Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH2:24][CH:25]([C:27]([O:29]CC)=[O:28])[CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[F:40])[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH2:24][CH:25]([C:27]([OH:29])=[O:28])[CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[F:40])[C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)COc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(COc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2F)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Temperature: 80 °C
Yield: 78.7 %

Procedure:
A mixture of racemic (2′R,3R,4′S)-6-chloro-4′-[5-chloro-2-(2-ethoxycarbonyl-2-methyl-ethoxy)-phenyl]-2′-(2,5-difluoro phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (400 mg), NaOH (111 mg), H2O (5 mL) and THF (10 mL) was heated at 80° C. for 1 h. Then THF was removed by vacuum. The water solution was acidified by concentrated hydrochloric acid to “pH” 1. The white precipitate was collected by filtration to give title compound as a white solid (300 mg).
Reaction SMILES: [C:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][CH:8]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:15](O)[CH2:16][OH:17].C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]2[O:17][CH2:16][CH2:15][O:14]2)=[CH:11][CH:12]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: OCCO
Reactant: C=C(C)C(=O)Oc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)Oc1ccc(C2OCCO2)cc1
Temperature: 25 °C

Procedure:
A 500 mL round bottom flask fitted with reflux condenser, Dean Stark trap and nitrogen line was charged with 30.0 g of 4-formylphenyl methacrylate, 19.0 g of ethylene glycol, 250 mL of toluene and a catalytic amount of p-toluenesulfonic acid monohydrate. The solution was heated at reflux for 1 day, during which time the water formed in the reaction was removed periodically from the Dean Stark trap. Toluene was added to make up for losses from the Dean Stark trap, and the solution was heated at reflux for an additional 15 hours. Thereafter the solution was cooled to room temperature, was washed with three 75 mL portions of saturated sodium bicarbonate solution, and the toluene extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude acetal was chromatographed on silica gel (20:1 silica gel to compound weight ratio) with hexane/ethylacetate (4:1 volume ratio) to give purified acetal (18.8 g). 1H NMR (CDCL3) 7,5 (d, 2H), 7,1 (d, 2H), 6.3 (s, 1H), 5.78 (s, 1H), 5.7 (s, 1H), 4.15-3.85 (m, 4H), 2.02 (s, 3H); 13C NMR (CDC13) 165, 151, 135, 128, 127, 121, 103, 65, 18; IR (neat) 1735 cm-1 ester carbonyl. The spectral data are consistent with the postulated structure. The chromatographed acetal was used directly in the free radical polymerizations.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([F:28])[C:14]=1[C:15]1[CH2:16][CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19][CH:20]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([F:28])[C:14]=1[C:15]1[CH2:16][CH2:17][NH:18][CH2:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c(F)cncc2Cl)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cncc(Cl)c1C1=CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
TFA (2 mL, 25.96 mmol) was added to a stirred solution of tert-butyl 4-(3-chloro-5-fluoro-4-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate (708 mg, 2.264 mmol) in DCM (10 mL) and the reaction stirred at ambient temperature for 2 hours. The solvent was removed in vacuo and the residue azeotroped with DCM (×2) and ether (×2). The residue was passed through a 10 g SCX-2 cartridge and washed with MeOH/DCM mixtures. The product was eluted by washing the cartridge with 2M NH3 in MeOH/DCM mixtures and concentrated in vacuo to give 3′-chloro-5′-fluoro-1,2,3,6-tetrahydro-4,4′-bipyridine as an off-white solid (468 mg, 97% Yield). MS (ES+) 213.1.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:13][CH3:14])[CH:4]=1)=[O:2].S(=O)(=O)([OH:17])N.Cl([O-])=O.[Na+]>CC(C)=O>[CH3:14][O:13][C:5]1[CH:4]=[C:3]([CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])[C:1]([OH:17])=[O:2]
Reactant: NS(=O)(=O)O
Reactant: COC(=O)c1ccc(C=O)cc1OC
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 123.1 %

