Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([N:4]1[N:8]=[N:7][C:6]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[O:26][CH3:27])[S:18][C:14]=3[C:13](=[O:28])[N:12]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[C:11]2=[O:35])=[N:5]1)[CH3:3].[CH2:36]([O:38][C:39]1[C:48]([O:49][CH3:50])=[CH:47][C:46]2[C:45]([C:51]3[CH:59]=[CH:58][C:54]([C:55](O)=[O:56])=[CH:53][CH:52]=3)=[N:44][C@@H:43]3[CH2:60][CH2:61][S:62][CH2:63][C@@H:42]3[C:41]=2[CH:40]=1)[CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:36]([O:38][C:39]1[C:48]([O:49][CH3:50])=[CH:47][C:46]2[C:45]([C:51]3[CH:52]=[CH:53][C:54]([C:55]([N:32]4[CH2:33][CH2:34][CH:29]([N:12]5[C:13](=[O:28])[C:14]6[S:18][C:17]([C:19]7[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=7[O:26][CH3:27])=[CH:16][C:15]=6[N:10]([CH2:9][C:6]6[N:7]=[N:8][N:4]([CH2:2][CH3:3])[N:5]=6)[C:11]5=[O:35])[CH2:30][CH2:31]4)=[O:56])=[CH:58][CH:59]=3)=[N:44][C@@H:43]3[CH2:60][CH2:61][S:62][CH2:63][C@@H:42]3[C:41]=2[CH:40]=1)[CH3:37]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccc(F)cc4OC)cc32)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccc(F)cc6OC)cc5n(Cc5nnn(CC)n5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-(4-fluoro-2-methoxyphenyl)-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (191 mg; compound B78) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (145 mg; compound C10) and HBTU (304 mg) in DCM/DMF (14 ml/1 ml) in the presence of DIPEA (377 mg) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: Cyclohexane/EtOAc/DCM, 100/0/0 to 65/30/5 to 30/60/10 to 0/90/10 (v/v/v)] and preparative HPLC as a solid.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C:11](=[O:13])[CH3:12]>C(OCC)C>[Br:1][CH2:12][C:11]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:10])[C:4]=1[Cl:3])=[O:13]
Reactant: CC(=O)c1cccc(Cl)c1Cl
Reactant: BrBr
Solvent: CCOCC
Product: O=C(CBr)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Bromine (2.54 g, 15.9 mmol) was slowly added dropwise to a solution of 1-(2,3-dichlorophenyl)ethanone (3.00 g, 15.9 mmol) in diethyl ether (60 ml), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was distilled off under reduced pressure to give 2-bromo-1-(2,3-dichlorophenyl)ethanone as an oil quantitatively.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:8][N:7]1[C:3]([CH2:2][O:1][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:4][C:5]([C:9]([O:11][CH3:12])=[O:10])=[N:6]1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(CO)n(C)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(COS(C)(=O)=O)n(C)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of methyl 5-(hydroxymethyl)-1-methyl-1H-pyrazole-3-carboxylate (0.60 g, 3.51 mmol) and triethylamine (1.22 mL, 8.77 mmol) in DCM (10 mL) was added methanesulfonyl chloride (0.41 mL, 5.26 mmol). The reaction mixture was stirred at this temperature for 15 minutes and the coolant removed. The reaction mixture was stirred at RT for 1 hour. The reaction mixture was diluted with DCM and washed with water and brine. The organic phase was dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The crude material was used in the next step without further purification.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(C(C)C)C(C)C.[CH3:22][C:23]1[C:28]2[O:29][CH2:30][C:31]3([CH2:33][CH2:32]3)[C:27]=2[C:26]([O:34][C:35]2[N:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)=[CH:25][CH:24]=1.Cl.[NH2:43][C@:44]([CH3:51])([CH2:49][CH3:50])[C:45](OC)=[O:46]>C(Cl)Cl>[CH2:49]([C@@:44]1([CH3:51])[NH:43][C:2](=[O:4])[N:41]([C:38]2[CH:39]=[N:40][C:35]([O:34][C:26]3[C:27]4[C:31]5([CH2:30][O:29][C:28]=4[C:23]([CH3:22])=[CH:24][CH:25]=3)[CH2:33][CH2:32]5)=[CH:36][CH:37]=2)[C:45]1=[O:46])[CH3:50]
