Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[F-].[K+].[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:27]=1B(O)O.Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>[Br-].C([N+](CC)(CC)CC)C1C=CC=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].O1CCCC1>[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:27]=1[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CCOC(=O)CBr
Reactant: Cc1cccc(C)c1B(O)O
Agent: [Pd]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: C1CCOC1
Product: CCOC(=O)Cc1c(C)cccc1C
Temperature: 50 °C
Reaction time: 24 h
Yield: 81.9 %

Procedure:
A 25 ml three-neck flask with magnetic stirrer, reflux condenser and dropping funnel is initially charged with 20 ml of tetrahydrofuran (THF) which has been dried over molecular sieve. The THF is heated to 50° C. while passing argon through for a few minutes, and then cooled again to room temperature. Still under argon, the following are now added: 17.2 mg [0.03 mmol=0.3 mol %] of bis(dibenzylideneacetone)palladium, 27.4 mg of P(o-tolyl)3 (tri-o-tolylphosphine) [0.09 mmol], 2.91 g of potassium fluoride (dried over P2O5 at 140° C.), 272 mg [1 mmol=10 mol %] of benzyltriethylammonium bromide, 1.5 g [10 mmol] of 2,6-dimethylphenylboronic acid and 2.56 g [15 mmol] of ethyl bromoacetate. This mixture is stirred under reflux in a gentle argon stream for 24 hours. Then it is filtered through a little Celite, and the filtercake is washed three times with 20 ml each time of ethyl acetate. The combined filtrates are extracted by shaking with 20 ml of 1 N hydrochloric acid. The aqueous phase is re-extracted twice with 20 ml of ethyl acetate each time. The combined organic phases are then washed with 20 ml of saturated aqueous NaCl solution, dried and concentrated. This gives 2.16 g of an oil which, according to GC-MS, as well as 8.9 area % of m-xylene, contains 72.9 area % of ethyl 2,6-dimethylphenylacetate. This corresponds to a yield of 81.9% of theory.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C@@H:8]([CH2:22][CH:23]1[C:28](=[O:29])[O:27][C:26]([CH3:31])([CH3:30])[O:25][C:24]1=[O:32])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:34]([O-])([O-])=O.[K+].[K+].CI.[Na+].[Cl-]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:33])[NH:7][C@@H:8]([CH2:22][C:23]1([CH3:34])[C:28](=[O:29])[O:27][C:26]([CH3:31])([CH3:30])[O:25][C:24]1=[O:32])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)CC1C(=O)OC(C)(C)OC1=O
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)CC1(C)C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Yield: 75.8 %

Procedure:
[(S)-2-Biphenyl-4-yl-1-(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylmethyl)-ethyl]carbamic acid t-butyl ester (5.0 g, 11 mmol) and K2CO3 (1.8 g, 13.2 mmol) were dissolved in DMF (33.9 mL) and cooled to 0° C. with stirring under nitrogen. Methyl iodide (892 μL) was added and the resulting mixture was stirred at 0° C. for 1 hour. The mixture was allowed to warm to room temperature. Saturated aqueous NaCl (35 mL) and EtOAc (35 mL) were added, and the resulting mixture was stirred for 2 minutes. The layers were separated and the organic layer was evaporated. The residue was triturated with EtOAc (20 mL). The solid was filtered off and dried under vacuum. The filtrate was concentrated and triturated again with EtOAc to yield the title compound (3.9 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([N:13]([CH2:23][CH2:24][CH3:25])[C:14](=O)[CH2:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH2:8]2.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([N:13]([CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]1)[CH2:23][CH2:24][CH3:25])[CH2:8]2
Reactant: CCCN(C(=O)CN1CCNCC1)C1CCc2c(cccc2OC)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCN(CCN1CCNCC1)C1CCc2c(cccc2OC)C1
Yield: 91.8 %

