Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([Cl:22])[N:16]=3)=[C:9]([F:23])[CH:8]=1>C1COCC1>[Cl:22][C:17]1[N:16]=[C:15]2[S:14][C:13]([C:10]3[CH:11]=[CH:12][C:7]([CH:2]=[O:1])=[CH:8][C:9]=3[F:23])=[N:21][C:20]2=[CH:19][CH:18]=1
Reactant: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(Cl)nc2s1
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2nc3ccc(Cl)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A slurry of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-chlorothiazolo[5,4-b]pyridine (5.00 g, 14.3 mmol) in 100 mL 1:1 THF/5N aq. HCl was heated in a sealed tube to 70° C. The thick orange mixture was cooled slightly and an additional 50 mL THF was added. The reaction mixture was sealed and heating continued. After 2 h, the reaction mixture was cooled and allowed to stir 3 days at ambient temperature. The reaction mixture was cooled and THF was removed in vacuo. The resulting yellow solid was collected by filtration through a frit, rinsing with water. The material was dried on the frit for several hours and dried in vacuo overnight to give 4-(5-chlorothiazolo[5,4-b]pyridine-2-yl)-3-fluorobenzaldehyde as a light yellow/orange solid. MS (ESI) m/z: calculated: 292.0: Observed: 292.9 (M++1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH:16]([CH:21]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[OH:22])[C:17]([O:19]C)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[OH-].[K+]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH:16]([CH:21]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[OH:22])[C:17]([OH:19])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(Cc1ccccc1OCc1ccccc1)C(O)C1CCCCC1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)C(Cc1ccccc1OCc1ccccc1)C(O)C1CCCCC1
Yield: 90.9 %

Procedure:
Methyl (2RS,3SR)-2-(2-benzyloxyphenylmethyl)-3-cyclohexyl-3-hydroxypropionate (1.14 g) was dissolved in a methanolic 1M solution of potassium hydroxide (11 ml) and the mixture was heated under reflux for 4 hours. The solution was concentrated in vacuo and the residue was dissolved in water and washed with diethyl ether. The aqueous layer was acidified by aqueous 1N hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, dried and evaporated under reduced pressure to give (2RS,3SR)-2-(2-benzyloxyphenylmethyl)-3-cyclohexyl-3-hydroxypropionic acid (0.998 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:7][C:8]=1[CH3:9].[Br:14]Br.O>C(O)(=O)C>[Br:14][C:6]1[CH:7]=[C:8]([CH3:9])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:10][C:11]([OH:13])=[O:12]
Reactant: COc1cc(CC(=O)O)ccc1C
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(CC(=O)O)c(Br)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.4 %

Procedure:
To a solution of (3-methoxy-4-methyl-phenyl)-acetic acid (6.1 g, 33.9 mmol) in glacial acetic acid (30 mL) under argon was added bromine (1.96 mL, 37.2 mmol). The mixture was stirred at room temperature for three hours. Water (100 mL) was added, and solid was filtered off, washed with water and dried to obtain (2-bromo-5-methoxy-4-methyl-phenyl)-acetic acid (6.8 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([CH2:25][CH2:26][OH:27])[N:21]=1)=[CH:16][CH:15]=3.[CH2:33]([O:35][CH2:36][CH2:37]Br)[CH3:34]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([CH2:25][CH2:26][O:27][CH2:34][CH2:33][O:35][CH2:36][CH3:37])[N:21]=1)=[CH:16][CH:15]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn(CCO)n4)ccc3n(C)c21
Reactant: CCOCCBr
Product: CCOCCOCCn1ccc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as in Example 101 above, with the compound from Example 51, 3-(2,4-dichlorophenyl)-6-[1-(2-hydroxyethyl)-1H-pyrazol-3-yl]-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and 2-bromoethyl ethyl ether.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[NH2:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[N:29][CH:28]=[CH:27]2.C([O-])(O)=O.[Na+]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH:30]1[C:31]2[C:26](=[CH:25][C:24]([NH:23][C:11](=[O:13])[CH:10]([C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:33][CH:32]=2)[CH:27]=[CH:28][N:29]=1
Reactant: CC(C)(C)OC(=O)NCC(C(=O)O)c1ccsc1
Reactant: Nc1ccc2cnccc2c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccsc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(tert-butoxycarbonylamino)-2-(thiophen-3-yl)propanoic acid (E47) in pyridine was added EDC, DMAP, and 6-aminoisoquinoline. The solution was stirred overnight at room temperature. The mixture was poured into NaHCO3 (sat) and extracted with EtOAc. The organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 3% MeOH/CH2Cl2) gave pure tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-2-(thiophen-3-yl)propylcarbamate (E48).
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C@@H:11]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)#[CH:28]>>[CH3:25][N:24]([CH3:26])[CH2:23][C@H:11]([NH:10][S:7]([C:5]1[S:6][C:2]([C:28]#[C:27][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:3][CH:4]=1)(=[O:9])=[O:8])[CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1ccccc1
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NS(=O)(=O)c1ccc(C#Cc2ccccc2)s1
Yield: 87 %

