Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([NH2:8])(=[O:7])=[O:6].C(Cl)CCl.[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22][N:23]([CH3:52])[C@@H:24]1[CH2:31][N:30]2[C:32]3[CH:33]=[C:34]([C:45](O)=[O:46])[CH:35]=[CH:36][C:37]=3[C:38]([CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[C:29]2[C:28]2[CH:48]=[CH:49][CH:50]=[CH:51][C:27]=2[O:26][CH2:25]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:13]([O:17][C:18](=[O:19])[NH:20][CH2:21][CH2:22][N:23]([C@@H:24]1[CH2:31][N:30]2[C:32]3[CH:33]=[C:34]([C:45]([NH:8][S:5]([CH2:4][CH2:3][CH2:2][Cl:1])(=[O:7])=[O:6])=[O:46])[CH:35]=[CH:36][C:37]=3[C:38]([CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[C:29]2[C:28]2[CH:48]=[CH:49][CH:50]=[CH:51][C:27]=2[O:26][CH2:25]1)[CH3:52])([CH3:16])([CH3:14])[CH3:15]
Reactant: NS(=O)(=O)CCCCl
Reactant: CN(CCNC(=O)OC(C)(C)C)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(CCNC(=O)OC(C)(C)C)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)CCCCl)cc3n2C1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
3-chloropropane-1-sulfonamide (1.8 eq), DMAP (2.9 eq) and EDC (1.8 eq), were added to a solution of (7R)-7-[{2-[(tert-butoxycarbonyl)amino]ethyl}(methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid (prepared as described in Example 1, Step 7) (0.025 M) in DCM. The reaction was stirred under N2 at 40° C. for 2 h, before being allowed to cool. Volatiles were removed in vacuo to leave the crude product as a yellow gum which could be taken on without further purification. (ES+) m/z 687 (M+H)+; 689 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8](Br)[CH2:9][Br:10])[CH:5]=[CH:6][CH:7]=1.[I-].[K+].II.[OH2:16]>>[Br:10][CH2:9][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:16]
Reactant: Clc1cccc(C(Br)CBr)c1
Reactant: O
Agent: II
Agent: [I-]
Agent: [K+]
Product: OC(CBr)c1cccc(Cl)c1
Temperature: 25 °C

Procedure:
To 996 g of 3-chloro-α,β-dibromoethylbenzene were added 10.8 g of potassium iodide and 3.5 l of water. The mixture was then heated under reflux for 49 hours while the released free iodine was being removed. After the termination of the reaction, the reaction solution was allowed to cool to room temperature. The oil phase separated was separated and then washed with water for neutralization to give 714 g of 2-bromo-1-(3-chlorophenyl)ethanol was obtained.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Br:10][C:11]1[CH:12]=[C:13]([CH2:18][C@@H:19]([OH:24])[C:20]([O:22][CH3:23])=[O:21])[CH:14]=[CH:15][C:16]=1[OH:17].Cl[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31]>C(Cl)Cl>[Br:10][C:11]1[CH:12]=[C:13]([CH2:18][C@@H:19]([OH:24])[C:20]([O:22][CH3:23])=[O:21])[CH:14]=[CH:15][C:16]=1[O:17][CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)[C@H](O)Cc1ccc(O)c(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](O)Cc1ccc(OCOCC[Si](C)(C)C)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6.7 mL (39.1 mmol) ethyldiisopropylamine were added to a solution of 10.2 g (34.6 mmol) methyl(R)-3-(3-bromo-4-hydroxy-phenyl)-2-hydroxy-propionate in 100 mL DCM and the reaction mixture was cooled in the ice bath. Then a solution of 7.9 mL (44.6 mmol) (2-chloromethoxy-ethyl)-trimethyl-silane in 20 mL DCM was added. The reaction mixture was stirred for 3 h at RT and then combined with another 0.67 mL ethyldiisopropylamine and 0.8 mL (4.5 mmol) (2-chloromethoxy-ethyl)-trimethyl-silane to complete the reaction and stirred for 1.5 h at RT. The reaction mixture was washed with 5% Na2CO3 solution and saturated NaCl solution and dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was purified by chromatography (silica gel, Cyc/EtOAc 75:25).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([CH:16]=O)=[CH:4][CH:3]=1.C(O)C.C([O-])(=O)C.[Na+].Cl.[NH2:27][OH:28]>O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([CH:16]=[N:27][OH:28])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(Cl)ccc1C=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1nc(Cl)ccc1C=NO
Reaction time: 0.08 h

