Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][C@@:19]([CH3:34])([S:30]([CH3:33])(=[O:32])=[O:31])[C:20]([NH:22][O:23]C4CCCCO4)=[O:21])[C:13](=[O:35])[CH:12]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.Cl.O>ClCCl.O1CCOCC1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][C@@:19]([CH3:34])([S:30]([CH3:33])(=[O:31])=[O:32])[C:20]([NH:22][OH:23])=[O:21])[C:13](=[O:35])[CH:12]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: C[C@@](CCn1ccc(-c2ccc3c(c2)OCCO3)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@](CCn1ccc(-c2ccc3c(c2)OCCO3)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 8 h

Procedure:
(2R)-4-[4-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (581 mg, 1 mmol) was dissolved in 3 mL of dichloromethane. To this solution was added 1 mL of 4M HCl in dioxane 1 mL of water. The reaction was monitored for completion by LCMS. After standing overnight, a solid precipitated. The solid was collected by filtration and dried in vacuo yielding 25 mg (68%) of light yellow solid. LCMS m/z 423.5 (M+1) 1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (s, 3H) 2.09-2.22 (m, 1H) 2.36-2.46 (m, 1H) 3.10 (s, 3H) 3.65-3.79 (m, 1H) 4.03-4.15 (m, 1H) 4.28 (s, 4H) 6.59-6.66 (m, 2H) 6.94 (d, J=8.20 Hz, 1H) 7.19-7.26 (m, 2H) 7.67-7.73 (m, 1H)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H](C(O)=O)CCC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([C:24]([OH:26])=O)[CH2:21][CH2:22][CH3:23].CC1(C)[C@@H](O)C(C)(C)[C@@H]1N>>[C:9]([NH:11][C:24](=[O:26])[C@H:20]([CH2:21][CH2:22][CH3:23])[NH2:19])([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: CCC[C@@H](N)C(=O)O
Reactant: CCC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC1(C)[C@H](N)C(C)(C)[C@H]1O
Product: CCC[C@H](N)C(=O)NC(=O)OCc1ccccc1

Procedure:
N-Benzyloxycarbonyl-D-norvaline (0.1 mole), prepared from commercial D-norvaline by the procedure of Example 19, is reacted with cis/trans 2,2,4,4-tetramethyl-3-hydroxycyclobutylamine by the method of Example 20, Part A, to provide the N-Cbz-norvaline amide.
Reaction SMILES: [Cl:1]C(N(C)C)=C(C)C.[CH2:9]([O:11][C:12]([C:14]1[CH:18]=[CH:17][N:16]([CH:19]([CH3:21])[CH3:20])[C:15]=1[CH:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)O)=[O:13])[CH3:10]>C(Cl)Cl>[CH2:9]([O:11][C:12]([C:14]1[CH:18]=[CH:17][N:16]([CH:19]([CH3:21])[CH3:20])[C:15]=1[CH:22]([Cl:1])[C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)=[O:13])[CH3:10]
Reactant: CCOC(=O)c1ccn(C(C)C)c1C(O)c1ccc(C#N)cc1
Reactant: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Product: CCOC(=O)c1ccn(C(C)C)c1C(Cl)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1-Chloro-N,N,2-trimethylpropenylamine [26189-59-3] (4.80 mmol) was added to a solution of 2-[(4-cyano-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester (Step H4) (3.20 mmol) in CH2Cl2 (15 mL) and the mixture was stirred at rt for 2.5 h. CH2Cl2 was added and the reaction mixture was concentrated to dryness (2×) to afford the title compound as a yellow-orange oil. tR: 5.71 min (sample in MeOH) (HPLC 4); ESI-MS: tR=1.26 min (LC-MS 1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8](=[CH:11][C:12]([OH:14])=O)[CH2:7][CH2:6]1.S(Cl)([Cl:17])=O>>[ClH:17].[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8](=[CH:11][C:12]([Cl:17])=[O:14])[CH2:7][CH2:6]1
Reactant: COCCN1CCC(=CC(=O)O)CC1
Reactant: O=S(Cl)Cl
Product: COCCN1CCC(=CC(=O)Cl)CC1
Product: Cl

