Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[CH:6][N:5]=[CH:4][N:3]=1.[NH2:9][CH:10]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([NH:9][CH:10]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]2)[CH:7]=1
Reactant: Clc1cncnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)ncn2)C1
Yield: 51.5 %

Procedure:
A solution of 4,5-dichloropyrimidine (0.6 g, 4.02 mmol), 3-amino-Boc-pyrrolidine (0.5 g, 2.6 mmol) and DIPEA (1.73 g, 13.3 mmol) in n-butanol (5.0 mL) was heated in a pressure tube (120° C., 12 h). It was cooled, quenched with water (10 mL) and was extracted with EtOAc (2×25 mL). The combined EtOAc extract was washed with water (5 mL), brine (5 mL), dried over Na2SO4 and concentrated under reduced pressure to afford tert-butyl 3-(6-chloropyrimidin-4-ylamino)pyrrolidine-1-carboxylate (0.4 g, 50%) as a yellow solid.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[F:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[N:13][NH:14]2)=[CH:10][C:9]=1[NH2:17]>C(#N)C.C(OCC)C.S([O-])([O-])(=O)=O.[Cu+2]>[F:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[N:13][NH:14]2)=[CH:10][C:9]=1[NH:17][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1]
Reactant: Nc1cc2cn[nH]c2cc1F
Reactant: C=C1CC(=O)O1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CC#N
Solvent: CCOCC
Product: CC(=O)CC(=O)Nc1cc2cn[nH]c2cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Diketene (stabilized w/copper sulfate, 1.0 mL, 12.9 mmol, 1.5 equiv) was added to a suspension of 6-fluoro-1H-indazol-5-amine (1.3 g, 8.6 mmol, 1 equiv) in acetonitrile (8 mL) at 0° C. over 30 minutes. The reaction mixture was then stirred at room temperature for 16 hours. The mixture was diluted with cold diethyl ether (20 mL) and the solid product was collected by filtration and washed several times with cold diethyl ether. The title compound was isolated as a pale brown powder (1.49 g, 74%). MS m/z 236 [M+H]+
Reaction SMILES: Cl[CH:2]([NH:7][C:8](=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:11])[C:3]([Cl:6])([Cl:5])[Cl:4].[F:17][C:18]([F:22])([F:21])[CH2:19][OH:20].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:4][C:3]([Cl:6])([Cl:5])[CH:2]([NH:7][C:8](=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:11])[O:20][CH2:19][C:18]([F:22])([F:21])[F:17]
Reactant: O=C(NC(Cl)C(Cl)(Cl)Cl)c1ccccc1O
Reactant: OCC(F)(F)F
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(NC(OCC(F)(F)F)C(Cl)(Cl)Cl)c1ccccc1O
Temperature: 25 °C
Yield: 71.6 %

Procedure:
A solution of N-(1,2,2,2-tetrachloroethyl) salicylamide (30 g) in toluene (100 ml) is added dropwise at less than 10° C. to a solution of 2,2,2-trifluoroethanol (10 g) and pyridine (18.6 g) in toluene (150 ml). After the addition, the mixture is stirred at room temperature for a while, and the contents are washed with water and a 1% aqueous solution of sodium hydrogen carbonate. The toluene layer is dehydrated, and the toluene is evaporated under reduced pressure to give the desired N-[2,2,2,-trichloro-1-(2,2,2,-trifluoroethoxy) ethyl]-salicylamide (26 g) represented by the foregoing formula as a colorless viscous mass. This compound gradually solidifies and shows a melting point of 78° to 82° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][CH2:14]Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:18]([O-:21])([O-:20])=[O:19].[Na+:22].[Na+]>C(O)(C)(C)C.O>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][CH2:14][S:18]([O-:21])(=[O:20])=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+:22]
Reactant: BrCCc1ccc(OCc2ccccc2)cc1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=S(=O)([O-])CCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-benzyloxyphenethyl bromide (11.8 g) and sodium sulfite (8.91 g) in tert-butyl alcohol (40 ml) and water (80 ml) is heated at reflux for 40 hours, cooled to room temperature, filtered and the solid washed with water and ether to give sodium 4-benzyloxyphenethyl sulfonate.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[N:12]O)[C:8]2=[O:11])=[CH:4][C:3]=1[O:14][CH3:15].[OH-].[Na+].C1(C)C=CC(S(Cl)(=O)=[O:25])=CC=1>>[C:7]([CH2:6][C:5]1[CH:4]=[C:3]([O:14][CH3:15])[C:2]([F:1])=[CH:10][C:9]=1[C:8]([OH:11])=[O:25])#[N:12]
Reactant: COc1cc2c(cc1F)C(=O)C(=NO)C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(CC#N)c(C(=O)O)cc1F
Temperature: 50 °C
Yield: 89.7 %