Procedure:
15.45 g (60.2 mmol) of tert-butyl (6-chloro-3-formylpyridin-2-yl)carbamate (Example 106A) are introduced into 750 ml of ethanol, and a solution of 225 ml of water and 9.38 g (120.4 mmol) of sodium acetate is added and stirred for 5 min. A solution of 225 ml of water and 8.36 g (114.4 mmol) of hydroxylamine hydrochloride is added, and the mixture is stirred at RT for 4 h. The reaction mixture is concentrated in a rotary evaporator at 20° C. The residue is taken up in ethyl acetate and washed twice with saturated sodium hydroxide carbonate solution and once with saturated sodium chloride solution. The organic phase is separated off, dried over magnesium sulphate and concentrated in a rotary evaporator at 20° C. 15.5 g (80% of theory) of the product are obtained as a solid.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10]Br)=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][O:20][Si](C(C)(C)C)(C)C)=[C:6]([CH:28]([CH3:30])[CH3:29])[N:5]=1)([CH3:3])[CH3:2].[N+:31]([C:34]1[CH:39]=[CH:38][C:37]([SH:40])=[CH:36][CH:35]=1)([O-:33])=[O:32].CN1CCOCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH:28]([C:6]1[C:7]([CH2:19][OH:20])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:9]([CH2:10][S:40][C:37]2[CH:38]=[CH:39][C:34]([N+:31]([O-:33])=[O:32])=[CH:35][CH:36]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=1)([CH3:29])[CH3:30]
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: CC(C)c1nc(C(C)C)c(CO[Si](C)(C)C(C)(C)C)c(-c2ccc(F)cc2)c1CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)c1nc(C(C)C)c(CSc2ccc([N+](=O)[O-])cc2)c(-c2ccc(F)cc2)c1CO
Temperature: 25 °C

Procedure:
The intermediate obtained in Step B (200 mg, 0.40 mmol) was dissolved in anhydrous THF (5 mL), stirred under argon at room temperature and treated with 4-nitrothiophenol (118 mg, 0.6 mmol, 80% tech. grade) and N-methylmorpholine (0.2 mL, 1.8 mmol). The reaction mixture was allowed to stir at reflux for 18 hr, then cooled to room temperature. The mixture was treated with tetrabutylammonium fluoride (0.8 mL, 0.8 mmol, 1.0M in THF) and allowed to stir at room temperature for 24 hr. The solvent was removed in vacuo, the residue dissolved in ethyl acetate (100 mL), washed with 1N HCl (50 mL), sat. NaHCO3 (50 mL) and brine (50 mL), dried (MgSO4) and concentrated. Purification by chromatography through silica (step gradient 5-10% ethyl acetate/hexane) afforded the title compound as a lightly colored solid (130 mg, 0.28 mmol, 70%). 1H NMR (300 MHz, CDCl3): δ 8.08 (d, J=8.5 Hz, 2 H), 7.27 (m, 2 H), 7.13 (m, 4 H), 4.37 (d, J=5.5 Hz, 2 H), 3.91 (s, 2 H), 3.46 (sept, J=6.6 Hz, 1 H), 3.33 (sept, J=6.6 Hz, 1 H), 1.35 (d, J=6.6 Hz, 6 H), 1.34 (d, J=6.6 Hz, 6 H), 1.27 (t, J=5 Hz, 1 H). FAB-MS calcd for (C25H27FSN2O3) 454, found 455 (M+H). mp 178-180° C. Rf=0.3 (20% ethyl acetate/hexane).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Cl[C:21]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][C:24]([C:30]([F:33])([F:32])[F:31])=[CH:23][C:22]=1[N+:34]([O-:36])=[O:35]>O1CCCC1.COC(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][C:21]2[C:22]([N+:34]([O-:36])=[O:35])=[CH:23][C:24]([C:30]([F:33])([F:31])[F:32])=[CH:25][C:26]=2[N+:27]([O-:29])=[O:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2c([N+](=O)[O-])cc(C(F)(F)F)cc2[N+](=O)[O-])C1

