Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2:17][C:18]([CH2:25][CH3:26])([CH2:23][CH3:24])[C:19]([NH:21][CH3:22])=[O:20]>>[CH2:23]([C:18]([NH:17][C:14]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:13]=1)=[O:16])([C:19](=[O:20])[NH:21][CH3:22])[CH2:25][CH3:26])[CH3:24]
Reactant: CCC(N)(CC)C(=O)NC
Reactant: O=C(O)c1cccc(-c2ccc(Cl)cc2)n1
Product: CCC(CC)(NC(=O)c1cccc(-c2ccc(Cl)cc2)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(4-chlorophenyl)-2-pyridinecarboxylic acid (CAN 135432-77-8) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70 b) as starting materials, MS (EI): m/e=360.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](Cl)=[O:5].C[O:13][C:14]([C:16]1[C:20]([NH2:21])=[CH:19][NH:18][N:17]=1)=[O:15].C(OC(C1C(N)=CNN=1)=O)C.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH:21][C:20]1[C:16]([C:14]([OH:15])=[O:13])=[N:17][NH:18][CH:19]=1)=[O:5]
Reactant: COC(=O)c1n[nH]cc1N
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: CCOC(=O)c1n[nH]cc1N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(O)c1n[nH]cc1NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2,6-dichlorobenzoyl chloride (8.2 g; 39.05 mmol) was added cautiously to a solution of 4-amino-1H-pyrazole-3-carboxylic acid methyl ester (prepared in a manner analogous to 165B) (5 g; 35.5 mmol) and triethylamine (5.95 ml; 42.6 mmol) in dioxan (50 ml) then stirred at room temperature for 5 hours. The reaction mixture was filtered and the filtrate treated with methanol (50 ml) and 2M sodium hydroxide solution (100 ml), heated at 50° C. for 4 hours, and then evaporated. 100 ml of water was added to the residue then acidified with concentrated hydrochloric acid. The solid was collected by filtration, washed with water (100 ml) and sucked dry to give 10.05 g of 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid as a pale violet solid.
Reaction SMILES: [N:1]([C@@H:4]1[NH:7][C:6](=[O:8])[C@H:5]1[NH:9]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[N+:2]=[N-:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[NH2:9][C@H:5]1[C@H:4]([N:1]=[N+:2]=[N-:3])[NH:7][C:6]1=[O:8]
Reactant: [N-]=[N+]=N[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=N[C@@H]1NC(=O)[C@H]1N

Procedure:
To a solution of 1.3 g of (3S,4S)-4-azido-3-tritylamino-2-oxoazetidine in 15 ml of acetone is added 0.736 g of p-toluenesulfonic acid monohydrate. The mixture is treated in a same manner to Reference Example 45B to give 0.886 g of tosyl salt of (3S,4S)-3-amino-4-azido-2-oxoazetidine.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[C:7](=O)[NH:8]2)=[CH:4][CH:3]=1.[C:13]1([NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19]>C(O)(=O)CCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:7]([NH:19][C:14]4[C:13]([N:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[N:8][C:9]=2[CH:10]=1
Reactant: O=C1Nc2cc(Br)ccc2C1=O
Reactant: Nc1ccccc1N
Solvent: CCCC(=O)O
Product: Brc1ccc2c3nc4ccccc4[nH]c-3nc2c1
Reaction time: 16 h