Procedure:
This compound was prepared from 37b (4.8 g, 13.8 mmol) and LiAlH4 (2.0 g, 55.2 mmol) by following Procedure E to give 38b (4.2 g, 91%). 1H NMR (400 MHz, CDCl3) 0.92-0.96 (t, 3H, J=7.6 Hz), 1.41-1.59 (m, 3H), 1.98-2.22 (m, 1H), 2.41-3.1 (m, 19H), 3.81 (s, 3H), 5.2 (bs, 1H), 6.58-6.60 (d, 1H, J=8 Hz), 6.70-6.72 (d, 1H, J=8 Hz), 7.04-7.1 (t, 1H, J=8 Hz).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:10]([C:11]([OH:13])=[O:12])[C:9]=1[C:17]([OH:19])=[O:18])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[N+]([O-])([O-])=O.[Nd+3:31].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(O)C>[Nd:31].[CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:10]([C:11]([OH:13])=[O:12])[C:9]=1[C:17]([OH:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: [Nd+3]
Agent: CCCCOCCc1cccc(C(=O)O)c1C(=O)O
Agent: O=[N+]([O-])[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: [Nd]
Temperature: 40 °C

Procedure:
The mono(2-butoxyethyl)phthalic acid obtained in 10-1 was formed into a triethylamine salt in anhydrous ethanol, after which an ethanol solution of neodymium nitrate was added while stirring. That is, a reactor similar to the above was used to stir a solution obtained by adding 50 ml of an anhydrous ethanol to 79.9 g of the mono(2-butoxyethyl)phthalic acid obtained in 10-1, while dripping 30.4 g of triethylamine while maintaining at 25° C. or less by cooling in an ice water bath. After dripping, the solution was heated for 1 hour at 40° C. to prepare a synthesis solution of mono(2-butoxyethyl)phthalic acid-triethylamine salts. Next, this synthesis solution was adjusted to 20° C., and a solution obtained by dissolving 43.8 g of neodymium nitrate into 120 ml of ethanol was dripped in while stirring. After dripping, the solution was heated to 40° C. for 1 hour, to produce a synthesis solution of a neodymium salt of mono(2-butoxyethyl)phthalic acid. Then, ethanol was distilled from this synthesis solution to concentrate, 200 ml of dichloromethane were added to the concentrate to form a solution, this solution was transferred to a 1 L separating funnel, shaken after pouring 400 ml of water into this separating funnel, and the resulting neodymium salts of mono(2-butoxyethyl)phthalic acid were washed. After further washing this chloromethane solution twice with 400 ml of water, the dichloromethane was distilled out. The solid obtained by distillation was crushed, then dried under reduced pressure at 50° C. to obtain 78.1 g of a neodymium salt of mono(2-butoxyethyl)phthalic acid (yield 83%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH2:10][CH2:11][O:12][CH3:13])[C:3]=1[NH2:14].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1.ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]2[C:3]=1[N:14]=[C:18]([C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[Cl:15])[N:9]2[CH2:10][CH2:11][O:12][CH3:13]
Reactant: O=Cc1ccccc1Cl
Reactant: COCCNc1nc(C)nc(Cl)c1N
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COCCn1c(-c2ccccc2Cl)nc2c(Cl)nc(C)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.4 %

Procedure:
Heat a solution of 6-chloro-N4-(2-methoxyethyl)-2-methylpyrimidine-4,5-diamine (5.0 g, 0.023 mol), 2-chlorobenzaldehyde (4.8 g, 0.03 mol), 15% FeCl3 on SiO2 (20 g) in 1,4-dioxane (150 mL) to 100° C. for 16 h. Remove the silica by filtration through diatomaceous earth, and concentrate the filtrate under reduced pressure to give a residue. Dissolve the residue in dry dichloromethane (150 mL) and add DDQ (5.2 g, 0.022 mol) at 0° C., and stir the reaction mixture at room temperature for 2 h. Dilute the reaction mixture with dichloromethane, wash with 1 N sodium hydroxide solution, water, and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give a residue. Purify the residue on a silica gel column eluting with ethyl acetate:n-hexane (40:60) to give the title compound (2.9 g). ES/MS m/z 337 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[C:11]([CH3:12])=[C:10]([O:13]C)[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])[CH3:2].B(Br)(Br)Br>ClCCl>[CH2:1]([C:3]1[C:11]([CH3:12])=[C:10]([OH:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCc1c(C(=O)O)ccc(OC)c1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1c(C(=O)O)ccc(O)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
10.0 g of 2-ethyl-4-methoxy-3-methylbenzoic acid (F1) are suspended in 50 ml of dichloromethane under a nitrogen atmosphere. 29.3 ml of boron tribromide are subsequently slowly added dropwise with cooling in an ice bath. The transparent, red solution obtained is stirred at room temperature for 1 h. The mixture is subsequently carefully poured with stirring into 600 ml of ice-water. The aqueous phase is stirred for 30 min and subsequently extracted twice with 200 ml of ethyl acetate each time. The combined organic phases are washed once with 200 ml of water, dried over Na2SO4, evaporated in vacuo and purified by flash column chromatography on silica gel (solvent gradient: cyclohexane/0-100% by vol. of ethyl acetate), giving 9.37 g of the title compound as a colourless, amorphous solid having a melting point of 139° C.; MS: 180.0 (M+); TLC: Rf=0.33 (cyclohexane/methyl tert-butyl ether 3:2 parts by volume).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[NH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][CH2:8]1>O1CCCC1>[C:1]1(=[O:5])[N:7]2[C:13]3[CH:12]([CH2:17][CH2:16][CH2:15][C:14]=3[CH:9]=[CH:8]2)[CH2:11][CH2:10][C:2]1=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1ccc2c(c1)CCCCN2
Solvent: C1CCOC1
Product: O=C1CCC2CCCc3ccn(c32)C1=O
Reaction time: 4 h

