Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[C:13]([N+:28]([O-])=O)[C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=3[F:27])=[C:15]([CH3:18])[C:16](=[O:17])[N:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].C(OC(=O)C)C>O.C1COCC1.[Zn]>[C:1]([O:5][C:6]([N:8]1[C:12]2=[C:13]([NH2:28])[C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=3[F:27])=[C:15]([CH3:18])[C:16](=[O:17])[N:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(Nc2ccc(I)cc2F)c([N+](=O)[O-])c2n(c1=O)CCN2C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCN2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
Zinc (296 mg, 0.005 mol) was added to a stirred solution of 7-(2-fluoro-4-iodo-phenylamino)-6-methyl-8-nitro-5-oxo-2,3-dihydro-5H-imidazo[1,2-a]pyridine-1-carboxylic acid tert-butyl ester (400 mg, 0.0008 mol) and NH4Cl (322 mg, 0.006 mol) in water and THF (15 mL). The resulting mixture was stirred at room temperature for 30 minutes. The reaction was monitored by TLC (100% ethylacetate). The reaction mixture was concentrated and partitioned between ethylacetate and water. The organic layer was washed with saturated NaHCO3 solution and concentrated to afford 350 mg of the crude product which was used in the next step without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH:3](O)[CH2:4][N+:5]([O-:7])=[O:6].S(Cl)(C)(=O)=O.C(N(CC)CC)C.O>ClCCl>[CH3:1][CH:2]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH:3]=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: CC(C)CC(C)C(O)C[N+](=O)[O-]
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)CC(C)C=C[N+](=O)[O-]
Reaction time: 1.5 h
Yield: 84.2 %