Procedure:
A solution of 15.18 g (67.2 mmol) of 6-bromoisatin and 7.26 g (1.0 eq.) of 1,2-phenylenediamine in 250 ml of butyric acid was refluxed for 4 hours, followed by allowing to stand at room temperature for 16 hours. The precipitate was collected by filtration to give 8-bromoindolo[2,3-b]quinoxaline.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:27][CH2:28][CH:29]5[CH2:31][O:30]5)=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[CH:12][C:11]([CH3:32])=[C:10]([CH3:33])[N:9]=2)[S:5][C:6]=1[CH3:7].FC(F)(F)C(O)=[O:37].[OH-].[Na+].O>C(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]([C:8]2[C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:27][CH2:28][CH:29]([OH:30])[CH2:31][OH:37])=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[CH:12][C:11]([CH3:32])=[C:10]([CH3:33])[N:9]=2)[S:5][C:6]=1[CH3:7]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3nc(C)c(C)s3)ccnc2cc1OCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3nc(C)c(C)s3)ccnc2cc1OCC(O)CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
4-[2-(4,5-Dimethyl-thiazol-2-yl)-5,6-dimethyl-pyridin-3-yloxy]-6-methoxy-7-oxiranylmethoxy-quinoline (compound 458) (40 mg) was dissolved in methylene chloride (2 ml) to prepare a solution which was then brought to 0° C. Trifluoroacetic acid (0.4 ml) was added thereto, the mixture was stirred at 0° C. for 30 min, and the mixture was then stirred at room temperature for 5 hr. The reaction solution was brought to 0° C., was stirred, and was made alkaline by the addition of a 10% aqueous sodium hydroxide solution. Water was added to the reaction solution, the mixture was extracted with chloroform, and the chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (41 mg, yield 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4](F)[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.[Cl:19]C1C=CC(F)=C(B(O)O)C=1>>[Cl:19][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:11]2[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=2)[CH:4]=1
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Reactant: OB(O)c1cc(Cl)ccc1F
Product: O=C(O)c1csc(-c2cc(Cl)ccc2F)n1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with (5-chloro-2-fluorophenyl)boronic acid gave the title compound.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([Cl:21])[CH:14]=1)[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:22][C:23](C)(O)[C:24]#N>CCO>[Cl:21][C:15]1[CH:14]=[C:13]([NH:12][C@H:3]([CH2:2][NH:1][CH:23]([CH3:24])[CH3:22])[CH2:4][C:5]([O:7][C:8]([CH3:10])([CH3:9])[CH3:11])=[O:6])[CH:18]=[CH:17][C:16]=1[C:19]#[N:20]
Reactant: CC(C)(O)C#N
Reactant: CC(C)(C)OC(=O)C[C@@H](CN)Nc1ccc(C#N)c(Cl)c1
Solvent: CCO
Product: CC(C)NC[C@H](CC(=O)OC(C)(C)C)Nc1ccc(C#N)c(Cl)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 93.8 %

Procedure:
A mixture of 1,1-dimethylethyl (3S)-4-amino-3-[(3-chloro-4-cyanophenyl)amino]butanoate (0.309 g, 1 mmol), acetone cyanohydrin (0.1 g, 1.18 mmol) and crushed 4 Å molecular sieves in EtOH (5 mL) was stirred at 60° C. for 6 h. After cooled down, the reaction mixture was filtered. The filtrate was treated with NaBH4 (excess amount) and stirred for 2.5 h. The reaction was diluted with H2O and extracted with Et2O (2×). The organic extracts were washed with H2O (2×), dried over Na2SO4, filtered, and concentrated to yield the titled product (0.33 g, 94%). LC-MS (ES) m/e 352.5 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[C:33]1([CH2:39][CH2:40][NH2:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:11][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]([NH:41][CH2:40][CH2:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:10])[CH2:6][CH2:7]1
Reactant: O=C(O)C1CCC(F)(F)CC1
Reactant: NCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NCCc1ccccc1)C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4,4-difluorocyclohexanecarboxylic acid (1.48 g) was dissolved in methylene chloride (20 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.68 g), 1-hydroxybenzotriazole (1.21 g), and (2-phenylethyl)amine (1.2 mL) were sequentially added thereto, followed by stirring at room temperature for 18 hours. Then, saturated aqueous sodium bicarbonate was added to the reaction liquid which was then extracted with chloroform. The extract was washed with water and further saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 4,4-difluoro-N-(2-phenylethyl)cyclohexanecarboxamide (1.96 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([CH:10]=[C:11](Br)Br)[C:3]=1[CH2:14][CH3:15].[CH2:16]([NH2:19])[CH2:17][NH2:18]>>[Cl:1][C:2]1[C:3]([CH2:14][CH3:15])=[C:4]([C:5]([CH2:8][CH3:9])=[CH:6][CH:7]=1)[CH2:10][C:11]1[NH:18][CH2:17][CH2:16][N:19]=1
Reactant: CCc1ccc(Cl)c(CC)c1C=C(Br)Br
Reactant: NCCN
Product: CCc1ccc(Cl)c(CC)c1CC1=NCCN1

Procedure:
2-(3-Chloro-2,6-diethyl-benzyl)-4,5-dihydro-1H-imidazole was prepared from 1-chloro-3-(2,2-dibromo-vinyl)-2,4-diethyl-benzene and ethylenediamine in analogy to Example 1e): yellow crystals; MS (ISP): 251.3 ([M+H]+, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[N:7][N:6]=[CH:5]2.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][C:20]=1B1OC(C)(C)C(C)(C)O1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:23][C:24]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[N:7][N:6]=[CH:5]2
Reactant: Cc1ccc(S(N)(=O)=O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccc2c(N3CCOCC3)nncc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Solvent: ClCCl
Product: Cc1ccc(S(N)(=O)=O)cc1-c1ccc2c(N3CCOCC3)nncc2c1
Temperature: 90 °C

