Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH:11]=O)[CH2:8][C:9]#[N:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([CH:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH2:22][CH3:23])=[O:20]>C(Cl)(Cl)Cl>[C:9]([CH2:8][C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:11]=[CH:24][C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:10]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#CCC(C=O)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C=CC(CC#N)(c1ccccc1)c1ccccc1
Yield: 63.5 %

Procedure:
3,3-Diphenyl-3-formylpropionitrile (0.85 g) and (carbethoxymethylene)triphenylphosphorane (1.46 g) were heated in chloroform (20 ml) on reflux for 7 hours. The reaction mixture was then concentrated to dryness and the group was purified by silica gel column chromatography to provide the title compound (0.7 g) as colorless oil.
Reaction SMILES: CSC.[Cl:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][CH:29]=1)[CH2:8][CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH:19]=[CH2:20])[CH:17]=2)[CH2:12][CH2:11][CH:10]1[NH:21][C:22](=[O:26])[O:23][CH2:24][CH3:25].[OH:30]O.[OH-].[Na+]>C1COCC1.O>[CH2:24]([O:23][C:22](=[O:26])[NH:21][CH:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][C:16]([CH2:19][CH2:20][OH:30])=[CH:15][CH:14]=2)[CH:9]1[CH2:8][C:7]1[CH:27]=[CH:28][CH:29]=[C:5]([Cl:4])[CH:6]=1)[CH3:25]
Reactant: C=Cc1ccc2c(c1)C(Cc1cccc(Cl)c1)C(NC(=O)OCC)CC2
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CSC
Solvent: O
Product: CCOC(=O)NC1CCc2ccc(CCO)cc2C1Cc1cccc(Cl)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 104.6 %

Procedure:
BH3.DMS (1 M in THF, 0.838 ml, 0.838 mmol) was added a solution of ethyl 1-(3-chlorobenzyl)-7-vinyl-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (1.55 g, 4.19 mmol) in 20 ml dry THF. The reaction was stirred at 60° C. for 1 h and cooled to room temperature. Some water was added to destroy the excess of borane complex and the resulting mixture refluxed for 1 h with 30% H2O2 (8.56 ml, 84 mmol) and 2N NaOH (9.74 ml, 19.49 mmol). The reaction mixture was extracted with CH2Cl2, washed with water and brine, dried, filtered and the solvent evaporated to obtain a pale brown solid (1.7 g), which was purified by chromatography to afford 854 mg of product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]=1)=[O:5]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1Cl

Procedure:
The reaction is carried out as in Example 10 a) by reacting benzene with 2-chloro-5-nitrobenzoyl chloride in the presence of aluminium chloride.
Reaction SMILES: CB1OB(C)OB(C)O1.ClCCl.[C:13](=O)([O-])[O-].[K+].[K+].COC1C=C(OC)C=CC=1C[N:24]([C:52]1[S:56][N:55]=[CH:54][N:53]=1)[S:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][C:36]=2[C:45]2[CH:50]=[CH:49][N:48]=[N:47][CH:46]=2)=[C:30](I)[CH:29]=1)(=[O:27])=[O:26].CC1CCCO1>>[CH3:13][C:30]1[CH:29]=[C:28]([S:25]([NH:24][C:52]2[S:56][N:55]=[CH:54][N:53]=2)(=[O:27])=[O:26])[CH:33]=[CH:32][C:31]=1[O:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:37][C:36]=1[C:45]1[CH:50]=[CH:49][N:48]=[N:47][CH:46]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3-c3ccnnc3)c(I)c2)c(OC)c1
Reactant: O=C([O-])[O-]
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: CC1CCCO1
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Oc1ccc(C(F)(F)F)cc1-c1ccnnc1
Temperature: 80 °C

Procedure:
A Reactivial™ containing trimethylboroxine (798 mg, 6.36 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium(II)dichloride, complex with dichloromethane (26 mg, 0.03 mmol), potassium carbonate (88 mg, 0.64 mmol), N-(2,4-dimethoxybenzyl)-3-iodo-4-[2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 38, 240 mg, 0.32 mmol) and 2-methyltetrahydrofuran (5 mL) was sparged with nitrogen and heated to 80° C. for 24 hours. The reaction mixture was cooled and purified directly by silica gel column chromatography (0% to 20% methanol in ethyl acetate gradient elution) followed by reverse phase HPLC to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C1COCC1>[CH2:14]([N:3]1[C:2]([CH3:1])=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:5]=[CH:4]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1[nH]cnc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ncn(Cc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.7 %

