Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH3:5].C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(S(O[CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH3:44])(=O)=O)=CC=1>CN(C)C=O>[CH3:5][C:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH2:3][CH2:2][S:1][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH3:44]
Reactant: CC(C)(CCS)NC(=O)OCc1ccccc1
Reactant: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOCCOCCSCCC(C)(C)NC(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 42.5 %

Procedure:
To a solution of benzyl 4-mercapto-2-methylbutan-2-ylcarbamate (2.05 g, 8.1 mmol) in N,N-dimethylformamide (10 ml) was added cesium carbonate (2.27 g, 6.97 mmol) and 2-(2-(2-methoxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (2.32 g, 7.29 mmol). The solution was heated to 60° C. for 2 hour, then 70° C. for 16 hour, cooled to room temperature, concentrated in vacuo, and the residue dissolved in 50 ml 5% NaHSO4, extracted with 3×50 ml ethyl acetate, dried on MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography (10% to 60% ethyl acetate in hexanes) to give the title compound as a clear oil (1.24 g, 3.10 mmol, 60%). 1H NMR (400 MHz, CDCl3) δ 1.32 (s, 6H), 1.99 (m, 2H), 2.53 (m, 2H), 2.73 (m, 2H), 3.39 (s, 3H), 3.5-3.7 (m, 10H), 4.8 (s, 1H), 5.05 (s, 2H), 7.3-7.4 (m, 5H). LRMS (ESI/APCI) m/z 422 [M+Na]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[O:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.[O-]S([O-])(=O)=O.[Na+].[Na+]>C(O)(=O)C>[Br:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][CH:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C1CCOCC1
Reactant: Nc1ccc(Br)cc1C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)c1cc(Br)ccc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
A mixture of 5 g of 2-amino-5-bromobenzoic acid, 9.27 g of tetrahydro-4H-pyran-4-one and 32 g of Na2SO4 in 50 ml of acetic acid is stirred overnight at room temperature. The reaction mixture is filtered. A further 9.27 g of tetrahydro-4H-pyran-4-one and 32 g of Na2SO4 are added and the resulting mixture is stirred overnight at room temperature. This mixture is filtered and 9.81 g of NaBH(OAc)3 are added. The resulting mixture is allowed to cool to room temperature over 2 hours. The reaction medium is evaporated under reduced pressure and the residue is taken up in EtOAc. It is washed with aqueous 1N HCl solution. The organic phase is dried over Na2SO4, filtered and evaporated under reduced pressure to give 3.35 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:40][C:39]([F:41])([F:42])[C:36]1[CH:35]=[CH:34][C:33]([NH:32][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:29])=[CH:38][CH:37]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(F)(F)F)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 14.5 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.2 g, 0.43 mmol) was reacted with 4-aminobenzotrifluoride (Alfa) (0.14 g, 0.86 mmol), HATU (0.29 g, 0.77 mmol) and iPr2NEt (0.15 mL, 0.86 mmol) in CH2Cl2 at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-trifluoromethyl-phenyl)-amide as a white solid (38 mg, 15%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][C@@H:5]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH:25]([F:27])[F:26])[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][C:11]=2[CH3:33])=[O:9])[C@H:4]([CH3:34])[CH2:3]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:30]1([CH2:29][O:28][C:20]2[CH:21]=[CH:22][C:23]([CH:25]([F:27])[F:26])=[CH:24][C:19]=2[C:18]2[C:13]3[NH:12][C:11]([CH3:33])=[C:10]([C:8]([NH:7][C@@H:5]4[CH2:6][C@@H:2]([NH:1][C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:3][C@H:4]4[CH3:34])=[O:9])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:32][CH2:31]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1C[C@@H](N)C[C@H]1C
Product: COCC(=O)N[C@H]1C[C@@H](C)[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C1

Procedure:
Starting from N-[(1R*,2R*,4S*)-4-amino-2-methylcyclopentyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (example D.f69) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][CH2:24]O)=[CH:19][CH:18]=4)[N:13]=3)[C:8]=2[CH2:26][CH2:27][CH3:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:30]>ClCCCl.ClCCl>[Br:30][CH2:24][CH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[N:13]=[C:12]([C:9]3[C:8]([CH2:26][CH2:27][CH3:28])=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[O:11][N:10]=3)[O:16][N:15]=2)=[CH:18][CH:19]=1
Reactant: CCCc1c(-c2nc(-c3ccc(CCO)cc3)no2)noc1-c1ccccc1
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCc1c(-c2nc(-c3ccc(CCBr)cc3)no2)noc1-c1ccccc1
Temperature: 70 °C

