Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]Cl.[Cl:3][C:4]1[C:5]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:6]=2[S:7][C:8]=1[C:9]([Cl:11])=[O:10]>C(Cl)(Cl)Cl>[Cl:3][C:4]1[C:5]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:1])[C:6]=2[S:7][C:8]=1[C:9]([Cl:11])=[O:10]
Reactant: ClCl
Reactant: COc1ccc2c(Cl)c(C(=O)Cl)sc2c1
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(Cl)c(C(=O)Cl)sc2c1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 63.8 %

Procedure:
Chlorine (24 g) is bubbled into a stirred suspension of 3-chloro-6-methoxy-benzo[b]thiophene-2-carbonyl chloride (9.2 g, 35 mmoles) in chloroform (200 mls) over a period of 30 minutes. After an additional 45 minutes of stirring at room temperature the mixture is stripped of volatiles under reduced pressure. The residue is recrystallized from tetrahydrofuran (100 mls) to afford the pure product (6.6 g): mp=174°-175° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:56][C:57]([F:61])([F:60])[CH2:58][NH2:59]>CN(C=O)C>[F:56][C:57]([F:61])([F:60])[CH2:58][NH:59][C:30]([C:26]1[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]2\[C:17](=[O:22])[NH:18][C:19]3[C:15]\2=[CH:14][C:13]([S:10]([CH2:9][C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:12])=[O:11])=[CH:21][CH:20]=3)[NH:28][C:27]=1[CH3:29])=[O:31]
Reactant: NCC(F)(F)F
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.2 mmol), HOBt (32 mg, 1.2 eq.), EDAC.HCl (45 mg, 1.2 eq.), TEA (0.068 mL, 2.5 eq.) and 2,2,2-trifluoro-ethylamine (48 mg, 2.5 eq.) in DMF (2 mL) was stirred at rt for 7 days. The reaction was concentrated, diluted with DCM, washed with sat. NaHCO3 and water, dried, concentrated and triturated with methanol to give the titled compound as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[C:30]([CH3:32])[CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:59][C:60]1[CH:61]=[C:62]([CH2:68][NH2:69])[CH:63]=[CH:64][C:65]=1[O:66][CH3:67]>ClCCl.CCOC(C)=O>[Br:59][C:60]1[CH:61]=[C:62]([CH2:68][NH:69][C:26]([C:25]2[CH:29]=[C:30]([CH3:32])[CH:31]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:33][CH3:34])=[O:22])[CH:24]=2)=[O:27])[CH:63]=[CH:64][C:65]=1[O:66][CH3:67]
Reactant: COc1ccc(CN)cc1Br
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(OC)c(Br)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[({[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-5-methylbenzoic acid (0.931 g, 2 mmol) was partially dissolved in the dichloromethane (DCM) (50 mL), and then HBTU (0.758 g, 2.000 mmol) was added followed sequentially by {[3-bromo-4-(methyloxy)phenyl]methyl}amine (0.432 g, 2.000 mmol) and TEA (0.558 mL, 4.00 mmol). The mixture was allowed to stir under argon overnight at room temperature. The solvent was removed on a rotavap to give the crude product. The residue was taken up in EtOAc (100 mL) and washed 3× with water (50 mL), 1× with brine, dried over anhydrous Na2SO4 filtered and the solvent concentrated. The residue was taken up in methylene chloride and absorbed on Isolute® Sorbent and purified by CombiFlash on an 80 g silica column eluted with 0-10% DCM/MeOH to give the title compound as a white solid. LC-MS m/z 663.0 (M+H)+, 0.91 min (ret time); mp 123-126° C.; analytical HPLC shows 97.6% purity, (ret time 13.411 min).
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[Mg].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH:11]=[O:12].S(=O)(=O)(O)O>C(OCC)C>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:11]([OH:12])[CH:2]([CH3:4])[CH3:3])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC(C)Br
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: COc1ccc(C(O)C(C)C)cc1OC
Temperature: 0 °C
Yield: 99.6 %

