Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:5]=1[Cl:11].[C:13]([Sn](CCCC)(CCCC)CCCC)([CH3:15])=[CH2:14]>C1COCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:13]([CH3:15])=[CH2:14])=[CH:6][C:5]=1[Cl:11]
Reactant: COC(=O)c1ccc(Br)cc1Cl
Reactant: C=C(C)[Sn](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: C=C(C)c1ccc(C(=O)OC)c(Cl)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 4-bromo-2-chlorobenzoic acid methyl ester (500 mg, 2 mmol) in THF (15 mL) was added isopropenyltributylstannane (700 mg, 2.1 mmol) and PdCl2(dppf)-2-DCM (165 mg, 0.2 mmol). The solution was heated to 60° C. for 12 hours. The crude reaction mixture was then concentrated down and taken up in 20 mL EtOAc and 100 mL concentrated KF solution. The reaction stirred at room temperature for 3 hours, filtered through a pad of celite and concentrated down. The residual oil was subjected to flash chromatography (Isco Companion, 40 g SiO2 cartridge, solid loaded SiO2, neat heptanes to EtOAc gradient) to give 2-chloro-4-isopropenyl-benzoic acid methyl ester as a yellow oil. Amount obtained: 230.6 mg (55%). LCMS (M/Z): 211 (M+H).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[N:16][C:8]=3[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)C.C(=O)(O)[O-].[Na+].[C:34]([O:38][C:39]([NH:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>C1(C)C=CC=CC=1>[C:20]1([C:3]2[N:4]=[C:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[NH:9][C:8]4[N:16]=[CH:17][CH:18]=[CH:19][C:7]=4[N:6]3[C:2]=2[C:46]2[CH:47]=[CH:48][C:43]([CH2:42][NH:41][C:39](=[O:40])[O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:44][CH:45]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Brc1c(-c2ccccc2)nc2n1-c1cccnc1Nc1ccccc1-2
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2c(-c3ccccc3)nc3n2-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To a suspension of 3-bromo-2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.250 g, 1 eq.) in a mixture of toluene (5 mL), ethanol (5 mL), and saturated sodium bicarbonate (1 mL) was added (4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (0.1 g, 1.5 eq.). The reaction was degassed (nitrogen) for 5 minutes and tetrakis(triphenylphosphine)palladium(0) added (0.025 g). The reaction was again degassed for 5 minutes and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and poured onto water (50 mL). The aqueous phase was extracted with dichloromethane (2×50 mL) and the organic extracts were combined and washed with water (1×50 mL), brine (1×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (25-75% ethyl acetate in hexanes) gave the product which was triturated with ether to give tert-butyl 4-(2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)benzylcarbamate (0.133 g, 40%). LCMS: 516 [M+H].
Reaction SMILES: Cl[C:2](Cl)([C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)[C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[CH:4]=1.[OH:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][C:31]=1[OH:32])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>ClCCl>[CH2:27]([O:26][C:24]([C:23]1[CH:29]=[CH:30][C:31]2[O:32][C:2]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=3)([C:3]3[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[CH:4]=3)[O:20][C:21]=2[CH:22]=1)=[O:25])[CH3:28]
Reactant: Fc1cc(F)cc(C(Cl)(Cl)c2cc(F)cc(F)c2)c1
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)OC(c1cc(F)cc(F)c1)(c1cc(F)cc(F)c1)O2
Yield: 87.8 %

Procedure:
