Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:28]=[CH:27][N:26]=[C:25]2[SH:29])=[C:20]([CH3:30])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:30][C:20]1[CH:19]=[C:18]([Br:17])[CH:23]=[CH:22][C:21]=1[N:24]1[CH:28]=[CH:27][N:26]=[C:25]1[S:29][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2
Reactant: Cc1cc(Br)ccc1-n1ccnc1S
Reactant: O=C1CCc2cc(OCCCCl)ccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1-n1ccnc1SCCCOc1ccc2c(c1)CCC(=O)N2
Temperature: 80 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
In 300 ml of dimethylformamide were dissolved 89 g of 6-(3-chloropropoxy)-3,4-dihydrocarbostyril and 110 g of 1-(4-bromo-2-methylphenyl)-2-mercaptoimidazole. To the solution was slowly added 66.7 g of potassium carbonate at room temperature. The mixture was stirred at 80° C. for 2 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate. The oily layer was washed with water thoroughly, washed with an aqueous solution saturated with sodium chloride, dried with anhydrous magnesium sulfate, and subjected to distillation to remove the solvent. The resulting brown oil was purified by a silica gel column chromatography (eluant: chloroform/methanol=50/1). The resulting crude crystals were recrystallized from ethanol to obtain 118 g of 6-{3-[1-(2-methyl-4-bromophenyl)-2-imidazolylthio]propoxy}-3,4-dihydrocarbostyril.
Reaction SMILES: [OH-].[Na+].C1COCC1.Cl.[NH2:9][C@H:10]([C:21]([NH2:23])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1.[CH2:24]([O:31][C:32](Cl)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([O:31][C:32](=[O:33])[NH:9][CH:10]([C:21](=[O:22])[NH2:23])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)C(Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Reaction time: 0.08 h

Procedure:
To a solution of 8.35 g (0.21 mol) NaOH in 100 ml of water was added 200 ml of THF followed by 25.0 g (0.104 mol) of L-tryptophanamide hydrochloride. The mixture was cooled on ice and 19.6 g (0.114 mol) of benzylchloroformate was added under vigorous stirring during 5 minutes. The ice bath was removed and the mixture was stirred for 1 hour.
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH2:4]([O:6][CH:7]([O:11][CH2:12][CH3:13])[CH2:8][CH:9]=[CH2:10])[CH3:5].N#N>CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:4]([O:6][CH:7]([O:11][CH2:12][CH3:13])[CH2:8][CH:9]1[CH2:3][CH2:10]1)[CH3:5]
Reactant: C=CCC(OCC)OCC
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: CCOCC
Product: CCOC(CC1CC1)OCC

Procedure:
Diazomethane (6.17 g, 147 mmol) was added dropwise to 3.02 g (21 mmol) of 3-butenal diethyl acetal in 10 ml of dry ether with intensive stirring at 0 C. Then 70 mg (0.312 mmol) of palladium (II) acetate in 50 ml of dry ether was added all at once. Then stirring at 0 C continued until the evolution of N2 ceased (10 min.). The ether was distilled off to the reduced volume of the reaction mixture ca 10 ml. The precipitate was filtered off on a fritted glass funnel and the filtrate evaporated. The crude product (2.57 g) contained 97% of the title compound (GC) and was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].Cl.O1CCOC[CH2:17]1>CO>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1)[C:5]([O:7][CH3:17])=[O:6]
Reactant: C1COCCO1
Reactant: O=C(O)c1cc(O)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-hydroxy-5-(trifluoromethyl)benzoic acid (3.56 g, 17.3 mmol) in methanol (110 mL) was added 4.0M hydrogen chloride in dioxane (110 mL, 460 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was concentrated. The residue was purified by flash chromatography on a silica gel column to give the desired product as white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])O)O)=O>O1CCOCC1>[CH:7]1[CH:5]=[C:3]([CH:2]=[O:1])[O:10][C:9]=1[CH2:11][OH:12]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: C1COCCO1
Product: O=Cc1ccc(CO)o1
Temperature: 100 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
14.3 g of high-fructose maize syrup (containing 10 g of carbohydrate, wherein fructose is 9 g, 50 mmol) was put into a 250 mL round-bottom flask, and 10 g of Amberlyst 15 resin was added therein. Next, 100 mL of dioxane was put into the reactor, and stirred for 3 hours at 100° C. After the reaction, Amberlyst 15 resin was filtered and removed, and the dioxane was distilled and thus to obtain a reactant compound. Ethyl acetate (100 mL) and distilled water (100 mL) were put into the obtained reactant compound. After conducting a delamination, the ethyl acetate layer was dried with magnesium sulfate (MgSO4), and the ethyl acetate was distilled, thus obtaining 4.5 g of HMF (yield rate: 71%). As a result of an 1H-NMR analysis on the obtained 5-hydroxymethyl-2-furfural (HMF), it can seen that a high-purity 5-hydroxymethyl-2-furfural (HMF) was obtained as illustrated in FIG. 2.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH:13]([CH3:16])[CH2:14][NH2:15].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH:22]=O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH:13]([CH3:16])[CH2:14][NH:15][CH2:22][C:18]1[S:17][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1cccs1
Reactant: CC(CN)Oc1ccc2ccccc2c1Cl
Product: CC(CNCc1cccs1)Oc1ccc2ccccc2c1Cl
Yield: 81 %

