Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][N:16](C(=O)C(F)(F)F)[CH2:15][CH2:14]1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Br)=[CH:29][CH:28]=1.[OH-].[Na+].O>C1COCC1>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([N:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[CH:5]=2)(=[O:10])=[O:11])=[CH:29][CH:28]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1N1CCN(C(=O)C(F)(F)F)CC1
Reactant: COc1ccc([Mg]Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(S(=O)(=O)c2ccc(OC)c(N3CCNCC3)c2)cc1
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of 4-methoxy-3-[4-(2,2,2-trifluoro-acetyl)-piperazin-1-yl]-benzenesulfonyl chloride (0.19 g), prepared as in Example 1 Step 2, in THF (0.5 ml) at 0° C. under argon atmosphere was added dropwise a solution of 4-methoxyphenylmagnesium bromide in THF (0.5M, 2 ml; 1 mmol). After stirring at this temperature for 1 h. A solution of 6N NaOH (0.5 ml) was added and the reaction mixture was stirred at ambient temperature for 20 h. Water was added (10 ml) and the mixture was extracted into ethyl acetate (20 ml). The organic phase was dried (Na2SO4) and concentrated in vacuo to give 1-[5-(4-methoxy-benzenesulfonyl)2-methoxy-phenyl]piperazine as a white solid (0.65 g, 36%), MS, MH+ 363.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:8](=[C:10]([C:14]([OH:16])=O)[CH:11]=[CH:12][CH:13]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[NH2:19][C@H:20]1[CH:25]2[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]2)[CH2:21]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:22]12[CH2:27][CH2:26][CH:25]([CH2:24][CH2:23]1)[C@H:20]([NH:19][C:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:7]3[O:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[N:9][C:8]=13)=[O:16])[CH2:21]2
Reactant: CC(C)(C)c1nc2c(C(=O)O)cccc2o1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1nc2c(C(=O)N[C@@H]3CN4CCC3CC4)cccc2o1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 64.9 %

Procedure:
A mixture of 2-tert-butylbenzoxazole-4-carboxylic acid (70 mg, 0.32 mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (64 mg, 0.32 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (123 mg, 0.64 mmol) and 1-hydroxybenzotriazole (86 mg, 0.64 mmol) in DMF (1.5 mL) was stirred at room temperature for 5 min, then triethylamine (0.17 mL, 1.28 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with dichloromethane (20 mL), then washed with a saturated solution of sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (3×15 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 89:10:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford (S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-tert-butylbenzoxazole-4-carboxamide (68 mg, 65%) as a colorless semi-solid: 1H NMR (500 MHz, CDCl3) δ 9.60 (d, J=7.5 Hz, 1H), 8.13 (dd, J=7.5, 1.0 Hz, 1H), 7.62 (dd, J=8.0, 2.0 Hz, 1H), 7.41 (t, J=8.0 Hz, 1H), 4.32-4.26 (m, 1H), 3.47 (ddd, J=11.5, 9.5, 2.0 Hz, 1H), 3.06-2.83 (m, 4H), 2.75 (dd, J=14.0, 4.5 Hz, 1H), 2.10-1.95 (m, 2H), 1.76-1.70 (m, 2H), 1.60-1.54 (m, 1H), 1.52 (s, 9H); MS (ESI+) m/z 328 (M+H); HPLC>99% (AUC), tR=11.84 min.
Reaction SMILES: [CH:1]1([C:4]2[C:15]3[O:14][C:11]4([CH2:13][CH2:12]4)[CH2:10][C:9]([CH3:17])([CH3:16])[C:8]=3[CH:7]=[C:6]([C:18]#[CH:19])[CH:5]=2)[CH2:3][CH2:2]1.[CH3:20][O:21][C:22](=[O:33])[C:23]([C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1)([CH3:25])[CH3:24]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[CH3:20][O:21][C:22](=[O:33])[C:23]([C:26]1[CH:27]=[CH:28][C:29]([C:19]#[C:18][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:15]3[O:14][C:11]4([CH2:13][CH2:12]4)[CH2:10][C:9]([CH3:16])([CH3:17])[C:8]=3[CH:7]=2)=[CH:30][CH:31]=1)([CH3:25])[CH3:24]
Reactant: C#Cc1cc(C2CC2)c2c(c1)C(C)(C)CC1(CC1)O2
Reactant: COC(=O)C(C)(C)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1