Procedure:
To a mixture of 2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol (400 mg, 1.065 mmol) in DCE (20 mL) was added phosphorus tribromide in DCM (1.065 mL, 1.065 mmol). The reaction mixture was heated at 70° C. overnight. The reaction mixture was diluted with dichloromethane and washed with 1N NaOH. The organic layer was dried MgSO4, filtered, and concentrated. The crude material was purified on a 40 gram silica column and eluting with EtOAc/Hex (0-50% gradient over 20 minutes) to afford 77 mg of 3-(4-(2-bromoethyl)phenyl)-5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazole. MS (m+1)=440. HPLC Peak RT=2.40 minutes. (Analytical Method B).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18]O)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:27]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34])([O-:29])=[O:28]>C(#N)C>[N+:27]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]2)=[CH:4][CH:3]=1)=[O:34])([O-:29])=[O:28]
Reactant: Nc1ccc2cccc(N3CCN(CO)CC3)c2c1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN1CCN(c2cccc3ccc(NC(=O)c4cccc([N+](=O)[O-])c4)cc23)CC1
Yield: 47.8 %

Procedure:
The title product was prepared following the procedure of example 3 from 7- amino-1-(4-methylol-piperazinyl)-naphthalene (0.15 g, 0.622 mmol) and triethylamine (0.09 mL, 0.68 mmol) and 3-nitrobenzoyl chloride (0.127 mL, 0.684 mmol) in acetonitrile (10 mL) with an overnight reflux. The product was purified by silica gel flash chromatography followed by recrystallization from ethyl acetate to yield 0.116 g (47%) of the title product: mp 182°-184° C. Analysis calculated for C22H22N4O3 : C, 67.68; H, 5.68; N, 14.35. Found: C, 67.47; H, 5.64; N, 14.08.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([F:4])[F:3].C1([Si:18]2([CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:23][CH2:22][CH:21]([C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)C=CC=CC=1>>[CH3:36][CH:35]([CH3:37])[CH2:34][CH2:33][Si@H:18]1[CH2:23][CH2:22][C@H:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([O:11][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:2]([F:3])([F:4])[F:1])=[O:29])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1
Reactant: CC(C)CC[Si]1(c2ccccc2)CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: Oc1ccccc1C(F)(F)F
Product: CC(C)CC[Si@H]1CC[C@H](c2ccc(C(=O)Oc3ccccc3C(F)(F)F)cc2)CC1

Procedure:
The general procedure of Example 3 was repeated using trifluoromethylphenol and 4-(4-phenyl-4-(3methylbutyl)-4-silacyclohexyl)benzoic acid, thereby obtaining the intended product.
Reaction SMILES: [N:1]1([C:7]([NH:9][C:10]2([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[CH2:34][O:35][C:36](=O)[O-:37]>C(Cl)Cl>[CH3:34][O:35][C:36]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([NH:9][C:10]2([C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])[CH2:2][CH2:3]1)=[O:37]
Reactant: O=C(NC1(C(=O)OCc2ccccc2)CCCCC1)N1CCNCC1
Reactant: O=C([O-])OCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCN(C(=O)NC2(C(=O)OCc3ccccc3)CCCCC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.1 %

Procedure:
Subsequently, 0.98 ml (2.83 mmol) of the phenylmethyl 1-[N-(piperazine-1-carbonyl)amino]cyclohexanecarboxylate and 0.39 ml (2.83 mmol) of triethylamine were dissolved in 20 ml of anhydrous methylenechloride and then 0.21 ml (2.83 mmol) of chloromethylcarbonate was added to the above prepared mixture and stirred for 12 hours at the room temperature. The reaction solution was successively washed with 1N hydrochloric acid, saturated sodium hydrogen-carbonate solution and saturated brine, and dried over anhydrous sodium sulfate and concentrated under reduced pressure, whereby 1.12 g of phenylmethyl 1-[N-[4-(methoxycarbonyl)piperazine-1-carbonyl]amino]cyclohexanecarboxylate was obtained.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH3:6][O:7][N:8]([CH3:35])[C:9]([C:11]1[S:12][C:13]([C:17]2[CH:18]=[C:19]([C:25]3[CH:30]=[CH:29][C:28]([S:31](=[O:34])(=[O:33])[NH2:32])=[CH:27][CH:26]=3)[C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[C:14]([CH3:16])[N:15]=1)=[O:10]>C(OCC)(=O)C>[CH3:1][N:2]([CH:4]=[N:32][S:31]([C:28]1[CH:29]=[CH:30][C:25]([C:19]2[C:20]([O:23][CH3:24])=[CH:21][CH:22]=[C:17]([C:13]3[S:12][C:11]([C:9]([N:8]([O:7][CH3:6])[CH3:35])=[O:10])=[N:15][C:14]=3[CH3:16])[CH:18]=2)=[CH:26][CH:27]=1)(=[O:34])=[O:33])[CH3:3]
Reactant: COc1ccc(-c2sc(C(=O)N(C)OC)nc2C)cc1-c1ccc(S(N)(=O)=O)cc1
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2sc(C(=O)N(C)OC)nc2C)cc1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.33 %