Procedure:
Prepared from 2-[(1-chloronaphthalen-2-yl)oxy]propan-1-amine and thiophen-2-carbaldehyde in 81% yield as a pale yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:7]2)(=O)[CH3:2].[H][H]>>[CH2:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([NH:13][C:14](=[O:19])[C:15]([F:17])([F:16])[F:18])[CH2:7]2)[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(NC(=O)C(F)(F)F)C2
Reactant: [H][H]
Product: CCc1ccc2c(c1)CC(NC(=O)C(F)(F)F)C2

Procedure:
Preferably in Step (iii), N-(5-acetyl-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide is treated with hydrogen gas to form N-(5-ethyl-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide having Formula (XI)
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].[Cl:35][C:36]1[CH:41]=[C:40](Cl)[N:39]=[CH:38][N:37]=1>>[F:32][C:29]([F:31])([F:30])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][N:13]([C:40]3[CH:41]=[C:36]([Cl:35])[N:37]=[CH:38][N:39]=3)[C:12]2=[O:23])[CH2:24][CH2:25]1)=[O:7]
Reactant: Clc1cc(Cl)ncn1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(c1cc(Cl)ncn1)CN2c1ccccc1Cl

Procedure:
The title compound, MS: m/e=618.0 (100, M+H+), 620.0 (80, M+H+), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one and 4,6-dichloropyrimidine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](N)[C:7](=[CH:12][CH:13]=1)[S:8]([OH:11])(=[O:10])=[O:9])([O-])=O.OC1C2C(=C(S(O)(=O)=O)C(N)=CC=2)C=C(S(O)(=O)=O)C=1>O>[S:8]([OH:11])(=[O:10])([C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:13][CH:12]=1)=[O:9]
Reactant: Nc1cc([N+](=O)[O-])ccc1S(=O)(=O)O
Agent: Nc1ccc2c(O)cc(S(=O)(=O)O)cc2c1S(=O)(=O)O
Solvent: O
Product: Nc1ccc(S(=O)(=O)O)cc1
Reaction time: 1 h

Procedure:
4-Nitro-o-sulfanilic acid is diazotized and coupled neutrally to I acid. 43 mmol of this dye are dissolved in 200 ml water and indirectly diazotized. After stirring for 1 hour, the excess nitrous acid is removed with amidosulfonic acid and a solution of 43 mmol 4-hydroxy- 7-aminonaphthalene-2,8-disulfonic acid in 200 ml water is added. Coupling is completed overnight at pH 8-9, the dye is filtered under suction and the sulfo groups are split off by boiling for 12 h in a 1:1 mixture of water and N-methyl pyrrolidone containing 60 ml concentrated hydrochloric acid. This dye is diazotized and added dropwise to a solution in 100 ml water of 7.2 mmol of a dye obtained by acidic coupling of p-sulfanilic acid onto 4-amino-5-hydroxynaphthalene sulfonic acid. After stirring overnight, the dye is precipitated by addition of acetone, optionally dissolved and allowed to crystallize once more and then washed with aqueous acetone. 0.1 g dye are dissolved in 9.9 g Mowiol® 28-99 (a product of Hoechst AG) and 190 ml water and a 500μ thick layer is cast from this solution. After evaporation of the water, an approx. 50μ thick dark-blue film is obtained. The film is stretched by 500% at 130° C. The dichroic ratio (CR) is 15.3 at 650 nm.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.Br[CH2:14][CH2:15][CH3:16].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:14][CH2:15][CH3:16])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Oc1ccc2c(Cl)nccc2c1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1ccc2c(Cl)nccc2c1
Yield: 63.2 %