Procedure:
2.4 g of 2-(1-(2-methoxyethyl)piperidin-4-ylidene)acetic acid was dissolved in 20 mL of thionyl chloride, refluxed for 2 hours, evaporated in vacuo to remove thionyl chloride and give a solid product.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:5]=[C:4]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>C(#N)C>[C:32]([O:31][C:29](=[O:30])[CH2:28][O:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:5]=[C:4]([O:13][S:14]([C:17]([F:20])([F:18])[F:19])(=[O:16])=[O:15])[CH:3]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: O=C1CCCc2c(O)cc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)COc1cc(OS(=O)(=O)C(F)(F)F)cc2c1CCCC2=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 59.1 %

Procedure:
To a suspension of trifluoro-methanesulfonic acid 4-hydroxy-8-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester (XXVIII, 177 mg, 0.57 mmol) and cesium carbonate (372 mg, 1.14 mmol) in acetonitrile (5 mL) was added tert-butyl bromoacetate (167 mg, 0.86 mmol) at room temperature under nitrogen. The resulting suspension was stirred for 15 h at room temperature, and then concentrated under vacuum. The residue was diluted with water (10 mL) and ethyl acetate (20 mL). The aqueous layer was separated and extracted with ethyl acetate (20 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by ISCO (40 g) column chromatography, (gradient elution with 5-25% ethyl acetate in hexanes) to provide (5-oxo-3-trifluoromethanesulfonyloxy-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (143 mg, 59%) as a white solid: ES(+)-HRMS m/e calcd. for C17H19F3O7S (M+H)+425.0877, obsd. 425.0876.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([CH3:10])=[C:7]([C:11](Cl)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:14].[Li+]>C1COCC1.O>[C:1]([C:5]1[O:9][C:8]([CH3:10])=[C:7]([C:11]([OH:12])=[O:14])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1oc(C(C)(C)C)cc1C(=O)Cl
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(C(C)(C)C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a solution of 5-tert-butyl-2-methylfuran-3-carbonyl chloride (0.341 g, 1.699 mmol) in THF (2 ml) added lithium hydroxide (0.107 g, 2.55 mmol) in water (1 mL) and the mixture was stirred for 2 h at RT. Solvent was removed in vacuo and the residue was acidified with 2N HCl to afford solid which was filtered and air dried to afford 5-tert-butyl-2-methylfuran-3-carboxylic acid (0.29 g, 94% yield) as a white solid. MS (ESI) m/z: 183.1 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20](O)=[O:21])=[O:13])=[C:4]1[CH3:23])[CH3:2].C[C:25]1[C:26]([C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)C=2)=[CH:27][N:28]2[C:33]=1[CH:32]=[CH:31][CH:30]=[CH:29]2.C(O[C:48](=O)[CH3:49])(=O)C.N>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2([C:33]3[N:28]4[C:27]([CH:32]=[CH:31][CH:30]=[CH:29]4)=[C:26]([C:34]4[CH:43]=[CH:42][C:41]5[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=5)[C:48]=4[CH3:49])[CH:25]=3)[C:14]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:20](=[O:21])[O:13]2)=[C:4]1[CH3:23])[CH3:2]
Reactant: Cc1c(-c2ccc3ccccc3c2)cn2ccccc12
Reactant: CC(=O)OC(C)=O
Reactant: CCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Agent: N
Solvent: Cc1ccccc1
Product: CCn1c(C)c(C2(c3cc(-c4ccc5ccccc5c4C)c4ccccn34)OC(=O)c3ccccc32)c2ccccc21

Procedure:
A mixture of 3.0 grams of (1-ethyl-2-methylindol-3-yl) (2-carboxyphenyl)ketone, 2.5 grams of 1-methyl-2-(2-naphthyl) indolizine and 10 ml. of acetic anhydride was heated at 39° C. for about two hours. The resulting solution was cooled and added to a mixture of ice, toluene and ammonia. The toluene layer was separated, dried, treated with charcoal and filtered. Petroleum ether was added and after fractional precipitation a crystalline product was obtained and recrystallized from a toluene-heptane mixture to a constant melting point of 191°-193° C. A chloroform solution of this final product gave a blue color when applied to a record sheet material coated with a zinc-modified phenolic resin.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH2:12]([O:19][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N+:9]([O-:11])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1c(F)cccc1F
Reactant: OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(F)cccc1OCc1ccccc1
Temperature: 60 °C