Procedure:
Following General Procedure B and using 8-cyclopropyl-6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane] (0.096 g, 0.38 mmol), methyl-2-(4-iodo phenyl)-2-methyl-propionate (Reagent 2, 0.127 g, 0.41 mmol), triethyl amine (3 mL), copper(I)iodide (0.040 g, 0.21 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.080 g, 0.11 mmol) followed by flash column chromatography over silica gel (230-400 mesh), the title compound was obtained as an oil (0.046 g, 47%).
Reaction SMILES: [CH2:1]([C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10](=[N:12]O)[CH3:11])[CH:5]=1)[CH2:2][CH3:3].N1C=CC=CC=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>CN(C)C(=O)C>[CH3:11][C:10]1[NH:9][C:6]2[N:7]([N:8]=[C:4]([CH2:1][CH2:2][CH3:3])[CH:5]=2)[N:12]=1
Reactant: CCCc1cc(NC(C)=NO)n[nH]1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: c1ccncc1
Product: CCCc1cc2[nH]c(C)nn2n1
Reaction time: 0.5 h

Procedure:
A 5.38 g portion of N-(5-propyl-1H-pyrazol-3-yl)acetamidoxime was dissolved in 45 ml of N,N-dimethylacetamide. With cooling on an ice bath, to this were added 2.39 ml of pyridine and 5.63 g of p-toluenesulfonic acid chloride, followed by 30 minutes of stirring at the same temperature and additional 3 hours of stirring at room temperature. The resulting reaction mixture was added to 350 ml of water and extracted with chloroform. After distilling off chloroform from the organic layer under a reduced pressure, the thus obtained residue was dissolved in 135 ml of methanol, mixed with 2.39 ml of pyridine and then heated under reflux for 2 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>[OH-].[Na+].CC(C)=O.O>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)Cc1ccc(NC(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.8 %

Procedure:
7.6 g 4-Aminophenylacetic acid are dissolved in 50 ml 2 N aqueous sodium hydroxide solution and 50 ml acetone. A solution of 8.8 g 4-chlorobenzoyl chloride in 10 ml acetone is added dropwise thereto at 0° C. The reaction mixture is further stirred for 3 hours at ambient temperature, then diluted with water, filtered and the filtrate acidified with dilute hydrochloric acid. The precipitate obtained is reprecipitated via its sodium salt and recrystallized from ethanol. There are obtained 4.2 g (29% of theory) 4-(4-chlorobenzamido)-phenylacetic acid; m.p. 252° C.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[O:87]=[C:88]1[N:92]([CH2:93][C:94]([OH:96])=O)[C@@H:91]([C:97]2[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=2)[CH2:90][O:89]1>>[CH3:20][C@:17]12[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5][C@@H:4]1[C@H:3]1[C@H:35]([C:38]([CH3:40])=[CH2:39])[CH2:36][CH2:37][C@:2]1([NH:1][C:94](=[O:96])[CH2:93][N:92]1[C@@H:91]([C:97]3[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=3)[CH2:90][O:89][C:88]1=[O:87])[CH2:19][CH2:18]2
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C(O)CN1C(=O)OC[C@@H]1c1ccccc1
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN3C(=O)OC[C@@H]3c3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 30 %

