Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([N:9]1[CH:13]=[C:12]([NH:14][C:15](=[O:39])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:34]([OH:36])=O)[CH:32]=4)[N:27]=[CH:26][CH:25]=3)=[CH:19][C:18]=2[O:37][CH3:38])[CH:11]=[N:10]1)[CH3:8].C(OCC)C.[CH3:45][NH2:46]>C(Cl)Cl>[CH2:7]([N:9]1[CH:13]=[C:12]([NH:14][C:15](=[O:39])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:34](=[O:36])[NH:46][CH3:45])[CH:32]=4)[N:27]=[CH:26][CH:25]=3)=[CH:19][C:18]=2[O:37][CH3:38])[CH:11]=[N:10]1)[CH3:8]
Reactant: CN
Reactant: CCn1cc(NC(=O)Cc2ccc(Oc3ccnc4ccc(C(=O)O)cc34)cc2OC)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCn1cc(NC(=O)Cc2ccc(Oc3ccnc4ccc(C(=O)NC)cc34)cc2OC)cn1

Procedure:
Oxalyl chloride (0.142 ml) was added to a mixture of N-(1-ethylpyrazol-4-yl)-2-[4-(6-carboxyquinolin-4-yloxy)-2-methoxyphenyl]acetamide (0.15 g) and methylene chloride (6 ml) and the resultant mixture was stirred at ambient temperature for 10 minutes. Diethyl ether (10 ml) was added and the resultant precipitate was recovered and dried under vacuum. The material so obtained was suspended in methylene chloride and methylamine gas was passed into the suspension until a clear solution was obtained. The solvent was evaporated and the residue was purified by column chromatography on silica using a gradient of 100:0 to 19:1 of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.102 g); 1H NMR: (DMSOd6) 1.33 (t, 3H), 2.85 (d, 3H), 3.61 (s, 2H), 3.78 (s, 3H), 4.07 (q, 2H), 6.7 (d, 1H), 6.87 (m, 1H), 7.01 (d, 1H), 7.37 (d, 1H), 7.42 (s, 1H), 7.88 (s, 1H), 8.08 (d, 1H), 8.24 (m, 1H), 8.77 (d, 1H), 8.82 (q, 1H), 8.87 (d, 1H), 10.06 (s, 1H); Mass Spectrum: M+H+ 460.
Reaction SMILES: [C:1]1([NH:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[C:26]([C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[C:25]([CH3:36])[NH:24][C:23]=1[CH:37]=O>>[C:1]1([NH:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[CH:37][C:23]2[NH:24][C:25]([CH3:36])=[C:26]([C:27]([N:29]3[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]3)=[O:28])[C:22]=2[CH3:21])(=[O:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1Cc2cc(S(=O)(=O)Nc3ccccc3)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(S(=O)(=O)Nc4ccccc4)cc32)c(C)c1C(=O)N1CCN(C)CC1
Yield: 24.1 %

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid phenylamide (110 mg, 0.4 mmol) was condensed with 3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (100 mg) to give 50 mg (24%) of the title compound as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(C(C)C)C(C)C)C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[N:27][C:26]=2[N:31]=[C:32](SC)[S:33][CH3:34])=[C:21]([CH3:37])[CH:20]=1.O>C(#N)C>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:26]3[N:27]([C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:32]([S:33][CH3:34])[N:31]=3)[N:28]=[CH:29][CH:30]=2)=[C:21]([CH3:37])[CH:20]=1
Reactant: COc1ccc(-c2ccnnc2N=C(SC)SC)c(C)c1
Reactant: CCOC(=O)CBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)c1c(SC)nc2c(-c3ccc(OC)cc3C)ccnn12
Temperature: 100 °C
Reaction time: 14 h