Procedure:
To a solution of oxalic chloride (27.5 ml) in tetrahydrofuran (THF; 500 ml) which was subjected to refluxing with heating, was dropwise added a solution of 2,3,4,5-tetrahydro-1H-1-benzazepine (28.8 g) in THF (100 ml), which was thereafter subjected to stirring for 4 hours as such. After cooled, the solvent was distilled off and the residue was dissolved into carbon disulfide (600 ml), to which then only small portions of aluminium chloride (52.27 g) were added at room temperature with stirring and was further subjected to stirring for 4 hours. With removal of supernatant solution from the reaction mixture, ice-water was added to the residue, which was then extracted with chloroform. The organic layer was thoroughly washed with water, dried over anhydrous sodium sulfate and then the solvent thereof was distilled off.
Reaction SMILES: C([N:8]1[CH2:15][CH2:14][C:13]2([CH3:16])[CH:9]1[CH2:10][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:16][C:13]12[CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][CH:9]1[NH:8][CH2:15][CH2:14]2
Reactant: CC(C)(C)OC(=O)N1CC2N(Cc3ccccc3)CCC2(C)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2NCCC2(C)C1

Procedure:
2.6 g (10.3 mmol) of tert.-butyl 2-benzyl-5-methyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate in 50 ml of ethanol are hydrogenated on 0.5 g of palladium/active carbon (10% Pd) at 130° C. and 100 bar. The catalyst is filtered off with suction, and the liquid phase is concentrated and distilled.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[CH2:49]([O:51][C:52](=[O:61])[C:53](=[O:60])[C:54]1[N:55]=[C:56]([NH2:59])[S:57][CH:58]=1)[CH3:50].N1C=CC=CC=1>C(Cl)Cl.O>[CH2:49]([O:51][C:52](=[O:61])[C:53]([C:54]1[N:55]=[C:56]([NH:59][C:40](=[O:42])[CH:39]([C:31]2[CH:32]=[CH:33][C:34]([S:35]([CH3:38])(=[O:36])=[O:37])=[C:29]([Cl:28])[CH:30]=2)[CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[S:57][CH:58]=1)=[O:60])[CH3:50]
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Yield: 66.5 %

Procedure:
A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirred at 0° C. until it was completely dissolved and became light purple in color. The reaction mixture was then treated with 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 92, 200 mg, 0.61 mmol) and stirred at 0° C. for 20 min and then warmed to 25° C. where it was stirred for 30 min. After such time, the reaction mixture was treated with 2-(amino-thiazol-4-yl)-oxo-acetic acid ethyl ester (182 mg, 0.91 mmol) and pyridine (0.088 mL, 1.09 mmol), and the reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (10 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded {2-[2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-oxo-acetic acid ethyl ester (208 mg, 67%) as a clear colorless oil: EI-HRMS m/e calcd for C22H25ClN2O6S2 (M+) 513.0921, found 513.0919.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11](=[O:22])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Cl:30])C(=O)C1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11](=[O:22])[NH:10][N:9]=2)=[CH:4][C:3]=1[Cl:30]
Reactant: Nc1ccc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)cc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 47.4 %

