Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22]CN4CCCC4)=[CH:17][CH:16]=3)=[N:11][CH:10]=2)=[CH:5][CH:4]=1.COC1C=CC(NC(N)=S)=CC=1.NC(N)=S.CCN(C(C)C)C(C)C>>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:12]2[S:13][C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:10][N:11]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(-c2cnc(Nc3ccc(OCCN4CCCC4)cc3)s2)cc1
Agent: COc1ccc(NC(N)=S)cc1
Agent: NC(N)=S
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2ncc(-c3ccc(OC)cc3)s2)cc1
Temperature: 25 °C

Procedure:
The title compound is prepared as described in Example 3 for [5-(4-methoxy-phenyl)-thiazol-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine but using (4-methoxy-phenyl)-thiourea. After addition of the thiourea and subsequent heating to reflux, the reaction mixture is allowed to cool to RT. DIEA (2.0 equiv) is added and the resulting mixture is heated to reflux for 70 min. Purification of the crude product by silica gel (40 g) column chromatography (CH2Cl2/Et2O, 95/5) affords the title compound as a beige solid: ES-MS: 312.9 [M+H]+; single peak at tR=7.66 min (System 1); Rf=0.11 (CH2Cl2/MeOH, 95/5).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([CH2:19][N:20]1[C:26](=[O:27])[C@@H:25]([NH:28][C:29](=[O:41])[C@@H:30]([N:32](C)[C:33](=O)OC(C)(C)C)[CH3:31])[CH2:24][O:23][C:22]3[CH:42]=[CH:43][CH:44]=[CH:45][C:21]1=3)=[C:14]([O:46][CH3:47])[CH:13]=[CH:12]2>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([CH2:19][N:20]1[C:21]3[CH:45]=[CH:44][CH:43]=[CH:42][C:22]=3[O:23][CH2:24][C@H:25]([NH:28][C:29](=[O:41])[C@@H:30]([NH:32][CH3:33])[CH3:31])[C:26]1=[O:27])=[C:14]([O:46][CH3:47])[CH:13]=[CH:12]2
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)N[C@H]1COc2ccccc2N(Cc2c(OC)ccc3cc(Br)ccc23)C1=O
Yield: 68.9 %

Procedure:
TFA (1.48 g, 1 mL, 13.0 mmol, Eq: 153) was added to a solution of tert-butyl (S)-1-((S)-5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (52 mg, 84.9 μmol, Eq: 1.00) in DCM and at 0° C. After 1 h the mixture was concentrated and the residue was triturated with Et2O to afford the title compound (30 mg, 58.5 μmol, 69.0%) as a light brown solid. MS m/z (MH+) 363.0
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([N+:16]([O-])=O)[C:12]([O:14][CH3:15])=[CH:13][C:8]=2[C:7](=[O:19])[N:6]([CH2:20][CH3:21])[CH2:5][CH2:4]1)[CH3:2].C(O)C>[Pd]>[NH2:16][C:11]1[C:12]([O:14][CH3:15])=[CH:13][C:8]2[C:7](=[O:19])[N:6]([CH2:20][CH3:21])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=2[CH:10]=1
Reactant: CCN1CCN(CC)c2cc([N+](=O)[O-])c(OC)cc2C1=O
Agent: [Pd]
Solvent: CCO
Product: CCN1CCN(CC)c2cc(N)c(OC)cc2C1=O
Reaction time: 4 h
Yield: 101.7 %

Procedure:
Into a round bottom flask, 1,4-diethyl-7-methoxy-8-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (230 mg), 10% Pd/C, (50.0 mg) and ethanol (20 mL, 0.4 mol) were added. The mixture was evacuated and charged with hydrogen (3×). The reaction was stirred under hydrogen balloon for 4 hours. The solid was filtered through Celite. The organic was removed under vacuum to give 8-amino-1,4-diethyl-7-methoxy-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one as a brown solid (0.21 g, 100%). 1H-NMR (CDCl3, 400 MHz): δ 7.08 (s, 1H), 6.24 (s, 1H), 4.17 (s, 2H), 3.78 (s, 3H), 3.59 (q, 2H), 3.33 (t, 2H), 3.16 (t, 2H), 3.02 (q, 2H), 1.23 (t, 3H), 1.10 (t, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10]CC)=O.[CH3:13][NH:14][CH3:15]>CO>[CH3:13][N:14]([CH3:15])[C:8](=[O:10])[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: CNC
Reactant: CCOC(=O)Cc1ccccn1
Solvent: CO
Product: CN(C)C(=O)Cc1ccccn1

Procedure:
To 5.0 g of ethyl 2-pyridylacetate dissolved in 25 ml of MeOH was added 20 ml of dimethyl amine. The mixture was heated at 90° in a steel autoclave for 96 hrs. The solvent/amine mixture was allowed to evaporate until a residual oil was obtained. The residual oil was distilled to afford 4.5 g of the desired N,N-dimethyl-(2-pyridyl)acetamide as a free-flowing yellow oil, bp 105°-110°/0.5 mm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([O:19][CH3:20])[CH:3]=1.N1C=CC=CC=1.[O:27]=[P:28](Cl)([Cl:30])[Cl:29]>C(Cl)Cl>[CH2:11]([O:10][C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][P:28]([Cl:30])([Cl:29])=[O:27])=[CH:3][C:4]=1[O:19][CH3:20])=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1cc(N)ccc1NC(=O)OCc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(NP(=O)(Cl)Cl)ccc1NC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
A solution of benzyl N-(4-amino-2-methoxyphenyl)carbamate (IV; X=PhCH2OCONH, R1 =OCH3) (20 g, 73.5 mM) in CH2Cl2 (25 mL) was added over 5 min to a stirred, icecold, mixture of dry pyridine (25 mL) and POCl3 (100 mL), and the resulting mixture was stirred below 5° C. for a further 2 h. Precipitation with petroleum ether (500 mL) at -10° C. for 15 h gave crude solid product, which was isolated by decantation and washed with two portions of petroleum ether.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])[C:9]=2[C:8]1=[O:31].[C:41]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:43])[CH3:42]>>[C:41]([N:44]1[CH2:49][CH2:48][N:47]([C:16]2[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])[C:9]3[C:8](=[O:31])[N:7]([CH2:6][C:5]4[CH:4]=[C:3]([C:2]([F:40])([F:1])[F:39])[CH:34]=[C:33]([C:35]([F:36])([F:38])[F:37])[CH:32]=4)[CH2:14][CH2:13][CH2:12][NH:11][C:10]=3[N:15]=2)[CH2:46][CH2:45]1)(=[O:43])[CH3:42]
Reactant: CC(=O)N1CCNCC1
Reactant: COc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Product: COc1ccccc1-c1nc(N2CCN(C(C)=O)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Yield: 80.9 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methoxyphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 18; 88.3 mg) was reacted with 1-acetylpiperazine (23.1 mg) to obtain 2-(4-acetylpiperazine-1-yl)-6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methoxyphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine (77.3 mg, 81%).
