Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[C:10](=[O:35])[N:11]([CH2:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29](C#N)[N:28]=2)[C:12]([CH3:25])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24]>C(O)(C)(C)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[C:10](=[O:35])[N:11]([CH2:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29]([OH:4])[N:28]=2)[C:12]([CH3:25])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccnc(C#N)n1
Solvent: CC(C)(C)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccnc(O)n1
Yield: 51.7 %

Procedure:
A mixture of 4-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrimidine-2-carbonitrile trifluoroacetate (0.2 g, 0.00035 mol) potassium fluoride on aluminum oxide (0.25 g) in t-butanol (5.0 mL) was refluxed for 4 h under argon atmosphere. The reaction mixture was cooled, filtered the precipitate and washed with ethanol. The combined filtrate and washings were concentrated to dryness and the residue was purified by reverse-phase HPLC using 10-90% acetonitrile/water gradient (30 min) at a flow rate of 100 mL/min. The appropriate fractions (m/z=452) were combined and freeze dried to afford the title compound (0.05 g) as a white powder:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([CH3:18])=[CH:13][O:14][C:15](=[O:17])[CH3:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[C:25]1([CH2:31]CC(Cl)=O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1.CCOCC>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([CH3:18])=[CH:13][O:14][C:15](=[O:17])[CH2:16][CH2:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CC(=O)OC=C(C)Cc1ccc(C(C)(C)C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=COC(=O)CCc1ccccc1)Cc1ccc(C(C)(C)C)cc1
Reaction time: 1.5 h
Yield: 83.5 %

Procedure:
A solution of 65.8 g acetic acid 3-(4-tert-butyl-phenyl)-2-methyl-propenyl ester in 200 ml of THF was cooled to −70° C. A solution of 42.3 g potassium-tert-butoxide in 200 ml of THF was added at −70° C. during 20 min. and the resulting reaction mixture was stirred for 90 min. at the same temperature. 53.5 g 3-phenyl-propionyl chloride was dropped in and the reaction mixture was stirred for another 3 hours at −70° C. Then the reaction mixture was diluted with ether, washed with saturated NaHCO3 and brine. The organic phase was dried, filtered and evaporated to dryness. The residue was thin-layer distilled to yield 75.0 g of a yellow oil.
Reaction SMILES: S(=O)(=O)(O)O.O.[CH3:7][N:8]([CH3:26])[S:9]([C:12]1[C:20]2[O:19]C(C(C)(C)C)=[N:17][C:16]=2[CH:15]=[CH:14][C:13]=1[Cl:25])(=[O:11])=[O:10]>O1CCOCC1>[NH2:17][C:16]1[C:20]([OH:19])=[C:12]([S:9]([N:8]([CH3:7])[CH3:26])(=[O:10])=[O:11])[C:13]([Cl:25])=[CH:14][CH:15]=1
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc2nc(C(C)(C)C)oc12
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Yield: 96.1 %

