Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([CH2:10][C:11]([O-:13])=[O:12])=[O:9])=[C:6]([CH3:14])[N:5]=[C:4]([Cl:15])[C:3]=1[Cl:16].[CH:17]([O-])([O-])[O:18][CH2:19][CH3:20].[C:23](OC(=O)C)(=O)[CH3:24]>>[Cl:1][C:2]1[C:7]([C:8]([C:10](=[CH:17][O:18][CH2:19][CH3:20])[C:11]([O:13][CH2:23][CH3:24])=[O:12])=[O:9])=[C:6]([CH3:14])[N:5]=[C:4]([Cl:15])[C:3]=1[Cl:16]
Reactant: CCOC([O-])[O-]
Reactant: Cc1nc(Cl)c(Cl)c(Cl)c1C(=O)CC(=O)[O-]
Reactant: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1c(C)nc(Cl)c(Cl)c1Cl

Procedure:
29.2 g (0.09 mol) of ethyl 2-(4,5,6-trichloro-2-methyl-nicotinoyl-acetate are heated with 20.9 g (0.141 mol) of ethyl orthoformate and 23.9 g (0.23 mol) of acetic anhydride at 150°-160° C. for two hours. All volatile components are removed, initially in vacuo and then under a high vacuum up to 80° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:11]23[CH:16]([CH:17]=[N:18][OH:19])[CH:15]2[CH2:14][N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]3)[CH:7]=[CH:8][C:9]=1[Cl:10].[CH2:27](I)[CH3:28]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]23[CH:16]([CH:17]=[N:18][O:19][CH2:27][CH3:28])[CH:15]2[CH2:14][N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]3)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1CC2C(C=NO)C2(c2ccc(Cl)c(Cl)c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCON=CC1C2CN(C(=O)OC(C)(C)C)CC12c1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
To a suspension of sodium hydride (23 mg, 0.96 mmol, 60% suspension in mineral oil) in dry DMF (2 mL) at 0° C. under nitrogen atmosphere, was added a solution of tert-butyl 1-(3,4-dichlorophenyl)-6-((hydroxyimino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (140 mg, 0.38 mmol), obtained in step-1 of example 6, in DMF (2 mL). The reaction mixture was stirred at the same temperature for 30 min followed by the addition of ethyl iodide (0.06 mL, 0.74 mmol). The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction as confirmed by TLC, the reaction mixture was quenched by saturated solution of ammonium chloride and the crude compound was extracted with ethyl acetate. The organic layer was washed with water, separated, dried over anhydrous sodium sulphate and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 1:9 EtOAc: Pet Ether) to afford pure tert-butyl 1-(3,4-dichlorophenyl)-6-((ethoxyimino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (75 mg, 50%) as a viscous oil as a mixture of isomers.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][S:11][C:12]1[N:13]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1.[H-].[Na+].CO.Cl>O1CCCC1.O>[C:29]1([N:13]2[C:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:16]=[C:12]2[S:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:35])=[O:2])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)CCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Reaction time: 24 h

Procedure:
170 g of 8-(1.4.5-triphenylimidazol-2-yl mercapto)-octanoic acid methyl ester are dissolved in 1.2 l of tetrahydrofurane. 42 g of sodium hydride dissolved in 700 cc. of methanol are added thereto. The mixture is stirred 24 hours at 40° to 50° C., cooled, diluted with about 2 l of water and acidified with delute hydrochloric acid. The crude acid is filtered off, dried and recrystallized from toluene.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](O)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH:19]([CH3:21])[O:18][CH:17]([CH3:22])[CH2:16]3)[CH:8]=2)[N:3]=1.P(Cl)(Cl)([Cl:25])=O.[OH-].[Na+]>>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([Cl:25])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH:19]([CH3:21])[O:18][CH:17]([CH3:22])[CH2:16]3)[CH:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1CN(c2ccc3nc(N)c(C#N)c(O)c3c2)CC(C)O1
Agent: [Na+]
Agent: [OH-]
Product: CC1CN(c2ccc3nc(N)c(C#N)c(Cl)c3c2)CC(C)O1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
The mixture of 1.7 g of 2-amino-3-cyano-4-hydroxy-6-(2,6-dimethylmorpholin-4-yl)quinoline and 3.4 ml of phosphoryl chloride is stirred at 120° C. for 4 hours. The cooled reaction mixture is poured onto 30 g of ice, the pH of the mixture is adjusted to 8 with 10% sodium hydroxide solution, and the precipitated material is filtered off. After drying 1.5 g of the title compound is obtained (MH+: 317).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[H+].[B-](F)(F)(F)F.CCOCC.[I:22]N1C(=O)CCC1=O>C(#N)C>[I:22][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[OH:1])[C:6]([OH:8])=[O:7]
Reactant: O=C1CCC(=O)N1I
Reactant: O=C(O)c1ccc(O)cc1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CC#N
Solvent: CCOCC
Product: O=C(O)c1ccc(O)c(I)c1
Reaction time: 16 h
Yield: 57.1 %

Procedure:
To a stirring solution of 4-hydroxy-benzoic acid (6.91 g, 50.03 mmol) in dry acetonitrile (250 mL) at −20° C. under an atmosphere of N2 was added HBF4.Et2O (10.50 g, 9.50 mL, 55.00 mmol) dropwise via syringe. The solution was stirred at 0° for 0.5 hours at which time solid N-iodosuccinimide (13.5 g, 60 mmol) was added at one time. The solution was left to stir for 16 hours and then filtered to remove precipitated succinimide. The solution was diluted with water (500 mL) and extracted with ethyl acetate (2×250 mL). The organic portions were combined and washed with 10% sodium bisulfite (250 mL), water (2×250 mL) and saturated aqueous NaCl (250 mL). The solvent was removed in vacuo to yield 8.76 g of crude solid. The crude solid was purified by column chromatography (6:4:0.1 hexane:ethyl acetate:formic acid) to yield 7.54 g (57%) of the desired product as white crystals. 1H NMR (DMSO-d6) δ 12.74 (br s, 1H), 11.18 (s, 1H), 8.20 (s, 8.20, 1H), 7.79 (d, 1H), 6.94 (d, 1H).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([C:23]#[C:24][Si](C)(C)C)[CH:22]=2)[O:19][C:18]([CH3:30])([CH3:29])[CH2:17][C:16]3([CH3:32])[CH3:31])=[CH:7][C:6]=1[F:33].CO.O1CCCC1.O.[OH-].[Li+]>O>[C:23]([C:21]1[CH:22]=[C:13]([C:12]#[C:11][C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:34])=[O:2])=[C:6]([F:33])[CH:7]=2)[CH:14]=[C:15]2[C:20]=1[O:19][C:18]([CH3:29])([CH3:30])[CH2:17][C:16]2([CH3:32])[CH3:31])#[CH:24]
Reactant: COC(=O)Cc1ccc(C#Cc2cc(C#C[Si](C)(C)C)c3c(c2)C(C)(C)CC(C)(C)O3)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C#Cc1cc(C#Cc2ccc(CC(=O)O)c(F)c2)cc2c1OC(C)(C)CC2(C)C

Procedure:
Following general procedure K and using [2-fluoro-4-(2,2,4,4-tetramethyl-8-trimethylsilanylethynyl-chroman-6-ylethynyl)-phenyl]-acetic acid methyl ester (Compound 39, 0.11 g, 0.23 mmol), methanol, tetrahydrofuran, water and lithium hydroxide monohydrate followed by recrystallization from hot acetonitrile, the title compound was obtained as a pale yellow solid (0.045 g, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)=[C:11]([CH2:13][C:14]([O:16]CC)=[O:15])[N:12]=1.CO.[OH-].[K+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=1
Reactant: CCOC(=O)Cc1nc(-c2ccccc2Cl)oc1-c1ccsc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1nc(-c2ccccc2Cl)oc1-c1ccsc1
Yield: 88.3 %

