Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:37][O:38][CH3:39])[O:5][C:6]1[CH:7]=[C:8]([O:26][C:27]2[CH:28]=[N:29][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:31][CH:32]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21]([O:23]CC)=[O:22])[CH2:18][N:19]=1)=[CH:11]2.[OH-].[Na+]>O1CCCC1.CO>[CH3:39][O:38][CH2:37][CH:4]([CH2:3][O:2][CH3:1])[O:5][C:6]1[CH:7]=[C:8]([O:26][C:27]2[CH:28]=[N:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:18][N:19]=1)=[CH:11]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC(COC)COC)c3[nH]2)S1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
Ethyl [2-(7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetate (390 mg) was dissolved in a mixture of tetrahydrofuran (5 mL) and methanol (5 mL). To the mixture was added 1M aqueous sodium hydroxide solution (2 mL) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The residue was dissolved in water and 1M hydrochloric acid (2 mL) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound (370 mg, 100%) as a pale orange amorphous solid. MS 550 (MH+).
Reaction SMILES: CS(O)(=O)=O.[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[C@H:14]1[CH2:20][N:19]2[C:21]([C:24](OC)([CH3:26])[CH3:25])=[CH:22][N:23]=[C:18]2[C@H:17]([NH:29]C(=O)OC(C)(C)C)[CH2:16][CH2:15]1.[N-:37]=[N+:38]=[N-:39].[Na+]>C(Cl)(Cl)Cl>[N:37]([C:24]([C:21]1[N:19]2[CH2:20][C@H:14]([C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([F:13])[C:7]=3[F:6])[CH2:15][CH2:16][C@@H:17]([NH2:29])[C:18]2=[N:23][CH:22]=1)([CH3:25])[CH3:26])=[N+:38]=[N-:39]
Reactant: COC(C)(C)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(N=[N+]=[N-])c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2N
Reaction time: 1 h
Yield: 95.4 %

Procedure:
Methanesulfonic acid (0.30 mL, 4.63 mmol) was added to a solution of tert-butyl [(6S,9R)-6-(2,3-difluorophenyl)-3-(1-methoxy-1-methylethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl]carbamate (50 mg, 0.115 mmol) and sodium azide (170 mg, 2.62 mmol) in chloroform (10 mL). After 1 h, additional methanesulfonic acid (0.95 mL, 14.65 mmol) was added. After 16 h, the reaction mixture was concentrated. Purification by reverse phase HPLC (100% water→100% acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (38 mg). MS 347.1 (M+1).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:14])[C:4]([C@@H:6]1[CH2:9][C@H:8]([CH2:10][C:11](O)=[O:12])[CH2:7]1)=[O:5].B>C1COCC1>[CH3:1][O:2][N:3]([CH3:14])[C:4]([C@H:6]1[CH2:9][C@@H:8]([CH2:10][CH2:11][OH:12])[CH2:7]1)=[O:5]
Reactant: CON(C)C(=O)[C@H]1C[C@@H](CC(=O)O)C1
Agent: B
Solvent: C1CCOC1
Product: CON(C)C(=O)[C@H]1C[C@@H](CCO)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice cold solution of 3.0 g of cis-[3-(methoxy-methyl-carbamoyl)-cyclobutyl]-acetic acid in 50 mL of THF was added 15 mL of 1M borane in THF. The mixture was allowed to stir for 15 min in the cold, then warm and stir for 30 min. The reaction was quenched with 25 mL of 10% HCl and extracted into 3×50 mL of ethyl acetate. The combined extracts were diluted with 50 mL of toluene, dried over magnesium sulfate and concentrated under reduced pressure. Drying under vacuum overnight gave 1.8 g of product as a colorless oil: MS (m+1)=188.45; 1H NMR (400 MHz, CDCl3) 3.62 (s, 3H), 3.6 (t, 2H), 3.18 (s, 3H), 2.35 (m, 1H), 2.3 (m, 3H), 1.984 (dd, 2H), 1.65 (dd, 2H).
Reaction SMILES: C([O:4][C@H:5]([CH2:10]Br)[CH2:6][C:7]([OH:9])=[O:8])(=O)C.[CH:12]([NH:15][CH:16]([CH3:18])[CH3:17])([CH3:14])[CH3:13]>O>[CH:12]([NH:15][CH:16]([CH3:18])[CH3:17])([CH3:14])[CH3:13].[O:4]1[CH2:10][C@@H:5]1[CH2:6][C:7]([OH:9])=[O:8]
Reactant: CC(=O)O[C@H](CBr)CC(=O)O
Solvent: CC(C)NC(C)C
Solvent: O
Product: O=C(O)C[C@H]1CO1
Reaction time: 2 h

