Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[C:7]([Si:11]([CH3:31])([CH3:30])[O:12][CH:13]1[CH2:18][CH:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:16][C:15]([OH:29])(CO)[CH2:14]1)([CH3:10])([CH3:9])[CH3:8].O>CO>[C:7]([Si:11]([CH3:31])([CH3:30])[O:12][CH:13]1[CH2:18][CH:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:16][C:15](=[O:29])[CH2:14]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OC1CC(O[Si](C)(C)C(C)(C)C)CC(O)(CO)C1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC1CC(=O)CC(O[Si](C)(C)C(C)(C)C)C1
Reaction time: 1 h
Yield: 89 %

Procedure:
Sodium periodate saturated water (28.5 mL) was added to the diol 15 (1.8 g, 4.7 mmol) in methanol (124 mL) at 0° C. The solution was stirred for 1 h, then poured into water and extracted with ether. The combined ether fractions were washed with brine, dried over anhydrous MgSO4, filtered and concentrated to give 16 (1.5 g, 90%). No further purification was required. 1H NMR (CDCl3, 500 MHz) 6 0.11 (s, 3H), 0.12 (s, 3H), 0.14 (s, 3H), 0.15 (s, 3H), 0.91 (s, 9H), 0.90 (s, 9H), 1.94 (m, 2H), 2.35 (m, 2H), 2.54 (m, 2H), 4.35 (m, 2×1H).
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:28][O:29][C:30](=[O:37])[C:31](=O)[C:32]([F:35])([F:34])[F:33]>C1COCC1>[CH3:28][O:29][C:30](=[O:37])[C:31]([C:32]([F:35])([F:34])[F:33])=[C:14]([C:11]1[CH:10]=[CH:9][C:8]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:13][CH:12]=1)[C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: COC(=O)C(=O)C(F)(F)F
Reactant: CCCCC(=O)Cc1ccc(OC2CCCCC2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC(=O)C(=C(C(=O)OC)C(F)(F)F)c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.1 %

Procedure:
To a stirred solution of 1-(4-cyclohexyloxy-phenyl)-hexan-2-one (Example 14, 4.46 mmol, 1.22 g) and triethylamine (4.46 mmol, 0.62 mL) in THF (5 mL) was added a solution of 3,3,3-trifluoro-2-oxo-propionic acid methyl ester (13.4 mmol, 2.09 g) and continued stirring for 12 h at room temperature. After removal of volatiles in vacuo, the crude product was purified on a 40 g SiO2 cartridge with ethyl acetate/hexanes gradient to afford 3-(4-cyclohexyloxy-phenyl)-4-oxo-2-trifluoromethyl-oct-2-enoic acid methyl ester (1.4 g).
Reaction SMILES: C([S:4][CH2:5][C:6]1[C@:7]2([CH2:24][CH2:23][C@H:22]3[C:12](=[CH:13][CH:14]=[C:15]4[C@:20]3([CH3:21])[C@@H:19]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:18][C@H:17]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:16]4)[C@@H:9]2[CH2:10][CH:11]=1)[CH3:8])(=O)C.Br[CH2:42][CH2:43][C:44]([OH:47])([CH3:46])[CH3:45].CO.[OH-].[K+]>O1CCCC1>[Si:26]([O:25][C@@H:19]1[C@@:20]2([CH3:21])[C:15](=[CH:14][CH:13]=[C:12]3[C@@H:22]2[CH2:23][CH2:24][C@@:7]2([CH3:8])[C@H:9]3[CH2:10][CH:11]=[C:6]2[CH2:5][S:4][CH2:42][CH2:43][C:44]([OH:47])([CH3:46])[CH3:45])[CH2:16][C@@H:17]([O:33][Si:34]([C:37]([CH3:38])([CH3:39])[CH3:40])([CH3:36])[CH3:35])[CH2:18]1)([C:29]([CH3:31])([CH3:32])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(=O)SCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(O)CCBr
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(O)CCSCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 93 %

