Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][CH2:19][C@H:12]2[NH:11][C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1(=[O:38])[N:28]([CH2:29][C:30](Cl)=[O:31])[C:27](=[O:33])[C:26]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:25]12.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>ClCCCl>[CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][CH2:19][C@H:12]2[N:11]([C:30](=[O:31])[CH2:29][N:28]2[C:27](=[O:33])[C:26]3=[CH:34][CH:35]=[CH:36][CH:37]=[C:25]3[C:24]2=[O:38])[C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Reactant: O=C1[C@H]2CCCC[C@H]2Nc2ccccc2N1Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCCl
Product: O=C1c2ccccc2C(=O)N1CC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCCC[C@H]21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43 %

Procedure:
To a solution of (4aR*,11aS*)-10-benzyl-1,2,3,4,4a,5,10,11a-octahydro-11H-dibenzo[b,e][1,4]-diazepin-11-one (200 mg, 0.65 mmol) in 1,2-dichloroethane (2 mL) was added phthalimidoacetyl chloride (175 mg, 0.78 mmol), and the mixture was stirred for 15 minutes at room temperature. To this solution was added pyridine (0.08 mL), and the mixture was stirred for 15 minutes at room temperature. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate. The aqueous layer was separated, and the organic layer was washed with water and a saturated aqueous solution of sodium chloride, which was dried over magnesium sulfate, followed by filtration and concentration under reduced pressure. The concentrate was crystallized from ethanol to give 138 mg (yield 43%) of the titled compound, m.p. 241°-242.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:19])=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:19][S:31]([C:27]2[S:26][CH:30]=[CH:29][CH:28]=2)(=[O:33])=[O:32])=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COC(=O)c1cc(OCc2ccccc2)ccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(OCc2ccccc2)ccc1NS(=O)(=O)c1cccs1
Reaction time: 1 h

Procedure:
Methyl 5-(benzyloxy)-2-(amino)benzoate ([116027-17-9], 1.3 g, 5.06 mmol) was stirred in DCM (20 mL) and pyridine (1.2 mL) at 0° C. Thiophene-2-sulfonyl chloride (1.02 g, 5.56 mmol) was added. After one hour, the cooling bath was removed and the reaction was stirred overnight. The mixture was washed once with 10% aqueous HCl. The organics were dried and concentrated. Chromatography (20 to 40% ethyl acetate in hexanes) gave the title compound. [M+H] calc'd for C19H17NO5S2, 404; found, 404.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].Cl.Cl.NC1C=[CH:30][C:31]([N:35]2[CH2:40][CH2:39][CH2:38][C@@H:37]([C:41](N3CCCC3)=O)[CH2:36]2)=[N:32]C=1N.NC1N=C(N2CCC[C@@H](C(N3CCOCC3)=O)C2)C=CC=1[N+]([O-])=O.C1(C2C=CN=C(C(=N)OCC)N=2)CC1>>[CH:37]1([C:38]2[CH:39]=[CH:40][N:35]=[C:31]([C:30]3[NH:10][C:9]4=[N:8][C:7]([N:11]5[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]6[CH2:20][CH2:21][O:22][CH2:23][CH2:24]6)=[O:18])[CH2:12]5)=[CH:6][CH:5]=[C:4]4[N:3]=3)[N:32]=2)[CH2:36][CH2:41]1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCOCC3)C2)nc1N
Agent: CCOC(=N)c1nccc(C2CC2)n1
Agent: Cl
Agent: Nc1nc(N2CCC[C@@H](C(=O)N3CCOCC3)C2)ccc1[N+](=O)[O-]
Product: O=C([C@@H]1CCCN(c2ccc3nc(-c4nccc(C5CC5)n4)[nH]c3n2)C1)N1CCOCC1