Procedure:
According to the method described in example S76a, (R)-benzyl 3-(5-bromothiophene-2-sulfonamido)-4-(dimethylamino)butanoate was reacted with ethynylbenzene to give the title compound as a brown oil (55 mg, 87%). MS ESI 483.3 [M+H]+, calcd for [C25H26N2O4S2+H]+ 483.13.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([O:22]CC)=[O:21])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[OH-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([OH:22])=[O:21])[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cccc(N2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(C(=O)O)c2)CC1
Temperature: 25 °C
Yield: 85.2 %

Procedure:
A solution of 4-(3-ethoxycarbonyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (5.00 g, 14.95 mmol) in EtOH (50 mL) and NaOH 10% (20 mL) was refluxed for 3 h, then the reaction mixture was cooled to room temperature and the organic solvent evaporated under reduced pressure. The resulting solution was neutralized by the dropwise addition of 1N HCl and the aqueous solution was extracted with EtOAc (3×50 mL) The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 3.90 g of the title compound (85%) without further purification.
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].[Cl:7][C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=2[C:21]2[C:22]([O:27][CH3:28])=[N:23][CH:24]=[CH:25][CH:26]=2)=[C:10]([O:31][CH3:32])[CH:9]=1.OO>CS(C)=O>[Cl:7][C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]([NH2:18])=[O:2])=[CH:15][C:14]=2[C:21]2[C:22]([O:27][CH3:28])=[N:23][CH:24]=[CH:25][CH:26]=2)=[C:10]([O:31][CH3:32])[CH:9]=1
Reactant: COc1cc(Cl)ccc1Oc1ccc(C#N)cc1-c1cccnc1OC
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(Cl)ccc1Oc1ccc(C(N)=O)cc1-c1cccnc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 113.8 %

Procedure:
Potassium carbonate (0.194 g, 1.40 mmol) was added to a solution of 4-(4-chloro-2-methoxyphenoxy)-3-(2-methoxypyridin-3-yl)benzonitrile (Preparation 2, 0.257 g, 0.701 mmol) in dimethylsulfoxide (6 mL), followed by dropwise addition of 30% hydrogen peroxide aqueous solution (0.422 mL, 14.00 mmol). The mixture was stirred at room temperature for 1 hour, then quenched by addition of saturated aqueous solution of ammonium chloride (20.0 mL) and water (20.0 mL). The pH of the aqueous was adjusted to pH=7 by dropwise addition of saturated aqueous solution of potassium hydrogen sulfate and then extracted with DCM (3×20 mL). The combined organics were washed with brine (50 mL) and filtered to give the title compound as a solid (0.307 g).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1.[CH:18]1([C:21]2[CH:22]=[C:23]([CH3:33])[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH2:20][CH2:19]1>>[CH:18]1([C:21]2[CH:22]=[C:23]([CH3:33])[C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:13]([C:12]4[CH:11]=[CH:10][C:9]([CH2:8][N:3]5[C@@H:2]([CH3:1])[CH2:6][O:5][C:4]5=[O:7])=[CH:17][CH:16]=4)=[O:15])[CH2:31][CH2:32]3)=[N:25][CH:26]=2)[CH2:20][CH2:19]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: C[C@H]1COC(=O)N1Cc1ccc(C(=O)O)cc1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(CN3C(=O)OC[C@@H]3C)cc2)CC1
Yield: 81.4 %