Procedure:
11 ml (205 mmol; 1.20 V) of sulfuric acid and 11 ml of water were added dropwise to a solution of 9.12 g (28.8 mmol; 1.0 eq) of 2-tert-butyl-6-chlorobenzooxazole-7-sulfonic acid dimethylamide in 41 ml of 1,4-dioxane. The reaction medium was refluxed for six and a half hours. The reaction medium was concentrated and 440 ml of 1 N sodium hydroxide were added (pH at 8). The solution was extracted with ethyl acetate. The organic phases were combined, dried over magnesium sulfate, filtered and evaporated. 6.94 g of 3-amino-6-chloro-2-hydroxy-N,N-dimethylbenzenesulfonamide were obtained in the form of a brown solid. Yield=96%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([O:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12](=[O:33])[N:13]2[C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:32].[CH:34]1([C:37](=O)[CH3:38])[CH2:36][CH2:35]1.C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([O:18][CH:19]2[CH2:20][CH2:21][N:22]([CH:37]([CH:34]3[CH2:36][CH2:35]3)[CH3:38])[CH2:23][CH2:24]2)[CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12](=[O:33])[N:13]2[C:25]1[C:26]([Cl:32])=[CH:27][CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: O=c1ccc2c(-c3ccccc3Cl)cc(OC3CCNCC3)cc2n1-c1c(Cl)cccc1Cl
Reactant: CC(=O)C1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C1CC1)N1CCC(Oc2cc(-c3ccccc3Cl)c3ccc(=O)n(-c4c(Cl)cccc4Cl)c3c2)CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 8.8 mg of 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-(piperidin-4-yloxy)quinolin-2(1H)-one in 0.9 mL of MeOH was added 0.1 mL of 1-cyclopropylethanone, then 6.5 mg of sodium cyanoborohydride. The mixture was stirred 4 d at rt. Another 0.5 mL of 1-cyclopropylethanone was added and the mixture was heated to reflux overnight, then concentrated and purified by preparative thin-layer chromatography, eluting with 95:5 CH2Cl2-2M NH3 in MeOH to yield the title compound. Mass spectrum (ESI) 567 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[CH:6][N:5]=[C:4]([S:17]([CH3:20])(=[O:19])=[O:18])[N:3]=1.[CH3:21][N:22]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:41]>>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][C:7]1[C:2]([C:30]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=[O:41])[N:22]([CH3:21])[CH:31]=2)=[N:3][C:4]([S:17]([CH3:20])(=[O:19])=[O:18])=[N:5][CH:6]=1
Reactant: CS(=O)(=O)c1ncc(Oc2ccc(F)cc2F)c(Cl)n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2c1=O
Product: Cn1cc(-c2nc(S(C)(=O)=O)ncc2Oc2ccc(F)cc2F)c2ccccc2c1=O

Procedure:
The title compound of Example 149, step 3 was reacted with the title compound of Example 89, step 1 in a manner similar to Example 149, step 4 to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.52 (d, J=8.0 Hz, 1H), 8.32 (s, 1H), 7.68 (s, 3H), 7.59-7.56 (m, 1H), 7.14-7.08 (m, 1H), 7.05-7.00 (m, 1H), 6.96-6.92 (m, 1H), 3.72 (s, 3H), 3.39 (s, 3H). LCMS: 443.9 (M+1)+
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([O:9][C:10]([NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15][CH2:14]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[N+:20]([C:23]1[CH:33]=[CH:32][CH:31]=[C:25]2[C:26]([O:28][C:29](=O)[C:24]=12)=[O:27])([O-:22])=[O:21].C(N1C=CN=C1)(N1C=CN=C1)=O>O>[C:5]([O:9][C:10]([NH:12][C@H:13]1[CH2:14][CH2:15][C@H:16]([N:19]2[C:29](=[O:28])[C:24]3[C:25](=[CH:31][CH:32]=[CH:33][C:23]=3[N+:20]([O-:22])=[O:21])[C:26]2=[O:27])[CH2:17][CH2:18]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
15 ml of a chloroform solution containing 500 mg of N-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine and 540 mg of 3-nitrophthalic anhydride was refluxed for 1 hour. After cooling, 756 mg of carbonyldiimidazole was added to the mixture and the resulting mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture and the resulting mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography to obtain 900 mg of N-tert-butoxycarbonyl-trans-4-(1,3-dioxo-4-nitro-2-isoindolinyl)-cyclohexylamine.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)=[CH:7][CH2:8]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH2:46]([O:48][C:49](=[O:63])[CH2:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([SH:58])=[CH:54][C:53]=1[C:59]([F:62])([F:61])[F:60])[CH3:47]>C1COCC1>[CH2:46]([O:48][C:49](=[O:63])[CH2:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([S:58][CH2:8][CH:7]=[C:6]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:54][C:53]=1[C:59]([F:60])([F:61])[F:62])[CH3:47]
Reactant: CCOC(=O)COc1ccc(S)cc1C(F)(F)F
Reactant: OCC=C(c1ccco1)c1ccco1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(SCC=C(c2ccco2)c2ccco2)cc1C(F)(F)F
Reaction time: 2 h

