Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8]2([S:14][CH2:13][CH2:12][CH2:11][S:10]2)[CH2:7][N:6]1[C:15](=[O:29])[CH:16]([NH:21]C(OC(C)(C)C)=O)[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:4].Cl.O1CCOCC1>O1CCOCC1>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8]2([S:10][CH2:11][CH2:12][CH2:13][S:14]2)[CH2:7][N:6]1[C:15](=[O:29])[CH:16]([NH2:21])[C:17]([CH3:18])([CH3:19])[CH3:20])=[O:4]
Reactant: COC(=O)C1CC2(CN1C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)SCCCS2
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C1CC2(CN1C(=O)C(N)C(C)(C)C)SCCCS2
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.3 %

Procedure:
Boc protected amine 28 (243 mg) in dioxane (1 mL) was treated with a 4.0N HCl/dioxane solution (2 mL) and stirred for 2 hours at room temperature. The mixture was concentrated in vacuo, slurried in CH2Cl2 and evaporated in vacuo to give 208 mg (100%) of desired 2-(2-amino-3,3-dimethyl-butyryl)-6,10-dithia-2-aza-spiro[4.5]decane-3-carboxylic acid methyl ester 29 as a white solid and as the HCl salt. Mass Spec. MH+=347.1.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O-:11])=[O:10].[Na+].[Cl:15][C:16]1[N:21]=[C:20]([CH2:22]I)[CH:19]=[C:18]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]2[CH3:30])[N:17]=1>C(#N)C>[Cl:15][C:16]1[N:17]=[C:18]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]2[CH3:30])[CH:19]=[C:20]([CH2:22][S:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:1])([F:12])[F:13])(=[O:11])=[O:10])[N:21]=1
Reactant: O=S([O-])c1ccccc1C(F)(F)F
Reactant: C[C@H]1COCCN1c1cc(CI)nc(Cl)n1
Agent: [Na+]
Solvent: CC#N
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccccc2C(F)(F)F)nc(Cl)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 59.2 %

Procedure:
Sodium 2-(trifluoromethyl)benzenesulfinate (10.24 g, 44 mmol) was added to 2-chloro-4-(iodomethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine (13 g, 36.77 mmol), in acetonitrile (500 mL) at RT under nitrogen. The resulting mixture was stirred at 80° C. for 3 hours. Additional sodium 2-(trifluoromethyl)benzenesulfinate (10.2 g, 44 mmol) was added and reaction heated at 80° C. for 1 hour. The reaction mixture allowed to cool and concentrated in vacuo. The material was dissolved in ethyl acetate (500 mL), and washed with water (200 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in isohexane, to give the desired material as an orange/cream solid (9.48 g).
Reaction SMILES: [CH3:1][C:2]([CH:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]=[CH:6][CH:5]1[CH3:12])=[O:3].[O-]CC.[Na+].C1CCCCCCCCCCC1.[CH3:29][C:30]([C@@H:32]1[C:37]([CH3:39])([CH3:38])[CH2:36][CH:35]=[CH:34][C@H:33]1[CH3:40])=[O:31]>CS(C)=O>[CH3:1][C:2]([CH:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH2:7][CH:6]=[C:5]1[CH3:12])=[O:3].[CH3:29][C:30]([C:32]1[C:37]([CH3:39])([CH3:38])[CH2:36][CH2:35][CH2:34][C:33]=1[CH3:40])=[O:31]
Reactant: CC(=O)C1C(C)C=CCC1(C)C
Reactant: CC(=O)[C@H]1[C@H](C)C=CCC1(C)C
Agent: C1CCCCCCCCCCC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)C1=C(C)CCCC1(C)C
Product: CC(=O)C1C(C)=CCCC1(C)C

