Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[Cl-].[OH:17][NH3+:18].C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(OCC)(=O)C>[OH:17][NH:18][C:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]1)=[NH:2]
Reactant: [NH3+]O
Reactant: CC(C)(C)OC(=O)N1CCN(C#N)CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C(=N)NO)CC1
Yield: 86.4 %

Procedure:
In a nitrogen atmosphere, a suspension of 7.52 g of tert-butyl 4-cyanopiperazine-1-carboxylate (JMC, 1988, 31, 1036), 7.46 g of hydroxyammonium chloride and 19.7 g of potassium carbonate in 40 ml of ethanol was heated to reflux for 2 hours. The residue prepared by evaporation of the solvent was diluted with ethyl acetate, washed with water and then with a saturated saline solution and dried over sodium sulfate. The solvent was evaporated in vacuo to give 7.51 g of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[NH2:30][CH2:31][C:32]1([CH2:36][OH:37])[CH2:35][CH2:34]C1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:37][CH2:36][C:32]1([CH2:31][NH:30][C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])[NH:10]2)=[O:28])[CH2:35][CH2:34]1
Reactant: NCC1(CO)CCC1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCC2(CO)CC2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 10.9 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example 1d was reacted with (1-aminomethyl-cyclobutyl)-methanol (34.5 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-hydroxymethyl-cyclopropylmethyl)-amide (11.2 mg, 10.6%).
Reaction SMILES: [OH:1][CH:2]([CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[CH2:3][CH2:4][CH2:5][N:6](CCCCCCC(OCC)=O)[S:7]([CH3:10])(=[O:9])=[O:8].[OH-].[Na+].O>C(O)C>[OH:1][CH:2]([CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)[CH2:3][CH2:4][CH2:5][NH:6][S:7]([CH3:10])(=[O:9])=[O:8]
Reactant: CCOC(=O)CCCCCCN(CCCC(O)COc1ccc(F)cc1)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)NCCCC(O)COc1ccc(F)cc1
Reaction time: 20 h

Procedure:
A solution composed of ethyl 7-{N-[4-hydroxy-5-(4-fluorophenoxy)pentyl]methanesulfonamido}heptanoate (4.7 g., 0.11 mole), sodium hydroxide (1.0 g.), water (13 ml.) and ethanol (130 ml.) is kept at room temperature for 20 hours. Most of the solvent is removed in vacuo, water (150 ml.) is added and the solution extracted with ether (100 ml.). The aqueous layer is acidified (hydrochloric acid) and extracted with ethyl acetate (2 × 100 ml.). The organic layer is dried over sodium sulfate then concentrated in vacuo to obtain the subject compound. The yield is 3.7 g. (84%) of heavy oil.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[CH:24]=[CH:23][C:22]2[NH:21][CH:20]3[CH2:25][CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][CH:19]3[C:18]=2[CH:17]=1>ClCCl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[CH:24]=[CH:23][C:22]2[NH:21][CH:20]3[CH2:25][CH2:26][NH:27][CH2:28][CH:19]3[C:18]=2[CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC2Nc3ccc(-c4ccc(Cl)cc4Cl)cc3C2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(-c2ccc3c(c2)C2CNCCC2N3)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 61.7 %

Procedure:
In a 50 ml flask, tert-butyl 8-(2,4-dichlorophenyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate (215 mg) was dissolved in 5 mL dichloromethane and cooled to 0° C. with an ice bath. After the addition of 5 mL trifluoroacetic acid, the reaction stirred at room temperature for 45 minutes. The reaction was concentrated in vacuo then diluted with 5M sodium hydroxide. After three ethyl acetate extractions, the combined organics were washed with brine then dried over magnesium sulfate and concentrated to give crude material which was purified by column chromatography (0.5/5/93.5 ammonium hydroxide/methanol/dichloromethane) to give 101 mg (62%) of the title compound as an off-white solid. MS (ESI+) for C17H16N2Cl2 m/z 319.1 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1.Br[C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([CH3:19])[CH:13]=1>>[CH3:19][C:14]1[CH:13]=[C:12]([C:2]2[CH:7]=[CH:6][N:5]3[CH:8]=[CH:9][N:10]=[C:4]3[CH:3]=2)[CH:17]=[C:16]([CH3:18])[N:15]=1
Reactant: Ic1ccn2ccnc2c1
Reactant: Cc1cc(Br)cc(C)n1
Product: Cc1cc(-c2ccn3ccnc3c2)cc(C)n1