Reactant: CC[C@@](C)(N)C(=O)OC
Reactant: Cc1ccc(Oc2ccc(N)cn2)c2c1OCC21CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@]1(C)NC(=O)N(c2ccc(Oc3ccc(C)c4c3C3(CC3)CO4)nc2)C1=O
Reaction time: 0.25 h

Procedure:
To a solution of triphosgene (30 mg, 0.1 mmol) in dry DCM (1 ml) at 0° C., under nitrogen atmosphere, DIPEA (0.175 ml, 1.0 mmol) was added followed by the addition (slowly added) of a solution of 6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyridin-3-amine (Intermediate 15, 27 mg, 0.1 mmol) in dry DCM (2 ml) and the reaction mixture was stirred for 15 minutes at the sane temperature. After that a solution of Methyl (R)-2-amino-2-methyl-butyrate hydrochloride (33 mg, 0.2 mmol) in dry DCM (2 ml) was added and the reaction mixture was stirred for 30 minutes at 0° C. The reaction was quenched with a 1M aqueous solution of HCl (5 ml), diluted with DCM (10 ml) and two phases were separated. The organic layer was washed with brine (10 ml), dried (Na2SO4), filtered and evaporated affording the urea intermediate as yellow foam.
Reaction SMILES: [CH2:1]([Si:7]([CH3:10])(Cl)Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:11]1[C:23]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:1]([Si:7]([CH3:10])([CH:22]1[C:23]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:16]2[C:21]1=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:23]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC[Si](C)(Cl)Cl
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Solvent: C1CCOC1
Product: CCCCCC[Si](C)(C1c2ccccc2-c2ccccc21)C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
n-Hexylmethyldichlorosilane (30.4 g, 0.152 mol) and 300 mL of dry THF were charged to a one liter Schlenk equipped with an addition funnel. Fluorene anion (52.4 g, 0.305 mol) was dissolved in approximately 200 mL of dry THF and charged to the addition funnel. The temperature of the stirring solution was lowered to -78° C. under positive nitrogen pressure. The fluorene anion was added dropwise over two hours. After the anion addition was complete, the reaction mixture was allowed to warm to room temperature. The solution was allowed to stir overnight. The solution was washed with three 200 mL aliquots of water, retaining the organic layer after each washing. The organic layer was dried with magnesium sulfate and filtered. The product was recrystallized from hexane. The yield of this reaction is 19.6%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:22]2[CH2:26][C@H:25]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:24][C:23]2=[O:32])[CH:5]=[C:6]([F:21])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1.FC(F)(F)C(O)=O.[CH3:40][O:41][CH2:42][CH2:43]Cl.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(#N)C>[F:21][C:6]1[CH:5]=[C:4]([N:22]2[CH2:26][C@H:25]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:24][C:23]2=[O:32])[CH:3]=[C:2]([F:1])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:43][CH2:42][O:41][CH3:40])[CH2:10][CH2:9]1
Reactant: COCCCl
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(N3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Product: COCCN1CCN(c2c(F)cc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Temperature: 25 °C
Yield: 53.3 %

Procedure:
A solution of (S)-N-[[3-[3,5-difluoro-4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (0.200 g, 0.441 mmol) in dichloromethane (1 mL) was treated with trifluoroacetic acid (4 mL) at room temperature for 1 h. The reaction mixture was concentrated in vacuo and the resultant residue combined with 2-chloroethyl methyl ether (403 μL, 4.41 mmol), potassium carbonate (0.730 g, 5.28 mmol), and acetonitrile (9 mL) and the mixture heated to reflux for 15 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was triturated with dichloromethane, the solids filtered off, and the filtrate concentrated in vacuo to give the crude product. This crude material was chromatographed over silica gel (10 g), eluting with 1%, 3%, and then 5% methanol/chloroform, to afford, after concentration of appropriate fractions, 0.097 g (53%) of the title compound as an off-white solid with mp 162°-164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-:8].[Al+3].[Cl-].[Cl-].[C:12](Cl)(=[O:18])/[CH:13]=[CH:14]/[C:15](Cl)=[O:16].Cl>C(=S)=S>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]([CH:13]=[CH:14][C:15](=[O:16])[C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=2)=[O:18])=[CH:4][CH:3]=1
Reactant: O=C(Cl)/C=C/C(=O)Cl
Reactant: [Cl-]
Reactant: Clc1ccccc1
Agent: Cl
Agent: [Al+3]
Solvent: S=C=S
Product: O=C(C=CC(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Chlorobenzene (0.4 mol) and aluminium chloride (0.5 mol) in carbon disulphide (30 ml) were stirred at 50°-60°. Fumaryl chloride (0.2 mol) was added dropwise at a brisk rate over 30 minutes and refluxing was continued for a further 15 minutes. The residue was poured into crushed ice (1 kg) and concentrated hydrochloric acid (15.0 ml). The semi-solid was filtered off, washed with ether and ethanol, and recrystallised from ethyl acetate/ethanol to give pale yellow needles of di-(p-chlorobenzoyl) ethylene m.p. 175°-176°. Analysis:
Reaction SMILES: [Cl:1]C1C=CC(OC)=C([C@@]2(F)C3C(=CC(C(F)(F)F)=CC=3)N(C([NH:23][C@@H:24]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=O)C2=O)C=1.C(N(CC)CC)C>>[ClH:1].[C:28]([O:27][C:25](=[O:26])[C@H:24]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[NH2:23])([CH3:31])([CH3:29])[CH3:30]
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)N[C@@H](Cc2ccccc2)C(=O)OC(C)(C)C)c2cc(C(F)(F)F)ccc21
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Product: Cl
Yield: 42 %

Procedure:
(S)-tert-butyl 2-((S)-3-(5-chloro-2-methoxyphenyl)-3-fluoro-2-oxo-6-(trifluoromethyl)indoline-1-carboxamido)-3-phenylpropanoate (XVIII7): Following general procedure (F), after forming the intermediate, L-phenylalanine t-butyl ester hydrochloride (0.394 g, 1.53 mmol) and triethylamine (0.41 mL, 2.92 mmol) were added. After work-up and purification, 0.343 g of the title compound as a white foam solid was obtained (42% yield). mp: 62–66° C. MS: 607 (MH+). Anal. Calcd. for C29H25ClF4N2O5.0.5H2O: C, 58.49; H, 4.58; N, 4.55. Found: C, 58.47; H, 4.57; N, 4.28. 1H NMR (CDCl3): δ 1.46 (s, 9H), 3.13 (dd, J=14.0 Hz, 7.6 Hz, 1H), 3.30 (dd, J=14.0 Hz, 5.6 Hz, 1H), 3.34 (s, 3H), 4.80 (m, 1H), 6.74 (dd, J=8.8 Hz, 1.3 Hz, 1H), 7.20–7.27 (m, 6H), 7.36 (dd, J=8.7 Hz, 2.6 Hz, 1H), 7.41 (d, J=7.9 Hz, 1H), 7.78 (dd, J=2.5 Hz, 0.8 Hz, 1H), 8.57 (s, 1H), 8.68 (d, J=7.4 Hz, 1H). IR (KBr, cm−1): 3332, 2980, 1763, 1737, 1716, 1521, 1491, 1439, 1367, 1319, 1262, 1171, 1131, 1061.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[CH2:10][CH:11]=[CH:12][CH2:13][O:14][CH3:15]>O1CCCC1.[Pt]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: COCC=CCc1cc(Br)ccc1OC
Agent: [Pt]
Solvent: C1CCOC1
Product: COCCCCc1cc(Br)ccc1OC

Procedure:
A solution of 50 g of 4-methoxy-3-(4-methoxy-2-butenyl)-bromobenzene in 700 ml of tetrahydrofuran is hydrogenated for 2 hours under normal pressure and at room temperature in the presence of 2.5 g of 5% Pt/C. The reaction mixture is filtered. The filtrate is concentrated by evaporation. The evaporation residue obtained from the filtrate is purified by PC (1.6 kg of silica gel, hexane/ethyl acetate=20:1). Distillation under a high vacuum yields the title compound: Rf (hexane/ethyl acetate=10:1)=0.38; HPLC Rt =19.92 minutes; FAB-MS (M+H)+ =273.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Si:13]([O:20][CH2:21][C:22]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:23]=1[S:24][C:25]1[C:26]([CH2:37]O)=[CH:27][CH:28]=[CH:29][C:30]=1[N:31]2[CH3:36])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[C:39]1(=[O:49])[NH:43][C:42](=[O:44])[C:41]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Si:13]([O:20][CH2:21][C:22]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:23]=1[S:24][C:25]1[C:26]([CH2:37][N:43]3[C:39](=[O:49])[C:40]4[C:41](=[CH:45][CH:46]=[CH:47][CH:48]=4)[C:42]3=[O:44])=[CH:27][CH:28]=[CH:29][C:30]=1[N:31]2[CH3:36])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CN1c2cccc(CO)c2Sc2c(CO[Si](C)(C)C(C)(C)C)cccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1c2cccc(CO[Si](C)(C)C(C)(C)C)c2Sc2c(CN3C(=O)c4ccccc4C3=O)cccc21
Reaction time: 3 h
Yield: 78.2 %

Procedure:
1.62 ml (10.34 mmol) of diethyl azodicarboxylate were slowly added dropwise while cooling with ice and under argon to a solution of 3.09 g (7.97 mmol) of [6-(tert-butyl-dimethylsilanyloxymethyl)-10-methyl-phenothiazin-4-yl]-methanol, 1.76 g (11.9 mmol) of phthalimide and 2.30 g (8.75 mmol) of triphenylphosphine in 65 ml of tetrahydrofuran. The reaction mixture was stirred at 0° for 3 hours and then worked-up analogously to that described in Example 2.1.1.ea. The residue was chromatographed on 500 g of silica gel with toluene/ethyl acetate (19:1), whereupon, after crystallization from ethanol/ethyl acetate, 3.22 g (78.2%) of 2-[6-(tert-butyl-dimethylsilanyloxymethyl)-10-methyl-phenothiazin-4-ylmethyl]-2,3-dihydro-1H-isoindole-1,3-dione were obtained as a light yellow solid of m.p. 195°-196°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=[C:10]2[C:15](=[O:16])OC(C)(C)OC2=O)=[CH:4][C:3]=1[F:20]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[F:20])[NH:8][CH:9]=[CH:10][C:15]2=[O:16].[Br:1][C:2]1[C:3]([F:20])=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:8][CH:9]=[CH:10][C:15]2=[O:16]
Reactant: CC1(C)OC(=O)C(=CNc2ccc(Br)c(F)c2)C(=O)O1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1cc[nH]c2cc(F)c(Br)cc12
Product: O=c1cc[nH]c2ccc(Br)c(F)c12
Temperature: 245 °C
Reaction time: 0.33 h
Yield: 88.4 %

Procedure:
5-(((4-Bromo-3-fluorophenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (61.14 g, 177.6 mmol) was added portion-wise to Dowtherm (270 mL) at 245° C. After the addition, stirred at 245° C. for 20 minutes. Cool to RT. Added hexanes (˜830 mL) and filtered the solid washing with additional hexanes and dried the solid to yield 6-bromo-7-fluoroquinolin-4(1H)-one/6-bromo-5-fluoroquinolin-4(1H)-one (38.02 g, 88.5%) as brown solid and as a mixture of regioisomers (46:54, by LCMS). MS: m/z: 242.0/244.0 [M+H]+. Used this mixture as is for the next step.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1([CH3:17])[CH2:13][C:12]2[C:7](=[CH:8][C:9]([N+:14]([O-:16])=[O:15])=[CH:10][CH:11]=2)[CH:6]=[N:5]1>CO>[CH3:3][C:4]1([CH3:17])[CH2:13][C:12]2[C:7](=[CH:8][C:9]([N+:14]([O-:16])=[O:15])=[CH:10][CH:11]=2)[CH2:6][NH:5]1