Procedure:
(R)-3-Hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (compound 20) is de-protonated with potassium tert-butoxide (KOtBu) in tetrahydrofuran (THF). The resulting anion is reacted 2-chloro-1,3-dinitro-5-trifluoromethylbenzene (compound 2) in tert-butyl methyl ether (MTBE)/THF. When the reaction is complete, the reaction mixture is quenched with water and partitioned with more MTBE. The organic layer is washed with brine and water and concentrated on a rotary evaporator. The solid concentrate is re-dissolved in methanol and re-precipitated with water. The resulting precipitate is filtered and dried to afford (R)-3-(2,6-dinitro-4-trifluoromethylphenoxy)pyrrolidine-1-carboxylic acid tert-butyl ester which can be used in the next step without further purification. This reaction has been carried out at a scale using 4.2 Kg of compound 2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[S:25][C:26]1[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=1)[NH2:21]>C(O)C>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][C:24]=1[S:25][C:26]1[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Reactant: Cn1ccnc1Sc1ccc(N)cc1Cl
Solvent: CCO
Product: Cn1ccnc1Sc1ccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)cc1Cl
Yield: 62.8 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-3-quinolinecarbonitrile, 250 ml ethanol, and 6.18 g (25.8 mmol) 3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-aniline (WO-9615118) was heated to reflux under N2. Removed heat at 3½ hours and made basic with a solution of saturated sodium bicarbonate. Stripped solvents and azeotroped with ethanol. Slurried residue with hexane and collected solids. Washed with water, dried in vacuo. Boiled solids in hexane to remove excess aniline, air dried. Boiled in 2 L ethyl acetate, and because of extreme insolubility, collected solids and dried in vacuo, giving 5.90 g of yellow solid: mass spectrum (electrospray m/e): M+H=437.2, 439.1.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:12])[CH:9]=2)[CH2:4]1.C([O-])([O-])=O.[K+].[K+].Cl[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=1>C1(C)C=CC=CC=1.CC(N(C)C)=O>[OH:1][CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=3)[CH:9]=2)[CH2:4]1
Reactant: OCC1Cc2ccc(O)cc2C1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CC(CO)C3)nc1
Reaction time: 5 h
Yield: 44 %

Procedure:
Combine in a round bottom flask equipped with a stir, Dean Stark Trap filled with toluene, and reflux condenser 2-Hydroxymethyl-indan-5-ol (630.2 mg, 3.84 mmol), K2CO3 (690.0 mg, 5.0 mmol), 6-Chloronicotinamide (600.0 mg, 3.84 mmol) and a solution of DMA:Toluene (15:5 mL). After the reaction refluxes under nitrogen atmosphere for 5 hours, concentrate under reduced pressure and then add ethyl acetate. Wash the organic layer several times with water, then brine, and dry over Na2SO4. After concentrating the reaction mixture under reduced pressure, flash chromatograph using 20% THF, 7% 1N NH3-MeOH, 73% DCM eluent to afforded 481.1 mg, 1.69 mmol (44% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 1.8-2.2 (4H, m), 2.6-2.8 (3H, m), 3.6-3.8 (2H, br d), 3.9-4.0 (1H, m), 6.1-6.6 (2H, br d), 6.8-7.0 (3H, m), 7.2-7.3 (1H, m), 8.1-8.2 (1H, m), 8.6 (1H, s); MS m/z 285 (M+1).
Reaction SMILES: Cl.[F:2][C:3]1[CH:24]=[C:23]([OH:25])[CH:22]=[C:21]([F:26])[C:4]=1[CH2:5][N:6]1[C:10]2[N:11]=[C:12]([NH2:20])[N:13]=[C:14]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[C:9]=2[N:8]=[N:7]1.[CH3:27]I>CN(C=O)C.O>[F:2][C:3]1[CH:24]=[C:23]([O:25][CH3:27])[CH:22]=[C:21]([F:26])[C:4]=1[CH2:5][N:6]1[C:10]2[N:11]=[C:12]([NH2:20])[N:13]=[C:14]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[C:9]=2[N:8]=[N:7]1
Reactant: CI
Reactant: Nc1nc(-c2ccco2)c2nnn(Cc3c(F)cc(O)cc3F)c2n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(F)c(Cn2nnc3c(-c4ccco4)nc(N)nc32)c(F)c1
Reaction time: 0.17 h
Yield: 100.1 %