Procedure:
Prepare from 7-iodo-imidazo[1,2,a]pyridine and 4-bromo-2,6-dimethylpyridine (Acta. Chemica. Scandinavica. B42, (1988) pages 373-377) using a procedure similar to Preparation 27A. MS(ES), m/z 224 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)[CH3:2].[I:17]I>C(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH2:6][CH2:7][C:8]1[C:13]([I:17])=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)[CH3:2]
Reactant: CCOC(=O)CCCc1cccc(OC)c1
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCCc1cc(OC)ccc1I

Procedure:
4(3-methoxyphenyl)butyric acid ethyl ester is iodinated with iodine and silver trifluoroacetate in methylene chloride to give 4(6-iodo-3-methoxyphenyl)butyric acid ethyl ester. This compound is heated at 80° C. with methylthiolithium in dimethylformamide in the presence of CuO. The resulting product is hydrolyzed with NaOH to give 4(6-methylthio-3-methoxyphenyl)butyric acid, which is cyclyzed with polyphosphoric acid to obtain 5-methylthio-8-methoxy-1,2,3,4-tetrahydro-1-naphthalenone.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][CH:35]1[CH2:39][CH2:38][O:37][CH2:36]1>CN(C=O)C>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:33][CH2:34][CH:35]3[CH2:39][CH2:38][O:37][CH2:36]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: BrCCC1CCOC1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCC1CCOC1
Temperature: 50 °C
Yield: 62.7 %

Procedure:
A mixture of 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate (0.16 g, 0.450 mmol) and anhydrous potassium carbonate (0.243 g, 1.762 mmol) in DMF (2.5 ml) was heated at 50° C. for 1 hour. The mixture was cooled to room temperature and 3-(2-bromoethyl)tetrahydrofuran (0.095 g, 0.528 mmol) was added and the mixture heated at 50° C. for 18 hours. The mixture was quenched with water (2 ml) and extracted with DCM (2×5 ml). The DCM was separated through a hydrophobic frit and evaporated by blowing down under a stream of nitrogen. The sample was dissolved in 1:1 MeOH:DMSO (3×0.5 ml) and purified by mass directed autopreparation. Product containing fractions were evaporated under a stream of nitrogen in a blowdown apparatus to give the title compound as a white solid (98 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[CH2:11][CH:10]([CH:23]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][OH:26].Cl.CC([O-])=O.[Na+].O>CCO>[CH2:1]([N:8]1[CH2:13][CH:12]([CH2:14][OH:15])[CH2:11][CH:10](/[CH:23]=[N:25]\[OH:26])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(C)(C)[Si](C)(C)OCC1CC(C=O)CN(Cc2ccccc2)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCC1CC(/C=N\O)CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 136.7 %

Procedure:
To a mixture of 1-benzyl-5-((tert-butyldimethylsilyloxy)methyl)piperidine-3-carbaldehyde (3.39 g, 9.75 mmol) in EtOH (50 mL) was added an aqueous solution of NH2OH—HCl (3.75M, 3.12 mL, 11.7 mmol) followed by an aqueous solution of NaOAc (1.5M, 5.2 mL, 7.8 mmol). The reaction mixture was stirred at room temperature for 18 h. H2O (30 mL) was then added and the EtOH was partially removed in vacuo (˜40 mL). The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3. The combined aqueous fractions were extracted with ethyl acetate (3×50 mL) and the combined organic fractions were washed with brine and dried (MgSO4) and concentrated in vacuo to afford 3.31 g (94% yield) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.25-7.35 (6 H, m), 3.58 (2 H, d, J=4.5 Hz), 3.43-3.54 (2 H, m), 3.03 (2 H, d, J=4.5 Hz), 2.57-2.68 (1 H, m) 1.90-2.01 (2 H, m), 1.80-1.89 (1 H, m), 1.65-1.77 (2 H, m), 0.93-1.01 (1 H, m). LCMS (+ESI, M+H+) m/z 249.
Reaction SMILES: [S:1]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].OCC(OC[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O>>[S:1]([O:8][CH2:9][C:10]([O:12][CH2:13][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:11])([C:4]([F:6])([F:7])[F:5])(=[O:3])=[O:2]
Reactant: O=C(CO)OCc1ccccc1
Reactant: COC(=O)COS(=O)(=O)C(F)(F)F
Product: O=C(COS(=O)(=O)C(F)(F)F)OCc1ccccc1