Reactant: CC1(C)Cc2ccc([N+](=O)[O-])cc2C=N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)Cc2ccc([N+](=O)[O-])cc2CN1
Yield: 89.3 %

Procedure:
Sodium borohydride (1.57 g; 41.38 mmol) was added portionwise to a solution of 3,4-dihydro-3,3-dimethyl-7-nitroisoquinoline (4.22 g; 20.69 mmol) in methanol (150 ml). The resultant solution was stirred at 25° C. for 2 h. The methanol was evaporated in vacuo and the residue partitioned between water and dichloromethane. The organic layer was dried over sodium sulphate and then evaporated in vacuo to afford the title compound (3.81 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([F:12])=[CH:8][C:9]=2Br)[CH:4]=[CH:3]1.C([Li])(C)(C)C.[C:18](OC)(=[O:23])[C:19]([O:21][CH3:22])=[O:20]>C1COCC1>[CH3:22][O:21][C:19](=[O:20])[C:18]([C:9]1[CH:8]=[C:7]([F:12])[CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2)=[O:23]
Reactant: COC(=O)C(=O)OC
Reactant: Cn1ccc2cc(F)cc(Br)c21
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1cc(F)cc2ccn(C)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
A solution of 1-methyl-5-fluoro-7-bromoindole (8.3 g, 36.4 mmol) in THF (250 mL) was cooled to −78° C. and a solution of tert-butyl lithium in pentanes (1.7 M, 47 mL, 80.1 mmol) added dropwise over 30 min. After 30 min at −78° C., the mixture was treated with dimethyl oxalate (10.75 g, 91 mmol) in one portion. After 15 min, the mixture was allowed to warm to room temperature and stirred 4 h. The reaction mixture was quenched with water, extracted with ethyl acetate and the extract washed with brine, dried (Na2SO4) and concentrated. Flash chromatography (EtOAc/hexanes) afforded the title compound (4.2 g, 49%). 1H NMR (400 MHz, CDCl3) 3.83(s, 3H), 4.01 (s, 3H), 6.56 (d, J=3.13 Hz, 1H), 7.15 (d, J=3.13 Hz, 1H), 7.35 (dd, J1=2.0 Hz, J2=9.4 Hz, 1H), 7.57 (dd, J1=2.34 Hz, J2=8.21 Hz, 1H); MS (ES, m/z): C12H10FNO3: 235.22 (M++1).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[C:5](=[O:16])[C:4]([CH2:17][S:18][CH3:19])=[CH:3]1.ClC1C=CC=C(C(OO)=[O:28])C=1>ClCCl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:14])([F:15])[F:13])[CH:10]=2)[C:5](=[O:16])[C:4]([CH2:17][S:18]([CH3:19])=[O:28])=[CH:3]1
Reactant: CSCc1cn(C)c2cc(C(F)(F)F)ccc2c1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1cc(CS(C)=O)c(=O)c2ccc(C(F)(F)F)cc21

Procedure:
To a stirred solution of 1-methyl-3-methylthiomethyl-7-trifluoromethyl-4-quinolone (6.5 g.) in dichloromethane (150 ml.) at -10° was added a solution of 3-chloroperbenzoic acid (85%, 4.2 g.) in dichloromethane (90 ml.) during 30 minutes. The solution was extracted with saturated aqueous sodium bicarbonate until free of per-acid. The organic phase was dried over anhydrous magnesium sulphate and evaporated to give a solid product. This was crystallised from ethyl acetate:dichloromethane to give the novel 1-methyl-3-methylsulphinylmethyl-7-trifluoromethyl-4-quinolone, m.p. 208°-210°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:40][N:41]([CH3:46])[C:42](=[O:45])[CH2:43]O.O>CN(C=O)C>[CH3:40][N:41]([CH3:46])[C:42](=[O:45])[CH2:43][O:24][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][C:19]([C:10]2[NH:11][C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=2)=[CH:20][CH:21]=1
Reactant: CN(C)C(=O)CO