Procedure:
3.5 g of ethyl 2-[2-(2-chlorophenyl)-5-(3-thienyl)-4-oxazolyl]acetate, 75 ml of methanol, 7.5 g of water and 1.4 g of potassium hydroxide are treated in the same manner as described in Example 8. 2.84 g of 2-[2-(2-chlorophenyl)-5-(3-thienyl)-4-oxazolyl]acetic acid are thereby obtained.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1)=[O:3].N1C=CC=CC=1.[C:19](O)(=[O:21])[CH3:20]>C1COCC1>[C:19]([O:10][C:9]1[CH:11]=[CH:12][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=1[O:7][CH3:8])(=[O:21])[CH3:20]
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: CC(=O)O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cc(C(C)=O)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
As shown in the above-described reaction formula, acetovanillone (500 mg, 3mM) dissolved in 20 ml of THF was mixed with 0.5 ml of pyridine and 0.6 ml of anhydrous acetic acid. The mixture was stirred for 3 hours at room temperature. The resulting product was recovered with the extraction with diethylether and dried with anhydrous magnesium sulfate to remove remaining solvent. The remaining residue was performed to Silica gel column chromatography with a mobile phase (n-hexane: ethylacetate =4:1) to obtain white solid type of 4-acetyl-2-methoxyphenyl acetate (1; 625mg).
Reaction SMILES: C1(C(F)(F)F)C=CC=CC=1.[F:11][C:12]([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)(F)[CH:13]([F:15])[F:14]>O>[F:11][C:12]([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)=[C:13]([F:15])[F:14]
Reactant: FC(F)C(F)(F)n1ccnc1
Solvent: FC(F)(F)c1ccccc1
Solvent: O
Product: FC(F)=C(F)n1ccnc1
Yield: 7 %

Procedure:
Then the entire crude reaction product was poured into water (30 ml), and subjected to extraction with ethyl acetate. After separation of an organic layer, drying was carried out with magnesium sulfate and concentration was conducted under reduced pressure. Then thereto was added 1.46 g (10 mmol) of benzotrifluoride, and it was confirmed by a 19F-NMR analysis based on benzotrifluoride that 1-(1,1,2,2-tetrafluoroethyl)imidazole had been produced at yield of 7% and 1-(1,2,2-trifluoroethenyl)imidazole had been produced at yield of 39%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].[NH:34]1[CH2:39][CH2:38][CH:37]([CH2:40]CO)[CH2:36][CH2:35]1.[OH2:43]>CN(C)C=O>[OH:16][CH:15]([CH2:17][N:34]1[CH2:35][CH2:36][CH:37]([CH2:40][OH:43])[CH2:38][CH2:39]1)[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:27])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCC1CO1
Reactant: OCCC1CCNCC1
Reactant: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCC(O)CN1CCC(CO)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
(2-{[6-Methoxy-7-(2-oxiranylmethoxy)-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (41 mg) and 4-piperidine ethanol (32 mg) were suspended in N,N-dimethylformamide (4 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (48 mg, yield 93%).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:30]1[CH:34]2[CH2:35][NH:36][CH2:37][CH:33]2[CH2:32][N:31]1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([N:36]5[CH2:35][CH:34]6[CH2:30][N:31]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:32][CH:33]6[CH2:37]5)=[O:22])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:27])[CH3:28])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CN(C(=O)OC(C)(C)C)CC5C4)cn3)nc2n1C1CCCC1
Yield: 63 %

Procedure:
The 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid was combined with tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate following amide formation method 3 which gave tert-butyl 5-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (45 mg) in 63% yield. HR-MS (m/z MH+) 589.33 RT 4.31 min
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:8]=2)[NH:3]1.[CH:22]1[C:30]2[C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[O:27][C:26]=2[C:25](B(O)O)=[CH:24][CH:23]=1.[CH2:38]([SH:41])[CH:39]=[CH2:40]>>[CH2:38]([S:41][CH2:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]3[C:26]4[O:27][C:28]5[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=5[C:30]=4[CH:22]=[CH:23][CH:24]=3)[CH:8]=2)[NH:3][C:2]([CH3:1])([CH3:21])[CH:11]=1)[CH:39]=[CH2:40]
Reactant: CC1=CC(C)(C)Nc2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: C=CCS
Reactant: OB(O)c1cccc2c1oc1ccccc12
Product: C=CCSCC1=CC(C)(C)Nc2ccc(-c3cccc4c3oc3ccccc34)cc21

Procedure:
Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-yl ester was coupled with 4-dibenzofuranboronic acid. Bromination and coupling reaction with allyl mercaptan gave 52 mg of the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[CH:10][CH:9]=1)[NH2:6].[CH3:24][O:25][CH2:26][CH2:27][C:28]1([C:33](O)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[CH:12][CH:13]=1)[NH:6][C:33]([C:28]1([CH2:27][CH2:26][O:25][CH3:24])[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:34]
Reactant: COCCC1(C(=O)O)CCCC1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cc(Cl)cn(C)c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCC1(C(=O)N[C@@H](Cc2ccc(-c3cc(Cl)cn(C)c3=O)cc2)C(=O)OC)CCCC1
Yield: 59.4 %

