Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CC(OC[C@H]([C@H](O)C[C@@H](OC(C)=O)C(O)(C)C)[C@@H]1[C@@]2(C)CCC3[C@@]4(C)CC[C@H](O)C(C)(C)[C@@H]4CCC=3[C@]2(C)CC1)=O>>[C:18]([O:17][C:15]([N:9]1[CH2:14][CH2:13][N:12]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)[CH2:11][CH2:10]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: Nc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)OC[C@H]([C@H](O)C[C@@H](OC(C)=O)C(C)(C)O)[C@H]1CC[C@@]2(C)C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1

Procedure:
The title compound was prepared from 4-iodoaniline and tert-butyl piperazinecarboxylate following the procedure described in Example ST-1. MS (ES+): m/z=278.2.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([C:18]3[CH:40]=[CH:39][C:21]([N:22]([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=4)[C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)=[CH:20][CH:19]=3)=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:11]=2)=[C:4]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH:3]=1.C1(C)C=CC=CC=1.[CH2:54]([PH:58](=[O:62])[O:59]CC)[CH2:55][CH2:56][CH3:57].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([N:22]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:21]2[CH:39]=[CH:40][C:18]([C:9]3[S:8][C:7]([C:5]4[S:6][C:2]([P:58]([CH2:54][CH2:55][CH2:56][CH3:57])(=[O:59])[OH:62])=[CH:3][C:4]=4[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:11][C:10]=3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:19][CH:20]=2)=[CH:24][CH:25]=1
Reactant: CCCCCCc1cc(-c2sc(Br)cc2CCCCCC)sc1-c1ccc(N(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Reactant: CCCC[PH](=O)OCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCCCc1cc(-c2sc(P(=O)(O)CCCC)cc2CCCCCC)sc1-c1ccc(N(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Temperature: 110 °C

Procedure:
The 5′-(4-(bis(4-methoxyphenyl)amino)phenyl)-3,4′-dihexyl-2,2′-bithiophen-5-yl(butyl)phosphinic acid was prepared applying a modified procedure of Y. Xu et al., Synthesis, 1984, 778. 4-(5′-Bromo-3′,4-dihexyl-2,2′-bithiophen-5-yl)-N,N-bis(4-methoxyphenyl)aniline (216 mg, 0.8 mmol) was placed in a Schlenck tube, and toluene (0.2 ml), ethyl butylphosphinate (152 mg, 0.88 mmol), triethylamine (0.36 ml, 2.6 mmol), and tetrakis[triphenylphosphine]palladium (46.2 mg, 0.04 mmol) was added under a stream of argon, stoppered, and heated in an oil bath at 110° C. for 10 h. After the mixture has been cooled, ethyl acetate (5 ml) is added and the solid is removed by filtration. The filtrate is concentrated on a rotatory evaporator and the residue is purified by column chromatography on silica gel eluting with petroleum ether (bp. 60-90° C.)/ethyl acetate. The ester thus obtained was hydrolised with 12% aqueous HCl (2×2 mL) evaporating to dryness on a waterbath yielding 5′-(4-(bis(4-methoxyphenyl)amino)phenyl)-3,4′-dihexyl-2,2′-bithiophen-5-yl(butyl)phosphinic acid (190 mg, 82%).
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH:10]=[CH:11][CH3:12])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[N+:13]([CH:16]=[CH:17][C:18]1[CH:26]=[CH:25][C:21]2[O:22][CH2:23][O:24][C:20]=2[CH:19]=1)([O-:15])=[O:14].C(OCC)(=O)C.CCCCCC>C(O)(C)C.C1COCC1.C1CCN2C(=NCCC2)CC1>[C:2]([CH:3]([CH:17]([C:18]1[CH:26]=[CH:25][C:21]2[O:22][CH2:23][O:24][C:20]=2[CH:19]=1)[CH2:16][N+:13]([O-:15])=[O:14])[C:4]([O:6][CH3:7])=[O:5])(=[O:1])[CH2:8][CH2:9][CH:10]=[CH:11][CH3:12]
Reactant: O=[N+]([O-])C=Cc1ccc2c(c1)OCO2
Reactant: CC=CCCC(=O)CC(=O)OC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CC=CCCC(=O)C(C(=O)OC)C(C[N+](=O)[O-])c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82 %