239 mg dichloro-bis(3,5-difluorophenyl)methane and 141 mg ethyl 3,4-dihydroxybenzoate were heated to 180° C. for 2 h 15 min. The brown mixture was diluted with dichloromethane, washed with sat. NaHCO3 solution and water. The dried solution was evaporated and the residue purified on silica gel to provide 284 mg resinous oil. MS: 419 ([M+H]+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][CH:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][N:22]([CH3:40])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][NH:30][C:31]2[CH:36]=[CH:35][C:34]([CH:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=2)=[CH:25][CH:24]=1>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][CH:13]2[C:18]([N:30]([CH2:29][C:26]1[CH:25]=[CH:24][C:23]([N:22]([CH3:40])[CH3:21])=[CH:28][CH:27]=1)[C:31]1[CH:32]=[CH:33][C:34]([CH:37]([CH3:39])[CH3:38])=[CH:35][CH:36]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCc2c(OCc3ccccc3)cccc21
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCc3c(OCc4ccccc4)cccc32)cc1
Yield: 110.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 4-benzyloxyindan-1-carboxylic acid (0.7 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.7 g) as starting materials, 4-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)indan-1-carboxamide (1.5 g) was obtained.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[CH3:23])=[CH:12]/[C:13]([NH:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:14])=[CH:7][CH:6]=1.Cl>CO>[OH:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[CH3:23])=[CH:12]/[C:13]([NH:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:14])=[CH:7][CH:6]=1
Reactant: COCOc1ccc(/C(C)=C/C(=O)NCc2cccnc2)cc1
Agent: Cl
Solvent: CO
Product: C/C(=C\C(=O)NCc1cccnc1)c1ccc(O)cc1
Yield: 69.6 %

Procedure:
1.94 g of (E)-3-[4-(methoxymethoxy)phenyl]-N-(3-pyridylmethyl)-2-buteneamide was dissolved in 38 ml methanol and stirred with 1.9 ml of concentrated hydrochloric acid at room temperature for 8 hours. The reaction mixture was extracted with ethyl acetate and water, and the aqueous layer was further extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and brine, and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the solvent was evaporated to give a residue, which was then recrystallized from ethyl acetate/n-hexane to provide (E)-3-(4-hydroxyphenyl)-N-(3-pyridylmethyl)-2-buteneamide (1.16 g, 96.5% after 2 steps).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]1[N:17]=[C:16]([CH3:18])[N:15]=[C:14]2[C:10]=1[N:11]=[C:12]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])[N:13]2[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1>C(O)C>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([N:13]2[C:12]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])=[N:11][C:10]3[C:14]2=[N:15][C:16]([CH3:18])=[N:17][C:9]=3[N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:24][CH:23]=1
Reactant: CN1CCNCC1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3F)n(-c3ccc(Cl)cc3)c2n1
Solvent: CCO
Product: Cc1nc(N2CCN(C)CC2)c2nc(-c3ccccc3F)n(-c3ccc(Cl)cc3)c2n1

Procedure:
A solution of 1-methylpiperazine (200 μl) in ethanol (0.8 ml) was added to 6-chloro-9-(4-chlorophenyl)-8-(2-fluorophenyl)-2-methyl-9H-purine I-(11A-1)c (24 mg, 0.06 mmol) and placed on a 60° C. shaker apparatus for 30 minutes. The reaction was loaded directly onto a TLC preparative plate for purification using 10% methanol/ethyl acetate as the solvent to obtain the desired title compound 11A-1: +ESI MS (M+1) 465. A solution of the material in methylene chloride/methanol was treated with excess 1 N HCl in diethyl ether, stirred, evaporated to dryness, and then triturated in diethyl ether to afford the hydrochloride salt of compound 11A-1 (35 mg, quantitative): +ESI MS (M+1) 437.2; 1H NMR (400 MHz, CD3OD) δ 7.70–7.25 (br m, 7H), 7.09 (t, J=9.1 Hz, 1H), 5.80 (br s, 2H), 3.74 (br s, 4H), 3.36 (br s, 2H), 2.99 (s, 3H), 2.64 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[Cl:13].[N-:14]=[N+:15]=[N-:16].[Na+]>CN(C=O)C.O>[N:14]([C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[Cl:13])=[N+:15]=[N-:16]