Procedure:
Using (S)-4-(4-methyl-2-oxooxazolidin-3-ylmethyl)benzoic acid (141 mg) described in Preparation Example 66 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (143 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 87, the title compound (212 mg) was obtained.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([F:19])[C:10]=1[C:20]1[N:25]=[CH:24][C:23]2[C:26](I)=[N:27][NH:28][C:22]=2[CH:21]=1.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][N:38]=2)[CH2:33][CH2:32]1>>[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([F:19])[C:10]=1[C:20]1[N:25]=[CH:24][C:23]2[C:26]([C:40]3[CH:39]=[N:38][C:37]([N:34]4[CH2:33][CH2:32][N:31]([CH3:30])[CH2:36][CH2:35]4)=[CH:42][CH:41]=3)=[N:27][NH:28][C:22]=2[CH:21]=1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: COc1cc(OC)c(F)c(-c2cc3[nH]nc(I)c3cn2)c1F
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4ccc(N5CCN(C)CC5)nc4)c3cn2)c1F

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 7, Step 3 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine and 1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine. LCMS (M+H)+=467.2.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>>[C:1]([Cl:12])(=[O:9])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccncc1
Product: O=C(Cl)c1ccncc1

Procedure:
Thionyl chloride (10 mL) was added to isonicotinic acid (370 mg, 3 mmol) and the mixture was stirred at reflux for 6 hr. Thionyl chloride was evaporated under reduced pressure and the residues was dried in vacuum to give isonicotinoyl chloride. Methyl 2-amino-3-hydroxybenzoate (167 mg, 1.0 mmol) and pyridine (240 mg, 3.0 mmol) were added to toluene (10 mL) and the mixture was stirred at room temperature for 30 min. isonicotinoyl chloride (420 mg, 3.0 mmol) was added and the mixture was stirred at room temperature for 30 min then at 80° C. for 2 hr. The resulting mixture was extracted with ethyl acetate (100 mL×4) and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate 20: to 5:1) to obtain methyl 2-hydroxy-3-(isonicotinamido)benzoate as a solid (210 mg, yield 77%). LC-MS (ESI) m/z 273 [M+1]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[C:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:9].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:14]([O:13][C:11]([C:10]([C:8]#[N:9])=[C:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:12])[CH3:15]
Reactant: CCOC(=O)CC#N
Reactant: O=C1CCOCC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C1CCOCC1

Procedure:
A mixture of tetrahydropyran-4-one (12 g), ethyl cyanoacetate (13.6 g), ammonium acetate (1.2 g), glacial acetic acid (2.4 ml) and toluene (15 ml) is stirred at reflux for 16 hours. The mixture is diluted with toluene and the organic layer is separated, washed with water, then brine, and dried over magnesium sulfate. It is concentrated at reduced pressure to an oil which solidifies. It is further purified by flash chromatography through silica gel with methylene chloride as eluent. The desired fractions are combined and concentrated to dryness at reduced pressure to afford 4-(alpha-ethoxycarbonyl-cyanomethylene)-tetrahydropyran.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH2:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][C:42](=O)[CH2:41][CH2:40]2)=[C:35]([F:46])[C:34]=1[F:47])[CH3:31].O>C1COCC1.C1(C)C=CC=CC=1>[CH2:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][C:42](=[CH:2][O:3][CH3:4])[CH2:41][CH2:40]2)=[C:35]([F:46])[C:34]=1[F:47])[CH3:31]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1ccc(C2CCC(=O)CC2)c(F)c1F
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOc1ccc(C2CCC(=COC)CC2)c(F)c1F
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 130.9 %

Procedure:
Methoxymethyltriphenylphosphonium chloride (dried; 26.3 g) and THF (100 ml) were mixed under a nitrogen atmosphere and cooled to −30° C. Then, potassium t-butoxide (t-BuOK) (8.6 g) was added in twice in the temperature range of −30° C. to −20° C. The stirring was continued at −20° C. for 30 minutes, and the compound (16) (15.0 g) dissolved in THF (100 ml) was added dropwise in the temperature range of −30° C. to −20° C. The reaction mixture was stirred at −10° C. for 30 minutes, poured into a mixture of water (200 ml) and toluene (200 ml), and mixed. The mixture was allowed to separate into organic and aqueous phases, and the extraction into an organic phase was carried out. The organic phase obtained was washed with water, and dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure and the residue was purified by means of column chromatography (silica gel; toluene). The eluent obtained was concentrated under reduced pressure, giving 21.8 g of 1-(4-ethoxy-2,3-difluorophenyl)-4-methoxymethylenecyclohexane (17). The compound obtained (17) was colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:14]=[CH:15][C:3]=12.[CH2:22]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)(=[O:32])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[H-].[Na+]>>[CH2:22]([N:29]([S:30]([C:33]1[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1)(=[O:32])=[O:31])[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:14]=[CH:15][C:3]=12)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Reactant: CCOC(=O)c1cnc2c(cnn2-c2ccccc2)c1Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cnc2c(cnn2-c2ccccc2)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1

