Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH:13]([Mg]Cl)(C)C.[CH2:18]1C[O:21][CH2:20][CH2:19]1>>[OH:21][CH:20]([C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1)[CH:19]([CH3:18])[CH3:13]
Reactant: CC(C)[Mg]Cl
Reactant: C1CCOC1
Reactant: CCOC(=O)c1ccc(I)cc1
Product: CCOC(=O)c1ccc(C(O)C(C)C)cc1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To a solution of 3.19 g (11.6 mmol) of ethyl 4-iodobenzoate in 10 mL of THF at −40° C. was added 6.4 mL (12.7 mmol) of isopropylmagnesium chloride (2.0 M in THF). After stirring at −40° C. for 1 h, 1.26 mL (13.9 mmol) of isobutylaldehyde was added. After stirring at −40° C. for 1 h, the reaction was quenched by adding 10 mL of saturated NaHCO3. The mixture was warmed to rt and poured into brine (20 mL). The aqueous layer was extracted with CH2Cl2 (3×20 mL). Organic layers were combined, dried over Na2SO4, and concentrated. Chromatography on a Biotage 40M cartridge using 1:9 v/v EtOAc/hexanes as the eluant gave 2.08 g of the title compound: 1H NMR (500 MHz, CDCl3) δ 0.82 (d, J=6.9, 3H), 0.96 (d, J=6.6, 3H), 1.39 (t, J=7.1, 3H), 1.95 (m, 1H), 2.09 (br. s, 1H), 4.36 (q, J=7.1, 2H), 4.45 (d, J=6.4, 1H), 7.37 (d, J=8.2, 2H), 7.99 (d, J=8.3, 2H).
Reaction SMILES: CO.[C:3]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH:12]=1)(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[C].[Pd].C(OCC)(=O)C>[CH2:3]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(c1ccccc1)c1ccc(C(=O)O)c(Nc2ccc(F)cc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1ccc(Cc2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 68.2 %

Procedure:
To a mixed solution of methanol 1.3 mL and ethyl acetate 1.3 mL of 4-benzoyl-2-(4-fluoroanilino)benzoic acid 0.13 g was added 5% palladium-carbon 26 mg, and it was stirred under hydrogen atmosphere at room temperature for 6 hours. Insoluble matter was filtrated, and the solvent was removed under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue, and solid matter was filtrated to give 4-benzyl-2-(4-fluoroanilino)benzoic acid 85 mg of white solid.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:33]([O:35][CH3:36])=[O:34])=[CH:12][C:13]=3[N:14]3[CH2:20][CH2:19][CH:18]([NH:21][CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[C:17]4[CH:29]=[CH:30][CH:31]=[CH:32][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:37]C(O)=O.C=O.[BH3-]C#N.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:33]([O:35][CH3:36])=[O:34])=[CH:12][C:13]=3[N:14]3[CH2:20][CH2:19][CH:18]([N:21]([CH3:37])[CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[C:17]4[CH:29]=[CH:30][CH:31]=[CH:32][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)O
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCC(NCCN1CCCC1)c1ccccc1-3
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCC(N(C)CCN1CCCC1)c1ccccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 13-cyclohexyl-5-[(2-pyrrolidin-1-ylethyl)amino]-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (prepared as in Example 3) was dissolved in DCM and the pH adjusted to 6 with AcOH; 37% aq HCHO and, after 30 min NaCNBH3 (3 eq), were added and the mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc and washed with IN NaOH and brine, dried and evaporated affording methyl 13-cyclohexyl-5-[methyl(2-pyrrolidin-1-ylethyl)amino]-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate. Hydrolysis of the foregoing methyl ester was done with IM aqueous KOH (6 eq) in dioxane (0.1M) at 60 ° C.; the reaction was complete in 2 h, and the title compound was obtained in 29% yield after RP-HPLC purification and lyophilisation (Conditions: Column: Waters X-TERRA MS C18, 10 micron, 19×150 mm; Gradient: A: H2O+0.1% TFA; B: MeCN+0.1% TFA; 75% A isocratic for 3 min, linear to 20% A in 12 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:34]([O:36]C)=[O:35])=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[O:21][C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[C:19]([C:29](=[O:32])[NH:30][CH3:31])[C:18]=3[CH:33]=2)=[CH:12][CH:13]=1.