Procedure:
To a solution of 3,3-bis-(2-furanyl)-prop-2-en-1-ol (104 mg, 0.55 mmol) and triphenylphosphine (275 mg, 1.09 mmol) in THF (10 ml) was added, at room temperature and under nitrogen atmosphere, DEAD (190 mg, 1.09 mmol). The reaction mixture was stirred for 5 min after which (2-trifluoromethyl4-mercapto-phenoxy)-acetic acid ethyl ester (230 mg, 0.82 mmol) was added over 15 min. The reaction mixture was stirred at 0oC for 2 hours followed by 18 hours at room temperature and 3 hours at 50° C. The reaction mixture was evaporated and the crude residue was purified on column chromatography using ethyl acetate as eluent. The desired {4-[3,3-bis-(2-furanyl)-allylsulfanyl]-2-trifluoromethyl-phenoxy}-acetic acid ethyl ester was isolated in 11 mg yield.
Reaction SMILES: [C:1]([CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([Mg]Br)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C1COCC1>[OH:8][C:1]([CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCC[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)c2ccccc2)C1
Solvent: C1CCOC1
Product: CCCCCCC(O)(c1ccccc1)C1CCCN(C(=O)OC(C)(C)C)C1
Temperature: -10 °C
Reaction time: 17 h

Procedure:
To a 100-mL round bottom flask were added tert-butyl 3-(benzoyl)piperidine-1-carboxylate (0.4733 g, 1.63 mmol, 1.0 equiv) and THF (5 mL). The flask was evacuated and refilled with N2. The mixture was cooled with a dry ice-acetone bath and hexylmagnesium bromide (2.0M solution in Et2O, 2.5 mL, 5.0 mmol, 3.0 equiv) was added. The reaction mixture was allowed to slowly warm to −10° C. while stirring overnight (17 h). The mixture was quenched with saturated NH4Cl (10 mL), extracted three times with EtOAc, and dried over Na2SO4. The crude product was purified by reversed-phase HPLC(XTerra® Prep MS C18 OBD™ Column, 5 μl, 19×50 mm, 10%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min, flow rate 20 mL/min) to give tert-butyl 3-(1-hydroxy-1-phenylheptyl)piperidine-1-carboxylate. LC-MS (3 min) tR=2.41 min, m/z 398 (M+Na+), 376 (MH+), 302, 276, 258.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[NH:4]1[C:12]2[C:7](=[C:8]([C:13]3[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=O)[CH:16]=[CH:17][CH:18]=3)[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[NH:4]1[C:12]2[C:7](=[C:8]([C:13]3[CH:14]=[C:15]([CH2:19][C:20]([N:2]([CH3:3])[CH3:1])=[O:22])[CH:16]=[CH:17][CH:18]=3)[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1
Reactant: CNC
Reactant: O=C(O)Cc1cccc(-c2cccc3[nH]ccc23)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)Cc1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dimethylamine (2M in THF, 5 mL) was added to a mixture of [3-(1H-indol-4-yl)-phenyl]-acetic acid (1.26 g, 5 mmol), EDC (1.19 g, 1.25 eq.) and HOBt (675 mg, 1 eq.) in THF (10 mL) was stirred at rt for 5 hours. The reaction was concentrated, diluted with ethyl acetate, washed with 10% Na2CO3 (3×), brine, dried and concentrated. The residue was purified on a silica gel column to give 658 mg of 2-[3-(1H-indol-4-yl)-phenyl]-N,N-dimethyl-acetamide as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:13]3[CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]5[NH:24][C:25]([CH:27]6[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]6)=[CH:26][C:19]=45)[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:5]=[N:6][CH:7]=1.FC(F)(F)C([O-])=O.C(N(CC)CC)C.[N:47]([CH3:50])=[C:48]=[O:49]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:13]3[CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]5[NH:24][C:25]([CH:27]6[CH2:32][CH2:31][N:30]([C:48]([NH:47][CH3:50])=[O:49])[CH2:29][CH2:28]6)=[CH:26][C:19]=45)[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:5]=[N:6][CH:7]=1