Procedure:
17-Acetylthiomethyl-1α,3β-bis(tert-butyldimethylsilyloxy)androsta-5,7,16-triene (67.7 mg, 0.112 mmol), 1-bromo-3-hydroxy-3-methylbutane (93.5 mg, 0.560 mmol), 1M potassium hydroxide methanol solution (1 ml) and tetrahydrofuran (1 ml) were subjected to reaction using a procedure similar to that of Example 31(1) (at room temperature for 30 min.), worked up and purified by preparative thin layer chromatography (2 sheets (each 0.5 mm thickness), hexane:ethyl acetate=3:1, developed once) to give the titled compound (67.4 mg, 93%) as a colorless oil.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH:17]=[C:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][CH2:21][C:20]3[CH:29]=[CH:30][CH:31]=[CH:32][C:19]2=3)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:36]CCl>C(O)C>[ClH:36].[CH:29]1[C:20]2[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:18](=[CH:17][CH2:16][O:15][CH2:14][CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[C:19]=2[CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCCOCC=C2c3ccccc3CCc3ccccc32)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCCOCC=C2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The above ester (2.5 g, 5.8 mmol) was dissolved in ethanol (15 ml) and a 4 N sodium hydroxide solution (4.3 ml) was added. The mixture was stirred vigorously at room temperature for 5 h. A 4 N hydrochloric acid solution was added until pH 1 followed by dichloromethane (400 ml). The mixture was stirred vigorously for a few minutes and the phases were separated. The organic phase was dried over sodium sulphate and the solvent was evaporated in vacuo. The residue was evaporated twice with acetone, once with ethyl acetate, dissolved in acetone (15 ml) and left for crystallization. This afforded 1.9 g of the title compound as a solid.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[N:5][C:6]([NH2:12])=[N:7][C:8]=1[S:9]([CH3:11])=O)[CH3:2].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24]CS.C1CCN2C(=NCCC2)CC1>COCCOC>[CH2:1]([C:3]1[C:4]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[N:5][C:6]([NH2:12])=[N:7][C:8]=1[S:9][CH2:11][CH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=1)[CH3:2]
Reactant: CCc1c(-c2ccco2)nc(N)nc1S(C)=O
Reactant: SCCc1ccccn1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1c(SCCc2ccccn2)nc(N)nc1-c1ccco1
Temperature: 90 °C
Yield: 19.1 %

Procedure:
To a stirred suspension of 100 mg (0.40 mmol) 5-ethyl-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-ylamine in 5 ml DME in a pressure tube were added 230 mg (1.65 mmol) 2-pyridylethyl mercaptan and 0.18 ml (1.19 mmol) DBU and the mixture heated at 90° C. for 16 hours. The reaction mixture was then concentrated in vacuo. Chromatography (ethyl acetate/hexane 1/1 then ethyl acetate) followed by trituration in ether afforded 25 mg (19%) 5-ethyl-4-furan-2-yl-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidin-2-ylamine as a beige crystalline solid. ES-MS m/e (%): 327 (M+H+, 100).
Reaction SMILES: [C:1]([O:4][CH2:5][C@:6]1([OH:24])[CH2:15][C:14]2[C:9](=[C:10]([O:18][CH3:19])[CH:11]=[CH:12][C:13]=2[O:16][CH3:17])[C:8]2(SCCS2)[CH2:7]1)(=[O:3])[CH3:2].O.C([O:28]CC)C>O1CCCC1.CO>[C:1]([O:4][CH2:5][C@:6]1([OH:24])[CH2:15][C:14]2[C:9](=[C:10]([O:18][CH3:19])[CH:11]=[CH:12][C:13]=2[O:16][CH3:17])[C:8](=[O:28])[CH2:7]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(OC)c2c1C[C@@](O)(COC(C)=O)CC21SCCS1
Reactant: CCOCC
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(OC)c2c1C[C@@](O)(COC(C)=O)CC2=O
Reaction time: 1 h