Procedure:
The title compound was prepared by a method analogous to the one used for Example 95, but using (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(morpholino)methanone dihydrochloride (synthesized by hydrogenation analogous to the one used for Intermediate 1, starting from Intermediate 40) and Intermediate 42. MS (ES+APCI) (M+H) 434.2; LCMS retention time 1.996 min (Method G).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2.[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([N-]C(C)C)(C)C.[Li+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:6][CH:7]([CH2:28][CH:25]3[CH2:24][CH2:23][N:22]([CH2:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:27][CH2:26]3)[C:8](=[O:14])[C:9]2=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2

Procedure:
As it was disclosed in Example 3 and 4 of JP-A 64-79151(1989), indanone derivative was produced by reacting 5,6-dimethoxy-1-indanone with 1-benzyl-4-formylpiperidine in the presence of strong base such as lithium diisopropylamide (Example 3), followed by reduction (Example 4) for example. According to this method, yield for Donepezil through Example 3 and 4 was 50.8% (62%×82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[CH3:12].[Br:13]N1C(=O)CCC1=O.C(OO)(C)(C)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[CH2:12][Br:13]
Reactant: COc1cccc([N+](=O)[O-])c1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C)OO
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc([N+](=O)[O-])c1CBr
Reaction time: 3 h
Yield: 10.2 %

Procedure:
A solution of 2-methoxy-6-nitrotoluene (28.2 g, 159 mmol) and N-bromosuccinimide (26.5 g, 159 mmol) in 350 mL CCl4 was treated with a catalytic amount of t-butylhydroperoxide and irradiated with a floodlamp while stirring for 3 hours. The solids formed were filtered and the filtrate concentrated to give 4.0 g of a yellow solid.
Reaction SMILES: [NH2:1][C@H:2]([CH3:19])[C@:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C@@:3]([OH:10])([CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1)[C@H:2]([NH:1][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:19]
Reactant: C[C@@H](N)[C@](O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CN[C@H](C)[C@](O)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
Following the procedure described in reference example 8, but starting from (2R*,3R*)-3-amino-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-dichlorophenyl)-2-butanol (obtained according to patent EP 332387) and using ethyl bromoacetate instead of benzyl bromoacetate, the title compound was obtained in a similar yield.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][NH:5][C:6]1[O:7][CH2:8][C:9](=[O:15])[C:10]=1[C:11]([O:13][CH3:14])=[O:12].C(OC)(=O)CC(OC)=O.ClCC(Cl)=O.FC1C=CC=CC=1CN.[NH:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][N:50]=2)[C:45]([CH:52]=O)=[CH:44]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:43]1[C:51]2=[N:50][CH:49]=[CH:48][CH:47]=[C:46]2[C:45]([CH:52]=[C:8]2[O:7][C:6]([NH:5][CH2:4][C:3]3[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=3[F:1])=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C:9]2=[O:15])=[CH:44]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: COC(=O)C1=C(NCc2ccccc2F)OCC1=O
Agent: NCc1ccccc1F
Agent: O=C(Cl)CCl
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Solvent: COC(=O)CC(=O)OC
Product: COC(=O)C1=C(NCc2ccccc2F)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 22 %

Procedure:
To a solution of methyl 2-[(2-fluorobenzyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.35 g, 1.5 mmol) which similarly prepared according to the procedure described in the Example 4, First step using dimethyl malonate, chloroacetyl chloride and 2-fluorobenzylamine, and 7-azaindole-3-carboxaldehyde (0.22 g, 1.5 mmol) in ethanol (10 mL), L-proline (0.018 g, 0.15 mmol) was added at ambient temperature. The mixture was refluxed for 3 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with methanol then dried to afford the titled compound as solid (0.13 g, y. 24%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:21]>ClCCl.CCOCC>[ClH:21].[NH:8]1[CH2:9][CH2:10][CH:11]([CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCCC2=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1CCCN1CC1CCNCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-(2-Oxo-pyrrolidin-1-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ester in dichloromethane was added 2M hydrogen chloride in ether (1.78 ml). The reaction mixture was stirred at room temperature for 6 hours. The solvents were removed in vacuo to yield 1-Piperidin-4-ylmethyl-pyrrolidin-2-one hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1.[I-].ClC1[CH:29]=[CH:28][CH:27]=[CH:26][N+]=1C.C(O)CCC>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)=[C:11]([CH2:13][C:14]([O:16][CH2:26][CH2:27][CH2:28][CH3:29])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccsc1
Reactant: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CCCCOC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccsc1
Yield: 69.6 %