Reactant: Fc1cncc(Cn2cnc3ccc(-c4ccnc5[nH]c(C6CCNCC6)cc45)cc32)c1
Reactant: CN=C=O
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)N1CCC(c2cc3c(-c4ccc5ncn(Cc6cncc(F)c6)c5c4)ccnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Example 12D trifluoroacetate salt (30.0 mg, 0.070 mmol) in N,N-dimethylformamide (0.3 mL) was added triethylamine (0.05 ml, 0.352 mmol) and isocyanatomethane (6.0 mg, 0.106 mmol). The mixture was stirred at room temperature for 1 hour, concentrated and purified by reverse-phase HPLC (Phenomenex Luna C8 AXIA column, 100 Å) eluting with a gradient of 10-95% acetonitrile/0.1% trifluoroacetic acid in water with 10 mM ammonium acetate to afford the title compound. 1H NMR (400 MHz, dimethylsulfoxide-d6) δ 1.51-1.66 (m, 2 H) 1.87-1.98 (m, 2 H) 2.61 (d, J=4.58 Hz, 3 H) 2.74-2.91 (m, 3 H) 4.04 (m, 2 H) 5.66 (s, 2 H) 6.11 (s, 2 H) 7.10 (d, J=4.88 Hz, 1 H) 7.57 (dd, J=8.54, 1.53 Hz, 1 H) 7.61-7.68 (m, 1 H) 7.76-7.83 (m, 2 H) 8.16 (d, J=5.19 Hz, 1 H) 8.42 (s, 1 H) 8.47-8.52 (m, 2 H) 11.32 (s, 1 H). MS (ESI) m/e 484 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]2[CH2:10][O:9][CH:8]([CH2:11]Br)[O:7][C:6]=2[CH:13]=1.[CH3:15][NH2:16]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]2[CH2:10][O:9][CH:8]([CH2:11][NH:16][CH3:15])[O:7][C:6]=2[CH:13]=1
Reactant: Fc1cc(Br)cc2c1COC(CBr)O2
Reactant: CN
Solvent: CCO
Product: CNCC1OCc2c(F)cc(Br)cc2O1
Yield: 94 %

Procedure:
Preparation according to Example 12. 7-bromo-2-(bromomethyl)-5-fluoro-4H-1,3-benzodioxine (0.50 g, 1.53 mmol), methanamine (2.0 ml, 33% in EtOH) and EtOH (4.0 ml) were heated in a micro wave oven at 120° C. for 1 h 5 min. The volatiles were evaporated in vacuum and the crude product was chromathographed twice on a silica column using EtOAc/MeOH (4:1) as eluent. Collection of the fractions containing pure product and evaporation of the solvent afforded the title compound (0.40 g, 94%). 1H-NMR (400 MHz, MeOD): δ 6.93 (2H, m), δ 5.26 (1H, t, J 4.8 Hz), δ 4.93 (2H, dd, J1 18.4 Hz, J2 15.2 Hz), δ 3.02 (2H, m), δ 2.53 (3H, s) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:19][C@H:20]2[CH2:40][CH2:39][C:22]3([O:26][C@H:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@@H:24]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:23]3)[CH2:21]2)[C:13](N(OC)C)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH:41]([Mg]Br)=[CH2:42].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:19][C@H:20]2[CH2:40][CH2:39][C:22]3([O:23][C@H:24]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C@@H:25]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[O:26]3)[CH2:21]2)[C:13](=[O:14])[CH:41]=[CH2:42])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: C=C[Mg]Br
Reactant: CON(C)C(=O)C(C[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)C(C[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
A solution of 2-[3-chloro-4-(methylsulfonyl)phenyl]-3-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]-N-methoxy-N-methylpropaneamide (3.05 g) in tetrahydrofuran (30 mL) was cooled to 0° C., and vinylmagnesium bromide (1.0M tetrahydrofuran solution, 22.1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 4 hr, and poured into 1M hydrochloric acid, and the mixture was stirred for 30 min. The reaction mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (2.58 g, yield 90%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1.CCCCC.[H-].[Na+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:28][C:27]1[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=1)[C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1
Reactant: O=C1CCCc2[nH]c3ccc(Cl)cc3c21
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: O=C1CCCc2c1c1cc(Cl)ccc1n2Cc1ccc(F)cc1
Reaction time: 0.33 h
Yield: 93.5 %