Procedure:
Prepared in the same way as described for TfO-CH2COOMe starting with HO—CH2COOBn
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)Cl.CO>[Br:11][C:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CO
Solvent: ClCCl
Product: Clc1ncnc2[nH]cc(Br)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (E-1) (3.99 g, 26.0 mmol, 1.0 eq) in dry DCM (150 mL) under argon, N-bromosuccinimide (6.02 g, 33.8 mmol, 1.3 eq) is added and the resulting mixture is stirred at RT for 3 h. The reaction mixture is diluted with MeOH (30 mL) and then concentrated in vacuo to yield a slight brown solid. The residue is triturated with H2O (150 mL). The solid is collected by filtration and then re-crystallized in MeOH to afford the product, 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (E-2).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:33]=1[CH2:34]Br.P([O-])([O-])([O-])=O>CN(C=O)C>[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:33]=1[CH2:34][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:14]1[CH2:13][C@@H:12]([C:10]2[CH:9]=[CH:8][C:6]3[O:7][C:2]([CH3:28])([CH3:1])[O:3][CH2:4][C:5]=3[CH:11]=2)[O:16][C:15]1=[O:17]
Reactant: Clc1cccc(Cl)c1CBr
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCO)C(=O)O3)ccc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4c(Cl)cccc4Cl)C(=O)O3)ccc2O1
Reaction time: 0.17 h
Yield: 55.2 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-[6-(2-hydroxyethoxy)hexyl]-1,3-oxazolidin-2-one (200 mg) in DMF (4 ml) under nitrogen was treated with sodium hydride (26 mg, 60% in oil) and the mixture was stirred at 20° for 10 min. 2,6-Dichlorobenzyl bromide (122 mg) was added and the mixture was stirred at 20° for 3 h. Phosphate buffer solution (20 ml, pH6.5) was added and the mixture was extracted with EtOAc (30 ml). The extract was washed with water (2×20 ml), dried (NaSO4) and the solvent evaporated in vacuo to give a residue. The residue was purified by chromatography on flash silica gel 20 mm diameter column. Elution with EtOAc-cyclohexane (1:1) gave the title compound (155 mg). LCMS RT=3.97 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.[CH3:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=1[NH2:21].Cl>O.C(O)C>[ClH:1].[CH3:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: Cc1ccc(C)c(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccncc2)n1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc(C)c(Nc2cc(C(F)(F)F)nc(-c3ccncc3)n2)c1
Temperature: 25 °C
Yield: 38.1 %

Procedure:
A mixture of 4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol), 2,5-dimethylaniline (36 μl, 0.290 mmol) and 2N HCl (150 μl) in water:ethanol (2:1, 10 ml) was refluxed for 24 h. The mixture was cooled to room temperature. The resulting precipitate was filtered, washed with water and aqueous ethanol to give a white solid (28 mg, 42%). 1H NMR (CDCl3): 8.77 (dd, J=1.5, 4.5 Hz, 2H), 8.27 (dd, J=1.5, 4.5 Hz, 2H), 7.24 (d, J=7.8 Hz, 1H), 7.18 (s, 1H), 7.11 (dd, J=1.8, 7.8 Hz, 1H), 6.99 (s, 1H), 6.62 (s, 1H), 2.38 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[O:27][C@H:28]([CH3:33])[C:29]([O:31]C)=O)[N:20]=[CH:19][N:18]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:33][C@@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[C:29](=[O:31])[N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12
Reactant: C1CCNC1
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12)C(=O)N1CCCC1
Yield: 59.3 %