[CH3:38]O.[OH-].[Na+].Cl>C(OCC)(=O)C.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:34]([OH:36])=[O:35])=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[O:21][C:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)=[C:19]([C:29](=[O:32])[NH:30][CH3:31])[C:18]=3[CH:33]=2)=[C:12]([CH3:38])[CH:13]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3ccc(-c4ccccc4Cl)c(C(=O)OC)c3)cc12
Reactant: CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(-c4ccccc4Cl)cc3C)cc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 96 %

Procedure:
To a 25 mL round-bottomed flask was added methyl 2′-chloro-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)biphenyl-2-carboxylate (43.8 mg, 0.079 mmol), methanol (1 mL), THF (1 mL) and 8 equivalents of a 1M solution of sodium hydroxide (0.63 mL, 0.63 mmol). The mixture was stirred at room temperature for 48 hours. The crude product was diluted with 20 mL of ethyl acetate, made acidic with 0.5M HCl, extracted, washed with brine, dried over sodium sulfate, filtered and evaporated to dryness giving 47.2 mgs (96% yield) of 2′-chloro-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-5-methylbiphenyl-2-carboxylic acid as yellow solid. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 μm C18, 2×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. LCMS m/z 500.2 (M+H), Rt=3.426 min., 90% purity.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[CH:21]([N:32]1[C@H:37]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:36](=[O:42])[NH:35][C@H:34]([CH:43]2[CH2:51][C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH2:44]2)[C:33]1=[O:52])[C:22]([NH:24][C:25]1C=CC=CC=1O)=[O:23].CNC.O1CCCC1>ClCCl>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C@@H:21]([N:32]1[C@H:37]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:36](=[O:42])[NH:35][C@H:34]([CH:43]2[CH2:44][C:45]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:51]2)[C:33]1=[O:52])[C:22]([N:24]([CH3:1])[CH3:25])=[O:23]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)Nc1ccccc1O)c1ccc(F)cc1F
Agent: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)N(C)C)c1ccc(F)cc1F
Reaction time: 0.25 h
Yield: 62 %

Procedure:
Carbonyldiimidazole (4.80 g, 1.54 equiv.) was suspended in anhydrous dichloromethane (40 mL) and the suspension was left at room temperature for 15 minutes. (2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)ethanamide (10.50 g, pre-dried in vacuo over P4O10 for 24 hours) was then added with stirring and the resultant solution was stirred at room temperature for 6 hours. The resulting yellow solution was then treated with a 2.0M solution of dimethylamine in tetrahydrofuran (54 mL, 5.6 equiv.) and the resulting mixture was stirred at room temperature for 16 hours. The solvents plus residual dimethylamine were removed under reduced pressure and the reaction mixture was taken up in dichloromethane (200 mL) and washed with 1M hydrochloric acid (200 mL). The organic phase was separated using a hydrophobic frit and was evaporated under reduced pressure to ca. 50 mL. The crude product was applied to 4×90 g silica Biotage™ columns on a Quad 3 system; each column being eluted with (i) 2:1 v/v ethyl acetate:cyclohexane (12×50 mL fractions), (ii) ethyl acetate (12×50 mL fractions), (iii) 9:1 v/v ethyl acetate:methanol to give (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide (5.753 g, 62%) as a colourless solid.