Procedure:
A mixture of 1-chloroisoquinolin-6-ol (0.898 g, 5 mmol), 1-bromopropane (1.230 g, 10.00 mmol), and K2CO3 (2.073 g, 15.00 mmol) in acetone (20 mL) was refluxed for 16 h. The reaction mixture was filtrated and washed with acetone. the filtrate was concentrated and purified by silica gel chromatography eluting with 10-20% ethyl acetate in hexane to give 700 mg of the product 1-chloro-6-propoxyisoquinoline as a solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.27-8.16 (m, 2H), 7.48 (d, J=5.8 Hz, 1H), 7.31 (dd, J=9.3, 2.5 Hz, 1H), 7.09 (d, J=2.5 Hz, 1H), 4.09 (t, J=6.5 Hz, 2H), 2.02-1.84 (m, 2H), 1.11 (d, J=14.8 Hz, 1H); MS: MS m/z 222.16 (M++1).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][C:16]3=[O:21])=[CH:11][CH:10]=2)[CH2:4]1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:28][C:29]1[S:33][C:32]([C:34](Cl)=[O:35])=[CH:31][CH:30]=1>O.CC(C)=O.C1(C)C=CC=CC=1>[Cl:28][C:29]1[S:33][C:32]([C:34]([NH:1][CH2:2][C@@H:3]2[O:7][C:6](=[O:8])[N:5]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][C:16]4=[O:21])=[CH:11][CH:10]=3)[CH2:4]2)=[O:35])=[CH:31][CH:30]=1
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Reactant: O=C(Cl)c1ccc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
1160 g of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one (VII) hydrochloride, 350 ml of water and 2.7 l of acetone are successively added to a solution of 464 g of sodium carbonate in 5.95 l of water at 10° C. At 8 to 12° C., 2535 g of 5-chlorothiophene-2-carbonyl chloride (IV) (30% strength solution in toluene) and a further 517 ml of toluene are added. The reaction mixture is then heated to 50° C., 2700 ml of acetone are added, and the mixture is stirred at 50 to 53° C. for a further 30 minutes. After cooling to 26° C., the precipitated reaction product is filtered off with suction and washed with water and acetone.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20]C)=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>CO>[CH2:3]([O:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([OH:20])=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCOc1cccc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCOc1cccc(C(=O)O)c1
Yield: 100 %

Procedure:
600 μL of 1 N sodium hydroxide solution (600 μmol) are added portionwise to 112 mg of 21 (366 μmol) in methanol (4 mL). The solution is refluxed for two hours. After evaporating off the solvent, the reaction medium is acidified with 0.5 N HCl and extracted with DCM. 107 mg of the expected acid are obtained in the form of a white solid, i.e. a yield of 99%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10](C=C)[N:9]2[C:16](=[O:20])[CH2:17][CH:18]=[CH2:19])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C>C(Cl)Cl.CC1C=C(C)C(N2[CH-]N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]3[N:9]2[C:16](=[O:20])[CH2:17][CH:18]=[CH:19]3)[CH:5]=[CH:6][CH:7]=1
Reactant: C=CCC(=O)N1[C@H](C=C)CCC[C@@H]1c1cccc(F)c1
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Agent: Cc1cc(C)c(N2[CH-]N(c3c(C)cc(C)cc3C)CC2)c(C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CC=C[C@@H]2CCC[C@H](c3cccc(F)c3)N12
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A solution of 1-[(2R*,6S*)-2-(3-fluorophenyl)-6-vinylpiperidin-1-yl]-3-buten-1-one (587 mg) and tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene][benzylidene]ruthenium (IV) dichloride (92 mg) in methylene chloride (250 mL) was heated under reflux in a nitrogen atmosphere for two hours. The reaction solution was left to cool to room temperature. Then, triethylamine (0.5 mL) was added thereto, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 460 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [C:1]1([N:7]2[C:11]([SH:12])=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.S(Cl)(Cl)=O.C1(N2C(=S)N(CCl)N=N2)C=CC=CC=1.[OH:33][C:34]1(C2C=CC3C(=CC=CC=3)C=2C(NOC(CCCCCCCCCCCC)C)=O)C=CC(O)=CC1.[O-]CC.[Na+]>C1C=CC=CC=1.CN(C=O)C>[C:1]1([N:7]2[C:11](=[S:12])[N:10]([CH2:34][OH:33])[N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: CCCCCCCCCCCCC(C)ONC(=O)c1c(C2(O)C=CC(O)=CC2)ccc2ccccc12
Agent: C=O
Agent: CC[O-]
Agent: S=c1n(CCl)nnn1-c1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: OCn1nnn(-c2ccccc2)c1=S