Procedure:
6-Fluoro-5-methoxy-indan-1,2-dione 2-oxime (3.9 g) was added to a solution of 36.4 ml 8% NaOH, and the mixture was heated to 50° C. Then p-Toluenesulfonyl chloride (4.62 g) was added in portions to the mixture, and the mixture was heated at 80° C. for 15 min. After cooled to room temperature, the precipitate was removed from the mixture. The filtrate was acidified with concentrated HCl to PH=3-4 and the precipitate was collected and dried to give product as colorless solid (3.5 g, 90% yield). LC-MS: m/e 208 (M−1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([C:25]#[C:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31](NC(OC(C)(C)C)=O)[CH3:32])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1)=[O:11].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([C:25]#[C:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][CH3:32])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1)=[O:11]
Reactant: COc1cc2c(NC(=O)Nc3c(Cl)cccc3Cl)ncnc2cc1C#CCCCCN(C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCCCC#Cc1cc2ncnc(NC(=O)Nc3c(Cl)cccc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1-(2,6-dichlorophenyl)-3-{7-[6-(N-tert-butoxycarbonylamino-N-methylamino)-1-hexynyl]-6-methoxyquinazolin-4-yl}urea (0.1 g), trifluoroacetic acid (1 ml) and methylene chloride (1 ml) was stirred at ambient temperature for 1.5 hours. The mixture was evaporated and a solution of hydrogen chloride gas in ethyl acetate was added. Toluene was added and the mixture was evaporated. The residue was triturated under diethyl ether and the resultant solid was isolated. There was thus obtained the title compound as the hydrochloride salt (0.095 g); NMR Spectrum: (DMSOd6) 1.65 (m, 2H), 1.78 (m, 2H), 2.55 (m, 5H), 2.95 (m, 2H), 4.0 (s, 3H), 7.38 (t, 1H), 7.6 (d, 2H), 7.89 (s, 1H), 8.16 (s, 1H), 8.7 (m, 3H), 10.9 (br, 1H), 11.8 (s, 1H); Mass Spectrum: M+H+ 472 and 474.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][C:15]2([CH2:19][C:20]([OH:22])=[O:21])O)=[CH:11][CH:10]=1>ClCCl>[F:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14]/[C:15]/2=[CH:19]\[C:20]([OH:22])=[O:21])=[CH:11][CH:10]=1
Reactant: O=C(O)CC1(O)CCc2ccc(F)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C1\CCc2ccc(F)cc21
Reaction time: 0.25 h
Yield: 95.4 %

Procedure:
Trifluoroactic acid (100 mL) was added to a stirred, chilled (ice-methanol bath) solution of 2-(6-Fluoro-1-hydroxy-1-indanyl)acetic acid (37.5 g, 0.18 mol) in dichloromethane (900 mL). After 15 min, the mixture was concentrated in vacuo to give (E)-2-(6-fluoro-1-indanylidene)acetic acid as a yellowish-tan solid (33.0 g, 95%), m.p., 203-205° C.;
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[CH:5][C:4]([OH:8])=[C:3]([O:9][C:10]2[CH:11]=[CH:12][C:13]([Cl:17])=[CH:14][C:15]=2[Cl:16])[CH:2]=1.[CH3:18][CH:19]1[CH2:25][C:24](=[O:26])[O:23][C:21](=[O:22])[CH2:20]1.C(N(CC)CC)C>CCOCC>[C:21]([CH2:20][CH:19]([CH3:18])[CH2:25][C:24]([O:8][C:4]1[CH:5]=[C:6]([Cl:7])[CH:1]=[CH:2][C:3]=1[O:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:17])=[CH:14][C:15]=1[Cl:16])=[O:26])([OH:23])=[O:22]
Reactant: CC1CC(=O)OC(=O)C1
Reactant: Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(CC(=O)O)CC(=O)Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Reaction time: 20 h
Yield: 23 %

Procedure:
A mixture of triclosan (22.3 g.), 3-methylglutaric anhydride (15.0 g.) and triethylamine (15 ml.) in ether (250 ml.) was stirred for 20 hours, and then washed first with 2M hydrochloric acid (50 ml.) and then with water (3×150 ml.). The ether phase was dried (MgSO4) and evaporated. A portion (20 g.) of the residual oil was purified by chromatography on silica gel using methylene chloride as eluant to give (D) as a colourless oil (7.4 g.) ; NMR (CDCl3): 0.8-1.3 (3H,d, CH3), 2.1-2.8 (5H,m,CH2CO+CH3CH), 6.7-7.6 (6H, m, aromatic H), 11.25 (1H,s, CO2H)ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([OH:18])=O)[C:13](=[O:19])[C:12]([CH3:21])([CH3:20])[C@@H:11]([OH:22])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:23][C:24]1[CH:25]=[C:26]2[C:39](=[CH:40][CH:41]=1)[CH2:38][C@:28]1([C:36]3[C:31](=[N:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]1=[O:37])[CH2:27]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([NH:23][C:24]3[CH:25]=[C:26]4[C:39](=[CH:40][CH:41]=3)[CH2:38][C@:28]3([C:36]5[C:31](=[N:32][CH:33]=[CH:34][CH:35]=5)[NH:30][C:29]3=[O:37])[CH2:27]4)=[O:18])[C:13](=[O:19])[C:12]([CH3:20])([CH3:21])[C@@H:11]([OH:22])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC1(C)C(=O)N(CC(=O)O)[C@H](c2cc(F)cc(F)c2)C[C@@H]1O
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC1(C)C(=O)N(CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)[C@H](c2cc(F)cc(F)c2)C[C@@H]1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of [(4S,6S)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetic acid (130 mg, 0.415 mmol, described in Intermediate 21), (R)-5-amino-1,3-dihydro spiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (140 mg, 0.557 mmol, described in Intermediate 9), HOBT (82 mg, 0.535 mmol), and EDC (95 mg, 0.498 mmol) in DMF (2 mL) was stirred at ambient temperature for 6 h. The reaction mixture was partitioned between H2O (50 mL), saturated aqueous NaHCO3 (30 mL) and EtOAc (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:CH3OH—100:0 to 90:10, to give the title compound. MS: m/z=547 (M+1). HRMS: m/z=547.2169; calculated m/z=547.2151 for C30H29F2N4O4.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[CH2:12]1[C@H:21]2[C@H:16]([CH2:17][CH2:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=32)[NH:15][CH2:14][CH2:13]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:12]1[C@H:21]2[C@H:16]([CH2:17][CH2:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=32)[N:15]([C:5]([C:4]2[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([OH:1])[CH:3]=2)=[O:7])[CH2:14][CH2:13]1
Reactant: Cc1ccc(C(=O)O)cc1O
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1ccc(C(=O)N2CCC[C@@H]3c4ccccc4CC[C@@H]32)cc1O
Yield: 77 %