Procedure:
Ethyl bromoacetate (0.87 mL) and i-Pr2EtN (1.36 mL) were added to a solution of methyl N-[4-(4-methoxy-2-methylphenyl)-3-pyridazinyl]-(methylsulfanyl)methaneimidothioate (1.25 g) in acetonitrile (10 mL), and the mixture was heated under stirring at 100° C. for 14 hours. The reaction mixture was cooled to room temperature, which was added with water, extracted with ethyl acetate, and washed with water. After that, it was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3) to give the title compound (628 mg) as a red brown oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH2:10][C@H:9]2[NH2:15])=[O:5].C(N(CC)CC)C.[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>ClCCl.C([O-])(O)=O.[Na+]>[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH2:10][C@H:9]2[NH:15][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[Cl:23])=[O:5]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Method 1 (3R)-3-Amino-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester hydrochloride (A-01) (8.784 mmol, 1 eq) was dissolved in dichloromethane, and triethylamine (3 eq) and 2-chlorobenzoic acid chloride (1.2 eq) were added at 0° C. under a protecting gas atmosphere. The reaction mixture was stirred for 1 h at RT. Then the reaction mixture was diluted with sat. NaHCO3 solution and the aqueous phase was extracted with dichloromethane (3×50 ml). The organic phase was dried over sodium sulfate and concentrated to yield (3R)-3-[(2-chloro-benzoyl)amino]-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester (B-01). Yield: 98%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](=[O:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12].C(N(CC)CC)C.CS([N:27]=[N+:28]=[N-])(=O)=O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](=[O:15])[C:10](=[N+:27]=[N-:28])[C:11]([O:13][CH3:14])=[O:12]
Reactant: CS(=O)(=O)N=[N+]=[N-]
Reactant: COC(=O)CC(=O)c1c(F)cccc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C(=[N+]=[N-])C(=O)c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.1 %

Procedure:
To a solution of 5.80 g (25.1 mmol) of methyl 3-(2-chloro-6-fluorophenyl)-3-oxopropionate in 60 mL acetonitrile was added 3.9 mL (28 mmol) of triethylamine followed by 3.05 g (25.2 mmol) of methanesulfonyl azide. The mixture was stirred at room temperature for 18 h and concentrated by rotary evaporation. The resulting solid mass was washed with ethyl acetate/hexanes and the washings were filtered through a plug of silica gel. The filtrate was concentrated to give 4.90 g (76%) of the title compound as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>O.[N+](C)([O-])=O>[C:13]1([S:9]([C:3]2[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:11])=[O:10])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccccc1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Product: O=S(=O)(c1ccccc1)c1cc(Cl)ccc1Cl
Temperature: 100 °C
Yield: 85.2 %

Procedure:
A modification of the published procedures of Hagberg, Olson, and Sheares in Macromolecules, 2004, 37, 4748 was used. A 200 mL round-bottom flask equipped with a reflux condenser, stirring bar, and gas inlet was charged with 2,5-dichlorobenzenesulfonyl chloride (12.28 g, 50 mmoles), benzene (13.4 mL, 150 mmoles), and anhydrous nitromethane (50 mL). Aluminum chloride (7.33 g, 55 mmoles) was added and the mixture stirred until dissolved under nitrogen. The solution was heated to 100° C. overnight. The solution was cooled to room temperature and poured into 100 g water mixed with 25 mL hydrochloric acid. The mixture was extracted several times with dichloromethane. The organic extracts were dried with sodium sulfate, filtered, and evaporated, then the solids were dried in a vacuum oven to give 14.38 g (100% crude yield). The solids were recrystallized from ethanol after treating with decolorizing carbon to give about 14 g in two crops. The solids were recrystallized from ethanol to give 12.24 g (85% yield) of 2-benzenesulfonyl-1,4-dichlorobenzene. 1H NMR (DMSO-d6): 7.65 (ddd, 8.4, 7.5, 1.7 Hz, 2H), 7.67 (d, 8.6 Hz, 1H), 7.76 (tt, 7.5, 1.2 Hz, 1H), 7.83 (dd, 8.6, 2.6 Hz, 1H), 7.98 (ddd, 8.4, 1.7, 1.2 Hz, 2H), 8.27 (d, 2.6 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:10]([S:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[F:18])=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.OO.[OH2:29].CCCCCC.C[OH:37]>C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH:10]([S:19]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)(=[O:37])=[O:29])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[F:18])=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1
Reactant: O
Reactant: CO
Reactant: OCc1cc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c(Br)cn1
Agent: OO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)c1cc(CO)ncc1Br
Reaction time: 19 h
Yield: 86 %