Procedure:
A solution of methyl 3-oxo-6-octenoate (502 mg, 2.95 mmol) in 10 mL of isopropanol was added to a solution of 5-(2-nitrovinyl)-1,3-benzodioxole (712 mg, 3.69 mmol) in 10 mL THF, then DBU (22 μL, 0.15 mmol) was added. The resulting reddish solution was stirred at room temperature for 20 minutes. TLC (ethyl acetate-hexane, 1:3) indicated complete consumption of ketoester. The solution was concentrated in vacuo and flash chromatographed on silica gel eluting with 18% ethyl acetate in hexane to produce 879 mg (2.42 mmol, 82%) of the title compound as a mixture of diastereomers in a 1:1 ratio. 1H NMR (CDCl3, 300 MHz) 61.55-1.66 (m, 3H), 2.02-2.17 (br m, 1H), 2.20-2.37 (m, 1.5H), 2.49-2.76 (m, 1.5H), 3.57 (s, 1.5H), 3.74 (s, 1.5H), 3.97 (d, J=7.5H, 0.5H) and 4.05 (d, J=8 Hz, 0.5H), 4.10-4.20 (m, 1H), 4.68-4.82 (m, 2H), 5.06-5.52 (m, 2H), 5.95 (2s, 2H), 6.65 (m, 1H), 6.68 (dr s, 1H), 6.75 (d, 7.5 Hz, 1H). MS (DCl/NH3) m/e 381 (M+NH4)+. Anal calcd for C18H21NO7: C, 59.50; H, 5.82; N, 3.85. Found: C, 59.32; H, 5.71; N, 3.72.
Reaction SMILES: BrC1C=CC(NC(=O)CC(OCC)=O)=C(C)C=1.BrCCCl.C(=O)([O-])[O-].[K+].[K+].[OH-].[K+].[Br:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38]([C:40]2([C:43]([O:45]CC)=[O:44])[CH2:42][CH2:41]2)=[O:39])=[C:33]([CH3:48])[CH:32]=1.Cl>O.CN(C)C=O>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38]([C:40]2([C:43]([OH:45])=[O:44])[CH2:41][CH2:42]2)=[O:39])=[C:33]([CH3:48])[CH:32]=1
Reactant: CCOC(=O)C1(C(=O)Nc2ccc(Br)cc2C)CC1
Agent: CCOC(=O)CC(=O)Nc1ccc(Br)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCBr
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1NC(=O)C1(C(=O)O)CC1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
Into a 250 milliliter Erlenmeyer flask equipped with a magnetic stirrer and condenser was added 15.0 grams (0.05 mol) of ethyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanoate, 150 milliliters of dimethylformamide and 14.0 grams (0.10 mol) of 1-bromo-2-chloroethane. The resulting mixture was stirred at ambient temperature and potassium carbonate (4.0 grams, 0.03 mol) was added at a rate of 1 gram every 30 minutes. After liquid chromatographic analysis showed the ethyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanoate peak disappeared, potassium hydroxide (5.0 grams, 0.09 mol) was added until no ethyl 1-(4-bromo-2-methylphenylaminocarbonyl)cyclopropanecarboxylate remained. The reaction mixture was diluted to 300 milliliters with water and acidified with concentrated HCl to a pH of 1 to afford a solid material. The solid was collected on a Buchner funnel and dried under ambient temperature to give 13.65 grams (0.046 mol) of 1-(4-bromo-2-methylphenylaminocarbonyl)cyclopropanecarboxylic acid. The total yield was 91.5 percent based on a 97.6 weight percent liquid chromatographic assay of the starting ethyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanoate.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[C:21]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=1>>[C:21]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:1]2[CH:2]([C:11]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=3[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]2=[O:9])[CH:22]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available [1,1′-biphenyl]-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.99 min.; [M+H]+: 416.24 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:15]([Mg]Br)[CH2:16][CH:17]=[CH2:18].CCOCC.[BH4-].[Na+]>C(O)C.O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:13]([NH2:14])[CH2:18][CH2:17][CH:16]=[CH2:15])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=CCC[Mg]Br
Reactant: N#CC1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: C=CCCC(N)C1(c2ccc(Cl)c(Cl)c2)CCC1

Procedure:
1-(3,4-Dichlorophenyl)cyclobutanecarbonitrile (13 g) was added to a solution of 3-butenylmagnesium bromide [prepared from 4-bromobut-1-en (10.6 g), magnesium (2 g) and ether (65 ml)]. The ether was replaced by toluene (60 ml) and the mixture heated for 21/2 hours. The mixture was then added to a solution of sodium borohydride (4.4 g) in ethanol (200 ml). The mixture was heated under reflux for one hour, cooled, added to water and the resulting mixture extracted with ether. The extract yielded 1-[1-(3,4-dichlorophenyl)cyclobutyl]pent-4-enylamine as an oil. This oil was added to a 1N solution of sodium dihydrogen phosphite [287 ml-prepared by mixing a solution of phosphorous acid (41 g) in water (100 ml) with sodium bicarbonate (42 g) and making the resulting solution up to 500 ml with water]. Methanol (350 ml) and 37-40% aqueous formaldehyde (25 ml) were added and the mixture heated under reflux for 11/2 hours and was then allowed to stand for 21/2 days. The methanol was removed by evaporation and the aqueous residue extracted with ether. The ether extract yielded an oil which was dissolved in ether. The solution was filtered and treated with an ethereal solution of maleic acid. An oil formed which was triturated with ether to give a semi-solid which was basified to give a N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]pent-4-enylamine.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH:1](=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]([O:17][CH2:18][CH3:19])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=Cc1ccccc1)C(=O)OCC

Procedure:
Into a one-liter three-necked conical flask are introduced 60 g (565.39 mmol) of benzaldehyde, 90.56 g (565.39 mmol) of diethyl malonate, 3.85 g (45.21 mmol) of piperidine, 130 ml of toluene and 2.71 g (45.16 mmol) of acetic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21](O)=[O:22])[C:16]=1[CH3:24].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.[CH3:55][O:56][C:57](=[O:63])[CH2:58][CH2:59][CH2:60][CH2:61][NH2:62]>[Cl-].[Na+].O.CN(C=O)C>[CH3:55][O:56][C:57](=[O:63])[CH2:58][CH2:59][CH2:60][CH2:61][NH:62][C:21]([C:17]1[C:16]([CH3:24])=[C:15]([CH:14]=[N:13][N:12]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:19][C:18]=1[CH3:20])=[O:22]
Reactant: COC(=O)CCCCN
Reactant: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCNC(=O)c1c(C)[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 68 %

Procedure:
5-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (328 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxybenzo-triazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 5-aminovaleric acid methyl ester hydrochloride (202 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (300mg, 68% yield) as a red solid. LC-MS (m/z) 442 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH:22]([C:24]#[N:25])[OH:23])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(=O)([O-])[O-:33].[K+].[K+].OO>CS(C)=O>[C:24]([CH:22]([OH:23])[C:19]1[N:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=2)[CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[N:17][CH:18]=1)(=[O:33])[NH2:25]
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C(O)C#N)cn2)cc1Cl
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C(O)C(N)=O)cn2)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 28.4 %

