Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Na+].[C:5]([NH:8][C:9](=[O:36])[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11]1[S:12][C:13]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)=[CH:14][C:15]=1[C:16]([O:18]CC)=O)(=O)C.IC>C(O)C>[CH3:5][N:8]1[C:16](=[O:18])[C:15]2[CH:14]=[C:13]([CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[S:12][C:11]=2[N:10]([CH2:32][CH:33]([CH3:34])[CH3:35])[C:9]1=[O:36]
Reactant: CCOC(=O)c1cc(Cc2cccc3ccccc23)sc1N(CC(C)C)C(=O)NC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CI
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cc(Cc3cccc4ccccc34)sc21
Reaction time: 6 h

Procedure:
Sodium ethoxide (0.18 g) was added to a stirred solution of N′-acetyl-N-(2-methylpropyl)-N-[3-ethoxycarbonyl-5-(1-naphthalenylmethyl)-2-thienyl]urea (Example 3, step c), 0.30 g) in ethanol (6 ml). After 6 hours, iodomethane (0.165 ml) was added. After a further 16 hours iodomethane (0.165 ml) was added, After a further 24 hours, the reaction mixture was poured onto hydrochloric acid (2M, 30 ml) and extracted with ethyl acetate (2×30 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica, eluting with ether:hexane (1:1) and then triturated with ether to give the title compound (0.24 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:13]2[S:29][C:16]3[C:17]4[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22][C:18]=4[O:19][CH2:20][CH2:21][C:15]=3[CH:14]=2)=[N:10][NH:11][CH:12]=1.[Cl-].[NH4+].C[N:33](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:13]2[S:29][C:16]3[C:17]4[CH:25]=[CH:24][C:23]([C:26]([NH2:33])=[O:27])=[CH:22][C:18]=4[O:19][CH2:20][CH2:21][C:15]=3[CH:14]=2)=[N:10][NH:11][CH:12]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc2c(c1)OCCc1cc(-c3n[nH]cc3-c3ccccc3Cl)sc1-2
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2c(c1)OCCc1cc(-c3n[nH]cc3-c3ccccc3Cl)sc1-2

Procedure:
Following Example 47, 2-(4-(2-chlorophenyl)-1H-pyrazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid and ammonium chloride were coupled with HATU and DIPEA in DMF to give 274.
Reaction SMILES: B.O1CCCC1.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19].Cl>O1CCCC1>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][OH:14])=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19]
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(CO)cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 89.7 %