Procedure:
A mixture of 1,3-difluoro-2-nitrobenzene (1.0 g, 6.29 mmol), benzyl alcohol (0.81 mL, 7.86 mmol) and potassium carbonate (1.74 g, 12.6 mmol) in DMF (5 mL) is heated at 60° C. for 18 h. The reaction mixture is poured into EtOAc, and washed with water and brine. The organic phase is concentrated and purified to give the title compound: 1H NMR (CDCl3) 7.36 (m, 6H), 6.83 (m, 2H), 5.20 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14](OC)=[O:15])[CH:13]=[C:8]2[C:7]([CH2:18]SC2C=CC=CC=2)=[CH:6]1.[CH3:31][C:32]1([CH3:39])[O:36][C@H:35]([CH2:37][OH:38])[CH2:34][O:33]1.[CH3:40]CN(C(C)C)C(C)C.O>CN(C=O)C>[F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14](=[O:15])[CH3:40])[CH:13]=[C:8]2[C:7]([CH2:18][O:38][CH2:37][C@@H:35]2[CH2:34][O:33][C:32]([CH3:39])([CH3:31])[O:36]2)=[CH:6]1
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: COC(=O)c1cc2c(CSc3ccccc3)cn(Cc3ccc(F)cc3F)c2cn1
Reactant: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cc2c(COC[C@@H]3COC(C)(C)O3)cn(Cc3ccc(F)cc3F)c2cn1
Temperature: 40 °C
Reaction time: 24 h
Yield: 88.1 %

Procedure:
To a solution of methyl 3-(chloromethyl)-1-(2,4-difluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (3 mL, 0.197M in CH2Cl2, 0.591 mmol) [prepared as described in step 2 of example 40] in anhydrous DMF (5 mL) was added (R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol (2.955 mmol, 0.37 mL, 5.0 eq.) followed by i-Pr2NEt (0.407 g, 3.14 mmol, 0.55 mL, 4 eq.). The mixture, under nitrogen, was placed in an oil bath and the bath was warmed to 40° C. After stirring for 24 hours (40° C.) the reaction was judged to be complete by HPLC-MS analysis. Water (0.5 mL) was added and after 45 minutes the volatiles were removed in vacuo (ca. 2 torr) to give a golden yellow oil. The crude material was purified by chromatography on a column of silica gel (40 mm OD, 100 g, 230-400 mesh, packed with CH2Cl2, eluted with CH2Cl2-EtOAc 70:30 v/v, 1.0 L, 1.0 L, 25 mL fractions) using the flash technique. Fractions were combined to afford 0.224 g (85%) of 1-[1-(2,4-difluorobenzyl)-3-({[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl]ethanone as a colorless oil. TLC (Merck, CH2Cl2:EtOAc 50:50, UV-+, cerium molybdate-+): Rf=0.26. LC-MS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95H2O (+0.1% HOAc):CH3CN—5 minutes, APCI, +mode): RT—3.456 min, m/e=447.20 (M+H+, base).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:14][C:13]3[C:12]([Cl:15])=[N:11][CH:10]=[N:9][C:8]=3[CH:7]=2)=[CH:2]1.O.[NH2:17][NH2:18]>C(O)C>[ClH:15].[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:14][C:13]3[C:12]([NH:17][NH2:18])=[N:11][CH:10]=[N:9][C:8]=3[CH:7]=2)=[CH:2]1
Reactant: NN
Reactant: Clc1ncnc2cc(-c3ccsc3)sc12
Solvent: O
Solvent: CCO
Product: Cl
Product: NNc1ncnc2cc(-c3ccsc3)sc12
Temperature: 25 °C
Yield: 64.8 %