Procedure:
After dissolving 9.0 g of 3,5-dimethyl-1-nitro-2-hexanol in 100 ml of dichloromethane, 6.5 g of mesyl chloride and 10.4 g of triethylamine were gradually dropped thereto at 4° C., respectively. The temperature of the solution was allowed to rise to room temperature, and the solution was stirred for 1.5 hours. Water was added to stop the reaction, and the solution was extracted with dichloromethane. The organic layer was dried with magnesium sulfate and concentrated, and then purified by silica gel chromatography (hexane/ethyl acetate=10/1), thereby obtaining 6.8 g of 3,5-dimethyl-1-nitrohex-1-ene (yield: 83.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]23[O:16][CH:8]2[C:9](=[O:15])[C:10]([CH3:14])([CH3:13])[CH2:11][CH2:12]3)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9](=[O:15])[C:8]=2[OH:16])=[CH:17][CH:18]=1
Reactant: CC1(C)CCC2(Cc3ccc(Cl)cc3)OC2C1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC1(C)CCC(Cc2ccc(Cl)cc2)=C(O)C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
38.7 g (146 mmol) 1-(4-chlorobenzyl)-1,2-epoxy-4,4-dimethylcyclohexan-3-one obtained in Example 2 above was added to a slurry of potassium tert-butoxide (33 g, 294 mmol) in tert-butanol (200 ml) at 40° C. The mixture was then warmed to 60 C and stirred for 2 hours before being cooled in ice and quenched with water (50 ml). 5M Hydrochloric acid (100 ml) was then added slowly followed by water (300 ml). The mixture was then cooled to 0° C., filtered and the residue washed with water (100 ml). Drying under vacuum at 40° C. gave 36.3 g 1-(4-chlorobenzyl)-2-hydroxy-4,4-dimethylcyclohex-1-en-3-one, m.pt. 80-82° C.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][CH:7]([CH3:14])[CH2:8][C:9]([O:11]CC)=[O:10].C(N(CC)CC)C.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH3:5][O:4][C:2]([NH:6][CH:7]([CH3:14])[CH2:8][C:9]([OH:11])=[O:10])=[O:3]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)CC(C)N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)NC(C)CC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl chloroformate (0.071 mL, 0.91 mmol) was added to a solution of ethyl 3-aminobutanoate (0.10 g, 0.76 mmol) (Aldrich, Cat. #E10556) and triethylamine (0.16 mL, 1.1 mmol) in tetrahydrofuran (2.0 mL) at r.t. After stirring at r.t. for 30 min, the mixture was diluted with water, and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was dissolved in methanol (3.0 mL) and water (1.0 mL). To the solution was added lithium hydroxide monohydrate (0.049 g, 1.2 mmol). The reaction mixture was stirred at r.t. overnight. The mixture was adjusted to pH=2 with aqueous HCl, and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to afford the desired product.
Reaction SMILES: [CH2:1]([O:3][CH:4]=[CH2:5])[CH3:2].C1C2NC3C(=CC=CC=3)SC=2C=CC=1.[C:20]([OH:25])(=[O:24])[C:21]([CH3:23])=[CH2:22].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>>[C:20]([O:25][CH:1]([O:3][CH2:4][CH3:5])[CH3:2])(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: C=COCC
Reactant: C=C(C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Product: C=C(C)C(=O)OC(C)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In 144.2 parts by weight (2 mol equivalent) of ethylvinyl ether, 0.5 parts by weight of phenothiazine were added. Then, 86.1 parts by weight (1 mol equivalent) of methacrylic acid were added dropwise while cooling the reaction system at 10° C. or less, and the mixture was stirred for 4 hours at room temperature (25° C.). After adding 5.0 parts by weight of pyridinium p-toluenesulfonate, the mixture was stirred for 2 hours at room temperature and allowed to stand overnight at room temperature. To the reaction solution, 5 parts by weight of sodium hydrogen carbonate and 5 parts by weight of sodium sulfate were added, and the mixture was stirred for 1 hour at room temperature. After removing insoluble substances by filtering, the resultant solution was concentrated under reduced pressure at 40° C. or lower. The residue, a yellow oily substance, was distilled under reduced pressure, thereby obtaining a colorless oily substance, i.e., 134.0 parts by weight of 1-ethoxyethyl methacrylate (MAEVE) as a fraction having a boiling point (b.p.) of 43 to 45° C. at 7 mmHg.
Reaction SMILES: C(O)(=O)C1C(=CC=CC=1)C(O)=O.[C:13]([C:15](=[N:19][O:20][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:23])[CH3:22])[C:16]([NH2:18])=[NH:17])#[N:14].BrBr.[S-:31][C:32]#[N:33].[K+]>CO.O.CN(C)C=O.C(N(CC)CC)C>[NH2:33][C:32]1[S:31][N:18]=[C:16]([C:15](=[N:19][O:20][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:23])[CH3:22])[C:13]#[N:14])[N:17]=1
Reactant: N#C[S-]
Reactant: CCOC(=O)C(C)(C)ON=C(C#N)C(=N)N
Agent: BrBr
Agent: O=C(O)c1ccccc1C(=O)O
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)ON=C(C#N)c1nsc(N)n1
Reaction time: 1 h

Procedure:
To a suspension of phthalic acid salt (10.0 g) of 2-cyano-2-(1-ethoxycarbonyl-1-methylethoxyimino)acetamidine in methanol (60 ml) were added dropwise triethylamine (9.01 g) and bromine (3.67 g) at -15°~10° C. After stirring for 15 minutes at the same temperature, N,N-dimethylformamide (6.0 ml) and a solution of potassium thiocyanate (2.23 g) in methanol (22.3 ml) were added dropwise thereto at -15°~10° C. After stirring for one hour at -5°~0° C., the solution was poured into cold water (300 ml) and the mixture was stirred for one hour under ice-cooling. The resulting precipitate was collected by filtration, washed with cold water (60 ml) and dried under reduced pressure to give 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-ethoxycarbonyl-1-methylethoxyimino)acetonitrile (3.82 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:11]([C:16]([O:18][CH3:19])=[O:17])C(OC)=O.O.[Cl-].[Li+].[Cl-].[Na+].Cl.[CH3:26]S(C)=O>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:16]([O:18][CH2:19][CH3:26])=[O:17]
Reactant: CS(C)=O
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1F
Temperature: 100 °C

