Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:24]([O-:26])=[O:25])[C:5]([O:22]C)=[C:6]([CH:21]=1)[CH:7]=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[Cl-].[Li+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([N+:24]([O-:26])=[O:25])[C:5]([OH:22])=[C:6]([CH:21]=1)[CH:7]=[C:8]1[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:12][CH2:13]1
Reactant: COc1c(C=C2CCN(C(=O)OC(C)(C)C)CC2)cc(Br)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cc(Br)cc([N+](=O)[O-])c2O)CC1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of tert-butyl 4-(5-bromo-2-methoxy-3-nitrobenzylidene)piperidine-1-carboxylate (2.5 g, 5.9 mmol) and lithium chloride (1 g) in anhydrous N,N-dimethylformamide was stirred at 120° C. for 4 h. It was allowed to cool to room temperature and evaporated in vacuo. The residue was treated with water (50 mL) and extracted with diethyl ether (2×100 mL). The combined organic layers was washed with water (50 mL) and dried (Na2SO4). Evaporation of solvent gave the title compound as a crude oil (2.1 g).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]([OH:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25][CH2:26][C:27](Cl)=[O:28]>C(N(C(C)C)CC)(C)C.C(Cl)Cl>[CH2:1]([N:8]([CH2:9][CH2:10][C:11]([OH:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:27](=[O:28])[CH2:26][Cl:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(CCNCc1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCl)N(CCC(O)(c1ccccc1)c1ccccc1)Cc1ccccc1

Procedure:
To the stirred solution of 15.6 g of N-benzyl-3-hydroxy-3,3-diphenylpropylamine in 7.0 g of di-isopropylethylamine and 150 ml of methylene chloride, that of 5.88 g of chloroacetyl chloride in 50 ml of methylene chloride is added dropwise while stirring and cooling with an ice-bath. Thereupon the solution is stirred for 15 minutes at 0°-5° and washed successively with N hydrochloric acid, 10% aqueous sodium bicarbonate and finally with saturated aqueous sodium chloride. The organic layer is separated, dried, filtered and evaporated, to yield the N-benzyl-N-chloroacetyl-3-hydroxy-3,3-diphenylpropylamine showing in the I.R.-spectrum a strong band at 1640 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])=[C:12]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[C:32](OC(=O)C)(=[O:34])[CH3:33].C(N(CC)CC)C>CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])=[C:12]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH:31][C:32](=[O:34])[CH3:33])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(O)COc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(Cl)c2)c1=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)NS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(Cl)c3)c(=O)c2OCC(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(3-chloro-4-fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone (Example 480, 1 equivalent), acetic anhydride (3 equivalents), 4-(dimethylamino)pyridine (0.3 equivalents), and triethylamine (1.2 equivalents) is stirred at room temperature for 16 hours. The reaction mixture is partitioned between ethyl acetate and water. The organic layer is washed with brine then dried over MgSO4 and filtered. The filtrate is concentrated in vacuo to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]=[C:18]([CH2:21][O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[NH:19][CH:20]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[N-:29]([C:32]#[N:33])[C:30]#[N:31].[Na+]>CN(C)C=O.Cl>[C:30]([N:29]=[C:32]([NH2:33])[NH:4][C:3]1[CH:5]=[CH:6][C:7]([O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[N:17]=[C:18]([CH2:21][O:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:19][CH:20]=3)=[CH:14][CH:15]=2)=[CH:8][C:2]=1[F:1])#[N:31]
Reactant: N#C[N-]C#N
Reactant: Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1F
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CN=C(N)Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1F
Yield: 31 %