Procedure:
To a solution of [5-bromo-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridin-2-yl]methanol (550 mg, 1.20 mmol) in a mixture of methanol (10 ml) and ethyl acetate (10 ml) were added hexaammonium heptamolybdate tetrahydrate (100 mg) and 30% aqueous hydrogen peroxide (10 ml). The resulting mixture was stirred for 19 hours. After addition of water, the resulting mixture was extracted with ethyl acetate. The extract was washed sequentially with water, a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of sodium thiosulfate and brine. The organic layer thus obtained was dried over magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=2:1 eluate was concentrated under reduced pressure, followed by recrystallization from hexane:ethyl acetate to give the title compound (506 mg, 1.04 mmol, 86%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11](SC(=O)N(C)C)=[CH:10][C:8]=2[CH:9]=1)=[O:4].[OH-].[K+].Cl.[OH:23]S(O)(=O)=O>CO.C(O)C.O>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([OH:23])=[CH:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: O=S(=O)(O)O
Reactant: COC(=O)c1cc2cc(SC(=O)N(C)C)ccc2o1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CO
Product: COC(=O)c1cc2cc(O)ccc2o1
Yield: 95 %

Procedure:
A solution of 5-dimethylcarbamoylsulfanyl-benzofuran-2-carboxylic acid methyl ester (0.5 g, 1.8 mmol) and potassium hydroxide (0.5 g, 12.5 mmol) in 25 ml 2:1 ethanol/water was heated at reflux for 18 hours. The reaction was then cooled, acidified with 2 M HCl, extracted 2×25 mL EtOAc, dried (Na2SO4) and the solvent removed in vacuo to give 350 mg of the crude product. The crude mixture was then refluxed overnight in 25 mL MeOH and catalytic H2SO4. The reaction was then cooled, concentrated in vacuo, taken up in EtOAc and washed with brine. The organic layer was then dried (Na2SO4) and concentrated in vacuo to give 330 mg (95%) of the title compound pure enough for subsequent use. 400 MHz 1H NMR (DMSO-d6) δ 7.66 (s, 1H), 7.62 (s, 1H), 7.57(d, 1H, J=9.0 Hz), 7.37 (d, 1H, J=9.0 Hz), 5.49 (s(br), 1H), 3.85 (s, 3H). Preparation of 5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-benzofuran-2-carboxylic acid methyl ester (Compound 6E)
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].Cl.Cl.[NH:25]1[CH2:65][CH2:64][CH2:63][C@H:26]1[C:27]([NH:29][C@H:30]([C:42]([N:44]1[CH2:62][CH2:61][CH2:60][C@H:45]1[C:46]([NH:48][C@H:49]([C:57]([NH2:59])=[O:58])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:47])=[O:43])[CH2:31][C:32](=[O:41])[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:28].CN1CCOCC1.C(P(=O)(OCC)OCC)#N>CC(N(C)C)=O>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([N:25]1[CH2:65][CH2:64][CH2:63][C@H:26]1[C:27]([NH:29][C@H:30]([C:42]([N:44]1[CH2:62][CH2:61][CH2:60][C@H:45]1[C:46]([NH:48][C@H:49]([C:57]([NH2:59])=[O:58])[CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:47])=[O:43])[CH2:31][C:32](=[O:41])[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:28])=[O:12])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8]
Reactant: NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)[C@@H]1CCCN1
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Product: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Reaction time: 4 h