Procedure:
1.9 g of (S)-3'-acetoxymethyl-1',2',3',4'-tetrahydro-3'-hydroxy-5',8'-dimethoxyspiro[1,3-dithiolane-2,1'-naphthalene] in 40 ml of tetrahydrofuran were added to a stirred suspension of 6.4 g of mercuric chloride and 6.4 g of mercuric oxide in 200 ml of methanol containing 18 ml of water. After standing at room temperature for 1 hour, ca 150 ml of solvent were removed by evaporation under reduced pressure, 200 ml of dichloromethane were added and the resulting suspension was filtered to remove insoluble material. The filtrate was washed with three 200 ml portions of water, dried over magnesium sulphate and evaporated to give a solid residue. Trituration with diethyl ether gave (S)-3-acetoxymethyl-1,2,3,4-tetrahydro-3-hydroxy-5,8-dimethoxy-1-oxo-naphthalene in the form of an off-white powder which was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[CH2:9][OH:10]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[NH2:1][C:2]1[C:3]([CH:9]=[O:10])=[CH:4][N:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1cc(Cl)ncc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Nc1cc(Cl)ncc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
Treat a solution of (4-amino-6-chloropyridin-3-yl)methanol (10 g, 63.3 mmol) in DCM (150 mL) with activated manganese dioxide (38 g, 443 mmol) and stir at RT overnight. Remove solids via filtration, concentrate the filtrate and purify by silica gel chromatography to afford the title compound (7.2 g, 73%). 1H NMR (400 MHz, DMSO-d6): δ 9.88 (s, 1H), 8.44 (s, 1H), 7.84 (s, 2H), 6.73 (s, 1H); MS (ESI) m/z: 157.0 (M+H+).
Reaction SMILES: [CH2:1]([N:8]([CH3:35])[C:9]1[CH:27]=[C:26]([CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:25]=[CH:24][C:10]=1[NH:11][CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14](OCC)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(OC2C=CC=CC=2)C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([N:8]([CH3:35])[C:9]1[CH:27]=[C:26]([CH2:28][N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)[CH:25]=[C:24]2[C:10]=1[N:11]=[CH:12][C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=CNc1ccc(CN2CCOCC2)cc1N(C)Cc1ccccc1)C(=O)OCC
Solvent: CCOC(C)=O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(N(C)Cc3ccccc3)cc(CN3CCOCC3)cc2c1O
Yield: 50.7 %

Procedure:
Diethyl 2-{[2-[benzyl(methyl)amino]-4-(4-morpholinylmethyl)anilino]-methylene}malonate (3.7 g, 7.7 mmol) is stirred in a mixture of phenyl ether (9 g) and biphenyl (3 g) at 260 ° C. A slow stream of nitrogen is passed through the solution to remove volatile materials produced in the reaction. The reaction is stopped as soon as HPLC shows that conversion of the starting material to product is complete (60 min). After cooling, the reaction mixture is applied in ethyl acetate to a silica gel column which is eluted with ethyl acetate (400 mL) to remove phenyl ether and biphenyl. The column is then eluted with 5-10% methanol/chloroform and the product obtained is recrystallized from ethyl acetate/hexane (3:1, 15 mL) to give 1.70 g of the title compound.
Reaction SMILES: C(OCC)C.[CH2:6]([C:8]1[O:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[CH:12]=1)[CH3:7].[Br:17]Br>C(OCC)(=O)C>[Br:17][C:12]1[C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[O:9][C:8]=1[CH2:6][CH3:7]
Reactant: BrBr
Reactant: CCc1cc2ccccc2o1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCc1oc2ccccc2c1Br
Temperature: 0 °C

Procedure:
To a 250 mL flask equipped with magnetic stirring is added 100 mL of diethyl ether and 2-ethylbenzofuran (20.00 g, 136.8 mmol). The reaction flask is cooled to 0° C. and bromine (8.40 mL, 164.2 mmol) is added to an addition funnel containing 50 mL of ethyl acetate. The mixture is added dropwise to the reactor while maintaining the 0° C. temperature. The addition funnel is rinsed with an additional 20 mL of ethyl acetate. The resulting mixture is stirred for 2 hours and the temperature maintained at 0° C. The reaction is quenched with 50 mL of water. The contents of the reactor are then transferred to a 1 L separatory funnel and rinsed with 2×50 mL of water. The organic layers are combined and rinsed with 200 mL of a saturated sodium thiosulfate solution. The layers are separated and the organic layer is dried over MgSO4 to give an amber colored solution. The solvent is removed in vacuo to give the product, 3-bromo-2-ethylbenzofuran, as a pale yellow liquid which is used without further purification (yield: 27.1 g, 88 percent).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14][CH3:15])=[O:13])[CH2:3]1>C(OC=C)(=O)C>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14][CH3:15])=[O:13])[CH2:3]1
Reactant: COC(=O)c1c(C)cccc1CO[C@H]1CCC[C@@H](O)C1
Solvent: C=COC(C)=O
Product: COC(=O)c1c(C)cccc1CO[C@@H]1CCC[C@H](O)C1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
8 g of methyl 2-(cis-3-hydroxycyclohexyloxymethyl)-6-methylbenzoate are dissolved in 100 ml of vinyl acetate, and 1 g of Candida antartika lipase B is added. The mixture is stirred at room temperature for seven hours and the enzyme is then filtered off and the solvent is removed under reduced pressure. The residue is purified by flash chromatography on silica gel (n-heptane/ethyl acetate=10:1). This gives 3.9 g of the alcohol methyl 2-((1R,3S)-3-hydroxycyclohexyloxymethyl)-6-methylbenzoate as a colorless oil. C16H22O4 (278.35), MS(ESI): 279 (M+H+), ee=98% (Chiralpak AD/2 250×4.6; n-heptane:ethanol:methanol=25:1:0.5+0.1% trifluoroacetic acid, Rt=8.9 min; retention time of the enantiomer: Rt=9.9 min).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=3)[C:19]([O:21]CC)=[O:20])[CH:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].O.[OH-].[Li+]>CO.O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=3)[C:19]([OH:21])=[O:20])[CH:11]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cccc(-c2cc(-c3ccc(C(C)C)cc3)ccn2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)c1ccc(-c2ccnc(-c3cccc(C(=O)O)c3)c2)cc1
Reaction time: 12 h
Yield: 85.3 %