Procedure:
In a sealed glass tube suitable for microwave heating, the compound 2-fluoro-4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}aniline (0.1 g, 0.27 mmol) and sodium dicyanamide (37 mg, 0.4 mmol) in 2.5 ml of dimethylformamide and 0.5 ml of hydrochloric acid 1N are heated at 75° C. in a microwave oven (Biotage, Emrys Optimiser) for 900 seconds. The reaction medium is evaporated to dryness. After passing the residue obtained through a silica column (eluent dichloromethane/ethanol 93/7), a solid in the form of white powder is obtained with a yield of 31%.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@H:13]([OH:21])[CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:7][C:5]=2[N:6]=1.[C:22]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([CH2:37]Cl)[O:34][N:33]=2)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>CN(C)C.C(O)C>[C:22]([C:26]1[CH:27]=[CH:28][C:29]([C:32]2[N:36]=[C:35]([CH2:37][N:18]3[CH2:17][CH2:16][N:15]([CH2:14][C@@H:13]([OH:21])[CH2:12][O:11][C:8]4[CH:9]=[CH:10][C:4]5[S:3][C:2]([CH3:1])=[N:6][C:5]=5[CH:7]=4)[CH2:20][CH2:19]3)[O:34][N:33]=2)=[CH:30][CH:31]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)c1ccc(-c2noc(CCl)n2)cc1
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Agent: CN(C)C
Solvent: CCO
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(Cc4nc(-c5ccc(C(C)(C)C)cc5)no4)CC3)ccc2s1
Reaction time: 8 h

Procedure:
A solution of (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazinylpropan-2-ol, a compound of formula (6) (75 mg, 0.14 mmol), and 3-(4-tert-butylphenyl)-5-chloromethyl-1,2,4-oxadiazole (40 mg, 0.16 mmol) in 10% trimethylamine/ethanol, was heated to 73° C. and allowed to stir overnight. The solvent was evaporated under reduced pressure, and the resulting residue chromatographed by preparative thin layer chromatography (PTLC) (3% methanol/methylene chloride). The resulting oil was diluted with methylene chloride and placed on the high Vac. overnight, to yield (2R)-3-[4-({3-[4-(tert-butyl)phenyl](1,2,4-oxadiazol-5-yl)}methyl)piperazinyl]-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[I:14]I>C1COCC1>[F:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][C:6]=1[I:14]
Reactant: Nc1ncccc1F
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1nccc(I)c1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 2-amino-3-fluoropyridine (1.0 g, 8.9 mmol) in anhydrous THF (40 ml) was treated dropwise at −78° C. with n-butyllithium (1.6 M in hexanes, 13.9 ml, 22.3 mmol). Following the addition, the mixture was stirred at −78° C. for 1 h, then a solution of iodine (10.2 g, 40.1 mmol) in THF (20 ml) was added. The mixture was extracted with ethyl acetate, and the organic extracts were washed with sodium thiosulfate, sodium bicarbonate and brine. The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (8:1 to 2:1 hexanes/ethyl acetate eluant) to provide the title compound. MS m/z 238.9 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=2[CH2:6][N:7]2[C:12]3[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=3[CH:10]=[CH:9][C:8]2=[O:19])[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:32])C=1>ClCCl>[CH:1]1([C:4]2[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=2[CH2:6][N:7]2[C:12]3[N:13]=[C:14]([S:17]([CH3:18])=[O:32])[N:15]=[CH:16][C:11]=3[CH:10]=[CH:9][C:8]2=[O:19])[CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc2ccc(=O)n(Cc3ccccc3C3CC3)c2n1
Solvent: ClCCl
Product: CS(=O)c1ncc2ccc(=O)n(Cc3ccccc3C3CC3)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.2 %

