Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:12].[Br:13]Br>C(O)(=O)C>[Br:13][CH:6]1[C:5](=[O:12])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[O:8][CH2:7]1
Reactant: BrBr
Reactant: O=C1CCOc2ccc(F)cc21
Solvent: CC(=O)O
Product: O=C1c2cc(F)ccc2OCC1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of 6-fluorochroman-4-one (21.0 g, 126 mmol) in acetic acid (105 ml) is added bromine (6.5 ml, 126 mmol) at such a rate as to not raise the temperature above 25° C. After the addition is complete, the reaction is allowed to stir for 2 hours before pouring into 1 liter of ice. The resulting mixture is stirred over night. The precipitate which formed is filtered and placed in drying oven to produce 21 g of 3-bromo-6-fluorochroman-4-one.
Reaction SMILES: [CH:1]1([N:7]([CH3:36])[C:8]2[C:9]([CH3:35])=[C:10]([CH:24]=[C:25]([C:27]3[CH:28]=[N:29][C:30]([CH:33]=O)=[CH:31][CH:32]=3)[CH:26]=2)[C:11]([NH:13][CH2:14][C:15]2[C:16](=[O:23])[NH:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:37][NH:38][CH3:39].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:1]1([N:7]([CH3:36])[C:8]2[C:9]([CH3:35])=[C:10]([CH:24]=[C:25]([C:27]3[CH:28]=[N:29][C:30]([CH2:33][N:38]([CH3:39])[CH3:37])=[CH:31][CH:32]=3)[CH:26]=2)[C:11]([NH:13][CH2:14][C:15]2[C:16](=[O:23])[NH:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CNC
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN(C)C)nc3)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
To a stirred solution of compound 3-(cyclohexyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(6-formylpyridin-3-yl)-2-methylbenzamide (1 equiv.) and dimethylamine (5 equiv.) in methanol (10 mL), acetic acid (2 equiv.) was added and reaction stirred at room temperature for 8 h. Then sodium cyanoborohydride (2.5 equiv.) was added at 0° C. and reaction stirred overnight at room temperature. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford the title compound (0.017 g, 11% yield). LCMS: 516.35 (M+1)+; HPLC: 90.32% (@254 nm) (Rt; 4.203; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.78 (s, 1H), 8.18 (t, 1H), 8.05 (d, 1H, J=6 Hz), 7.50 (d, 1H, J=8.4 Hz), 7.34 (s, 1H), 7.20 (s, 1H), 5.86 (s, 1H), 4.28 (d, 2H, J=4.8 Hz), 3.75 (bs, 2H), 2.75 (m, 1H), 2.65 (s, 3H), 2.34 (bs, 6H), 2.22 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.69-1.71 (m, 4H), 1.54-1.56 (m, 2H), 1.42-1.45 (m, 2H), 1.08-1.23 (m, 2H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:13]([CH:27]=[O:28])=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:32])(=O)=O>CC(O)=O.C(Cl)Cl>[Cl:32][C:10]1[C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[C:13]([CH:27]=[O:28])[N:14]2[S:18]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)(=[O:19])=[O:20]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=Cc1cc2cc(OCc3ccccc3)ccc2n1S(=O)(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=Cc1cc2c(Cl)c(OCc3ccccc3)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.7 %

Procedure:
To a solution of 5-[(phenylmethyl)oxy]-1-(phenylsulfonyl)-1H-indole-2-carbaldehyde (3.22 g, 8.22 mmol) in 1:1 AcOH—CH2Cl2 (140 mL) was added sulfuryl chloride (1.24 g, 9.19 mmol) dropwise and the resulting mixture was stirred at rt for 15 h. Additional sulfuryl chloride (0.084 g, 0.62 mmol) was added and stirring was continued for 1 h. The mixture was partially concentrated to ˜½ volume under a stream of N2 and the resulting light yellow crystals were collected by filtration and washed sequentially with cold AcOH and hexanes, to afford the title compound (2.58 g, 74% yield): 1H NMR (400 MHz, CDCl3) δ 10.49 (s, 1H), 8.05 (d, J=9.3 Hz, 1H), 7.74 (d, J=7.6 Hz, 2H), 7.58-7.54 (m, 2H), 7.46-7.30 (m, 7H), 7.22 (d, J=9 Hz, 1H), 5.19 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:13][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[CH:7][C:8](=[O:12])[O:9][C:10]=2[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2ccc(=O)oc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1ccc2ccc(CBr)cc2o1
Temperature: 25 °C
Yield: 73.7 %