Procedure:
The title compound is prepared from 3-hydroxy-4-methyl-benzoic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 77% of theory; LC (method 4): tR=2.00 min; Mass spectrum (ESI+): m/z=322 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:27][C:28]([N:30]1[C@H:34]([CH3:35])[CH2:33]OS1(=O)=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].CC(C)([O-])C.[K+]>>[CH2:21]([O:20][C:18]([C:13]1[N:14]([CH2:35][C@H:34]([NH:30][C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:29])[CH3:33])[C:15]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[CH:17][CH:16]=2)=[O:19])[CH3:22]
Reactant: C[C@@H]1COS(=O)(=O)N1C(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2n1C[C@@H](C)NC(=O)OC(C)(C)C
Yield: 100 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate b), from ethyl 5-benzyloxyindole-2-carboxylate (commercially available), (R)-4-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (prepared according to WO02/010169) and potassium tert-butoxide, to give the desired compound as a light yellow solid (>100%). The so-obtained product was used in the next step without further purification.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([Cl:14])[C:5]=1[N:15]=[N:16][CH:17]([C:20](=[O:22])[CH3:21])[C:18]#[N:19]>C(Cl)(Cl)Cl>[Br:1][CH2:21][C:20](=[O:22])[CH:17]([N:16]=[N:15][C:5]1[C:4]([Cl:3])=[CH:9][C:8]([C:10]([F:12])([F:13])[F:11])=[CH:7][C:6]=1[Cl:14])[C:18]#[N:19]
Reactant: BrBr
Reactant: CC(=O)C(C#N)N=Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: ClC(Cl)Cl
Product: N#CC(N=Nc1c(Cl)cc(C(F)(F)F)cc1Cl)C(=O)CBr
Temperature: 50 °C

Procedure:
A solution of bromine (2.2 ml) in chloroform (20 ml) was added dropwise to a stirred solution of 2-(2,6-dichloro-4-trifluoromethylphenylazo)-3-oxobutanenitrile (13.0g) in chloroform (20 ml) maintained at 50° C. The solution was then refluxed for 20 minutes, cooled, washed with water (4×50 ml), dried over magnesium sulfate, filtered and evaporated to give 4-bromo-2-(2,6-dichloro-4-trifluoromethylphenylazo)-3-oxobutanenitrile (16.0g) as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4](F)[CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13]C1.CC(N(C)C)=O>CCOC(C)=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N:11]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=Cc1ccc(Br)cc1N1CCCC1
Temperature: 120 °C
Yield: 96679.6 %

Procedure:
A 20 mL screwtop vial was charged with 4-bromo-2-fluorobenzaldehyde (200 mg, 0.985 mmol), piperadine (116 μL, 1.19 mmol), and DMA (1 mL). The reaction was heated to 120° C. for 3 h. The reaction was diluted in EtOAc and extracted with brine (3×). The organics were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (0% to 20% EtOAc in hexanes) and yielded 4-bromo-2-(pyrrolidin-1-yl)benzaldehyde (242 g, 92%). 1H NMR 400 MHz (CDCl3) δ 10.21 (s, 1H), 7.66 (dd, J=8.3, 2.4 Hz, 1H), 7.31-7.17 (m, 2H), 4 (m, 4H), 1.78 (m, 4H), 1.71-1.60 (m, 2H). LCMS (ESI, m/z): 268 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH2:8])=[CH:3][CH:2]=1.Br[C:10]1[CH:15]=[N:14][N:13]([CH2:16][CH3:17])[C:12](=[O:18])[C:11]=1[C:19]#[N:20]>C(O)C>[C:19]([C:11]1[C:12](=[O:18])[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:10]=1[NH:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)#[N:20]
Reactant: CCn1ncc(Br)c(C#N)c1=O
Reactant: NCc1ccncc1
Solvent: CCO
Product: CCn1ncc(NCc2ccncc2)c(C#N)c1=O
Yield: 62.5 %