Procedure:
Part A: To a magnetically stirred suspension of ethyl 4-methyl-1H-imidazole-5-carboxylate (15.42 gram, 0.100 mol) in anhydrous THF was slowly added sodium hydride (NaH) (4.88 g of a 60% suspension, 0.120 mol) and the resulting mixture was stirred at room temperature for 30 minutes. Benzyl bromide (13.8 ml, 0.120 mol) was slowly added and the resulting mixture was reacted for 16 hours. Water was added to the mixture. The organic layer was separated from the water layer. The water layer was extracted 3 times with ethylacetate. The organic layer was dried over MgSO4, filtered and thoroughly concentrated to give an oil. The resulting residue was purified (in order to separate the two formed regioisomers) by flash chromatography (diethyl ether/ethyl acetate gradient) to give ethyl N-benzyl-5-methyl-1H-imidazole-4-carboxylate (11.4 gram, 47% yield). 1H-NMR (400 MHz, CDCl3): 1.40 (t, J=7, 3H), 2.45 (s, 3H), 4.37 (q, J=7, 2H), 5.10 (s, 2H), 7.03-7.08 (m, 2H), 7.28-7.38 (m, 3H), 7.48 (s, 1H).
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Cl:32].[CH2:41]([C:43]1[S:44][C:45]([CH:49]=O)=[C:46]([CH3:48])[N:47]=1)[CH3:42]>ClCCl>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Cl:32])=[CH:49]/[C:45]1[S:44][C:43]([CH2:41][CH3:42])=[N:47][C:46]=1[CH3:48]
Reactant: CCc1nc(C)c(C=O)s1
Reactant: COC(=O)C(NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Solvent: ClCCl
Product: CCc1nc(C)c(/C=C(\NC(=O)c2ccc(C(=O)NCc3cccc(O)c3)cc2Cl)C(=O)OC)s1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
1,1,3,3-Tetramethylguanidine (107 mg, 0.9 mmol) was added to a solution of rac.-N-[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 141; 300 mg, 0.6 mmol) in dichloromethane (10 mL) at ˜5° C. The solution was stirred at ˜5° C. for 30 min and then 2-ethyl-4-methylthiazole-5-carboxaldehyde (Example 60; 192 mg, 1.2 mmol) was added. The solution was stirred overnight at room temperature, then silica gel was added and the solvent was evaporated. The residue was applied to a column of silica gel and unreacted 2-ethyl-4-methylthiazole-5-carboxaldehyde was eluted with 50% ethyl acetate/hexanes. Evaporation of the appropriate fractions eluted with 5% methanol/dichloromethane gave (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(2-ethyl-4-methylthiazole-5-yl)propenoic acid methyl ester (110 mg, 35% yield) as a colorless solid, mp>200° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([OH:12])=O.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][C:21]2=[O:26])=[CH:16][CH:15]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CCN(CC)CC>C(Cl)Cl.O>[O:26]=[C:21]1[CH2:22][O:23][CH2:24][CH2:25][N:20]1[C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:10]([C:2]2[NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[O:12])=[CH:19][CH:18]=1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Reactant: O=C(O)c1nc2ccccc2[nH]1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 100 mg 1H-Benzoimidazole-2-carboxylic acid and 118 mg 4-(4-Amino-phenyl)-morpholin-3-one in 2 mL DCM, 157 mg BOP-Cl and 0.3 mL NEt3 were added and the mixture was stirred for 16 h at RT. Then, after the reaction mixture was diluted with 20 mL water, the precipitated product was collected by filtration. The crude product was subjected to the next reaction step without further purification. Yield: 122 mg.
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)([CH2:9][F:10])[CH2:5][CH2:4]1.Cl>C(OCC)(=O)C>[CH:20]1([O:19][C:13]2[CH:12]=[C:11]([C:6]3([CH2:9][F:10])[CH2:5][CH2:4][C:3](=[O:2])[CH2:8][CH2:7]3)[CH:16]=[CH:15][C:14]=2[O:17][CH3:18])[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: COc1ccc(C2(CF)CCC(OC)(OC)CC2)cc1OC1CCCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(C2(CF)CCC(=O)CC2)cc1OC1CCCC1
Yield: 24.6 %