Procedure:
A suspension of 6-(3-thienyl)-4-chlorothieno[3,2-d]pyrimidine (220, 65 mg, 0.26 mmol) and hydrazine monohydrate (0.1 mL, 2.1 mmol) in ethanol (1 mL) was heated at reflux for 1 hour. After cooling to room temperature, the solid product was collected by vacuum filtration to give (6-(3-thienyl)thieno[3,2-d]pyrimidin-4-yl) hydrazine hydrochloride (48 mg, 66% yield) as a white solid.
Reaction SMILES: C1(C)C(C)=CC=CC=1.[CH2:9]([O:11][C:12](=[O:24])[C:13]([N:21]=[N+]=[N-])=[CH:14][C:15]1[N:16]=[C:17]([Br:20])[S:18][CH:19]=1)[CH3:10]>C(Cl)Cl>[CH2:9]([O:11][C:12]([C:13]1[CH2:14][C:15]2[N:16]=[C:17]([Br:20])[S:18][C:19]=2[N:21]=1)=[O:24])[CH3:10]
Reactant: CCOC(=O)C(=Cc1csc(Br)n1)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Solvent: ClCCl
Product: CCOC(=O)C1=Nc2sc(Br)nc2C1
Temperature: 25 °C
Yield: 25.4 %

Procedure:
Add dropwise to hot xylene (130° C., 4 ml) a solution of 2-azido-3-(2-bromo-4-thiazolyl)propenoic acid ethyl ester (60 mg, 0.2 mmol) in DCM (1 ml). Heat the mixture for one hour, then cool to room temperature, deposit the mixture on a pad of silica gel and elute with heptane:DCM (50%-100%) to provide the title compound (14 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=[O:4].[H-].[Na+].[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1>CN(C=O)C>[ClH:17].[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH:8]2[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33][N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1)=[O:4]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: COC(=O)c1ccc2c(c1)CC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)C(c1ncnc3cc(OCCCN4CCOCC4)c(OC)cc13)C(=O)N2
Product: Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 34.7 %

Procedure:
A solution of 5-methoxycarbonyloxindole (169 mg, 0.88 mmol), (Eur. J. Med. Chem. 1983, 18, 107-111), in DMF (2 ml) was added dropwise under nitrogen to sodium hydride (35 mg, 0.88 mmol, prewashed with hexane) in DMF (1.5 ml). The mixture was stirred for 20 minutes at ambient temperature and 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (100 mg, 0.3 mmol), (prepared as described for the starting material in Example 5), was added as a solid. The mixture was heated at 60° C. for 45 minutes, allowed to cool and partitioned between ethyl acetate and water. The aqueous layer was adjusted to pH8. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (92/8). The solid was dissolved in methylene chloride/methanol and 3M ethereal hydrogen chloride (1 ml) was added. The volatiles were removed by evaporation, the solid residue suspended in ether, collected by filtration, washed with ether and dried under vacuum to give 4-(5-methoxycarbonyloxindol-3-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline hydrochloride (55 mg. 32%).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:16])=[CH:11][CH:10]=2)=[O:7])[CH2:3][CH2:2]1.[F:23][C:24]([F:41])([F:40])[C:25]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)([OH:30])[C:26]([F:29])([F:28])[F:27].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>[CH:1]1([CH2:4][NH:5][C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([C:35](=[O:36])[C:34]4[CH:33]=[CH:32][C:31]([C:25]([OH:30])([C:24]([F:23])([F:40])[F:41])[C:26]([F:27])([F:28])[F:29])=[CH:39][CH:38]=4)[CH2:19][CH2:18]3)=[O:16])=[CH:13][CH:14]=2)=[O:7])[CH2:2][CH2:3]1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)N2CCNCC2)cc1
Reactant: O=C(O)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC1CC1)Nc1ccc(C(=O)N2CCN(C(=O)c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Reaction time: 2 h
Yield: 19 %