Procedure:
10 g (62.4 mmol) of 7-methyl-coumarin were suspended in 115 ml of carbon tetrachloride. After the addition of 12.2 g (68.7 mmol) of N-bromosuccinimide and 0.122 g (0.5 mmol) of benzoyl peroxide the reaction mixture was boiled under reflux for 7 hours. After cooling to room temperature the mixture was filtered. The residue was washed in succession with carbon tetrachloride and a small amount of diethyl ether and subsequently digested in 500 ml of water. The crude product was filtered off, dried and recrystallized from about 150 ml of acetone. After drying in a water-jet vacuum at 60° C. there were obtained 11 g of 7-bromomethyl-2H-1-benzopyran-2-one as white crystals.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][C:22]#[N:23])[C:17]=3[CH:24]=2)[C:3]1=[O:25].I[CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[CH3:1][N:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH:21]([CH2:27][CH3:28])[C:22]#[N:23])[C:17]=3[CH:24]=2)[C:3]1=[O:25]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CC#N)c3c2)c1=O
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCC(C#N)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Yield: 28 %

Procedure:
To a solution of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-acetonitrile (0.730 g, 0.00199 mol) in dimethyl sulfoxide is added iodoethane (0.170 ml, 0.00210 mol) followed by potassium carbonate (0.750 g, 0.00543 mol). The resultant mixture is stirred overnight at room temperature and poured onto a mixture of ice and 5% aqueous hydrochloric acid. The resultant solid is filtered, dried and taken up in a minimal amount of methylene chloride. Flash column chromatography using silica gel and 100% to 99:1 methylene chloride/diethyl ether gives the title compound as a white solid (0.220 g, 28.0%, mp 107-109° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH:2]([CH3:4])[CH3:3].Cl.Cl.C([O:13][C@@H:14]1[C@@H:55]([O:56]C(=O)C)[C@H:54]([O:60]C(=O)C)[C@@H:53]([CH2:64][O:65]C(=O)C)[O:52][C@H:15]1[O:16][C:17]1[C:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][C:35]4([CH2:43][CH2:42][N:41]([C:44](=[O:47])[CH2:45][NH2:46])[CH2:40][CH2:39]4)[CH2:34]3)=[CH:25][C:24]=2[CH3:48])=[C:20]([CH:49]([CH3:51])[CH3:50])[NH:19][N:18]=1)(=O)C.C(N(C(C)C)CC)(C)C>ClCCl>[C@@H:15]1([O:16][C:17]2[C:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[CH2:31][CH2:32][N:33]4[CH2:38][CH2:37][CH2:36][C:35]5([CH2:43][CH2:42][N:41]([C:44](=[O:47])[CH2:45][NH:46][C:6]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:7])[CH2:40][CH2:39]5)[CH2:34]4)=[CH:25][C:24]=3[CH3:48])=[C:20]([CH:49]([CH3:51])[CH3:50])[NH:19][N:18]=2)[O:52][C@H:53]([CH2:64][OH:65])[C@@H:54]([OH:60])[C@H:55]([OH:56])[C@H:14]1[OH:13]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCN3CCCC4(CCN(C(=O)CN)CC4)C3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)CN=C=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(/C=C/CCN2CCCC3(CCN(C(=O)CNC(=O)NCC(C)C)CC3)C2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
Add isobutyl isocyanate (77 mg, 0.78 mmol) to a solution of 4-(4-{(1E)-4-[9-(aminoacetyl)-2,9-diazaspiro[5.5]undec-2-yl]but-1-en-1-yl]-2-methylbenzyl}-5-(propan-2-yl)-1H-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside dihydrochloride (350 mg, 0.39 mmol) and diisopropylethylamine (302 mg, 2.34 mmol) in dichloromethane (1.0 mL). After 30 min at room temperature, concentrate to dryness under the reduced pressure. Treat the residue with 2.0 M NH3/methanol (1.0 mL) for 3 hours at room temperature, remove the solvent under the reduced pressure. Purify the resulting residue by preparative HPLC method: high pH, 29% B for 4 min, 29-44% B for 5 min @ 85 mL/min using a 30×75 mm, 5 um C18XBridge ODB column, solvent A—H2O w NH4HCO3 @ pH 10, solvent B—acetonitrile to yield the title compound as solid (134 mg, 0.18 mmol). MS (m/z): 755.2 (M+1), 753.2 (M−1).
Reaction SMILES: OO.[F:3][C:4]([F:24])([F:23])[C:5]1[CH:6]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([S:19][CH2:20][CH2:21][CH3:22])[CH:13]=2)[CH:8]=[CH:9][CH:10]=1.C(O)(=[O:27])C>O>[F:24][C:4]([F:23])([F:3])[C:5]1[CH:6]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([S:19]([CH2:20][CH2:21][CH3:22])=[O:27])[CH:13]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCCSc1cc(Oc2cccc(C(F)(F)F)c2)ccc1C
Reactant: CC(=O)O
Agent: OO
Solvent: O
Product: CCCS(=O)c1cc(Oc2cccc(C(F)(F)F)c2)ccc1C
Reaction time: 5 h
Yield: 92.5 %