Procedure:
1-Phenyl-4-hydroxymethyltetrazolin-5-thione which was prepared from 1-phenyl-5-mercaptotetrazole and an excess amount of formaldehyde was reacted with 2 to 5 times on a molar basis of thionyl chloride in benzene at 50° C. for 3 hours to prepare 1-phenyl-4-chloromethyltetrazolin-5-thione. This was reacted with an equimolar amount of 1,4-dihydroxy-N-(2-tetradecyloxy)-phenylnaphthamide in DMF in the presence of 1.5 to 3 times on a molar basis of sodium ethoxide to obtain Coupler (42).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:14]=[CH:15][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:18]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)CCC(=O)c1ccc(Br)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: Cc1ccccc1
Product: COC(=O)CCC(=O)c1ccc(-c2ccc(OC)cc2)cc1

Procedure:
In a manner similar to Example 12, Step (b), (4-methoxyphenyl)boronic acid (0.913 g, 0.00601 mol) was allowed to react with 4-(4-bromo-phenyl)-4-oxo-butyric acid, methyl ester (1.356 g, 0.00500 mol) in the presence of tetrakis(triphenylphosphine)palladium(0) (0.173 g, 0.000150 mol) and 2.0 M aqueous sodium carbonate (5.0 mL, 0.010 mol) in toluene (10 mL) to give, after chromatography on silica gel (270 g, 230-400 mesh), eluting with dichloromethane (15×250 mL); dichloromethane-methanol (100:1, 19×225 mL; 50:1, 5×225 mL), 1.386 g of 4-(4′-methoxy-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester as a white solid; mp 96.0-100.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1CCCCC1>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:5]=[CH:15][C:16]([OH:18])=[O:17])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C=O)c(OC)c1Cl
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1ccc(C=CC(=O)O)c(OC)c1Cl
Yield: 95 %

Procedure:
A solution of compound (2a) (11.07 g, 55.2 mmol), malonic acid (8.639 g, 83 mmol) and piperidine (2 ml, 1.722 g, 20.2 mmol) in 80 ml of anhydrous pyridine was refluxed (bath temperature 110° C.) for 2 h. Reaction mixture was cooled, concentrated under vacuum and acidified 250 ml of 5% aqueous citric acid to a pH of 3. Resulted heterogeneous mixture was sonicated for a few minutes. The precipitated material was filtered off, washed with water (2×20 ml) and dried in vacuum over KOH to give 12.7 g (52.3 mmol, 95% yield) of pure (HPLC, 1H NMR) desired acid 3a as a white solid. 1H NMR (DMSO-d6): δ 7.77 (d, J=9.0 Hz, 1H), 7.67 (d, J=16.0 Hz, 1H), 7.01 (d, J=9.0 Hz, 1H), 6.51 (d, J=16.0 Hz, 1H), 3.90 (s, 3H), 3.77 (s, 3H).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][C:12]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:15](O)=[O:16])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O>[C:1]([N:9]1[CH2:14][CH2:13][C:12]2([CH2:18][C:19]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:15]2=[O:16])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCC(Cc2ccccc2)(C(=O)O)CC1
Solvent: O
Product: O=C(c1ccccc1)N1CCC2(CC1)Cc1ccccc1C2=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.2 %