Procedure:
Using the same procedure as in Example 26, methyl (2R)-2-[(4-{[1-(1,3-thiazol-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (250 mg, 0.54 mmol) was reacted with pyrrolidine (0.45 ml, 5.4 mmol) to give the title compound (160 mg, 59%) as a solid, except that the mixture was heated at 55° C. for 20 hours and purified by chromatography on silica gel (eluant: 1-5% methanol in DCM); NMR Spectrum 1.61 (d, 3H), 1.82 (m, 2H), 1.94 (m, 2H), 3.47-3.30 (m, 3H), 3.77 (m, 1H), 5.63 (q, 1H), 6.04 (s, 2H), 7.27 (d, 1H), 7.35 (d, 1H), 7.65 (d, 1H), 7.74 (m, 3H), 7.88 (dd, 1H), 8.20 (s, 1H), 8.52 (s, 1H), 8.56 (s, 1H), 11.09 (br s, 1H); Mass spectrum 500.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].I[CH2:17][CH2:18][C:19]#[CH:20]>CN(C=O)C.CCOCC>[CH2:20]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:19][C:18]#[CH:17]
Reactant: C#CCCI
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C#CCCC(C(=O)OCC)C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
A suspension of NaH (60%, 8.50 g, 213 mmol) in 200 mL of DMF was added tert-butyl ethyl malonate (36.3 g, 193 mmol) drop-wise at 25° C. The mixture was stirred for 1 hour and 4-iodobut-1-yne (38.2 g, 212.2 g) was added drop-wise. The resulting suspension was stirred overnight and diluted with 1 L of ether, and washed with water (3×200 mL), brine, dried over anhydrous Na2SO4 and concentrated to afford tert-butyl ethyl but-3-yn-1-ylpropanedioate, which was used directly in the next step.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.[NH3:12]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:12]
Reactant: N
Reactant: Oc1ccc2ccccc2c1
Product: Nc1ccc2ccccc2c1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
In a sealed reactor, 4.32 g (30 mmol, 1 eq) of 2-naphthol, 2.85 g (30 mmol, 1 eq) of (NH4)2SO3 and 50 mL of aqueous ammonia were mixed. The mixture was heated to 150° C., the pressure was raised to 10 bars and the mixture was stirred overnight. The mixture was then cooled down to room temperature.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][OH:11])=[N:8][CH:9]=1.I[CH3:13]>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][CH3:13])=[N:8][CH:9]=1
Reactant: OCc1ccc(Cl)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1ccc(Cl)cn1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
Sodium hydride (0.61 g, 60% in mineral oil, 15.32 mmol) was added to a solution of (5-chloropyridin-2-yl)methanol (2 g, 13.93 mmol) in THF (50 mL) and stirred at room temperature until no further gas evolution was observed. Iodomethane (0.95 mL, 15.32 mmol) was injected slowly and the reaction was allowed to stir at room temperature for 18 hours. The reaction was concentrated in vacuo, acidified with 2N HCl in water (25 mL) and extracted with EtOAc (2×20 mL). The aqueous layer was collected, basified with potassium hydroxide and extracted with DCM (3×20 mL). The organic layers were combined, washed with water, dried over sodium sulfate and concentrated in vacuo to afford the title compound (2 g, 91%).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[C:6]([NH:9][CH:10]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1)[C:11]([NH:13][CH2:14][C:15](=O)[CH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][CH3:19])=O)(=[O:8])[CH3:7]>C1(C)C(C)=CC=CC=1>[Br:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][CH:10]([NH:9][C:6](=[O:8])[CH3:7])[C:11]2[NH:13][CH:14]=[C:15]([CH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][CH3:19])[N:5]=2)=[CH:25][CH:26]=1
Reactant: CCC(C)(C)CC(=O)CNC(=O)C(Cc1ccc(Br)cc1)NC(C)=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Product: CCC(C)(C)Cc1c[nH]c(C(Cc2ccc(Br)cc2)NC(C)=O)n1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
Ammonium acetate (1.17 g, 79 mmol) was added to an ambient temperature solution of 2-(acetylamino)-3-(4-bromophenyl)-N-(4,4-dimethyl-2-oxohexyl)propanamide (650 mg, 1.58 mmol) in xylene (10 mL). After stirring at 150° C. for 1 h, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate and methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% acetone/methylene chloride afforded N-{2-(4-bromophenyl)-1-[4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]ethyl}acetamide.
Reaction SMILES: OO.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C([O-])([O-])=[O:17].[K+].[K+].O>CS(C)=O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:14]([NH2:15])=[O:17])[CH2:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: N#CC1(c2ccc(Br)cc2)CCC1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)C1(c2ccc(Br)cc2)CCC1
Temperature: 27 °C