Reaction SMILES: O[CH2:2][C:3]1[C:17]2=[C:18]3[C:10]([C:11]4[C:16]2=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:9][CH:8]=[CH:7][C:6]3=[CH:5][CH:4]=1.O=S(Cl)[Cl:21]>C1(C)C=CC=CC=1>[Cl:21][CH2:2][C:3]1[C:17]2=[C:18]3[C:10]([C:11]4[C:16]2=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:9][CH:8]=[CH:7][C:6]3=[CH:5][CH:4]=1
Reactant: OCc1ccc2cccc3c2c1-c1ccccc1-3
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: ClCc1ccc2cccc3c2c1-c1ccccc1-3

Procedure:
To a RB flask equipped with magnetic stirring bar, condenser, addition funnel, thermometer and N2 inlet line with bubbler was added 1-hydroxymethylfluoranthene (3B, 12.0 g, 0.052 mol), and dry PhCH3 (500 mL). To the mixture was added SOCl2 (Aldrich, 15.73 g, 0.132 mol, 9.5 mL) dropwise over 15 min. The mixture was then heated at 80° overnight and then refluxed for 1 h. The solvent was removed by rotary evaporation to give a crude off white solid. The material was redissolved in PhCH3 (300 mL) followed again by rotary evaporation. The process was repeated two additional times to give the crude product 1-chloromethylfluoranthene which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].O.O.O.[C:15]([O-])(=O)C.[Na+].[C:20]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:23])[CH:21]=[CH2:22].C([O-])(=O)C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CN1CCCC1=O>[CH3:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1/[C:22](/[CH3:15])=[CH:21]/[C:20]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23]
Reactant: C=CC(=O)OCCCC
Reactant: CC(=O)[O-]
Reactant: Cc1cc([N+](=O)[O-])ccc1Br
Agent: [Pd+2]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCCOC(=O)/C=C(\C)c1ccc([N+](=O)[O-])cc1C
Temperature: 120 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
A 0.28 mM palladium acetate solution (3.28 ml) was added to N-methylpyrrolidone (7 ml) solution of 2-bromo-5-nitrotoluene (1 g) and sodium acetate trihydrate (417 mg) in an argon atmosphere. The mixture was warmed to 120° C., and n-butyl acrylate (923 μl) was added thereto. The obtained mixture was stirred at 135° C. for 2 hours. A 0.28 mM palladium acetate solution (3.28 ml) and n-butyl acrylate (396 μl) were further added thereto, and the mixture was stirred for 4 hours. Subsequently, sodium acetate (265 mg) was added, and the mixture was further stirred for 1 hour. After the reaction was over, water (30 ml) was added to the resulting reaction mixture, and the mixture was separated with toluene and water. The organic layer was washed three times with water and once with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After the solvent was distilled off, the obtained residue was isolated and purified by silica gel column chromatography (n-hexane to ethyl acetate=8:1) to obtain Compound 5a (1.05 g, 86%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][CH3:18])=O.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][CH3:18]
Reactant: CSc1ccccc1C(=O)c1cc(C)ccc1C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CSc1ccccc1Cc1cc(C)ccc1C
Yield: 92.9 %

Procedure:
To a solution of 0.758 g (2,5-dimethylphenyl)(2-(methylthio)phenyl)methanone and 1 ml triethylsilane was added 5 ml TFA. The reaction mixture was stirred at RT for 1 hour before water was added. The reaction mixture was extracted with ethyl acetate (2×70 ml) and the combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Flash silica chromatography (hexane:ethyl acetate 80:20) yielded 0.666 g product.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:3]=1[CH:4]=[CH:5][NH:6][C:7]2=[O:8].[CH2:13]1[O:15][CH:14]1[CH2:16][OH:17]>[OH-].[Na+]>[OH:15][CH:14]([CH2:16][OH:17])[CH2:13][O:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:3]=1[CH:4]=[CH:5][NH:6][C:7]2=[O:8]
Reactant: OCC1CO1
Reactant: O=c1[nH]ccc2c(O)cccc12