Procedure:
To a solution of 1-(cyclopropylmethyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea (1.654 mmol, 500 mg), 4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzoic acid (1.654 mmol, 476 mg) and triethylamine (4.96 mmol, 0.691 mL, 502 mg) in dichloromethane (50 mL) was added 1-propanephosphonic acid cyclic anhydride (2.480 mmol, 0.738 mL, 789 mg; 50% solution in ethyl acetate). The reaction mixture was stirred for 2 hours then was diluted with ethyl acetate and sodium carbonate (aqueous). The organic layer was separated, dried (magnesium carbonate) and concentrated under reduced pressure. The residue was chromatographed on silica eluting with a gradient of dichloromethane to ethyl acetate to give the title compound (180 mg). MS (ESI) m/z 571.0 [M−H]−
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:13]([C:18](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:19])([O:15][CH2:16][CH3:17])=[O:14].C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1.CO.O>[CH2:16]([O:15][C:13](=[O:14])[C:18]([CH3:19])=[CH:11][CH:8]1[CH2:7][CH2:6][CH:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:9]1)[CH3:17]
Reactant: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)C1CCC(C=O)CC1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: CCOC(=O)C(C)=CC1CCC(C(C)(C)C)CC1

Procedure:
A mixture of 20.2 g of 4-tert.butyl-cyclohexane-1-carboxaldehyde, 52 g of (α-carbethoxy-ethylidene)-triphenyl-phosphorane and 3.6 g of benzoic acid in 120 ml of toluene is heated at reflux for 16 hours under nitrogen gasification and the toluene is evaported. The oily-crystalline residue is dissolved in 600 ml of methanol/water (4:1) and exhaustively extracted with hexane. The combined hexane extracts are washed with sodium bicarbonate solution and water, dried over sodium sulphate and evaporated. By distillation there is obtained pure 3-(4-tert.butyl-cyclohexyl)-2-methyl-acrylic acid ethyl ester of boiling point 99° C./0.03 Torr.
Reaction SMILES: [CH:1]1[C:15]2=[C:16]3[C:8]([C:9]4[C:14]2=[CH:13][C:12]([C:17](Cl)=[O:18])=[CH:11][CH:10]=4)=[CH:7][CH:6]=[CH:5][C:4]3=[C:3]([C:20](Cl)=[O:21])[CH:2]=1.[CH2:23]([N:26]([CH2:31][CH:32]=[CH2:33])[CH2:27][CH2:28][CH2:29][OH:30])[CH:24]=[CH2:25].[C:34]1([NH2:45])[C:39](F)=[C:38](F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)(Cl)Cl>[CH2:31]([N:26]([CH2:23][CH:24]=[CH2:25])[CH2:27][CH2:28][CH2:29][O:30][C:20]([C:3]1[CH:2]=[CH:1][C:15]2[C:14]3[C:9]([C:8]4[C:16]=2[C:4]=1[CH:5]=[CH:6][CH:7]=4)=[CH:10][CH:11]=[C:12]([C:17]([O:18][CH2:17][CH2:12][CH2:11][N:45]([CH2:34][CH:39]=[CH2:38])[CH2:15][CH:1]=[CH2:2])=[O:18])[CH:13]=3)=[O:21])[CH:32]=[CH2:33]
Reactant: O=C(Cl)c1ccc2c(c1)-c1ccc(C(=O)Cl)c3cccc-2c13
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: C=CCN(CC=C)CCCO
Agent: Cl
Solvent: ClC(Cl)Cl
Product: C=CCN(CC=C)CCCOC(=O)c1ccc2c(c1)-c1ccc(C(=O)OCCCN(CC=C)CC=C)c3cccc-2c13

Procedure:
To 500 ml of chloroform is added 9.8 g (0.03 mole) of fluoranthene-3,9-dicarbonyl chloride and 9.3 g (0.06 mole) of 3-diallylaminopropanol and the solution is refluxed for 16 hours. The dihydrochloride salt is converted to the free base by treating the chloroform solution with saturated aqueous sodium bicarbonate, separation of the organic and water layer, drying the organic layer over anhydrous magnesium sulfate and finally removing the solvent in vacuo. The residue is dissolved in butanone and acidified with ethereal hydrogen chloride. The salt is crystallized twice from methanol-butanone or water-methanol-butanone, M.P. 229°-231°C, and converted back to the free base to give a yellow viscous oil of bis(3-diallylaminopropyl)fluoranthene-3,9-dicarboxylate, λmax 0.1 NHCl 229 m μ, E1 cm 1% 605.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[CH:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.O1CCCC1.ClCCl>[CH3:36][S:33]([C:30]1[CH:29]=[CH:28][C:27]([C:19]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)=[CH:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[CH:32][CH:31]=1)(=[O:34])=[O:35]
Reactant: CS(=O)(=O)c1ccc(C(=CC2CCCCO2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(=CC2CCCCO2)c2cc3cccnc3[nH]2)cc1
Yield: 8.3 %