Procedure:
In a 100-ml four-necked flask equipped with a thermometer, a condenser and a stirrer, placed were 2,6,6-trimethyl-3-cyclohexenyl methyl ketone (10 g) synthesized in Referential Example 1, sodium ethoxide (2.5 g), dimethyl sulfoxide (30 ml) and, as an internal standard substance for the analysis by gas chromatography, cyclododecane (3 g). They were reacted at 130 to 140° C. for 6 hours. The reaction mixture was treated in an usual manner. Analysis by gas chromatography showed that the content of trans-2,6,6-trimethyl-3-cyclohexenyl methyl ketone was 34.7%, while those of 2,6,6-trimethyl-2-cyclohexenyl methyl ketone and 2,6,6-trimethyl-1-cyclohexenyl methyl ketone produced by the above reaction were 45.4% and 19.9%, respectively. As a result of calculation, the yield of a mixture of these three methyl ketones was found to be 6.9 g.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[C:13]([F:14])=[CH:12][C:11]([C:15]2[N:16]=[C:17]([N:24]3[CH2:30][CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]3)[C:18]3[S:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[C:10]([F:32])[CH:9]=1.C1(C)C=CC(S([CH2:42][N+:43]#[C-])(=O)=O)=CC=1.Cl.CCOC(C)=O>CCOC(C)=O.C1COCC1.COCCOC>[ClH:7].[Cl:7][C:8]1[C:13]([F:14])=[CH:12][C:11]([C:15]2[N:16]=[C:17]([N:24]3[CH2:30][CH2:29][CH2:28][CH:27]([C:42]#[N:43])[CH2:26][CH2:25]3)[C:18]3[S:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[C:10]([F:32])[CH:9]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CCCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3ccsc23)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: N#CC1CCCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3ccsc23)CC1
Reaction time: 1 h
Yield: 41.2 %

Procedure:
440 mg of potassium tert-butoxide was added to a mixture of 650 mg of 1-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]azepane-4-one, 380 mg of p-toluensulfonylmethyl isocyanide, 20 ml of 1,2-dimethoxyethane and 10 ml of THF and the resultant was stirred for one hour under ice cooling. After the reaction mixture was concentrated under reduced pressure, 50 ml of water was added to the obtained residue and extracted twice with 100 ml of EtOAc. After the organic layer washed with a saturated saline solution and dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography chloroform-MeOH) and a foam-like substance was obtained. 50 ml of EtOAc and 0.5 ml of 4M HCl-EtOAc solution were added to the foam-like substance and the solvent was removed under reduced pressure to give a solid. The obtained solid was washed with ethyl acetate to give 150 mg of 1-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]azepane-4-carbonitrile hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[C:15]([CH:17]=[C:18]([O-])[CH3:19])#[N:16].[Na+].[NH2:22][C:23]([CH3:33])=[CH:24][C:25](=[O:32])[CH2:26][CH2:27][CH:28]1[CH2:31][CH2:30][CH2:29]1.C(O)(=O)C>CC(O)C>[CH:28]1([CH2:27][CH2:26][C:25]([C:24]2[CH:13]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[O:3][C:2]([CH3:1])=[CH:11][C:10]4=[O:12])[C:17]([C:15]#[N:16])=[C:18]([CH3:19])[NH:22][C:23]=2[CH3:33])=[O:32])[CH2:29][CH2:30][CH2:31]1
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: CC(N)=CC(=O)CCC1CCC1
Reactant: CC([O-])=CC#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC1=C(C#N)C(c2cccc3c(=O)cc(C)oc23)C(C(=O)CCC2CCC2)=C(C)N1

Procedure:
100 mg (0.53 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 55.8 mg (0.53 mmol) of sodium 1-cyanoprop-1-en-2-olate, 88.8 mg (0.53 mmol) of 5-amino-1-cyclobutylhex-4-en-3-one (example 15, stage a) and 30 μl (0.53 mmol) of acetic acid in 3 ml of 2-propanol and heated under reflux under argon for 4 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 61 mg (28% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH3:4].Br[CH2:6][C:7]1[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]=[C:9]([C:17]([O:19]CC)=[O:18])[CH:8]=1.O.[OH-].[Li+]>C(Cl)Cl.O1CCCC1.O>[CH2:3]([N:2]([CH2:6][C:7]1[N:12]=[C:11]([C:13]([F:16])([F:14])[F:15])[N:10]=[C:9]([C:17]([OH:19])=[O:18])[CH:8]=1)[CH3:1])[CH3:4]
Reactant: CCOC(=O)c1cc(CBr)nc(C(F)(F)F)n1
Reactant: CCNC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CCN(C)Cc1cc(C(=O)O)nc(C(F)(F)F)n1
Reaction time: 0.5 h