Procedure:
To a stirred solution of Z-Arg.HCl (5.17 g, 15 mmoles) in dimethylacetamide (25 mL) at 25° C. was added a solution of HCl.Pro-Asp(OBzl)-Pro-Phe-NH2 and N-methylmorpholine (1.65 mL, 15 mmoles) in dimethylacetamide (25 mL). To the resulting solution, diethyl cyanophosphonate (2.45 g, 15 mmoles) and N-methylmorpholine (1.65 mL, 15 mmoles) were added and the mixture stirred for 4 hours. The reaction was quenched by the addition of 10% aqueous acetic acid (10 mL) and the solvents were removed on a rotary evaporator under reduced pressure. The resulting solid was triturated with 10% potassium carbonate and then with water and filtered.
Reaction SMILES: N1CCOC[CH2:2]1.[CH:7](=O)[CH2:8][CH:9](C)C.S([O-])([O-])(=O)=O.[Mg+2].[CH3:19][C:20]1[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([CH3:31])O[C:22](=O)[CH:21]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:19][C:20]1[C:21]([CH:8]([CH3:9])[CH3:7])=[CH:22][CH:2]=[C:24]([CH3:31])[C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CC(C)CC=O
Reactant: CCOC(=O)c1c(C)cc(=O)oc1C
Reactant: C1COCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)ccc(C(C)C)c1C
Reaction time: 3 h
Yield: 8.3 %

Procedure:
Morpholine (13.34 g), isovaleraldehyde (13.18 g), p-toluene sulfonic acid (0.2 g), and toluene (300 ml) were combined and heated at reflux using a Soxhlet extractor containing magnesium sulfate to remove any water produced. After three hours the Soxhlet extractor was replaced with a condenser, and ethyl 4,6-dimethyl-2-oxo-2H-pyran-5-carboxylate (30 g) was added. The reaction mixture was heated under reflux for approximately 64 hours. The solvent was evaporated, and the resultant oil was distilled at atmospheric pressure to give 11.1 g of crude product which was chromatographed to yield ethyl 2,6-dimethyl-3-(1-methylethyl)benzoate (2.8 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].Cl.[NH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.[OH-].[K+]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:17]1[CH2:18][CH2:19][NH:14][CH2:15][CH:16]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc2[nH]cc(C3=CCNCC3)c2c1

Procedure:
Using the procedure of Example 1, a mixture of 0.8 g of 5-nitro-1H-indole, 1.53 g of the hydrate of 4-piperidone hydrochloride and 16 ml of 2 N methanolic potassium hydroxide was reacted to obtain 0.86 g of raw product which was crystallized from isopropanol to obtain 0.74 g of 5-nitro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole melting at 250° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH2:12])=[CH:6][CH:5]=1.C(N(CC)CC)C.Cl[C:23]1[C:28]([I:29])=[C:27]([CH:30]([Br:32])[CH3:31])[N:26]=[CH:25][N:24]=1>C1(C)C=CC=CC=1>[Br:32][CH:30]([C:27]1[N:26]=[CH:25][N:24]=[C:23]([NH:12][CH2:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=2)[C:28]=1[I:29])[CH3:31]
Reactant: CC(Br)c1ncnc(Cl)c1I
Reactant: NCCc1ccc(OC(F)(F)F)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(Br)c1ncnc(NCCc2ccc(OC(F)(F)F)cc2)c1I
Temperature: 60 °C

Procedure:
In toluene (50 ml) were dissolved 2-(4-trifluoromethoxyphenyl)ethylamine (1.0 g) and triethylamine (1.0 g) then, 4-chloro-6-(1-bromoethyl)-5-iodopyrimidine (1.8 g) was added to the solution, and the mixture was heated at about 60° C. for 3 hours while stirring.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[CH2:5]1)(=[O:3])[CH3:2].[CH2:12](Cl)[C:13](=[CH2:15])[CH3:14].C(N(CC)CC)C>O>[C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[CH2:5]1)(=[O:3])[CH3:2].[C:1]([C:4]1([CH2:14][C:13]([CH3:15])=[CH2:12])[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[CH2:5]1)(=[O:3])[CH3:2].[CH3:10][C:6]1([CH3:11])[CH2:7][CH2:8][CH2:9][CH:4]([C:1](=[O:3])[CH2:2][CH2:14][C:13]([CH3:15])=[CH2:12])[CH2:5]1
Reactant: C=C(C)CCl
Agent: CC(=O)C1CCCC(C)(C)C1
Solvent: O
Solvent: CCN(CC)CC
Product: C=C(C)CC1(C(C)=O)CCCC(C)(C)C1
Product: C=C(C)CCC(=O)C1CCCC(C)(C)C1
Temperature: 25 °C