Procedure:
Thirty-five percent hydrogen peroxide solution (1.6 g, 0.016 mole) was added at 8°-10° C to a mixture of 4-methyl-3-n-propylthiophenyl 3-trifluoromethylphenyl ether (3.8 g, 0.012 mole) and glacial acetic acid (30 ml). After 5 hr at room temperature, the reaction mixture was poured into water (100 ml) and extracted three times with benzene. The combined organic layers were washed with 5 % sodium carbonate solution, then water and dried over sodium sulfate. Evaporation of the solvent gave 3.8 g (92.5 %) of 4-methyl-3-n-propylsulfinylphenyl 3-trifluoromethylphenyl ether, colorless oil, nD25 1.5350. Anal. Found: C, 59.50; H, 5.11. Calcd. for C17H17F3O2S : C, 59.64; H, 5.01 %.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH3:19])[CH2:14][CH2:13]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:20]1[CH2:48][O:47][C:22]2([CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][C:31]([Sn](CCCC)(CCCC)CCCC)=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)[O:21]1>C1(C)C(C)=CC=CC=1>[CH2:20]1[CH2:48][O:47][C:22]2([CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][C:31]([C:2]4[N:3]=[C:4]([N:12]5[CH2:17][CH2:16][N:15]([CH2:18][CH3:19])[CH2:14][CH2:13]5)[C:5]5[C:10]([CH:11]=4)=[CH:9][CH:8]=[CH:7][CH:6]=5)=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)[O:21]1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(N2CCC3(CC2)OCCO3)cc1
Solvent: Cc1ccccc1C
Product: CCN1CCN(c2nc(-c3ccc(N4CCC5(CC4)OCCO5)cc3)cc3ccccc23)CC1
Yield: 51.6 %

Procedure:
3-Bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (1.72 g) and 4-(4,4-ethylenedioxypiperidin-1-yl)phenyltributylstannum (3.12 g) were reacted in the presence of tetrakistriphenylphosphine dichioride (0.5 g) in xylene (50 ml) at 140° C. for 5 hr. The reaction solution was concentrated, and ethyl acetate and an aqueous saturated solution of sodium bicarbonate were added to the resulting residue, for partitioning. The resulting organic layer was washed with water and brine, dried over magnesium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give 1.27 g of the title compound as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:11][O:10][N:9]=2)=[CH:4][C:3]=1[F:18].S(=O)(=O)(O)O.[CH3:24]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([O:17][CH3:24])=[O:16])=[CH:11][O:10][N:9]=2)=[CH:4][C:3]=1[F:18]
Reactant: CO
Reactant: O=C(O)CCc1conc1-c1ccc(Cl)c(F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1conc1-c1ccc(Cl)c(F)c1
Yield: 96 %