Procedure:
To a 2 l of three-necked flask equipped with thermometer pH meter and mechanical stirrer were charged distilled water (1 l), (S)-3-acetoxy-4-bromobutyric acid (90 g, 0.4 mol) and diisopropylamine (121 g, 1.2 mol). The reaction mixture was stirred at 0˜5° C. for 2 hours to afford (S)-3,4-epoxybutyric acid diisopropylamine salt. Over 99% of conversion was detected by NMR.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[N:12]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([OH:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=1)[CH3:13].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O.O>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[N:12]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=1)[CH3:13]
Reactant: COC(=O)C(O)Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 0.14 g) was added portionwise to a stirred solution of methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-hydroxypropanoate (1.20 g) in dry N,N-dimethyl formamide (20 mL) under a nitrogen atmosphere. The mixture was stirred at room temperature for 15 minutes prior to the addition of benzyl bromide (0.6 mL). Stirring was continued at room temperature for 3 hrs, then at 80° C. for 17 hrs before the mixture was cooled, diluted with water (500 mL) and extract with ethyl acetate (3×200 mL). The combined ethyl acetate layers were washed with water (4×500 mL) and brine (500 mL), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel with 1% methanol in dichloromethane to afford the title compound, a gum, which was used in the next stage without further purification.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([CH2:30]O)[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1(C)C=CC=CC=1.C(Br)(Br)(Br)[Br:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:1]([O:19][CH2:20][CH:21]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:30][Br:40])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCCCCCCCCCCCCCCOCC(CO)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOCC(CBr)OCc1ccccc1

Procedure:
In a 250 ml round bottom flask equipped with a magnetic stir bar, 2.00 g (4.6 mmoles) of 1-O-octadecyl-2-O-benzyl-glycerol (Bachem, Switzerland) was dissolved into 120 ml of toluene. To this solution were added 4.58 g. (13.8 mmoles) of carbon tetrabromide and 3.62 g. (13.8 mmoles) of triphenylphosphine and the reaction mixture stirred for 4 hours at room temperature. The yellow suspension was filtered and the filtrate concentrated on a rotary evaporator to afford a white solid. This residue was dissolved into 50 ml chloroform, washed twice with 30 ml saturated sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under vacuum on a rotary evaporator to afford 2.5 g of the crude product as a white powder. This crude product was purified by flash column chromatography on a silica gel 60 (E. Merck, Germany) column by sequential elution with 100 ml each of hexane, 1% ethyl acetate in hexane, 2% ethyl acetate in hexane and finally with 3% ethyl acetate in hexane. Fractions collected were screened by TLC and those fractions that contained pure product (silica gel, 5% ethyl acetate in hexane, Rf=0.56) were pooled. The pooled fractions were concentrated under vacuum on a rotary evaporator to afford a quantitative yield of the 1-O-octadecyl-2-O-benzyl-3-bromo-1,2-propanediol as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N+:8]([O-])=[CH:7][C:6]([N+:13]([O-:15])=[O:14])=[CH:5]2.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:7]1[C:6]([N+:13]([O-:15])=[O:14])=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cc2cc(Cl)ccc2[n+]([O-])c1
Product: O=[N+]([O-])c1cc2cc(Cl)ccc2nc1Cl