Procedure:
To a cold solution of methyl 4-formyl-2-methoxybenzoate (6.0 g, 7.73 mmol) in acetone (50 mL) was added aqueous sulphamic acid solution (4.5 g, 11.59 mmol) and aqueous sodium chlorite solution (4.04 g, 11.59 mmol) at 0-5° C. The reaction mixture was stirred at RT for 3-4 h. Excess of solvent was removed under vacuum. The obtained residue was diluted with water and basified with saturated sodium bicarbonate solution. The aqueous layer was washed with diethyl ether to remove organic impurities and the obtained aqueous layer was again acidified with conc.HCl. The solid obtained was filtered and suck dried to afford 2.00 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.80 (s, 3H), 3.87 (s, 3H), 7.55-7.59 (m, 2H), 7.70 (d, J=7.8 Hz, 1H), 13.37 (s, 1H); MS (m/z): 210.97 (M+H)+.
Reaction SMILES: [Br-:1].[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([C:11]#[C:12]/[C:13](/[CH3:35])=[CH:14]\[CH2:15][P+:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([CH3:36])[C:5]=1[CH3:37].O.[H][H]>CO>[Br-:1].[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7](/[CH:11]=[CH:12]\[C:13](\[CH3:35])=[CH:14]/[CH2:15][P+:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:6]([CH3:36])[C:5]=1[CH3:37]
Reactant: COc1cc(C)c(C#C/C(C)=C\C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1C
Reactant: [H][H]
Agent: [Br-]
Solvent: O
Solvent: CO
Product: COc1cc(C)c(/C=C\C(C)=C/C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1C
Yield: 89 %

Procedure:
In a manner analogous to Example 2, a solution of 3.42 g of (Z)-[5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2-penten-4-ynyl]triphenylphosphonium bromide in 240 ml of methanol was hydrogenated in the presence of 1.8 g of water-moist Raney-nickel. 188 ml of hydrogen were taken up within 28 hours. The crude product (3.4 g), which contained 89.4% of (2Z,4Z)-[5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2,4-pentadienyl]triphenylphosphonium bromide (yield 89%), obtained after filtration and evaporation was dissolved in 20 ml of methylene chloride and crystallized by the dropwise addition of 50 ml of ethyl acetate while stirring. The suspension was left to stand at 0° C. overnight, filtered and the product, washed with a small amount of ethyl acetate/methylene chloride (volume ratio 5:1), was dried at 40°C./0.01 mbar. There were obtained 1.8 g of 99.6% (2Z,4Z)-[5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2,4-pentadienyl]triphenylphosphonium bromide as white crystals of melting point 202°-204° C.; yield 52.5%.
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]([NH2:26])=[NH:25])[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH3:44])([CH3:43])[C:35](=O)[C:36]([CH3:41])=[CH:37]N(C)C)=[CH:30][CH:29]=1.C(N(CC)CC)C>CN1CCCC1=O>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([C:35]2[C:36]([CH3:41])=[CH:37][N:26]=[C:24]([NH:23][C:13]3[CH:14]=[CH:15][C:16]([N:17]4[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]4)=[C:11]([O:10][CH3:9])[CH:12]=3)[N:25]=2)([CH3:43])[CH3:44])=[CH:30][CH:29]=1
Reactant: CC(=CN(C)C)C(=O)C(C)(C)c1ccc(Cl)cc1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COc1cc(Nc2ncc(C)c(C(C)(C)c3ccc(Cl)cc3)n2)ccc1-n1cnc(C)c1
Reaction time: 2.5 h

Procedure:
The title compound was prepared in analogous manner as described in example 4c) from N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]guanidine dinitrate, 4-(4-chloro-phenyl)-1-dimethylamino-2,4-dimethyl-pent-1-en-3-one and triethylamine using 1-methyl-2-pyrrolidone as the solvent. The reaction was performed in a microwave oven at 200° C. for 2.5 h. The title compound was isolated as a yellow solid in 52% yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:32]=[CH:31][C:11]3[N:12]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:13]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=4[N:22]4[CH:26]=[N:25][CH:24]=[N:23]4)=[N:14][C:10]=3[CH:9]=2)=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:40][C:41]([CH3:48])([CH3:47])[C:42]([O:44][CH2:45][CH3:46])=[O:43]>CN(C=O)C>[CH2:45]([O:44][C:42](=[O:43])[C:41]([CH3:48])([CH3:47])[CH2:40][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[N:12]([C:27]([CH3:29])([CH3:28])[CH3:30])[C:11]3[CH:31]=[CH:32][C:8]([C:5]4[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=4)=[CH:9][C:10]=3[N:14]=2)=[C:16]([N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[CH:17]=1)[CH3:46]
Reactant: CCOC(=O)C(C)(C)CCl
Reactant: CC(C)(C)n1c(-c2ccc(O)cc2-n2cncn2)nc2cc(-c3cnc(N)nc3)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)COc1ccc(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c(-n2cncn2)c1
Temperature: 90 °C
Yield: 51.5 %