Reaction SMILES: C([O:5][C:6]1[C:7]([CH2:12][N:13]2[CH2:18][CH2:17][C@H:16]([OH:19])[C@H:15]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[CH2:14]2)=[N:8][CH:9]=[CH:10][N:11]=1)(C)(C)C.C(=O)(O)[O-].[Na+].ClCCl>C(OCC)(=O)C.Cl.C(OCC)(=O)C>[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[O:21][CH2:20][C@H:15]1[C@@H:16]([OH:19])[CH2:17][CH2:18][N:13]([CH2:12][C:7]2[C:6](=[O:5])[NH:11][CH:10]=[CH:9][N:8]=2)[CH2:14]1
Reactant: CC(C)(C)Oc1nccnc1CN1CC[C@H](O)[C@H](COc2ccccc2F)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=c1[nH]ccnc1CN1CC[C@H](O)[C@H](COc2ccccc2F)C1
Reaction time: 1 h
Yield: 40.1 %

Procedure:
After dissolving 198 mg of cis-1-(3-tert-butoxy-2-pyrazinylmethyl)-3-(2-fluorophenoxymethyl)piperidin-4-ol in 3 ml of ethyl acetate, 3 ml of 4N hydrogen chloride/ethyl acetate was added while stirring on ice. After 1 hour, aqueous sodium bicarbonate solution was added to the reaction solution and extraction was performed with dichloromethane. The extract was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue and the mixture was filtered to obtain the title compound (68 mg, 40% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[CH3:34][N:35]([N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[N:48]1[CH2:54][CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[C:36](=[O:38])[CH3:37]>CO.ClCCl>[CH3:32][O:31][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:51]2[CH2:52][CH2:53][CH2:54][N:48]([C:40]3[N:39]([N:35]([CH3:34])[C:36](=[O:38])[CH3:37])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:49][CH2:50]2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)=[O:7]
Reactant: CC(=O)N(C)n1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Agent: I
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5n4N(C)C(C)=O)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 45.1 using 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) and 4-(1-(N-methylacetamido)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt to give, after chromatography on silica gel eluting with 5% methanol/dichloromethane/0.5% concentrated aqueous ammonia solution, the title compound; Rf=0.32 (silica gel, 5% methanol/dichloromethane/0.5% concentrated aqueous ammonia solution).
Reaction SMILES: [H-].[K+].[CH:3]1[C:8]([OH:9])=[CH:7][CH:6]=[C:5]([CH3:10])[CH:4]=1.Br[CH:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])[C:13]([O:15][CH3:16])=[O:14]>CN(C=O)C.C1OCCOCCOCCOCCOCCOC1>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:12]([O:9][C:8]1[CH:7]=[CH:6][C:5]([CH3:10])=[CH:4][CH:3]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(Br)c1ccccc1Cl
Reactant: Cc1ccc(O)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1ccc(C)cc1)c1ccccc1Cl
Temperature: 25 °C
Yield: 76.5 %

Procedure:
To a stirred (0° C.) suspension of 0.530 g (4.63 mmol) of a 35% oil dispersion of potassium hydride in 5 mL of anhydrous DMF was added 0.50 g (4.63 mmol) of p-cresol and 0.050 g of 18-crown-6. After stirring at room temperature for 15 minutes, a solution of 1.22 g (4.63 mmol) of the product of Step B in 5 mL of DMF was slowly added. The reaction mixture was stirred and allowed to warm to room temperature during 45 minutes. The reaction mixture was then partitioned between ethyl acetate and water, separated, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane to afford 1.03 g (77%) of the title compound.
Reaction SMILES: [N+](C1C=CC(C([O:10][C@H:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([N:20]4[C:33]5[C:28](=[C:29]([CH2:35][NH:36][CH:37]([CH3:39])[CH3:38])[C:30]([Cl:34])=[CH:31][CH:32]=5)[C:22]5([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH2:21]4)[C:14]=3[C@H:13]([CH3:40])[CH2:12]2)=O)=CC=1)([O-])=O.O[Li].O.[ClH:46]>C1COCC1.C(Cl)Cl.CCOCC>[ClH:34].[ClH:46].[ClH:34].[Cl:34][C:30]1[C:29]([CH2:35][NH:36][CH:37]([CH3:39])[CH3:38])=[C:28]2[C:22]3([CH2:23][CH2:24][NH:25][CH2:26][CH2:27]3)[CH2:21][N:20]([C:19]3[C:14]4[C@H:13]([CH3:40])[CH2:12][C@@H:11]([OH:10])[C:15]=4[N:16]=[CH:17][N:18]=3)[C:33]2=[CH:32][CH:31]=1