Procedure:
Part E. A solution of ethyl 3-[4-(4-isopropyl-phenyl)-pyridin-2-yl]-benzoate (116 mg, 0.34 mmol) in methanol-water (3 mL/1 mL) is treated with lithium hydroxide hydrate (41 mg, 1.7 mmol). The mixture is stirred at ambiemperature for 12 h., then partitioned between water and diethyl ether. The aqueous phase is neutralized to pH 7 with 3 N aq. HCl and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, filtered and evaporated to afford the title compound as a white powder (92 mg, 85%), m.p. 233-234° C. 1H NMR (300 MHz, methanol-d4): δ 8.66 (1H, s), 8.65 (1H, d, J=8 Hz), 8.25 (1H, d, J=8 Hz), 8.14-8.11 (2H, m), 7.78 (2H, d, J=9 Hz), 7.69-7.62 (2H, m), 7.42 (2H, d, J=9 hz), 3.00 (1H, heptet, J=7 Hz), 1.30 (6H, d, J=7 Hz). MS (ES+): m/e x. MS (ES−): m/e 319 (20), 318 (100).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C@H:15]([CH3:23])[CH2:16][CH:17]([CH3:22])[CH2:18][CH2:19][CH:20]=[CH2:21])[C:10]([O:12]CC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[Li+].[OH-]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][CH:9]([C@H:15]([CH3:23])[CH2:16][CH:17]([CH3:22])[CH2:18][CH2:19][CH:20]=[CH2:21])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To a solution of (3R)-ethyl 2-(tert-butoxycarbonylamino)-3,5-dimethylnon-8-enoate (20 g, 0.061 moles) in THF/water (200 mL, 1:1) was added methanol (60 mL) followed by LiOH (7.7 g, 0.183 moles) at room temperature. The reaction mass was stirred at room temperature overnight. The solution was concentrated under reduced pressure and the residue was diluted with water (200 mL). The aqueous solution was acidified with aqueous 1.5 N HCl solution to pH ˜3 and extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduce pressure to get crude compound. The crude compound was purified by column chromotography (Silica gel, 3% methanol in DCM) to get 12.4 g (68%) of (3R)-2-(tert-butoxycarbonylamino)-3,5-dimethylnon-8-enoic acid as gummy liquid. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.4 (sb, 1H), 6.92-6.85 (m, 1H), 5.81-5.75 (m, 1H), 5.04-4.93 (m, 2H), 4.12-3.91 (m, 1H), 2.18-1.98 (m, 4H), 1.5 (s, 9H), 1.35-1.02 (m, 3H), 0.98-0.85 (m, 6H).
Reaction SMILES: [OH-].[Na+].Cl.[NH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[OH:11].I[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CS(C)=O>[Cl-].[Na+].O.[Cu]I>[C:13]1([NH:4][C@@H:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]2[OH:11])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC1CCCCC1O
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: Cl
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: O
Product: O[C@@H]1CCCC[C@H]1Nc1ccccc1
Temperature: 90 °C
Reaction time: 48 h
Yield: 91.7 %