Procedure:
0.55 g of 2-[2-(4-chlorophenyl)-5-(3-thienyl)-4-oxazolyl]acetic acid, 0.44 g of 2-chloro-1-methyl-pyridinium iodide, 0.13 ml of n-butanol and 0.2 g of triethylamine are treated in the same manner as described in Example 20. 0.45 g of n-butyl 2-[2-(4-chlorophenyl)-5-(3-thienyl)-4-oxazolyl]acetate is thereby obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[C:13]([O:17][C:18]([NH:20][C@H:21]([CH:26]=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])([CH3:16])([CH3:15])[CH3:14]>O1CCCC1>[C:13]([O:17][C:18]([NH:20][CH:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C@H:26]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[OH:27])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: Brc1ccccn1
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)CC(NC(=O)OC(C)(C)C)[C@@H](O)c1ccccn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 21.6 %

Procedure:
To 2-bromopyridine (3.16 g) in 20 ml of dry tetrahydrofuran cooled to -78° C. under argon was added slowly 11.2 ml of n-butyl lithium in tetrahydrofuran (2M). The solution was stirred for 5 minutes and then 2.1 g of N-t-butoxycarbonyl-L-leucinal in 10 ml of tetrahydrofuran was added. The mixture was stirred for 35 minutes, then quenched with 10 ml of saturated sodium sulfate solution, warmed to room temperature and poured into 50 ml of water. The mixture was extracted with ethyl acetate. The extract was dried (Na2SO4) and the solvent removed under vacuum. The residue was chromatographed over silica gel with ethyl acetatheexane (3:7) as eluent and then ethyl acetate-hexane (1:1) as eluent to give 0.62 g of (S) 2-tert-butoxycarbonyl-amino-4-methyl(R,S)1-(2-pyridinyl)pentan-1-ol as a yellow oil; [α]D26 -21°±3° (C, 0.329, dichloromethane). A4.12 sample of the preceding compound in a mixture of 15 ml of dichloromethane and 5 ml of acetic anhydride was stirred at room temperature for 22 hours. The mixture was concentrated under vacuum. The residue was dissolved in dichloromethane and the solution washed with saturated agneous sodium carbonate, dried (Na2SO4) and the solvent removed. The residue was chromatographed over silica gel with 30% ethyl acetate in hexane to give 1.55 g of (S) 2-tert-butoxycarbonylamino-4-methyl-(S)1-(2-pyridinyl)pentan-1-ol, 0-acetate as crystals, mp 83°-84° C.; [α]D26 -62°±1° (C. 1.01, dichloromethane) and (S) 2-tert-butoxycarbonylamino-4-methyl-(R)1-(2-pyridinyl)pentan-1-ol, 0-acetate as an amber oil; [α]D26 +3°±1° (C, 1.-66, methanol).
Reaction SMILES: [C:1]1([NH:7][S:8]([C:11]2[CH:12]=[C:13]([C:17]#[C:18]/[CH:19]=[CH:20]/[C:21]([OH:23])=O)[CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>O>[OH:29][NH:28][C:21](=[O:23])/[CH:20]=[CH:19]/[C:18]#[C:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([S:8](=[O:10])(=[O:9])[NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=1
Reactant: O=C(O)/C=C/C#Cc1cccc(S(=O)(=O)Nc2ccccc2)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(/C=C/C#Cc1cccc(S(=O)(=O)Nc2ccccc2)c1)NO
Reaction time: 0.17 h