Procedure:
DMF (0.7 ml) and DMF acetal (0.22 g, 0.25 ml, 1.88 mmol) were added subsequently to a solution of N-methoxy-5-(6-methoxy-4′-sulfamoyl-[1,1′-biphenyl]-3-yl)-N,4-dimethylthiazole-2-carboxamide (8c, 0.70 g, 1.56 mmol) in ethyl acetate (12 ml) at room temperature. The reaction mixture was then stirred at room temperature for 15 hr under nitrogen atmosphere. The progress of the reaction was monitored by TLC. The solid obtained was filtered and washed with ether (10 ml) to obtain the title compound 8d (0.60 g, 76.33%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7](CCC(O)=O)[NH:8]2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:22]1C[O:25][CH2:24][CH2:23]1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1cc2ccc(F)cc2[nH]1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCCc1c[nH]c2cc(F)ccc12
Temperature: 20 °C
Reaction time: 15 h
Yield: 65 %

Procedure:
To a solution of 3-(6-fluoroindolyl)propionic acid (235 mg, 1.13 mmol) in THF (5.3 mL) was added LiAlH4 (86 mg, 2.26 mmol) slowly at 0° C. under N2. The reaction mixture was warmed to 20° C. and stirred for 15 h. The reaction was quenched by addition of H2O (0.5 mL) and diluted with EtOAc. The resulting solution was dried over MgSO4, filtered through Celite and concentrated in vacuo. The residue was chromatographed to give 6-fluoro-3-(3-hydroxypropyl)indole (142 mg, 65%) as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:9]=1.[NH:17]1[C:21](=[O:22])[CH2:20][CH2:19][C:18]1=[O:23]>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[N:9]=[C:5]([CH:4]=[CH:3][CH2:2][N:17]3[C:21](=[O:22])[CH2:20][CH2:19][C:18]3=[O:23])[S:6][CH:7]=2)=[CH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1
Reactant: Fc1ccc(-c2csc(C=CCCl)n2)cc1
Product: O=C1CCC(=O)N1CC=Cc1nc(-c2ccc(F)cc2)cs1

Procedure:
The compound was prepared analogously to example 3e) from 100 mg (0.39 mmol) of 2-(3-chloropropenyl)-4-(4-fluorophenyl)thiazole and 46.8 mg (0.47 mmol) of pyrrolidine-2,5-dione. Yield: 24 mg (17%).
Reaction SMILES: [OH:1][C:2]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]2([CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]2)[O:3]1.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O>[OH:3][C:4]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[CH:2]([OH:1])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1
Reactant: CN1CCC2(CC1)OC(O)(c1ccccc1)c1ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(O)(c2ccccc2C(O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 8.5 g. of 1,3-dihydro-3-hydroxy-1'-methyl-3-phenylspiro[isobenzofuran-1,4'-piperidine], Example 1, in 150 ml. of tetrahydrofuran is added dropwise in 30 minutes to a stirred suspension of 2.0 g. of lithium aluminum hydride in 150 ml. of anhydrous tetrahydrofuran. The mixture is stirred at room temperature for 30 minutes and at 50° for 1 hour, cooled, diluted cautiously with water, and extracted with chloroform. The chloroform solution is dried over potassium carbonate and concentrated to a solid. Recrystallization from benzene gives colorless crystals, m.p. 190°-191° of 4-hydroxy-4-(α-hydroxy-α-phenyl-2-tolyl)-1-methylpiperidine.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][C:17]3=[O:27])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:32][CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35].Cl>CN(C=O)C.O>[ClH:32].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[C:17]3=[O:27])[CH2:10][CH2:9]2)=[O:7])=[CH:28][CH:29]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3ccccc3c2=O)CC1
Reactant: CN(C)C(=O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)Cn1c(=O)n(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-{2-[4-(4-Fluorobenzoyl)-1-piperidinyl]ethyl}-2,4(1H,3H)-quinazolinedione was dissolved in DMF (5 ml) and NaH (60% dispersion in mineral oil) added. After 0.5 hours, 2-chloro-N,N-dimethylacetamide was added and the solution stirred at room temperature for 16 hours. Water and ethyl actetate were added, the organic phase separated, dried and concentrated to an oil. Purification by chromatography (dichloromethane:methanol 95:5) gave an oil which was treated with 1.0 M ethereal hydrogen chloride solution to give the titled product as a solid(0.015 g).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[CH2:21][O:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])(=[O:14])=[O:13])=[C:7]([CH3:31])[CH:6]=1>C1COCC1.CO>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[CH2:21][O:22][CH2:23][C:24]([OH:26])=[O:25])(=[O:14])=[O:13])=[C:7]([CH3:31])[CH:6]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)OC(C)(C)C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)O)c(C)c1
Temperature: 25 °C