Procedure:
N-methylethanamine (96 μL, 1.1 mmol) was added to a solution of ethyl 6-(bromomethyl)-2-(trifluoromethyl)pyrimidine-4-carboxylate (0.13 g, 0.28 mmol, prepared as in Example 5, Step A) in methylene chloride (2.6 mL). After stirring for 30 minutes, solvent was removed in vacuo. The ester was hydrolyzed by stirring with lithium hydroxide monohydrate (0.12 g, 2.8 mmol) in tetrahydrofuran (4 mL) and water (2 mL) for 1 hour. 1N HCl was added dropwise to adjust the pH to 7. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded product. Yield: 0.043 g (58%); LC-MS: 264.1 (M+H)+. 1H NMR (300 MHz, DMSO-d6): δ 8.03 (s, 1H), 3.75 (s, 2H), 2.51 (q, 2H), 2.22 (s, 3H), 1.05 (t, 3H).
Reaction SMILES: [C:1]([N:9]([CH3:30])[C@@H:10]([CH:27]([CH3:29])[CH3:28])[C:11]([NH:13][C@@H:14]([CH3:26])[C:15]([N:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([C:23](O)=[O:24])[NH:18]1)=[O:16])=[O:12])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].C([N:34](CC)[CH:35]([CH3:37])[CH3:36])(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:53]2N=[CH:55][CH:56]=[CH:57][C:52]=2N=N1.F[P-](F)(F)(F)(F)F>C(#N)C>[CH:27]([C@@H:10]1[N:9]([CH3:30])[C:1](=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH:7][C:52]2[CH:53]=[C:37]([CH:55]=[CH:56][CH:57]=2)[C@@H:35]([CH3:36])[NH:34][C:23](=[O:24])[C@H:19]2[NH:18][N:17]([CH2:22][CH2:21][CH2:20]2)[C:15](=[O:16])[C@H:14]([CH3:26])[NH:13][C:11]1=[O:12])([CH3:28])[CH3:29]
Reactant: CCN(C(C)C)C(C)C
Reactant: C=CCCCCC(=O)N(C)[C@H](C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)O)N1)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CC(C)[C@H]1C(=O)N[C@@H](C)C(=O)N2CCC[C@H](N2)C(=O)N[C@H](C)c2cccc(c2)/C=C/CCCCC(=O)N1C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: CC(C)[C@H]1C(=O)N[C@@H](C)C(=O)N2CCC[C@H](N2)C(=O)N[C@H](C)c2cccc(c2)C=CCCCCC(=O)N1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 17b (710 mg, 1.3 mmol) in tetrahydrofuran (30 mL) was stirred at room temperature under nitrogen. Zinc dust (1.86 g, 28.6 mmol) was added followed by a solution of ammonium acetate (1.50 g, 19.5 mmol) in water (20 mL) and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered through Celite and the filter pad was washed with ethyl acetate and potassium hydrogen sulfate solution (pH ˜2). The filtrate was acidified to pH 2 with 2 M hydrochloric acid and the mixture was extracted with ethyl acetate. The organic extracts were combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was co-evaporated with toluene and dried to afford (S)-1-{(S)-2-[(S)-2-(hept-6-enoyl-methyl-amino)-3-methyl-butyrylamino]-propionyl}-hexahydro-pyridazine-3-carboxylic acid (468 mg, 85%) as a gum. A solution of (S)-1-{(S)-2-[(S)-2-(hept-6-enoyl-methyl-amino)-3-methyl-butyrylamino]propionyl}-hexahydropyridazine-3-carboxylic acid (468 mg, 1.1 mmol) in acetonitrile (25 mL) was stirred at room temperature under nitrogen. 1j (200 mg, 1.1 mmol) and N,N-diisopropylethylamine (710 mg, 1.0 mL, 5.5 mmol) was added followed by 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (585 mg, 1.54 mmol) and the reaction mixture was stirred at room temperature for 72 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with 2 M hydrochloric acid, water, saturated sodium hydrogen carbonate solution, water and brine, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanelethyl acetate 1:1 to ethyl acetate to afford the title compound as a white solid (300 mg, 49%).
Reaction SMILES: [O:1]=[C:2]([CH3:22])[CH2:3][C:4]1[C:5](=[O:21])[NH:6][CH2:7][CH2:8][CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[C:10]=12.[CH2:23](O)[CH2:24][OH:25].B(F)(F)F.CCOCC.[OH-].[Na+]>C1C=CC=CC=1.O>[CH3:22][C:2]1([CH2:3][C:4]2[C:5](=[O:21])[NH:6][CH2:7][CH2:8][CH:9]3[CH2:18][CH2:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=4)[C:10]=23)[O:25][CH2:24][CH2:23][O:1]1
Reactant: COc1ccc2c(c1)CCC1CCNC(=O)C(CC(C)=O)=C21
Reactant: OCCO
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc2c(c1)CCC1CCNC(=O)C(CC3(C)OCCO3)=C21

Procedure:
The starting material is prepared as follows: The mixture of 20 g of 1(2-oxopropyl)-3,4,5,5a,6,7-hexahydro-9-methoxy-2H-naphth[1,2-d]azepin-2-one, 37.5 ml of ethylene glycol and 0.95 g of boron trifluoride etherate in benzene is refluxed under a water trap for 6 hours. It is cooled and 10 g of sodium hydroxide in 140 ml of water are added rapidly and the mixture is extracted with chloroform. The extract is dried, evaporated and the residue is crystallized from diethyl ether, to yield the 1-(2-methyl-1,3-dioxolan-2-yl-methyl)-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one melting at 192°-194°.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]1[C:15](=[O:18])[CH:16]=[CH2:17])=[O:5])C.CS(C)=O.[OH-].[K+]>O.[OH-].[Na+]>[O:18]=[C:15]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH:6]1[C:4]([OH:5])=[O:3])[CH:16]=[CH2:17]
Reactant: C=CC(=O)N1c2ccccc2CC1C(=O)OCC
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C=CC(=O)N1c2ccccc2CC1C(=O)O
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of 2,3-dihydro-1-(1-oxo-2-propenyl)-1H-indole-2-carboxylic acid ethyl ester (14.4 g.), 80% aqueous dimethyl-sulfoxide (200 ml.) and potassium hydroxide (86% pellets, 3.83 g.) was stirred under nitrogen atmosphere for 2.5 days at room temperature, then evaporated under reduced pressure on a rotary evaporator to give an oily residue. The residue was dissolved in water with the aide of a small amount of dilute sodium hydroxide solution. The aqueous solution was washed with ether twice, then made acidic by addition of dilute hydrochloric acid to pH ca. 2. The oil thus separated was extracted with ether three times. The combined ether extract was washed with water, then with saline, and dried over anhydrous magnesium sulfate. Evaporation of the ether on a rotary evaporator under reduced pressure gave a solid residue which melted at 158°-160°, and weighed 9.2 g. Recrystallization from ethyl acetate improved the melting point to 167°-169°.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH:7]1([S:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:34][C@@H:33]([C:35]4[CH:46]=[CH:45][C:38]5[O:39][C:40]([CH3:44])([CH3:43])[O:41][CH2:42][C:37]=5[CH:36]=4)[O:32][C:31]3=[O:47])[CH:16]=[CH:17][CH:18]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1>C(O)C.O>[CH:7]1([S:12]([C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:34][C@@H:33]([C:35]4[CH:46]=[CH:45][C:38]5[O:39][C:40]([CH3:43])([CH3:44])[O:41][CH2:42][C:37]=5[CH:36]=4)[O:32][C:31]3=[O:47])[CH:16]=[CH:17][CH:18]=2)=[O:2])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCCCc4cccc(SC5CCCC5)c4)C(=O)O3)ccc2O1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCCCc4cccc(S(=O)C5CCCC5)c4)C(=O)O3)ccc2O1
Yield: 66.2 %