Reactant: CC(C)NCc1c(Cl)ccc2c1C1(CCNCC1)CN2c1ncnc2c1[C@H](C)C[C@H]2OC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Li]O
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)NCc1c(Cl)ccc2c1C1(CCNCC1)CN2c1ncnc2c1[C@H](C)C[C@H]2O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
A solution of (5R,7R)-4-(5-chloro-4-((isopropylamino)methyl)spiro[indoline-3,4′-piperidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate (6 mg, 0.01 mmol) in THF (0.2 mL) was cooled to 0° C. and treated with 1N LiOH—H2O (0.020 mL, 0.020 mmol). The reaction was stirred at room temperature overnight. The reaction was partitioned between DCM and saturated aqueous NaHCO3 solution. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried, and concentrated. The crude residue was purified by column chromatography (10% 7N ammonia in MeOH/DCM) to yield the free base, which was taken up in DCM and acidified with 2N HCl in Et2O. The solvents were removed in vacuo. (5R,7R)-4-(5-chloro-4-((isopropylamino)methyl)spiro[indoline-3,4′-piperidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol trihydrochloride (4 mg, 71%) was obtained as a solid. LCMS (APCI+) m/z 442, 444 [M+H]+; Rt=1.90 min.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8](=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:4]1.[C:29]([C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([C:44]([CH3:47])([CH3:46])[CH3:45])[C:41]=1[O:42][CH3:43])[C:36](O)=[O:37])([CH3:32])([CH3:31])[CH3:30].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH:13]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:12][CH2:11][CH2:10][CH2:9][C:8]([N:5]2[CH2:6][CH2:7][CH:3]([CH2:2][NH:1][C:36](=[O:37])[C:35]3[CH:39]=[C:40]([C:44]([CH3:45])([CH3:46])[CH3:47])[C:41]([O:42][CH3:43])=[C:33]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:34]=3)[CH2:4]2)=[O:28])=[CH:15][CH:16]=1
Reactant: NCC1CCN(C(=O)CCCCC(c2ccc(F)cc2)c2ccc(F)cc2)C1
Reactant: COc1c(C(C)(C)C)cc(C(=O)O)cc1C(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1c(C(C)(C)C)cc(C(=O)NCC2CCN(C(=O)CCCCC(c3ccc(F)cc3)c3ccc(F)cc3)C2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(3-aminomethyl-pyrrolidin-1-yl)-6,6-bis-(4-fluoro-phenyl)-hexan-1-one (0.49 g, 1.26 mmol) in dry CH2Cl2 (35 ml) was added 3,5-di-tert-butyl-4-methoxy benzoic acid (0.33 g, 1.26 mmol) under nitrogen. To the reaction was added EDC (0.48 g, 2.52 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue dissolved in ethyl acetate: water (10:1) (130 ml). The organic was washed with water (30 ml, 2×) and 10% NaOH (30 ml) and dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2:CH3OH (15:1) to give a desired product in good yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:3]=1.[H-].[Na+].[CH2:17](Br)[CH:18]=[CH2:19]>CN(C)C=O>[CH2:19]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH:18]=[CH2:17]
Reactant: Oc1ccc(Cl)cc1C1CCCCC1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(Cl)cc1C1CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 106.1 %

Procedure:
To a solution of 4-chloro-2-cyclohexylphenol (23.00 g, 0.109 mol) in N,N-dimethylformamide (600 mL) was added sodium hydride (4.56 g, 0.114 mol, 60 wt. %) followed by allyl bromide (14.51 g, 0.120 mol) and the reaction mixture was allowed to stir at room temperature for 5 h. The solvent was removed in vacuo and the residue diluted with water (500 mL) and extracted with ethyl acetate (2×300 mL). The combined organic layers were washed with water (500 mL), saturated aqueous sodium chloride (500 mL), dried (magnesium sulfate), and the solvent removed in vacuo to give 29.0 g of 1-(allyloxy)-4-chloro-2-cyclohexylbenzene as a brown oil. Treatment of the allyl ether in refluxing mesitylene generally according to the procedure described for Intermediate 8 provided 18.0 g of 2-allyl-4-chloro-6-cyclohexylphenol. Treatment of the phenol (6.5 g, 0.026 mol) with 3-chloroperoxybenzoic acid (9.88 g, 0.045 mol, 77%) followed by potassium carbonate (10.00 g, 0.072 mol) generally according to the procedure described for Intermediate 9 afforded 4.6 g (67%) of (±)-(5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran-2-yl)methanol as a white solid. mp 67-69° C.; Anal. calcd. for C15H19ClO2: C, 67.54; H, 7.18. Found: C, 67.81; H, 6.98.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]#[N:15])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([OH:12])[C:6]=2[Cl:13].[Si]([O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(C(C)(C)C)(C)C>>[Cl:13][C:6]1[C:7]([OH:12])=[CH:8][CH:9]=[C:10]2[C:5]=1[C:4]([C:14]#[N:15])=[CH:3][C:2]([C:27]1[CH:28]=[CH:29][C:24]([OH:23])=[CH:25][CH:26]=1)=[CH:11]2
Reactant: N#Cc1cc(Br)cc2ccc(O)c(Cl)c12
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Product: N#Cc1cc(-c2ccc(O)cc2)cc2ccc(O)c(Cl)c12

Procedure:
The title compound was prepared by reacting 3-bromo-8-chloro-7-hydroxy-1-naphthonitrile (0.10 g, 0.37 mmol) with 4-tert-butyldimethylsilyloxyphenylboronic acid (0.13 g, 0.52 mmol) according to Method A to yield 0.036 g (33%) of a white solid: mp 254–256° C.; 1H NMR (DMSO-d6): δ 6.90 (2H, d, J=8.64 Hz), 7.43 (1H, d, J=8.95 Hz), 7.72 (2H, d, J=8.64 Hz), 7.99 (1H, d, J=8.97 Hz), 8.38 (1H, d, J=1.95 Hz), 8.47 (1H, d, J=1.92 Hz), 9.73 (1H, s), 11.08 (1H, s); MS (ESI) m/z 294/296 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4](=[CH2:16])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C(#N)C.CO>[C:6]([NH:5][CH:4]([CH2:16][N:28]1[CH2:27][CH2:26][N:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH2:30][CH2:29]1)[C:3]([O:2][CH3:1])=[O:17])([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: C=C(NC(=O)OCc1ccccc1)C(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CO
Product: COC(=O)C(CN1CCN(C(=O)OC(C)(C)C)CC1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To N-carbobenzyloxydehydroalanine methyl ester (2.0 g, 8.4 mmol) was added 4-tert-butoxycarbonylpiperazine (1.56 g, 1.0 eq), ferric chloride (0.220 g, 0.2 eq) in a 6:1 mixture of acetonitrile/methanol. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was evaporated under reduced pressure. EtOAc was added and the organic layer washed with a soldium sulfate solution. Upon removal of the solvent under reduced pressure, the crude material was purified by column chromatography (silica gel; CH2Cl2:MeOH 4:1) to afford the title compound.
Reaction SMILES: S(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)(=O)(=O)C.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[CH2:20][N:21]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[C:22]1=[O:36]>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[CH2:20][N:21]1[CH2:25][CH2:24][C:23]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)([CH2:26][CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[C:22]1=[O:36]
Reactant: COc1cc(CN2CCC(CCO[Si](C)(C)C(C)(C)C)C2=O)cc(OC)c1OC
Reactant: COc1ccc(COS(C)(=O)=O)cc1
Product: COc1ccc(CC2(CCO[Si](C)(C)C(C)(C)C)CCN(Cc3cc(OC)c(OC)c(OC)c3)C2=O)cc1

Procedure:
Prepare by the method of Example 17.3 using 4-methoxybenzyl mesylate and 1-(3,4,5-trimethoxybenzyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine to give the title compound: Rf=0.15 (silica gel, 1/4 ethyl acetate/hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14]([C:16](OC)=[O:17])=[CH:15][C:8]=23)=[CH:4][CH:3]=1.[CH3:22][NH2:23].[H-].[Na+].O>C1COCC1>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14]([C:16]([NH:23][CH3:22])=[O:17])=[CH:15][C:8]=23)=[CH:4][CH:3]=1
