Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[OH:30].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][O:30][C:21]2[CH:22]=[CH:23][C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: Oc1ccc2ccccc2c1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccc3ccccc3c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and naphthalen-2-ol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid. MS (ES) for C22H22O5 [M+NH4]+: 389.3.
Reaction SMILES: COC1C=C2C(=CC=1)CC(C1C(C)=CC=CC=1N)CC2.Cl.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:26](Cl)=O.FC1C=[C:44](C=CC=1OCCN1CCCCC1)[CH2:45][NH:46][C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[C:48]=1[CH:54]1[CH2:63][CH2:62][C:61]2[C:56](=[CH:57][CH:58]=[C:59]([O:64][CH3:65])[CH:60]=2)[CH2:55]1>>[CH2:45]([N:46]([CH2:26][C:25]1[CH:29]=[CH:30][C:31]([O:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:23]([F:22])[CH:24]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[C:48]=1[CH:54]1[CH2:63][CH2:62][C:61]2[C:56](=[CH:57][CH:58]=[C:59]([O:64][CH3:65])[CH:60]=2)[CH2:55]1)[CH3:44]
Reactant: O=C(Cl)c1ccc(OCCN2CCCCC2)c(F)c1
Reactant: COc1ccc2c(c1)CCC(c1c(C)cccc1NCc1ccc(OCCN3CCCCC3)c(F)c1)C2
Agent: COc1ccc2c(c1)CCC(c1c(C)cccc1N)C2
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cccc(C)c1C1CCc2cc(OC)ccc2C1

Procedure:
Synthesized from 2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-3-methylphenylamine and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoyl chloride hydrochloride according to an analogous synthetic method to Example 152, [3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-3-methylphenyl]amine (578 mg) was used according to an analogous synthetic method to Example 36 to provide ethyl[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-3-methylphenyl]amine (449 mg). This compound (447 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (317 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8]C(C2C=C(NC(=O)OCC=C)C=CC=2)=O)[CH:5]=[CH:4][N:3]=1.[F:24][C:25]1[C:34]([NH:35][C:36]([O:38][CH2:39][CH:40]=[CH2:41])=[O:37])=[CH:33][CH:32]=[C:31]([F:42])[C:26]=1[C:27]([O:29]C)=O.ClC1N=C(C)C=CN=1>>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:27]([C:26]2[C:25]([F:24])=[C:34]([NH:35][C:36](=[O:37])[O:38][CH2:39][CH:40]=[CH2:41])[CH:33]=[CH:32][C:31]=2[F:42])=[O:29])[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1ccc(F)c(C(=O)OC)c1F
Reactant: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1
Agent: Cc1ccnc(Cl)n1
Product: C=CCOC(=O)Nc1ccc(F)c(C(=O)Cc2ccnc(Cl)n2)c1F
Yield: 60.2 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 11 using methyl 2,6-difluoro-3-{[(2-propen-1-yloxy)carbonyl]amino}benzoate (80 g, 295 mmol) and 2-chloro-4-methylpyrimidine (41.6 g, 324 mmol) the title compound of Step E was obtained (65 g, 60.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.49-9.60 (m, 1H), 8.72-8.77 (m, 0.3H), 8.58-8.64 (m, 0.6H), 7.57-7.83 (m, 2H), 7.15-7.25 (m, 1H), 5.89-6.01 (m, 1H), 5.75-5.82 (m, 0.6H), 5.20-5.40 (m, 2H), 4.55-4.62 (m, 2H), m/z (ES+): 368 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])(C)(C)C.C(O[C:27](=[O:50])[CH2:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[S:37][CH:38]=[C:39]([CH2:41][O:42]C3CCCCO3)[N:40]=2)[CH:31]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])=[CH:13][C:8]2[N:7]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]4[S:37][CH:38]=[C:39]([CH2:41][OH:42])[N:40]=4)[CH:31]=3)[CH2:28][C:27](=[O:50])[NH:20][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)cs2)c1