Procedure:
A solution of 6.14 g (19.0 mmoles) 1-benzoyl-4-(phenylmethyl)-4-piperidinecarboxylic acid in 61 ml concentrated sulfuzic acid was stirred 18 hours at room temperature to give a deep red solution. The solution was carefully diluted with ice-bath cooling with 300 ml H2O and extracted with 3×300 ml ethyl acetate. The extract was washed with 25 ml water and brine, dried, and the solvent wam removed in vacuo to give a white foam. The foam was stirred under ether and filtered off to give 3.61 g (62%) product, m.p. 149°-154° C. 1H NMR (deuteriochloroform): δ1.50 (m, 2H), 2.00 (m, 2H), 3.12 (m, 2H), 3.25 (d of d of d, 2H), 3.90 (d, 1H), 4.62 (m, 1H), 7.43 (m, 7H), 7.63 (d of d, 1H), 7.79 (d, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:35])[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH2:29][C:30]3[NH:31][CH:32]=[CH:33][N:34]=3)[CH2:23][C:24]3[NH:25][CH:26]=[CH:27][N:28]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>CO>[NH:25]1[CH:26]=[CH:27][N:28]=[C:24]1[CH2:23][N:22]([CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:35])=[CH:20][CH:19]=1)[CH2:29][C:30]1[NH:34][CH:33]=[CH:32][N:31]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
The compound (111 mg) obtained in Example 32-1 was dissolved in anhydrous methanol (1.0 ml) and then added with a 4 mol/l hydrogen chloride/dioxane solution (3.0 ml) and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off and the residue was added with a 1 mol/l sodium hydroxide aqueous solution, followed by washing with dichloromethane. The aqueous layer was evaporated to dryness, followed by distilling azeotropically with chloroform. Consequently, the subject compound (48.5 mg) was obtained as a yellow oily substance.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][OH:14])=[O:6])#[N:2].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.N1C=CC=CC=1>C(#N)C>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:14][CH2:13][C@@H:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]2[C:5]([NH:4][CH2:3][C:1]#[N:2])=[O:6])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@H]1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCC[C@H]2C(=O)NCC#N)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To (1R,2R)-N-(cyanomethyl)-2-(hydroxymethyl)cyclohexanecarboxamide (62 mg, 0.31 mmol) in a 4 mL sample vial was added 4-toluenesulfonyl chloride (73 mg, 0.38 mmol), 0.63 mL acetonitrile and pyridine (33 SL, 0.41 mmol). The reaction mixture was stirred at ambient temperature for 5 h after which the solvent was removed on a rotary evaporator. Chromatography of the residue on silica gel with 4:96 methanol:chloroform as eluent provided ((1R,2R)-2-{[(cyanomethyl)amino]carbonyl}cyclohexyl)methyl 4-methylbenzenesulfonate as a colorless, waxy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:23]3=[C:24]([CH2:27][S:28][C:29](=O)[CH3:30])[CH:25]=[CH:26][N:22]3[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.N#N.C[O-].[Na+].BrCC[OH:40]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:23]3=[C:24]([CH2:27][S:28][CH2:29][CH2:30][OH:40])[CH:25]=[CH:26][N:22]3[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: OCCBr
Reactant: CC(=O)SCc1ccn2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Agent: C[O-]
Agent: N#N
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCSCc1ccn2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
A solution of thioacetic acid S-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl}ester (80 mg, 0.175 mmole) in dry THF (4 mL) was sparged with N2 for 15 min. NaOMe (0.40 mL, 0.5 M in MeOH, 1.1 equiv), 2-bromoethanol (0.013 mL, 1 equiv) were added and the reaction was left stirring at RT. After 16 h, the solvents were removed and the residue was partitioned between DCM and water. The organic phase was separated, dried (Na2SO4), and the solvent removed. Radial chromatography (silica gel plate eluted with DCM containing 0, 0.5, 1, 2% MeOH) afforded 2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethylsulfanyl}-ethanol (35 mg, 44%): 1H NMR (CDCl3) δ 2.73 (t, 2H, J=5.9 Hz), 3.81 (t, 2H, J=5.9 Hz), 4.11 (s, 2H), 5.13 (s, 2H), 6.55 (d, 1H, J=2.6 Hz), 6.92–7.93 (m, 10H), 8.99 (s, 1H). Solid m-chloroperbenzoic acid (19 mg, 58 to 70%, 1 equiv) was added to an ice-cooled solution of the alcohol (35 mg, 0.18 mmole) in CHCl3 (4 mL). After 1 h, this was removed from the bath and washed with a 6% aq. solution of NaHSO3, sat. aq. NaHCO3 (3×) and then dried (Na2SO4). Radial chromatography (silica gel plate eluted with DCM containing 0, 0.5, 1, 2, 3% MeOH) afforded the title compound (22 mg, 60%): MS: 475 (M+H)+; HPLC Ret Time: 1.66 min (YMC Xterra C18 S7, 3.0×50 mm column, 2 min gradient, 5 mL/min).