Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]1([N:19]=[C:20]=NC2CCCCC2)CCCCC1.O=C1C2C=CC=CC=2C(=O)N1CCCS(OCC(C)(C)[C@@H](OCC1C=CC=CC=1)C(O)=O)(=O)=O.CNC>ClCCl.O1CCCC1>[CH3:13][N:19]([CH3:20])[C:10](=[O:12])[CH2:9][O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)COCc1ccccc1
Agent: CC(C)(COS(=O)(=O)CCCN1C(=O)c2ccccc2C1=O)[C@@H](OCc1ccccc1)C(=O)O
Agent: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
Adapting procedures or variations thereof according to Benington et al., J. Org. Chem. 1961, 26, 194-197; and Griffiths et al., Tetrahedron, 1997, 53(52), 17815-17822, a 250 mL round-bottomed flask equipped with a magnetic stirring bar and rubber septum was charged with 1.22 mL (1.41 g, 8.51 mmol) of 2-(phenylmethoxy)acetic acid. The acid was dissolved in 30 mL of anhydrous dichloromethane (DCM). To the solution was added 1.86 g (9.0 mmol) of dicyclohexylcarbodiimide (DCC) and the reaction mixture was stirred for two hours at room temperature. Twenty (20) mL (40 mmol) of a two molar (2 M) solution of dimethyl amine (Me2NH) in tetrahydrofuran was added and the mixture stirred overnight at room temperature. The precipitated dicyclohexyl urea (DCU) was filtered off and the solvents removed under reduced pressure using a rotary evaporator. The residue was diluted with ethyl acetate (EtOAc) and the solution filtered again to remove residual DCU. The solution was washed successively with one molar (1.0 M) hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate (NaHCO3), brine, dried over anhydrous magnesium sulfate (MgSO4), filtered, and the solvent removed under reduced pressure using a rotary evaporator to yield a brown solid. Final purification by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) as eluent (EtOAc/Hxn=1:9) provided 1.08 g (65% yield) of the title compound (36a). Rf=0.30 (EtOAc/Hxn=1:9). 1H NMR (400 MHz, CDCl3): δ=2.97 (s, 3H), 2.99 (s, 3H), 4.18 (s, 2H), 4.62 (s, 2H), 7.28-7.37 (m, 5H) ppm. MS (ESI) m/z: 194.1 (M+H)+, 216.1 (M+Na)+. The analytical data was consistent with the proposed structure and the data in the literature.
Reaction SMILES: Cl[C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[N:7]([NH:11]C(=O)OCC)[CH:8]=[CH:9][CH:10]=1)=[O:5].[OH-].[K+]>C(O)C.O>[Cl:21][C:19]1[CH:20]=[CH:2][C:3]2[C:4](=[O:5])[C:6]3[N:7]([CH:8]=[CH:9][CH:10]=3)[NH:11][C:17]=2[CH:18]=1
Reactant: CCOC(=O)Nn1cccc1C(=O)c1ccc(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=c1c2ccc(Cl)cc2[nH]n2cccc12
Yield: 99.4 %

Procedure:
A solution of [2-(2,4-dichlorobenzoyl)-1H--pyrrol-1-yl]carbamic acid, ethyl ester (102.4 g) in 500 ml of ethanol was treated with a solution of potassium hydroxide (84 g) in 200 ml of water and then the mixture was stirred under reflux for 1 hour. The ethanol was evaporated and the aqueous layer was washed with 3×500 ml of ether. The aqueous phase was then adjusted to pH 5 with 6N HCl and the product collected by filtration. Oven drying yielded 68 g of a yellow green powder, mp >300° C.
Reaction SMILES: [CH2:1]1[CH2:10][N:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=O)[CH2:8][C:7]2[CH:6]=[N:5][C:4]3[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=3[C:2]1=2.C(N(CC)CC)C.CCCP(=O)=O.[F:37][C:38]([F:47])([F:46])[C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42]>CN(C1C=CN=CC=1)C.ClCCCl>[CH2:1]1[CH2:10][N:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([NH:42][C:41]2[CH:43]=[CH:44][CH:45]=[C:39]([C:38]([F:37])([F:46])[F:47])[CH:40]=2)=[O:16])[CH2:8][C:7]2[CH:6]=[N:5][C:4]3[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=3[C:2]1=2
Reactant: O=C(O)c1cccc(N2CCc3c(cnc4ccccc34)C2)c1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc(N2CCc3c(cnc4ccccc34)C2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
To a mixture of 3-(1,4-dihydrobenzo[c]-2,7-naphthyridin-3(2H)-yl)benzoic acid (0.20 mmol, 61 mg), triethylamine (0.40 mmol, 0.056 mL), and catalytic DMAP in 2.0 mL 1,2-dichloroethane at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.24 mmol, 0.143 mL). After 10 min at rt, 3-(trifluoromethyl)aniline (0.30 mmol, 0.037 mL) was added and the reaction stirred at rt for 24 hours. The reaction was quenched into dilute aqueous Na2CO3 solution, extracted into EtOAc, the EtOAc layer washed with H2O, dilute aqueous Na2CO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was recrystallized from EtOAc/hexane to give the title compound as a light yellow solid (59 mg, 66%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[F:21][C:22]([F:38])([F:37])[CH2:23][NH:24][C:25](=O)[O:26]C1C=CC([N+]([O-])=O)=CC=1>CC#N>[F:21][C:22]([F:38])([F:37])[CH2:23][NH:24][C:25]([N:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:9]1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=1)=[O:26]
Reactant: O=C(NCC(F)(F)F)Oc1ccc([N+](=O)[O-])cc1
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Solvent: CC#N
Product: O=C(NCC(F)(F)F)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (150 mg, 541 μmol, Example 87, Step 3) in MeCN (2 mL) was added 4-nitrophenyl 2,2,2-trifluoroethylcarbamate (286 mg, 1082 μmol). The resulting mixture was then subjected to a microwave irradiation at 100° C. for 15 min. Then, the solvent was removed and the residue was dissolved in a solution of DMSO and MeOH (1:1, 2 mL). The solution mixture was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the desired product, which was then dissolved in MeOH (2.0 mL). The solution was then washed through PL-HCO3 MP-resin and the resin was then washed with MeOH (2×2 mL). The combined washings were concentrated and dried under vacuum to give the title compound as a light yellow solid. MS (ESI, positive ion) m/z: 403 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:7]=[C:6]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[N:5]=1)([CH3:3])=[CH2:2].[N+](=[CH2:27])=[N-]>C(OCC)C.C(O)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:2][C:1]1([C:4]2[CH:9]=[C:8]([S:10]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)(=[O:11])=[O:12])[CH:7]=[C:6]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[N:5]=2)[CH2:27][CH2:3]1
Reactant: C=[N+]=[N-]
Reactant: C=C(C)c1cc(S(=O)(=O)c2ccc(N)cc2)cc(N2CCCC2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC1(c2cc(S(=O)(=O)c3ccc(N)cc3)cc(N3CCCC3)n2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
0.164 g (0.00048 Mol) 4-(2-Isopropenyl-6-pyrrolidin-1-yl-pyridine-4-sulfonyl)-phenylamine were dissolved in ethyl ether (100 ml) and cooled to 0° C. A solution of diazomethane in ethyl ether (30 ml) was carefully added. Upon addition of a catalytic amount of Pd(OAc)2 gas evolution started. The reaction mixture was allowed to warm to ambient temperature and stirred for 30 min. After addition of a few drops of acetic acid the solvent was evaporated and the residue chromatographed on SiO2 with ethyl acetate hexane 1:2. It was obtained 0.136 g (71%) of 4-[2-(1-Methyl-cyclopropyl)-6-pyrrolidin-1-yl-pyridine-4-sulfonyl]-phenylamine as pale yellow cristals; mp.: 235-236° C. (dec.).
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9](=O)[CH2:10][CH2:11][CH:12]([NH:20][C:21](=[O:47])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[NH2:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH2:56][C:57]([NH:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][C:67]([OH:69])=[O:68])=[O:58].CCN(C(C)C)C(C)C>C(O)C>[C:43]([O:42][C:40](=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:21](=[O:47])[NH:20][C@H:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:10][C:9](=[O:8])[NH:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH2:56][C:57](=[O:58])[NH:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][C:67]([OH:69])=[O:68])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NC(CCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C
Reactant: NCCOCCOCC(=O)NCCOCCOCC(=O)O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)NCCOCCOCC(=O)NCCOCCOCC(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 2-(19-tert-Butoxycarbonylnonadecanoylamino)pentanedioic acid 1-tert-butyl ester 5-(2,5-dioxopyrrolidin-1-yl) ester (2.50 g) and [2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetic acid (alternative name: H-OEG-OEG-OH)(1.47 g) in ethanol (40 ml) was added DIPEA (1.26 ml). The mixture was stirred at room temperature overnight and then concentrated in vacuo. To the residue was added aqueous 0.1 N HCl (150 ml) and ethyl acetate (200 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layers were washed with water and brine, dried (magnesium sulphate) and concentrated in vacuo to give an oil, which crystallised on standing. Yield 96% (3.1 g). LCMS: Theoretical mass: 874.2. Found: 874.49.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:22])[CH:7]([CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:8]([O:10]CC)=[O:9])[CH3:4]>C(O)C>[CH2:3]([O:5][C:6](=[O:22])[CH:7]([CH2:13][CH2:14][CH2:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[C:8]([OH:10])=[O:9])[CH3:4]
Reactant: CCOC(=O)C(CCCC1CCCCC1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(CCCC1CCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 13.5 g of potassium hydroxide in 160 ml of ethanol is added dropwise in the course of one hour and while stirring to 68 g of (3-cyclohexylpropyl)-malonic acid diethyl ester (prepared analogously to Example 4d), dissolved in 160 ml of ethanol. After stirring for 24 hours at room temperature, the mixture is concentrated considerably in vacuo and the residue is dissolved in 400 ml of water and extracted with 300 ml of diethyl ether. 40 ml of half-concentrated hydrochloric acid are added to the aqueous phase, while cooling with ice, and the mixture is extracted with 3 times 300 ml of diethyl ether. The combined organic phases are dried over sodium sulphate and concentrated. This gives 51 g of (3-cyclohexylpropyl)-malonic acid ethyl ester in the form of a viscous, yellowish oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:34])[CH2:15][CH:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[C:23]=1[O:32][CH3:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:4])([CH3:3])[CH3:2]>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:34])[CH2:15][CH:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[C:23]=1[O:32][CH3:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(CO)ccc1C(C)(C)C)c1ccc(OC)c(OC)c1OC
Solvent: ClC(Cl)Cl
Product: CCCCCC(CC(=O)Nc1cc(C=O)ccc1C(C)(C)C)c1ccc(OC)c(OC)c1OC
Reaction time: 1.5 h
Yield: 86.9 %

Procedure:
31.0 g of mangenese dioxide were added to a solution of 3.10 g (6.57 mmol) of N-[2-t-butyl-5-(hydroxymethyl)phenyl]-3-(2,3,4-trimethoxyphenyl)octanamide (prepared as described in Preparation 68A) in 60 ml of chloroform, and the resulting mixture was stirred for 1.5 hours. At the end of this time, the reaction mixture was filtered using a Celite (trade mark) filter aid, and the manganese dioxide used was thoroughly washed with methylene chloride. The filtrate and the washings were combined and concentrated by evaporation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 2.68 g (yield 87%) of the title compound as a foam-like substance.
Reaction SMILES: [H-].[Na+].[CH:3]([OH:6])([CH3:5])[CH3:4].Cl[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=1>C1COCC1>[Cl:14][C:13]1[C:8]([O:6][CH:3]([CH3:5])[CH3:4])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)O
Reactant: Clc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Oc1ncccc1Cl
Temperature: 5 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a 3-necked flask equipped with a dropping funnel, thermometer and a condenser was added sodium hydride (64.10 g; 1.07 mol) followed by THF (1.65 L). The suspension was cooled to 5° C. and iso-propanol (128 mL; 1.07 mol) was added dropwise over 50 minutes. Upon complete addition the ice bath was removed and the mixture was brought to room temperature and was left to stir for 1 hour. Then 2,3-dichloropyridine (154.6 g; 1.11 mol) was added and the reaction mixture brought to a gentle reflux and left to stir for 18 hours. The reaction mixture was cooled to 5-10° C. and was carefully quenched with brine:water mixture (50:50; 100 mL) followed by water (300 mL). The aqueous layer was extracted with EtOAc (3×600 mL), the organic layers combined and washed with brine, dried (MgSO4), filtered and evaporated to give the title compound as a dark red oil (164.1 g; 89%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH:15]=[CH:14][O:13]1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:1]([O:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH:15]=[CH:14][O:13]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CCC=CO1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: O=C(OCC1CCC=CO1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
9.77 g of benzoyl chloride were slowly added dropwise to a solution of 7.20 g of 2-hydroxymethyl-3,4-dihydro-2H-pyran in 14 ml of dry pyridine, whilst cooling the solution on an ice-water bath. When the addition was complete, the mixture was stirred at room temperature for 2 hours and then poured into an aqueous solution of sodium bicarbonate. The mixture was extracted with diethyl ether and the ethereal extract was washed with aqueous sodium chloride and dried over anhydrous sodium sulphate. The solvent was then evaporated off under reduced pressure and the residue was purified by distillation under reduced pressure, to give the title compound boiling at 112°-113° C./10 mmHG.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:9]([N:11]2[CH2:16][CH2:15][C@@H:14]([C:17]([O:19]C)=[O:18])[CH2:13][C@@H:12]2[C:21]([NH:23][CH2:24][CH2:25][N:26]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])[CH3:27])=[O:22])=[O:10])[CH:5]=[CH:6][CH:7]=1.O.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:9]([N:11]2[CH2:16][CH2:15][C@@H:14]([C:17]([OH:19])=[O:18])[CH2:13][C@@H:12]2[C:21]([NH:23][CH2:24][CH2:25][N:26]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])[CH3:27])=[O:22])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1CCN(C(=O)N(c2ccccc2)c2cccc(Cl)c2)[C@@H](C(=O)NCCN(C)Cc2ccccc2OC)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1CN(C)CCNC(=O)[C@H]1C[C@H](C(=O)O)CCN1C(=O)N(c1ccccc1)c1cccc(Cl)c1

Procedure:
A solution of 0.108 g (0.18 mmole) of trans methyl 1-(N-(3-chlorophenyl)-N-(phenyl)-aminocarbonyl)-2-(RS)-(2-(N-(2-methoxybenzyl) -N-methylamino)ethylaminocarbonyl)piperidine-4-(RS)carboxylate in 2.2 mL of dry THF was treated with 1.5 mL of water and then 0.073 mL of a 2.5N aqueous solution of sodium hydroxide, and the mixture was stirred at room temperature for 15 hr. The mixture was concentrated partly in a vigorous stream of nitrogen and partly in vacuo, and was used as is in further reactions.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][NH:7][C:8](=[O:19])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][CH:12]=1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:40]>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH2:6][NH:7][C:8](=[O:19])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][Cl:40])=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CNC(=O)COc1ccc(CO)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)COc1ccc(CCl)cc1

Procedure:
A mixture of N-(ethoxycarbonylmethyl)-2-(4-hydroxymethylphenoxy)acetamide (3.96 g), triphenylphosphine (3.88 g), carbon tetrachloride (10 ml) and methylene chloride (20 ml) was heated at reflux for 1.5 hours. The reaction mixture was evaporated under reduced pressure, and ethyl acetate was added to the residue. After removal of the insolubles by filtration, the filtrate was chromatographed on silica gel column (eluent; ethyl acetate), and the desired fractions were collected and recrystallized from ethyl acetate/ether to give N-(ethoxycarbonylmethyl)-2-(4-chloromethylphenoxy)acetamide (2.8 g).
Reaction SMILES: O[CH:2]([C:18]1[N:19]=[CH:20][N:21](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:22]=1[CH3:23])[CH:3]1[C:16](=[O:17])[N:7]2[C:8]3[C:13]([C:14]([CH3:15])=[C:6]2[CH2:5][CH2:4]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.C([O-])=O.[NH4+]>C(O)(=O)C.[Pd]>[CH3:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]2[C:16](=[O:17])[CH:3]([CH2:2][C:18]3[N:19]=[CH:20][NH:21][C:22]=3[CH3:23])[CH2:4][CH2:5][C:6]=12
Reactant: Cc1c2n(c3ccccc13)C(=O)C(C(O)c1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: Cc1[nH]cnc1CC1CCc2c(C)c3ccccc3n2C1=O
Yield: 76.4 %

Procedure:
To a solution of 8,9-dihydro-7-[(hydroxy)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]-10-methylpyrido[1,2-a]-indol-6(7H)-one (4.6 g) in acetic acid (92 ml) were added 10% palladium on carbon (2.3 g) and ammonium formate (7.89 g), and the mixture was refluxed gently for 3 hours. After being cooled, the catalyst was filtered off. The filtrate was evaporated, and diluted with water (50 ml) and diisopropyl ether (50 ml). Aqueous sodium hydroxide was added to neutralized the solution. Resulted precipitates were collected, and washed with water and diisopropyl ether successively, to give 8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]-indol-6(7H)-one (1.87 g).
Reaction SMILES: [Cl:1][C:2]1[CH:43]=[CH:42][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16]CC4C=CC5C(=CC=CC=5)N=4)=[CH:13][CH:14]=3)[C:9]([C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:8]2[CH2:34][C:35]([CH3:41])([CH3:40])[C:36]([O:38][CH3:39])=[O:37])=[CH:4][CH:3]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:43]=[CH:42][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[C:9]([C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:8]2[CH2:34][C:35]([CH3:41])([CH3:40])[C:36]([O:38][CH3:39])=[O:37])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Reaction time: 7 h

Procedure:
To a solution of methyl 3-[1-(4-chlorobenzyl)-3-trimethylacetyl-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (EP 419,049, Mar. 27, 1991, Example 54, Step A) (11.5 g) in 150 mL DMF at 100° C. was added CuCl2 ·2H2O (4.9 g) in 26 mL H2O. After 7 hours, the solution was cooled, poured onto aqueous NH4OAc, and extracted with EtOAc. The organic phase was washed twice with NH4OAc (aq), washed with brine, dried (MgSO4), and evaporated. Purification of the residue by chromatography on silica gel (8% EtOAc in toluene) gave the title compound as a brown gum.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([CH2:10][OH:11])[CH:3]=1>ClCCl.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([CH:10]=[O:11])[CH:3]=1
Reactant: OCc1cc(Cl)c(Cl)c(Cl)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cc(Cl)c(Cl)c(Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.3 %

Procedure:
A mixture of (4,5,6-trichloropyridin-2-yl)methanol (3.83 g, 18 mmol) and manganese (IV) oxide (7.8 g, 90 mmol) in dichloromethane (50 mL) was stirred at room temperature for 24 hours. More manganese (IV) oxide (4 g, 46 mmol) was added and stirring was continued. After another 24 hours, the reaction mixture was suction filtered through a silica gel plug (10 g). After washing the silica gel plug with additional dichloromethane (2×25 mL), manganese (IV) oxide (8 g, 92 mmol) was added to the filtrate, and the mixture was stirred at room temperature for 72 hours. The reaction mixture was refiltered and the solvent was removed to provide 4,5,6-trichloropyridine-2-carbaldehyde (2.36 g, 11.4 mmol), mp 84-88° C.
Reaction SMILES: [F:1]/[C:2](=[C:14](/[F:22])\[C:15]1[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=1)/[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH3:13])=[CH:7][CH:6]=1.C(N)CCC.[C:28]1([CH3:36])[CH:33]=[CH:32][C:31]([C:34]#[CH:35])=[CH:30][CH:29]=1.C([O-])(O)=O.[Na+]>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.C1COCC1>[F:1]/[C:2](=[C:14](/[F:22])\[C:15]1[CH:20]=[CH:19][C:18]([C:35]#[C:34][C:31]2[CH:32]=[CH:33][C:28]([CH3:36])=[CH:29][CH:30]=2)=[CH:17][CH:16]=1)/[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH3:13])=[CH:7][CH:6]=1
Reactant: CCCc1ccc(C#C/C(F)=C(\F)c2ccc(Br)cc2)cc1
Reactant: C#Cc1ccc(C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCN
Solvent: C1CCOC1
Product: CCCc1ccc(C#C/C(F)=C(\F)c2ccc(C#Cc3ccc(C)cc3)cc2)cc1
Temperature: 25 °C
Yield: 64.9 %

Procedure:
Into a 100 ml three-necked flask, 2.86 g of cuprous iodide, 4.33 g (0.012 mol) of (E)-3,4-difluoro-1-(4-propylphenyl)-4-(4-bromophenyl)-3-buten-1-yne obtained in Example 4 and 30 ml of dry THF were charged under an argon atmosphere, followed by stirring at room temperature. Then, 1.42 g of n-butylamine and 1.53 g of p-toluylacetylene were added thereto. Then, 10 ml of a dry THF solution containing 0.69 g of (Ph3P)4Pd was added thereto, and the mixture was stirred at room temperature for 2 hours. After an addition of 30 ml of a saturated NaHCO3 aqueous solution, the mixture was subjected to liquid separation, and then extracted with methylene chloride. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 3.09 g (yield: 65%) of (E)-3,4-difluoro-1-(4-propylphenyl)-4-[4-(2-p-toluylethynyl)phenyl]-3-buten-1-yne.
Reaction SMILES: S(Cl)(=O)(=O)O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1>O>[Br:6][C:7]1[CH:8]=[C:9]2[C:10]([CH2:13][CH2:14][C:15]2=[O:17])=[CH:11][CH:12]=1
Reactant: O=C(O)CCc1ccc(Br)cc1
Agent: O=S(=O)(O)Cl
Solvent: O
Product: O=C1CCc2ccc(Br)cc21
Reaction time: 2 h

Procedure:
To chlorosulfuric acid (1.19 L) was added 3-(4-bromophenyl)propanoic acid (91.1 g) under ice cooling and the mixture was stirred for 2 hours. To H2O (2.00 L), the reaction mixture was slowly added under ice cooling, and extracted 6 times with CHCl3. The combined organic layers were washed with a saturated aqueous NaHCO3 solution, dried over Na2SO4 and concentrated under reduced pressure. To the resultant residue, MeOH was added and the mixture was heated to reflux for 30 minutes. A solid substance was obtained by filtration to give solid A. The filtrate was concentrated under reduced pressure and solid B was obtained in the same manner. Thereafter, the filtrate was again concentrated under reduced pressure and solid C was obtained in the same manner. Solids A, B and C were combined to obtain 6-bromo-2,3-dihydro-1H-inden-1-one (59.3 g, a light yellow solid).