Procedure:
A solution of 4-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester hydrochloride (47.4 mg, 0.25 mmol), 1-(2-methoxyethyl)cyclopentane carboxylic acid (47 mg, 0.28 mmol), DIEA (175 μL, 1.0 mmol) and HBTU (133 mg, 0.35 mmol) in DMF (3 mL) was stirred at room temperature for 4 hr. The mixture was concentrated, the residue was dissolved in ethyl acetate (15 mL), was washed with 0.5 N HCl (1×5 mL), sat. NaHCO3 (1×5 mL), brine (1×5 mL) and was dried (MgSO4). The residue obtained upon evaporation was chromatographed on 25 g of silica gel, eluting with ethyl acetate to give 4-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-N-[[1-(2-methoxyethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester (70.5 mg, 59%). LR-Electrospray: m/z positive ion, 943 (2M+Na), 483 (M+Na), 478, (M+NH4), 461 (M+H); negative ion 919 (2M-H), 521, 459 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]2[CH2:10][CH2:11][N:12]([CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: CCOC(=O)COCCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)COCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Yield: 89 %

Procedure:
The present inventors have found that when the reaction is performed in a tertiary amine as both solvent and acid scavenger at elevated temperature, significantly higher yield is obtained. Namely, when 1-[(4-chlorophenyl)phenylmethyl]piperazine is reacted in a pressure vessel with ethyl 2-chloroethoxyacetate in triethylamine at 135° C. for 10 hours, ethyl [2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetate is obtained in 89% yield. When catalytic amounts of potassium iodide or tetrabutylammonium iodide are present in the reaction, slightly higher yield is obtained. If triisopropylamine or pyridine are used instead of triethylamine and the reaction is carried out at the same temperature at atmospheric pressure, a drop of 30-40% in the reaction yield is observed.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22]N3C4C=CC=CC=4N=N3)=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:43]([NH2:47])[CH2:44][CH2:45][CH3:46]>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:17][CH2:16][C:15]([C:20]([NH:47][CH2:43][CH2:44][CH2:45][CH3:46])=[O:22])([CH2:18][CH2:19]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Reactant: CCCCN
Product: CCCCNC(=O)C12CCC(N(CC(=O)N3C[C@@H](F)C[C@H]3C#N)C(=O)OCc3ccccc3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and butylamine (11.5 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-butylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (44.0 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:28])[C:12]3[S:25][C:24]([CH2:26]O)=[CH:23][C:13]=3[N:14]([CH2:16][C:17]([N:19]([O:21][CH3:22])[CH3:20])=[O:18])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS([Cl:44])(=O)=O.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:28])[C:12]3[S:25][C:24]([CH2:26][Cl:44])=[CH:23][C:13]=3[N:14]([CH2:16][C:17]([N:19]([O:21][CH3:22])[CH3:20])=[O:18])[CH:15]=2)=[O:9])=[CH:29][CH:30]=1
Reactant: CON(C)C(=O)Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CO)cc21
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: CON(C)C(=O)Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CCl)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.9 %

Procedure:
To a mixture of N-(4-chlorobenzyl)-2-(hydroxymethyl)-4-{2-[methoxy(methyl)amino]-2-oxoethyl}-7-oxo-4,7-dihydrothieno [3,2-b]pyridine-6-carboxamide (80 mg, 0.18 mmol), collidine (59 μL, 0.44 mmol) and DMAP (3.2 mg) in DMF (2.6 mL) was added methanesulfonyl chloride (35 μL, 0.44 mmol). The reaction was stirred at room temperature for 24 hrs, then cooled to 0° C. before the addition of water (5 mL). The resulting ppt was collected by filtration and washed with water and dried in vacuo, leaving the title compound as an off-white solid (80 mg). The title compound is also a compound of formula I.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=3)[NH:11][CH:10]=2)[CH2:4]1.CC([O:25][C:26]([O:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=O)(C)C.C(N(CC)CC)C>O1CCOCC1>[C:26](=[O:28])([OH:25])[NH2:2].[CH3:1][N:2]([C@@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=3)[NH:11][CH:10]=2)[CH2:4]1)[C:29](=[O:30])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35]
Reactant: CNC1CCCC(c2c[nH]c3ccc([N+](=O)[O-])cc23)C1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CCC[C@H](c2c[nH]c3ccc([N+](=O)[O-])cc23)C1
Product: NC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 126.1 %