Procedure:
A solution of 3-(2,6-difluoro-4-hydroxybenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine hydrochloride (130 mg, 0.34 mmol) in DMF (5 mL) at 0° C., was treated with CsCO3 (223 mg, 0.68 mmol), stirred for 10 min, treated with methyl iodide (21 μL, 0.34 mmol) and stirred at room temperature for 30 min. The reaction mixture was diluted with water (10 mL) and filtered to give the title compound (122 mg, 100%) as a white solid.
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:9]([C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])=[CH:10][CH3:11].Cl.C(OCC)(=O)C>C1COCC1>[OH:13][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH:9]=[CH:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C[Zn]Br
Reactant: CC=CC(=O)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC=CC(O)(CC(=O)OCC)c1ccccc1
Yield: 93 %

Procedure:
Under nitrogen atmosphere, 15 mL of THF was added to 3.05 g (5 mmol, 1.0 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.73 g (5 mmol) of phenyl propenyl ketone in 2.5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 3 hours. 7.5 mL of 1N hydrochloric acid was added at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 10 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, purification with silica gel column (developing solvent; ethyl acetate/n-hexane=1/3) afforded 1.09 g of the desired product (yield 93%).
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][C@H:4]([N:8]1[CH2:12][C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:10][C:9]1=[O:21])[C:5]([OH:7])=O.[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([NH2:29])=[N:25]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([NH:29][C:5](=[O:7])[C@@H:4]([N:8]2[CH2:12][C:11]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])=[CH:10][C:9]2=[O:21])[CH2:3][CH:2]([CH3:1])[CH3:22])=[N:25]1
Reactant: Cc1ccccc1OC1=CC(=O)N([C@@H](CC(C)C)C(=O)O)C1
Reactant: Cn1ccc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccccc1OC1=CC(=O)N([C@@H](CC(C)C)C(=O)Nc2ccn(C)n2)C1
Temperature: 0 °C
Yield: 18.9 %

Procedure:
To a solution of (S)-4-methyl-2-(2-oxo-4-o-tolyloxy-2,5-dihydro-pyrrol-1-yl)-pentanoic acid (0.208 g, 0.69 mmol) in N,N-dimethylformamide (4 mL) was added 1-methyl-1H-pyrazol-3-ylamine (0.080 g, 0.82 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.620 g, 1.40 mmol). The mixture was stirred at 0° C. and triethylamine (0.150 g, 1.48 mmol) was added. The mixture was stirred at room temperature for 3 h and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 25 g, 20% to 100% ethyl acetate/hexanes) which afforded (S)-4-methyl-2-(2-oxo-4-o-tolyloxy-2,5-dihydro-pyrrol-1-yl)-pentanoic acid (1-methyl-1H-pyrazol-3-yl)-amide (0.050 g, 19%) as a tan solid: HR-ES-MS m/z calculated for C21H26N4O3 [M+H]+ 383.2078, observed 383.2077, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00-0.90 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H), 1.20-1.92 (m, 3H), 2.19 (s, 3H), 3.73 (s, 3H), 4.20 (d, J=18.1 Hz, 1H), 4.57 (d, J=18.1 Hz, 1H), 4.63 (s, 1H), 4.87 (dd, J=10.3, 4.8 Hz, 1H), 6.40 (d, J=1.8 Hz, 1H), 7.17-7.33 (m, 3H), 7.36 (d, J=7.2 Hz, 1H), 7.55 (d, J=1.8 Hz, 1H), 10.72 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]([C:10]([O:12]CC)=[O:11])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:15](=[O:25])[C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:24])=[O:23])=[CH:18][CH:17]=1.[OH-].[Na+].[H][H].Cl>CO>[CH3:1][C:2]1[S:6][C:5]2[CH:7]([C:10]([OH:12])=[O:11])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:15](=[O:25])[C:16]1[CH:17]=[CH:18][C:19]([S:22]([CH3:24])=[O:23])=[CH:20][CH:21]=1
Reactant: CCOC(=O)C1CCc2c1sc(C)c2C(=O)c1ccc(S(C)=O)cc1
Reactant: [H][H]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1sc2c(c1C(=O)c1ccc(S(C)=O)cc1)CCC2C(=O)O
Yield: 68.2 %