Procedure:
2,6-Dichloro-3-nitroquinoline was prepared by heating a mixture of 6-chloro-3-nitroquinoline-1-oxide and phosphorous oxychloride under reflux. The product was isolated as a nearly colourless crystalline solid, mp 190° C. Mass spectrum (m/e): 242 (parent ion; 90%); 196 (100%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([CH3:36])([CH3:35])[C:33]#[N:34])=[CH:28][CH:27]=3)[CH:24]=2)[N:19](C2CCCCO2)[N:18]=1>C(Cl)Cl>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([CH3:36])([CH3:35])[C:33]#[N:34])=[CH:28][CH:27]=3)[CH:24]=2)[NH:19][N:18]=1
Reactant: CC(C)(C#N)c1ccc(-c2ccc3c(c2)c(-c2nc4ccccc4[nH]2)nn3C2CCCCO2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C#N)c1ccc(-c2ccc3[nH]nc(-c4nc5ccccc5[nH]4)c3c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
TFA (0.25 mL, 3.245 mmol) was added to a solution of 2-(4-(3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)phenyl)-2-methylpropanenitrile (7 mg, 0.015 mmol) in CH2Cl2 (4 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound in a 55% yield. 1H NMR (400 MHz, CD3OD): δ 8.66 (bs, 1H), 7.87-7.80 (m, 6H), 7.66 (m, 2H), 7.56 (m, 2H), 1.78 (s, 6H); ESI-MS [M+H]+: 378.3.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH:14]([O:18][CH3:19])[CH:13]([CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[CH2:12]2.[CH3:31][N:32]1[CH:36]=[CH:35][N:34]=[C:33]1[CH:37]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH:14]([O:18][CH3:19])[CH:13]([CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[CH2:12]2)[CH2:37][C:33]1[N:32]([CH3:31])[CH:36]=[CH:35][N:34]=1
Reactant: CCCN(CCC)CCCCC1Cc2cc(CNCc3ncc[nH]3)ccc2C1OC
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCC1Cc2cc(CN(Cc3ncc[nH]3)Cc3nccn3C)ccc2C1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound (54.8 mg) obtained in Example 127-14 was dissolved in methanol (2.74 ml) and added with 1-methyl-2-imidazole carboxaldehyde (21.9 mg) and sodium cyanoborohydride (16.7 mg). Then, the solution was adjusted to pH 4 with acetic acid and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and added with saturated saline solution. The solution was subjected to separation/extraction with chloroform. The extract was dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (35.9 mg) of the subject compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:35]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:39]([CH:35]3[CH2:38][CH2:37][CH2:36]3)=[O:40])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[N:12]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(Cl)C1CCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)C1CCC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with cyclobutanecarbonyl chloride (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C34H39N2O2Cl2 [(M+H)+] 577.2383, observed 577.2382.
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].FC(F)(F)S(O[CH2:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])(=O)=O.C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC>[F:1][C:2]([F:18])([C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])[CH2:3][C:4]([CH2:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])([C:7]#[N:8])[C:5]#[N:6]
Reactant: O=S(=O)(OCC(F)(F)C(F)F)C(F)(F)F
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: N#CC(C#N)(CC(F)(F)C(F)F)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.3 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 4.0 g of 2,2,3,3-tetrafluoropropyl trifluoromethanesulfonate were dissolved in 10 ml of ethylene glycol dimethyl ether, 1.4 g of potassium carbonate was added, and the mixture was stirred at room temperature for 8 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.36 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)-2-(2,2,3,3-tetrafluoropropyl)malononitrile (hereinafter, referred to as the present compound (61)).
Reaction SMILES: [NH2:1][C:2]([CH2:7][CH3:8])([CH2:5][CH3:6])[C:3]#[CH:4].[F:9][C:10]1[C:11](I)=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:25][CH:24]=[N:23][C:22]=1[CH3:26]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[NH2:1][C:2]([CH2:7][CH3:8])([CH2:5][CH3:6])[C:3]#[C:4][C:11]1[C:10]([F:9])=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:20]/[C:21]1[NH:25][CH:24]=[N:23][C:22]=1[CH3:26])/[C:14](=[O:19])[NH:15]2
Reactant: C#CC(N)(CC)CC
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(N)(C#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2)CC