Procedure:
The title compound was prepared in 30% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except (S)-(+)-2-oxo-4-phenyl-3-oxazolidineacetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 733.5 (M+H)+, 2.25 min (method 6). 1H NMR (400 MHz, 1:1 CDCl3:MeOD) δ=7.92 (d, J=8.3 Hz, 2H), 7.47-7.39 (m, 3H), 7.37-7.32 (m, 2H), 7.20 (d, J=8.3 Hz, 2H), 6.60 (s, 1H), 5.28 (d, J=4.5 Hz, 1H), 5.04 (t, J=8.3 Hz, 1H), 4.75 (t, J=8.9 Hz, 1H), 4.71 (s, 1H), 4.61 (br. s., 1H), 4.25-4.19 (m, 1H), 4.04 (d, J=16.3 Hz, 1H), 3.40 (d, J=16.3 Hz, 1H), 2.65-2.59 (m, 1H), 2.47 (dt, J=4.8, 11.0 Hz, 1H), 2.37 (dd, J=8.2, 11.7 Hz, 1H), 2.11 (dd, J=6.3, 17.1 Hz, 1H), 1.84-1.70 (m, 4H), 1.69 (s, 3H), 1.66-1.59 (m, 1H), 1.58-1.40 (m, 7H), 1.39-1.22 (m, 6H), 1.09 (br. s., 1H), 1.07 (s, 3H), 1.00 (s, 6H), 0.95 (s, 3H), 0.94 (br. s., 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25]=1[OH:26])[CH:21]=O)[CH3:16].[NH2:30][C:31]([NH2:33])=[O:32].Cl>CCO.CCOC(C)=O>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:21]2[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[NH:33][C:31](=[O:32])[NH:30]2)[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25]=1[OH:26])[CH3:16]
Reactant: O=C(Cc1ccccc1)c1ccco1
Reactant: NC(N)=O
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOc1cc(C2NC(=O)NC(c3ccco3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 9 %

Procedure:
A mixture of 1-(furan-2-yl)-2-phenylethanone (commercially available) (420 mg, 2.26 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (433 mg, 2.05 mmol), urea (369 mg, 6.15 mmol), concentrated HCl (0.2 mL, 2.05 mmol) in EtOH (5 mL) was refluxed overnight. Followed standard aqueous/EtOAc workup procedure, then purified by preparative HPLC to give Compound 111 (83 mg, yield 9%). 1H NMR (DMSO-d6 400 MHz): δ 10.32 (s, 1H), 8.63 (s, 1H), 7.60 (s, 1H), 7.53 (s, 1H), 7.37 (d, J=1.6 Hz, 1H), 7.21-7.18 (m, 3H), 7.10 (d, J=1.2 Hz, 1H), 6.93-6.91 (m, 2H), 6.43 (d, J=3.2 Hz, 1H), 6.29 (d, J=3.2 Hz, 1H), 5.12 (d, J=2.8 Hz, 1H), 4.06-3.96 (m, 2H), 1.32 (t, J=6.8 Hz, 3H); MS (ESI): m/z 422.0 [M+1]+.
Reaction SMILES: [K].[C:2]1([S:8]([NH:11][C:12](=[O:24])[C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:22])[CH3:21])=[C:15]([NH2:23])[CH:14]=2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])O.[K+]>CN(C)C=O>[C:2]1([S:8]([NH:11][C:12](=[O:24])[C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:22])[CH3:21])=[C:15]([NH:23][CH2:37][C:36]3[CH:39]=[CH:40][C:33]([O:32][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:34][CH:35]=3)[CH:14]=2)(=[O:9])=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccc(OCc2ccccc2)cc1
Reactant: CC(=O)Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1N
Agent: O=C([O-])O
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1NCc1ccc(OCc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture containing 0.500 g of N-benzenesulfonyl-3-amino-4-acetylaminobenzamide potassium salt, 0.470 g of 4-benzyloxybenzyl bromide, 0.925 g of a 20% potassium hydrogencarbonate aqueous solution and 3 ml of N,N-dimethylformamide was stirred at 90° C. for 1 hour. The reaction solution was concentrated, and was purified through silica-gel column chromatography (eluent: a mixture of ethyl acetate and methanol at a ratio of 9:1) to obtain crude N-benzenesulfonyl-4-acetylamino-3-(4-benzyloxybenzylamino)benzamide. This crude product was cyclized in the same manner as in Example 183 to give 0.160 g of 6-benzenesulfonylcarbamoyl-1-(4-benzyloxybenzyl)-2-methylbenzimidazole (251).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[C:5]([O:12]CC=C(C)C)[CH:4]=1.Cl.[C:19](OC)([CH3:22])([CH3:21])[CH3:20].[CH2:25](N(CC)C1C=CC=CC=1)C>>[OH:12][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([CH2:25][CH:20]=[C:19]([CH3:22])[CH3:21])=[CH:7][C:6]=1[C:9](=[O:11])[CH3:10]
Reactant: CCN(CC)c1ccccc1
Reactant: COC(C)(C)C
Reactant: COc1ccc(C(C)=O)c(OCC=C(C)C)c1
Agent: Cl
Product: COc1cc(O)c(C(C)=O)cc1CC=C(C)C