Procedure:
To a solution of 2.29 g (0.0061 moles) ethyl 5,6-dihydro-2-methyl-3-(4-(methylsulfinyl) benzoyl)-4H-cyclopenta[b]thiophene-6-carboxylate, the product of Example 1a. in 40 ml of methanol at reflux was added 9.1 ml (0.0091 moles) of 1N sodium hydroxide dropwise. After 20 min. of refluxing the mixture was cooled in an ice bath and poured into 3N hydrogen chloridede dropwise. After 20 min. of refluxing the mixture was cooled in an ice bath and poured into 3N hydrogen chloride and ice. Solid 5,6-dihydro-2-methyl-3-[4-(methylsulfinyl) benzoyl]-4H-cyclopenta[b]thiophene-6-carboxylic acid was collected. The filtrate was extracted with chloroform, washed with brine and dried (MgSO4). Evaporation of the solvent gave solid acid which was recrystallized from acetonitrile. The two batches of solid were combined and recrystallized from acetonitrile to give 1.45 g of 5,6-dihydro-2-methyl-3-(4(methylsulfinyl)benzoyl)-4H-cyclopenta[b]thiophene-6-carboxylic acid, mp 209-213° C.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=1)#[CH:12].N>>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[CH:12]=2)[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=1
Reactant: ON=C(Cl)c1cccnc1
Reactant: C#Cc1cc(OC)cc(OC)c1
Agent: N
Product: COc1cc(OC)cc(-c2cc(-c3cccnc3)no2)c1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 1-ethynyl-3,5-dimethoxybenzene (Aldrich, 81 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ3.85 (s, 6H), 6.69 (t, J=2.2 Hz, 1H), 7.07 (d, J=2.4 Hz, 2H), 7.68 (ddd, J=8.0, 4.9, 1.0 Hz, 1H), 7.78 (s, 1H), 8.38 (dt, J=7.6, 1.9 Hz, 1H), 8.77 (dd, J=4.9, 1.5 Hz, 1H), 9.14 (d, J=1.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 283 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:26]2[CH:30]=[CH:29][N:28]=[CH:27]2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=O)[CH:13]=[C:12]3[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:33])=O>>[Cl:33][C:14]1[CH:13]=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:26]3[CH:30]=[CH:29][N:28]=[CH:27]3)[CH:10]=2)[N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(-c2ccccc2)c2cc(C(c3ccc(Cl)cc3)n3ccnc3)ccc2[nH]1
Product: Clc1ccc(C(c2ccc3nc(Cl)cc(-c4ccccc4)c3c2)n2ccnc2)cc1
Yield: 85 %

Procedure:
A mixture of (±)-6-[(4-chlorophenyl)-1H-imidazol-1-ylmethyl]4-phenyl-2(1H)-quinolinone (0.022 mol) in phosphoryl chloride (100 ml) was stirred and refluxed for 2 hours. The mixture was evaporated in vacuo, the residue was taken up in CH2Cl2 and basified with K2CO3 (10%). The organic layer was dried (MgSO4), filtered off and evaporated. The product was used without further purification, yielding 8 g (85%) of (±)-2-chloro-6-[(4-chlorophenyl)-1H-imidazol-1-ylmethyl]-4-phenylquinoline (interm. 5).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:22][N+:23]([O-])=O)[CH2:9][P:10]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])(=[O:14])[O:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.N.[H][H]>C(O)C.[Ni]>[NH2:23][CH2:22][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:9][P:10]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])(=[O:14])[O:11][CH2:12][CH3:13]
Reactant: [H][H]
Reactant: CCOC(OCC)P(=O)(CC(C[N+](=O)[O-])c1ccc(Cl)cc1)OCC
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(CC(CN)c1ccc(Cl)cc1)OCC