Procedure:
Into 5 ml of an absolute ethanol solution of 0.16 g of 4-picolylamine, 5 ml of an absolute ethanol suspension of 0.11 g of 5-bromo-4-cyano-2-ethylpyridazin-3-(2H)-one, was dropwise added under cooling with ice over a period of 20 minutes. After completion of the dropwise addition, the mixture was reacted at room temperature for one hour. Then, ethanol was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed once with water and dried over anhydrous sodium sulfate and then concentrated. To the residue, n-hexane and ethyl ether were added in a small amount for crystallization. The crystals were collected by filtration and dried to obtain 77 mg of the desired product (Compound No. 47) having a melting point of from 193° to 195° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][NH:21][C@@H:20]1[CH2:25][NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=1>>[CH3:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:7]([C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:9])[C@@H:20]1[CH2:25][NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][N:28]=1
Reactant: Cc1ccc(-c2cnccc2C)c(C(=O)O)c1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1ccc(C(F)(F)F)cn1
Product: Cc1ccc(-c2cnccc2C)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using 5-methyl-2-(4-methylpyridin-3-yl)benzoic acid and N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 483 [M+1]+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[S:6][C:7]([C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)=[CH:8][N:9]=1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[CH3:15][C:10]1([C:7]2[S:6][C:5]([CH2:4][NH2:1])=[N:9][CH:8]=2)[O:14][CH2:13][CH2:12][O:11]1
Reactant: CC1(c2cnc(CN=[N+]=[N-])s2)OCCO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC1(c2cnc(CN)s2)OCCO1
Temperature: 60 °C

Procedure:
To a solution of the crude azide (565 mg, 2.50 mmol) in THF (12 mL) were added polymer-supported Ph3P (2.0 eq.) and water (4 mL). The reaction mixture was stirred at 60° C. until completion of the reaction, cooled down to rt, filtered and partitioned between EA and sat. aq. NaHCO3. The layers were separated and the aq. layer extracted with EA. The combined org. extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a brown oil after purification by FC (CH2Cl2-MeOH 1:0 to 9:1). LC-MS-conditions 01: tR=0.38 min; [M+H]+=200.96.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]([CH2:23][CH3:24])[C:11](=[O:25])[CH2:10][N:9]=2)=[CH:4][CH:3]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1>[C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]([CH2:23][CH3:24])[C:11](=[O:25])[CH2:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CCN1C(=O)CN=C(c2ccc(Br)cc2)c2cc(OC)c(OC)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCN1C(=O)CN=C(c2ccc(-c3ccccc3)cc2)c2cc(OC)c(OC)cc21
Temperature: 90 °C
Yield: 57.3 %

Procedure:
Heat at 90° C. for 12 hours under an inert atmosphere a mixture of 100 mg (0.27 mmol) of 5-(4-bromophenyl)-1-ethyl-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (IIbl), 35 mg (0.30 mmol) of benzene boronic acid, 215 μl of 2M Na2CO3, 25 mg (0.020 mmol) of tetrakis(triphenylphosphine)Pd(0) and 250 μl of EtOH in 5 ml of degassed toluene. Allow to cool to room temperature. Evaporate to dryness. Purify by chromatography (AcOEt). Recrystallize in Et2O. One obtains 62 mg of the abovenamed product in the form of colorless crystals. Yield: 52%. M: 149–150° C. 1H-NMR (CDCl3, 200 MHz): d 1.13 (s, 3H, CH3), 3.78 (s, 3H, OCH3), 3.95 (AB system, ? d=0.57, JAB=13.7, 2H, —NCH2), 3.98 (s, 3H, OCH3), 4.29 (AB system, ? d=0.99 JAB=10.0, 2H, CH2), 6.75 (s, 1H Ar), 6.86 (s, 1H Ar), 7.37–7.75 (m, 9H Ar).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][C:7]([OH:26])([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=3)[CH:10]=2)[CH2:6][CH2:5][O:4]1)[CH3:2].[CH3:27]I>>[CH2:1]([CH:3]1[CH2:8][C:7]([O:26][CH3:27])([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:20][CH:21]=3)[CH:10]=2)[CH2:6][CH2:5][O:4]1)[CH3:2]
Reactant: CCC1CC(O)(c2cccc(Sc3ccc(C(C)(C)C)cc3)c2)CCO1
Reactant: CI
Product: CCC1CC(OC)(c2cccc(Sc3ccc(C(C)(C)C)cc3)c2)CCO1
Yield: 57 %