Procedure:
To a solution of (E)-5-(3-phenylsulfamoylphenyl)pent-2-en-4-ynoic acid (56a) (0.25 g 0.77 mmol) in methylene chloride (5 ml) oxalyl chloride (0.42 g 3.1 mmol) was added. The resultant mixture was stirred for 1 hour at ambient temperature and the solvents were removed under reduced pressure. The crude product (57a) was dissolved in acetonitrile (5 ml) and the obtained solution to a mixture of hydroxylamine hydrochloride (0.3 g, 4.3 mmol) and NaHCO3 (0.3 g, 3.6 mmol) in water (8 ml) was added. The reaction mixture was stirred for 10 min. and the product was extracted with ethyl acetate (30 ml). The extract was washed with 10% Na2CO3, and the aqueous phase was acidified with 3% HCl. The precipitate was filtered and dried to give the title compound (0.12 g, (46%). M.p 88-90° C. 1H NMR (DMSO-d6, HMDSO) δ: 6.41 (1H, d, J=15.8 Hz, CH); 6.82 (1H, d, J=15.8 Hz, CH); 6.92-7.41 (5H, m, C6H5); 7.47-8.01 (4H, m, C6H4); 8.94-11.21 (3H, br s, NH, NH, OH). Anal. Calcd for C17H14N2O4S*0.4H2O: C 58.58, H 4.27, N 8.01. Found: C 58.12, H 4.03, N 7.80.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:15]3[C@@H:14]4[CH2:16][C@@H:13]4[CH2:12][C:11]=3[C:10]([C:17](O)=[O:18])=[N:9]2)[CH:3]=1.[NH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:23][CH2:22][C:21]([NH:20][C:17]([C:10]1[C:11]2[CH2:12][C@H:13]3[CH2:16][C@H:14]3[C:15]=2[N:8]([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][N:5]=2)[N:9]=1)=[O:18])([CH3:25])[CH3:24]
Reactant: O=C(O)c1nn(-c2cc(F)ccn2)c2c1C[C@H]1C[C@@H]21
Reactant: CC(C)(N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(CO)NC(=O)c1nn(-c2cc(F)ccn2)c2c1C[C@H]1C[C@@H]21
Temperature: 23 °C
Reaction time: 0.33 h
Yield: 92.4 %

Procedure:
To a solution of (1aR,5aR)-2-(4-fluoro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (68 mg, 0.262 mmol), 2-amino-2-methylpropan-1-ol (23.38 mg, 0.262 mmol), and triethylamine (0.073 mL, 0.525 mmol) in DMF (1 mL) was added HATU (105 mg, 0.275 mmol). The reaction was stirred at 23° C. for 20 min then concentrated. The residue was purified by silica gel column chromatography to give the title compound (80 mg) as a white solid. LCMS m/z=331.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.46 (td, J=4.6, 3.4 Hz, 1H), 1.26 (td, J=7.8, 4.9 Hz, 1H), 1.41 (s, 3H), 1.42 (s, 3H), 2.24-2.30 (m, 1H), 2.79-2.84 (m, 1H), 2.91 (d, J=16.8 Hz, 1H), 3.00 (dd, J=16.6, 6.3 Hz, 1H), 3.70 (d, J=6.4 Hz, 2H), 4.69 (t, J=6.3 Hz, 1H), 6.93-6.98 (m, 2H), 7.63 (dd, J=10.1, 2.4 Hz, 1H), 8.43 (dd, J=8.5, 5.7 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH3:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Cl)=[CH:9][CH:8]=1.CCOCC>O1CCCC1>[CH3:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][S:3][C:2](=[NH:4])[NH2:1])=[CH:9][CH:8]=1
Reactant: NC(N)=S
Reactant: COc1ccc(CCl)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(CSC(=N)N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 116.8 %