Procedure:
A mixture of 1-acetyl-3,3-dimethylcyclohexane (156 grams, 1 mole) sodium hydroxide (60 grams, 1.5 moles), methallyl chloride (135 grams, 1.5 moles) and triethylamine (10 grams) is stirred and heated at 80°-84° C. for 12 hours. The reaction mass is cooled to room temperature. Water is added with stirring, and the aqueous layer is discarded. The organoc layer is distilled to afford 1-acetyl-3,3-dimethylcyclohexane (62.4 gm), 1-acetyl-3,3-dimethyl-1-(2-methyl-2-propenyl)cyclohexane (80 gm), (NMR spectrum, FIG. 1; IR spectrum, FIG. 2), and 3,3-dimethyl-1-(4-methyl-4-pentenoyl)cyclohexane (8 gm).
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@H:22]([C:24](=[O:44])[N:25]([CH:41]4[CH2:43][CH2:42]4)[CH2:26][C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=4)[CH2:21][C@H:20]([NH2:45])[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.ClC(Cl)C.[C:50]([N:54]=[C:55]=[O:56])([CH3:53])([CH3:52])[CH3:51]>C(Cl)Cl>[CH:41]1([N:25]([CH2:26][C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=2)[C:24]([C@@H:22]2[CH2:21][C@H:20]([NH:45][C:55]([NH:54][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:56])[CH2:19][NH:18][CH2:23]2)=[O:44])[CH2:42][CH2:43]1
Reactant: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](N)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)c2ccccc21
Reactant: CC(C)(C)N=C=O
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: COCCCn1cc(CN(C(=O)[C@H]2CNC[C@@H](NC(=O)NC(C)(C)C)C2)C2CC2)c2ccccc21
Reaction time: 1 h

Procedure:
A mixture of (3S,5R)-3-amino-5-{cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (115 A.) (374 mg, 0.62 mmol), dichloroethane (5 mL) and tert-butyl isocyanate (142 μl, 1.24 mmol) is shaken for 14 h at 50° C. The mixture is diluted with CH2Cl2 and washed with 1 N HCl and saturated NaHCO3 solution. The organic layer is dried (Na2SO4) and evaporated. The crude product is stirred with a solution of CH2Cl2/piperidine 4:1 (6 ml) for 1 h, the mixture is evaporated and the residue purified by preparative HPLC (YMC Pack Pro C18, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, 20 min, flow 20 mL/min). The combined pure fractions are treated with K2CO3, CH3CN is removed in vacuo and the residual aqueous phase is extracted three times with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to afford the title compound as a yellow resin. MS: 484.2 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.05 min.
Reaction SMILES: C(OC([CH2:11][NH:12][C@H:13]1[CH2:38][CH2:37][C@:15]2([O:19][CH2:18][C@H:17]([C:20]3[CH:25]=[C:24]([N:26]4[CH:30]=[CH:29][N:28]=[C:27]4[C:31]([F:34])([F:33])[F:32])[CH:23]=[CH:22][C:21]=3[O:35][CH3:36])[CH2:16]2)[C@@H:14]1[C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1)=O)C1C=CC=CC=1>C(O)C.C(O)(=O)C.[OH-].[Pd+2].[OH-]>[CH3:11][NH:12][C@H:13]1[CH2:38][CH2:37][C@:15]2([O:19][CH2:18][C@H:17]([C:20]3[CH:25]=[C:24]([N:26]4[CH:30]=[CH:29][N:28]=[C:27]4[C:31]([F:33])([F:34])[F:32])[CH:23]=[CH:22][C:21]=3[O:35][CH3:36])[CH2:16]2)[C@@H:14]1[C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1
Reactant: COc1ccc(-n2ccnc2C(F)(F)F)cc1[C@H]1CO[C@]2(CC[C@H](NCC(=O)OCc3ccccc3)[C@H]2c2ccc(F)cc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CN[C@H]1CC[C@@]2(C[C@@H](c3cc(-n4ccnc4C(F)(F)F)ccc3OC)CO2)[C@@H]1c1ccc(F)cc1
Reaction time: 3 h