Procedure:
Using Method C above, 3-amino-3-ethyl-1-pentyne (37.6 mg, 0.34 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (50 mg, 0.135 mmol) using (Ph3P)4Pd (16 mg) and CuI (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 6 h to give (Z)-4-[3-amino-3-ethyl-1-pentynyl]-1,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 45 mg, 95%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]([OH:16])=O)=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:41][C@@H:42]1[CH2:47][CH2:46][CH2:45][C@H:44]([OH:48])[CH2:43]1>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:14]([NH:41][C@@H:42]2[CH2:47][CH2:46][CH2:45][C@H:44]([OH:48])[CH2:43]2)=[O:16])=[N:4][O:5][C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1
Reactant: O=C(O)c1noc(-c2ccc(Cl)cc2)c1Cl
Reactant: N[C@@H]1CCC[C@H](O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CCC[C@H](O)C1)c1noc(-c2ccc(Cl)cc2)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 18 mg (0.07 mmol) of 4-chloro-5-(4-chlorophenyl)isoxazole-3-carboxylic acid in anhydrous N,N-dimethylformamide (1 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU; 27 mg, 0.07 mmol), followed by (1S,3R)-3-aminocyclohexanol (8.1 mg, 0.07 mmol) with stirring at room temperature. After 18 h, the solvent was removed in vacuo, and the residue was partitioned between water and ethyl acetate. The aqueous layer was separated and repeatedly extracted with ethyl acetate, the combined organic extracts were dried (MgSO4), the solvent removed in vacuo and the residue was purified by preparative HPLC to afford the title compound: (5.3 mg, 0.015 mmol). MS (ESI) m/z (M+H+): 354.9/356.9.
Reaction SMILES: Cl.C([O-])(=O)C.[F:6][C:7]1[C:8]([N:22]2[C:31]3[C:26](=[CH:27][C:28]([F:34])=[C:29]([F:33])[C:30]=3[Cl:32])[C:25](=[O:35])[C:24]([C:36]([O:38]CC)=[O:37])=[CH:23]2)=[N:9][C:10]([NH:13]C(C)(C)CC(C)(C)C)=[CH:11][CH:12]=1>>[NH2:13][C:10]1[N:9]=[C:8]([N:22]2[C:31]3[C:26](=[CH:27][C:28]([F:34])=[C:29]([F:33])[C:30]=3[Cl:32])[C:25](=[O:35])[C:24]([C:36]([OH:38])=[O:37])=[CH:23]2)[C:7]([F:6])=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cn(-c2nc(NC(C)(C)CC(C)(C)C)ccc2F)c2c(Cl)c(F)c(F)cc2c1=O
Agent: CC(=O)[O-]
Agent: Cl
Product: Nc1ccc(F)c(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)n1
Yield: 85.1 %

Procedure:
To 1.2 ml of the mixed solution of 4N hydrochloric acid and acetate (1:1) was added 235 mg of ethyl 1-[3-fluoro-6-(1,1,3,3-tetramethylbutylamino)pyridin-2-yl]-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate and the mixture was heated under reflux for 6 hours with stirring and allowed to cool. The precipitate was collected by filtration and washed with ethanol to obtain 145 mg of the title compound as a gray powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:14]1([C:11]([C:8]2[N:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[O:13])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)N2CCOCC2)nc1
Reaction time: 16 h
Yield: 87.4 %