Procedure:
49.2 g of 4′-methoxy-2′-(3-methyl-2-butenyl)oxyacetophenone was dissolved in 100 ml of N,N-diethylaniline. The reaction solution was heated to reflux under nitrogen atmosphere. 3 hours later, the reaction solution was stood to cool, and then, 5 N hydrochloric acid (300 ml) and t-butylmethyl ether (1,000 ml) were added thereto, so as to separate an organic layer. The obtained organic layer was washed with 5 N hydrochloric acid (300 ml×2) and a saturated sodium chloride solution (500 ml), and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure, and the residue was then purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain the subject compound. The reaction was further carried out using 4′-methoxy-2′-(3-methyl-2-butenyl)oxyacetophenone (49.0 g) under the above described conditions. The total amount of the subject compounds was 74.1 g.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5][CH2:4]1.C([Cl:20])(=O)C>C(O)C>[ClH:20].[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH2:9])[CH2:5][CH2:4]1
Reactant: CO[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: CC(=O)Cl
Solvent: CCO
Product: CO[C@H]1CC[C@H](N)CC1
Product: Cl

Procedure:
tert-Butyl (trans-4-methoxycyclohexyl)carbamate in ethanol (5 mL) was stirred with acetyl chloride (1.5 mL) for one day under cooling with ice, and the solvent was concentrated under reduced pressure to give the title compound (475 mg, yield 95%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:33](OCC)=[O:34])=[N:4][C:5]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][Si](C(C)(C)C)(C)C)[CH:19]=2)=[N:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16].NC1C(C(OCC)=O)=NC(NC2C=CC=C(CO)C=2)=NC=1NC1C=CC=C[C:47]=1[O:52]C.[Si](Cl)(C(C)(C)C)(C)C.[NH:76]1C=CN=C1>C(Cl)Cl>[OH:25][CH2:24][C:20]1[CH:19]=[C:18]([NH:17][C:5]2[N:6]=[C:7]3[C:2]([NH:1][C:47](=[O:52])[N:8]3[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:3]([C:33]([NH2:76])=[O:34])[N:4]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)c1nc(Nc2cccc(CO[Si](C)(C)C(C)(C)C)c2)nc(Nc2ccccc2OC)c1N
Reactant: CCOC(=O)c1nc(Nc2cccc(CO)c2)nc(Nc2ccccc2OC)c1N
Agent: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(Nc3cccc(CO)c3)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
Ethyl 5-amino-2-(3-((tert-butyldimethylsilyloxy)methyl)phenylamino)-6-(2-methoxy-phenylamino)pyrimidine-4-carboxylate. Ethyl 5-amino-2-(3-(hydroxymethyl)phenylamino)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate (0.277 g, 0.677 mmol), tert-butyldimethylsilyl chloride (0.132 g, 0.880 mmol), imidazole (0.047 g, 0.693 mmol) were combined in methylene chloride (10 mL) and stirred for 16 h at room temperature. The solution was condensed under reduced pressure and purified using Biotage chromatography (0 to 100% EtOAc in hexanes) to afford the title compound (0.242 g, 68%). MS (ESI) m/z 524.7 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Br:10])[CH:3]=1.C([Li])CCC.CN([CH:19]=[O:20])C>C(OCC)C>[Br:10][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1)[CH:19]=[O:20]
Reactant: COc1cc(Br)cc(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cc(Br)cc(C=O)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 98 %