Procedure:
A mixture of 3-[3-(4-chloro-3-fluorophenyl)-4-isoxazolyl]propionic acid (5.00 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[3-(4-chloro-3-fluorophenyl)-4-isoxazolyl]propionate (5.01 g, yield 96%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 57–58° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:23])=[CH:5][C:6]=1[C:7]1[N:8]=[C:9]2[N:13]([C:14]=1[CH2:15][C:16]([OH:18])=O)[C:12]1[CH:19]=[CH:20][CH:21]=[CH:22][C:11]=1[S:10]2.[CH3:24][NH2:25]>O1CCCC1>[CH3:1][C:2]1[S:3][C:4]([CH3:23])=[CH:5][C:6]=1[C:7]1[N:8]=[C:9]2[N:13]([C:14]=1[CH2:15][C:16]([NH:25][CH3:24])=[O:18])[C:12]1[CH:19]=[CH:20][CH:21]=[CH:22][C:11]=1[S:10]2
Reactant: CN
Reactant: Cc1cc(-c2nc3sc4ccccc4n3c2CC(=O)O)c(C)s1
Solvent: C1CCOC1
Product: CNC(=O)Cc1c(-c2cc(C)sc2C)nc2sc3ccccc3n12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 1.5 g (0.0044 mole) of 2-(2,5-dimethylthien-3-yl)imidazo[2,1-b]benzothiazole-3-acetic acid in 30 ml of anhydrous tetrahydrofuran is treated, at room temperature, with 0.85 g (0.005 mole) of N,N'-carbonyldiimidazole for 30 minutes. The solution which has become clear is cooled to 0° C. and a stream of methylamine is passed through it for 30 minutes. The mixture is allowed to return to room temperature, the stirring is continued for 3 h, the solvent is evaporated under reduced pressure, the residue is taken up in 10 ml of water, it is extracted with dichloromethane, the organic phase is separated, it is washed with water, it is dried over sodium sulphate, the solvent is evaporated under reduced pressure, and the residue is crystallized from ethyl acetate. 1 g of pale yellow crystals is finally obtained. Melting point: 238°-239° C.
Reaction SMILES: Br[C:2]1[N:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6](=[O:16])[NH:5][C:4](=[O:17])[C:3]=1[CH2:18][CH3:19].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([SH:26])[CH:21]=1>>[CH2:18]([C:3]1[C:4](=[O:17])[NH:5][C:6](=[O:16])[N:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]=1[S:26][C:22]1[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=1)[CH3:19]
Reactant: Sc1cccnc1
Reactant: CCc1c(Br)n(COc2ccccc2)c(=O)[nH]c1=O
Product: CCc1c(Sc2cccnc2)n(COc2ccccc2)c(=O)[nH]c1=O

Procedure:
Likewise, 6-bromo-5-ethyl-1-(phenoxymethyl)-uracil and 3-pyridinethiol can be reacted according to the present method in order to yield a 5-ethyl-1-(phenoxymethyl)-6-(3-pyridylsulfanyl)uracil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[S:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=O)[C:20]3=[O:27])(=[O:16])=[O:15])[CH2:4][CH2:3]1.Cl[CH2:29][C:30]1([C:35]#[N:36])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C@@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[S:14]([C:17]2[CH:25]=[CH:24][C:23]3[N:22]4[CH2:29][C:30]5([CH2:34][CH2:33][CH2:32][CH2:31]5)[CH2:35][N:36]=[C:21]4[C:20](=[O:27])[C:19]=3[CH:18]=2)(=[O:16])=[O:15])[CH2:6][CH2:7]1
Reactant: CN1CCN(C[C@@H]2CCCN2S(=O)(=O)c2ccc3c(c2)C(=O)C(=O)N3)CC1
Reactant: N#CC1(CCl)CCCC1
Product: CN1CCN(C[C@@H]2CCCN2S(=O)(=O)c2ccc3c(c2)C(=O)C2=NCC4(CCCC4)CN23)CC1