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]ccc2c(OCC(O)CO)cccc12
Yield: 85.6 %

Procedure:
16 g of 5-hydroxyisocarbostyril was dissolved in 110 ml of a 1N aqueous sodium hydroxide solution, and 8 g of glycidol was added to the solution. The mixture was then refluxed for 2 hours while stirring. After allowing the mixture to cool, the precipitated crystals were filtered, and recrystallized from water to give 20 g of 5-(2,3-dihydroxy)propoxyisocarbostyril as colorless needle-like crystals having a melting point of 228° - 230° C.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)(=[O:5])=[O:4].[Li]CCCC.[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19].[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH:30]=[O:31]>C1COCC1>[CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[C:9]([CH:30]([OH:31])[C:26]2[S:25][CH:29]=[CH:28][CH:27]=2)[N:8]=[C:7]1[Si:21]([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22])(=[O:4])=[O:5]
Reactant: O=Cc1cccs1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(C)S(=O)(=O)n1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(C(O)c2cccs2)nc1[Si](C)(C)C(C)(C)C
Temperature: -20 °C
Reaction time: 3 h

Procedure:
A solution of N,N-dimethyl imidazole-1-sulfonamide (commercially available from Aldrich) (1.5 g, 8.57 mmol) in THF (35 mL) at −78° C. was treated with nBuLi (5.4 mL of a 1.6 M soln) for 1 h. Solid TBSCl: tert-butyldimethylsilyl chloride (1.29 g, 8.6 mmol) in THF (5 mL) was added at rt for 16 h. The mixture was cooled to −20° C. and treated with nBuLi (5.9 mL of a 1.6 M soln) for 1 h. Thiophene-2-carbaldehyde (commercially available from Aldrich) (0.96 mL, 10.3 mmol) in THF (10 mL) is added and the mixture was stirred for 3 h at rt. The mixture was washed with brine and dried over Na2SO4. The solvent was removed under vacuum and the residue was purified by chromatography on silical gel with 30% EtOAc: hexane to give 2-(tert-butyl-dimethyl-silanyl)-4-(hydroxy-thiophen-2-yl-methyl)-imidazole-1-sulfonic acid dimethylamide (Intermediate-E1) 2.5 g.
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][C:38]([C:42](O)=[O:43])=[CH:39][CH:40]=3)[C:35]([CH3:45])=[C:34]2[CH3:46])=[CH:28][CH:27]=1)=[O:19])(C)(C)C>>[CH3:46][C:34]1[N:33]([CH2:32][C:29]2[CH:30]=[CH:31][C:26]([C:21]3[C:20]([C:18]([OH:19])=[O:17])=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:27][CH:28]=2)[C:41]2[C:36]([C:35]=1[CH3:45])=[CH:37][C:38]([C:42](=[O:43])[NH:12][CH2:11][C:1]1[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=1)=[CH:39][CH:40]=2
Reactant: NCc1cccc2ccccc12
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3cccc4ccccc34)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 1-naphthylmethylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([C@H:7]([OH:10])[CH:8]=[CH2:9])[O:5][C:4](=[O:11])[C@@H:3]1[O:12][CH3:13].[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1C=C.C1COCC1>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl.C(Cl)Cl>[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1/[CH:9]=[CH:8]/[C@H:7]([C@@H:6]1[O:5][C:4](=[O:11])[C@H:3]([O:12][CH3:13])[C@@H:2]1[OH:1])[OH:10]
Reactant: C=C[C@@H](O)[C@@H]1OC(=O)[C@H](OC)[C@@H]1O
Reactant: C=Cc1ccccc1Br
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CO[C@H]1C(=O)O[C@@H]([C@H](O)/C=C/c2ccccc2Br)[C@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 26 %

Procedure:
400 mg of 31 (2.13 mmol), 1.56 g of 2-bromostyrene (8.5 mmol), 1 mL of THF, 16 mL of CH2Cl2 and 54 mg of 2nd generation Grubb's catalyst (C46H65Cl2N2PRu, MW 848.98, 0.06 mmol) are added to a 100 mL round-bottomed flask. The medium is stirred for 24 h at RT. The solvent is evaporated, the crude product (1.9 g) is chromatographed on a silica cartridge (90 g), eluting with a CH2Cl2/MeOH (95/5) mixture. 190 mg of expected product 45 are obtained.