Procedure:
Following the procedure of Example 49, the product of Example 47 is reacted with benzyl-(4-methoxybenzenesulfonyl)amine and sodium hydride to provide ethyl 4-[benzyl-(4-methoxybenzenesulfonyl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate. m.p. 124°-126° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([CH2:9][CH:10]2[CH2:12][CH2:11]2)[C:4](=[O:13])[N:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>CC#N>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]([NH:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([CH2:9][CH:10]2[CH2:12][CH2:11]2)[C:4](=[O:13])[N:3]=1)=[O:23]
Reactant: Nc1nc(=O)n(CC2CC2)cc1F
Reactant: O=C=Nc1ccccc1Cl
Solvent: CC#N
Product: O=C(Nc1ccccc1Cl)Nc1nc(=O)n(CC2CC2)cc1F
Reaction time: 1 h
Yield: 58 %

Procedure:
To a stirred solution of 4-amino-1-(cyclopropylmethyl)-5-fluoropyrimidin-2(1H)-one (150 mg, 0.819 mmol) in dry CH3CN (7.5 mL) at room temperature and under nitrogen was added 2-chlorophenylisocyanate (138.3 mg, 0.90 mmol). After stirring for 1 h, the crude reaction mixture was filtered, and the solids were rinsed with CH3CN (10 mL). The collected filtrate was then concentrated in vacuo and dried under high vacuum to afford 1-(2-chlorophenyl)-3-(1-(cyclopropylmethyl)-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)urea (160 mg, 58%) as an off-white solid: mp 197-199° C.; 1H NMR (400 MHz, methanol-d4) δ 8.26 (d, J=6.0 Hz, 1H), 8.21 (dd, J=8.3, 1.5 Hz, 1H), 7.47 (dd, J=8.0, 1.4 Hz, 1H), 7.35-7.28 (m, 1H), 7.13 (td, J=7.8, 1.5 Hz, 1H), 3.74 (d, J=7.3 Hz, 2H), 1.32 (m, 1H), 0.69-0.58 (m, 2H), 0.50-0.38 (m, 2H); ESIMS m/z 337 ([M+H]+).
Reaction SMILES: [CH:1]([S:3]([CH3:6])(=[O:5])=[O:4])=[CH2:2].[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[N:20]([CH2:21][C:22]([CH3:25])([OH:24])[CH3:23])[C:19]([CH2:26][O:27][CH2:28][CH3:29])=[N:18][C:13]=3[CH:14]=[N:15][C:16]=2[CH:17]=1.[H-].[Na+].O>C1COCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[N:20]([CH2:21][C:22]([O:24][CH2:2][CH2:1][S:3]([CH3:6])(=[O:5])=[O:4])([CH3:23])[CH3:25])[C:19]([CH2:26][O:27][CH2:28][CH3:29])=[N:18][C:13]=3[CH:14]=[N:15][C:16]=2[CH:17]=1
Reactant: C=CS(C)(=O)=O
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1CC(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOCc1nc2cnc3cc(Br)ccc3c2n1CC(C)(C)OCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
A solution of methyl vinyl sulfone (3.0 g, 29 mmol) and 1-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (5.4 g, 14 mmol) in anhydrous THF (57 mL) was purged with nitrogen; solid sodium hydride (available as a 60% dispersion in mineral oil, 57 mg, 1.4 mmol) was added. The reaction was stirred for 70 minutes at ambient temperature, at which time an analysis by HPLC indicated a ratio of product to starting material of 3:1. The reaction mixture was combined with material from another run, and water (100 mL) was added. The aqueous layer was separated and extracted with ethyl acetate (100 mL, 50 mL). The combined organic fractions were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with 95:5 dichloromethane:methanol) to provide 7-bromo-2-ethoxymethyl-1-{2-[2-(methanesulfonyl)ethoxy]-2-methylpropyl}-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([C:22]1[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=1)[CH:16]=[CH:15]2>C1COCC1>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([C:22]1[C:23]3=[N:28][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:24]3[CH:25]=[CH:26][CH:27]=1)[CH:16]=[CH:15]2
Reactant: COc1ccc2cc(-c3cccnc3N)ccc2c1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2cc(C3=CC=CN4CCS(=O)(=O)N=C34)ccc2c1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 951 mg) in THF (dry) (40 mL) was added 2-chloroethanesulfonyl chloride (1.50 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(6-methoxynaphthalen-2-yl)pyridin-2-amine (1190 mg) in THF (dry) (25 mL) was added at 0° C. and the mixture was stirred at room temperature overnight. The mixture was quenched with water. Water and EtOAc were added and the precipitates were collected, washed with water/EtOAc, dried in vacuo to give the title compound (835.3 mg). A part of this was recrystallized from MeCN-THF/IPE.
Reaction SMILES: C(OC([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[CH:13][C:14]([C:20]#[N:21])=[CH:15][C:16]=32)[CH2:9]1)=O)(C)(C)C.C(OCC)(=O)C.[ClH:28]>>[ClH:28].[CH:17]12[CH2:19][CH:10]([CH2:9][NH:8][CH2:18]1)[C:11]1[CH:12]=[CH:13][C:14]([C:20]#[N:21])=[CH:15][C:16]2=1
Reactant: CC(C)(C)OC(=O)N1CC2CC(C1)c1cc(C#N)ccc12
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(c1)C1CNCC2C1
Reaction time: 18 h