Reactant: O=C(O)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)COC(=O)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-[4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]benzoic acid (0.15 g, 0.42 mmol) [See Ex. 9 above] in DMF(10 ml) was added carbonyldiimidazole (0.34 g, 2.1 mmol). After stirring for 18 h at rt, N,N-dimethylglycolamide (0.43 g, 4.2 mmol) was added and stirring was continued for an additional 3h at rt. The reaction mixture was poured into H2O, extracted with EtOAc and evaporated. The residue was purified by flash chromatography eluting with a solvent gradient of 2% MeOH/CHCl3 to afford the title compound: CIMS (NH3,m/z): 445 (M+ +H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5](/[C:7](/[CH3:16])=[CH:8]/[CH2:9][CH2:10][C:11]([O:13]CC)=O)=[CH:4][CH:3]=1.[CH2:17]([Mg]Cl)[CH3:18].[CH2:21](OCC)[CH3:22]>>[Br:1][C:2]1[S:6][C:5](/[C:7](/[CH3:16])=[CH:8]/[CH2:9][CH2:10][C:11]([CH2:17][CH3:18])([OH:13])[CH2:21][CH3:22])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC/C=C(\C)c1ccc(Br)s1
Reactant: CC[Mg]Cl
Reactant: CCOCC
Product: CCC(O)(CC)CC/C=C(\C)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.3 g of ethyl (E)-5-(5-bromo-2-thienyl)-4-hexenoate (10.9 mmol) are dissolved in 50 mL of ethyl ether. 22 mL of 2.0 M ethylmagnesium chloride solution (44 mmol) are then added dropwise and the reaction medium is stirred at room temperature for 30 minutes. After treatment with saturated ammonium chloride solution, extraction with ethyl ether and then drying and evaporation of the solvents from the organic phase, the residue obtained is purified by chromatography on a column of silica. A colourless oil is obtained (m=2.4 g; Y=70%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([S:15]([O:18]C)(=[O:17])=[O:16])[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)([O:3][CH3:4])=[O:2].[C:20]([C:24]1[CH:29]=[CH:28][C:27]([P:30]([C:37]2[CH:42]=[CH:41][C:40]([C:43]([O:45][CH3:46])=[O:44])=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)([O:22][CH3:23])=[O:21]>>[C:11]([C:9]1[CH:8]=[C:7]([S:15]([O-:18])(=[O:17])=[O:16])[CH:6]=[C:5]([C:1]([O:3][CH3:4])=[O:2])[CH:10]=1)([O:13][CH3:14])=[O:12].[CH3:1][P+:30]([C:27]1[CH:28]=[CH:29][C:24]([C:20]([O:22][CH3:23])=[O:21])=[CH:25][CH:26]=1)([C:37]1[CH:38]=[CH:39][C:40]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:42]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)c1ccc(P(c2ccccc2)c2ccc(C(=O)OC)cc2)cc1
Reactant: COC(=O)c1cc(C(=O)OC)cc(S(=O)(=O)OC)c1
Product: COC(=O)c1cc(C(=O)OC)cc(S(=O)(=O)[O-])c1
Product: COC(=O)c1ccc([P+](C)(c2ccccc2)c2ccc(C(=O)OC)cc2)cc1
Temperature: 130 °C

Procedure:
A mixture of 14.414 g (0.05 mol) of methyl 3,5-bis(carbomethoxy)benzenesulfonate and 19.368 g (0.05 mol) bis(4-carbomethoxyphenyl)phenylphosphine was heated in a 130° C. bath with nitrogen bubbling through the melt for 2 hours.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][N:7]2[C:8](=[O:11])[C:9]=1[Br:10])[CH3:3].C(N(CC)CC)C.[CH:24]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH2:25]>CO>[Br:10][C:9]1[C:8](=[O:11])[N:7]2[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:6]2=[N:5][C:4]=1[CH:2]([NH:1][CH2:25][CH2:24][S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])[CH3:3]
Reactant: C=CS(=O)(=O)CC
Reactant: CC(N)c1nc2ccc(F)cn2c(=O)c1Br
Solvent: CO
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)CCNC(C)c1nc2ccc(F)cn2c(=O)c1Br
Temperature: 50 °C
Yield: 100.3 %

Procedure:
E3 (222 mg, 0.78 mmol) was dissolved in 5 mL methanol. Triethylamine (0.11 mL, 0.78 mmol) was added followed by ethyl vinyl sulfone (0.082 mL, 0.78 mmol). The reaction was heated at 50° C. overnight. After removal of methanol, the mixture was purified by chromatography with 1:1 dichloromethane:ethyl acetate then gradient methanol in dichloromethane (2% to 4% to 6%) to give 318 mg E4 as an oil.