Procedure:
To a solution of 8-(2-cyclopropylbenzyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (88 mg, 0.27 mmol) in dichloromethane (1 mL) was added 3-chloroperbenzoic acid (70%, 67 mg, 0.27 mmol) at 0-5° C. and the mixture was stirred at room temperature for 18 h. After completion, it was diluted with dichloromethane (10 mL) and washed with saturated sodium bicarbonate solution (1×5 mL) then with water (1×5 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to give 8-(2-cyclopropylbenzyl)-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one as a pale yellow solid (80 mg, 0.23 mmol, 85%). ESMS m/z 340 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][C:7]2[CH:11]=[C:12]([N+:15]([O-])=O)[CH:13]=[CH:14][C:6]1=2>[Pd]>[CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][C:7]2[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:6]1=2
Reactant: CN(C)CCN1CCOc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Product: CN(C)CCN1CCOc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of N,N-dimethyl-2-(7-nitro-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethanamine (210 mg, 0.836 mmol) and Pd—C (10% wt, 89 mg, 0.084 mmol) in dry EtOH (15 mL) was purged with hydrogen gas. The reaction was stirred at room temperature for 3 hours under hydrogen atmosphere (balloon pressure). The reaction mixture was then filtered through a Celite pad and washed with EtOH (15 mL). The light purple filtrate was concentrated to give crude 4-(2-(dimethylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-amine. A solution of this crude 4-(2-(dimethylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-amine (185 mg, 0.836 mmol) in dry EtOH (10 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (477 mg, 1.672 mmol) and stirred overnight at room temperature. The reaction was diluted with saturated NaHCO3 solution (50 mL) and the product was extracted into CH2Cl2 (3×25 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was subjected to flash chromatography on silica gel using 2:98 MeOH:CH2Cl2, followed by 5:95 (2M NH3 in MeOH):CH2Cl2, to give a yellow solid (150 mg, 54%). 1H-NMR (DMSO-d6) δ 7.69 (dd, J=3.6, 0.9 Hz, 1H), 7.56 (dd, J=5.1, 0.9 Hz, 1H), 7.07 (dd, J=5.1, 3.9 Hz, 1H), 6.64 (d, J=8.4 Hz, 1H), 6.35-6.26 (m, 4H), 4.14 (t, J=3.9 Hz, 2H), 3.33-3.29 (m, 4H), 2.42 (t, J=6.9 Hz, 2H), 2.19 (s, 6H); ESI-MS (m/z, %): 331 (MH+, 100), 260 (25); ESI-HRMS calculated for C17H23N4OS (MH+): 331.1587, Observed: 331.1594; HPLC purity: 99.0% by area.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.C[O:10][CH:11](OC)[CH2:12][NH2:13].O.[BH4-].[Na+]>C1C=CC=CC=1>[OH:10][CH:11]1[CH2:12][NH:13][CH2:7][C:5]2[S:6][C:2]([CH3:1])=[CH:3][C:4]1=2
Reactant: Cc1ccc(C=O)s1
Reactant: COC(CN)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: Cc1cc2c(s1)CNCC2O
Temperature: 60 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A mixture of 5-methyl-thiophene-2-carboxaldehyde (30 g; 0.237 mole) and aminoacetaldehyde dimethylacetal (27.4 g; 0.261 mole) in benzene (250 ml) is refluxed for 2 hours in a flask provided with a Dean-Stark water separator with overhead condenser. After evaporating to dryness, the residue is dissolved in ethanol (250 ml). Sodium borohydride (13.5 g; 0.355 mole) is added portionwise, and the resulting material is left aside overnight at room temperature. Excess sodium borohydride is destroyed by addition of acetone and the mixture is evaporated to dryness. The residue is taken up into water and extracted with methylene chloride. The organic extracts are dried over sodium sulfate and evaporated to dryness. The resulting residual oil is distilled under reduced pressure; b.p.2 =127° C.; Yield: 90% The resulting N-(5-methyl-2-thienyl)methyl aminoacetaldehyde dimethylacetal is heated at 60° C. for 1 hour in 6N hydrochloric acid (250 ml). After evaporating to dryness, the residue is triturated with acetone. The off-white crystals of the desired hydrochloride are recrystallized from acetonitrile; M.p.=120° C. Overall yield: 61%.
Reaction SMILES: Br[C:2]1[C:3]([CH3:21])([CH3:20])[O:4][C:5]2[CH:12]=[C:11]([O:13][CH2:14][O:15][CH3:16])[C:10]([N+:17]([O-:19])=[O:18])=[CH:9][C:6]=2[C:7]=1[OH:8].[OH-].[Na+].O>O1CCOCC1>[O:8]1[CH:7]2[CH:2]1[C:3]([CH3:21])([CH3:20])[O:4][C:5]1[CH:12]=[C:11]([O:13][CH2:14][O:15][CH3:16])[C:10]([N+:17]([O-:19])=[O:18])=[CH:9][C:6]=12
Reactant: COCOc1cc2c(cc1[N+](=O)[O-])C(O)=C(Br)C(C)(C)O2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COCOc1cc2c(cc1[N+](=O)[O-])C1OC1C(C)(C)O2
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of 3-bromo-7-methoxymethoxy-2,2-dimethyl-6-nitro-1-benzopyran-4-ol (550 mg, 1.52 mmol) in dioxane (5.5 mL), 1 mol/L sodium hydroxide aqueous solution (1.82 mL, 1.82 mmol) was added at room temperature, and the resulting mixture was stirred for 2 hours. Upon the completion of the reaction, water was added thereto, the resulting solution was extracted with ethyl acetate, washed with saturated sodium thiosulfate aqueous solution and then with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The resulting mixture was purified by silica gel column (hexane/ethyl acetate=4/1) and the aimed product was obtained (yield: 78%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][NH:37][C:36](=[O:40])[CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:39][CH2:38][NH:37][C:36](=[O:40])[CH2:35]3)(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=C1CN(S(=O)(=O)c2ccccc2Br)CCN1
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCNC(=O)C3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 4-((2-bromophenyl)sulfonyl)piperazin-2-one. MS (ESI): mass calcd. for C20H18FN5O3S, 427.11; m/z found, 428.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1H), 8.27 (d, J=1.4, 1H), 8.17-8.13 (m, 1H), 7.98 (m, 1H), 7.77-7.72 (m, 1H), 7.67-7.62 (m, 1H), 7.47-7.43 (m, 1H), 7.34-7.26 (m, 2H), 3.39 (s, 2H), 3.14 (s, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=O.[CH3:11][S:12]([NH2:15])(=[O:14])=[O:13].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][NH:15][S:12]([CH3:11])(=[O:14])=[O:13]
Reactant: O=Cc1cc(F)cc(Br)c1
Reactant: CS(N)(=O)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CS(=O)(=O)NCc1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
To a solution of 3-bromo-5-fluorobenzaldehyde (LXXIX) (2.03 g, 10.01 mmol) in DCE (50 mL) was added methanesulfonamide (1.43 g, 15.01 mmol) and TEA (2.79 mL, 20.02 mmol). NaBH(OAc)3 (3.00 g, 14.13 mmol) was added and stirred at room temperature overnight. The solvent was removed under vacuum and the residue was partitioned between EtOAc and water. The organic layer separated and washed with water, brine, dried over MgSO4 and evaporated under vacuum to produce N-(3-bromo-5-fluorobenzyl)methanesulfonamide (LXXX) as a colorless oil (2.653 g, 9.40 mmol, 93.9% yield). ESIMS found C8H9BrFNO2S m/z 282.0 (M+H).
Reaction SMILES: C(O)=O.[C:4]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@H:13]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[C@H:12]1[CH2:24][O:25]CC1C=CC=CC=1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>CO.[Pd]>[C:4]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@H:13]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19])[C@H:12]1[CH2:24][OH:25])=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1COCc1ccccc1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1CO
Yield: 98.4 %