Procedure:
A solution of 1,3-dibromo-5-methoxybenzene (5.00 g, 18.8 mmol) in anhydrous diethyl ether (100 mL) was cooled to −78° C. Then a solution of n-butyllithium in hexanes (2.5 M, 8.3 mL, 20.68 mmol) was added drop-wise at −78° C. under nitrogen. After the addition was complete, the reaction was stirred at −78° C. for 45 min. After that time, anhydrous DMF (7.3 mL), 94.0 mmol) was added, the cooling bath was removed and the reaction mixture was allowed to warm to rt. The reaction was diluted with saturated aqueous NH4Cl solution (100 mL) and diethyl ether (100 mL). The organic phase was separated, washed with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 3-bromo-5-methoxybenzaldehyde (3.95 g, 98%) as yellow oil: 1H NMR (400 MHz, CDCl3) δ9.90 (s, 1H), 7.57-7.60 (m, 1H), 7.31-7.33 (m, 2H), 3.86 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=O)[CH2:5][C:6]([CH3:12])=[N:7]2.O=P(Cl)(Cl)Cl.C(OC([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[CH:5][C:6]([CH3:12])=[N:7]2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC1=Nc2cccc(Cl)c2C(=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(N2CCNCC2)c2c(Cl)cccc2n1

Procedure:
4,5-Dichloro-2-methylquinoline, obtained by treating 5-chloro-2-methyl-4-quinolone with POCl3 (cf. De, D., Byers L. D., Krogstad, D. J. J. Heterocyclic Chem. 1997, 34, 315; 1H NMR (CDCl3), δ 2.68 (s, 3H), 7.41 (s, 1H), 7.55 (t, 1H), 7.59 (dd, 1H), 7.95 (dd, 1H)), (125 mg, 0.59 mmol) and 1-tert-butoxycarbonylpiperazine (559 mg, 3.0 mmol) are reacted according to method A. The Boc group is cleaved with trifluoroacetic acid (3 mL) in CH2Cl2 (5 mL) giving 0.18 g of the piperazine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16]C)=[O:15])[CH:2]=1.[OH-].[Na+].Cl>O.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([OH:16])=[O:15])[CH:2]=1
Reactant: COC(=O)c1cccc(OCC=C(c2ccccc2)c2cccnc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(OCC=C(c2ccccc2)c2cccnc2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
Methyl 3-[3-(3-pyridyl)-3-phenyl-2-propenyloxy]benzoate (If-56, 1.5 g, 4.35 mmoles) was dissolved in a mixture of water (3 ml) and methanol (10 ml). To the solution was added sodium hydroxide (700 mg, 17.5 mmoles). The mixture was stirred for 2 hours at 60° C., which was then left standing for cooling. To the reaction solution was added water, the pH of which was adjusted to 5 with 1N hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried and the solvent was evaporated off. The residue was subjected to silica-gel column chromatography using ethyl acetate as eluant to yield 3-[3-(3-pyridyl)-3-phenyl-2-propenyloxy]benzoic acid (Ie-46) (1.15 g, 80%). Hydrolysis analogous to the above afforded substituted vinyl carboxylic acid derivatives (Ie-45-Ie-51, Ie-53, Ie-54) shown in Table 4-1.
Reaction SMILES: [NH2:1][C@@H:2]([C@H:13]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[O:14][Si](C)(C)C)[CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].CCN(C(C)C)C(C)C.C1N=CN([C:39]([N:41]2[CH:45]=N[CH:43]=[CH:42]2)=[O:40])C=1.[Cl:46][C:47]1[C:52]([F:53])=[CH:51][CH:50]=[CH:49][C:48]=1[C@@:54]([OH:69])([C@@H:63]1CCCN[CH2:64]1)[CH2:55][CH2:56][CH2:57][NH:58][C:59](=[O:62])[O:60][CH3:61]>C(Cl)Cl>[Cl:46][C:47]1[C:52]([F:53])=[CH:51][CH:50]=[CH:49][C:48]=1[C@:54]([C@@H:63]1[CH2:64][CH2:43][CH2:42][N:41]([C:39](=[O:40])[NH:1][C@H:2]([CH2:3][N:4]([CH3:12])[C:5]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:11])[C@H:13]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[OH:14])[CH2:45]1)([OH:69])[CH2:55][CH2:56][CH2:57][NH:58][C:59](=[O:62])[O:60][CH3:61]
Reactant: COC(=O)NCCC[C@@](O)(c1cccc(F)c1Cl)[C@@H]1CCCNC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C[C@@H](N)[C@@H](O[Si](C)(C)C)C1CCCCC1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NCCC[C@@](O)(c1cccc(F)c1Cl)[C@@H]1CCCN(C(=O)N[C@H](CN(C)C(=O)OC(C)(C)C)[C@@H](O)C2CCCCC2)C1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 46.8 %