Procedure:
Using a similar procedure to that described in Example 3, (2SR,4SR)-2-ethyl-4-hydroxy-4-[3-(4-tert-butylphenylthio)phenyl]tetrahydropyran was reacted with methyl iodide to give (2SR,4SR)-2-ethyl-4-methoxy-4-[3-(4-tert-butylphenylthio)phenyl]tetrahydropyran in 57% yield as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[N+:11]([C:6]1[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[CH:8][C:7]=1[OH:10])([O-:13])=[O:12]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 79.8 %

Procedure:
5.00 g (36.7 ml) of 4-acetylphenol was dissolved in 50 ml of sulfuric acid. To the solution, 3.10 ml (40.7 mM) of nitric acid (60%, density=1.38) was gradually added dropwise under stirring at 2°-10° C. on an ice bath, followed by stirring at 2°-10° C. after the addition. After the reaction, the reaction mixture was poured into ice water to precipitate a crystal. The crystal was recovered by filtration and washed with water, followed by recrystallization from methanol to obtain 5.84 g of 2-nitro-4-acetylphenol (Yield: 79.8%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1.[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:15]([CH2:16][CH3:17])[CH2:13][CH3:14])(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1
Reactant: CCNCC
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)c1ccc(Br)cc1F
Yield: 42 %

Procedure:
According to general procedure C, 4-Bromo-2-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and diethylamine (0.38 mL, 3.65 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N,N-diethyl-2-fluorobenzenesulfonamide (0.19 g, 43%) was provided after purification. HRMS: calcd for C10H13BrFNO2S+H+, 309.99071; found (ESI, [M+H]+), 309.9917. HPLC purity 100.0% at 210-370 nm, 9.6 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18]2[C:23]([CH3:24])=[CH:22][N:21]=[C:20]([SH:25])[N:19]=2)[CH:17]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:26](I)[CH2:27][CH3:28]>N>[OH:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[N:14]=[CH:15][CH:16]([C:18]2[C:23]([CH3:24])=[CH:22][N:21]=[C:20]([S:25][CH2:26][CH2:27][CH3:28])[N:19]=2)[CH:17]=1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCI
Reactant: Cc1cnc(S)nc1-c1c[nH]c(C(=O)N[C@H](CO)c2ccccc2)c1
Agent: N
Product: CCCSc1ncc(C)c(C2C=NC(C(=O)N[C@H](CO)c3ccccc3)=C2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(2-mercapto-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid (2-hydroxy-1-(S)-phenyl-ethyl)-amide (7.7 mmol, 2.74 mmol) in aqueous ammonia (15%) was added at room temperature n-propyliodide (11.6 mmol, 1.1 mL). The solution was stirred overnight at room temperature. The resulting solid was collected by filtration and used directly for the next step. 1H NMR consistent with the structure.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[C:30]3[CH:29]=[C:28]4[C:31]5([CH2:37][O:38][C:27]4=[CH:26][C:25]=3[CH2:24][CH2:23]2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)=[O:21])=[CH:16][CH:15]=1.[CH:39]1([CH2:42]Br)[CH2:41][CH2:40]1>>[CH:39]1([CH2:42][N:34]2[CH2:35][CH2:36][C:31]3([C:28]4[C:27](=[CH:26][C:25]5[CH2:24][CH2:23][N:22]([C:20]([C:17]6[CH:18]=[CH:19][C:14]([C:3]7[CH:4]=[CH:5][C:6]([N:8]8[CH2:12][CH2:11][CH2:10][C:9]8=[O:13])=[CH:7][C:2]=7[CH3:1])=[CH:15][CH:16]=6)=[O:21])[C:30]=5[CH:29]=4)[O:38][CH2:37]3)[CH2:32][CH2:33]2)[CH2:41][CH2:40]1
Reactant: BrCC1CC1
Reactant: Cc1cc(N2CCCC2=O)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCNCC2)CO4)cc1
Product: Cc1cc(N2CCCC2=O)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCN(CC3CC3)CC2)CO4)cc1

Procedure:
The title compound was prepared from 5-[2'-methyl-4'-(2-oxopyrrolidin-1-yl)biphenyl-4-carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E18) and cyclopropylmethyl bromide using a similar procedure to Example 19, as a cream foam (52%). This was converted to the hydrochloride salt, isolated as a white powder.