Procedure:
0.4 ml of formic acid were added to a solution of 800 mg (1.90 mmol) of (2R,3S)-1-t-butoxycarbonyl-2-benzyloxymethyl-3-t-butyldimethylsilyloxypyrrolidine [which had been prepared from 1-t-butoxycarbonyl-D-seline benzyl ether in a similar manner to that described by W. R. Ewing et al. in Heterocycles, 27, 2843 (1988)] in 8 ml of methanol, and the mixture was stirred for 3 hours in the presence of 400 mg of palladium black under an atmosphere of hydrogen. At the end of this time, the catalyst was filtered off, and the filtrate was freed from the solvent by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 6:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 620 mg of the title compound as an oil.
Reaction SMILES: C(#N)C.[F:4][C:5]1[N:10]=[C:9]([F:11])[C:8]([F:12])=[C:7](F)[C:6]=1[F:14].[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16]>C(Cl)(Cl)Cl>[C:15]([NH:19][C:7]1[C:8]([F:12])=[C:9]([F:11])[N:10]=[C:5]([F:4])[C:6]=1[F:14])([CH3:18])([CH3:17])[CH3:16]
Reactant: Fc1nc(F)c(F)c(F)c1F
Reactant: CC(C)(C)N
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CC(C)(C)Nc1c(F)c(F)nc(F)c1F
Temperature: 25 °C
Yield: 71.4 %