Procedure:
An isopropyl magnesium bromide ether solution prepared by using 5.6 g of 2-bromopropane, 0.94 g of magnesium and 30 ml of diethyl ether, was dropwise added to a mixture comprising 5.0 g of 3,4-dimethoxybenzaldehyde and 50 ml of diethyl ether, followed by a reaction for 15 hours under reflux. The reaction mixture was put into ice water, and dilute sulfuric acid was added, followed by stirring. Then, the mixture was extracted with methylene chloride, followed by washing with water. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 6.3 g of oily 1-(3′,4′-dimethoxyphenyl)-2-methylpropanol.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[S:8][C:4]=2[CH:3]=1.[CH3:15][CH2:16][O:17][P:18](Cl)([O:20][CH2:21][CH3:22])=[O:19].Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:15][CH2:16][O:17][P:18]([O:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[S:8][C:4]=2[CH:3]=1)([O:20][CH2:21][CH3:22])=[O:19]
Reactant: NS(=O)(=O)c1nc2ccc(O)cc2s1
Reactant: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CCOP(=O)(OCC)Oc1ccc2nc(S(N)(=O)=O)sc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.4 %

Procedure:
To a stirred solution of 6-hydroxy-2-benzothiazolesulfonamide (2.3 g, 0.01 mole) and 4-dimethylaminopyridine (200 mg) in pyridine (20 ml) was added chlorodiethylphosphate (1.45 ml, 0.01 mole). After stirring for 4 hours at 25° C. additional chlorodiethylphosphate (1.5 ml) was added and the reaction mixture was stirred at 25° C. for 18 hours then poured into ice water and excess hydrochloric acid to give 1.15 g of diethyl(2-sulfamoyl-6-benzothiazolyl)phosphate m.p. 142°-144° C. after recrystallization from ethylene chloride.
Reaction SMILES: OCC[N:4]1[C:8](=[O:9])[CH:7]([CH3:10])[S:6][CH:5]1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.N1C=CC=CC=1.S(Cl)(Cl)=O>C(Cl)Cl>[CH3:10][CH:7]1[S:6][CH:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[NH:4][C:8]1=[O:9]
Reactant: CC1SC(c2cccnc2)N(CCO)C1=O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1SC(c2cccnc2)NC1=O
Reaction time: 5 h
Yield: 20.3 %

Procedure:
3-(2-Hydroxyethyl)-5-methyl-2-(3-pyridyl)- thiazolidin-4-one (18.75 g, 78.7 mmol) was dissolved in methylene chloride (200 ml). Pyridine (9.55 ml, 118 mmol) was added and further, thionyl chloride (20 ml, 274 mmol) was added dropwise over 2 hours at 0 to 5° C. This reaction mixture was kept between those temperatures for 5 hours. The resulting mixture was washed with aqueous NaHCO3 and aqueous NaCl, dried, and the solvent was removed in vacuo. The residue was chromatographed on silica gel and upon recrystallization from hexane-ether, gave 2,5-cis-3-(2-chloroethyl)-5-methyl-2-(3-pyridyl)thiazolidin-4-one (7.11 g) and 2,5-2-chloroethyl)-5-methyl-2-(3-pyridyl)thiazolidin-4one (3.11 g), (51% yield).
Reaction SMILES: C(O[C:6]([C:8]1[N:13]=[C:12](O)[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[S:17][C:10]=2[C:9]=1[OH:25])=[O:7])CCC.C([O:30][C:31]([C:33]1C(O)=C2C=C(C3C=CC(F)=CC=3)SC2=C(O)[N:38]=1)=[O:32])CCC>>[F:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]2[S:17][C:10]3[C:9]([OH:25])=[C:8]([C:6]([NH:38][CH2:33][C:31]([OH:32])=[O:30])=[O:7])[N:13]=[CH:12][C:11]=3[CH:15]=2)=[CH:23][CH:22]=1
Reactant: CCCCOC(=O)c1nc(O)c2cc(-c3ccc(F)cc3)sc2c1O
Reactant: CCCCOC(=O)c1nc(O)c2sc(-c3ccc(F)cc3)cc2c1O
Product: O=C(O)CNC(=O)c1ncc2cc(-c3ccc(F)cc3)sc2c1O