Reactant: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CO)cs3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(isopropyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (0.17 g) (Example J26) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-thiazol-2-yl]-phenyl]-propionic acid tert-butyl ester (Example K27) (0.23 g) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light-brown solid (0.05 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:10].Cl[CH2:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:10])[O:8][CH2:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([N:30]([CH3:31])[CH3:32])=[O:29])=[CH:26][CH:25]=1
Reactant: O=C(c1ccc(O)cc1F)N1CCC[C@H]1CN1CCCC1
Reactant: CN(C)C(=O)c1ccc(CCl)cc1
Product: CN(C)C(=O)c1ccc(COc2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure C using (2-Fluoro-4-hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 4-chloromethyl-N,N-dimethyl-benzamide [CAS 121083-51-0]. MS (ES+) 454.2
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[N:17]=[C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:19][C:20]=3[C:21]([F:24])([F:23])[F:22])=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.F[C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][N:33]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:25]1([C:18]2[O:19][C:20]([C:21]([F:22])([F:23])[F:24])=[C:16]([C:14]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([CH:4]4[CH2:5][CH2:6][N:1]([C:32]5[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][N:33]=5)[CH2:2][CH2:3]4)=[CH:12][CH:11]=3)=[O:15])[N:17]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: O=C(O)c1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)c1ccc(N2CCC(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)nc1
Temperature: 135 °C
Yield: 15.1 %

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (208 mg, 0.5 mmol) and 6-fluoronicotinic acid (72 mg, 0.5 mmol) in DMSO (2 L) containing potassium carbonate (135 mg, 1 mmol) was heated in a microwave at 135° C. for 35 minutes. The mixture was extracted with ethyl acetate and 0.1N hydrochloric acid. The organic layer was washed with water and brine. Solvents were evaporated and the residue was purified through ISCO column chromatography (silica gel, ethyl acetate in hexanes, 10% to 100% linear gradient). The collected fractions were concentrated and the white crystalline material was filtered to give 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (40.5 mg). LC-MS for C28H23F3N4O4 (m/e) calcd 536, obsd 537 (M+H). 1H-NMR is consistent with the desired structure.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH3:14])=[C:8](B(O)O)[CH:9]=1)([CH3:3])[CH3:2].Br[C:16]1[CH:17]=[C:18]([CH:22]([C:27]2[O:28][C:29]([CH3:32])=[N:30][N:31]=2)[CH2:23][C:24]([OH:26])=[O:25])[CH:19]=[CH:20][CH:21]=1>CN(C=O)C.O.[NH4+].[Cl-]>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH3:14])=[C:8]([C:20]2[CH:21]=[CH:16][CH:17]=[C:18]([CH:22]([C:27]3[O:28][C:29]([CH3:32])=[N:30][N:31]=3)[CH2:23][C:24]([OH:26])=[O:25])[CH:19]=2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: Cc1nnc(C(CC(=O)O)c2cccc(Br)c2)o1
Reactant: COc1ccc(C(C)C)cc1B(O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(C)C)cc1-c1cccc(C(CC(=O)O)c2nnc(C)o2)c1
Yield: 57 %

Procedure:
12.83 g (66.11 mmol) of 5-isopropyl-2-methoxybenzeneboronic acid, 48.97 g (150.3 mmol) and 18.7 g (60.1 mmol) of 3-(3-Bromo-phenyl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionic acid are heated together with 3 mmol of bis(triphenylphosphine)palladium (II)dichloride in 200 ml of DMF and 30 ml of water for 10 hours at 100° C. The reaction mixture is diluted with conc. NH4Cl solution (200 ml) and extracted with methyl-tetrahydrofurane. The organic phase is filtrated over Celite and 100 g of SiO2 and the solvent is removed in vacuo. The obtained crude 3-(5′-Isopropyl-2′-methoxy-biphenyl-3-yl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionic acid is used directly in the next step. (Yield=57%, 28 g)
Reaction SMILES: B(F)(F)F.CCOCC.[C:10]([C:14]1[CH:15]=[C:16]([C:20]2(O)[CH2:25][CH2:24][C:23](=[CH2:26])[CH2:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1)([CH3:13])([CH3:12])[CH3:11].[N:28]([Si](C)(C)C)=[N+:29]=[N-:30].C(OCC)(=O)C>C(OCC)C.[Cl-].[NH4+]>[N:28]([C:20]1([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:15]=2)[CH2:25][CH2:24][C:23](=[CH2:26])[CH2:22][CH2:21]1)=[N+:29]=[N-:30]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C=C1CCC(O)(c2cccc(C(C)(C)C)c2)CC1
Agent: FB(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C=C1CCC(N=[N+]=[N-])(c2cccc(C(C)(C)C)c2)CC1
Yield: 36.9 %

Procedure:
Borontrifluoride-etherate (2.0 mL, 15.7 mmol) was added to a solution of 1-(3-tert-butyl-phenyl)-4-methylene-cyclohexanol (3.60 g, 14.7 mmol) and azidotrimethylsilane (4.0 mL, 30.1 mmol) in diethyl ether (30 mL) and placed into a preheated oil bath at 45° C. After heating at reflux for 4 h, the solution was diluted with saturated aqueous ammonium chloride and extracted with diethyl ether. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was flash chromatographed with 99:1, 49:1, and 24:1 hexanes:ethyl acetate as the eluant to yield 1.46 g (37% yield) of 1-(1-azido-4-methylene-cyclohexyl)-3-tert-butyl-benzene as a clear oil.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[C:14]([CH3:21])[CH:13]=1>O1CCOCC1>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([N:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:1]2)=[O:20])=[C:14]([CH3:21])[CH:13]=1
Reactant: COc1ccc(N=C=O)c(C)c1
Reactant: c1ccc2c(c1)CNC2
Solvent: C1COCCO1
Product: COc1ccc(NC(=O)N2Cc3ccccc3C2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.5 %

Procedure:
To a solution of isoindoline (576 mg, 4.0 mmol) in dry 1,4-dioxane (20 mL) was added 4-methoxy-2-methylphenyl isocyanate (815 mg, 5.0 mmol) under argon at room temperature. The reaction mixture was then stirred at RT overnight. The solvent was evaporated under reduced pressure, and the residue was purified by chromatography on silica gel (EtOAc/hexanes: 1:1) to give the title compound (1.18 g, 84%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12](C(O)=O)[CH2:13][O:14][C:15]([C@@H:17]1[CH2:21][C@@H:20]([CH3:22])[CH2:19][N:18]1[C:23](=[O:49])[C@@H:24]([NH:26][C:27]([C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][N:30]1[C:35]([C@@H:37]1[CH2:41][CH2:40][CH2:39][N:38]1[C:42](OC(C)(C)C)=[O:43])=[O:36])=[O:28])[CH3:25])=[O:16])=[O:10])C1C=CC=CC=1.F[C:54]1[C:59](O)=[C:58](F)[C:57](F)=[C:56](F)[C:55]=1F.C(Cl)CCl>ClCCl>[CH3:22][C@H:20]1[CH2:19][N:18]2[C@H:17]([C:15](=[O:16])[O:14][CH2:13][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:42](=[O:43])[N:38]3[C@H:37]([C:35](=[O:36])[N:30]4[C@H:29]([C:27](=[O:28])[NH:26][C@@H:24]([CH3:25])[C:23]2=[O:49])[CH2:34][CH2:33][CH2:32][CH2:31]4)[CH2:41][CH2:40][CH2:39]3)[CH2:21]1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: C[C@@H]1C[C@@H](C(=O)OC[C@H](NC(=O)OCc2ccccc2)C(=O)O)N(C(=O)[C@H](C)NC(=O)[C@@H]2CCCCN2C(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)C1
Solvent: ClCCCl
Solvent: ClCCl