Procedure:
To a stirred solution of 4-[5-(2-Amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzoimidazol-2-yl]-3-[1,2,4]-triazol-1-yl-phenol (300 mg, 0.7 mmol) in DMF (10 mL) is added cesium carbonate (687 mg, 2.1 mmol) followed by Ethyl 3-chloro-2,2-dimethylpropanoate (231 mg, 1.4 mmol) at room temperature. The solution is heated to 90° C. for 72 hours. The solution is cooled to room temperature and is extracted with H2O (10 mL) and EtOAc (3×10 mL). The combined organic layer is dried with Mg2SO4 (500 mg) and is filtered. The filtrate is concentrated and the residue is purified by silica gel flash column chromatography with 10% MeOH in CH2Cl2 as the eluent to afford the title compound (200 mg, 51%). LCMS (ESMS): m/z: 555.40 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1([C:28](Cl)=[O:29])[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:28]([C:15]2([CH2:14][CH2:13][CH2:12][CH2:11][Br:10])[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:29])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: NCc1ccc(F)cc1
Product: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 4-fluoro-benzylamine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: [CH3:1][C@:2]12[CH2:21][CH2:20][C@H:19]3[C@@H:8]([CH2:9][CH2:10][C:11]4[C@:17]3([CH3:18])[CH2:16][CH2:15][C:13](=[O:14])[CH:12]=4)[C@@H:7]1[CH2:6][CH2:5][C:3]2=[O:4].C(OCC)(OCC)OCC.[C:32]1(C)[CH:37]=CC(S(O)(=O)=O)=C[CH:33]=1>CC(O)C.N1C=CC=CC=1>[CH:32]([O:14][C:13]1[CH2:15][CH2:16][C@@:17]2([CH3:18])[C:11](=[CH:10][CH2:9][C@@H:8]3[C@@H:19]2[CH2:20][CH2:21][C@@:2]2([CH3:1])[C@H:7]3[CH2:6][CH2:5][C:3]2=[O:4])[CH:12]=1)([CH3:37])[CH3:33]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: CCOC(OCC)OCC
Solvent: c1ccncc1
Solvent: CC(C)O
Product: CC(C)OC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1
Yield: 1677.5 %

Procedure:
Androstenedione (10 g.) was dissolved in propan-2-ol (500 ml). Triethyl orthoformate (7.15 ml) was added, followed by p-toluenesulphonic acid (250 mg) and the solution refluxed for fifteen minutes. A few drops of pyridine were added and the solution evaporated under reduced pressure to give a pale yellow solid. This was recrystallised from methanol to give 3-iso-propoxy-androsta-3,5-dien-17-one (8.0 g) as white crystals, M.p. 147°-151°. ##STR14##
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[C:27]([NH:39][C:40](=[O:53])[C:41]3[CH:46]=[CH:45][C:44]([C:47]4[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=4)=[CH:43][CH:42]=3)[CH:26]=2)=[CH:22][CH:21]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O>C(Cl)Cl>[OH:18][CH2:19][C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[C:27]([NH:39][C:40](=[O:53])[C:41]3[CH:42]=[CH:43][C:44]([C:47]4[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=4)=[CH:45][CH:46]=3)[CH:26]=2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)s2)cc1NC(=O)c1ccc(-c2cccnc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(CO)s2)cc1NC(=O)c1ccc(-c2cccnc2)cc1
Yield: 90 %

Procedure:
Following the same procedure as described in Example 20, step 5 (scheme 20) but substituting compound 189 for compound 198, title compound 199 was obtained in 90% yield [after column chromatography (eluent: 25% AcOEt in DCM)].
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:20]=[C:21]([N:25]=[C:26]=[O:27])[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:25][C:26]([CH:2]2[CH2:3][NH:4][CH2:5][CH2:6][N:1]2[C:7]2[C:8]3[N:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:9]=3[N:10]=[CH:11][N:12]=2)=[O:27])[CH:22]=[CH:23][CH:24]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: Clc1ccc2ncnc(N3CCNCC3)c2n1
Product: O=C(Nc1cccc(Cl)c1)C1CNCCN1c1ncnc2ccc(Cl)nc12
Yield: 99.2 %

Procedure:
This compound was synthesized from 4-(piperazin-1-yl)-6-chloro-pyrido[3,2-d]pyrimidine (2.5 g, 10 mmole) and 3-chlorophenyl isocyanate (1.54 g, 10 mmole) using the procedure of example 69, resulting in the pure title compound (4.0 g, 99%) as a white solid which was characterized by its mass spectrum as follows: MS (m/z): 403.1 ([M+H]+, 100).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].Cl.[CH:13]1([N:19]2[C:23]3([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:22](=[O:29])[NH:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>N1C=CC=CC=1>[CH:13]1([N:19]2[C:23]3([CH2:24][CH2:25][N:26]([C:2]([O:4][CH2:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=4)=[O:3])[CH2:27][CH2:28]3)[C:22](=[O:29])[NH:21][CH2:20]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1NCN(C2CCCCC2)C12CCNCC2
Agent: Cl
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)N1CCC2(CC1)C(=O)NCN2C1CCCCC1
Temperature: 25 °C
Yield: 50 %

Procedure:
Benzyl chloroformate (1.74 mL, 0.0116 mmol) was added dropwise at 0° C. to 1-cyclohexyl-1,3,8-triazaspiro[4.5]decan-4-one, hydrochloride (prepared as described in J. Med. Chem. 1998, 41, 5084-5093); 1H NMR (DMSO-d6); δ1.11 (m, 2H); 1.24 (m, 4H); 1.58 (m, 4H); 1.77 (m, 4H); 2.38 (m, 2H); 3.32 (m, 3H); 4.21 (s, 2H); 9.35 (br s, 1H); 12.7 (br s, 1H); (3.59 g, 0.0116 mol) in pyridine (35 mL). The mixture was allowed to warm to room temperature and then evaporated. The residue was diluted with ethyl acetate, washed with water and brine, dried (MgSO4) and evaporated. The residue was purified by Biotage flash chromatography (5% methanol/dichloromethane) to give product as a white solid (2.15 g, 50%); 1H NMR (DMSO-d6); δ1.04 (m, 1H); 1.23-1.31 (m, 4H); 1.55-1.58 (m, 6H); 1.67 (d, J=10.4 Hz, 2H); 2.52 (m, 2H); 3.51 (m, 2H); 3.74-3.77 (m, 2H); 4.10 (s, 2H); 5.08 (s, 2H); 7.31-7.39 (m, 5H); 8.20 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[S:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].CN(C=O)C.[Br:23]N1C(=O)CCC1=O.CCOC(C)=O>CCCCCC>[Br:1][C:2]1[C:6]([Br:23])=[C:5]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[S:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1sc(N2CCOCC2)cc1Br
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(=O)c1sc(N2CCOCC2)c(Br)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.1 %

Procedure:
To a degassed solution of ethyl 3-bromo-5-morpholin-4-ylthiophene-2-carboxylate (0.688 g, 2.15 mmol) in DMF (14 mL, 180 mmol) was added N-bromosuccinimide (0.7648 g, 4.297 mmol) dropwise as a solution in degassed DMF (4.1 mL, 52 mmol). The mixture was wrapped in foil to protect from ambient light, and the reaction was stirred under argon at room temperature for 2 hours. The reaction mixture was quenched via addition of 10% sodium thiosulfate solution (10 mL) and then diluted with EtOAc (30 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (eluent: 0-25% EtOAc:hexane) afforded ethyl 3,4-dibromo-5-(morpholin-4-yl)thiophene-2-carboxylate (593 mg, yield 69%). LCMS: (FA) ES+ 398, 400, 402; 1H NMR (400 MHz, DMSO) δ 4.26 (q, J=7.1 Hz, 2H), 3.75 (dd, J=5.5, 3.8 Hz, 4H), 3.24-3.10 (m, 4H), 1.27 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][CH:17]([C:21]([OH:23])=O)[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][CH:17]([C:21]([NH:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[O:23])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CC(C(=O)O)CC4)cc1
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2ncc3c4c(cnc32)CC(C(=O)Nc2ccccc2)CC4)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinoline-7-carboxylic acid (0.072 g, 0.21 mmol), diisopropylethylamine (0.1 mL), aniline (23 μl, 0.21 mmol) in dimethylformamide (5 mL) was added HBTU (0.121 g). The mixture was stirred at room temperature for 24 hours, poured into ethyl acetate (100 mL) and washed with water (200 mL). The organic layer was dried with anhydrous magnesium sulfate and evaporated to dryness to give crude 3-(4-methoxybenzyl)-N-phenyl-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinoline-7-carboxamide as a brown oil, which was used in the next step without any further purification. LCMS [M+H]: 413.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([NH:12][C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)=[O:23])=[O:11])[CH2:6][CH2:5]1.CO[CH:34]1[CH2:38][CH2:37][CH:36](OC)O1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[N:3]1([C@H:4]2[CH2:9][CH2:8][C@H:7]([C:10]([NH:12][C:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[O:15][C:14]=3[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=3)=[O:23])=[O:11])[CH2:6][CH2:5]2)[CH:34]=[CH:38][CH:37]=[CH:36]1
Reactant: N[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Reactant: COC1CCC(OC)O1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(Nc1ccc(Cl)cn1)c1oc2ccccc2c1NC(=O)[C@H]1CC[C@H](n2cccc2)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Trans-3-(4-aminocyclohexylcarbonylamino)-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide dihydrochloride (200 mg) obtained in Example 219, tetrahydro-2,5-dimethoxyfuran (53 μl), sodium acetate (68 mg) are stirred at 80° C. for 2 hours in acetic acid (3 ml). To the mixture is added tetrahydro-2,5-dimethoxyfuran (26 μl), and the mixture is further stirred at 80° C. for 2 hours. After cooling, the reaction solution is poured into ice-water, and the mixture is extracted with chloroform. The organic layer is washed with a saturated aqueous sodium hydrogen carbonate solution, a saturated brine, and dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: ethyl acetate/hexane=1/5→ethyl acetate/hexane=1/3) to give the title compound (96 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])=[C:4]([CH:9]=[C:10]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:11]=1F)[C:5]([O:7][CH3:8])=[O:6].[N-:31]=[N+:32]=[N-:33].CCOCC.S1(CCCC1)(=O)=O>CN(C)C(=O)C.CN(C)C=O.CN1C(=O)N(C)CCC1.CN(P(N(C)C)(N(C)C)=O)C.CS(C)=O>[N:31]([C:11]1[C:10]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[C:2]=1[F:1])=[N+:32]=[N-:33]
Reactant: COC(=O)c1cc(SCc2ccc(OC)cc2)c(F)c(F)c1Nc1ccccc1F
Reactant: [N-]=[N+]=[N-]
Solvent: CN1CCCN(C)C1=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: COC(=O)c1cc(SCc2ccc(OC)cc2)c(N=[N+]=[N-])c(F)c1Nc1ccccc1F

Procedure:
Methyl 3,4-difluoro-2-((2-fluorophenyl)amino)-5-((4-methoxy benzyl)thio)benzoate can be reacted with azide (such as NaN3, KN3) at high temperature (60-120° C., prefer 80-100° C.) in appropriate solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane, chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone (such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), ester (such as ethyl acetate, methyl acetate), nitrile (such as acetonitrile, propiononitrile), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer N,N-dimethylformamide and N,N-dimethylacetamide) for some time (1-12 h, prefer 3-10 h). Methyl 4-azido-3-fluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate is obtained after conventional workup.
Reaction SMILES: CN(C)CCCN=C=NCC.[O:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]([OH:23])=O)[CH2:14][CH2:13]1.[NH:24]1[CH2:34][CH2:33][CH:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:26][CH2:25]1.C(N(CC)CC)C>ClCCl.O.OC1C2N=NNC=2C=CC=1>[N:15]1([CH2:18][CH2:19][CH2:20][C:21]([N:24]2[CH2:34][CH2:33][CH:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:26][CH2:25]2)=[O:23])[CH2:14][CH2:13][O:12][CH2:17][CH2:16]1
Reactant: O=C(O)CCCN1CCOCC1
Reactant: CCOC(=O)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C1CCN(C(=O)CCCN2CCOCC2)CC1
Temperature: 20 °C
Reaction time: 20 h
Yield: 83.9 %

Procedure:
0.95 g of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide in solution in 20 cm3 of dichloromethane is added, at 20° C., to 1.0 g of 4-morpholinobutyric acid, 0.78 g of ethyl isonipecotate, 2.1 cm3 of triethylamine and 20 mg of hydroxybenzotriazole hydrate, in solution in 80 cm3 of dichloromethane. After stirring for 20 hours at 20° C., the reaction mixture is washed with 20 cm3 of water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give a pale yellow oil which is purified by chromatography on a CBT1 alumina column [eluent: dichloromethane/methanol (97/3 by volume)]. 1.30 g of ethyl 1-(4-morpholin-4-ylbutyryl)4-piperidinecarboxylate are thus obtained in the form of a pale yellow oil.