Procedure:
The title compound was prepared as a light brown foam from 5-({(2S)-2-[(4-methylpiperazin-1-yl)methyl]pyrrolidin-1-yl}sulfonyl)-1H-indole-2,3-dione and 1-(chloromethyl)cyclopentanecarbonitrile (Syn. Comm. 20(12) 1757, 1990), using a procedure similar to that of steps 2-5 of Example 12. NMR (400 Mz, DMSO-d6): consistent. MS: (ES+) m/z 486.2 [M+H].
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][NH:6][C:5](=[O:10])[C:4]=2[CH:3]=[CH:2]1.C1C(=O)N([Br:18])C(=O)C1.O.C(=O)(O)[O-].[Na+]>C(#N)C>[Br:18][C:8]1[C:9]2[O:1][CH:2]=[CH:3][C:4]=2[C:5](=[O:10])[NH:6][CH:7]=1
Reactant: O=c1[nH]ccc2occc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=c1[nH]cc(Br)c2occc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
To a suspension of 5H-furo[3,2-c]pyridin-4-one (11.1 g, 0.082 mol) in anhydrous acetonitrile (200 mL) was added a solution of NBS (19.0 g, 0.107 mol) in anhydrous acetonitrile (100 ml) at 0° C. over 1 h. The resulting suspension was stirred at 0° C. for 1 h and then warmed to rt for 10 min. Water (500 mL) and saturated sodium bicarbonate aqueous solution (4 ml) were added to the mixture. Off-white solids were collected by filtration and dried under vacuum to afford 7.33 g of desired product (yield: 42%). 1H NMR (DMSO-d6, 400 MHz): δ=7.06 (d, J=2.3 Hz, 1H), 7.60 (s, 1H), 8.00 (d, J=2.0 Hz, 1H). MS (ES+): 214.04/216.04 (1/1) [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:15][C:16](N)=[O:17]>O>[F:12][C:11]([F:14])([F:13])[C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:15][C:16](=[O:17])[NH:1]2)=[CH:7][CH:8]=1
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: NC(N)=O
Solvent: O
Product: O=c1[nH]c(=O)c2ccc(C(F)(F)F)cc2[nH]1
Temperature: 200 °C
Reaction time: 1 h

Procedure:
2-Amino-4-trifluoromethylbenzoic acid (25.0 g, 122 mmol) and urea (75.0 g, 1.2 mol) were combined and heated at 200° C. while stirring. After 1 h, the reaction mixture was allowed to cool to 100° C. and water (100 mL) was added. The reaction mixture was then allowed to cool to room temperature and the solid was isolated by vacuum filtration washing with water (500 mL). The solid was then dried under vacuum (10 mbar, 50° C.). Yield=24 g, 86%; LC-MS: 2.1 min, 230 (M+); 1H NMR (DMSO-d6) δ 7.44 (s, 1 H) 7.47 (d, 1 H), 8.07 (d, 1 H), 11.43 (br s, 1 H), 11.56 (br s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[N:11][NH:12][N:13]=1.[CH3:14][C:15](O)([CH3:17])[CH3:16].S(=O)(=O)(O)O.[OH-].[K+]>C(O)(C(F)(F)F)=O.C(OCC)(=O)C>[CH3:14][C:15]([N:13]1[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[N:10][NH:11][NH:12]1)([CH3:17])[CH3:16]
Reactant: COc1ccccc1-c1nn[nH]n1
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COc1ccccc1C1=NNNN1C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.5 %

Procedure:
A mixture of 5-(2-methoxyphenyl)-2H-tetrazole (0.83 g, 4.71 mmol), 2-methyl-2-propanol (0.7 g, 9.4 mmol), and sulfuric acid (0.24 g, 2.4 mmol) in 4.6 mL of TFA was stirred under nitrogen at room temperature for 16 hours. The reaction mixture then was diluted with ethyl acetate, pouredinto 2M potassium hydroxide, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated. Purification of the residue by column chromatography on silica gel (elution: 10% ethyl acetate/hexane) gave 1-(1,1-dimethylethyl)-5-(2-methoxyphenyl)-2H-tetrazole (0.5102 g, 1.67 mmol), as an oil.
Reaction SMILES: [SH:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]([CH3:15])([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:4]1.[CH2:16]([C:19]1[C:29]([OH:30])=[C:28]([C:31](=[O:33])[CH3:32])[CH:27]=[CH:26][C:20]=1[O:21][CH2:22][CH2:23][CH2:24]Br)[CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+]>>[C:31]([C:28]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][CH2:23][CH2:24][S:1][CH2:2][CH:3]2[CH2:7][O:6][C:5]([CH3:15])([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:4]2)=[C:19]([CH2:16][CH2:17][CH3:18])[C:29]=1[OH:30])(=[O:33])[CH3:32]
Reactant: CCOC(=O)CCC1(C)OCC(CS)S1
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCc1c(OCCCSCC2COC(C)(CCC(=O)OCC)S2)ccc(C(C)=O)c1O