Product: C[C@@H]1C[C@H]2C(=O)OC[C@H](NC(=O)OCc3ccccc3)C(=O)N3CCC[C@H]3C(=O)N3CCCC[C@H]3C(=O)N[C@@H](C)C(=O)N2C1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
3.95 g (5.41 mm ol) of the acid from example 25A and 3.98 g (21.65 mmol) of pentafluorophenol are dissolved in dichloromethane (13 ml) and cooled to −20° C. under argon. 1.14 g (5.95 mmol) of EDC are added, and the reaction mixture is stirred overnight with slow warming to RT. The reaction solution is concentrated to dryness and the residue is treated at 0° C. with 4N hydrogen chloride solution in dioxane (80 ml). The mixture is stirred for 3 h and the solvent is subsequently removed in vacuo. The residue is dissolved in dichloromethane (about 900 ml) and slowly added dropwise at RT to a vigorously stirred two-phase mixture of 1N aqueous sodium hydrogencarbonate solution (700 ml) and dichloromethane (1200 ml). The reaction mixture is stirred overnight. The phases are separated, the aqueous phase is extracted three times with dichloromethane and the combined organic phases are dried over sodium sulfate, filtered and concentrated to dryness. The residue (2.7 g of yellow hard foam) is purified by chromatography in 3 portions by means of preparative RP-HPLC using acetonitrile/water (gradient). 1.98 g (60% of th.) of the product are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][NH:24][C:17]=23)[C:12]([CH3:25])=[CH:11][N:10]=1.[N:26]([CH2:29][CH3:30])=[C:27]=[O:28]>C(#N)C.N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][N:24]([C:27]([NH:26][CH2:29][CH3:30])=[O:28])[C:17]=23)[C:12]([CH3:25])=[CH:11][N:10]=1
Reactant: CCN=C=O
Reactant: Cc1cnc(-c2cc(F)ccc2F)cc1Nc1ccnc2cn[nH]c12
Solvent: CC#N
Solvent: c1ccncc1
Product: CCNC(=O)n1ncc2nccc(Nc3cc(-c4cc(F)ccc4F)ncc3C)c21
Temperature: 75 °C

Procedure:
N-(2-(2,5-Difluorophenyl)-5-methylpyridin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine (106 mg, 0.314 mmol) was suspended in acetonitrile (3.1 mL). Isocyanatoethane (30.8 μl, 0.393 mmol) and 1 drop of pyridine were added and the mixture was heated at 75° C. for 2 hours. The mixture was cooled to give a solid which was collected by filtration to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (3H, t, J=7.07 Hz) 2.38 (3H, s) 3.34-3.45 (2H, m) 7.25-7.42 (3H, m) 7.76 (1H, ddd, J=9.47, 6.06, 3.16 Hz) 7.93 (1H, s) 8.41 (1H, d, J=5.30 Hz) 8.54 (1H, s) 8.60 (1H, s) 9.09 (1H, t, J=5.81 Hz) 11.05 (1H, s). MS [M+H] found 409.4.
Reaction SMILES: [CH:1]1[N:6]=[C:5]2[N:7]([C@H:10]3[C@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][OH:18])[CH2:11]3)[CH:8]=[N:9][C:4]2=[C:3]([NH2:19])[N:2]=1.CN(C)C=O.N1C=CN=C1.[CH3:30][Si:31](Cl)([CH3:38])[C:32]([CH:35]([CH3:37])[CH3:36])([CH3:34])[CH3:33]>O>[NH2:19][C:3]1[N:2]=[CH:1][N:6]=[C:5]2[C:4]=1[N:9]=[CH:8][N:7]2[C@@H:10]1[CH2:11][C@H:12]([CH2:17][O:18][Si:31]([C:32]([CH3:34])([CH:35]([CH3:37])[CH3:36])[CH3:33])([CH3:38])[CH3:30])[C@@H:13]([OH:16])[C@H:14]1[OH:15]
Reactant: Nc1ncnc2c1ncn2[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CC(C)C(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Temperature: 25 °C

Procedure:
A mixture of aristeromycin (50 g) and dimethylformamide (250 ml) was stirred at room temperature and imidazole (50 g) and then dimethylthexylsilyl chloride (10 ml) were added. Three further 10 ml portions of dimethylthexylsilyl chloride were added after 20 min, 1 h and 1.75 h. After 4 h the resulting mixture was poured into rapidly stirred water (2.5 L). The suspension was filtered and the residue washed with water (2×250 ml). The air dried solid was added to di-isopropyl ether (500 ml) and stirred for 20 min. The suspension was filtered and the residue collected, stirred with diethyl ether (500 ml) and filtered to give the title compound (49 g); 1H nmr (DMSO-d6) δ8.13 (1H), 8.09 (1H), 7.18 (2H), 5.03-4.93 (1H), 4.76-4.60 (2H), 4.41-4.28 (1H), 3.88-3.78 (1H), 3.72-3.57 (2H), 2.28-1.70 (3H), 1.67-1.52 (1H), 0.95-0.75 (12H), 0.1 (6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16]>C(Cl)Cl>[Si:18]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc(Br)c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
3-Bromophenol (6 mmol, 1.04 g), imidazole (10 mmol, 0.68 g) and TBDMSCl (6.6 mmol, 0.99 g) were dissolved in DCM (20 ml). The solution was allowed to stir at room temperature overnight. The solid generated during the reaction was filtered off and the solvent removed under reduced pressure. The resulting residue was subjected to flash chromatography (EtOAc/Hexanes=3%˜15%) giving compound 2 (1.56 g, 5.44 mmol, yield 91%). 1H NMR (CDCl3): δ 7.11-7.08 (m, 2H), 7.03-7.02 (m, 1H), 6.80-6.77 (m, 1H), 0.99 (s, 9H), 0.31 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>ClCCl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1ccc(Br)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a solution of 2-(4-bromophenyl)ethanol (5 g, 25 mmol) in anhydrous dichloromethane (150 mL) was added triethylamine (7.5 g, 75 mmol), DMAP (300 mg, 2.5 mmol) and tert-butyldimethylsilyl chloride (7.5 g, 50 mmol) sequentially. The resulting pale brown solution was stirred at room temperature for overnight. The reaction mixture was extracted with dichloromethane and water three times. The combined organic layers were dried over anhydrous sodiumsulphate, filtered and concentrated in vacuo. The crude product was subjected to column chromatography with PE as eluant to afford the subtitle compound as a brown oil (7.1 g).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]([C@:11]12[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][C@H:12]1[CH2:13][CH2:14][O:15][C:16]1[C:17]2=[CH:18][C:19]2[CH:20]=[N:21][N:22]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=3)[C:23]=2[CH:24]=1)[CH3:10]>CS(C)=O.C1COCC1>[CH2:9]([C:11]12[CH2:35][CH2:34][C:33]3([CH2:4][O:36]3)[CH2:32][CH:12]1[CH2:13][CH2:14][O:15][C:16]1[C:17]2=[CH:18][C:19]2[CH:20]=[N:21][N:22]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=3)[C:23]=2[CH:24]=1)[CH3:10]
Reactant: C[S+](C)(C)=O
Reactant: CC[C@]12CCC(=O)C[C@H]1CCOc1cc3c(cnn3-c3ccnc(C)c3)cc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCC12CCC3(CO3)CC1CCOc1cc3c(cnn3-c3ccnc(C)c3)cc12
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 82.1 %

Procedure:
A 100 mL round-bottom flask equipped with rubber septum and nitrogen inlet needle was charged with sodium hydride (60 wt % in oil, 0.212 g, 5.29 mmol) in DMSO (13 mL) and then the mixture was heated at about 60° C. in a heating block for about 30 min. The mixture was allowed to cool to rt, at which point trimethylsulfoxonium iodide (1.16 g, 5.29 mmol) was added in one portion and the reaction mixture was stirred for about 15 min. A solution of rac-(4aR,12bS)-12b-ethyl-9-(2-methylpyridin-4-yl)-4,4a,5,6,9,12b-hexahydro-1H-benzo[4,5]oxepino[3,2-f]indazol-3 (2H)-one (92, R1=2-methylpyridin-4-yl, R2=Ethyl) (0.993 g, 2.64 mmol) in THF (13 mL) was added in one portion. After about 30 min the reaction was concentrated under reduced pressure and the residue was partitioned between EtOAc (50 mL) and water (50 mL). The layers were separated and the aqueous phase was extracted with EtOAc (2×10 mL). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified on silica gel (40 g, EtOAc). Collection and concentration of the appropriate fractions gave rac-(2′R,4aS,12bR)-12b-ethyl-9-(2-methylpyridin-4-yl)-1,2,4,4a,5,6,9,12b-octahydrospiro[benzo[4,5]oxepino[3,2-f]indazole-3,2′-oxirane] (93, R1=2-methylpyridin-4-yl, R2=Ethyl) (0.844 g, 82%). LC/MS, method 3, Rt=2.40 min, MS m/z 390 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.61-8.55 (m, 1H), 8.23 (s, 1H), 7.91-7.76 (m, 2H), 7.69 (s, 1H), 7.56 (s, 1H), 4.43-4.31 (m, 1H), 3.84-3.71 (m, 1H), 2.98-2.70 (m, 3H), 2.71-2.56 (m 2H), 2.56-2.16 (m, 4H), 2.07-1.93 (m, 1H), 1.93-1.77 (m, 1H), 1.73-1.33 (m, 4H), 0.97-0.83 (m, 1H), 0.74-0.56 (t, J=7.5 Hz, 3H).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[Cl:23][C:24]1[C:25]([C:32]([NH:34][NH:35][C:36](=O)[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=O)=[N:26][C:27]([S:30][CH3:31])=[N:28][CH:29]=1>N1C=CC=CC=1.O>[CH2:37]([C:36]1[S:10][C:32]([C:25]2[C:24]([Cl:23])=[CH:29][N:28]=[C:27]([S:30][CH3:31])[N:26]=2)=[N:34][N:35]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CSc1ncc(Cl)c(C(=O)NNC(=O)Cc2ccccc2)n1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccncc1
Solvent: O
Product: CSc1ncc(Cl)c(-c2nnc(Cc3ccccc3)s2)n1
Temperature: 100 °C
Yield: 47 %

Procedure:
Lawesson's Reagent (0.487 g (1.2 mmol) and 5-chloro-2-(methylthio)-N′-(2-phenyl-acetyl)pyrimidine-4-carbohydrazide (0.442 g, 1.2 mmol) were dissolved in 8 mL pyridine. This solution was heated to 100° C. for 30 h, giving ˜50% conversion. Upon cooling, the reaction mixture was diluted with excess H2O. The aqueous layer was extracted with EtOAc. The combined organic layers were dried with magnesium sulfate and concentrated under vacuum. Flash chromatography was used to obtain 0.190 g (47% yield) product as a brown solid. MS (M+H)+ 335.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5]Br)[CH3:2].[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[S:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]([NH:28][C:29]2[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[C:31]([OH:38])[C:30]=2[CH:39]([CH3:41])[CH3:40])=[O:27])[CH2:21][CH2:20]1>[F-].[K+].C(#N)C>[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[S:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]([NH:28][C:29]2[C:34]([CH:35]([CH3:36])[CH3:37])=[CH:33][CH:32]=[C:31]([O:38][CH2:2][CH2:1][O:3][CH2:4][CH3:5])[C:30]=2[CH:39]([CH3:41])[CH3:40])=[O:27])[CH2:21][CH2:20]1
Reactant: CC(C)c1ccc(O)c(C(C)C)c1NC(=O)CN1CCN(CCSc2nc3ccccc3o2)CC1
Reactant: CCOCCBr
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: CCOCCOc1ccc(C(C)C)c(NC(=O)CN2CCN(CCSc3nc4ccccc4o3)CC2)c1C(C)C
Reaction time: 41 h
Yield: 70 %

Procedure:
2-Bromoethyl ethyl ether (2 ml) and potassium fluoride catalyst carried on alumina (40 wt %, 225 mg, 1.51 mmol) were added to a solution of 2-[4-[2-(benzoxazol-2ylthio)ethyl]piperazin-1-yl]-N-(2,6-diisopropyl-3-hydroxyphenyl)acetamide (150 mg, 0.30 mmol) in acetonitrile (3 ml) followed by stirring for 41 hours. The catalyst was filtered off and the filtrate was diluted with water and extracted with ethyl acetate. The organic layer was washed with a sodium chloride solution and dried over anhydrous sodium sulfate and the solvent was evaporated therefrom. The residue was purified by a preparative thin layer chromatography (developing solvent, chloroform:ammonia-saturated methanol=20:1) and the resulting crude crystals were recrystallized from ethyl acetate-hexane to provide 120 mg (yield 70%) of the desired compound as colorless powdery crystals.