Procedure:
Sodium periodate (1.5 g) was added to a stirred solution of (5R)-3-(6-{4-[3-(cyclopentylthio)phenyl]butoxy}hexyl)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (1.0 g) in ethanol (20 ml) and water (10 ml) at room temperature. After 2 h the solution was concentrated in-vacuo (ca 50% vol), diluted with water and extracted into dichloromethane. The extracts were dried (Na2SO4) and evaporated to dryness. The residual oil was purified on a biotage cartridge (40 g) using ethyl acetate as the eluent. The appropriate fractions were evaporated to give the title compound (0.68 g). LCMS RT=3.66 min
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1[CH2:17][CH2:18][CH3:19].[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1[CH2:17][CH2:18][CH3:19]
Reactant: CCCc1cnn(C)c1-c1cc(C(=O)OC)sc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1cnn(C)c1-c1cc(C(=O)O)sc1C
Yield: 100 %

Procedure:
A solution of methyl 5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (217 mg, 0.78 mmol) in 6N sodium hydroxide (2.60 ml, 15.59 mmol) and tetrahydrofuran (5.4 ml) was stirred at 70° C. in a sealed tube for 1 h. The resulting solution was cooled and then partitioned between H2O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated affording 5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (242 mg, 0.78 mmol, 100% yield) as a white foam: LCMS (ES) m/e 265 (M+H)+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Cl.[H][H].[CH2:13]1[C@@H:21]2[C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:15][NH:14]1>[C].[Rh]>[CH2:1]1[C@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][NH:2]1.[CH3:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:21]1[CH2:13][NH2:14]
Reactant: [H][H]
Reactant: C1CC[C@H]2CNC[C@H]2C1
Reactant: c1ccc2c(c1)CNC2
Agent: [Rh]
Agent: Cl
Product: C1CC[C@H]2CNC[C@@H]2C1
Product: CC1CCCCC1CN
Yield: 0.4 %
Yield: 0.4 %

Procedure:
In a 3-liter GL autoclave fitted with a electromagnetic stirrer are added 129 g of isoindoline, 545 g of 7.2% hydrochloric acid aqueous solution (pH 4.0) and 2.6 g of 5% rhodium-carbon catalyst (50% water-containing). The reaction mixture is subjected to a hydrogen-pressure of 20 kg/cm2 and a temperature of 130° C. After a 1 hour hydrogen introduction, the drop in the rate of the hydrogen-absorption is observed, at this point the introduction of hydrogen is ceased to terminate the reaction. After the termination of reaction, the catalyst is filtered out from the reacted solution. By the result of the capillary chromatographic analysis, the yield of cis-hexahydroisoindoline is 98.7%. In addition, 0.4% of trans-hexahydroisoindoline and 0.4% of 2-methylcyclohexylmethylamine is formed. After cooling the reacted solution, 240 g of 20% sodium hydroxide aqueous solution is added to neutralize, and it is extracted with toluene. After concentrating the organic phase, the residue is purified by distillation to give 130.0 g of cis-hexahydroisoindoline (yield 95.9%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([C:18](=S)[NH2:19])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1.[CH3:21][N:22]([CH:24]=O)[NH2:23]>>[CH3:24][N:22]1[CH:21]=[N:19][C:18]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:10]3[CH:9]=[N:8][N:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:11]=3)[N:17]=2)=[N:23]1
Reactant: NC(=S)c1cccc(-c2cnn(-c3cccnc3)c2)n1
Reactant: CN(N)C=O
Product: Cn1cnc(-c2cccc(-c3cnn(-c4cccnc4)c3)n2)n1