Reactant: COC(=O)c1nc(Br)cc(Br)c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(Br)cc(N=[N+]=[N-])c1Cl
Temperature: 50 °C
Yield: 66.7 %

Procedure:
To a solution of methyl 4,6-dibromo-3-chloropyridine-2-carboxylate (6.0 g 0.018 mol) in DMF (50 mL) was added sodium azide (2.0 g 0.03 mol) and the solution warmed to 50° C. for 1 hr. The reaction was diluted with water (200 mL) and cooled to 0° C. for 1 hr. The solid was collected to give methyl 4-azido-6-bromo-3-chloropyridine-2-carboxylate (4.4 g, 0.012 mol, 66%); mp 84-86° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[S:5][CH:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]=1[CH:20]=O.Cl.[NH2:23][OH:24].O>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[S:5][CH:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]=1[CH:20]=[N:23][OH:24]
Reactant: COc1cccc2c1SC(c1ccccc1)C(C=O)=C2Cl
Reactant: NO
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c1SC(c1ccccc1)C(C=NO)=C2Cl

Procedure:
As in example 10 but starting with 1 g 4-chloro-3-formyl-8-methoxy-thioflav-3-ene in 1.5 ml DMF. 220 mg hydroxylamine hydrochloride dissolved in 2 ml DMF are added. After 11/2 hours of reflux, the solution is cooled at room temperature before the addition of 20 ml of water. After extraction with CH2Cl2 a gum is obtained which is purified by column chromatography on silicagel using n-hexane/acetone 9:1 as eluant. Pure 4-chloro-3-hydroxyiminomethyl-8-methoxy-thioflav-3-ene is obtained as a yellow solid. TLC (SiO2, n-hexane/acetone 4:1): Rf =0.15.-NMR (90 MHz, CDCl3): δ(ppm)=3.76 (s, 3H, OCH3), 5.5 [s, 1H, H-C(2)], 6.76-7.69 [m, 3H, H-C(5,6,7)], 7.17 [s, 5H, H-C(2',3',4',5',6')], 8.53 [s, 1H, CH=N], 11.4 [s, 1H, OH].-M.p. 190°-203° C. (n-hexane/toluene).
Reaction SMILES: [Br-].[O:2]1[CH2:7][CH2:6][CH2:5][O:4][CH:3]1[CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[F:35][C:36]1[C:41]([F:42])=[C:40]([O:43][CH2:44][CH3:45])[CH:39]=[CH:38][C:37]=1[CH:46]1[CH2:51][CH2:50][C:49](=O)[CH2:48][CH2:47]1>C1COCC1>[F:35][C:36]1[C:41]([F:42])=[C:40]([O:43][CH2:44][CH3:45])[CH:39]=[CH:38][C:37]=1[CH:46]1[CH2:51][CH2:50][C:49](=[CH:9][CH2:8][CH:3]2[O:2][CH2:7][CH2:6][CH2:5][O:4]2)[CH2:48][CH2:47]1
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOc1ccc(C2CCC(=O)CC2)c(F)c1F
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOc1ccc(C2CCC(=CCC3OCCCO3)CC2)c(F)c1F
Temperature: -5 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
A mixture of 2-(1,3-dioxane-2-yl)-ethyltriphenyl phosphonium bromide (60.4 mmol) and 30 ml of THF was cooled down 20 to −30° C. by use of a refrigerant under a nitrogen flow. To this mixture, t-BuOK (60.4 mmol) was added, and the mixture was stirred for one hour. A solution of the crude 4-(2,3-difluoro-4-ethoxyphenyl)-cyclohexanone (50.3 mmol) dissolved in 100 ml of THF was added dropwise to this mixture while temperature was maintained at −30° C. or below. After completion of the addition, the reaction temperature was gradually elevated to room temperature, and the mixture was stirred for 2 hours. The reaction mixture was filtered with celite, the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (eluent: a mixed solvent of ethyl acetate/toluene=3/7), the solvent was distilled off under reduced pressure, and the product was re-crystallized from heptane to form 2-(2-(4-(2,3-difluoro-4-ethoxyphenyl)cyclohexylidene)-ethyl)-1,3-dioxane (36.9 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=O)O[C:8](=O)[C:4]=2[CH:3]=1.[CH:13]([NH2:16])([CH3:15])[CH3:14].[ClH:17].O1CCOCC1>C1(C)C=CC=CC=1>[ClH:17].[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][CH:12]=1)[CH2:6][N:16]([CH:13]([CH3:15])[CH3:14])[CH2:8]2
Reactant: CC(C)N
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CC(C)N1Cc2ccc(Br)cc2C1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
5-bromo-2-benzofuran-1,3-dione (1 wt) was suspended in toluene (5 vol) with stirring under nitrogen. Isopropylamine (1.1 eq, 0.416 vol) was then added dropwise over 10-30 mins at such a rate as to maintain the temperature between 15-25° C. (exothermic addition). The batch was stirred for a further 30 mins at 15-25° C. once the addition was complete, before heating to reflux under Dean-Stark conditions. The batch was held at reflux for 5-8 hrs until residual 5-bromo-2-benzofuran-1,3-dione by HPLC is <1% a/a uncorrected, then the batch was concentrated atmospherically to ca 2.5 vols2. Added toluene (3 vols) and reconcentrated atmospherically to ca 2.5 vols. Batch then cooled to 55-60° C., diluted with THF (1.5 vols), and then further cooled to 15-25° C. This was added to a solution of borane-THF complex (1.0M, 4 eq, 14.1 vol) and the resultant solution was stirred at 20-30° C. for ca 30 mins. The batch was then heated to 48-52° C., and held thus for 16-24 hrs until complete by HPLC, before cooling back to 15-25° C. The reaction was quenched inversely into aqueous hydrochloric acid (2N, 9 vol) over at least 30 mins maintaining an internal temp of 15-30° C. (initially effervescent, evolves hydrogen). Once the addition was complete, the batch was heated to 60-63° C., and held thus for 1-1.5 hrs before cooling to 15-25° C. Ethyl acetate (6 vols) was added and the resultant biphase was shaken, settled and separated1. Organics back-extracted with 2N HCl (3 vols) before being discarded. The combined aqueous liquors were then neutralized to pH>12 with 40% w/v aq NaOH (approx 3.9 vols). Overlain with ethyl acetate (6 vols) then the resultant biphase was shaken, settled and separated. Aqueous back extracted with ethyl acetate (3 vols) before being discarded. The organics were combined and washed with saturated brine (2×2 vols) before being concentrated in vacuo to ca 4 vols. Ethyl acetate (8 vols) was added and the batch was reconcentrated in vacuo to ca 4 vols. Ethyl acetate (9 vols) was added and the batch was adjusted to 0±3° C. 4M HCl in dioxane (0.89 eq, 0.98 vol) was then added slowly maintaining the batch temp within the range 0±3° C. The batch was then aged within this range for 30 min before product was collected by vacuum filtration. Washed with chilled ethyl acetate (<5° C., 2×2 vols) and dried o/n in vacuo at 30° C. to constant weight.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH:3]=[C:4]1[C:13](=O)[C:12]2[C:7](=[CH:8][C:9]([C:15]([O:17]C)=[O:16])=[CH:10][CH:11]=2)[O:6][CH2:5]1.Cl.[Cl:21][C:22]1[CH:29]=[C:28]([NH:30][NH2:31])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25].O1CCCC1>>[Cl:21][C:22]1[CH:29]=[C:28]([N:30]2[CH:3]([CH:2]([CH3:19])[CH3:1])[CH:4]3[CH2:5][O:6][C:7]4[CH:8]=[C:9]([C:15]([OH:17])=[O:16])[CH:10]=[CH:11][C:12]=4[C:13]3=[N:31]2)[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: N#Cc1ccc(NN)cc1Cl
Reactant: COC(=O)c1ccc2c(c1)OCC(=CC(C)C)C2=O
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)C1C2COc3cc(C(=O)O)ccc3C2=NN1c1ccc(C#N)c(Cl)c1

Procedure:
The title compound was prepared from methyl 3-(2-methylpropylidene)-4-oxochroman-7-carboxylate; Preparation 32 (260 mg, 1.0 mmol) and 2-chloro-4-hydrazinylbenzonitrile hydrochloride; Preparation 1 (306 mg, 1.5 mmol) according to Method B and Method C. The crude product was purified by reverse-phase HPLC (30 to 95% acetonitrile/water/0.05% trifluoroacetic acid) followed by flash chromatrography (0 to 20% methanol/ethyl acetate) to give 2-(3-chloro-4-cyanophenyl)-3-isopropyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid (yellow solid, 18.4 mg). The title compound was largely present as (±)-(3RS,3aSR)-2-(3-chloro-4-cyanophenyl)-3-isopropyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.10 (br. s., 1H), 7.95 (d, J=7.8 Hz, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.58 (dd, J=8.2, 1.6 Hz, 1H), 7.47 (d, J=1.2 Hz, 1H), 7.42 (d, J=2.3 Hz, 1H), 7.19 (dd, J=9.0, 1.6 Hz, 1H), 4.77-4.88 (m, 2H), 4.41 (dd, J=13.3, 10.5 Hz, 1H), 4.00-4.09 (m, 1H), 2.04-2.16 (m, 1H), 0.83 (d, J=7.0 Hz, 3H), 0.82 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([CH2:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:7]=2[C:6]([C:16]([O:18]C)=[O:17])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].CO>O>[CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([CH2:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:7]=2[C:6]([C:16]([OH:18])=[O:17])=[CH:5][CH:4]=1
Reactant: CCCc1ccc2c(C(=O)OC)ccc(OC)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCc1ccc2c(C(=O)O)ccc(OC)c2n1
Yield: 45.5 %

Procedure:
A mixture of methyl 8-methoxy-2-n-propylquinoline-5-carboxylate (1.0 g, Reference Example 27), potassium carbonate (0.8 g), methanol (30 ml), and water (2 ml) was refluxed or 5 hours. The solution was concentrated, then diluted with water and then washed with diethyl ether. The pH of the aqueous phase was adjusted to 6 by addition of hydrochloric acid (6M). The resulting cream precipitate was washed with water and then dried at 60° C. to give the title compound (0.43 g) as a cream coloured solid, m.p. 214-217° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:13][CH2:14][CH2:15][CH:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH3:21])([O-])=O.O.Cl>CCO>[CH3:21][N:17]1[CH2:18][CH2:19][CH2:20][CH:16]1[CH2:15][CH2:14][NH:13][C:5]1[C:4]([NH2:1])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][CH:6]=1
Reactant: CN1CCCC1CCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN1CCCC1CCNc1ccc([N+](=O)[O-])cc1N
Temperature: 65 °C
Yield: 45 %

Procedure:
(2,4-Dinitro-phenyl)-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-amine 31 (0.979 g, 3.329 mmol) was dissolved in anhydrous EtOH (16 mL) in a 2 neck 100 mL argon purged flask. The reaction vessel was fitted with a condenser and dropping funnel and heated in an oil bath to 65° C. H2O (16 mL), EtOH (32 mL) and aqueous (NH4)2S (50 wt %, 1.59 g, 11.652 mmol) were charged to the dropping funnel and added to the hot reaction mixture dropwise over 45 minutes. The reaction was heated at 65-70° C. for 2 hours then cooled to room temperature overnight. Mixture was acidified by the addition of aqueous 4M HCl to adjust pH to 2. The reaction mixture was filtered to remove any insoluble material and the filtrate was concentrated under reduced pressure to remove EtOH. The resulting aqueous solution was basified by the addition of aqueous 2M ammonium hydroxide solution to adjust pH to 10. The aqueous solution was diluted with dichloromethane and transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with dichloromethane and the combined organic layers were washed with H2O, brine, and dried over magnesium sulphate, filtered and concentrated to afford a dark red oil. The product was purified using silica gel dry column chromatography with a solvent system of (5% 2M NH3 in methanol/95% dichloromethane to 10% 2M NH3 in methanol/90% dichloromethane) to afford an orange-red oil/solid 32 N1-[2-(1-Methyl-pyrrolidin-2-yl)-ethyl]-4-nitro-benzene-1,2-diamine Yield: 0.396 grams (45.1%). 1H NMR (DMSO) δ: 1.39-1.69 (m, 5H), 1.86-1.98 (m, 2H), 2.01-2.10 (m, 1H), 2.10-2.16 (m, 1H), 2.22 (s, 3H), 2.91-2.98 (m, 1H), 3.16-3.24 (m, 2H), 5.11 (br s, 2H), 5.92-5.98 (m, 1H), 6.46 (d, 1H, J=8.8), 7.40 (d, 1H, J=2.5), 7.52 (dd, 1H, J=8.9, 2.5); MS (ESI): 265 (MH+, 100%).
Reaction SMILES: [OH-].[Na+].[OH:3][CH:4]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[N:28]=[CH:27][C:26]=1[Cl:37])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][S:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][CH:8]1[C:21]([O:23]C)=[O:22]>O1CCOCC1>[OH:3][CH:4]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[N:28]=[CH:27][C:26]=1[Cl:37])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][S:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][CH:8]1[C:21]([OH:23])=[O:22]
Reactant: COC(=O)C1CN(CCSc2cccs2)CCC1CCC(O)c1c(Cl)cnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc2ncc(Cl)c(C(O)CCC3CCN(CCSc4cccs4)CC3C(=O)O)c2c1
Temperature: 70 °C
Reaction time: 12 h
Yield: 85.6 %

Procedure:
1.7 cm3 of a 1 N aqueous sodium hydroxide solution are added to 300 mg of methyl 4-[3-hydroxy-3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylsulfanyl)ethyl]piperidine-3-carboxylate (ester isomer C) solubilized in 10 cm3 of dioxane. The reaction medium is then heated at 70° C. for 5 h 30 min. The temperature is allowed to return to 19° C. for 12 hours and then heating is carried out again at 70° C. for 2 hours. Evaporation is then carried out under reduced pressure (20 kPa; 45° C.). The residue is taken up in 25 cm3 of distilled water and then extraction is carried out with 25 cm3 of diethyl ether. The aqueous phase is acidified with 1.6 cm3 of a 1 N aqueous hydrochloric acid solution (pH=6) and then this phase is extracted with 3 times 70 cm3 of ethyl acetate. The organic phase is dried under magnesium sulfate, filtered through a sintered glass funnel, and then evaporated under reduced pressure (20 kPa; 45° C.). After having dried under vacuum (50 kPa), the residue is taken up with 20 cm3 of acetone and then concentrated again under reduced pressure (20 kPa; 45° C.). Drying is carried out under reduced pressure (50 kPa; 20° C.) for 12 hours and 250 mg of 4-[3-hydroxy-3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylsulfanyl)ethyl]piperidine-3-carboxylic acid, in the form of a pale yellow solid (isomer C), are obtained.
Reaction SMILES: [C:1]1([CH:7]2[O:11][CH:10]([CH2:12][CH2:13][OH:14])[C:9](=[C:15]=[C:16]=C=C)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[C:20]([O:23][CH2:24]C)(=[O:22])C>CO.Cl[Pd]Cl>[C:1]1([CH:7]2[O:11][CH:10]3[CH2:12][CH2:13][O:14][C:9]3([C:15](=[CH2:16])[C:20]([O:23][CH3:24])=[O:22])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(C)=O
Reactant: C=C=C=C=C1CC(c2ccccc2)OC1CCO
Agent: Cl[Pd]Cl
Solvent: CO
Solvent: O
Product: C=C(C(=O)OC)C12CC(c3ccccc3)OC1CCO2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(5-phenyl-3-vinylidenevinylidene-tetrahydrofuran-2-yl)ethanol (39 mg, 0.18 mmol) was dissolved in 2 mL of methanol, and then was filled with CO gas (1 atm), followed by addition of PdCl2 (2.4 mg, 0.014 mmol) and CuCl2 (73 mg, 0.54 mmol). The solution was stirred for 4 hours at room temperature. When the reaction was completed, H2O was added and the solution was stirred for 5 minutes. The mixture was diluted with ethyl acetate, washed with H2O and NaCl. Organic layer was separated and dried with anhydride MgSO4. Solvent was removed under reduced pressure, and the remnant was purified through silica gel tube chromatography (EtOAc:n-Hexane=1:25, v/v), thus providing products (47 mg, 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH:17]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(O)C>[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH2:17][NH:6][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: COc1ccc(CN)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(CNCc2ccc(OC)cc2OC)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2,4-dimethoxybenzylamine (8.98 mL) and 2,4-dimethoxybenzaldehyde (9.94 g) in ethanol (200 mL) was stirred at room temperature for 2 hr. To the reaction mixture was added sodium triacetoxyborohydride (20.3 g), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (8 g).