Procedure:
To a solution of N-methyl-3-(5-nitro-1H-indol-3-yl)cyclohexanamine (0.40 g, 1.46 mmol) in 1,4-dioxane (10 mL) was added (Boc)2O (0.35 g, 1.61 mmol) and triethyl amine (0.40 mL, 2.92 mmol) and the resulting mixture left to stir overnight at room temperature. The solvent was evaporated and the crude purified on column chromatography (EtOAc:Hexanes, 1:1) to give the title compound as a yellow solid (0.40 g, 73%). 1H-NMR (CDCl3) δ 1.34-1.44 (m, 1H), 1.49 (s, 9H), 1.57-1.69 (m, 3H), 1.78-1.86 (m, 1H), 1.92-2.00 (m, 1H), 2.03-2.10 (m, 2H), 2.78 (s, 3H), 2.95-3.06 (m, 1H), 3.96-4.27 (m, 1H), 7.11 (d, 1H, J=1.8 Hz), 7.38 (d, 1H, J=9.0 Hz), 8.10 (dd, 1H, J=2.1, 9.0 Hz), 8.37 (s, 1H, NH), 8.61 (d, 1H, J=2.1 Hz); EI-MS (m/z, %), 242 (100), 373 (20).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([NH:13][NH2:14])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].Cl.C(OC(N1CCC(NN)CC1)=O)(C)C.[Cl:30][C:31]1[C:36]([CH:37]=O)=[C:35](Cl)[N:34]=[CH:33][N:32]=1.ClC1N=CN=C2N(C3CCC(C4ON=C(C(C)C)N=4)CC3)N=CC=12>>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([N:13]2[C:35]3=[N:34][CH:33]=[N:32][C:31]([Cl:30])=[C:36]3[CH:37]=[N:14]2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(NN)CC1
Reactant: O=Cc1c(Cl)ncnc1Cl
Agent: CC(C)c1noc(C2CCC(n3ncc4c(Cl)ncnc43)CC2)n1
Agent: Cl
Product: CC(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1

Procedure:
4-(4-Chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid isopropyl ester was prepared from the reaction of 4-hydrazino-piperidine-1-carboxylic acid isopropyl ester (Intermediate 10) and 4,6-dichloro-pyrimidine-5-carbaldehyde (Intermediate 16) using the procedure described for 4-chloro-1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 23). The product was purified by flash chromatography eluting with 40% ethyl acetate/hexanes to give 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid isopropyl ester as a white solid. Mass spectrum M+=323.0.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]I)C.C(OC(=O)CCCCCCI)C.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:33](Cl)=[O:34].C(Cl)(=O)C1C=CC=CC=1.[NH2:45][OH:46].Cl>C(N(CC)CC)C>[OH:46][NH:45][C:4](=[O:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:33]([C:25]1[NH:24][C:32]2[C:27]([CH:26]=1)=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:34]
Reactant: CCOC(=O)CCCCCI
Reactant: O=C(Cl)c1cc2ccccc2[nH]1
Reactant: NO
Agent: CCOC(=O)CCCCCCI
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=C(Cl)c1ccccc1
Product: O=C(CCCCCC(=O)c1cc2ccccc2[nH]1)NO
Yield: 35 %

Procedure:
Following the procedure described in Example 1, step 4, but substituting indole-2-carboxylic acid for 5, followed by Example 18, step 1, 2, 3, but substituting respectively ethyl-6-iodohexanoate for ethyl-7-iodoheptanoate and indole-2-carbonyl chloride for benzoyl chloride, and then the resulting carboxylic acid was substituted for 37 in Example 14, step 3, using 1.1 equivalent of NH2OH.HCl and triethylamine each, to afford the title compound 112 in 35% yield. 1H NMR: (300 MHz, CDCl3) δ 7.62 (m, 2H), 7.20-7.00 (m, 3H), 2.82 (m, 2H), 2.00 (m, 2H), 1.62 (m, 2H), 1.22 (m, 4H).