Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:13][CH2:14][O:15][CH3:16])[C:9](=[O:12])[CH2:10][NH:11][C:5]2=[N:4][CH:3]=1.C[Sn](C)(C)[C:19]1[CH:20]=[CH:21][C:22]([C:25]([OH:28])([CH3:27])[CH3:26])=[N:23][CH:24]=1>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:28][C:25]([C:22]1[N:23]=[CH:24][C:19]([C:2]2[N:7]=[C:6]3[N:8]([CH2:13][CH2:14][O:15][CH3:16])[C:9](=[O:12])[CH2:10][NH:11][C:5]3=[N:4][CH:3]=2)=[CH:20][CH:21]=1)([CH3:27])[CH3:26]
Reactant: CC(C)(O)c1ccc([Sn](C)(C)C)cn1
Reactant: COCCN1C(=O)CNc2ncc(Br)nc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COCCN1C(=O)CNc2ncc(-c3ccc(C(C)(C)O)nc3)nc21
Temperature: 140 °C
Yield: 38 %

Procedure:
7-Bromo-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1 equiv), 2-(5-(trimethylstannyl)pyridin-2-yl)propan-2-ol (See Example 5.E) (1 equiv) and dichlorobis(triphenylphosphine)-palladium(II) (0.2 equiv) were suspended in dimethylformamide. The reaction was purged with nitrogen and was heated to 140° C. for 2 h. The reaction was cooled to room temperature, filtered through Celite and washed with ethyl acetate. Volatiles were removed under reduced pressure and the resulting purple slurry was purified using silica gel column chromatography (0-100% (5% methanol in ethyl acetate) in hexanes). The desired fractions were combined and organic volatiles removed under reduced pressure. The solid was triturated in 5% ethyl acetate in hexanes and washed with hexanes to afford the desired product in 38% yield. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.02 (d, J=1.6 Hz, 1H), 8.27 (s, 1H), 8.24 (dd, J=8.6, 2.3 Hz, 1H), 7.71 (d, J=0.8 Hz, 1H), 7.69 (s, 1H), 5.25 (s, 1H), 4.28 (t, J=6.2 Hz, 2H), 4.20 (d, 2H), 3.60 (t, J=6.2 Hz, 2H), 3.26 (s, 3H), 1.46 (s, 6H); MS (ESI) m/z 344.3 [M+1]+.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:13]=[C:14](Br)[C:15]2[N:16]([C:18]([CH3:22])=[C:19]([CH3:21])[N:20]=2)[CH:17]=1>CN(C)C=O>[CH2:1]([O:8][C:14]1[C:15]2[N:16]([C:18]([CH3:22])=[C:19]([CH3:21])[N:20]=2)[CH:17]=[C:12]([Br:11])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: Cc1nc2c(Br)cc(Br)cn2c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2c(OCc3ccccc3)cc(Br)cn2c1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
34.8 ml of benzyl alcohol are added dropwise with ice-cooling to a suspension of 13.5 g of sodium hydride (60% strength suspension in paraffin) in 510 ml of dimethylformamide and the mixture is stirred for 1 h until the evolution of gas is complete. 51.2 g of 6,8-dibromo-2,3-dimethylimidazo[1,2-a]pyridine are then introduced in small portions and the mixture is stirred at room temperature for 40 h. It is then poured onto 1 l of ice water and extracted three times with 100 ml of dichloromethane each time. The combined organic extracts are washed with saturated ammonium chloride solution and twice with water, and concentrated to dryness in vacuo and the residue is stirred with a little ethyl acetate. The precipitate obtained here is filtered off and dried in vacuo. 43.2 g of the title compound of melting point 151–3° C. (ethyl acetate) are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:23]1[CH2:28][CH2:27][CH:26]([CH2:29][C:30](O)=[O:31])[CH2:25][CH2:24]1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)[C:30](=[O:31])[CH2:29][CH:26]2[CH2:27][CH2:28][O:23][CH2:24][CH2:25]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)CC1CCOCC1
Reactant: Cc1cccc(CNC2CCN(C(=O)OC(C)(C)C)CC2)c1
Product: Cc1cccc(CN(C(=O)CC2CCOCC2)C2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 42 %