Procedure:
4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-(fluoromethyl)cyclohexan-1-one dimethyl ketal (0.35 g, 0.95 mmol) in ethyl acetate (2 mL) was treated with 1N hydrochloric acid (2 mL) and the mixture was stirred vigorously and gently heated for 10 min. The mixture was extracted with ethyl acetate, the organic extract was washed with 5% aqueous sodium carbonate, dried (magnesium sulfate) and the solvent was removed in vacuo. Purification by flash chromatography, eluting with 25% ethyl acetate/hexanes, followed by trituration with ether/hexanes, provided a white solid (0.075 g, 24%): m.p. 72°-74 C. Analysis Calc. for C19H25FO3 : C 71.23, H 7.87; found: C 71.22, H 7.70.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1>CCOCC>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2cc[nH]c2c1
Solvent: CCOCC
Product: Cc1ccc2c(c1)NCC2
Temperature: 22 °C
Reaction time: 72 h
Yield: 90 %

Procedure:
6-Methylindole (2.785 g, 21.2 mmol) in dry Et2O (30 mL) was chilled to 0° C. and a solution of ZnBH4 in Et2O (~1.5 eq.; 215 mL of 0.15M) was added. The mixture was stirred 3 days at 22° C. in darkness and then quenched by addition of 1M aqueous HCl (until no further H2(g) evolved on mixing) followed by basification to pH >10 with 2N NaOH. The ether phase was separated and washed with brine, tided over MgSO4(s), filtered, and concentrated in vacuo to afford >90% pure 6-methyl-indoline as a syrup (2.82 g; GC/MS: RT=0.63 min., M+ =133). This material can be purified by chromatography on silica (25% EtOAc/hexanes) or vacuum distillation but was typically used without further purification. The following indolines were prepared in an analogous manner from the appropriately substituted indoles:
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:25]=[CH:24][C:6]2[N:7]([C@@H:10]3[O:22][C@H:21]([CH3:23])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]3[O:12][C:13](=[O:15])[CH3:14])[CH:8]=[N:9][C:5]=2[CH:4]=1.[Br:28]N1C(=O)CCC1=O.C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C1COCC1>[Br:28][C:8]1[N:7]([C@@H:10]2[O:22][C@H:21]([CH3:23])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]2[O:12][C:13](=[O:15])[CH3:14])[C:6]2[CH:24]=[CH:25][C:3]([C:2]([F:1])([F:26])[F:27])=[CH:4][C:5]=2[N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1cnc2cc(C(F)(F)F)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Br)nc2cc(C(F)(F)F)ccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 115.7 %

Procedure:
To a refluxing solution of 0.2 g (0.52 mmol) of 5-Trifluoromethyl-1-(2,3-di-O-Acetyl-5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole in 10 mL of dry THF was added 0.2 g (1.1 mmol) of N-bromosuccinimide (NBS). The reaction mixture was further refluxed for 10 min. Additional 0.1 g of NBS was added. After 5 min, the mixture was poured into an ice-cooled solution of 20 mL CHCl3 and 20 mL sat. NaHCO3. The CHCl3 solution was separated and was further washed with sat. NaHCO3. After drying (MgSO4) and solvent removal, 0.28 g of the title compound was obtained as a semi-solid which was used without further purification in the following reaction.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[O:5]=[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[C:20]1[CH:27]=[N:26][CH:25]=[CH:24][C:21]=1[CH:22]=O.CO.C([O-])(O)=O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[CH:1]1([NH:4][CH2:22][C:21]2[CH:24]=[CH:25][N:26]=[CH:27][C:20]=2[N:7]2[CH2:8][CH2:9][C:10]3[C:15](=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)[C:6]2=[O:5])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: O=Cc1ccncc1N1CCc2ccc(C(F)(F)F)cc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C1c2cc(C(F)(F)F)ccc2CCN1c1cnccc1CNC1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 22.2 %

Procedure:
Cyclopropanamine (25.8 μL, 0.3737 mmol) was added to a stirred solution of 3-(1-oxo-7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)isonicotinaldehyde (I-53c: 100 mg, 0.3114 mmol) in acetic acid (5 mL) and resulting reaction mixture was stirred for 4 hours at room temperature. The reaction mass was cooled to 0° C. and added NaBH(OCH3)3 (99 mg, 0.4674 mmol). The resulting reaction mass was stirred for 12 hours at room temperature. The reaction was monitored by TLC (10% methanol in CHCl3). The reaction mass was concentrated under reduced pressure, the crude residue obtained was diluted with ice, basified using saturated NaHCO3 solution to pH 7 and extracted using CHCl3. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 25 mg of the product (22% yield).
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:13])[C@H:6]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[NH2:7]>O.[OH-].[Na+]>[NH2:7][C@H:6]([C:5]([OH:13])=[O:4])[CH2:8][CH2:9][CH2:10][CH2:11][NH2:12]
Reactant: COC(=O)[C@@H](N)CCCCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NCCCC[C@H](N)C(=O)O
Temperature: 110 °C

Procedure:
2.33 Grams (10 mmol) of L-lysine methyl ester dihydrochloride was dissolved in 5.0 ml of water to prepare a treating agent solution. A cotton cloth (150 mm×170 mm, 4.8 g) was in advance treated to be immersed in 25% aqueous sodium hydroxide solution for an hour at room temperature, washed with water and dried. This treated cotton cloth was allowed to uniformly absorb the total amount of the above treating agent solution and then air-dried for 3 hours at room temperature. The dried cloth was heat-treated for 20 minutes at 140° C. in a batch type hot air oven (“IPHH-2000”, an inert oven manufactured by Tabaiesbeck Co., Ltd.) and washed with water. It was further washed with 5% aqueous sodium bicarbonate solution and rinsed three times with water and subsequently was washed with 10% aqueous citric acid solution and rinsed three times with water, and finally washed with household washing detergent solution, rinsed with water and air-dried. The identification of L-lysine cellulose ester was conducted by the following method. A part of the cloth was cut and a solution of ninhydrin in butanol was sprayed on it. Thereafter, it was heated for 10 minutes in an oven of 110° C. to cause coloring thereby the presence of the amino acid was confirmed. Also, a part of the cloth was cut and subjected to an infrared spectroscopic analysis whereby there was confirmed a peak based on ester bond at 1720–1740 cm1. As a result of determination for the amount of the L-lysine bonded, it was 0.10 mmol based on 1 g of the cloth. The degree of esterfication was 0.016.
Reaction SMILES: [OH:1][C:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH2:24][C:25]([CH3:27])=[CH2:26])[CH2:3][CH2:4][N:5]([C:10]([C:13]1[N:14]=[N:15][N:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=1)([CH3:12])[CH3:11])[C:6](=O)[O:7]C.[H-].[Na+]>C1COCC1.Cl.CO>[CH3:27][C:25](=[CH2:26])[CH2:24][C:2]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:1][C:6](=[O:7])[N:5]([C:10]([C:13]2[N:14]=[N:15][N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)([CH3:11])[CH3:12])[CH2:4][CH2:3]1
Reactant: C=C(C)CC(O)(CCN(C(=O)OC)C(C)(C)c1cn(-c2ccccc2)nn1)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(C)CC1(c2ccccc2)CCN(C(C)(C)c2cn(-c3ccccc3)nn2)C(=O)O1
Yield: 67.4 %