Procedure:
6-Chloro-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.4042 g, 0.0018 mol) is added to a slurry of pentane-washed NaH (0.091 g, 0.0023 mol) in DMF (2 mL) and after stirring for 20 min, p-fluorobenzyl bromide (0.28 mL, 0.0023 mol) is added. Additional DMF (1 mL) is added and the mixture is stirred for 4 h, at which time the mixture is partitioned between aq. sodium bicarbonate and ethyl acetate. The combined organic layers are washed with water, dried over sodium sulfate and concentrated to dryness. The resulting solids are chromatographed on silica gel (200 mL) using dichloromethane/heptane (60/40 and 80/20) to give 0.5519 g (92%) of the title compound; mp 207-207.75° C.; MS (ESI+) for C19H15ClFNO m/z 328.1 (M+H)+; IR (drift) 1628, 1511, 1467, 1448, 1360, 1226, 1218, 1145, 1096, 878, 849, 840, 804, 764, 649 cm−1; 1H NMR (CDCl3) δ2.23, 2.58, 2.86, 5.27, 6.99, 7.16, 8.27. Anal. Calcd for C19H15ClFNO: C, 69.62; H, 4.61; N, 4.27. Found (av): C, 69.08; H, 4.50; N, 4.26.
Reaction SMILES: Cl.C([O:4][C:5](=[O:25])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1)C.C(N(C(C)C)C(C)C)C.[CH3:35][O:36][C:37]1[CH:46]=[CH:45][CH:44]=[CH:43][C:38]=1[CH2:39][N:40]=[C:41]=[S:42]>C(Cl)Cl>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]([OH:4])=[O:25])=[C:9]([CH:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][N:16]2[C:41](=[S:42])[NH:40][CH2:39][C:38]2[CH:43]=[CH:44][CH:45]=[CH:46][C:37]=2[O:36][CH3:35])[CH:10]=1
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1NCCc2ccccc21
Reactant: COc1ccccc1CN=C=S
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1CNC(=S)N1CCc2ccccc2C1c1cc(Cl)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of (±)-[4-chloro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (76 mg, 0.20 mmol, 1.0 eq.) and N-ethyldiisopropylamine (42 μL, 0.24 mmol, 1.2 eq) in DCM (2 mL), 2-methoxybenzyl isothiocyanate (36 mg, 0.20 mmol, 1.0 eq.) was added. The resulting mixture was stirred at r.t. for 19 hours. The mixture was diluted with DCM (20 mL), washed with 10% aq. AcOH (2×5 mL) and with sat. aq. NaCl (1×5 mL). The org. layer was concentrated in vacuo. The residue was dissolved in DMF (1 mL). 1M aq. NaOH soln. (0.5 mL) was added. The mixture was stirred at r.t. for 7 hours. The solution was carefully neutralized with formic acid (0.5 mL), filtered, and purified by prep. HPLC (column: Waters X-bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) to give the desired acid as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[C:7]3[C:11](=[CH:12][CH:13]=[C:5]2[S:4][CH:3]=1)[NH:10][C:9]1[CH2:14][CH2:15][NH:16][CH2:17][C:8]3=1.[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22]Cl>CN(C)C=O>[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][N:16]1[CH2:15][CH2:14][C:9]2[NH:10][C:11]3[C:7]([C:8]=2[CH2:17]1)=[C:6]1[C:2]([CH3:1])=[CH:3][S:4][C:5]1=[CH:13][CH:12]=3
Reactant: CN(C)CCCCl
Reactant: Cc1csc2ccc3[nH]c4c(c3c12)CNCC4
Solvent: CN(C)C=O
Product: Cc1csc2ccc3[nH]c4c(c3c12)CN(CCCN(C)C)CC4