Procedure:
To a mixture of thiourea (3.8 g, 50.0 mmol) in tetrahydrofuran (30 mL) was added dropwise 4-methoxybenzyl chloride (8.0 g, 51.1 mmol) and the reaction mixture was stirred at room temperature for 2 h before heating to reflux for 4 h. After the reaction was stirred at room temperature for 18 h the product was isolated from ether to yield the title compound (11.46 g). Electrospray MSm /z 197 [M+H]+.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:10][C:11]([OH:13])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:25]1(O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Si:1]([O:8][C@H:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:10][C:11]([O:13][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCCCCCCCCCC[C@H](CC(=O)O)O[Si](C)(C)C(C)(C)C
Reactant: Oc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCC[C@H](CC(=O)Oc1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 5 °C
Yield: 82 %

Procedure:
A solution of 2.71 g (R)-3-t-butyldimethylsilyloxytetradecanoic acid (0.0076 moles) in 20 mL dichloromethane was cooled with stirring to 5° C. 0.72 g Phenol (0.0076 moles), then 1.72 g N,N'-dicyclohexylcarbodiimide (0.0084 moles) were added and the resultant mixture was allowed to warm to room temperature and stirred there for about 16 hours. The mixture was filtered through a coarse sintered glass funnel, and the collected solids were washed with about 5 mL dichloromethane. The combined filtrate and washes were concentrated to dryness on a rotary evaporator (about 100 mm Hg, 30° C.). The residue was chromatographed on a 2" column slurry packed with silica gel (about 150 g) in dichloro- methane. The product was eluted with dichloromethane. The chromatography was monitored by TLC (silica gel, dichloromethane, phosphomolybdic acid visualization, product Rf ca 0.95). Fractions containing only product were pooled and concentrated to an oil on a rotary evaporator (ca. 125 mm Hg, 30° C.). The oil was blown dry by passing a stream of nitrogen over it for 1 hour. A clear oil (2.71 g, 82% yield) was obtained.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]([C:20]2[C:21]([CH:32]=[O:33])=[N:22][O:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=[O:19])[N:9]=[N:8]1.[CH3:43][Mg]Br>C1COCC1.C(Cl)Cl>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]([C:20]2[C:21]([CH:32]([OH:33])[CH3:43])=[N:22][O:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=[O:19])[N:9]=[N:8]1
Reactant: C[Mg]Br
Reactant: O=Cc1noc(-c2ccccc2Cl)c1C(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(O)c1noc(-c2ccccc2Cl)c1C(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 6 %

Procedure:
To a solution of 4-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carbonyl]-5-(2-chloro-phenyl)-isoxazole-3-carbaldehyde (75 mg, 0.12 mmol) in THF (0.6 mL) at −78° C. under N2, add methylmagnesium bromide (120 μL, 3.0 M in Et2O). Allow the reaction to warm to 0° C. and stir for two h., then quench the reaction with a saturated solution of NH4Cl (1 mL). Dilute the mixture with CH2Cl2 (1 mL), wash with H2O (1 mL) and brine (1 mL). Pass the organic layer through a Varian ChemElute® drying cartridge and concentrate. Purify the residue by chromatography on silica gel using a gradient of 10:1 Hex/EtOAc to 2:1 Hex/EtOAc to afford the title compound (4.3 mg, 6%). MS/ES (M+1)=620.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([O:18]C)[CH:15]=[C:14]2[C:9]=1[CH2:10][CH:11]([CH3:28])[CH2:12][N:13]2[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27].ClC1C=CC=C(Cl)C=1N1C2C(=C(C3C=CC(F)=CC=3F)C=C([OH:47])C=2)CCC1=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]2[C:9]=1[CH2:10][CH:11]([CH3:28])[C:12](=[O:47])[N:13]2[C:20]1[C:21]([Cl:27])=[CH:22][CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: COc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)CC(C)C2
Reactant: O=C1CCc2c(-c3ccc(F)cc3F)cc(O)cc2N1c1c(Cl)cccc1Cl
Product: CC1Cc2c(-c3ccccc3Cl)cc(O)cc2N(c2c(Cl)cccc2Cl)C1=O