Procedure:
H2O2 (30% 11.3 mL, 118 mmol) was added over 3 h to a stirred mixture of nitrile 1-2c (13.88 g, ˜58.9 mmol) and K2CO3 (1.62 g, 11.8 mol) in 59 mL of DMSO at 40-87° C., cooling with a water bath. The resulting mixture was cooled to 27° C. and water (100 mL) was added over 30 min. Crystalline product 1-3c formed. More water (100 mL) was added over 1 h. The resulting slurry was aged at RT for 16 h before filtration. The cake was rinsed with 100 mL of water and then with 100 mL of heptane. After drying in a vacuum oven at 50° C., product 1-3c was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:17][CH:16]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH2:14][CH2:13]1>C1COCC1.[Pd]>[F:25][C:20]1[CH:19]=[C:18]([CH:15]2[CH2:14][CH2:13][N:12]([C:3]3[C:4]([F:11])=[CH:5][C:6]([NH2:8])=[CH:7][C:2]=3[F:1])[CH2:17][CH2:16]2)[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: O=[N+]([O-])c1cc(F)c(N2CC=C(c3ccc(F)c(F)c3)CC2)c(F)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cc(F)c(N2CCC(c3ccc(F)c(F)c3)CC2)c(F)c1
Reaction time: 24 h
Yield: 100.6 %

Procedure:
To a solution of 1-(2,6-difluoro-4-nitrophenyl)-4-(3,4-difluorophenyl)-1,2,3,6-tetrahydropyridine (0.67 g, 1.90 mmol) in THF (20 mL) was added 10% Pd on carbon (50 mg). The reaction flask was flushed with N2 gas, and the resulting mixture was vigorously stirred under 1 atm H2 gas for 24 hours. The mixture was filtered through diatomaceous earth and concentrated in vacuo to give the title compound as a solid (0.62 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([CH:8]=[C:9]2[C:13]([CH3:15])([CH3:14])[O:12][C:11]([CH3:17])([CH3:16])[C:10]2=[O:18])[CH:7]=1.[OH:20]O.[OH-].[Li+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([CH:8]2[C:9]3([C:10](=[O:18])[C:11]([CH3:17])([CH3:16])[O:12][C:13]3([CH3:14])[CH3:15])[O:20]2)[CH:7]=1
Reactant: CC1(C)OC(C)(C)C(=Cc2cc(Br)ccc2F)C1=O
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)OC(C)(C)C2(OC2c2cc(Br)ccc2F)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
To a solution of 4-[1-(5-bromo-2-fluorophenyl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (9.30 g, 29.00 mmol) in methanol (280 ml) at 35° C. is added 50% aqueous hydrogen peroxide (3.36 ml, 50.40 mmol), followed immediately by 2M aqueous lithium hydroxide (3.68 ml, 7.36 mmol). Stirring is continued at this temperature for 1 hour, then the reaction mixture is allowed to cool to room temperature, then quenched with saturated sodium metabisulfite (100 ml) and extracted with ether (×3). Organics are combined, dried over magnesium sulfate, then filtered and the filtrate concentrated in vacuo to afford 2-(5-bromo-2-fluorophenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one (6.60 g, 68%) as a yellow gum.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:12][S:13]([C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[C:18]([F:24])[CH:17]=2)(=[O:15])=[O:14])[N:3]=1.[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH:27]([NH2:34])[CH2:26]1>O1CCOCC1>[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH:27]([NH:34][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[NH:12][S:13]([C:16]3[CH:21]=[C:20]([F:22])[C:19]([F:23])=[C:18]([F:24])[CH:17]=3)(=[O:15])=[O:14])[N:3]=2)[CH2:26]1
Reactant: O=S(=O)(Nc1cccc2nc(Cl)ccc12)c1cc(F)c(F)c(F)c1
Reactant: NC1COc2ccccc21
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cccc2nc(NC3COc4ccccc43)ccc12)c1cc(F)c(F)c(F)c1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
N-(2-Chloro-quinolin-5-yl)-3,4,5-trifluoro-benzenesulfonamide (150 mg, 0.402 mmol) was dissolved in 5 mL dioxane. Argon was bubbled through the solution for 2 minutes to remove oxygen. rac-2,3-Dihydro-benzofuran-3-ylamine (CAS 109926-35-4, 82 mg, 0.607 mmol), sodium tert.-butylate (97 mg, 1.01 mmol), 1,1′-bis(diphenylphosphin)ferrocen (33 mg, 0.06 mmol) and 1,1′-bis(diphenylphosphin)ferrocen-palladium(II) chloride (16 mg, 0.02 mmol) were added. The reaction mixture was stirred in a sealed tube at 120° C. for 6 hours. The solvent was evaporated and the residue purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0->70:30 gradient). The title compound was obtained as a yellow foam (100 mg, 53%), MS: m/e 472.4 (M+H+).