Procedure:
10 g of 1-methyl-7,8,9,10-tetrahydrothieno[3,2-e]pyrido[4,3-b]indole, dissolved in 200 ml of dimethylformamide at 90° C., are heated to 90° with a solution of 12 ml of 3-dimethylaminopropyl chloride in 50 ml of dimethylformamide for 3 hours. The reaction mixture is filtered, the filtrate is evaporated and the residue is taken up in chloroform. After washing with water and drying, the organic phase is concentrated, the residue is chromatographed on SiO2 with chloroform/methanol/NH4OH (7:3:0:1) and the product is recrystallised from isopropanol. Melting point: 184° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:10][C:3]=12.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=1)=[O:25].C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[NH:23][C:24]([NH:26][C:27]1[CH:28]=[CH:29][C:30]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:10][C:3]=23)=[CH:31][CH:32]=1)=[O:25]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1
Reactant: COC(=O)c1cc2nccc(Br)c2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc2nccc(-c3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)c2s1
Temperature: 70 °C

Procedure:
To a mixture of methyl 7-bromothieno[3,2-b]pyridine-2-carboxylate (68 mg, 0.25 mmol) and 1-(2-fluoro-5-methylphenyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea (102 mg, 0.28 mmol) in 8 ml of 1,4-dioxane, was added PdCl2(PPh3)2 (10 mg, 0.014 mmol) and 1M Na2CO3 aqueous solution (0.25 ml, 0.5 mmol). The mixture was heated at 70° C. under N2 for 1 hour, cooled to room temperature and poured into 100 ml of water. The brown precipitates were filtered, washed with water and dried to give the crude product, which was purified by silica gel chromatography, eluting with 2-3% MeOH/CHCl3 to give methyl 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thieno[3,2-b]pyridine-2-carboxylate as light yellow solid. Yield: 30 mg, 28%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([C:16]2[C:35]([CH:36]3[CH2:38][CH2:37]3)=[CH:34][C:19]3[C:20]([C:30]([NH:32][CH3:33])=[O:31])=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[O:22][C:18]=3[CH:17]=2)[S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>[Pt].C1COCC1.CO>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([N:11]([C:16]2[C:35]([CH:36]3[CH2:38][CH2:37]3)=[CH:34][C:19]3[C:20]([C:30]([NH:32][CH3:33])=[O:31])=[C:21]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[O:22][C:18]=3[CH:17]=2)[S:12]([CH3:15])(=[O:14])=[O:13])=[CH:3][C:2]=1[Cl:1]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [Pt]
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Yield: 99 %

Procedure:
A solution of 6-(N-(3-chloro-4-nitrophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (11.0 g, 19.7 mmol) in 1:1 THF/MeOH (75 mL) was subjected to hydrogenation at 40 psi in the presence of 5% sulfided platinum on carbon (0.560 g). After 4 hours an additional portion of catalyst was added (0.250 g). After another 16 hours the reaction vessel was purged with nitrogen, catalyst removed by filtration through celite, and the filtrate concentrated to dryness at reduced pressure. The residue was recrystallized from hexane/EtOAc to afford the title compound (10.3 g, 99%) as a white solid. LCMS (m/z, ES+)=528 (M+H+).