Procedure:
Under an argon atmosphere and cooling with ice, borane-tetrahydrofuran complex (1.00 mol/L, tetrahydrofuran solution, 100 mL, 100 mmol) was added dropwise to a solution of 4-methoxy-3-nitrobenzoic acid (15.3 g, 76.1 mmol) in anhydrous tetrahydrofuran (200 mL) under stirring. After completion of the dropwise addition, the mixture was allowed to stand overnight at room temperature. The reaction mixture was cooled with ice again and 6 mol/L hydrochloric acid (20 mL) was added dropwise. After stirring for 30 minutes, the mixture was concentrated under reduced pressure. The residue was poured into 1 L of ice water and, after stirring for 30 minutes, the precipitates produced were collected by filtration, washed with water and dried to afford 12.5 g (90%) of the title compound as pale yellow crystals.
Reaction SMILES: C[O:2][C:3]1[C:20]([O:21]C)=[CH:19][C:6]2[S:7][C:8]([C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[O:12])=[C:9]([CH3:10])[C:5]=2[CH:4]=1.CO>ClCCl>[OH:2][C:3]1[C:20]([OH:21])=[CH:19][C:6]2[S:7][C:8]([C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[O:12])=[C:9]([CH3:10])[C:5]=2[CH:4]=1
Reactant: COc1cc2sc(C(=O)N3CCOCC3)c(C)c2cc1OC
Solvent: CO
Solvent: ClCCl
Product: Cc1c(C(=O)N2CCOCC2)sc2cc(O)c(O)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (5,6-dimethoxy-3-methylbenzo[b]thiophen-2-yl)morpholin-4-yl-methanone (0.80 g) in dichloromethane (8 ml) boron tribromide (5.2 ml, 2 M solution in dichloromethane) was added at 0° C. The mixture was allowed to warm to room temperature. After 2 hours at room temperature methanol (16 ml) was added and solvents were evaporated. To the residue sodium sulfite solution (16 ml, 5% in water) was added and after stirring for 0.5 hour the precipitate was filtered.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[CH2:9][NH:10][CH2:11][C:12]([F:15])([F:14])[F:13].C(N(CC)CC)C.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][C:24](=[O:26])[N:10]([CH2:11][C:12]([F:14])([F:15])[F:13])[CH2:9][C:3]=12
Reactant: Nc1ncnc(Cl)c1CNCC(F)(F)F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1Nc2ncnc(Cl)c2CN1CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
Combine 6-chloro-5-((2,2,2-trifluoroethylamino)methyl)pyrimidin-4-amine (9.57 g, 39.78 mmol), triethylamine (5.50 mL, 2.0 eq), and dichloromethane (795 mL). Cool to 0° C. under nitrogen. Add a solution of triphosgene (11.85 g, 1.0 eq) in dichloromethane (228 mL). Stir at 0° C. for 30 min, and allow to warm to room temperature. Heat the reaction mixture to 40° C. overnight. Add aqueous sodium bicarbonate and extract with ethyl acetate. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by silica gel chromatography, eluting with 9:1 dichloromethane:methanol, to give the title compound (4.50 g, 42%). 1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.41 (s, 1H), 4.20 (m, 2H), 3.25 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30].C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[Cl:25][CH2:26][CH2:27][CH2:28][C:29]([NH:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1)=[O:30]
Reactant: COC(=O)c1ccc(-c2ccc(N)nc2C)cc1
Reactant: O=C(Cl)CCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-c2ccc(NC(=O)CCCCl)nc2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
A stirred suspension of methyl 4-(6-amino-2-methylpyridin-3-yl)benzoate (D7, 1.0 g, 4.1 mmole) in dichloromethane (80 ml) was treated with pyridine (0.66 ml, 8.2 mmole), followed by 4-chlorobutyryl chloride (0.47 ml, 4.3 mmole). The resulting solution was stirred at 25° C. for 2 h, then treated with 5% Na2CO3 solution and after 30 minutes, the organic layer was separated, dried (Na2SO4) and concentrated in vacuo to leave a pale yellow solid. This was recrystallised from ethyl acetate/60-80 petrol to afford the title compound as a beige solid (1.13 g, 80%).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:16]1[CH:17]=[CH:18][C:19]([N+:31]([O-:33])=[O:32])=[C:20]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:21]=1.[H-].[Na+]>CN(C)C=O>[CH3:30][N:22]([C:20]1[CH:21]=[C:16]([O:14][C:11]2[CH:10]=[CH:9][C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:19]=1[N+:31]([O-:33])=[O:32])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(Cc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(Cc3ccccc3)cc2)ccc1[N+](=O)[O-]
Yield: 88 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 4-benzylphenol (7 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (9.15 g), sodium hydride (55 wt. %, 1.74 g) and anhydrous N,N-dimethylformamide (70 ml) and the reaction mixture was purified to give the title compound (12.2 g).
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([O+](CC)CC)[CH3:7].[CH3:13][C:14]1([CH3:21])[NH:17][C:16](=[O:18])[C:15]1([CH3:20])[CH3:19].C([O-])([O-])=O.[K+].[K+]>ClCCl>[CH2:6]([O:18][C:16]1[C:15]([CH3:20])([CH3:19])[C:14]([CH3:21])([CH3:13])[N:17]=1)[CH3:7]
Reactant: CC[O+](CC)CC
Reactant: CC1(C)NC(=O)C1(C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC1=NC(C)(C)C1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 60 ml (1M) of triethyloxonium tetraflouroborate in dichloromethane was added 5 g (0.039 mol) of tetramethylazetidinone in 10 ml of dry CH2Cl2 under an inert atmosphere. The reaction mixture was stirred for 1 hour at room temperature and then was refluxed for 1 hour. After cooling, the reaction mixture was added dropwise to 20 ml of a 50% K2CO3 solution at -10° C. and the mixture was diluted with 20 ml of CH2Cl2 and then filtered. The organic phase was separated out and immediately dried over MgSO4. After filtration, the solvent was stripped off under vacuum and the residue was distilled at 78° to 80° C./50 mmHg to obtain the product as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[C:12]([OH:16])(=[O:15])[CH:13]=[CH2:14].S(=O)(=O)(O)O>O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[CH2:14][CH2:13][C:12]([OH:16])=[O:15]
Reactant: CNc1ccc([N+](=O)[O-])cc1
Reactant: C=CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CN(CCC(=O)O)c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 90.6 %

