Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:18][CH2:19][C:20]([F:23])([F:22])[F:21].C1C(=O)N([Cl:31])C(=O)C1>C(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:3]([O:18][CH2:19][C:20]([F:21])([F:22])[F:23])=[CH:4][C:5]([C:8]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][C:7]=1[Cl:31]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C1(c2ccc(N)c(OCC(F)(F)F)c2)CCCC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1(c2cc(Cl)c(N)c(OCC(F)(F)F)c2)CCCC1
Temperature: 25 °C
Yield: 76.3 %

Procedure:
To a stirred solution of ethyl 1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (1.2 g, 3.6 mmol) in dry CHCl3 (60 mL), NCS (0.411 g, 3.08 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 at room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×100 mL), the combined organic solvents was dried over Na2SO4, filtered and concentrated in vacuo. The crude reaction mixture was purified by Flash column chromatography to yield ethyl 1-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (0.860 g) as a thick syrup.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:38]3[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: OC1CCNC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(O)C1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with pyrrolidin-3-ol (Aldrich) to give the title compound as a mixture of diastereomers. HR-MS (ES, m/z) calculated for C33H39Cl2N4O3 [(M+H)+] 609.2394, observed 609.2393.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]2[N:14]=[CH:15][N:16]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)[C:12]=2[CH:11]=[CH:10][N:9]=1)=[O:7].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][C:29]=1[C:37]([F:40])([F:39])[F:38]>>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]2[N:14]=[CH:15][N:16]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:35]([NH:34][C:31]4[CH:32]=[CH:33][C:28]([Cl:27])=[C:29]([C:37]([F:39])([F:38])[F:40])[CH:30]=4)=[O:36])=[CH:19][CH:18]=3)[C:12]=2[CH:11]=[CH:10][N:9]=1)=[O:7]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CN(C)CCNC(=O)c1nccc2c1ncn2-c1ccc([N+](=O)[O-])cc1
Product: CN(C)CCNC(=O)c1nccc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-(4-nitrophenyl)-1H-imidazo[4,5-c]pyridine-4-carboxylic acid (2-(dimethylamino)ethyl)amide and 4-chloro-3-(trifluoromethyl)phenyl isocyanate in the same manner as in Steps B and C of Example 1.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27]O)=[CH:21][N:20]=1)[P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C(Br)(Br)(Br)[Br:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>ClCCl>[CH2:1]([O:3][P:4]([CH:9]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][Br:30])=[CH:21][N:20]=1)[P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CCOP(=O)(OCC)C(Nc1ccc(CCCO)cn1)P(=O)(OCC)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CCOP(=O)(OCC)C(Nc1ccc(CCCBr)cn1)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of [(5-(3-hydroxypropyl)-2-pyridinyl)aminomethylene]-bis(phosphonic acid] tetraethyl ester (10 mmol), carbon tetrabromide (11 mmol) and triphenyl phosphine (11 mmol) in dichloromethane (100 ml) is stirred at room temperature for 5 h. Water is added and the product is extracted with dichloromethane. The combined organic extracts are dried and concentrated. The residue is purified by flash column chromatography to give [(5-(3-bromopropyl)-2-pyridinyl)aminomethylene]bis[phosphonic acid] tetraethyl ester.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.NO.[OH-].[K+].CO>C1COCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:14]=[CH:15][C:10]([S:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:23])=[O:2])=[CH:11][CH:12]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)CCCCCSc1ccc(-c2ccc(Cl)cc2)cc1
Agent: NO
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCCCCSc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of 6-(4′-chloro-biphenyl-4-ylsulfanyl)-hexanoic acid methyl ester (1.0 g, 2.9 mmol) in distilled THF (20 mL) containing 50% aqueous hydroxylamine (1.9 mL, 28.8 mmol) was added at 0° C. a solution of potassium hydroxide in methanol (5.0 mL, 1M, 5.0 mmol) in a dropwise manner. After stirring at 0° C. for 1 h, distilled water (20 mL) was added and the mixture was made neutral by dropwise addition of concentrated hydrochloric acid (10 M) at 0° C. The aqueous solution was extracted with ethyl acetate (2×40 mL) and the combined extracts were washed with brine (80 mL), dried over anhydrous MgSO4, filtered and evaporated to dryness. The residue was recrystallised from acetone to give the title compound (923 mg, 91%) as a white powder, mp 156-157° C.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[C:13]([Br:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][N:9]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C(#N)C>[Br:14][C:13]1[C:8]([NH:7][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9][CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ncc([N+](=O)[O-])cc1Br
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(Nc1ncc([N+](=O)[O-])cc1Br)c1ccccc1
Yield: 89.1 %

Procedure:
20 mλ of pyridine was added to 2-amino-3-bromo-5-nitropyridine (A) (21.8 g; 0.1 mole) in 300 ,λ of acetonitrile at room temperature in a stream of nitrogen followed by addition of benzoylchloride (24.4 g; 0.2 mole) and agitation for 3 hours. Then dilute hydrochloric acid (0.1N) was added to the resulting mixture. After extraction with ethyl acetate, the resulting ethyl acetate solution was dried over anhydrous sodium sulfate. The solvent was distilled off under a reduced pressure. The residue was recrystallized from methanol to give 3-bromo-2-benzoylamino-5-nitropyridine (B) (28.7 g; 89%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@H:9]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[C@@H:10]([NH:12][C:13](=[O:28])[C:14]([O:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=2)([CH3:16])[CH3:15])[CH3:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[F:37][CH2:38]I>>[C:1]([C:3]1[CH:4]=[C:5]([C@H:9]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:38][F:37])=[CH:32][CH:31]=2)[C@@H:10]([NH:12][C:13](=[O:28])[C:14]([O:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][N:19]=2)([CH3:16])[CH3:15])[CH3:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: FCI
Reactant: C[C@H](NC(=O)C(C)(C)Oc1cc(C(F)(F)F)ccn1)[C@@H](Cc1ccc(O)cc1)c1cccc(C#N)c1
Product: C[C@H](NC(=O)C(C)(C)Oc1cc(C(F)(F)F)ccn1)[C@@H](Cc1ccc(OCF)cc1)c1cccc(C#N)c1

Procedure:
N-(1S,2S)-[2-(3-Cyanophenyl)-3-(4-fluoromethoxyphenyl)-1-methylpropyl]-2-(4-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide was prepared from N(1S,2S)-[2-(3-cyanophenyl)-3-(4-hydroxyphenyl)-1-methylpropyl]-2-(4-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide (Example 12, Step B) and fluoromethyliodide following the procedure described in Example 4.
Reaction SMILES: [C:1]1([CH:7]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)(=[O:15])=[O:14])[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH3:37][NH:38][CH:39]1[C:48]2[C:43](=[CH:44][C:45]([CH2:49][N:50]3[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]3)=[CH:46][CH:47]=2)[O:42][CH2:41][CH2:40]1>C(Cl)Cl>[CH3:37][N:38]([CH:39]1[C:48]2[C:43](=[CH:44][C:45]([CH2:49][N:50]3[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]3)=[CH:46][CH:47]=2)[O:42][CH2:41][CH2:40]1)[C:9](=[O:11])[CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[NH:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=1)(=[O:14])=[O:15]
Reactant: O=C(O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccccc1
Reactant: CNC1CCOc2cc(CN3CCCCC3)ccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C(=O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccccc1)C1CCOc2cc(CN3CCCCC3)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-phenyl-3-(3-trifluoromethyl-benzenesulfonylamino)-propionic acid (100 mg, 0.268 mmol, 1.0 eq) and DMF (one small drop) in CH2Cl2 (2.5 mL) was added oxalyl chloride (68 mg, 0.536 mmol, 2.0 eq). The reaction was stirred at 0° C. for 1 h. It was warmed to RT and stirred at RT for additional 15 min. Solvent was removed with a rotary evaporator. The newly formed acid chloride was dissolved in CH2Cl2 (2 mL) and the solution was cooled down to 0° C. A solution of methyl-(7-piperidin-1-ylmethyl-chroman-4-yl)-amine (70 mg, 0.268 mmol, 1.0 eq) in CH2Cl2 (0.95 mL) was added slowly. The resulting mixture was stirred at 0° C. for 20 min. The mixture was warmed to RT and stirred at this temperature for additional 20 min. The reaction was quenched with saturated Na2CO3 (60 mL) The crude was extracted with CH2Cl2 (60 mL×3). The extract phase was washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. Flash column chromatography (silica gel, 0-4% MeOH—CH2Cl2) afforded the title compound as a colorless thin film. MS (ESI, pos. ion) m/z: 616 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[O:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5]1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CN(C)C=O>[N:17]1([CH2:2][CH2:3][CH:4]2[CH2:10][N:9]([CH3:11])[C:8](=[O:12])[C:7]3[CH:13]=[CH:14][CH:15]=[N:16][C:6]=3[O:5]2)[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: c1c[nH]cn1
Reactant: CN1CC(CCCl)Oc2ncccc2C1=O
Solvent: CN(C)C=O
Product: CN1CC(CCn2ccnc2)Oc2ncccc2C1=O
Temperature: 130 °C

Procedure:
To a solution of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-one, 9.12 g (0.038 mole) in dimethylformamide (30 ml) was added imidazole, 5.66 g (0.083 mole). The solution was heated to 130° C. for 18 hr. Dimethylformamide was removed by rotary evaporation (80° C., vacuum pump) and the residue taken up in chloroform (100 ml). The chloroform was washed with dilute aqueous sodium hydroxide (30 ml), dried over sodium sulfate and concentrated by rotary evaporation (70° C., water aspirator) to an oil. Crystallization was induced with ethanol. White crystals, 1.5 g (14.5%) were collected, m.p. 150°-152° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.F[B-](F)(F)F.[CH2:15]([O:17][CH+:18][O:19][CH2:20][CH3:21])[CH3:16]>>[CH2:15]([O:17][CH:18]([O:19][CH2:20][CH3:21])[CH:4]1[CH2:3][C:2]([CH3:9])([CH3:1])[CH2:7][CH2:6][C:5]1=[O:8])[CH3:16]
Reactant: CC1(C)CCC(=O)CC1
Reactant: CCO[CH+]OCC
Agent: F[B-](F)(F)F
Product: CCOC(OCC)C1CC(C)(C)CCC1=O

Procedure:
reacting 4,4-dimethylcyclohexanone, diethoxycarbenium fluoroborate and a fifth base to provide (2-(diethoxymethyl)-4,4-dimethylcyclohexanone and isolating or not isolating the 2-(diethoxymethyl)-4,4-dimethylcyclohexanone;
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([NH:21][NH2:22])=[O:20])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([C:17]#[N:18])([CH3:16])[CH3:15])[CH:9]=2)=[CH:6][N:7]=1.[C:23]([O:27][C:28]([N:30]1[CH2:39][CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:40](O)=[O:41])[CH:36]=2)[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[NH2:1][C:2]1[C:3]([C:19]([NH:21][NH:22][C:40]([C:35]2[CH:36]=[C:37]3[C:32](=[CH:33][CH:34]=2)[CH2:31][N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[CH2:39][CH2:38]3)=[O:41])=[O:20])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([C:17]#[N:18])([CH3:16])[CH3:15])[CH:9]=2)=[CH:6][N:7]=1
Reactant: CC(C)(C#N)c1cc(-c2cnc(N)c(C(=O)NN)n2)ccn1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C(=O)O)ccc2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2cc(C(=O)NNC(=O)c3nc(-c4ccnc(C(C)(C)C#N)c4)cnc3N)ccc2C1

Procedure:
3-amino-6-[2-(1-cyano-1-methyl-ethyl)-4-pyridyl]pyrazine-2-carbohydrazide (49.5 mg, 0.1665 mmol), 2-tert-butoxycarbonyl-3,4-dihydro-1H-isoquinoline-6-carboxylic acid (50.80 mg, 0.1832 mmol), diisopropyl ethyl amine (25.82 mg, 34.80 μL, 0.1998 mmol) and (benzotriazol-1-yloxy-dimethylamino-methylene)-dimethyl-ammonium tetrafluoroborate (58.82 mg, 0.1832 mmol) was stirred at ambient temperature in N,N-dimethyl formamide (495.0 μL) for 1 hour. The reaction mixture was partitioned between water and ethyl acetate. The combined organic extracts were washed with aqueous saturated sodium bicarbonate, then 0.5 N hydrochloric acid, followed by brine. The organic extracts were then dried over MgSO4 and concentrated in vacuo to give the sub-titled product. (92 mg, 99.27%) LC/MS m/z 557.2 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([O:18]C)=[O:17])=[CH:8]2)=[CH:3][CH:2]=1.[OH-].[K+]>O.CO>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([OH:18])=[O:17])=[CH:8]2)=[CH:3][CH:2]=1
Reactant: COC(=O)c1cn(-c2ccncc2)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cn(-c2ccncc2)c2ccccc12
Temperature: 90 °C

Procedure:
To a solution of methyl 1-(pyridin-4-yl)-1H-indole-3-carboxylate (92 mg, 0.365 mmol) in water (365 μl) and MeOH (365 μl) was added KOH (102 mg, 1.823 mmol). The mixture was heated at 90° C. for 1 h then the MeOH was removed under reduced pressure. The residual aqueous layer was neutralized with 1M HCl (pH=6-7) then extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4, filtered, concentrated to afford the title compound as a yellow solid, which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].O.O.O.O.O.O.O.O.O.[S-2:22].[Na+].[Na+]>C(O)C.O>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[SH:22]
Reactant: [S-2]
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc([N+](=O)[O-])ccc1S
Temperature: 100 °C

Procedure:
To a suspension of 2-chloro-5-nitroanisole (1.00 g; 5.33 mmol) in 10 mL of ethanol at rt was added a solution of sodium sulfide nonahydrate (1.30 g; 5.41 mmol) in 1.4 mL of water and 0.8 mL of ethanol in three portions over 3 minutes. The resulting suspension was heated at 100° C. for 10 min. The suspension was cooled and concentrated under reduced pressure to a dark solid which was used immediately in the next step. HPLC 2.23 min retention time; LCMS (ES): m/z 186 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:8]2[CH:12]=[C:11]([O:13][CH3:14])[O:10][C:9]2=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:8]2[CH:12]([C:11]([O:13][CH3:14])=[O:10])[CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:29][C:9]2=[O:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccccc1
Reactant: COc1cn(C(c2ccccc2)c2ccccc2)c(=O)o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1C(c2ccccc2)OC(=O)N1C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under argon atmosphere, in 3 ml of methylene chloride was dissolved 141 mg (0.5 mmol) of 3-diphenylmethyl-5-methoxy-2(3H)oxazolone, and after cooling the solution to −78° C., 53.1 mg (0.5 mmol) of benzaldehyde and 0.05 ml (0.05 mmol) of a methylene chloride solution containing 1.0 M-trimethylsilyl triflate were added to the solution and the mixture was reacted under stirring for one hour. After the temperature of the mixture was raised up to 0° C., 15 ml of a saturated aqueous sodium hydrogen carbonate solution was added to the resulting reaction mixture and the mixture was extracted with 20 ml of methylene chloride. The organic layer was washed with 15 ml of a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 184 mg (0.476 mmol) of 3-diphenylmethyl-4-methoxycarbonyl-5-phenyl-2-oxzolidinone as white crystal. (Yield based on 3-diphenylmethyl-5-methoxy-2(3H)oxazolone: 95%.) According to HPLC analysis, a formation ratio of cis/trans-isomers of the formed product was 5/95.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:41])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH:24]4[CH2:29][O:28][CH2:27][CH2:26][N:25]4[C:30](=[O:39])[CH:31]([NH2:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:23])=[CH:17][CH:16]=3)=[CH:11][N:10]([CH3:40])[N:9]=2)[CH:7]=1.[CH:42]1([C:45](O)=[O:46])[CH2:44][CH2:43]1.CC(C)N=C=NC(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:41])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH:24]4[CH2:29][O:28][CH2:27][CH2:26][N:25]4[C:30](=[O:39])[CH:31]([NH:38][C:45]([CH:42]4[CH2:44][CH2:43]4)=[O:46])[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[O:23])=[CH:17][CH:16]=3)=[CH:11][N:10]([CH3:40])[N:9]=2)[CH:7]=1
Reactant: O=C(O)C1CC1
Reactant: Cn1cc(C#Cc2ccc(NC(=O)C3COCCN3C(=O)C(N)c3ccccc3)cc2)c(-c2cc(Cl)ccc2O)n1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: Cn1cc(C#Cc2ccc(NC(=O)C3COCCN3C(=O)C(NC(=O)C3CC3)c3ccccc3)cc2)c(-c2cc(Cl)ccc2O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of compound 9D (4.0 g, 7.02 mmol) and cyclopropanecarboxylic acid (10D, (0.91 g, 10.53 mmol) in anhydrous CH2Cl2 (100 mL) was added DIPC (1.63 mL, 10.53 mmol). The reaction mixture was stirred at rt overnight. It was filtered to remove diisopropylurea. The filtrate was purified with silica column chromatography eluting with dichloromethane/EtOAc (v/v 1/1, 7/1, 4/1) to give the title compound (11D, 3.4 g, crude), which was recrystallized from hexanes/acetone to provide pure compound 11D (2.2 g) as white powder in 49% yield. 1H NMR (CDCl3, 500 MHz) δ 10.68 (s, 1H), 8.75 (s, 1H), 8.71 (s, 1H), 7.90 (d, 2H, J=8.5 Hz), 7.63 (s, 1H), 7.56 (d, 2H, J=9.0 Hz), 7.50 (m, 2H), 7.45 (m, 3H), 7.20 (dd, 1H, J=8.5, 2.5 Hz), 6.97 (d, 1H, J=9.0 Hz), 6.57 (s, 1H), 5.69 (d, 1H, J=5.5 Hz), 5.23 (s, 1H), 4.82 (d, 1H, J=12.0 Hz), 3.97 (s, 3H), 3.81 (d, 1H, J=11.5 Hz), 3.72 (d, 1H, J=12.5 Hz), 3.64 (t, 1H, J=12.0 Hz), 3.43 (dd, 1H, J=11.0, 3.0 Hz), 3.11 (t, 1H, J=11.5 Hz), 1.49 (m, 1H), 1.00 (m, 2H), 0.84 (m, 2H). LCMS (ESI) m/z 669.43 (MNa+), 638.39 (MH+), 437.28. HPLC: tR=4.98 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.C1CCN2C(=NCCC2)CC1.F[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([N+:31]([O-:33])=[O:32])=[CH:23][CH:22]=1>C(#N)C>[N+:31]([C:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=2)=[CH:22][CH:23]=1)([O-:33])=[O:32]
Reactant: O=[N+]([O-])c1ccc(F)c2ccccc12
Reactant: Nc1cc(O)ccn1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a stirred suspension of 2-aminopyridin-4-ol (53.9 g, 489 mmol) in acetonitrile (500 mL) was added DBU (102 mL, 678 mmol) dropwise over 30 min. The resulting solution was stirred at RT for 30 min and was then treated dropwise with a solution of 1-fluoro-4-nitronaphthalene (72.0 g, 377 mmol) in acetonitrile (400 mL) over 50 min. After stirring overnight at RT the reaction was heated at 50° C. for 2 hr. The reaction was removed from the heat, but not cooled and with stirring, treated with water (6×100 mL). The mixture was allowed to cool to RT over 2 hr and was then cooled further to 0° C. The yellow precipitate was collected by filtration and washed sequentially with a mixture of water and acetonitrile (1:1, 2×100 mL) and then with water (500 mL) to give the title compound as a yellow solid (76.0 g, 70%): m/z 283 (M+H)+ (ES+).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=[O:11])[C:4]=2[CH:3]=[CH:2]1.Cl.[CH3:14]N(C)CCCN=C=NCC.CO>ClCCl>[NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:14])=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(O)c1cccc2[nH]ccc12
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
N,N-Dimethylaminopyridine (7.6 mg, 0.06 mmol) was added to a mixture of 1H-indole-4-carboxylic acid (100 mg, 0.62 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (131 mg, 0.68 mmol), and methanol (1 mL, 24.7 mmol) in dichloromethane (2 mL). The mixture was allowed to stir at room temperature overnight, then the solvent was evaporated and ethyl acetate (20 mL) was added. The solution was washed with 1 M HCl (2×15 mL), saturated sodium hydrogen carbonate (15 mL) and brine (10 mL), dried (MgSO4), filtered and evaporated to give 1H-indole-4-carboxylic acid, methyl ester (85.4 mg, 79%) as a pale yellow solid.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([NH:14][C:15]1[C:16](=[O:26])[O:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][C:19]=2[OH:25])(=[O:13])[CH3:12].C(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]1([S:7]([O:25][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[O:17][C:16](=[O:26])[C:15]([NH:14][C:11](=[O:13])[CH3:12])=[CH:24]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Nc1cc2cccc(O)c2oc1=O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc2cccc(OS(=O)(=O)c3ccccc3)c2oc1=O
Yield: 85.4 %

Procedure:
Benzenesulfonyl chloride (4.0 g, 22.8 mmol) was added to a solution of 3-acetylamino-2-oxo-8-hydroxychromen (5.0 g, 22.8 mmol) in pyridine (50 mL) followed by stirring for one night. Chloroform (100 mL) was added thereto and crystals were filtered therefrom and washed with hexane. The crystals were dried to give 7.0 g (85%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([NH2:16])([C:13]([OH:15])=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[CH3:17][O:14][C:13]([C:10]1([NH2:16])[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(=O)O)C1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1(N)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 102.6 %

Procedure:
In a round-bottomed flask 3-aminopyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (0.20 g, 0.87 mmol) was dissolved in dichloromethane (3.2 mL) and MeOH (1.6 mL). (Trimethylsilyl)diazomethane (2.0 M in hexanes, 0.75 mL, 1.5 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with a small portion of acetic acid and concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with saturated aqueous Na2CO3. The aqueous layer was extracted with dichloromethane and the combined organics were dried over Na2SO4 and concentrated to afford 0.218 g of 3-amino-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester as a light yellow oil.