Procedure:
To a solution of tert-butyl (2R,3S)-2-amino-3-cyclohexyl-3-(trimethylsilyloxy)propyl(methyl)carbamate (79.8 mg, 0.223 mmol) in anhydrous CH2Cl2 (2 mL) were added DIEA (190 μL, 1.12 mmol) and CDI (36.2 mg, 0.223 mmol). The mixture was stirred at 0° C. for 45 min, and methyl (S)-4-(2-chloro-3-fluorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butylcarbamate (80.0 mg, 0.223 mmol) was added in one portion and the mixture was allowed to warm to rt and stirred overnight. The reaction was quenched with water and extracted with CH2Cl2 (3×20 mL). The organic extracts were washed with brine and concentrated to give crude product, which was purified by preparative HPLC to afford methyl (S)-4-(2-chloro-3-fluorophenyl)-4-((R)-1-((1S,2R)-1-cyclohexyl-1-hydroxy-3-(N-methyl-N-(t-butoxycarbonyl)amino)propan-2-ylcarbamoyl)piperidin-3-yl)-4-hydroxybutylcarbamate (70 mg, 46.8%). MS (E/Z): 671 (M+H+).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:14]2[O:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:11][C:10]=2[CH:9]=[C:8]([O:23][CH3:24])[CH:7]=1)=[O:5].[CH3:26][Li].Cl>C1COCC1>[CH3:24][O:23][C:8]1[CH:7]=[C:6]([C:4](=[O:5])[CH3:26])[C:14]2[O:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:11][C:10]=2[CH:9]=1
Reactant: COc1ccc(-c2cc3cc(OC)cc(C(=O)N(C)OC)c3o2)cc1
Reactant: [Li]C
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3cc(OC)cc(C(C)=O)c3o2)cc1
Reaction time: 1 h
Yield: 67 %

Procedure:
To a cooled (−78° C.) solution of 121 (0.6 g, 1.7 mmol) in THF (10 ml) was added Methyl lithium (3.4 ml of 1.0 M in THF) and the reaction was stirred for 1 hr. The solution was then poured into 2 N HCl and extracted with EtOAc which was separated, dried over MgSO4, and concentrated to give a solid which was triturated with MeOH and collected by filtration to give 122 as a white solid (0.35 g, 67%); 1H NMR (CDCl3) δ 7.78(d, 2 H, J=8.7 Hz), 7.44 (d, 1 H, 2.6 Hz), 7.24 (s, 1 H), 6.99 (d, 2 H, J=8.7 Hz), 6.89 (s, 1 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 2.96 (s, 3 H).