Procedure:
Using general procedure E, 4-(3-methylbenzylamino)-piperidine-1-carboxylic acid tert-butyl ester (365 mg, 1.2 mmol) and (tetrahydropyran-4-yl)-acetic acid (173 mg, 1.2 mmol) afforded 4-[(3-methylbenzyl)-(2-tetrahydropyran-4-yl-acetyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (217 mg, 42%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].[N:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1>>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:30]([C:27]2[CH:26]=[CH:25][C:24]([C:21]3[CH:20]=[CH:19][N:18]=[CH:23][CH:22]=3)=[CH:29][CH:28]=2)(=[O:31])=[O:32])[C:4]1=[O:17])#[N:13]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccncc2)cc1
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Agent: Cl
Product: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3ccc(-c4ccncc4)cc3)C2=O)c1

Procedure:
The title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)benzonitrile hydrochloride (0.2 g, 0.79 mmol) as in EXAMPLE 24, Part B using 4-pyridin-4-ylbenzene sulfonyl chloride (0.50 g, 1.98 mmol) in place of 6-methoxynaphthalene-2-sulfonyl chloride. The crude product is purified by chromatography (2.5 to 5% MeOH/CH2Cl2) to obtain a white solid (0.25 g, 0.58 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[S:9][C:10]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=2[N:12]=1)([CH3:4])([CH3:3])[CH3:2].[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>CC(C)=O>[C:1]([O:5][C:6]([NH:7][C:8]1[S:9][C:10]2[CH:16]=[C:15]([O:17][S:24]([C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)(=[O:26])=[O:25])[CH:14]=[CH:13][C:11]=2[N:12]=1)=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc(O)cc2s1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)Nc1nc2ccc(OS(=O)(=O)c3cccs3)cc2s1
Yield: 76.1 %

Procedure:
A solution of (6-hydroxybenzothiazol-2-yl)carbamic acid tert-butyl ester (intermediate 14) (527 mg, 1.979 mmol), 2-thiophenesulfonyl chloride (433 mg, 2.37 mmol) and triethylamine (677 μl, 4.75 mmol) in 10 ml of acetone is stirred overnight at room temperature. The reaction medium is concentrated to dryness. The residue obtained is washed with water, with acetone and then with ethyl ether to give 621 mg of thiophene-2-sulfonic acid 2-tert-butoxycarbonylaminobenzothiazol-6-yl ester (light gray powder) in a yield of 76%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: Sc1ccc(Cl)cc1
Product: Cc1cc(Nc2cc3ccccc3c(Sc3ccc(Cl)cc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 305 was used, starting from 4-chloro-benzenethiol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-chloro-phenylsulfanyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 367 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[CH2:19]([O:26][C:27](=[O:32])[NH:28][CH2:29][CH2:30][NH2:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[CH2:19]([O:26][C:27](=[O:32])[NH:28][CH2:29][CH2:30][NH:31][C:4]1[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:2]([NH2:1])[N:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCCNC(=O)OCc1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(NCCNC(=O)OCc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (2-amino-ethyl)-carbamic acid benzyl ester hydrochloride and DBU in DME. ES-MS m/e (%): 401 (M+Na+, 20), 379 (M+H+, 100).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][C:10]=2[C:9]([CH:21]=O)=[CH:8][CH:7]=1.[CH:24]([NH2:26])=[O:25].[OH-].[Na+]>C(O)=O>[CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][C:10]=2[C:9]([CH2:21][NH:26][CH:24]=[O:25])=[CH:8][CH:7]=1
Reactant: NC=O
Reactant: CN(C)CCNc1ccc(C=O)c2sc3ccccc3c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CN(C)CCNc1ccc(CNC=O)c2sc3ccccc3c(=O)c12
Temperature: 170 °C

Procedure:
A mixture of 1-[[2-(dimethylamino)ethyl]amino]-9-oxothioxanthen-4-carboxaldehyde (4.75 g) , formamide (66.5 mL) and formic acid (7.6 mL) was heated at 170° C. for 4 hours. The mixture was poured into ice water (250 mL) , basified with 35% NaOH and extracted with chloroform. The organic layer was washed with water (2×), then brine (1×) and the solvent was dried over Na2SO4 and concentrated in vacuo to afford 6.2 g of N-[[1-[[2-(dimethylamino) ethyl]amino]-9-oxothioxanthen-4-yl ]methyl ]formamide.
Reaction SMILES: [Na].[Br:2][C:3]1[CH:4]=[N:5][C:6](Cl)=[N:7][CH:8]=1.[CH3:10][OH:11]>>[Br:2][C:3]1[CH:4]=[N:5][C:6]([O:11][CH3:10])=[N:7][CH:8]=1
Reactant: CO
Reactant: Clc1ncc(Br)cn1
Agent: [Na]
Product: COc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium metal (74 mg, 3.10 mmol) was added in portions to CH3OH (25 mL) at 0° C. and the mixture was stirred for 30 min at RT. 5-Bromo-2-chloropyrimidine (500 mg, 2.58 mmol) was added to the above mixture at 0° C., and the resulting reaction mixture was gradually heated to reflux temperature and stirred for 2 h. After complete consumption of the starting material (by TLC), the volatiles were concentrated under reduced pressure; the residue was quenched with ice-cold water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude S (400 mg). The crude material was used directly in the next step without any further purification.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(=O)(O)O.[CH:19]1([C@H:25]2[CH2:29][NH:28][C@H:27]([CH2:30][OH:31])[CH2:26]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)(=O)C>[CH:19]1([C@H:25]2[CH2:29][NH:28][C@H:27]([C:30]([OH:3])=[O:31])[CH2:26]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CC(C)=O
Reactant: OC[C@@H]1C[C@@H](C2CCCCC2)CN1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(O)[C@@H]1C[C@@H](C2CCCCC2)CN1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of Jones reagent (2 ml) was added sulfuric acid (0.5 ml) and acetic acid (2.5 ml). (2S-trans)-4-Cyclohexyl-2-pyrrolidinemethanol (0.5 g) in 5 ml of acetic acid was added to the above solution and after the addition, it was stirred at room temperature for 15 minutes. The reaction mixture was filtered through a Celite pad and washed with 10 ml of acetic acid. Isopropyl alcohol (2 ml) was added to the filtrate, stirred well, and a clear solution decanted and concentrated to a thick oil. The oil was dissolved in 5 ml of water and the pH was brought to 6.0 by the addition of concentrated ammonium hydroxide. The resultant precipitate was filtered, washed with 5 ml of water and excess ether, and vacuum dried to yield 0.42 g of (trans)-4-cyclohexyl-L-proline as a pink solid, which was crystallized from methanol to obtain colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]([F:38])([F:37])[C:13]([CH2:32][NH:33][CH2:34][CH2:35][CH3:36])([OH:31])[CH2:14][NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:33]([CH2:34][CH2:35][CH3:36])[CH2:32][C:13]([OH:31])([CH2:14][NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]([F:37])([F:11])[F:38])=[O:6]
Reactant: Cc1ccccc1C(=O)O
Reactant: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F
Product: CCCN(CC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccccc1C

Procedure:
Prepared similarly to Example 1 from 2-methylbenzoic acid and 1,1,1-trifluoro-3-[(1-phenyl-1H-indazol-4-yl)amino]-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([C:16](O)=[O:17])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.[NH3:32].Cl>C1COCC1.C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][C@@:9]([C:16](=[O:17])[NH2:32])([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: CCOC(=O)C[C@@](NC(=O)OC(C)(C)C)(C(=O)O)C(=O)OCC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@](NC(=O)OC(C)(C)C)(C(N)=O)C(=O)OCC
Yield: 73 %