Procedure:
A solution of 8.0 g of ethyl 2-(4-chlorophenyl)-3-nitropropyl-(diethoxymethyl)phosphinate in 70 ml of ethanol is added to 64 g of an 8% solution of ammonia in ethanol. To this are added 8 ml of Raney Nickel and the resulting mixture is hydrogenated at 1 bar until the theoretical amount of hydrogen has been taken up. The mixture is then filtered and the filtrate is concentrated under reduced pressure to give ethyl 3-amino-2-(4-chlorophenyl)propyl-(diethoxymethyl)phosphinate as a viscous oil, 31P=+44.2 and 44.1 ppm (CDCl3).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=O)=[CH:36][CH:35]=1.[CH3:45][N:46]1[C:50]([C:51]2[CH:52]=[C:53]([NH2:66])[CH:54]=[CH:55][C:56]=2[O:57][CH2:58][CH2:59][N:60]2[CH2:65][CH2:64][O:63][CH2:62][CH2:61]2)=[CH:49][CH:48]=[N:47]1>C1COCC1>[CH3:45][N:46]1[C:50]([C:51]2[CH:52]=[C:53]([NH:66][C:38](=[O:40])[C:37]3[CH:36]=[CH:35][C:34]([C:33]([F:32])([F:44])[F:43])=[CH:42][CH:41]=3)[CH:54]=[CH:55][C:56]=2[O:57][CH2:58][CH2:59][N:60]2[CH2:65][CH2:64][O:63][CH2:62][CH2:61]2)=[CH:49][CH:48]=[N:47]1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc(NC(=O)c2ccc(C(F)(F)F)cc2)ccc1OCCN1CCOCC1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 28.5 %

Procedure:
A solution of HATU (98.0 mg, 0.260 mmol), triethylamine (55.7 μl, 0.400 mmol) and 4-trifluoromethyl-benzoic acid (49.0 mg, 0.260 mmol) in THF (1.0 mL) was stirred at room temperature. After 15 min, 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine (60.0 mg, 0.200 mmol) was added, and the mixture was stirred at 100° C. for 10 minutes in microwave. The mixture was purified by HPLC to give title compound as a white solid (TFA salt, 27 mg, 28%). 1H NMR (DMSO-d6, 400 MHz) δ 2.96-3.10 (m, 2H), 3.16-3.19 (m, 2H), 3.52-3.60 (m, 4H), 3.70 (s, 3H), 3.84-3.87 (m, 2H), 4.39 (t, J=5.05 Hz, 2H), 6.31 (d, J=1.77 Hz, 1H), 7.28 (d, J=9.09 Hz, 1H), 7.51 (d, J=1.77 Hz, 1H), 7.75 (d, J=2.78 Hz, 1H), 7.94 (d, J=8.34 Hz, 2H), 8.16 (d, J=8.84 Hz, 2H), 8.89 (s, 1H), 10.5 (s, 1H). Exact mass calculated for C24H25F3N4O3 474.2, found 475.4 (MH+).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:11][CH:12]=2)[O:7]1)[CH2:2][CH3:3].[C:21]([O-:26])(=O)[C:22]([O-])=O>>[NH2:16][C:10]1[CH:11]=[C:21]([CH:22]=[CH:8][CH:9]=1)[O:26][CH2:3][CH2:2][CH2:1][NH:4][CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([NH:16][S:17]([CH3:20])(=[O:18])=[O:19])=[CH:11][CH:12]=2)[O:7]1
Reactant: O=C([O-])C(=O)[O-]
Reactant: CCCNCC1CCc2ccc(NS(C)(=O)=O)cc2O1
Product: CS(=O)(=O)Nc1ccc2c(c1)OC(CNCCCOc1cccc(N)c1)CC2

Procedure:
N-(2-Propylaminomethyl-chroman-7-yl)-methanesulfonamide as the oxalate, hemihydrate, mp 204°-205° C.