Procedure:
To a stirred solution of methyl 3-hydroxy-5-methyl-3-phenylhex-5-enyl(2-(1-phenyl-1H-1,2,3-triazol-4-yl)propan-2-yl)carbamate (14 mg, 0.031 mmol) in dry THF (1 mL) was added 60% NaH in oil (10 mg, 0.25 mmol). The mixture was heated at 50 C in an oil bath for 1.5 h, cooled, diluted with 5% aq HCl (0.5 mL) and MeOH (0.5 mL) and purified by prep HPLC to afford the title compound (8.7 mg, 67%) as an oil. LC-MS Method 1 tR=1.90 min, m/z=417; 1H NMR (CDCl3) 1.58 (s, 3H), 1.76 (s, 6H), 2.25 (m, 1H), 2.36 (m, 1H), 2.56 (dd, 2H), 3.03 (m, 1H), 3.52 (m, 1H), 4.58 (s, 1H), 4.81 (s, 1H), 7.25-7.80 (11H).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]([C:16]1[O:20][N:19]=[C:18]([CH3:21])[CH:17]=1)=[C:8]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)CO.I([O-])(=O)(=O)=O.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:21][C:18]1[CH:17]=[C:16]([C:9]2[C:10](=[O:15])[NH:11][C:12]3[C:7]([C:8]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:6][C:5]([CH:2]=[O:1])=[CH:14][CH:13]=3)[O:20][N:19]=1
Reactant: Cc1cc(-c2c(-c3ccccc3)c3cc(C(O)CO)ccc3[nH]c2=O)on1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClCCl
Product: Cc1cc(-c2c(-c3ccccc3)c3cc(C=O)ccc3[nH]c2=O)on1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
A mixture of 6-(1,2-dihydroxy-ethyl)-3-(3-methyl-isoxazol-5-yl)-4-phenyl-1H-quinolin-2-one (40 mg, 0.11 mmol), sodium periodate (94 mg, 0.44 mmol), saturated aqueous sodium bicarbonate (0.2 mL), and DCM (5 mL) was stirred for 4 h at room temperature, then filtered and concentrated. The residue was purified by flash chromatography on silica gel to provide 3-(3-methyl-isoxazol-5-yl)-2-oxo-4-phenyl-1,2-dihydroquinoline-6-carboxaldehyde (a) as a white solid (31 mg, 85%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH2:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[C:12]1([CH:18]([C:24](OCC)=[O:25])[C:19](OCC)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CCCC)CCCC)CCC.[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]1[C:19]([OH:20])=[C:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:24]([OH:25])=[N:11][C:6]=21
Reactant: Nc1n[nH]c2cc(Br)ccc12
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Product: Oc1nc2c3ccc(Br)cc3nn2c(O)c1-c1ccccc1
Yield: 97.4 %

Procedure:
9.9 g (46.7 mmol) 6-Bromo-1H-indazol-3-ylamine, 11 g (46.7 mmol) diethyl phenylmalonate and 19.8 mL (83.1 mmol) tributyl amine were heated for 15 h at 180° C. The reaction mixture was treated with 2M sodium hydroxide and water and extracted three times with tert-butyl methyl ether. The organic phase was discarded and the aqueous phase was acidified with conc. hydrochloric acid. The precipitate was collected by filtration and washed with water to obtain the desired product (16.2 g) which was however contaminated and which was used in the next step without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH3:8])[C:3]([OH:5])=[O:4].[CH2:9]([C:15](=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:16]=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[OH:17][CH:16]([C:15](=[CH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:2]([CH3:1])([CH2:6][CH2:7][CH3:8])[C:3]([OH:5])=[O:4]
Reactant: CCCCCCC(C=O)=Cc1ccccc1
Reactant: CCCC(C)C(=O)O
Product: CCCCCCC(=Cc1ccccc1)C(O)C(C)(CCC)C(=O)O

Procedure:
The reaction of 5.8 g (0.05 mole) 2-methylvaleric acid with 10.8 (0.05 mole) of α-hexylcinnamaldehyde was conducted in the manner described in Example III, Method B. The product was isolated as a viscous yellow oil. NMR spectra confirmed the title structure.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19]([C:24]2[C:25](=[O:34])[NH:26][C:27]4[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:18]3)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[O:34]=[C:25]1[C:24]([C:19]2[NH:20][C:21]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:14][CH2:13][CH2:12][N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[CH:23][CH:22]=3)=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26]1
Reactant: CCOC(=O)C1CCN(CCOc2ccc3[nH]c(-c4cc5ccccc5[nH]c4=O)cc3c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCN(CCOc2ccc3[nH]c(-c4cc5ccccc5[nH]c4=O)cc3c2)CC1
Temperature: 50 °C

