-3-carboxylate in 100 ml of DMF. The reaction medium is heated at 90° C. for 2 h. 0.384 g (2.78 mmol) of potassium carbonate and 0.173 ml (2.78 mmol) of methyl iodide are added and then the heating is continued for 40 minutes. The reaction medium is hydrolysed with water and then extracted with ethyl acetate and with dichloromethane. The organic phase is washed with a saturated solution of sodium chloride, dried over sodium sulphate, and then concentrated under reduced pressure. The residue obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (90/10) mixture. 3.15 g of a yellow solid are obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1S(C)(=O)=O)[CH3:2].CN1CCCC1=[O:31].[OH-].[Na+].O>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1[OH:31])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(C)(=O)=O)c(C)nn(C)c1=O
Reactant: CN1CCCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1-c1c(O)c(C)nn(C)c1=O
Temperature: 70 °C
Reaction time: 6 h

Procedure:
To a 25 mL volume three-necked flask, 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfonyl-2,3-dihydro-3-pyridazinone ((2-34)-(1)-39) (1.71 g), N-methyl-2-pyrrolidone (3.1 ml), and 27 w/w % of aqueous sodium hydroxide solution (2.99 g) were added, and stirred at 70° C. for 6 hours. To the mixture was added water (4.0 ml) and toluene (4.6 ml), and then the organic layer was removed. To the resulting aqueous layer, 35 w/w % of hydrochloric acid was added to adjust to pH to less than 1. The precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to give 1.23 g of 4-(2,6-diethyl-4-methylphenyl)-5-hydroxy-2,6-dimethyl-2,3-dihydro-3-pyridazinone ((1-4)-(1)-39).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[NH2:22][CH2:23][C@H:24]1[C@H:28]([CH3:29])[CH2:27][NH:26][CH2:25]1>CN(C)C=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:26]2[CH2:27][C@@H:28]([CH3:29])[C@H:24]([CH2:23][NH2:22])[CH2:25]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: C[C@@H]1CNC[C@H]1CN
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C[C@H]1CN
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In the same manner as described in Example 16 (1), a mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, trans-3-aminomethyl-4-methylpyrrolidine, and dimethylformamide was stirred at room temperature for 24 hours to give 5-amino-7-(trans-3-aminomethyl-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro4-oxoquinoline-3-carboxylic acid, which was recrystallized from ethanol, m.p. 223°-225° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)([CH2:12][CH2:13][OH:14])[CH2:8]1)=[O:6].C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)([CH2:12][CH2:13][O:14][S:42]([CH3:41])(=[O:44])=[O:43])[CH2:8]1)=[O:6]
Reactant: COc1ccc(C2(CCO)CCN(C(=O)c3cc(-n4cnnn4)ccc3OC)C2)cc1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2(CCOS(C)(=O)=O)CCN(C(=O)c3cc(-n4cnnn4)ccc3OC)C2)cc1OC
Temperature: -5 °C
Reaction time: 18 h

Procedure:
Combine 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(3,4-dimethoxyphenyl)-3-(2-hydroxyethyl)pyrrolidine (0.43 g, 0.97 mmol), triethylamine (3.3 mL, 2.4 mmol), and anhydrous dichloromethane (30 mL). Cool the reaction mixture to -5° C. with an salt-ice bath. Slowly, add methanesulfonyl chloride (0.082 mL, 1.06 mmol) at such a rate that the temperature of the reaction mixture does not rise above 2° C. Warm to ambient temperature. After 18 hours, quench the reaction by the addition of ice. Separate the organic layer and extract 3 times with 1M hydrochloric acid solution and 2 times with a saturated solution of sodium bicarbonate. Dry the organic layer over Na2SO4, filter, and concentrate invacuo to obtain the title compound.
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]>C(OCC)(=O)C.[C].[Pd]>[CH3:17][Si:2]([CH3:1])([CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: C[Si](C)(C)C#CCCCCCCCCC(=O)O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.9 %

Procedure:
At the same time, 11-trimethylsilyl-10-undecynoic acid (0.23 g) was dissolved in ethyl acetate (5 ml), and 10% palladium-carbon (10 mg) was added to the solution. After the air within the reactor was purged with hydrogen, the mixture was stirred at room temperature for 12 hours. Then, the mixture was filtered, and the filtrate was concentrated to give 11-trimethylsilylundecanoic acid (0.21 g).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]2[C:10]([C:11]=1[CH2:12][C:13]([NH2:15])=[O:14])=[C:9]([OH:16])[CH:8]=[CH:7][CH:6]=2)[CH3:2].[H-].[Na+].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>CN(C=O)C.O>[CH3:31][O:30][C:28](=[O:29])[CH2:27][O:16][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[C:11]([CH2:12][C:13]([NH2:15])=[O:14])=[C:3]([CH2:1][CH3:2])[N:4]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCc1c(CC(N)=O)c2c(O)cccc2n1Cc1ccccc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(CC(N)=O)c2c(OCC(=O)OC)cccc2n1Cc1ccccc1
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
2-Ethyl-4-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide (135 mg, 0.44 mmol) was added to 17.6 mg (0.44 mmol) of NaH/mineral oil (washed with hexanes) in 5 mL of DMF, stirred 0.5 hour, 0.04 mL (0.44 mmol) of methyl 2-bromoacetate added and stirring maintained for 5 hours. The mixture was diluted with water, extracted with ethyl acetate. Some material was insoluble and was filtered. The ethyl acetate was washed with brine, dried (MgSO4) and concentrated. The residue was combined with the filtered material to give 119 mg (71% yield) of 2-[[3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][C:13]([O:15]CC)=O)[C:6]3[CH2:18][CH2:19][N:20]([CH3:22])[CH2:21][C:5]=3[C:4]=2[CH:3]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][C:13]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:15])[C:6]3[CH2:18][CH2:19][N:20]([CH3:22])[CH2:21][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)CCn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Reactant: C1CCNC1
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCC(=O)N2CCCC2)C1
Temperature: 120 °C

Procedure:
A mixture of ethyl 3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)propanoate (100 mg) and pyrrolidine (2 ml) was heated at 120° C. for 3 h to obtain 39 mg of 3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(pyrrolidin-1-yl)propan-1-one after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=[O:14].O.FC(F)(F)C(O)=O>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH2:9][OH:14])=[CH:4][CH:3]=1
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Reactant: CC(=O)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: O=C(CO)c1ccc(F)cc1
Reaction time: 8 h
Yield: 42.9 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 4′-fluoroacetophenone (1.15 g, 8.32 mmol) in acetonitrile (42 ml) was treated with [bis(trifluoroacetoxy)iodo]benzene (7.16 g, 16.6 mmol) followed by water (8.3 ml) and trifluoroacetic acid (1.3 ml). The resultant solution was heated under reflux for 2 hr before standing overnight at ambient temperature. The solvent was then removed in vacuo; water (30 ml) was added and the mixture extracted with dichloromethane (3×30 ml). The combined extracts were washed with saturated sodium hydrogen carbonate solution (30 ml) followed by brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo to give the crude 1-(4-fluorophenyl)-2-hydroxyethanone which was purified by flash chromatography (silica) eluting with ethyl acetate and 40°-60° C. petroleum ether (3:1) to give a white solid (0.55 g).