Procedure:
Methyl-(4-nitro-phenyl)-amine (3.0 g, 19.7 mmol) and acrylic acid (4.06 mL, 59.2 mmol) were added at 0° C. to a solution of concentrated sulfuric acid (2.15 mL, 39.5 mmol) in water (28 mL). The reaction mixture was heated at 80° C. for 30 min, cooled to room temperature and diluted with water. The precipitated solid was filtered and dried to give a crude product which was purified by washing with diethyl ether and pentane, affording 3-[methyl-(4-nitro-phenyl)-amino]-propionic acid (4.0 g, 91%) as a yellow solid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH3:6][C:7]1[CH:8]=[C:9]([S:21](Cl)(=[O:23])=[O:22])[CH:10]=[CH:11][C:12]=1[NH:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15]>O1CCCC1>[CH2:1]([N:3]([CH2:4][CH3:5])[S:21]([C:9]1[CH:10]=[CH:11][C:12]([NH:13][S:14]([C:17]([F:20])([F:18])[F:19])(=[O:16])=[O:15])=[C:7]([CH3:6])[CH:8]=1)(=[O:23])=[O:22])[CH3:2]
Reactant: CCNCC
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NS(=O)(=O)C(F)(F)F
Solvent: C1CCOC1
Product: CCN(CC)S(=O)(=O)c1ccc(NS(=O)(=O)C(F)(F)F)c(C)c1
Reaction time: 8 h
Yield: 58.3 %

Procedure:
A solution of diethylamine (1 g) and 3-methyl-4-(trifluoromethanesulfonamido)benzenesulfonyl chloride (1.5 g) in tetrahydrofuran (20 ml) was allowed to stand overnight. The resultant mixture was concentrated and shaken with chloroform and 5% aqueous hydrochloric acid. The chloroform extract was concentrated and recrystallized from a mixture of ethanol and water to give 0.97 g of N,N-diethyl-3-methyl-4-(trifluoromethanesulfonamido)benzenesulfonamide. M.P., 128°-128.5° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.N1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20]>CN(C)C(=O)C>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([NH:11][C:19](=[O:20])[O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1nc2ccc(N)cc2o1
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: Cc1nc2ccc(NC(=O)OCC(Cl)(Cl)Cl)cc2o1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methyl-1,3-benzoxazol-6-amine (1.00 g, 6.74 mmol) and pyridine (1.64 ml, 20.2 mmol) in N,N-dimethylacetamide (20 ml) was added 2,2,2-trichloroethyl chloroformate (1.39 ml, 10.1 mmol) under ice-cooling, and the mixture was stirred for 2 hours under ice-cooling. The reaction mixture was poured into ice-water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate, and 1.45 g (66.5%) of the desired product was collected by filtration as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([O:14][CH3:15])[CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:30]([C:32]1[CH:45]=[CH:44][C:35]([CH2:36][N:37]2[C:41]([CH:42]=O)=[CH:40][N:39]=[CH:38]2)=[CH:34][CH:33]=1)#[N:31]>ClCCCl.C(O)(=O)C>[C:30]([C:32]1[CH:33]=[CH:34][C:35]([CH2:36][N:37]2[C:41]([CH2:42][NH:1][C:2]3[CH:7]=[CH:6][C:5]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)=[C:4]([O:14][CH3:15])[CH:3]=3)=[CH:40][N:39]=[CH:38]2)=[CH:44][CH:45]=1)#[N:31]
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Reactant: COc1cc(N)ccc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cc(NCc2cncn2Cc2ccc(C#N)cc2)ccc1-c1ccccc1
Reaction time: 15 h