Procedure:
5-(Methoxycarbonyl)pyridine-2-carboxylic acid (758 mg, 4.18 mmol) was dissolved in DMF (25 mL) and morpholine (603 uL, 5.23 mmol), Et3N (2.45 mL, 16.7 mmol) and HBTU (1.67 g, 4.39 mmol) were added. The reaction mixture was stirred for 16 h and concentrated in vacuo. The residue was dissolved in EtOAc (100 mL), washed with sat aq Na2CO3 (100 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (914 mg, 87.3%) as a yellow oil. LCMS (ES+): 251.2 [MH]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@@H:10]([OH:13])[CH:11]=[CH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.Cl[Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29].O>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:10]([O:13][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[CH:11]=[CH2:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: C=C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C=C[C@H](O[Si](C(C)C)(C(C)C)C(C)C)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 82 %

Procedure:
A solution of (3S,4S)-N-[(tertbutyloxy)carbonyl]-4-amino-3-hydroxy-5-phenyl pentene [prepared by the method of Hanson et al, J. Org. Chem., 50, 5399 (1985)] (10.0 g, 64.5 mmol), imidazole (9.14g, 13 mmol), and chlorotriisopropylsilane (12.44 g, 43.3 mmol) in anhydrous DMF (40 mL) was stirred for 5 days at room temperature under an N2 atmosphere. The solution was poured into H2O (500 mL) and extracted with Et2O (2×25 mL). The combined organic layers were washed with H2O (250 mL), a 0.5M citric acid solution (2×120 mL), a 5% KHCO3 solution (2×100 mL), and brine (2×100 mL). After the organic layer was dried over MgSO4, the filtrate was concentrated and purified by medium pressure column chromatography (silica gel, 10% ethyl acetate in hexane, Rf 0.23) to give 12.9 g (82 % yield) of the title compound as a clear, colorless oil. 1H and 13C NMR spectral data were consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[OH:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:34]=[CH:33][C:29]([C:30]([O-])=[O:31])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH:1][C:30](=[O:31])[C:29]4[CH:28]=[CH:27][C:26]([N:23]5[CH2:24][CH2:25][CH:20]([OH:19])[CH2:21][CH2:22]5)=[CH:34][CH:33]=4)=[CH:10][CH:9]=3)[CH:5]=[N:6]2)=[CH:12][CH:13]=1)#[N:18]
Reactant: N#Cc1ccc(-n2ncc3cc(N)ccc32)cc1
Reactant: O=C([O-])c1ccc(N2CCC(O)CC2)cc1
Product: N#Cc1ccc(-n2ncc3cc(NC(=O)c4ccc(N5CCC(O)CC5)cc4)ccc32)cc1

Procedure:
Compound 404 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-cyanophenyl)indazole and 4-(4-hydroxypiperidino)benzoate. [M+H]+ calcd for C26H23N5O2: 438.19; found: 437.99.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)OCC[O:3]1.CN(C)CCN(C)C.C([Li])CCC.[C:25](=[O:27])=[O:26]>O1CCCC1>[C:2]([C:7]1[S:8][C:9]([C:25]([OH:27])=[O:26])=[CH:10][CH:11]=1)(=[O:3])[CH3:1]
Reactant: CC1(c2cccs2)OCCO1
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(=O)O)s1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
2-Methyl-2-(2-thienyl)-1,3-dioxolan (6.6 g) (synthesized in accordance with the method described in Tetrahedron, 41, 3803 (1985)) was dissolved in tetrahydrofuran (200 ml), and N,N,N', N'-tetramethylethylenediamine (5.87 ml) was added. The mixture was cooled to -78° C., and n-butyllithium (1.6M in hexane, 25 ml) was slowly added dropwise. The mixture was stirred at the same temperature for 2 hours, and warmed slowly to room temperature for a period of 2 hours with introducing carbon dioxide gas. The reaction mixture was concentrated under reduced pressure, and 2N hydrochloric acid (200 ml) was added. The mixture was stirred for 3 hours, and precipitated crystals were collected by filtration, washed with water and dried to give 5-acetyl-2-thiophenecarboxylic acid (3.87 g) as crystals.