Procedure:
A solution of (R)-1-ethyl hydrogen 3-t-butyloxycarbonylamino-3-ethoxycarbonylsuccinate (1.0 g) obtained in Example 14 in THF (20 mL) was added with triethylamine (0.62 mL) and isobutyl chloroformate (0.55 mL, 0.57 g) in this order at −15° C. with stirring, and the mixture was stirred for 30 minutes. A solution of 25% aqueous ammonia (0.30 mL) was dropped into the reaction mixture at the same temperature. The reaction mixture was stirred at the same temperature for 30 minutes, and then poured into diluted hydrochloric acid, the mixture was extracted with ethyl acetate, and then the extract was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, in which elution was performed with n-hexane/ethyl acetate (1:1) for purification, and then crystallized from ethyl acetate/n-hexane to obtain the title compound (0.67 g, yield: 73%) as colorless crystals. Optical rotation [α]D22 was +2.74° (c 0.50, ethanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[O:5][C:6]2[CH:20]=[C:19]([O:21]C(=O)C)[CH:18]=[CH:17][C:7]=2[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C[O-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:4](=[O:25])[O:5][C:6]2[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:7]=2[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1c(OCc2ccccc2)c2ccc(OC(C)=O)cc2oc1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1c(OCc2ccccc2)c2ccc(O)cc2oc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
To a mixture of 3.64 g of 3-methoxy-4-benzyloxy-7-acetoxy-2H-1-benzopyran -2-one (10.7 mmol) in 50 ml of methanol was added 0.58 g of sodium methoxide (10.7 mmol) and the mixture was stirred at room temperature for 1 hour. Then 2.31 g of Amberlyst-15 (Trademark: Organo corp.) was added, and the mixture was stirred at room temperature for 1 hour. Amberlyst-15 was filterd off, the filtrate was concentrated under reduced pressure. The precipitate was obtained during concentration and filtered to give 2.59 g of the title compound. (yield=77%)
Reaction SMILES: [OH-].[Na+].Br[CH2:4][CH2:5]Cl.[N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][C:18]#[N:19])=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3([C:18]#[N:19])[CH2:5][CH2:4]3)=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: ClCCBr
Reactant: N#CCc1ccc2ncccc2c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: N#CC1(c2ccc3ncccc3c2)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
60 mL of 50% aqueous sodium hydroxide was added to a mixture of 1-bromo-2-chloroethane (22.0 mL, 265 mmol), quinolin-6-ylacetonitrile (16.0 g, 66.6 mmol), and benzyltriethylammonium chloride (990 mg, 4.3 mmol) at 50° C. The reaction mixture was stirred at 50° C. for 3 h. After cooling to RT, the reaction mixture was poured into 100 mL water, and extracted with dichloromethane (3×100 mL). The combined organic extracts were dried over sodium sulfate, filtered through a pad of silica gel eluting with 20% ethyl acetate in dichloromethane. The filtrate was concentrated to give the desired product which was used in the next step without further purification. (12.4 g, 96%).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH2:29][CH:30]([CH3:32])[CH3:31])=[N:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=[CH:10][C:9]([NH:20][CH2:21][C:22]([O:24][C:25](C)(C)C)=[O:23])=[CH:8][CH:7]=2)#[N:2].FC(F)(F)C(O)=O.CI.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:1]([C:3]1[C:4]([CH2:29][CH:30]([CH3:32])[CH3:31])=[N:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)=[CH:10][C:9]([NH:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:8][CH:7]=2)#[N:2]
Reactant: Cc1ccc(-c2c(C#N)c(CC(C)C)nc3ccc(NCC(=O)OC(C)(C)C)cc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COC(=O)CNc1ccc2nc(CC(C)C)c(C#N)c(-c3ccc(C)cc3)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59 %

Procedure:
To a solution of tert-butyl N-[3-cyano-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]glycinate (3.0 g, 7.0 mmol) in tetrahydrofuran (10 ml) was added trifluoroacetic acid (820 ml), and the mixture was stirred at room temperature for 6 hrs. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl-acetate and water. The aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue (3.0 g) was dissolved in N,N-dimethylformamide (10 ml). Thereto were added methyl iodide (1.5 g, 5.3 mmol) and potassium carbonate (0.73 g, 5.3 mmol) and the mixture was stirred at room temperature for 2 days. The reaction mixture was partitioned between ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed successively with 0.1 M aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give methyl N-[3-cyano-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]glycinate (1.6 g, yield 79%) as a pale-yellow powder. Subsequently, methyl N-[3-(aminomethyl)-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]glycinate (1.0 g, yield 62%, pale-yellow powder) was synthesized by a method similar to the method shown in Example 25(2).
Reaction SMILES: [CH:1](=[CH:8][C:9](=[O:11])C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[O-:13].[Na+].O.[Br-].[K+]>C(Cl)(Cl)Cl>[C:9]([OH:11])(=[O:13])[CH:8]=[CH:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-]Cl
Reactant: CC(=O)C=Cc1ccccc1
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(O)C=Cc1ccccc1
Yield: 98.5 %