Procedure:
To a solution of 1-amino-3-methoxy-4-phenylbenzene in 1,2-dichloroethane at 0° C. was added 4A powdered molecular sieves and sodium triacetoxyborohydride. 1-(4-Cyanobenzyl)-5-imidazole-carboxaldehyde was added, followed by 5 drops of acetic acid. The cooling bath was removed after 5 hours, and the reaction was stirred for another 15 hours. The reaction was poured into ethyl acetate and water. The organic layer was extracted with sat. aq. NaHCO3 solution and brine, then dried (Na2SO4) and concentrated in vacuo to provide the product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][C:13](=O)[O:12][C:10](=[O:11])[CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[SH:24]>ClCCl>[Cl:23][C:21]1[CH:20]=[CH:19][C:18]2[S:24][C:13]([CH2:14][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:9][C:10]([OH:12])=[O:11])=[N:16][C:17]=2[CH:22]=1
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Reactant: Nc1cc(Cl)ccc1S
Solvent: ClCCl
Product: O=C(O)CC(Cc1nc2cc(Cl)ccc2s1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
A mixture of 3-(4-chlorophenyl)glutaric anhydride (0.5 g) and commercial 2-amino-4-chlorothiophenol (0.37 g) is dissolved in boiling dichloromethane (3 ml). The solution is stirred overnight at rt. The precipitate is isolated by suction filtration, washed with dichloromethane, and dried in vacuo. The crude product is recrystallised from acetone to give 0.3 g of 4-(5-chloro-2-benzothiazolyl)-3-(4-chlorophenyl)butanoic acid as colourless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:23][S:24]([Cl:27])(=[O:26])=[O:25].[ClH:28]>>[ClH:27].[ClH:28].[CH2:16]([N:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:7][CH:6]=2)[CH2:13][CH2:12]1)[CH3:15])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN(Cc1ccccc1)C1CCN(c2ccc(N)cc2)CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: CN(Cc1ccccc1)C1CCN(c2ccc(NS(C)(=O)=O)cc2)CC1

Procedure:
The product from Example 8 was reacted in a similar manner to Example 4 with methanesulfonyl chloride and then converted into the hydrochloride. 4-(N-Benzyl-N-methylamino)-1-(4-methanesulfonylaminophenyl)piperidine dihydrochloride was obtained. Melting point 221° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[CH3:19][N:20]([CH3:29])[C:21]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22]>>[CH3:19][N:20]([CH3:29])[C:21]([CH:23]1[CH2:24][CH2:25][N:26]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[C:5]=3[CH:10]=2)[CH2:27][CH2:28]1)=[O:22]
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: CN(C)C(=O)C1CCNCC1
Product: CN(C)C(=O)C1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde (General Procedure D-2) and piperidine-4-carboxylic acid dimethylamide (Example 42) using General Procedure B-3 yielded 1-(2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidin-6-ylmethyl)-piperidine-4-carboxylic acid dimethylamide.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[O:19][CH:18]=[CH:17][C:16]=12)=[O:10].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=[O:26]>>[F:20][C:21]([F:31])([F:32])[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([N:3]1[CH2:4][C@H:5]2[C@H:1]([CH2:6]2)[C@H:2]1[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[O:19][CH:18]=[CH:17][C:16]=12)=[O:10])=[O:26]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(NC[C@H]1NC[C@@H]2C[C@@H]21)c1cccc2occc12
Product: O=C(NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1cccc(C(F)(F)F)c1)c1cccc2occc12

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 3-trifluoromethyl-benzoic acid.
Reaction SMILES: C([C:3]1[CH:8]([C:9]([O:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[N:7]2[C:25](=[O:36])[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C@H:6]2[S:5][CH:4]=1)=O>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].C1(C)C=CC=CC=1>[CH:12]([O:11][C:9]([C:8]1[N:7]2[C:25](=[O:36])[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C@H:6]2[S:5][CH2:4][CH:3]=1)=[O:10])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=CC1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12