Procedure:
A mixture of 1-benzenesulfonyl-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-2-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (0.36 g, 6.9 mmol) in ethanol (3 mL), tetrahydrofuran (3 mL) and an aqueous sodium hydroxide solution (10%, 1 mL) was heated at 50° C. for 2 h. The mixture was diluted with dichloromethane (50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-2-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (220 mg, 84%): LC/MS m/e calcd for C21H22N2O3S [M+H]+ 383.49, observed 383.1.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:4][C@H:3]1[C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[NH:7][N:6]=1.[F:15][C:16]1[C:24]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])=[CH:23][CH:22]=[C:21]([F:32])[C:17]=1[C:18](O)=[O:19].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:15][C:16]1[C:24]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:27])=[O:28])=[CH:23][CH:22]=[C:21]([F:32])[C:17]=1[C:18]([NH:14][C:11]1[CH:12]=[C:13]2[C:5]([C@@H:3]3[CH2:4][C@@H:2]3[CH3:1])=[N:6][NH:7][C:8]2=[N:9][CH:10]=1)=[O:19]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Reactant: C[C@H]1C[C@H]1c1n[nH]c2ncc(N)cc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc([C@@H]4C[C@@H]4C)c3c2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
3-(cis-2-Methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-5-amine (0.0399 g, 0.212 mmol), 2,6-difluoro-3-(propylsulfonamido)benzoic acid (0.0651 g, 0.233 mmol), EDCI (0.0488 g, 0.254 mmol), and HOBt (0.0344 g, 0.254 mmol) were dissolved in DMF and stirred overnight at room temperature. The solution was partitioned between water and EtOAc. The organic layer was washed with water (3×), brine, dried over Na2SO4 and concentrated to an oil, which was purified by column chromatography (1:2 hexanes/EtOAc) to give 2,6-difluoro-N-(3-((1R,2S)-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (66 mg, 69%) as a solid. 1H NMR (400 MHz, d6-DMSO) 13.16 (s, 1H), 11.07 (s, 1H), 9.81 (s, 1H), 8.63 (s, 1H), 8.55 (s, 1H), 7.53-7.59 (m, 1H), 7.26-7.31 (m, 1H), 3.11-3.15 (m, 2H), 1.99-2.03 (m, 1H), 1.75-1.80 (m, 2H), 1.32-1.34 (m, 1H), 1.14-1.22 (m, 3H) 0.99-1.02 (m, 3H), 0.78-0.83 (m, 3H); m/z (APCI-pos) M+1=450.1.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[CH2:10]([O:12][C:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=[O:14])[CH3:11].C(OC(C1CCN(C2C=CC(C(=O)NC3C=CC=C(C(C)(C)C)C=3)=CC=2)CC1)=O)C>CCOCC>[CH2:10]([O:12][C:13]([CH:15]1[CH2:16][CH2:17][N:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27](=[O:28])[NH:5][C:4]3[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([I:1])[CH:3]=3)=[CH:25][CH:26]=2)[CH2:19][CH2:20]1)=[O:14])[CH3:11]
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: Cc1ccc(N)cc1I
Agent: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3cccc(C(C)(C)C)c3)cc2)CC1
Solvent: CCOCC
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(I)c3)cc2)CC1

Procedure:
1-[4-(3-Iodo-4-methyl-phenylcarbamoyl)-phenyl]-piperidine-4-carboxylic acid ethyl ester was prepared from 3-iodo-4-methyl aniline and 1-(4-carboxy-phenyl)-piperidine-4-carboxylic acid ethyl ester following a procedure similar to the one described in the synthesis of 1-[4-(3-tert-Butyl-phenylcarbamoyl)-phenyl]-piperidine-4-carboxylic acid ethyl ester above. The product was isolated after a silica gel column with a 20-50% Et2O in hexanes gradient followed by a 50% EtOAc in hexanes elution. HRMS m/z calcd for C22H25N2O3I [M+H]+: 493.0983. Found: 493.0982.