Procedure:
A 50-mL flask under argon were added 6-bromo-1-morpholinophthalazine (150 mg, 0.51 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (227 mg, 0.76 mmol), tetrakis(triphenylphosphine)palladium (29 mg, 0.025 mmol), ethyl alcohol (1 mL), and 1,2-dimethoxyethane (4 mL), followed by 2M potassium carbonate aqueous solution (0.77 mL, 1.53 mmol). The reaction was heated at 90° C. for 2 h. The cooled reaction was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3 and brine; dried (MgSO4) and concentrated in vacuo. Trituration of the resulting crude solid with CH2Cl2 afforded a pure batch of the title compound as a white solid. Found MS (ES+): 385.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]#[N:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C:12]#[N:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: N#CC=Cc1cccc([N+](=O)[O-])c1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: N#CCCc1cccc([N+](=O)[O-])c1
Temperature: 40 °C

Procedure:
There are introduced into a cylinder 3 g of the product obtained in Step 1, 1.59 g of tris(triphenylphosphine)rhodium(I) chloride and 90 ml of benzene. The whole is heated for 5 hours at 40° C. under a hydrogen pressure of 5 bar. The solvent is evaporated off and the residue is purified by chromatography on silica gel using dichloromethane as eluant.
Reaction SMILES: S(S([O-])=O)([O-])(=O)=[O:2].[Na+].[Na+].[C:10]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](=NO)[CH3:22])=[CH:16][CH:15]=1)([O:12][CH3:13])=[O:11].Cl>O.CO>[C:10]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](=[O:2])[CH3:22])=[CH:16][CH:15]=1)([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1ccc(CC(C)=NO)cc1
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(CC(C)=O)cc1

Procedure:
Sodium metabisulphite (131 g) in water (300 ml) was added to 1-(4-carbomethoxyphenyl)propan-2-one oxime (37.5 g) in methanol (200 ml) and the mixture refluxed for 6 hours. The reaction mixture was cooled, concentrated hydrochloric acid (100 ml) added, the mixture extracted with chloroform and the combined chloroform extracts washed with water followed by sodium bicarbonate solution. The chloroform layer was dried (MgSO4) and evaporated to give the title compound as an oil (bp 126°-129°/0.7 mm) which crystallised on standing, (mp 40°-47°). τ(CDCl3) 7.88 (3H, s), 6.28 (2H, s), 6.14 (3H, s), 2.77 (2H, d, J=8 Hz), 2,04 (2H, d, J=8 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH3:51][NH:52][O:53][CH3:54]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:54][O:53][N:52]([CH3:51])[C:10]([C@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:12]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.3 %

Procedure:
N-(tert-Butoxycarbonyl)-D-proline (1.505 g, 6.99 mmol), DCC (1.443 g, 6.99 mmol), HOBt (1.071 g, 6.99 mmol), and Hunig's base (2.78 mL, 15.89 mmol) in DCM (31.8 mL) were stirred at room temperature for 1 h. N,O-Dimethylhydroxylamine hydrochloride (0.62 g, 6.36 mmol) and DMAP (0.078 g, 0.636 mmol) were added and the solution stirred at room temperature for 4 h. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (10%→100% ethyl acetate in hexanes). Obtained (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (794 mg, 3.07 mmol, 48.4% yield) as a colorless oil. Rotomers (a and b) seen in NMR: 1H NMR (500 MHz, CDCl3) δ 4.52-4.76 (m, 1H), 3.77 (s, 1.5 Ha), 3.71 (s, 1.5 Hb), 3.51-3.64 (m, 1H), 3.33-3.51 (m, 1H), 3.18 (s, 3H), 2.08-2.27 (m, 1H), 1.74-2.04 (m, 3H), 1.45 (s, 4.5 Ha), 1.40 (s, 4.5 Hb); LRMS (ESI) m/e 158.76.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH2:17])[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)CN(Cc1ccccc1)C2
Solvent: c1ccccc1
Product: CC(=O)Nc1ccc2c(c1)CN(Cc1ccccc1)C2
Reaction time: 2 h

Procedure:
2-benzyl-5-aminoisoindoline prepared above was dissolved in 50 ml of anhydrous benzene, and 1.77 g of acetic anhydride was added. After standing for 2 hours at room temperature, the mixture was washed with 5% sodium bicarbonate and brine. The organic layer was concentrated to afford 2-benzyl-5-acetamidoisoindoline.
Reaction SMILES: O.O.O.O.O.O.[NH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl.Cl.N1CCNCC1.Br[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1>CO>[N:7]1([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: C1CNCCN1
Agent: Cl
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(CN2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64 %

Procedure:
A mixtue of 38 g. (0.2 mole) piperazine hexahydrate, 28 g. (0.2 mole) piperazine dihydrochloride and 150 ml. methanol is mixed, while stirring at ambient temperature, with 45 g. (0.2 mole) methyl 4-bromomethylbenzoate. The reaction mixture is left to stand for 2 days and suction filtered from the precipitate. The clear solution is evaporated and the residue is recrystallised from ethanol to give 39 g. (64%) of the desired compound as a monohydrochloride; m.p. 226°-227° C.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+](C)C.[CH2:10]([N:14]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]([C:24](=[S:26])[NH2:25])[N:16]=[C:15]1[N:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)[C:11]#[C:12][CH3:13]>ClCCl>[CH2:10]([N:14]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]([C:24]([S:26][CH3:6])=[NH:25])[N:16]=[C:15]1[N:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:29][CH2:28]1)[C:11]#[C:12][CH3:13]
Reactant: C[O+](C)C
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C(N)=S)c1C(=O)OCC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C(=N)SC)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.235 of trimethyl oxonium tetrafluoroborate was added to a 20-ml dichloromethane solution of 0.58 g of t-butyl 4-[1-(2-butynyl)-5-ethoxycarbonyl-4-thiocarbamoyl-1H-imidazol-2-yl]piperazine-1-carboxylate, and the mixture was stirred at room temperature for 18 hours. 50 ml of dichloromethane was added to the solution, and the mixture was washed with 20 ml of a saturated sodium bicarbonate solution. The mixture was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 0.55 g of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:14]2[CH2:15][CH2:16][CH:6]1[C:7]1[CH:8]=[C:9]([NH2:17])[CH:10]=[CH:11][C:12]=1[CH2:13]2.Cl[C:19]1[N:24]=[C:23]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:22]([Cl:37])=[CH:21][N:20]=1>>[Cl:37][C:22]1[C:23]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[N:24][C:19]([NH:17][C:9]2[CH:10]=[CH:11][C:12]3[CH2:13][CH:14]4[N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH:6]([CH2:16][CH2:15]4)[C:7]=3[CH:8]=2)=[N:20][CH:21]=1
Reactant: COCCN1C2CCC1c1cc(N)ccc1C2
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: COCCN1C2CCC1c1cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)ccc1C2
Yield: 46.5 %

Procedure:
Following procedures analogous to 61e, 12-(2-Methoxy-ethyl)-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamine (95 mg, 0.41 mmol) and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (139 mg, 0.41 mmol) were converted to the title compound as a white solid (102 mg, 47%) %) isolated as a mixture of diastereomers. 1HNMR (400 MHz, CDCl3) δ 7.9 (s, 1H), 7.3-7.2 (m, 2H), 7.0 (d, 1H, J=7.8 Hz), 6.8 (s, 1H), 5.4 (m, 1H), 5.3 (m, 1H), 4.0 (m, 1H), 3.9 (m, 1H), 3.7-3.5 (m, 3H), 3.3 (appt d, 3H), 3.2-3.1 (m, 2H), 2.9-2.7 (m, 5H), 2.4-2.2 (m, 4H), 1.9-1.8 (m, 3H), 1.7-1.5 (m, 3H), 1.4-1.3 (m, 3H); MS (m/e) 535 (M+1); mp 130-134° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]([NH:21][NH2:22])=[O:20])=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[CH:6][CH:7]=1.O.[F:24][C:25]([F:32])([C:28]([F:31])([F:30])[F:29])[CH:26]=O.O>C(O)(=O)C.C(OCC)(=O)C.O>[F:24][C:25]([F:32])([C:28]([F:31])([F:30])[F:29])[CH:26]=[N:22][NH:21][C:19](=[O:20])[C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=2)[N:4]=1
Reactant: NNC(=O)c1nc(Oc2cccc(C(F)(F)F)c2)ccc1Cl
Reactant: O=CC(F)(F)C(F)(F)F
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(NN=CC(F)(F)C(F)(F)F)c1nc(Oc2cccc(C(F)(F)F)c2)ccc1Cl

Procedure:
3-chloro-6-[3-(trifluoromethyl)phenoxy]-2-picolinic acid hydrazide (0.4 g, 0.0012 mol) was dissolved in 5 ml of acetic acid. The obtained solution was mixed with 2,2,3,3,3-pentafluoropropionaldehyde monohydrate (0.199 g, 0.0012×1.0 mol), and the resultant mixture was stirred at 80° C. for 3 hours. A chilled water was poured into the obtained reaction solution which was then distributed in ethyl acetate-water. The organic phase separated from the solution was washed with water and then dried with anhydrous sodium sulfate. After distilling off the solvent from the dried product, the obtained distillation residues were purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[K].Cl[C:11](=[CH:17]O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].S(=O)(=O)(O)O>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:17][N:8]=2)[CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CCOC(=O)C(Cl)=CO
Agent: O=S(=O)(O)O
Agent: [K]
Solvent: CCO
Product: CCOC(=O)c1cnc2ccc(Br)cn12
Temperature: 78 °C

Procedure:
To a stirring suspension of 5-bromopyridin-2-amine (1.2 g, 7.05 mmol) and ethyl 2-chloro-3-hydroxyacrylate potassium salt (6.6 g, 28.19 mmol) (prepared in a similar manner as 22) in EtOH (100 mL) at room temperature was added sulfuric acid (751 μL, 14.10 mmol) dropwise. The reaction mixture was heated at 78° C. overnight. The reaction was cooled to room temperature and the solvent was concentrated. The residue was taken in water and the pH was adjusted between 6-8 with saturated sodium bicarbonate. The crude product was extracted with ethyl acetate. The organic was washed with brine and dried over anhydrous sodium sulfate. The crude product was purified by silica chromatography to yield ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate (24s). MS m/z 270.2 (M+1)+.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@@H:4]([CH2:13][CH3:14])[C@H:5]([OH:12])[C:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)=[O:7].[CH:15]1(C[C@H](NC(=O)OC(C)(C)C)CO)[CH2:20][CH2:19]C[CH2:17][CH2:16]1>>[ClH:1].[ClH:1].[NH2:3][C@@H:4]([CH2:13][CH:14]1[CH2:19][CH2:20][CH2:15][CH2:16][CH2:17]1)[C@H:5]([OH:12])[C:6]([NH:8][CH:9]1[CH2:10][CH2:11]1)=[O:7]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1CCCCC1
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Agent: Cl
Product: N[C@@H](CC1CCCCC1)[C@H](O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide dihydrochloride, Representative Procedure A, starting with (S)-tert-butyl 1-cyclohexyl-3-hydroxypropan-2-ylcarbamate in the second step (A2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:22])[C:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1.[BH4-].[Na+].[NH4+].[Cl-]>C1COCC1.CCO>[OH:22][CH:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[S:10][CH2:9][C:8]1([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[CH3:13]
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2=O)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
To a solution of 7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-one (6.29 g, 20 mmol) in THF (20 ml) and EtOH (10 ml) was added NaBH4 (1.51 g, 40 mmol), which was stirred overnight at room temperature. The reaction solution was added saturated aqueous NH4Cl solution, extracted with CHCl3, and washed with brine. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. The residue was purified by recrystallization with CHCl3-hexane to give 5.33 g (84%) of 4-hydroxy-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:16][C@H:15]3[O:17][C@H:12]([CH2:13][CH2:14]3)[CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.O.[Zn]>[C@@H:12]12[O:17][C@@H:15]([CH2:14][CH2:13]1)[CH2:16][N:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[NH2:1])[CH2:11]2
Reactant: O=[N+]([O-])c1cccc(N2C[C@H]3CC[C@@H](C2)O3)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1cccc(N2C[C@H]3CC[C@@H](C2)O3)c1
Yield: 87.6 %

Procedure:
To a stirred solution of (1R,5S)-3-(3-nitrophenyl)-8-oxa-3-azabicyclo[3.2.1]octane (0.08 g, 0.341 mmol) and Zn (0.223 g, 3.41 mmol) in dioxane (10 mL) and H2O (2 mL) was added dropwise conc. HCl (0.34 mL, 3.41 mmol) at 25° C. for 2 h. It was adjusted to pH=8 by the addition of solid NaHCO3. It was filtered and the filtration was extracted with ethyl acetate (2×10 mL) and the extraction was concentrated to dryness. The residue was purified by column chromatography (silica gel, 200˜300 mesh, eluting with ethyl acetate:petroleum ether=1:2) to afford 3-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)aniline (0.061 g, 88%) as a yellow oil. LC-MS: 205 [M+H]+, tR=1.09 min.