Procedure:
The title compound was prepared from 2-(4-fluoro-phenyl)-4,7-dihydroxy-thieno[3,2-c]pyridine-6-carboxylic acid butyl ester and 2-(4-fluoro-phenyl)-4,7-dihydroxy-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester, example 34-b, under conditions analogous to experimental example 30-g. MS: (+) m/z 424.0, 425.9 (M+1, 79Br/81Br).
Reaction SMILES: C1(C[O:8][C@H:9]2[C@@H:14]([NH:15]CC3C=CC=CC=3)[CH2:13][CH2:12][N:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:10]2)C=CC=CC=1.[H][H]>[Pd].CO>[NH2:15][C@H:14]1[CH2:13][CH2:12][N:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:10][C@H:9]1[OH:8]
Reactant: CCOC(=O)N1CC[C@H](NCc2ccccc2)[C@H](OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)N1CC[C@H](N)[C@H](O)C1

Procedure:
A mixture of 170 parts of ethyl cis-3-(phenylmethoxy)-4-[(phenylmethyl)amino]-1-piperidinecarboxylate and 400 parts of methanol was hydrogenated at normal pressure and at 80° C. with 20 parts of palladium-on-charchoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The oily residue was distilled, yielding 75 parts of ethyl cis-4-amino-3-hydroxy-1-piperidinecarboxylate; bp. 175°-185° C. at 0.4 mm. pressure. (intermediate 49).
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[F:33]>C1C=CC=CC=1.C(O)C.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>[Cl:26][C:27]1[CH:28]=[C:29]([C:2]2[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH:30]=[CH:31][C:32]=1[F:33]
Reactant: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Reactant: OB(O)c1ccc(F)c(Cl)c1
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: c1ccccc1
Solvent: CCO
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2ccc(F)c(Cl)c2)C1=O
Yield: 25 %

Procedure:
To a stirred solution of 4-bromo-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone (112 mg) and tetrakis(triphenylphosphine)palladium(0) (54 mg) in 7 ml benzene and 1 ml ethanol, were added 2 M aqueous sodium carbonate (0.22 ml) and (3-chloro-4-fluorophenyl)boronic acid (82 mg). The reaction solution was kept at reflux for 24 hours. Then the solvent was evaporated off under reduced pressure. The resulting residue was extracted with 50 ml water and dichloromethane (50 ml×3). The organic layer was concentrated in vacuo and the resulting residue was separated by column chromatography (hexane/ethylacetate) to yield 32 mg of 4-(3-chloro-4-fluorophenyl)-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone as a solid. mp: 162-164° C. NMR: δ1.58 (s, 6H), 3.09 (s, 3H), 7.13 (m, 2H), 7.40 (d, J=6.6 Hz, 1H), 7.83 (d, J=8.1 Hz, 2H), 7.97 (d, J=8.1 Hz, 2H). IR (cm−1): 2930, 1700, 1587, 1503, 1404, 1317, 1150, 1068, 913, 771, 744.
Reaction SMILES: N1CCC([N:7]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)CC1.[C:24]([O-])(=O)[CH3:25].[Na+]>C(OC(=O)C)(=O)C>[N:7]1([C:21]2[CH:20]=[CH:19][C:18]([S:15]([N:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]3=[O:14])(=[O:16])=[O:17])=[CH:23][CH:22]=2)[CH2:25][CH2:24][CH2:10][CH2:9][CH2:8]1
Reactant: O=C(O)CCCCN(C1CCNCC1)S(=O)(=O)c1ccccc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C1CCCCN1S(=O)(=O)c1ccc(N2CCCCC2)cc1
Temperature: 25 °C
Yield: 185.8 %