Procedure:
NaOH (6 M, 200 ml, 1200 mmole) was added to a solution of tert.-butyl 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetate (26.8 g, 62.7 mmole) in THF (200 ml) and methanol (200 ml). The reaction mixture was stirred at RT. After 1 hour the organic solvent was distilled off on a rotary evaporator and HCl (6 M, 210 ml) was added at 0° C. The aqueous phase was extracted with DCM (200 ml) and ethyl acetate (200 ml). The combined organic phases were dried over sodium sulfate and concentrated. Diisopropyl ether was added twice and evaporated. Yield: 21.92 g, 94%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([NH:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:26])[CH3:25]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:31]4[CH:32]=[CH:33][C:28]([NH:27][C:24](=[O:26])[CH3:25])=[CH:29][CH:30]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Product: CC(=O)Nc1ccc(-c2cc3c(cn2)OC(C2CCN(C(=O)OC(C)(C)C)CC2)C3)cc1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-(acetylamino)phenylboronic acid following a procedure analogous to that described in Example 28. LC (method 7): tR=1.16 min; Mass spectrum (ESI+): m/z=438 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[N+:40]([O-])=O)=[C:4]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:5]=[C:6]([CH:8]2[C:17]3[C:16](=[O:18])[CH2:15][CH:14]([CH2:19][CH2:20][CH3:21])[CH2:13][C:12]=3[NH:11][C:10]([CH3:22])=[C:9]2[C:23]#[N:24])[CH:7]=1.C(O)(=O)C>C1COCC1.[Zn]>[NH2:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][NH:32][C:3]1[C:2]([Br:1])=[CH:7][C:6]([CH:8]2[C:17]3[C:16](=[O:18])[CH2:15][CH:14]([CH2:19][CH2:20][CH3:21])[CH2:13][C:12]=3[NH:11][C:10]([CH3:22])=[C:9]2[C:23]#[N:24])=[CH:5][C:4]=1[NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:27])=[O:28]
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(NCc2ccccc2[N+](=O)[O-])c(NS(=O)(=O)CCC)c1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(NCc2ccccc2N)c(NS(=O)(=O)CCC)c1
Reaction time: 3 h

Procedure:
Propane-1-sulfonic acid [3-bromo-5-(3-cyano-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinolin-4-yl)-2-(2-nitro-benzylamino)-phenyl]-amide (1.21 g) and acetic acid (1.6 ml) were dissolved in THF (150 ml). Zinc dust (2.32 g) was added under vigorous stirring. After 3 h, the mixture was filtered, diluted with ethyl acetate and washed with sat. aq. NaHCO3. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/0→0/1 (v/v) as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([NH:13][CH2:14][C:15]([CH2:21][NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([OH:20])[C:16]([F:19])([F:18])[F:17])[CH3:12]>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:13]([CH2:11][CH3:12])[CH2:14][C:15]([OH:20])([CH2:21][NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:16]([F:18])([F:17])[F:19])=[O:6]
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F
Reactant: O=C(O)c1ccccc1Cl
Product: CCN(CC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccccc1Cl