Reaction SMILES: [OH:1]O.COC1CCN(CCCNC2N=[N+:17]([O-:28])[C:18]3[CH:27]=[C:26]4[C:22]([CH2:23][CH2:24][CH2:25]4)=[CH:21][C:19]=3[N:20]=2)CC1.[C:29](O)([C:31](F)(F)F)=[O:30]>C(Cl)Cl.N>[N+:17]([C:18]1[CH:27]=[C:26]2[C:22]([CH2:23][CH2:24][CH2:25]2)=[CH:21][C:19]=1[NH:20][C:29](=[O:30])[CH3:31])([O-:28])=[O:1]
Reactant: OO
Reactant: COC1CCN(CCCNc2nc3cc4c(cc3[n+]([O-])n2)CCC4)CC1
Reactant: O=C(O)C(F)(F)F
Agent: N
Solvent: ClCCl
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CCC2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
H2O2 (70%, 0.92 mL, ca. 18.3 mmol) was added dropwise to a stirred solution of TFM (2.6 mL, 18.3 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 58 (655 mg, 1.8 mmol) and TFA (0.71 mL, 9.2 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 20° C. for 8 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with DCM (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 58 (360 mg, 55%) and (ii) 1,4-dioxide 59 (213 mg, 31%) as a red solid: mp (MeOH/EtOAc) 128-130° C.; 1H NMR δ 8.42 (br s, 1H, NH), 8.11 (s, 1H, H-9), 8.10 (s, 1H, H-5), 3.62-3.68 (m, 2H, CH2N), 3.28-3.36 (m, 4H, OCH3, CHO), 3.08 (dt, J=7.5, 1.1 Hz, 2H, H-6), 3.03 (dt, J=7.5, 1.1 Hz, 2H, H-8), 2.69-2.76 (m, 2H, CH2N), 2.55 (br t, J=6.2 Hz, 2H, CH2N), 2.26-2.34 (m, 2H, CH2N), 2.17 (p, J=7.5 Hz, 2H, H-7), 1.94-2.03 (m, 2H, CH2), 1.88 (p, J=6.2 Hz, 2H, CH2), 1.72-1.81 (m, 2H, CH2); 13C NMR δ 155.4, 149.5, 145.5, 138.1, 129.5, 115.7, 111.7, 75.8, 57.2, 55.4, 50.8 (2), 41.6, 33.3, 32.3, 30.3 (2), 25.5, 25.1. Anal. calcd for C19H27N5O3.H2O: C, 58.3; H, 7.5; N, 17.9. Found: C, 58.4; H, 6.8; N, 17.6%.
Reaction SMILES: C(#N)C=C.CO[CH2:7][O:8][CH3:9].COC1C=C(C=C(OC)C=1OC)C=O.C1N2CCN(CC2)C1.C(OC)=O.O[CH:37]([C:42]1[CH:47]=[C:46]([O:48][CH3:49])[C:45]([O:50][CH3:51])=[C:44]([O:52][CH3:53])[CH:43]=1)[C:38](=C)[C:39]#[N:40]>CO>[CH3:53][O:52][C:44]1[CH:43]=[C:42]([CH:37]=[C:38]([CH2:7][O:8][CH3:9])[C:39]#[N:40])[CH:47]=[C:46]([O:48][CH3:49])[C:45]=1[O:50][CH3:51]
Reactant: C=C(C#N)C(O)c1cc(OC)c(OC)c(OC)c1
Reactant: COCOC
Agent: C1CN2CCN1CC2
Agent: COc1cc(C=O)cc(OC)c1OC
Solvent: C=CC#N
Solvent: CO
Solvent: COC=O
Product: COCC(C#N)=Cc1cc(OC)c(OC)c(OC)c1
Reaction time: 25 h

Procedure:
55 ml of acrylonitrile, 50 ml of dimethoxymethane, 100 g of 3,4,5-trimethoxybenzaldehyde and 30 g of DABCO are introduced into a 500 ml reactor fitted with a stirrer. After stirring for 25 hours, 50 g of methyl formate and 100 ml of methanol are added and the mixture is stirred at room temperature for more than 24 hours until the 3-hydroxy-2-methylene-3-(3,4,5-trimethoxyphenyl)propionitrile has disappeared; the 3-(3,4,5-trimethoxyphenyl)-2-methoxymethylacrylonitrile formed is isolated or reacted with sodium methylate, after removal of the volatile reactants and solvents, to give the acetal of the formula III.