Procedure:
50 parts of benzalacetone are added slowly and in portions, in the course of 20 minutes at from 30° to 35° C, to a mixture of 900 parts by volume of sodium hypochlorite solution (containing 149 parts of sodium hypochlorite), 150 parts by volume of water and 1 part of potassium bromide. After a further reaction time of 1.5 hours at 40° C, the chloroform which has formed is separated off, the aqueous phase is acidified and the organic phase which forms is combined with the chloroform phase. The aqueous solution is extracted by shaking with a further 100 parts by volume of chloroform and the chloroform is distilled from the combined organic phases. 49.5 parts (98.5% of theory) of cinnamic acid melting at 122° C are obtained. ##SPC5##
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[S:12]([CH3:15])(=[O:14])=[O:13]>CO.[Pd]>[CH3:15][S:12]([C:3]1[CH:4]=[C:5]([CH2:8][C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:2]=1)(=[O:13])=[O:14]
Reactant: CC(=O)Cc1ccc(Cl)c(S(C)(=O)=O)c1
Agent: [Pd]
Solvent: CO
Product: CC(=O)Cc1cccc(S(C)(=O)=O)c1

Procedure:
A solution of 1-(4-chloro-3-methanesulphonyl-phenyl)-propan-2-one (5.49 g, 22.28 mmol) in methanol (250 ml) is stirred under hydrogen in the presence of 10% Pd on carbon (3 g) for 2 hours. The reaction mixture is filtered and concentrated in vacuo to yield a yellow oil of the titled compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]([CH3:44])([CH3:43])[C:20]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C:33]3[C:34](=[O:41])[NH:35][NH:36][C:37]=3[CH:38]([CH3:40])[CH3:39])=[C:28]([CH3:42])[CH:27]=2)=[O:21])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:45][C:46]([O:48][CH2:49][C@H:50]1[O:55][C@H:54](Br)[C@H:53]([O:57][C:58]([CH3:60])=[O:59])[C@@H:52]([O:61][C:62]([CH3:64])=[O:63])[C@H:51]1[O:65][C:66]([CH3:68])=[O:67])=[O:47].CC(OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O)=O>>[C:58]([O:57][C@@H:53]1[C@@H:52]([O:61][C:62](=[O:63])[CH3:64])[C@@H:51]([O:65][C:66](=[O:67])[CH3:68])[C@@H:50]([CH2:49][O:48][C:46](=[O:47])[CH3:45])[O:55][C@H:54]1[O:41][C:34]1[C:33]([CH2:32][C:29]2[CH:30]=[CH:31][C:26]([O:25][CH2:24][CH2:23][NH:22][C:20](=[O:21])[C:19]([C:17]([N:14]3[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])[CH2:16][CH2:15]3)=[O:18])([CH3:44])[CH3:43])=[CH:27][C:28]=2[CH3:42])=[C:37]([CH:38]([CH3:39])[CH3:40])[NH:36][N:35]=1)(=[O:59])[CH3:60]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: Cc1cc(OCCNC(=O)C(C)(C)C(=O)N2CCN(C(=O)OCc3ccccc3)CC2)ccc1Cc1c(C(C)C)[nH][nH]c1=O
Agent: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCNC(=O)C(C)(C)C(=O)N3CCN(C(=O)OCc4ccccc4)CC3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 17 using 4-[(4-{2-[2-{[4-(benzyloxycarbonyl)piperazin-1-yl]carbonyl}-2-(methyl)propionylamino]ethoxy}-2-methylphenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-galactose instead of 4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-glucose, respectively.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([CH2:17]Br)[N:3]=1.[CH3:19][NH:20][CH3:21]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([CH2:17][N:20]([CH3:21])[CH3:19])[N:3]=1
Reactant: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(CBr)n1
Reactant: CNC
Solvent: CCO
Product: CN(C)Cc1nc(N)nc(N)c1-c1ccc(Cl)cc1Cl

Procedure:
This compound was prepared from 2,4-diamino-5-(2,4-dichlorophenyl)-6-bromomethyl-pyrimidine (Example 53) by reaction with dimethylamine in ethanol at room temperature, mp. 170°-172° C.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[CH3:22][O:23][C:24]1[CH:29]=[C:28]([C:2]2[C:3]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=3)[CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)c1
Yield: 82.2 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, using methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv) and 3-methoxyphenylboronic acid (86.13 mg, 0.57 mmol, 2.00 equiv) as reactants. Purification via silica gel column (dichloromethane/methanol (10:1)) yielded 85 mg (80%) of 3-(3-methoxyphenyl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.