Procedure:
Prepared similarly to Example 1 from 2-chlorobenzoic acid and 3-(ethylamino)-1,1,1-trifluoro-2-{[(1-phenyl-1H-indazol-4-yl)amino]methyl}-2-propanol.
Reaction SMILES: [CH:1](=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:7][NH:8][CH2:9][CH2:10][CH2:11][NH2:12].O>C1CCCCC1>[CH3:7][NH:8][CH2:9][CH2:10][CH:11]=[N:12][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C=O
Reactant: CNCCCN
Solvent: O
Solvent: C1CCCCC1
Product: CNCCC=NCC(C)(C)C

Procedure:
75.0 g (0.87 mol) of pivalaldehyde are added dropwise to a solution of 76.7 g (0.87 mol) of 3-methylaminopropylamine in 200 ml of dry cyclohexane. After the addition, the solution is heated under reflux in a water separator for 3 hours. The solvent is then removed in a rotary evaporator and the residue is distilled. Boiling point: 69° C./67 mbar
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][CH:38]=1)[C:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH:15]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Br[CH:49]([C:52]1[CH:57]=[CH:56][C:55]([CH2:58][CH:59]([CH3:61])[CH3:60])=[CH:54][CH:53]=1)[CH2:50][CH3:51]>ClCCl>[CH2:1]([N:8]([C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][CH:38]=1)[CH2:12][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH:15]=1)[CH:49]([C:52]1[CH:53]=[CH:54][C:55]([CH2:58][CH:59]([CH3:60])[CH3:61])=[CH:56][CH:57]=1)[CH2:50][CH3:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(Br)c1ccc(CC(C)C)cc1
Reactant: O=C(CCCn1cc(C(=O)c2cccc(NCc3ccccc3)c2)c2ccccc21)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(c1ccc(CC(C)C)cc1)N(Cc1ccccc1)c1cccc(Cc2cn(CCCC(=O)OCc3ccccc3)c3ccccc23)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 25.8 %

Procedure:
To a solution of benzyl 4-[3-(3-benzylaminobenzoyl)indol-1-yl]butyrate (88 mg) and diisopropylethylamine (45 mg) in dichloromethane (3 ml) was added a solution of 1-bromo-1-(4-isobutylphenyl)propane (90 mg) in dichloromethane (1 ml). The mixture was stirred at room temperature for 24 hours and evaporated. The residue was dissolved in ethyl acetate. The solution was washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (5 g) eluting with a mixture of n-hexane and ethyl acetate (4:1) to give benzyl 4-[3-[3-[N-benzyl-N-[1-(4-isobutylphenyl)propyl]amino]benzyl]indol-1-yl]butyrate (30 mg) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][OH:20])[CH2:15][C@H:14]1[C@@H:13]([CH3:21])[S:12][C:11]([NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[N:10]2.C(NC1SC[C@@H]2C[C@H](C(O)=O)OC[C@]2(C2C=CC(F)=CC=2F)N=1)(=[O:38])C1C=CC=CC=1>>[C:23]([NH:22][C:11]1[S:12][C@H:13]([CH3:21])[C@@H:14]2[CH2:15][C@H:16]([C:19]([OH:38])=[O:20])[O:17][CH2:18][C@:9]2([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[N:10]=1)(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](C(=O)O)C[C@H]2CS1)c1ccccc1
Reactant: C[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CO)C[C@@H]12
Product: C[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](C(=O)O)C[C@@H]12

Procedure:
The product, obtained as a pink/white solid, was prepared from N-[(4R,4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(hydroxymethyl)-4-methyl-4,4a, 5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (P5) according to the procedure for the synthesis of (4aR,6R,8aS)-2-(benzoylamino)-8a-(2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazine-6-carboxylic acid (P2) in Preparation 2. Yield: 2.92 g, 6.54 mmol, 95%. LCMS m/z 447.2 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 8.08-8.12 (m, 2H), 7.52-7.58 (m, 1H), 7.41-7.49 (m, 3H), 7.02-7.11 (m, 2H), 4.34 (dd, J=12.1, 2.7 Hz, 1H), 4.20 (br d, J=11.9 Hz, 1H), 3.98 (d, J=11.9 Hz, 1H), 3.18-3.26 (m, 1H), 3.06 (ddd, J=12.1, 3.9, 3.9 Hz, 1H), 2.15 (ddd, J=13.6, 4.0, 2.9 Hz, 1H), 1.71-1.83 (m, 1H), 1.27 (d, J=6.8 Hz, 3H).