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[C:40]1([CH:46]2[CH2:48][CH:47]2[NH2:49])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>ClCCl.CN(C=O)C>[C:40]1([CH:46]2[CH2:48][CH:47]2[NH:49][C:18]([C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]3[CH:11]=[C:10]4[C:5]([CH:6]([C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:8][O:9]4)=[CH:4][C:3]=3[C:1]#[N:2])=[CH:22][CH:21]=2)=[O:20])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: NC1CC1c1ccccc1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CC4c4ccccc4)cc3)c(C#N)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 2) (21.8 mg, 0.0617 mmol) in dichloromethane (1 ml) with a drop of DMF was added oxalyl chloride (2M in dichloromethane) (0.0370 ml, 0.0740 mmol). Gas evolution was observed. The mixture was stirred for 0.5 hours at ambient temperature. Triethylamine (0.0430 ml, 0.3085 mmol) and 2-phenylcyclopropanamine, hemisulfate (28.11 mg, 0.1542 mmol) were added sequentially to the mixture. The mixture was stirred for 17 hours at ambient temperature. The crude mixture was purified on silica gel (MeOH in dichloromethane gradient) to provide 25.9 mg of the title compound as a thin film (90%).
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH2:6].CC(C)([O-])C.[K+].[Cl:13][C:14]1[CH:39]=[CH:38][C:17]([O:18][C:19]2[C:24]([F:25])=[CH:23][C:22]([S:26](OC3C=CC(Cl)=CC=3)(=[O:28])=[O:27])=[C:21]([F:37])[CH:20]=2)=[C:16]([C:40]2[N:45]3[CH:46]=[CH:47][N:48]=[C:44]3[CH:43]=[CH:42][CH:41]=2)[CH:15]=1.Cl>CS(C)=O.C(OCC)(=O)C.O>[Cl:13][C:14]1[CH:39]=[CH:38][C:17]([O:18][C:19]2[C:24]([F:25])=[CH:23][C:22]([S:26]([NH:6][C:2]3[S:1][CH:5]=[N:4][N:3]=3)(=[O:27])=[O:28])=[C:21]([F:37])[CH:20]=2)=[C:16]([C:40]2[N:45]3[CH:46]=[CH:47][N:48]=[C:44]3[CH:43]=[CH:42][CH:41]=2)[CH:15]=1
Reactant: Nc1nncs1
Reactant: O=S(=O)(Oc1ccc(Cl)cc1)c1cc(F)c(Oc2ccc(Cl)cc2-c2cccc3nccn23)cc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: O=S(=O)(Nc1nncs1)c1cc(F)c(Oc2ccc(Cl)cc2-c2cccc3nccn23)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42 %

Procedure:
To a stirred solution of 1,3,4-thiadiazol-2-amine (0.083 g, 0.8 mmol) in anhydrous dimethylsulfoxide (1.0 mL) at ambient temperature was added potassium tert-butoxide (0.092 g, 0.8 mmol). The mixture was stirred at ambient temperature for 10 minutes and 4-chlorophenyl 4-(4-chloro-2-(imidazo[1,2-a]pyridin-5-yl)phenoxy)-2,5-difluorobenzenesulfonate (0.15 g, 0.27 mmol) was added. The reaction mixture was stirred for 1 h at ambient temperature and water (6 mL), 1 M hydrochloric acid (0.85 mL) and ethyl acetate (25 mL) were added. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a 0-10% gradient of methanol in ethyl acetate to afford 4-(4-chloro-2-(imidazo[1,2-a]pyridin-5-yl)phenoxy)-2,5-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide as a beige solid in 42% yield (0.060 g): 1H NMR (300 MHz, DMSO-d6) δ8.76 (s, 1H), 7.79 (d, J=2.6 Hz, 1H), 7.71-7.57 (m, 5H), 7.37-7.28 (m, 3H), 7.00 (dd, J=7.0, 0.9 Hz, 1H); MS (ES+) m/z 519.8 (M+1), 521.8 (M+1).