Procedure:
4-Cyano-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-10-carboxylic acid tert-butyl ester was treated with 3N HCl ethyl acetate (6 mL) and warmed to reflux for 2 hours, then concentrated, dissolved in a minimum of methanol which was saturated with Et2O and stirred 18 hours. The product was collected by filtration (49 mg, 73%). 1H NMR (400 MHz, DMSO-d6) δ 9.66 (br s, NH), 7.86 (br s, NH), 7.74–7.70 (m, 2H), 7.49 (d, J=7.5 Hz, 1H), 3.33–2.97 (m, 6H), 2.17 (m, 1H), 2.01 (d, J=11.0 Hz, 1H). GCMS m/e 184 (M+). M.p. 268–273° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1I.[CH3:20][C:21]1([CH3:28])[C:25]([CH3:27])([CH3:26])[O:24][BH:23][O:22]1.C(N(CC)CC)C>O1CCOCC1.[Pd+2].ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[B:23]1[O:24][C:25]([CH3:27])([CH3:26])[C:21]([CH3:28])([CH3:20])[O:22]1
Reactant: CC(=O)NCC1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: CC1(C)OBOC1(C)C
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Clc1cc[c-](P(c2ccccc2)c2ccccc2)c1Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)NCC1CN(c2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 94.1 %

Procedure:
A suspension of N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]acetamide 62 (20.0 g, 52.8 mmol) in anhydrous 1,4-dioxane (130 mL) was treated with 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (10.2 g, 11.6 mL, 80.0 mmol) and triethylamine (16.0 g, 22.4 mL, 158.4 mmol) at room temperature, and the resulting reaction mixture was degassed three times under a steady stream of argon before being treated with dichloro[1,1′-bis(diphenylphosphino)ferrocene] palladium (II) (Pd(dppf)2Cl2, 1.32 g, 1.6 mmol, 0.03 equiv) at room temperature. The reaction mixture was then degassed three times again under a steady stream of argon before being heated to reflux for 7 h. When TLC and LCMS showed that the reaction was complete, the reaction mixture was cooled down to room temperature before being treated with water (100 mL) and ethyl acetate (100 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water (2×50 mL) and saturated aqueous NaCl solution (50 mL), dried over magnesium sulfate (MgSO4), and concentrated in vacuo. The residual brown oil was further dried in vacuo to afford the crude desired N-{3-[3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}acetamide 81 (18.8 g, 20.0 g theoretical, 94%) as a brown solid which was of sufficient purity to be used in subsequent reactions.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C@@H:11]([CH3:16])[C:12]([F:15])([F:14])[F:13])=[N:8][CH:9]=1)([O-])=O.[H][H]>[Pd].CO>[F:15][C:12]([F:13])([F:14])[C@H:11]([CH3:16])[O:10][C:7]1[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: C[C@H](Oc1ccc([N+](=O)[O-])cn1)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: C[C@H](Oc1ccc(N)cn1)C(F)(F)F

Procedure:
5-Nitro-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine (81.9 g) and palladium on carbon (10% Pd, 0.0065 mol-eq) were added to MeOH and the mixture was hydrogenated until uptake of hydrogen was ceasing. The catalyst was removed by filtration and the filtrate was concentrated and further dried in vacuo to provide the title compound as a dark oil. MS (m/e): 207.0 (MH+).