Procedure:
500 mg (1.84 mmol) of dimethyl (2-fluoro-4-nitrophenyl)malonate are dissolved in 10 ml of DMSO. 33.2 mg (1.84 mmol) of water and 313 mg (7.37 mmol) of lithium chloride are added, and the mixture is heated at 100° C. for 3 hours. The reaction solution is then poured into 30 ml of ethyl acetate and shaken with saturated sodium chloride solution and with dilute hydrochloric acid. The mixture is dried over sodium sulfate and the solvent is removed under reduced pressure. The oil obtained is purified by preparative HPLC. The product fractions are extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is removed under reduced pressure. This gives an oil which, after seeding with product crystals, quickly crystallizes.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:12]([C:16]4[CH:17]=[N:18][NH:19][CH:20]=4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:28])=[O:5])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.Br[CH:41]1[CH2:46][CH2:45][S:44](=[O:48])(=[O:47])[CH2:43][CH2:42]1>C(OCC)(=O)C>[CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:12]([C:16]4[CH:20]=[N:19][N:18]([CH:42]5[CH2:41][CH2:46][CH2:45][S:44](=[O:48])(=[O:47])[CH2:43]5)[CH:17]=4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:28])=[O:5])[CH2:2][CH2:3]1
Reactant: O=S1(=O)CCC(Br)CC1
Reactant: C[C@H]1CCc2c(ccc(-c3cn[nH]c3)c2Oc2ccccc2)N1C(=O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H]1CCc2c(ccc(-c3cnn(C4CCCS(=O)(=O)C4)c3)c2Oc2ccccc2)N1C(=O)C1CC1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A 100-mL, round-bottom flask was charged with (S)-cyclopropyl(2-methyl-5-phenoxy-6-(1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone (0.200 g, 0.56 mmol), cesium carbonate (0.114 g, 0.35 mmol), N,N-dimethylformamide (5 mL), and 4-bromo-1λ6-thiane-1,1-dione (0.114 g, 0.53 mmol). The resulting mixture stirred at 100° C. for 4 h and was then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (3×10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (gradient elution with 25-50% ethyl acetate/petroleum). The product was further purified by preparative-HPLC with the following conditions (Waters I): Column, SunFire Prep C18, 5 um, 19×100 mm; mobile phase, Water and acetonitrile (55% to 75% acetonitrile in 7 min, flow rate: 20 mL/min); Detector, UV 220&254 nm. This afforded 3-{4-[(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl}-1λ6-thiane-1,1-dione (0.122 g, 43%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 0.76-0.82 (m, 1H), 0.92-1.02 (m, 2H), 1.13-1.22 (m, 4H), 1.42-1.50 (m, 1H), 1.95-2.08 (m, 3H), 2.08-2.13 (m, 1H), 2.14-2.37 (m, 3H), 2.68-2.77 (m, 1H), 3.11-3.19 (m, 2H), 3.37 (s, 1H), 3.53-3.60 (m, 1H), 4.66-4.72 (m, 1H), 4.74-4.81 (m, 1H), 6.79 (d, J=8.00 Hz, 2H), 6.98 (t, J=7.60 Hz, 1H), 7.23 (t, J=7.60 Hz, 2H), 7.62 (d, J=8.40 Hz, 1H), 7.83 (s, 1H), 8.05 (s, 1H). MS (ESI, pos. ion) m/z 506 [M+H]+.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]2[C:14]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:15][O:16][CH:17]=2)=[CH:7][N:6]=1)=[O:4].[NH2:25][CH2:26][CH:27]1[CH2:29][CH2:28]1>>[CH:27]1([CH2:26][NH:25][C:3]([C:5]2[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]3[C:14]([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)=[N:15][O:16][CH:17]=3)=[CH:7][N:6]=2)=[O:4])[CH2:29][CH2:28]1
Reactant: COC(=O)c1cnc(OCc2conc2-c2ccc(F)cc2)cn1
Reactant: NCC1CC1
Product: O=C(NCC1CC1)c1cnc(OCc2conc2-c2ccc(F)cc2)cn1
Yield: 52 %