Procedure:
1-(2-{[2-(2-oxo-1,2-dihydro-3-quinolinyl)-1H-indol-5-yl]oxy}ethyl)-4-piperidinecarboxylic acid ethyl ester (4-1, 138 mg, 0.30 mmol, 1 equiv) was dissolved in MeOH (20 mL). 1 N NaOH (6 mL, 20 equiv) was added and the solution warmed at 50° C. for 5 h. The reaction was concentrated, and the residue was suspended in 4 mL of water. This suspension was neutralized with 1 N HCl to provide 1-(2-{[2-(2-oxo-1,2-dihydro-3-quinolinyl)-1H-indol-5-yl]oxy}ethyl)-4-piperidinecarboxylic acid (4-2) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.45 (s, 1H), 7.74 (d, 1H, J=8 Hz), 7.53 (t, 1H, J=8 Hz), 7.38 (m, 2H), 7.28 (t, 1H, J=8 Hz), 7.19 (s, 1H), 7.16 (s, 1H), 6.88 (dd, 1H, J=9, 2 Hz), 4.34 (t, 2H, J=5 Hz), 3.53 (m, 2H), 3.47 (m, 2H), 3.07 (m, 2 H), 2.42 (m, 1H), 2.11 (m, 2H), 1.95 (m, 2H).
Reaction SMILES: [C:1]([C:3]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:20])[CH:18]=2)[N:13](C(OC(C)(C)C)=O)[CH:12]=1)=[CH:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)#[N:2].[CH2:28](I)[CH3:29].C(=O)([O-])[O-].[K+].[K+].C[O-].[Na+]>CS(C)=O.C(OCC)C>[CH2:28]([O:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2/[C:3](=[CH:4]/[C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)/[C:1]#[N:2])[CH3:29]
Reactant: CC(C)(C)OC(=O)n1cc(C(C#N)=Cc2cccnc2)c2cc(O)ccc21
Reactant: CCI
Agent: C[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCOc1ccc2[nH]cc(/C(C#N)=C/c3cccnc3)c2c1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 3-(1-cyano-2-(pyridin-3-yl)vinyl)-5-hydroxy-1H-indole-1-carboxylate (110 mg, 0.30 mmol, 1.0 eq.) and ethyl iodide (32 μL, 0.40 mmol, 1.3 eq.) in DMSO (8 mL) was added potassium carbonate (100 mg, 0.73 mmol, 2.4 eq.). The reaction apparatus was protected from light and the mixture was stirred at room temperature for 24 hours before sodium methanolate (41 mg, 0.75 mmol, 2.5 eq.) was added. The reaction was pursued at room temperature for 1 hour, and then quenched with a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, and then dried over MgSO4. The solvent was removed under reduced pressure, and the residue purified by silica gel flash-column chromatography (eluent: heptane/EtOAc, 60:40 to 40:60) to afford, after trituration with diethyl ether, the compound (22) as a yellow powder (60 mg, 69%). mp: 196° C.; IR νmax (cm-1): 2216 (νCN); 1H NMR (DMSO, 300 MHz): δ (ppm): 1.36 (3H, t, J9′-8′=7.0 Hz, 3H9′), 4.10 (2H, q, J8′-9′=7.0 Hz, 2H8′), 6.90 (1H, dd, J6′-7′=8.9 Hz, J6′-4′=2.1 Hz, H6′), 7.40 (1H, d, J7′-6′=8.9 Hz, H7′), 7.48 (1H, d, J4′-6′=2.1 Hz, H4′), 7.54 (1H, dd, J5″-4″=7.9 Hz, J5″-6″=4.7 Hz, H5″), 7.74 (1H, s, H3), 7.78 (1H, s, H2′), 8.32 (1H, d, J4″-5″=8.1 Hz, H4″), 8.58 (1H, dd, J6″-5″=4.8 Hz, J6″-4″=1.6 Hz, H6″), 8.98 (1H, d, J2″-4″=2.3 Hz, H2″), 11.65 (1H, s, indolic H); 13C NMR (DMSO, 75.5 MHz): δ (ppm): 15.3 (C9′), 64.1 (C8′), 103.3 (C4′), 108.7 (C2), 110.6 (C3′), 113.3 (C6′), 113.6 (C7′), 118.6 (C1), 124.1 (C5″), 124.5 (C3a′), 128.1 (C2′), 131.4 (C3″), 132.7 (C3 and C7a′), 135.1 (C4″), 150.0 (C6″), 150.4 (C2″), 154.2 (C5′); ESI-MS: m/z 290.1 ([M+H]+), 312.1 ([M+Na]+); HRESI-MS: m/z 290.1293 (calcd for C18H16N3O, 290.1293).