Procedure:
(3S,5R,6R,7S)-7-(N-(Benzyloxycarbonyl)methylamino)-6-(4-fluorophenyl)-3-(2-methoxy-5-(2-(trifluoromethyl)imidazol-1-yl)phenyl)-1-oxaspiro[4.4]nonane (7.0 mg, 0.011 mmol) in 0.30 mL of ethanol and 0.24 mL of acetic acid was hydrogenated on the Parr shaker at 47 psi, using 2.3 mg of 20% palladium(II) hydroxide on carbon. After 3 h, the mixture was filtered through 0.45 micron filter and the filtrate was evaporated. The residue was taken in 2.0 mL of ethyl acetate and washed with 1.0 mL of saturated aqueous sodium bicarbonate followed by 1.0 mL of brine. Drying over sodium sulfate and evaporation gave N-methyl((3S,5R,6R,7S)-6-(4-fluorophenyl)-3-(2-methoxy-5-(2-(trifluoromethyl)imidazol-1-yl)phenyl)-1-oxaspiro[4.4]non-7-yl)amine. 1NMR (400 MHz, CD3OD): δ7.45 (dd, 2H, J=9, 6 Hz ), 7.29 (d, 1H, J=1 Hz ), 7.21 (d, 1H, J=1 Hz ), 7.19 (dd, 1H, J=9, 2 Hz ), 7.01 (t, 2H, J=9 Hz ), 7.00 (d, 1H, J=9 Hz ), 6.58 (d, 1H, J=2 Hz ), 4.12-4.00 (m, 2H), 3.84-3.75 (m, 1H), 3.79 (s, 3H), 3.13 (d, 1H, J=10 Hz ), 3.05 (t, 1H, J=8 Hz ), 2.54-2.42 (m, 1H), 2.52 (s, 3H), 2.28 (dd, 1H, J=13, 8 Hz ), 2.27-2.20 (m, 1H), 2.07 (ddd, 1H, J=13, 10, 9 Hz ), 1.91 (dd, 1H, J=13, 11 Hz ), 1.90-1.80 (m, 1H). Mass spectrum (NH3/CI): m/z=490.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]3([CH3:26])[CH2:25][O:24]3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[Li+].[B-](CC)(CC)CC.OO>O1CCCC1.O.C(OC)(C)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:24])([CH3:25])[CH3:26])([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC2(C)CO2)(c2ccccc2)NC1=O
Agent: CC[B-](CC)CC
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: O
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)NC1=O
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
To a solution of (4S)-1-((S)-1-(4-bromophenyl)ethyl)-4-((2-methyloxiran-2-yl)methyl)-4-phenyltetrahydropyrimidin-2(1H)-one (0.61 g, 1.42 mmol) in anhydrous tetrahydrofuran (5 mL) was added to Super Hydride (2.56 mL, 2.56 mmol) at 0-5° C. The addition is exothermic and addition was controlled to maintain Tint=<8° C. The mixture was stirred for 2 h at 0-5° C. and allowed to warm to 10-15 0° C. over 3 h. A solution of hydrogen peroxide (5 mL of a 30 wt % aqueous solution diluted with 50 mL of water) was added. The temperature was controlled to maintain Tint=<25° C. The resulting solution was diluted with methyl tert-butyl ether (MTBE) (200 mL) and washed with water (200 mL) followed by 30 wt % aq solution of sodium thiosulfate (300 mL). The organic solution was dried over Na2SO4, filtered and then concentrated to dryness. The residue was purified by column to afford (S)-1-((S)-1-(4-bromophenyl)ethyl)-4-(2-hydroxy-2-methylpropyl)-4-phenyltetrahydropyrimidin-2(1H)-one (0.5 g, Yield: 82%). 1H NMR (MeOD): 0.58 (s, 3H), 1.17 (s, 3H), 1.44-1.46 (d, 3H), 1.90-1.94 (m, 2H), 2.05-2.08 (m, 1H), 2.16-2.18 (m, 1H), 2.24-2.27 (m, 1H), 2.83-2.86 (m, 1H), 5.65-5.67 (m, 1H), 7.04-7.06 (m, 2H), 7.22-7.23 (m, 1H), 7.27-7.33 (m, 6H). LC-MS Method 2 tR=1.296 min, m/z=433.