Procedure:
To 100 ml of acetonitrile was added 24.5 g of pentafluoropyridine, and the mixture was stirred in an ice bath simultaneously with the dropwise addition of 30 g of t-butylamine. When the mixture warmed to room temperature, 150 ml of chloroform was added, and the mixture was washed twice with 800 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 23 g of the title compound as a pale yellow oil.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Br[C:44]1[CH:53]=[C:52]2[C:47]([C:48]([C:56]3[CH:61]=[CH:60][C:59]([C:62]([F:65])([F:64])[F:63])=[CH:58][C:57]=3[O:66][CH3:67])=[N:49][C:50]([O:54][CH3:55])=[N:51]2)=[CH:46][CH:45]=1.CCN(C(C)C)C(C)C.[CH2:77]([SH:84])[C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:77]([S:84][C:44]1[CH:53]=[C:52]2[C:47]([C:48]([C:56]3[CH:61]=[CH:60][C:59]([C:62]([F:65])([F:64])[F:63])=[CH:58][C:57]=3[O:66][CH3:67])=[N:49][C:50]([O:54][CH3:55])=[N:51]2)=[CH:46][CH:45]=1)[C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1
Reactant: COc1nc(-c2ccc(C(F)(F)F)cc2OC)c2ccc(Br)cc2n1
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1nc(-c2ccc(C(F)(F)F)cc2OC)c2ccc(SCc3ccccc3)cc2n1
Reaction time: 1 h

Procedure:
A solution of Pd2(dba)3 (9.20 mg, 10.04 μmol), Xantphos (0.012 g, 0.020 mmol), 7-bromo-2-methoxy-4-(2-methoxy-4-(trifluoromethyl)phenyl)quinazoline (0.166 g, 0.402 mmol), and n,n-diisopropylethylamine (0.211 ml, 1.205 mmol) in 2 mL dioxane was heated to 60° C. and was treated with benzyl mercaptan (0.048 ml, 0.402 mmol). After stirring for one hour, LC/MS showed mostly product, so the reaction mixture was concentrated. This material was carried on to step 5 without purification. (M+H)+=457.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[N:31]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:33][C:34]=1[CH3:35])[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[N:9]=1.C(OP([CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])(OCC)=O)C.CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[N:31]=[C:32]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[O:33][C:34]=1[CH3:35])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:50]/[C:51]([O:53][CH2:54][CH3:55])=[O:52])=[CH:11][N:10]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=2)[N:9]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1cc(COc2nn(-c3ccc(C(F)(F)F)cc3)cc2C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cn(-c2ccc(C(F)(F)F)cc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
To a mixture of 3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-carbaldehyde (3.30 g), ethyl diethylphosphonoacetate (1.32 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60% in oil, 0.236 g) at room temperature, and the mixture was stirred for 30 min at the same temperature. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration, and recrystallized from tetrahydrofuran to give ethyl (2E)-3-{3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-2-propenoate as a colorless powder (2.59 g, yield 69%). melting point: 205-206° C.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([CH3:25])[C:22]([OH:26])=[C:21]([CH3:27])[CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40]([OH:42])=[O:41])=[C:38]([OH:45])[CH:37]=1)(=[O:35])=[O:34]>>[CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[C:21]([CH3:27])[C:22]([O:26][S:33]([C:36]3[CH:44]=[CH:43][C:39]([C:40]([OH:42])=[O:41])=[C:38]([OH:45])[CH:37]=3)(=[O:35])=[O:34])=[C:23]([CH3:25])[CH:24]=2)=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: Cc1cc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc(C)c1O
Product: Cc1cc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc(C)c1OS(=O)(=O)c1ccc(C(=O)O)c(O)c1

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzofuran-3-yl)-3,5-dimethyl-biphenyl-4-ol and 4-chlorosulfonyl-2-hydroxy-benzoic acid, in substantially the same manner, as described in Example 1 step g, and was obtained as a white solid, mp 165-167° C.; MS m/e 603 (M−H)+;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][OH:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]>CCOC(C)=O.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][CH:5]=[C:4]([CH:3]=1)[CH:14]=[O:15]
Reactant: OCc1cnc(OCC(F)(F)F)c(Cl)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: O=Cc1cnc(OCC(F)(F)F)c(Cl)c1
Temperature: 120 °C
Yield: 85.2 %

Procedure:
To a solution of (5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol (4.00 g, 16.56 mmol) in EtOAc (15 mL) was added manganese(IV) oxide (16.93 g, 166 mmol). The reaction was heated with microwave at 120° C. for 30 minutes. The mixture was then filtered through a pad of celite, and rinsed with EtOAc. The filtrated was concentrated to give crude product (3.38 g).