Procedure:
5 g of product obtained in Stage B are heated to reflux for 4 hours with 5 g of sodium acetate in 50 cm3 of acetic anhydride. The mixture is cooled to room temperature and evaporated to dryness, the residue is taken up in 50 cm3 of water, filtered off and dried and 4.4 g of expected crude product are obtained. M.p. 140°-145° C. After crystallization in ethanol, 3.4 g of pure product are obtained. M.p. 145°-146° C.
Reaction SMILES: CO[C:3]1([O:10]C)[CH:8]=[CH:7][C:6](=[O:9])[CH:5]=[CH:4]1.[C:12]1([S:18]([N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([S:18]([N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[C:22]2[C:3]2([OH:10])[CH:4]=[CH:5][C:6](=[O:9])[CH:7]=[CH:8]2)(=[O:20])=[O:19])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2ccccc21
Reactant: COC1(OC)C=CC(=O)C=C1
Product: O=C1C=CC(O)(c2cc3ccccc3n2S(=O)(=O)c2ccccc2)C=C1
Yield: 18 %

Procedure:
The title compound was prepared from 4,4-dimethoxy-cyclohexa-2,5-dienone and 1-benzenesulfonyl-1H-indole (available commercially), according to Method C, described above. Yield 18%; mp 170-172° C.; 1H NMR (CDCl3) δ 8.0 (d, J=8 Hz, 1H), 7.87 (d, J=8 Hz, 2H), 7.51-7.60 (m, 3H), 7.30-7.46 (m, 3H), 7.18-7.27 (m, 2H), 6.80 (s, 1H), 6.32 (d, J=10 Hz, 2H), 5.50 (s, 1H); 13C NMR (CDCl3) δ 185.3, 147.9, 141.2, 138.6, 137.8, 134.7, 129.7, 128.7, 128.1, 127.0, 126.6, 125.0, 122.1, 115.6, 114.1, 67.9.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[CH3:12][O:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COCc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Yield: 30.5 %

Procedure:
A mixture of (4-nitro-phenyl)-methanol (3.0 g, 19.6 mmol), potassium carbonate (3.9 g, 28.1 mmol), acetonitrile (100 ml), and iodomethane (11 ml, 176 mmol) was heated at 50° C. for 48 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium chloride solution (100 ml). The organic layer was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with hexane-dichloromethane (1:1 followed by 1:2) to yield 1-methoxymethyl-4-nitro-benzene (1.0 g, 31% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([CH:14]([CH3:16])[CH3:15])[C:10](=[NH:13])[O:11][CH3:12])=[CH:4][CH:3]=1.[O:17]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)CO)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]([CH:14]([CH3:16])[CH3:15])[C:10](=[NH:13])[O:11][CH2:12][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:25]=2)=[CH:6][CH:7]=1
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: COC(=N)C(Nc1ccc(Cl)cc1)C(C)C
Solvent: CO
Product: CC(C)C(Nc1ccc(Cl)cc1)C(=N)OCc1cccc(Oc2ccccc2)c1

Procedure:
A solution of 2.25 g (10 mmol) of methyl 2-(4-chlorophenylamino)-3-methylbutanimidate and 4.00 g (20 mmol) of 3-phenoxybenzyl alcohol is heated with continuous removal of methanol. Upon cessation of methanol evolution, there is obtained an oil, 3-phenoxybenzyl 2-(4-chlorophenylamino)-3-methylbutanimidate.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])=[N:25][N:26]2COCC[Si](C)(C)C)=[CH:22][C:21]=1[C:43]1[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=1>O1CCCC1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])=[N:25][NH:26]2)=[CH:22][C:21]=1[C:43]1[CH:44]=[CH:45][N:46]=[CH:47][CH:48]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(-c3ccncc3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(Cl)c(-c3ccncc3)cc12
Yield: 58.8 %

Procedure:
10.4 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 770 mg of N-[6-chloro-5-(4-pyridyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 30 cm3 of tetrahydrofuran, and the mixture is refluxed for 18 hours. The reaction medium is diluted with 75 cm3 of ethyl acetate and 75 cm3 of saturated sodium hydrogen carbonate solution. The organic phase is separated out after settling of the phases has taken place, washed with 50 cm3 of saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.). The crude product obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with ethyl acetate. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); the residue is taken up in 20 cm3 of ethyl acetate, filtered off, washed with 5 cm3 of ethyl acetate and 20 cm3 diethyl ether, and dried under reduced pressure (90 Pa; 45° C.) to give 320 mg of N-[6-chloro-5-(4-pyridyl)-1H-indazol-3-yl]butanamide in the form of white crystals melting above 260° C.
Reaction SMILES: N1C=CC=CC=1.[ClH:7].[CH3:8][NH:9][N:10]=[CH:11][NH:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1.Cl.[C:23]([C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32]([CH2:36][C:37](=[O:39])[NH2:38])=[C:31](O)[CH:30]=[CH:29]2)(=[NH:25])[NH2:24].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(C(C)=O)C.O.C(O)(=O)C>[ClH:7].[ClH:7].[CH3:8][NH:9][N:10]=[CH:11][NH:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([O:19][C:31]2[CH:30]=[CH:29][C:28]3[C:33](=[CH:34][CH:35]=[C:26]([C:23](=[NH:24])[NH2:25])[CH:27]=3)[C:32]=2[CH2:36][C:37](=[O:39])[NH2:38])=[O:18])=[CH:15][CH:14]=1
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Reactant: CNN=CNc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccncc1
Product: CNN=CNc1ccc(C(=O)Oc2ccc3cc(C(=N)N)ccc3c2CC(N)=O)cc1
Reaction time: 2 h
Yield: 103 %

Procedure:
20 Milliliters of 20% hydrous pyridine was added to 600 mg of 4-methylaminoiminomethylaminobenzoic acid.hydrochloride, 730 mg of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 646 mg of DCC and 32 mg of DMAP, followed by stirring for 2 hours under cooling with ice and then 48 hours at room temperature. The precipitate was filtered and the filtrate was concentrated under reduced pressure. To the residue was added 20 ml of DMF, and the solution was added dropwise to 300 ml of acetone, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain a crude product. Then, the product was subjected to silica gel column chromatography using methyl ethyl ketone-water-acetic acid (80:15:5) as an eluent, and the desired fractions were collected and the solvent was distilled off under reduced pressure. To the residue were added 15 ml of methanol and 440 μl of concentrated hydrochloric acid, and the solution was added dropwise to a mixed liquid of 300 ml of acetone and 100 ml of ether, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain 661.1 mg of the desired product.
Reaction SMILES: [NH2:1][CH:2]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([F:21])[CH:16]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)[OH:4].[C:22]1(=O)[CH2:26][CH2:25][CH2:24][CH2:23]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[F:21][C:17]1[CH:16]=[C:15]([CH:2]([NH:1][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:12])([F:13])[F:14])[CH:6]=2)[OH:4])[CH:20]=[CH:19][N:18]=1
Reactant: O=C1CCCC1
Reactant: NC(c1ccnc(F)c1)C(O)c1cccc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: OC(c1cccc(C(F)(F)F)c1)C(NC1CCCC1)c1ccnc(F)c1
Yield: 90.5 %

Procedure:
The 2-amino-2-(2 -fluoro-pyridin-4-yl)-1-(3-trifluoromethyl-phenyl)-ethanol (5) (1.0 g, 3.3 mmol), cyclopentanone (0.42 g, 5.0 mmol), and Na(OAc)3BH (1.4 g, 6.7 mmol) in 1,2 dichloroethane (20 mL) were stirred under argon at RT for 15 hrs. The resulting mixture was treated with sat. aqueous NaHCO3 (50 mL), extracted with ethyl acetate (3×75 mL), dried (sodium sulfate), and concentrated. The resulting residue was purified by silica gel chromatography using 50% ethyl acetate in methylene chloride to give the title product (1.1 g, 92%). 1H NMR (300 MHz, CDCl3) d 8.05 (d, J=4.9 Hz, 1 H, Pyr), 7.51 (d, J=7.9 Hz, 1 H, Ar), 7.36 (t, J=7.8 Hz, 1 H, Ar), 7.32 (s, 1 H, Ar), 7.22 (d, J=7.9 Hz, 1 H, Ar), 6.81 (d, J=4.9 Hz, 1 H, Pyr), 6.64 (s, 1 H, Pyr), 5.00 (d, J=4.6 Hz, 1 H, PhCHOH), 4.01 (d, J=4.9 Hz, 1 H, CHCHNH), 2.99 (quin, J=3.0 Hz, 1 H, CH2CHCH2), 1.85-1.25 (m, 8 H, CH2).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH2:4][N:3]1[CH:13]1[CH2:18][CH2:17][N:16](C(OCC2C=CC=CC=2)=O)[CH2:15][CH2:14]1.[H][H]>C(O)C.[Pd]>[NH:16]1[CH2:15][CH2:14][CH:13]([N:3]2[CH2:4][CH:5]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)[NH:6][C:2]2=[O:1])[CH2:18][CH2:17]1
Reactant: O=C(OCc1ccccc1)N1CCC(N2CC(c3ccncc3)NC2=O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C1NC(c2ccncc2)CN1C1CCNCC1
Reaction time: 16 h

Procedure:
A solution of benzyl 4-(2-oxo-4-pyridin-4-ylimidazolidin-1-yl)piperidine-1-carboxylate (55 mg, 0.145 mmol) in ethanol (15 mL) was hydrogenated at 1 atm hydrogen over palladium on carbon (50 mg). After 16 h, the reaction was filtered and concentrated to give the title product. MS 247.2 (M+1)
Reaction SMILES: Br.[NH2:2][C:3]1[N:8]=[C:7]2[N:9]([CH3:21])[N:10]=[C:11]([C:12]3[CH:17]=[C:16]([F:18])[C:15]([OH:19])=[C:14](Br)[CH:13]=3)[C:6]2=[CH:5][N:4]=1.[CH3:22][N:23](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[NH2:2][C:3]1[N:8]=[C:7]2[N:9]([CH3:21])[N:10]=[C:11]([C:12]3[CH:17]=[C:16]([F:18])[C:15]([OH:19])=[C:14]([CH:13]=3)[C:22]#[N:23])[C:6]2=[CH:5][N:4]=1
Reactant: Cn1nc(-c2cc(F)c(O)c(Br)c2)c2cnc(N)nc21
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: Br
Product: Cn1nc(-c2cc(F)c(O)c(C#N)c2)c2cnc(N)nc21
Temperature: 180 °C

Procedure:
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-bromo-6-fluoro-phenol hydrobromide (Example 42a) (0.07 g, 0.167 mmol), Zn(CN)2 (0.020 g, 0.167 mmol), Pd2(dba)3 (0.076 g, 0.08 mmol) and DPPF (0.092 g, 0.167 mmol) are dissolved in DMF (2.5 ml) and heated to 180° C. for 40 minutes. The reaction mixture is flitered through Celite® (filter agent) washing with MeOH, the filtrate is concentrated in vacuo and purification of the resulting residue is by preparative HPLC (water/acetonitrile, 0.1% TFA) affords the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([NH:43][CH2:44][CH3:45])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][NH:43][CH2:44][CH3:45])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCNC(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCNCCOc1ccc(CN(CC)c2cc(OC)ccc2C2CCc3cc(O)ccc3C2)cc1F
Yield: 21.1 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N-ethylacetamide (11 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (5.0 mg) was obtained.