Procedure:
As described for example 13 g, 5-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-pyrazine-2-carboxylic acid methyl ester (75 mg, 0.23 mmol) was converted, using aminomethylcyclopropane instead of 2,2,2-trifluoroethylamine, to the title compound (44 mg, 52%) which was obtained as a light yellow solid. MS: m/e=427.0 [M+OAc]+.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][N:5]([C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=O)[C:4](=[O:13])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:20]([Li])[CH2:21][CH2:22][CH3:23]>O1CCCC1.CCCCCC>[CH3:11][C:7]([N:5]1[CH2:6][C:2]([CH3:1])=[C:3]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:4]1=[O:13])([CH3:12])[C:8](=[O:10])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)O)C1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC(=O)C(C)(C)N1CC(C)=C(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.7 %

Procedure:
5 g (19.3 mmol) of 2-(4-methyl-2-oxo-3-phenyl-3-pyrrolin-1-yl)isobutyric acid was dissolved in 50 ml of tetrahydrofuran, and a solution of 41 g (97 mmol) of 15% n-butyl lithium in n-hexane was dropwise added at 0° C. under a nitrogen stream. After completion of the dropwise addition, the mixture was stirred at room temperature for one day. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was treated by a conventional method, and the crude product thereby obtained was purified by column chromatography to obtain 2.7 g (yield: 47%) of the desired product having a melting point of from 87° to 89° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([N:6]1[CH2:11][CH2:10][CH2:9][CH:8]([NH:12][C:13]([NH:15][C:16]2[N:17]=[C:18]3[CH:24]=[CH:23][N:22](COCC[Si](C)(C)C)[C:19]3=[N:20][CH:21]=2)=[O:14])[CH2:7]1)=[O:5])#[N:2].F[B-](F)(F)F.[Li+].C(N)CN>O.C(#N)C>[C:1]([CH2:3][C:4]([N:6]1[CH2:11][CH2:10][CH2:9][CH:8]([NH:12][C:13]([NH:15][C:16]2[N:17]=[C:18]3[CH:24]=[CH:23][NH:22][C:19]3=[N:20][CH:21]=2)=[O:14])[CH2:7]1)=[O:5])#[N:2]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCN(C(=O)CC#N)C3)cnc21
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: O
Solvent: CC#N
Solvent: NCCN
Product: N#CCC(=O)N1CCCC(NC(=O)Nc2cnc3[nH]ccc3n2)C1
Temperature: 85 °C
Reaction time: 24 h
Yield: 14 %

Procedure:
A mixture of 1-[1-(2-cyano-acetyl)-piperidin-3-yl]-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (0.09 g, 0.197 mmol) and lithium tetrafluoroborate (0.184 g, 1.967 mmol) in 2 mL of a 9/1 mixture of acetonitrile and H2O was stirred at 85° C. for 24 hours before being cooled to RT (almost no solvent left). The reaction mixture was diluted in 2 mL of a 9/1 mixture of acetonitrile and H2O, ethylenediamine (0.066 mL, 0.983 mmol) was added and the resulting mixture was stirred at RT for 3 hours before being evaporated. The residue was partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was back extracted twice with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and evaporated. The fairly insoluble residue was adsorbed onto silica purified by SiO2 flash chromatography (DCM/(DCM:MeOH:NH4OH 60:10:1] 90% to 0% DCM) to give 0.008 g of (1-[1-(2-cyano-acetyl)-piperidin-3-yl]-3-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-urea (14% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([Cl:15])=[C:11](Cl)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23][OH:24])=[CH:21][CH:20]=1.[OH-].[K+]>CN(C)C=O>[Cl:15][C:12]1[C:13](=[O:14])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[CH:10][C:11]=1[O:24][CH2:23][C:22]1[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:27])[F:28])=[CH:26][CH:25]=1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=c1c(Cl)c(OCc2ccc(C(F)(F)F)cc2)cnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.7 %