Reactant: CN
Reactant: COC(=O)c1cc2c(Oc3ccc(Cl)cc3)cncc2s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1cc2c(Oc3ccc(Cl)cc3)cncc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Example 61A (100 mg, 0.3135 mmol) and methylamine (2M solution in THF, 0.467 mL, 0.941 mmol) in THF (2 mL) at 0° C. was treated with NaH (12 mg, 0.47 mmol), stirred at room temperature for 1 hour, treated with water (0.1 mL), and concentrated. The residue was purified by flash chromatography on silica gel with 20% acetone/hexane to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[CH:4][CH:3]=1.[BH4-].[Na+].[O:12]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14]C1>[OH-].[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:18][CH:15]2[CH2:16][CH2:17][O:12][CH2:14]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: OC1CCOCC1
Reactant: C=Cc1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: CC(OC1CCOC1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To the solution of 1-bromo-4-vinylbenzene (500 mg, 2.75 mmol) in tetrahydro-2H-pyran-4-ol (20 mL) was added mercuric trifluoroacetate (1.18 g, 2.75 mmol), the mixture was stirred for 1 hour at room temperature, then at 0° C. 3 mol/L sodium hydroxide (20 mL) was added with vigorous stirring, after 2 minute, sodium borohydride (0.5 mol/L) in sodium hydroxide (20 ml, 3 mol/L) was added. After 12 hours, the mixture was extracted with ethyl acetate (50 mL*3). The organics were washed with water (5×20 mL) and dried with sodium sulfate, the solvent was removed and purified by column chromatography (silica gel, dichloromethane/methanol=20:1). to give 3-(1-(4-bromo phenyl)ethoxy)-tetrahydrofuran (461 mg, 59%) as oil.
Reaction SMILES: C([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[F:12])(=O)C.C[OH:14]>N>[F:12][C:5]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=1[OH:14]
Reactant: COc1ccc(C(C)=O)c(F)c1
Reactant: CO
Agent: N
Product: COc1ccc(O)c(F)c1
Yield: 94 %

Procedure:
A suspension of 2-fluoro-4-methyl acetophenone (10.0 g, 0.059 mol), mCPBA (26.0 g, 0.128 mol) and MgSO4 (30.0 g) in 500 mL of CHCl3 was stirred for 12 hrs. at RT. The mixture was then filtrated, washed with 2M NaOH, dried over Na2SO4 and concentrated in vacuo to give 1-acetyl-2-fluoro-4-methoxybenzene as a solid (10.7 g, 98%). A solution of the 1-acetyl-2-fluoro-4-methoxybenzene (5.3 g, 0.029 mol) in 100 mL of MeOH and 20 mL of 25% NH3 (aq) was stirred for 1 hr. at RT. The mixture was then concentrated in vacuo, diluted with water, extracted with EtOAc, dried over Na2SO4 and concentrated in vacuo to give 2-fluoro-4-methoxyphenol as an oil (3.85 g, 94%). 2-Ethoxy-1-fluoro-4-methoxybenzaldehyde was prepared according to method described in Example 362 of WO 93/03022 and converted to a cis/trans mixture of 2-(2-ethoxy-1-fluoro-6-methoxyphenyl) cyclopropylisocyanates according to the methods described in Examples 375 and 348 of WO 93/03022. This product was then condensed with 2-amino-5-bromo-pyridine in a manner analogous to the method in Example 7 to provide cis/trans mixture of N-2-(2-ethoxy-1-fluoro-6-methoxyphenyl)cyclopropyl-N′-(5-bromopyrid-2-yl)-ureas. The two products were separated on a silica-gel column eluated with mixtures of hexane and ethylacetate to yield N-(cis)-(3-ethoxy-2-fluoro-6-methoxyphenyl)-cyclopropyl-N′-(5-bromopyrid-2-yl)-urea: 1H NMR (250 MHz, CDCl3) δ 7.88 (s, 1H), 7.55 (dd, 1H), 6.83 (t, 1H),6.58 (dd, 1H), 4.03 (q, 2H), 3.79 (s, 3H), 3.32-3.19 (m, 1H), 1.54-1.20 (m, 2H), 1.46 (t, 3H).