Procedure:
A mixture of the benzhydryl ester from Example 28 (2.5 g, 4.79 mmol) tris-(triphenylphosphine)chlororhodium (3.5 g. 4.79 mmol) and dry toluene (75 ml) was refluxed under nitrogen for 5.5 hours. The reaction mixture was cooled the rhodium complex was removed by filtration and the filtrate was poured slowly into petroleum ether (250 ml) with stirring. The precipitated solid, which was a mixture of rhodium complex and product, was collected. The product was purified by chromatography on a silica gel column (250 g) using 99:0.5 chloroform:ethyl acetate as eluent. Fractions of 4.5 ml were collected; fractions 1-47 discarded, 48-66 contained bis-(triphenylphosphine)carbonylchlororhodium, and 67-198 contained the product. NMR data indicated the product after chromatography to be the Δ3 isomer instead of the Δ2 isomer. A decoupling experiment showed the 2-methylene group at 3.3 ppm. to be coupled with the 3-proton at 6.6 ppm.
Reaction SMILES: [C-]#N.[K+].[F:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9].[C:13]([O:17][CH2:18]C)(=[O:16])[CH:14]=[CH2:15].O>CN(C)C=O>[CH3:18][O:17][C:13](=[O:16])[CH2:14][CH2:15][C:8]([C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([F:4])[CH:6]=1)=[O:9]
Reactant: C=CC(=O)OCC
Reactant: O=Cc1cccc(F)c1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)c1cccc(F)c1
Temperature: 45 °C

Procedure:
To a stirred suspension of potassium cyanide (3.25 g) in N,N-dimethylformamide (30 cm3), being maintained at a temperature of 45° C., was added 3-fluorobenzaldehyde (25.0 g). Ethyl acrylate (18.46 cm3) was then added and the resultant mixture was stirred at 40° C. for 2 h. Water (200 cm3) was added and the aqueous mixture was extracted with diethyl ether (2×125 cm3). The organic extracts were washed with water (100 cm3) and saturated aqueous sodium chloride solution (100 cm3) before being dried (Na2SO4) and the solvent was removed under reduced pressure to yield the title compound (25.27 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([OH:16])[CH:13]=[CH:12]2)=[C:4]([Cl:17])[N:3]=1.N1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C1COCC1>[CH2:28]([O:27][C:25](=[O:26])[O:16][C@H:14]1[CH2:15][C@@H:11]([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([Cl:1])=[N:3][C:4]=3[Cl:17])[CH:12]=[CH:13]1)[CH3:29]
Reactant: O[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1S,4R)-4-(2,6-Dichloro-purin-9-yl)-cyclopent-2-enol (9.5 g, 35.05 mmol) is placed in an oven-dried flask under an atmosphere of argon. Dry THF (200 mL) is added followed by dry pyridine (5.54 g, 70.1 mmol). Ethyl chloroformate (15.21 g, 140.2 mmol) is added slowly so that the temperature does not rise above 40° C. and the reaction mixture is stirred at RT. The reaction is shown to be complete by LCMS after 1 hour. The solvent is removed in vacuo and the residue is partitioned between DCM (200 mL) and water (200 mL). The organic layer is washed with water (150 mL) and brine (150 mL), dried over MgSO4, filtered and the solvent is removed in vacuo. The title compound is obtained after crystallisation from methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:28][C:29]1([C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([NH:28][C:29]1([C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)=[O:9]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=C(O)c1cc(Cl)cnc1N1CCC(Oc2cccc(C(F)(F)F)c2)C1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCC(Oc4cccc(C(F)(F)F)c4)C3)CC2)cc1
Yield: 87.8 %

Procedure:
The title compound (D195) (150 mg) was prepared according to the experimental procedure described in Description 146 starting from 5-chloro-2-(3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)nicotinic acid (D137) (120 mg, 0.305 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (65.57 mg, 0.305 mmol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH2:22]([C:29]1([CH3:32])[CH2:31][O:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[OH:30][C:29]([CH3:32])([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:31][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: CC1(Cc2ccccc2)CO1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: CC(O)(Cc1ccccc1)CN1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 179 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-benzyl-2-methyloxirane and conditions outlined in procedure X. M.p.=186-187° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.89 (d, J=7.8 Hz, 1H), 7.82-7.76 (m, 2H), 7.64-7.54 (m, 1H), 7.28-7.16 (m, 5H), 4.22 (s, 1H), 4.11 (q, J=5.1 Hz, 1H), 3.38 (d, J=1.1 Hz, 1H), 3.17 (d, J=5.5 Hz, 3H), 3.08 (s, 2H), 2.94-2.76 (m, 2H), 2.63-2.72 (m, 2H), 2.41-2.20 (m, 2H), 2.02-1.94 (m, 2H), 1.92-1.80 (m, 2H). LCMS: 450 [M+H].