Procedure:
In 30 ml of N,N-dimethylformamide were dissolved 1.0 g (3.6 m mol) of 2-(4-chlorophenyl)-4,5-dichloro-3(2H)-pyridazinone and 0.64 g (3.6 m mol) of p-trifluoromethylbenzyl alcohol, and thereto was added 0.24 g of powdery potassium hydroxide. The reaction mixture was stirred at room temperature for one day. Then, the procedures in Synthesis Example 2 were repeated to give 900 mg of the intended compound.
Reaction SMILES: [S:1](=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:7][CH:6]([C:14]([O:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[C:19]([O:27][CH3:28])[CH:18]=2)=[O:15])[CH2:5]1)(=[O:3])=[O:2].O.O[Li].O>C1COCC1>[S:1](=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:7][CH:6]([C:14]([O:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[C:19]([O:27][CH3:28])[CH:18]=2)=[O:15])[CH2:5]1)(=[O:2])=[O:3]
Reactant: COC(=O)c1ccc(OC(=O)C2CC(=S(=O)=O)c3ccccc3O2)cc1OC
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC(=O)C2CC(=S(=O)=O)c3ccccc3O2)ccc1C(=O)O
Temperature: 45 °C

Procedure:
To a stirred solution of methyl 4-[4-sulfonylchromanoyloxy]-2-methoxybenzoate (500 mg, 1.38 mmol) in THF:H2O (18 mL: 2 mL) was added LiOH.H2O (175 mg, 4.14 mmol). The reaction was heated to 45° C. over 12 h and then cooled to ambient temperature. The solvent was removed under reduced pressure. The crude solid was passed through a plug of silca gel packed in 50:50 MeOH:CH2Cl2 and eluted with same. The solvent was removed under reduced pressure to afford 4-[4-sulfonylchromanoyloxy]-2-methoxybenzoic acid as a white solid.
Reaction SMILES: [C:1]([C:9]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]([O:28][CH3:29])=[CH:16][C:10]=1[C:11]([O:13]CC)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C.Cl>C(OCC)(=O)C>[C:1]([C:9]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]([O:28][CH3:29])=[CH:16][C:10]=1[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(OC)c(OCc2ccccc2)cc1C(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(C(=O)O)c(C(=O)c2ccccc2)cc1OCc1ccccc1
Yield: 99 %

Procedure:
A mixture of ethyl 2-benzoyl-4-benzyloxy-5-methoxy-benzoate (reference example 11-1) (947 mg), a 2 mol/L aqueous solution of sodium hydroxide (3.64 mL) and ethanol (12 mL) was stirred at 70° C. for 3 hours. Ethyl acetate and 2 mol/L hydrochloric acid were added to the mixture. The separated organic layer was washed with water and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.87 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:30])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21](Cl)[C:22]3[C:27]([CH3:28])=[CH:26][S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1>>[CH3:10][O:11][C:12](=[O:30])[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:20]=[C:21]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:22]3[C:27]([CH3:28])=[CH:26][S:25][C:23]=3[N:24]=2)=[CH:17][CH:18]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(C)csc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(F)cc3)c3c(C)csc3n2)cc1

Procedure:
The reaction procedure as above wherein 4-fluorobenzylamine is reacted with 4-(4-chloro-5-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(4-fluorobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=2)=[CH:7][CH:6]=1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl.O1CCCC1>[CH2:21]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=2)=[CH:19][CH:20]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccccc1
Reactant: CNCCc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CN(CCc1ccc(Oc2ccc(C(N)=O)cn2)cc1)Cc1ccccc1
Yield: 58 %

Procedure:
Combine 6-[4-(2-Methylamino-ethyl)-phenoxy]-nicotinamide (135 mg, 0.5 mmol), benzaldehyde (53 μL, 0.52 mmol), sodium triacetoxyborohydride (0.21 g, 1.0 mmol), acetic acid (30 μL, 0.52 mmol), tetrahydrofuran (1 mL), and 1,2-dichloroethane (5 mL) then stir at room temperature for 18 hours. Dilute the reaction with saturated aqueous sodium bicarbonate solution and extract with ethyl acetate (3×50 mL). Dry the combined ethyl acetate extracts with sodium chloride/magnesium sulfate, filter, and concentrate on a rotary evaporator to yield 200 mg of the crude product. The crude product is purified by flash column chromatography on silica gel eluting with (0.5% conc. ammonium hydroxide/5% ethanol) to (1% conc. ammonium hydroxide/10% ethanol) in chloroform to yield 6-{4-[2-(benzyl-methyl-amino)-ethyl]-phenoxy}-nicotinamide (106 mg, 0.29 mmol): m/z=362.07 (M+1); 1H NMR (CDCl3, 300.00 MHz): 8.58 (s, 1H); 8.16 (dd, 3.0 Hz, 1H); 7.33-7.22 (m, 7H); 7.05 (d, 2H); 6.95 (d, 1H); 5.86 (br s, 2H); 3.63 (s, 2H), 2.89-2.72 (m, 4H); 2.34 (s, 3H), HPLC=100% (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax® SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([NH2:12])[CH:10]=[CH:11][C:5]2=[N:4][CH:3]=1.[CH2:13]([N:15]=[C:16]=[O:17])[CH3:14]>N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([NH:12][C:16]([NH:15][CH2:13][CH3:14])=[O:17])[CH:10]=[CH:11][C:5]2=[N:4][CH:3]=1
Reactant: CCN=C=O
Reactant: Nc1ccc2ncc(Cl)nc2n1
Solvent: c1ccncc1
Product: CCNC(=O)Nc1ccc2ncc(Cl)nc2n1
Temperature: 75 °C

Procedure:
100 mg 3-chloropyrido[2,3-b]pyrazine-6-yl-amine (0.55 mmol) was presented in 5 ml predried pyridine and add 44 μL ethyl isocyanate (0.55 mmol) at room temperature. The mixture was stirred at 75° C. and then a total of 132 μL ethyl isocyanate (1.65 mmol) was added again over 18 hours to the reaction mixture in small amounts. Then the volatile components were removed in vacuum. The resulting solid was cleaned through column chromatography on silica gel (solvent dichloromethane/methanol). A light yellow solid was obtained.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[C@@H:17]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][NH:18]2)[CH:12]=[CH:11][C:10]=1[N:27]1[S:31](=[O:33])(=[O:32])[N:30](CC[Si](C)(C)C)[C:29](=[O:40])[CH2:28]1)C1C=CC=CC=1.[C:41]1([S:47](Cl)(=[O:49])=[O:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:41]1([S:47]([N:18]2[C@H:17]([CH2:16][CH2:15][C:13]3[CH:12]=[CH:11][C:10]([N:27]4[S:31](=[O:33])(=[O:32])[NH:30][C:29](=[O:40])[CH2:28]4)=[C:9]([OH:8])[CH:14]=3)[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)(=[O:49])=[O:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/[C@@H]3Cc4ccccc4CN3)cc2OCc2ccccc2)S1(=O)=O
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=C1CN(c2ccc(CC[C@@H]3Cc4ccccc4CN3S(=O)(=O)c3ccccc3)cc2O)S(=O)(=O)N1

Procedure:
The title compound is prepared from 5-{2-benzyloxy-4-[(E)-(S)-2-(1,2,3,4-tetrahydroisoquinolin-3-yl)-vinyl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and benzenesulfonyl chloride analogous to Example 200, steps F, G and H: LC retention time=1.26 min (Method A); (M+NH4)+=545.