Procedure:
0.57 g (2 mmol) of 6-(1-pyridin-3-yl-1H-pyrazol-4-yl)pyridine-2-carbothioamide and 2.5 ml (27 mmol) of 1-methyl-1-formylhydrazine were stirred at 145° C. for 6 h. After cooling, the mixture was purified by chromatography on silica gel (cyclohexane/acetone).
Reaction SMILES: C([C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]([CH3:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])=[O:8])=[CH:5][C:4]=1[O:21][CH2:22][O:23][CH3:24])=O.[CH:25]([O:30][CH3:31])([O:28][CH3:29])OC.C(=O)([O-])O.[Na+].O>CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:24][O:23][CH2:22][O:21][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:3]=1[CH:25]([O:28][CH3:29])[O:30][CH3:31])[C:7]([NH:9][C:10]([CH3:18])([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:11])=[O:8]
Reactant: COCOc1cc(C(=O)NC(C)(C)c2ccccc2)ccc1C=O
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCOc1cc(C(=O)NC(C)(C)c2ccccc2)ccc1C(OC)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
4-Formyl-3-methoxymethoxy-N-(1-methyl-1-phenylethyl)benzamide (3.12 g, 9.53 mmol) was dissolved in methanol (30 mL), and the solution was added with trimethyl orthoformate (2.09 mL, 19.1 mmol) and p-toluenesulfonic acid monohydrate (16.4 mg, 0.0952 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and water, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 3-methoxymethoxy-4-dimethoxymethyl-N-(1-methyl-1-phenylethyl)benzamide (3.61 g, yield 100%).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].[C:12](Cl)(=[O:14])[CH3:13]>C(Cl)Cl.O>[C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH:7][C:12](=[O:14])[CH3:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1ccccc1N
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1ccccc1C(C)(C)C
Temperature: 25 °C
Yield: 106.5 %

Procedure:
A solution of 2-tert-butylaniline (2.0 g, 2.1 mL, 13.4 mmol) and TEA (2.8 mL, 20.1 mmol) in DCM (100 mL) was cooled to 0° C. Acetyl chloride (1.0 mL, 14.7 mmol) was added dropwise. The resulting solution was allowed to stir and warm to rt over 2 h. The reaction mixture was diluted with water and DCM. The organic phase was washed with 1N HCl and brine, dried over Na2SO4, filtered and concentrated to give the title compound as a white solid (2.73 g, >100%). 1H NMR (400 MHz, CDCl3) δ: 7.51-7.53 (m, 1H), 7.39-7.41 (m, 1H), 7.14-7.24 (m, 2H), 2.21 (s, 2.2H), 1.92 (s, 0.9H), and 1.41 (s, 9H).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15]C(C1C=CC=CC=1)C1C=CC=CC=1)(=O)=O.[Cl:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][CH:34]=[C:33]2[CH2:39][C:40]([NH2:43])([CH3:42])[CH3:41].N1C2C(=CC=CC=2)C(CC(N)(C)C)=C1>>[ClH:29].[NH:35]1[C:36]2[C:32](=[CH:31][CH:30]=[CH:38][CH:37]=2)[C:33]([CH2:39][C:40]([NH:43][CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])([CH3:42])[CH3:41])=[CH:34]1
Reactant: CS(=O)(=O)OCCOc1ccccc1OC(c1ccccc1)c1ccccc1
Reactant: CC(C)(N)Cc1c[nH]c2ccc(Cl)cc12
Agent: CC(C)(N)Cc1c[nH]c2ccccc12
Product: CC(C)(Cc1c[nH]c2ccccc12)NCCOc1ccccc1O
Product: Cl

Procedure:
Proceeding as in Example 3, but replacing 2-[2-(cyclopropylmethyloxy)phenoxy]ethyl methanesulfonate with 2-[2-(diphenylmethyloxy)phenoxy]ethyl methanesulfonate and [2-(5-chloro-1H-indol-3-yl)-1,1-dimethylethyl]amine with [2-(1H-indol-3-yl)-1,1-dimethylethyl]amine, and then deprotecting, gave [2-(1H-indol-3-yl)-1,1-dimethylethyl][2- (2-hydroxyphenoxy)ethyl]amine hydrochloride.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:4]=1[I:11].[C:12]([O-:15])(=[O:14])[CH3:13].[Na+]>CC(O)=O.C(Cl)Cl>[C:12]([O:15][CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:4]=1[I:11])(=[O:14])[CH3:13]
Reactant: Clc1cc(Cl)c(I)c(CBr)c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)OCc1cc(Cl)cc(Cl)c1I
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of 1-(bromomethyl)-3,5-dichloro-2-iodobenzene (1.29 mmol) [WO2011/027156] and sodium acetate (9.91 mmol) in 4 mL AcOH was heated to 100° C. for 1 h and then to 80° C. for 20 h. The mixture was diluted with DCM and extracted with water and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification by CC (KP-SIL™ from Biotage) using Hept to Hept/EtOAc (9/1) gives the desired compound as white solid.