Procedure:
A 15 mL screw top test tube fitted with a PTFE septum cap was purged with argon before addition of CuI (5.0 mg, 0.026 mmol, 2.6 mol %), NaOH (83.0 mg, 2.08 mmol) and rac-2-amino-1-cyclohexanol HCl (158 mg, 1.04 mmol). Iodobenzene (139 μL, 1.25 mmol), dimethyl sulfoxide (670 μL), and a stock solution of 9.45 M NaOH (330 μL, 3.12 mmol) were added, via syringe, under argon. The septum cap was replaced with a solid, Teflon-lined cap and the reaction was stirred magnetically at 90° C. for 48 h. The resulting homogeneous solution was allowed to cool before dilution with 10 mL brine. The reaction mixture was transferred to a separatory funnel and extracted with diethyl ether (3×10 mL). The organic extracts were washed with 3 M HCl (3×10 mL). The acid extracts were then cooled in an ice bath and the solution was basified using a saturated NaOH solution. When the pH of the solution became basic, as indicated by pH paper, the solution became opaque. The mixture was transferred to a separatory funnel and extracted with methylene chloride (3×10 mL). The organic extract was washed with brine, dried over MgSO4 and concentrated. A pale yellow oil was obtained and placed under high vacuum overnight. While under vacuum the oil solidified to give 182.5 mg (92% yield) of an off-white solid, mp 57-58° C.
Reaction SMILES: COC(=O)[CH2:4][CH2:5][S:6][C:7]1[CH:8]=[C:9]([O:34][C:35]2[C:36]([CH3:41])=[N:37][CH:38]=[CH:39][CH:40]=2)[C:10]([NH:13][C:14]2[S:18][N:17]=[C:16]([CH:19]3[CH2:25][CH:24]4[N:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:21]([CH2:22][CH2:23]4)[CH2:20]3)[N:15]=2)=[N:11][CH:12]=1.C[C:44]([O-:47])(C)C.[K+].BrCCOC>C1COCC1>[CH3:44][O:47][CH2:4][CH2:5][S:6][C:7]1[CH:8]=[C:9]([O:34][C:35]2[C:36]([CH3:41])=[N:37][CH:38]=[CH:39][CH:40]=2)[C:10]([NH:13][C:14]2[S:18][N:17]=[C:16]([CH:19]3[CH2:20][CH:21]4[N:26]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH:24]([CH2:23][CH2:22]4)[CH2:25]3)[N:15]=2)=[N:11][CH:12]=1
Reactant: COC(=O)CCSc1cnc(Nc2nc(C3CC4CCC(C3)N4C(=O)OC(C)(C)C)ns2)c(Oc2cccnc2C)c1
Reactant: CC(C)(C)[O-]
Agent: COCCBr
Agent: [K+]
Solvent: C1CCOC1
Product: COCCSc1cnc(Nc2nc(C3CC4CCC(C3)N4C(=O)OC(C)(C)C)ns2)c(Oc2cccnc2C)c1
Reaction time: 0.08 h
Yield: 77.4 %