Procedure:
To a solution of 1-(4-aminophenyl)-7,8-methylenedioxy-3,5-dihydro-2,3-benzodiazepin-4(4H)-one (118 mg, 0.400 mmol) in DMF (3 mL) was added NCS (51 mg, 0.38 mmol). The mixture was stirred at room temperature for 20 h, diluted with EtOAc (50 mL), washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (1:1 hexane/EtOAc) to afford the title compound as a tan solid (60 mg, 0.18 mmol, 45%), mp: 256°-258° C. 1H NMR (CDCl3) 8.50 (s, 1H), 7.54 (s, 1H), 7.32(d, J=8.3, 1H), 6.82 (s, 1H), 6.77 (d, J=8.3, 1H), 6.69 (s, 1H), 6.04 (s, 2H), 4.33 (s, 2H), 3.42 (s, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([Cl:12])=[N:10][C:9]2=[N:13][N:14]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:15]=[C:8]2[C:7]=1[NH2:25])=[O:5])C.CO.C1COCC1.CC(O)=O>[OH-].[Na+]>[NH2:25][C:7]1[C:8]2[C:9](=[N:13][N:14]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:15]=2)[N:10]=[C:11]([Cl:12])[C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(Cl)nc2nn(Cc3ccc(OC)cc3)cc2c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc3c(N)c(C(=O)O)c(Cl)nc3n2)cc1
Yield: 101.1 %

Procedure:
A solution of 4-amino-6-chloro-2-(4-methoxyphenyl)methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (800 mg) in NaOH (1N)/MeOH/THF (1:1:1, 15 mL) was stirred for 4 days. The acidity of the reaction mixture was adjusted to pH 5-6 with AcOH. The THF and MeOH were removed. The residue was dissolved in water (30 mL) then extracted with EtOAc (3×100 mL). The combined extracts were dried (NaSO4). Removal of the solvent gave the desired product (746 mg) as white solid. LC: 3.13 (Gradient 1), MH+: 333
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[C:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][N:22]2C(=O)C3=CC=CC=C3C2=O)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.NN>>[NH2:22][CH2:21][CH2:20][CH2:19][N:16]1[CH2:17][CH2:18][C:13](=[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:14][CH2:15]1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1CCC(=C(c2ccccc2)c2cccs2)CC1
Agent: NN
Solvent: O
Product: NCCCN1CCC(=C(c2ccccc2)c2cccs2)CC1
Yield: 92 %

Procedure:
The title compound was prepared in a yield of 92% in a similar manner to that described in Preparation 15' by reacting 4-[α-(2-thienyl)benzylidene]-1-(3-phthalimidopropyl) piperidine (prepared as described in Preparation 54') and hydrazine hydrate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C([Li])CCC.FC(F)(F)S(O[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]#[N:27])(=O)=O>C1COCC1.CCCCCC.[Cl-].[Zn+2].[Cl-].[Zn].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>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[N:3][CH:4]=1
Reactant: Cc1ccc(Br)nc1
Reactant: N#Cc1ccccc1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(-c2ccccc2C#N)nc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 2-bromo-5-methylpyridine (1.2 g) in THF (15 ml) at -78° C. under argon atmosphere was added 1.65M solution of butyl lithium in hexane (4.4 ml) dropwise and the reaction mixture was stirred for 10 minutes followed by addition of zinc chloride (1M ether solution, 7.2 ml) and then stirring at 0° C. for 30 minutes. The resulting zinc compound was poured into an ice-cooled, stirred mixture of 2-cyanophenyl trifluoromethanesulfonate (1.2 g) and tetrakistriphenylphosphine paladium (Pd(PPh3)4, 0.42 g) in THF (15 ml) under argon atmosphere and the mixture was stirred for 15 hours and concentrated to dryness. The residue was purified by column chromatography on silica gel to give crystals. Recrystallization from hexane afforded colorless needles (0.4 g, 29%), m.p. 80°-81° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:15]4[CH2:18][CH:17]([OH:19])[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:21])[C:6]([C:22]([O:24]CC)=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.C(O)C.[OH-].[Na+]>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:15]4[CH2:16][CH:17]([OH:19])[CH2:18]4)[C:12]=3[F:14])[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CC(O)C3)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC(O)C3)c(F)cc2c1=O
Yield: 100 %

Procedure:
A solution of 0.4 g (1.10 mmoles) of ethyl 1-cyclopropyl-6,8-difluoro-7-(3-hydroxy-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 2 ml of ethanol and 10 ml of 0.5N sodium hydroxide is left to reflux for 1.5 hours. It is then allowed to cool, diluted with water, adjusted to pH 5 and a precipitate is obtained which is filtered and washed with water. The solid is dried under vacuum yielding 0.37 g (100%) of 1-cyclopropyl-6,8-difluoro-7-(3-hydroxy-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid melting at 286°-288° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Reaction time: 3 h
Yield: 60.4 %

Procedure:
To a suspension of ethyl 5-nitro-1H-indole-2-carboxylate (0.100 g, 0.43 mmol) in 5 mL of absolute ethanol was added 5% palladium on carbon (0.045 g, 0.021 mmol). The mixture was evacuated and flushed with nitrogen, then filled with hydrogen at 50 psi. After 3 h, the reaction mixture was filtered through Celite and the filtrate was evaporated to give the title compound (0.053 g, 60%) as a light brown solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.33 (s, 1H), 7.10 (d, 1H), 6.78 (d, 1H), 6.58-6.69 (m, 2H), 4.70 (br. s., 2H), 4.25 (q, 2H), 1.27 (t, 3H). MS: m/z 205 (M+1).
Reaction SMILES: [CH:1](=[O:3])[CH3:2].[NH:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9]>>[OH:3][CH:1]([N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])[CH3:2]
Reactant: CC=O
Reactant: O=C1CCCN1
Product: CC(O)N1CCCC1=O

Procedure:
Immediately after the supply of acetaldehyde was over, the reaction mixture was analyzed by a liquid chromatography. The reaction ratio of 2-pyrrolidone was 87.1 mol % and the selectivity in forming N-(α-hydroxyethyl)pyrrolidone based on 2-pyrrolidone was 43.7 mol %.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C@H:11]([O:13][CH2:14][C:15]2([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH3:12])[C:8]2[C:4](=[CH:5][N:6](COCC[Si](C)(C)C)[N:7]=2)[CH:3]=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C@H:11]([O:13][CH2:14][C:15]3([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH3:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: C[C@@H](OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(R)-tert-Butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (850 mg, 1.375 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 30 mL) and stirred at room temperature for 4 h. The reaction was concentrated, loaded onto a strong cation exchange cartridge (4×2 g cartridges) in methanol, and flushed with several volumes of methanol which were discarded. The product was eluted with 2M ammonia in methanol and concentrated. The crude piperidine was dissolved in dichloromethane (10 mL), and treated with di-tert-butyl dicarbonate(0.48 mL, 2.062 mmol). The reaction was quenched by addition of ethylene diamine (200 mg) in dichloromethane (2 mL). The reaction was concentrated and purified by column chromatography (25%→37% ethyl acetate/n-hexane) to give 650 mg (97%) as a white foam solid. 1H-NMR (CDCl3, 500 MHz) δ 9.66 (bs, 1H), 7.90 (s, 1H), 7.57 (d, J=1.8 Hz, 1H), 7.26 (dd, J=8.9, 5.5 Hz, 2H), 7.07 (dd, J=8.9, 8.6 Hz, 2H), 6.98 (d, J=1.5 Hz, 1H), 4.49 (q, J=6.4 Hz, 1H), 3.74 (m, 2H), 3.38 (d, J=9.2 Hz, 1H), 3.25 (d, J=9.2 Hz, 1H), 3.22 (bs, 2H), 3.05 (m, 1H), 2.97 (m, 1H), 2.26 (m, 1H), 2.06 (m, 1H), 1.84 (m, 1H), 1.73 (m, 1H), 1.43 (m. 12H); 13C NMR (75 MHz, CDCl3) δ ppm 171.0, 161.5 (d, J=247 Hz), 154.8, 137.9, 137.8, 135.4, 133.7, 128.5 (d, J=7.5 Hz), 127.3, 125.9, 124.6, 124.0, 118.9, 115.5 (d, J=21 Hz), 79.4, 78.5, 78.1, 60.3, 41.0, 39.8 (br), 32.3, 32.0, 28.3, 22.0, 20.9, 14.1. Mass spec.: 488.17 (MH)+.