Procedure:
The title compound was prepared from 43 mg of 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-methoxy-3-methyl-3,4-dihydroquinolin-2(1H-one by a procedure analogous to that described in INTERMEDIATE 3.
Reaction SMILES: [CH3:1][C:2]([CH3:35])([O:4][C:5]([N:7]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:8]1[C:13]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[N:17]=[N:16][N:15]=2)=[CH:12][C:11](Br)=[CH:10][N:9]=1)=[O:6])[CH3:3].[C:36]([Si:38]([CH3:41])([CH3:40])[CH3:39])#[CH:37]>C(NCC)C.C(Cl)Cl.[Cu]I>[CH3:1][C:2]([CH3:35])([O:4][C:5]([N:7]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:8]1[C:13]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[N:17]=[N:16][N:15]=2)=[CH:12][C:11]([C:37]#[C:36][Si:38]([CH3:41])([CH3:40])[CH3:39])=[CH:10][N:9]=1)=[O:6])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)cc1-c1nnnn1-c1cccc(F)c1F
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCNCC
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(C#C[Si](C)(C)C)cc1-c1nnnn1-c1cccc(F)c1F
Temperature: 50 °C
Yield: 29.3 %

Procedure:
In a tube was placed N,N-di(1,1-dimethylethoxycarbonyl)-3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-bromopyridin-2-amine (2.3 g, 4.1 mmol) in diethylamine (10 mL) with ethynyltrimethylsilane (1.5 g, 15.3 mmol) and the reaction was deoxygenated with a stream of nitrogen gas. To the mixture was added copper(I) iodide (554 mg, 2.9 mmol). The reaction vessel was sealed and warmed to 50° C. to achieve dissolution. To the mixture was added PdCl2dppf2.CH2Cl2 (190 mg, 0.06 eq). The reaction vessel was sealed and the mixture sonicated at 50° C. for 10 minutes. The reaction was diluted with methylene chloride, filtered through Celite™, concentrated, and purified by silica gel chromatography (10% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give N,N-di(1,1-dimethylethoxycarbonyl)-3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-(2-(trimethylsilyl)ethynyl)pyridin-2-amine (713 mg, 1.2 mmol, 30%) as a yellow solid; LC-MS: m/e=471.3 [M-Boc+H].
Reaction SMILES: ClC1N=C(Cl)C(Cl)=CN=1.CN1CCNCC1.Cl[C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[C:21]([Cl:31])=[CH:20][N:19]=1.[CH3:32][P:33]([C:36]1[N:41]=[C:40]([O:42][CH3:43])[C:39]([NH2:44])=[CH:38][CH:37]=1)([CH3:35])=[O:34]>>[Cl:31][C:21]1[C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[N:23][C:18]([NH:44][C:39]2[C:40]([O:42][CH3:43])=[N:41][C:36]([P:33]([CH3:32])([CH3:35])=[O:34])=[CH:37][CH:38]=2)=[N:19][CH:20]=1
Reactant: COc1nc(P(C)(C)=O)ccc1N
Reactant: CN1CCN(c2nc(Cl)ncc2Cl)CC1
Agent: CN1CCNCC1
Agent: Clc1ncc(Cl)c(Cl)n1
Product: COc1nc(P(C)(C)=O)ccc1Nc1ncc(Cl)c(N2CCN(C)CC2)n1

Procedure:
This compound can be prepared by reacting 2,4,5-trichloropyrimidine with 1-Methyl piperazine as described in Example 32 to generate 2,5-dichloro-4-(4-methylpiperazin-1-yl)pyrimidine. 2,5-dichloro-4-(4-methylpiperazin-1-yl)pyrimidine is then reacted with 6-(dimethylphosphoryl)-2-methoxypyridin-3-ylamine (prepared in Example 32) as described in Example 32.