Procedure:
A mixture of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-[5-(cyano-hydroxy-methyl)-pyrazin-2-yl]-3-cyclopentyl-propionamide (prepared as in Example 26, 100 mg, 0.22 mmol) and potassium carbonate (400 mg, 2.9 mmol) in dimethyl sulfoxide (6 mL) was cooled to 0° C. and then was treated dropwise with a 30% aqueous hydrogen peroxide solution (2 mL). The reaction was stirred at 0° C. for 1 h. The resulting mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with water (3×30 mL) and a saturated aqueous sodium chloride solution (1×30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, ethyl acetate) afforded N-[5-(carbamoyl-hydroxy-methyl)-pyrazin-2-yl]-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (30 mg, 28%) as a white solid: (ES)+-HRMS m/e calcd for C21H25ClN4O5S (M+H)+ 481.1314, found 481.1307.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].Cl[C:6]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:17])(=[O:16])[NH:8][N:7]=1.[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:28])=[CH:22]2>ClCCCl.O>[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:28])=[C:22]2[C:6]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:17])(=[O:16])[NH:8][N:7]=1
Reactant: Cc1cc2cc(F)ccc2[nH]1
Reactant: O=S1(=O)NN=C(Cl)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: Cc1[nH]c2ccc(F)cc2c1C1=NNS(=O)(=O)c2ccccc21
Temperature: 70 °C
Reaction time: 8 h
Yield: 19.1 %

Procedure:
AlCl3 (1.2 g, 10.5 mmol) was added to a solution of 4-chloro-2H-benzo[e][1,2,3]thiadiazine 1,1-dioxide (1.5 g, 7.0 mmol) and 5-fluoro-2-methyl indole (1.0 g, 7.0 mmol) in DCE (35 mL), and stirred overnight at 70° C. The reaction solution was diluted with H2O, and the product was extracted with a solution of CH2Cl2/EtOH (9/1, v/v). The extracted product was concentrated and purified via silica gel chromatography eluting with a gradient of 0 to 70% EtOAc in hexanes to afford 0.44 g (19%) of the sub-title compound. MS calculated for C16H12FN3O2S—H: 328, observed: 328.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:5]1=[O:22])(=O)C.[CH3:23][N:24]([CH2:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[CH3:25].[OH-].[Na+]>CN(C=O)C.CO>[CH3:25][N:24]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([NH:31]/[C:13](=[C:6]2\[C:5](=[O:22])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[CH:32][CH:33]=1)[CH3:23]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccc(Cl)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)Cc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccc(Cl)cc2)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(4-chlorophenyl)-methylidene)-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH:1]([CH:4]1[C:11]2[CH:10]=[C:9]([C:12]([O:14]C)=[O:13])[NH:8][C:7]=2[CH2:6][CH2:5]1)([CH3:3])[CH3:2].O.[OH-].[Li+]>>[CH:1]([CH:4]1[C:11]2[CH:10]=[C:9]([C:12]([OH:14])=[O:13])[NH:8][C:7]=2[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc2c([nH]1)CCC2C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(C)C1CCc2[nH]c(C(=O)O)cc21
Yield: 21.7 %

Procedure:
The title compound was synthesized from methyl 4-isopropyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.09 g, 0.43 mmol) and lithium hydroxide monohydrate (185 mg, 4.3 mmol) according to General Procedure 7. The crude product was dried onto Silica gel and was purified by chromatography (0 to 100% EtOAc/heptane) to give 4-isopropyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid (10) as brown solid (0.018 g, 21%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.93 (d, J=2.68 Hz, 3H) 0.95 (d, J=2.68 Hz, 3H) 1.67 (dq, J=13.37, 6.67 Hz, 1H) 2.04-2.14 (m, J=12.81, 8.91, 5.71, 5.71 Hz, 1H) 2.44-2.55 (m, 1H) 2.56-2.80 (m, 3H) 6.63 (s, 1H). LCMS m/e 194 (M+H). 92.0% pure by HPLC.
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[Cl:11].[F:12][C:13]([F:27])([F:26])[C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:18][CH:19]=1.CC(C)([O-])C.[Na+].O>C1(C)C=CC=CC=1>[Cl:11][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[C:7]([Cl:8])[C:2]=1[N:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:16]=[CH:15][C:14]([C:13]([F:27])([F:12])[F:26])=[CH:19][N:18]=2)[CH2:21][CH2:22]1
Reactant: COc1cc(Cl)c(Br)c(Cl)c1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(Cl)c(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)c(Cl)c1
Temperature: 80 °C

Procedure:
A stirred mixture of 3.0 grams (0.012 mole) of 2-bromo-1,3-dichloro-5-methoxybenzene (Step A), 2.7 grams (0.012 mole) of [5-(trifluoromethyl)-2-pyridylpiperazine (Step B), 0.02 gram (0.00024 mole) of tris(ydroxide eneacetone)dipalladium (0), 0.45 gram (0.00072 mole) of ydroxi-2,2′bis(diphenylphosphino)-1,1′-binaphthyl and 2.1 grains (0.022 mole) of sodium tert-butoxide in 150 mL of toluene was warmed to 80° C. where it was maintained during a 24-hour period. After this time the reaction mixture was cooled and poured into 250 mL of water. The organic layer was separated, and the aqueous layer was extracted with two 75 mL portions of diethyl ether. The organic layer and the extracts were combined and washed with 50 mL of an aqueous solution saturated with sodium chloride. The organic layer-extract combination was dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue, which was a mixture of products, was separated into its components by column chromatography on silica gel using 25% methylene chloride in hexane, then 50% methylene chloride in hexane as eluants. Appropriate fractions were combined and concentrated under reduced pressure, yielding 1.8 grams of 1,3-dichloro-5-methoxy-2-{4-[5-(trifluoromethyl)(2-pyridyl)]piperazinyl}benzene, and other appropriate fractions were combined and concentrated under reduced pressure, yielding 0.45 gram of 2-bromo-3-chloro-5-methoxy-1-{4-[5-(trifluoromethyl)(2-pyridyl)]piperazinyl}benzene. The NMR spectra of both compounds were consistent with the proposed structures.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][N:44]=[N+]=[N-])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][NH2:44])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCN=[N+]=[N-])C[C@@H]3c3ccc(OC)cc3)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCN)C[C@@H]3c3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 70.0 mg of (2S,4R,5R)-2-(2-azido-ethyl)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester in 4.0 ml of tetrahydrofuran and 0.4 ml of water are added 30 mg of triphenyl-phosphine. The reaction mixture is stirred for 2 days at room temperature; concentrated under reduced pressure and the residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a colourless oil. Rf=0.05 (dichlormethane-methanol 10:1); Rt=4.27.
Reaction SMILES: Cl.[F:2][C:3]([F:32])([F:31])[C:4]1[CH:5]=[C:6]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:7]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)=[O:8].[N+:33]([C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Cl)=[CH:38][CH:37]=1)([O-:35])=[O:34].C(N(CC)CC)C>O1CCCC1>[F:30][C:27]([F:29])([F:28])[C:25]1[CH:24]=[C:6]([CH:5]=[C:4]([C:3]([F:2])([F:31])[F:32])[CH:26]=1)[C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:40][C:39]2[CH:42]=[CH:43][C:36]([N+:33]([O-:35])=[O:34])=[CH:37][CH:38]=2)[CH2:11][C@H:10]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)=[O:8]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(Cc2ccc([N+](=O)[O-])cc2)C[C@H]1Cc1ccc(Cl)c(Cl)c1
Yield: 71.4 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)piperazine hydrochloride (200 mg), 4-nitrobenzyl chloride (158 mg) and triethylamine (268 μl) in tetrahydrofuran (5 ml) was refluxed overnight. After cooling, the precipitates were filtered off and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of toluene and ethyl acetate as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)-4-(4-nitrobenzyl)piperazine (169.8 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl[CH2:12][C:13]#[C:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:12][C:13]#[C:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: CC(C)(C)OC(=O)NCC#CCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCC#CCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.51 g), tert-butyl (4-chlorobut-2-yn-1-yl)carbamate (2.60 g), cesium carbonate (4.80 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 2 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→33:67) to give the title compound (2.61 g) as an orange oil.