Procedure:
The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 36 (1.5 g, 0.006 mol), 3-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-1-bromopropane (1.9 g, 0.006 mol) and anhydrous potassium carbonate (2.5 g). The crude product was chromatographed on silica gel using 20% ethyl acetate/hexane as eluent to give 2.7 g (93%) of the product as an oil.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10](I)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[O:13]1[CH:17]=[CH:16][C:15]([N:18]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)[S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]([C:32]2[C:37]([OH:38])=[CH:36][C:35]([C:39]4[CH:44]=[C:43]([F:45])[CH:42]=[C:41]([F:46])[CH:40]=4)=[C:34]([F:47])[CH:33]=2)[C:27](=[O:48])[CH:26]=[CH:25]3)(=[O:21])=[O:20])=[N:14]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C>[F:45][C:43]1[CH:44]=[C:39]([C:35]2[C:34]([F:47])=[CH:33][C:32]([N:28]3[C:29]4[C:24](=[CH:23][C:22]([S:19](=[O:21])(=[O:20])[N:18]([C:15]5[CH:16]=[CH:17][O:13][N:14]=5)[CH2:49][C:50]5[CH:51]=[CH:52][C:53]([O:56][CH3:57])=[CH:54][CH:55]=5)=[CH:31][CH:30]=4)[CH:25]=[CH:26][C:27]3=[O:48])=[C:37]([O:38][CH:10]3[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]3)[CH:36]=2)[CH:40]=[C:41]([F:46])[CH:42]=1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: COc1ccc(CN(c2ccon2)S(=O)(=O)c2ccc3c(ccc(=O)n3-c3cc(F)c(-c4cc(F)cc(F)c4)cc3O)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(CN(c2ccon2)S(=O)(=O)c2ccc3c(ccc(=O)n3-c3cc(F)c(-c4cc(F)cc(F)c4)cc3OC3CN(C(=O)OC(C)(C)C)C3)c2)cc1

Procedure:
N-boc-3-iodoazetidine (0.076 ml, 0.268 mmol) was added to a solution of N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1-(2,3′,5′-trifluoro-5-hydroxy-[1,1′-biphenyl]-4-yl)-1,2-dihydroquinoline-6-sulfonamide (0.085 g, 0.134 mmol) and cesium carbonate (0.087 g, 0.268 mmol) in acetonitrile (0.335 ml) and stirred over night. LCMS indicated that the reaction was complete (mass—Boc group). The resulting mixture was transferred to a sep. funnel containing water and the aqueous layer was washed 3× with DCM. The organic layers were combined, dried with MgSO4, filtered and concentrated to an oil. The yield was assumed to be quantitative and taken directly on to the next step. m/z (ESI) 691.0 (M+1-Boc)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([NH2:29])(=O)C.B(F)(F)F.CCOCC>C1(C)C(C)=CC=CC=1>[CH2:19]([O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[N:29]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:8][CH:9]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(N)=O
Reactant: O=C(COCc1ccccc1)c1ccccc1OCc1ccccc1
Agent: FB(F)F
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: c1ccc(COc2ccccc2-c2coc(-c3ccccc3)n2)cc1
Yield: 29.3 %

Procedure:
3.46 g of 2-benzyloxy-1-(2-benzyloxy-phenyl)-ethanone according to step (c) are refluxed with 2.95 g of acetamide and 0.9 ml of boron trifluoride etherate in 100 ml of anhydrous xylene over 20 hours. After the solution obtained has been cooled and washed with water it is dried over sodium sulphate, the solvent is distilled off in vacuo and the residue remaining is chromatographed on silica gel (toluene). In addition to re-isolated educt, 1 g (31%) of the target compound is isolated.