Procedure:
tert-Butyl 3-(5-(5-(3-methoxy-3-oxopropylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (347 mg, 0.566 mmol) was dissolved in THF (5 mL) and potassium 2-methylpropan-2-olate (1699 μL, 1.70 mmol) was added. The reaction was stirred for 5 minutes. 1-Bromo-2-methoxyethane (53.2 μL, 0.566 mmol) was added and the reaction was stirred at ambient temperature for 1 hour. The reaction was partitioned between saturated aqueous NH4Cl and CH2Cl2, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (100% EtOAc) to afford tert-butyl 3-(5-(5-(2-methoxyethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (256 mg, 0.438 mmol, 77.3% yield) as a white solid.
Reaction SMILES: OP(O)(O)=O.[N:6]([C:9]([CH3:17])([CH3:16])[CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)=[C:7]=[O:8]>ClCCCl>[CH3:16][C:9]1([CH3:17])[NH:6][C:7](=[O:8])[C:15]2[CH:14]=[CH:13][S:12][C:11]=2[CH2:10]1
Reactant: CC(C)(Cc1cccs1)N=C=O
Agent: O=P(O)(O)O
Solvent: ClCCCl
Product: CC1(C)Cc2sccc2C(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of dry DCE (60 mL) and anhydrous H3PO4 (35 mL, prepared from 85% H3PO4 and P2O5) is added a solution of isocyanate 46 (5.12 g, 28.3 mmol) in DCE (20 mL). The resulting mixture is stirred vigorously at rt for 2 h, then at reflux for 4 h. The reaction mixture is allowed to cool and separate into two layers. The upper, organic layer is decanted, diluted with EtOAc and Na2Co3 solution, and extracted with EtOAc (2×). The organic extract is washed with brine (2×) and dried (MgSO4), filtered, and evaporated. The residue is purified by FC (6:4 CH2Cl2 /CH3CN) to give a yellow solid, mp 153-154° C. Yield: 2.10 g (41%) . 1H NMR (CDCl3) 7.43 (d, 1, J=5.2), 7.10 (d, 1, J=5.2), 6.82 (s, 1), 2.99 (s, 2), 1.38 (s, 6); 13C NMR (CDCl3) 162.64, 144.99, 130.86, 125.70, 122.96, 54.00, 37.31, 29.05; MS (EI, eE=70 eV) m/z 181 (M+), 166, 151, 148, 125, 124 (base peak), 96, 83, 70, 45; Anal. Calcd for C9H11NOS (MW=181.3): C, 59.64 H, 6.12 N, 7.73. Found: C, 59.76 H, 6.17 N, 7.87.
Reaction SMILES: C(N(CC)CC)C.C(O[C:13]([N:15]([CH3:24])[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)=O)(C)(C)C.[CH3:25][C@:26]12[C:32]([CH3:34])([CH3:33])[C@H:29]([CH2:30][CH2:31]1)[CH:28]([C:35](Cl)=[O:36])C2=O.Cl.O1CCOCC1>ClCCCl.ClCCl>[F:23][C:19]1[CH:18]=[C:17]([N:16]2[C:35](=[O:36])[C:28]3[C@@H:29]4[C:32]([CH3:34])([CH3:33])[C@@:26]([CH3:25])([CH2:31][CH2:30]4)[C:13]=3[N:15]2[CH3:24])[CH:22]=[CH:21][CH:20]=1
Reactant: CN(Nc1cccc(F)c1)C(=O)OC(C)(C)C
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: Cn1c2c(c(=O)n1-c1cccc(F)c1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 27.4 %

Procedure:
Triethylamine (1.1 mL, 7.9 mmol) was added dropwise to a cooled (0° C.) solution of N′-(3-fluoro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (380 mg, 1.58 mmol) in 1,2-dichloroethane (8 mL) over 1 min. A solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 980 mg, 4.56 mmol) in 1,2-dichloroethane (16 mL) was added. The reaction mixture was stirred at 0° C. for 15 min, at room temperature for 15 min, and then in an oil bath at 50° C. for 2 h. The reaction mixture was cooled. A solution of HCl in dioxane (4 M; 8 mL, 32 mmol) was added and the mixture was heated in an oil bath at 100° C. for 1 h. Dichloromethane (100 mL) was added and the mixture was washed with 1:1 water/brine (20 mL), dried (magnesium sulfate), filtered, evaporated, and purified using an ISCO 40 g column, eluting with 20-50% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, and then co-evaporated with dichloromethane and then petroleum ether. The residue was dried under high vacuum at 70° C. overnight to give (4S,7R)-2-(3-fluoro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (130 mg, 27%) as an off-white solid. ES(+)-MS (M+H) 301.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:22]2[CH:30]=[C:29]3[C:25]([CH2:26][CH2:27][N:28]3[C:31](=[O:33])[CH3:32])=[CH:24][CH:23]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19]C2)=[O:14])=[N:9][CH:8]=1)C.[CH:35]1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=C3C(CCN3C(=O)C)=CC=2)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[C:31]([N:28]1[C:29]2[C:25](=[CH:24][CH:23]=[C:22]([N:15]([CH:16]3[CH2:19][CH2:20][CH2:21][CH2:17]3)[C:13](=[O:14])[N:12]([CH3:35])[C:10]3[S:11][C:7]([S:6][CH2:5][C:4]([OH:3])=[O:34])=[CH:8][N:9]=3)[CH:30]=2)[CH2:26][CH2:27]1)(=[O:33])[CH3:32]
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc3c(c2)N(C(C)=O)CC3)s1
Reactant: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: CC(=O)N1CCc2ccc(NCC3CCCC3)cc21
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CC(=O)N1CCc2ccc(N(C(=O)N(C)c3ncc(SCC(=O)O)s3)C3CCCC3)cc21

Procedure:
The title compound was prepared via {2-[3-(1-acetyl-2,3-dihydro-1H-indol-6-yl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 1-[6-(cyclopentylmethyl-amino)-2,3-dihydro-indol-1-yl]-ethanone and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester