Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([S:4][C:5]1[S:6][CH:7]=[C:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[N:9]=1)([CH3:3])[CH3:2].OO.[OH2:17].[OH-:18].[Na+]>C(O)(=O)C>[CH:1]([S:4]([C:5]1[S:6][CH:7]=[C:8]([O:10][S:11]([CH3:14])(=[O:12])=[O:13])[N:9]=1)(=[O:18])=[O:17])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: O
Reactant: CC(C)Sc1nc(OS(C)(=O)=O)cs1
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)S(=O)(=O)c1nc(OS(C)(=O)=O)cs1
Reaction time: 2 h
Yield: 88.7 %

Procedure:
2.5 g of 2-isopropylthio-4-methylsulfonyloxy-1,3-thiazole was dissolved in 10 ml of acetic acid. 2.9 ml of 35% aqueous hydrogen peroxide was added to the solution and the reaction was continued at 70° to 80° C. for 2 hours. The reaction mixture was poured into cold water and neutralized with 5% aqueous sodium hydroxide. The neutral solution was extracted by ethyl acetate and washed with saturated aqueous solution of common salt, followed by drying over anhydrous sodium sulfate to be concentrated to 2.5 g of a white crystal of the objective compound (yield: 88.7%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:8])=[C:5]([Cl:7])[N:6]=1.O1CCOCC1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:2]2[S:3][C:4]([Br:8])=[C:5]([Cl:7])[N:6]=2)=[CH:19][CH:18]=1
Reactant: Clc1nc(Br)sc1Br
Reactant: COc1ccc(CN)cc1
Solvent: C1COCCO1
Product: COc1ccc(CNc2nc(Cl)c(Br)s2)cc1
Temperature: 75 °C
Reaction time: 4 h
Yield: 78.5 %

Procedure:
To a 250 mL round-bottomed flask was added 2,5-dibromo-4-chlorothiazole (5.9 g, 21 mmol), p-dioxane (50 mL, 587 mmol), and 4-methoxybenzylamine (3 mL, 21 mmol). The solution was stirred at 75° C. for 4 hours. The reaction was cooled to room temperature, and the solvent was removed. The residue was dissolved in EtOAc and washed with saturated NaHCO3 (1×25 mL), saturated sodium chloride (1×25 mL), water (1×25 mL), and dried over Na2SO4, filtered and concentrated in vacuum. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient (5%→50% EtOAc in hexane) to provide N-(4-methoxybenzyl)-5-bromo-4-chlorothiazol-2-amine (5.5 g, 80% yield), m/z (%): 334.1 (100%, M++H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:11][C:12]2[CH:13]=[CH:14][C:15]3[C:21]4[C:22]([O:30][CH3:31])=[C:23]([O:28][CH3:29])[C:24]([O:26][CH3:27])=[CH:25][C:20]=4[CH2:19][CH2:18][C@H:17]([NH:32][C:33](=[O:35])[CH3:34])[C:16]=3[CH:36]=2)=[O:10])=[CH:5][CH:4]=1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[O:40]1[CH2:41][CH2:42][N:37]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]([O:11][C:12]3[CH:13]=[CH:14][C:15]4[C:21]5[C:22]([O:30][CH3:31])=[C:23]([O:28][CH3:29])[C:24]([O:26][CH3:27])=[CH:25][C:20]=5[CH2:19][CH2:18][C@H:17]([NH:32][C:33](=[O:35])[CH3:34])[C:16]=4[CH:36]=3)=[O:10])=[CH:5][CH:4]=2)[CH2:38][CH2:39]1
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)c3ccc(CCl)cc3)cc1[C@@H](NC(C)=O)CC2
Reactant: C1COCCN1
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)c3ccc(CN4CCOCC4)cc3)cc1[C@@H](NC(C)=O)CC2
Yield: 86 %

Procedure:
Using an analogous procedure to that described for Example 16, N-[(5S)-3-(4-chloromethylphenylcarbonyloxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide was reacted with morpholine to give N-[(5S)-3-(4-{morpholinomethyl}phenylcarbonyloxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide.
Reaction SMILES: [Na].[C:2](=[O:7])([O:5][CH3:6])OC.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[O:18]=[C:16]([C:13]1[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1)[CH2:17][C:2]([O:5][CH3:6])=[O:7]
Reactant: COc1ccc(C(C)=O)cc1
Reactant: COC(=O)OC
Agent: [Na]
Solvent: Cc1ccccc1
Product: COC(=O)CC(=O)c1ccc(OC)cc1
Temperature: 93 °C

Procedure:
30.7 g of sodium was added to 300 ml of toluene, and the mixture was heated to 93° C., followed by cooling while vigorous stirring, to give sandy products. To the product, 600 ml of toluene containing 300 g of dimethyl carbonate was added, and further 250 ml of a toluene solution containing 100 g of p-methoxyacetophenone was added dropwise over 2 hours and 15 minutes at 84° to 86° C. After the dropwise addition, the mixture was stirred under heating at 82° to 83° C. for 1.5 hours, and then the solvent was evaporated. To the residue was added 1 l of isopropyl ether, and crystals were collected by filtration and washed with 500 ml of isopropyl ether. These crystals were added to a mixture of ice and ethyl acetate containing 100 g of acetic acid, and extracted with ethyl acetate. The extract was washed with 5 % sodium hydrogen carbonate and then with water, and dried. Subsequently, the solvent was evaporated to obtain 131.6 g of methyl 3-oxo-3-(p-methoxyphenyl)propionate as an oily product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:21]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:20][C:19]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)=[N:18]3)=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:40][CH2:41][C:42]([O:44]CC)=[O:43].[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:21]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:20][C:19]([C:30]4[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:37])[F:39])=[CH:34][CH:35]=4)=[N:18]3)=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:40][CH2:41][C:42]([OH:44])=[O:43]
Reactant: CCOC(=O)CCc1ccc(NCc2ccc(Cn3nc(-c4ccc(C(F)(F)F)cc4)cc3CCc3ccccc3)cc2)cc1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1ccc(NCc2ccc(Cn3nc(-c4ccc(C(F)(F)F)cc4)cc3CCc3ccccc3)cc2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To a solution of ethyl 3-(2-fluoro-4-{[4-({5-(2-phenylethyl)-3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)benzyl]amino}phenyl)propanoate in ethanol (10 mL) and tetrahydrofuran (10 mL) was added 1 M aqueous sodium hydroxide solution (4 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was weakly acidified with 10% aqueous citric acid solution and extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-80% ethyl acetate/hexane) to give the title compound (620 mg, yield 51%, 2 steps) as a yellow oil.
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9].Cl[C:11]1[N:16]=[CH:15][N:14]=[C:13]2[N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[N:18]=[CH:19][C:12]=12>C1COCC1.CN(C=O)C>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:17]1[C:13]2=[N:14][CH:15]=[N:16][C:11]([O:3][C@H:4]3[CH2:8][CH2:7][NH:6][C:5]3=[O:9])=[C:12]2[CH:19]=[N:18]1
Reactant: O=C1NCC[C@@H]1O
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1NCC[C@@H]1Oc1ncnc2c1cnn2-c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24.8 %

Procedure:
Sodium hydride (60% in oil) (0.435 g, 10.88 mmol) was added to (S)-3-hydroxypyrrolidin-2-one (CAS no. 34368-52-0) (1 g, 9.89 mmol) in THF (50 mL) at 0° C. under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes. A solution of 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B15) (4.01 g, 15.13 mmol) in DMF (25 mL) was added and the resulting mixture was stirred at r.t. for 16 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were dried (MgSO4) and evaporated (3.8 g). The crude product was purified by flash silica chromatography, eluting with 0-50% MeOH in ethyl acetate to afford the product (0.810 g, 24.8%). 1H NMR (400 MHz, CDCl3) δ 2.30-2.42 (1H, m), 2.81-2.91 (1H, m), 3.45-3.64 (2H, m), 6.05 (1H, t), 6.44 (1H, s), 7.42-7.51 (2H, m), 7.51-7.56 (1H, m), 7.57-7.66 (1H, m), 8.33 (1H, s), 8.60 (1H, s); m/z (ES+) (M+H)+=330.27; HPLC tR=1.61 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([N:12]([CH2:14][C:15]2[S:23][C:22]3[C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:20][C:19]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:37][CH2:38][O:39][Si](C(C)(C)C)(C)C)[CH:31]=4)=[N:18][C:17]=3[CH:16]=2)[CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([N:12]([CH2:14][C:15]2[S:23][C:22]3[C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:20][C:19]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:37][CH2:38][OH:39])[CH:31]=4)=[N:18][C:17]=3[CH:16]=2)[CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(N(C)Cc2cc3nc(-c4cccc(OCCO[Si](C)(C)C(C)(C)C)c4)nc(N4CCOCC4)c3s2)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(N(C)Cc2cc3nc(-c4cccc(OCCO)c4)nc(N4CCOCC4)c3s2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
2-[(2-{3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-phenyl}-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amino]-pyrimidine-5-carboxylic acid ethyl ester (680 mg, 1.02 mmol) was taken into THF (20 mL) followed by the addition of tetrabutyl ammonium fluoride (533 mg, 2.04 mmol). The resulting mixture was stirred at room temperature for 30 min. TLC showed reaction complete. Reaction mixture was diluted with ethyl acetate, washed with water and dried with Na2SO4. The crude product was purified by column chromatography eluted with hexanes/ethyl acetate to afford titled compound as an off-white solid (540 mg, 96%). m.p.: 216-220° C. LC-MS: 551.3 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 1.38 (t, J=6.8 Hz, 3H), 3.31 (s, 3H), 3.86 (t, J=5.2 Hz, 4H), 3.99-4.02 (m, 6H), 4.20 (t, J=4.4 Hz, 2H), 4.37 (q, J=7.2 Hz, 2H), 5.19 (s, 2H). 7.01 (dd, J=8 Hz, 2 Hz, 1H), 7.35-7.39 (m, 2H). 8.01-8.05 (m, 2H), 8.92 (s, 2H).
Reaction SMILES: [Cl:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].C(N([CH2:17][CH3:18])CC)C.C[OH:20]>O>[Cl:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([O:20][CH2:17][CH3:18])=[O:4]
Reactant: CO
Reactant: CCN(CC)CC
Reactant: O=C(Cl)C(Cl)c1ccccc1
Solvent: O
Product: CCOC(=O)C(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 83.4 %

Procedure:
Chlorophenyl acetyl chloride (53 mmol, 7.6 ml) was added dropwise to a solution of triethylamine (63.5 mmol, 8.7 ml) in methanol at 0° C. and the mixture was subsequently stirred for 3.5 h at room temperature. The reaction mix was then placed in 100 ml of water and repeatedly extracted with EtOAc (3×100 ml). Once combined, the organic phases were dried over MgSO4, concentrated under vacuum and 8.76 g (83.4%) of product was obtained.
Reaction SMILES: [O-][N+:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[N:12]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]([CH3:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:23])[CH:13]=[N:14][C:4]=2[CH:3]=1.ClC(Cl)(Cl)C([N:36]=C=O)=O>ClCCl>[NH2:36][C:3]1[C:4]2[N:14]=[CH:13][N:12]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]([CH3:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:23])[C:5]=2[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[N:2]=1
Reactant: CN(C(=O)CCCCOCCn1cnc2c[n+]([O-])c3ccccc3c21)c1ccccc1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: CN(C(=O)CCCCOCCn1cnc2c(N)nc3ccccc3c21)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Using the general method of Parts C and D of Example 11, 2-(1H-imidazo[4,5-c]quinolin-1-yl)ethanol (0.63 g, 2.9 mmol) and 5-bromo-N-methyl-N-phenylpentanamide (1.3 g, 4.8 mmol) were combined to provide 0.24 g of 5-[2-(5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]-N-methyl-N-phenylpentanamide as a colorless oil. The resulting N-oxide product was dissolved in dichloromethane and trichloroacetyl isocyanate (0.11 ml) was added dropwise. The reaction was stirred at room temperature for 2 hours and then the solvent was removed under vacuum. The resulting oil was dissolved in methanol and sodium methoxide (0.2 ml, 25% by weight in methanol) was slowly added. The reaction was maintained overnight and then concentrated under vacuum. Purification by flash column chromatography (silica gel, 9:1 ethyl acetate\methanol) provided 24 mg of 5-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]-N-methyl-N-phenylpentanamide as a white solid. 1H NMR (300 MHz, CDCl3) δ7.94 (d, J=8.1 Hz, 1H), 7.83 (m, 2H), 7.52 (dt, J=7.7,1.3 Hz, 1H), 7.41-7.28 (m, 4H), 7.12 (d, J=7.8 Hz, 2H), 5.55 (broad s, 2H), 4.65 (t, J=5.3 Hz, 2H), 3.85 (t, J=5.3 Hz, 2H), 3.31 (t, J=6.3 Hz, 2H), 3.24 (s, 3H), 2.02 (m, 2H), 1.56 (m, 2H), 1.40 (m, 2H); IR (KBr) 3429, 3104, 2946, 2877, 1646, 1595, 1584, 1532, 1496, 1482, 1398, 1360, 1254, 1121, 749, 705 cm−1; MS (EI) m/e 417.2160 (417.2165 calcd for C24H27N5O2).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[NH2:44][C:45]1([CH2:48][NH:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])[CH2:47][CH2:46]1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:44][C:45]5([CH2:48][NH:49][C:50](=[O:56])[O:51][C:52]([CH3:54])([CH3:53])[CH3:55])[CH2:47][CH2:46]5)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCC1(N)CC1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(CNC(=O)OC(C)(C)C)CC4)c3n2)c2ccc(F)cc21
Reaction time: 16 h

Procedure:
To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.10 g, 0.32 mmol), EDCI (0.123 g, 0.64 mmol), DMAP (0.122 g, 1 mmol) and DIPEA (0.11 g, 0.90 mmol) in 6 mL of DMF was added tert-butyl (1-aminocyclopropyl)methylcarbamate (0.20 g, 1.07 mmol) in one portion at room temperature and stirred for 16 hours. The mixture was poured into 50 mL of water, and filtered. The filter cake was washed with water, dried and used in the next step without further purification. MS: (M+H)+=480.2.
Reaction SMILES: [CH2:1]1[CH2:7][CH:6]([C:8]([NH2:10])=[O:9])[C:4](=O)[CH2:3][CH2:2]1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC=CC=1>O>[CH2:11]([NH:18][C:4]1[CH2:3][CH2:2][CH2:1][CH2:7][C:6]=1[C:8]([NH2:10])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: NC(=O)C1CCCCC1=O
Solvent: O
Solvent: Cc1ccccc1
Product: NC(=O)C1=C(NCc2ccccc2)CCCC1

Procedure:
A mixture of cyclohexanone-2-carboxamide (U.S. Pat. No. 4,169,952 to du Pont de Nemours, (1979)) (10.0 g), benzylamine (8.4 g), toluene (35 mL) and molecular sieves (Union Carbide 3A, 2 g) was refluxed for 2 h in a Dean-Stark water separator. The reaction mixture was filtered, and the filtrate was evaporated. The residue was crystallized from light petroleum to give the title compound (16 g). Mp 73-74° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)=[CH:8][CH:7]=1.Cl.[CH3:22][C@@H:23]1[CH2:27][CH2:26][CH2:25][NH:24]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:22][C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)=[CH:8][CH:7]=1
Reactant: C[C@@H]1CCCN1
Reactant: CC1(C)OB(c2ccc(OCCCBr)cc2)OC1(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CCCN1CCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 78 °C
Reaction time: 12 h
Yield: 84.2 %

Procedure:
2-[4-(3-Bromopropoxy)phenyl]-4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane (20.47 g, 60 mmol), (R)-2-methylpyrrolidine hydrochloride (7.663 g, 63 mmol) and dry, pulverized K2CO3 (24.96 g, 180 mmol) were mixed in dry CH3CN (650 mL). After stirring for 12 h at 78° C. under a nitrogen atmosphere, the reaction mixture was cooled and further (R)-2-methylpyrrolidine hydrochloride (10.0 g, 82 m mol) was introduced and heating at 78° C. was continued for 24 h. The reaction mixture was cooled, filtered and the filtrate was evaporated. Chromatography on silica gel, eluting initially with CH2Cl2, then with a mixture of CH2Cl2/EtOH/aq. NH3 (290:10:1) and later with a (90:10:1) and (40:10:1) mixture of these solvents provided the title compound (17.44 g, 84%). The material crystallized on seeding. A sample was converted into a hydrochloride salt, m.p. 212-214° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:29]1([C:35]2[NH:39][N:38]=[N:37][CH:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:39]4[C:35]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:36][N:37]=[N:38]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Reactant: c1ccc(-c2cnn[nH]2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Cn4nncc4-c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 3, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 5-phenyl-1H-[1,2,3]triazole.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][C:4](=O)[CH2:3]1.[C:10]([O:14]C)(=O)[C:11]#[CH:12].[NH3:16]>>[CH3:1][C:2]1([CH3:9])[CH2:3][C:4]2[NH:16][C:10](=[O:14])[CH:11]=[CH:12][C:5]=2[CH2:6][CH2:7]1
Reactant: C#CC(=O)OC
Reactant: N
Reactant: CC1(C)CCCC(=O)C1
Product: CC1(C)CCc2ccc(=O)[nH]c2C1
Temperature: 140 °C
Reaction time: 16 h
Yield: 55.4 %

Procedure:
A solution of 3,3-dimethylcyclohexanone (10 g, 71.3 mmol) and methyl propiolate (11.5 g, 136 mmol) in ammonia (390 ml, 2.73 mol) was heated and stirred in an autoclave at 140° C. for 16 h. The autoclave was cooled to ambient temperature, and the reaction mixture was transferred into a 1 L round-bottomed flask and was evaporated in vacuo to give a solid residue which was purified by gradient chromatography on silica with ethyl acetate in heptane to give 7.0 g (55%) of the title compound as colorless oil; LC-MS (UV peak area/EIC) 85%, 178.1228 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH3:16][S:17][CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20].C(OCl)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:4](=[O:5])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:12][CH:13]=[CH:14][C:15]=1[CH:18]([S:17][CH3:16])[C:19]([N:21]([CH3:23])[CH3:22])=[O:20]
Reactant: CSCC(=O)N(C)C
Reactant: Nc1ccccc1C(=O)c1ccccc1
Agent: CC(C)(C)OCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSC(C(=O)N(C)C)c1cccc(C(=O)c2ccccc2)c1N
Temperature: 25 °C
Yield: 80.8 %

Procedure:
A solution of 29.6 g (0.15 mole) of 2-aminobenzophenone in 350 ml of methylene chloride was cooled to -70° C. and 20.0 g (0.15 mole) of 2-methylthio-N,N-dimethylacetamide was added. To the mixture (-70° C.) was added dropwise a solution of 17.2 g (0.15 mole) of 95% t-butylhypochlorite in 30 ml of methylene chloride. The temperature was maintained at or below -65° C. for 1.5 hr, then 15.1 g (0.15 mole) of triethylamine was added rapidly. The solution was allowed to warm to room temperature and was washed with water. The organic solution was concentrated and the residue crystallized when mixed with isopropyl ether. The solid was recrystallized from isoproyl alcohol to give 39.8 g (81%) bright yellow crystals, m.p. 153°-155° C.
Reaction SMILES: [CH2:1](P(CCCC)CCCC)[CH2:2][CH2:3]C.BrCCCCl.[Cl:19][SiH:20]([Cl:22])[Cl:21]>>[Cl:19][Si:20]([Cl:22])([Cl:21])[CH2:1][CH2:2][CH2:3][Si:20]([Cl:22])([Cl:21])[Cl:19].[Cl:19][SiH:20]([Cl:22])[Cl:21]
Reactant: CCCCP(CCCC)CCCC
Agent: ClCCCBr
Agent: Cl[SiH](Cl)Cl
Product: Cl[Si](Cl)(Cl)CCC[Si](Cl)(Cl)Cl
Yield: 235.8 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.30 g (1.5 mmol) of tri-n-butylphosphine, 1.18 g (7.5 mmol) of 1-bromo-3-chloropropane, and 10.2 g (75.0 mmol) of trichlorosilane were reacted at 150° C. for 18 hrs. The resulting mixture was distilled to give 1.1 g of 1,3-bis(trichlorosily)propane (bp; 104° C./12.5 mmHg, yield; 48%), 0.3 g of 3-bromopropyl)trichlorosilane (yield; 21%), and 0.2 g of 3-(chloropropyl)trichlorosilane (bp; 88-90° C./12.5 mmHg, yield; 11%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.C([Li])CCC.CON(C)[C:20]([C:22]1[CH:30]=[C:29]2[C:25]([CH:26]=[CH:27][NH:28]2)=[CH:24][CH:23]=1)=[O:21].C(O)(C)C>C1COCC1.O>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([C:20]([C:22]2[CH:30]=[C:29]3[C:25]([CH:26]=[CH:27][NH:28]3)=[CH:24][CH:23]=2)=[O:21])[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1
Reactant: CON(C)C(=O)c1ccc2cc[nH]c2c1
Reactant: COc1cc(Br)cc(OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: COc1cc(OC)cc(C(=O)c2ccc3cc[nH]c3c2)c1
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
A solution of 1-bromo-3,5-dimethoxybenzene (12.86 g, 59.3 mmol) in THF (60 mL) was cooled to −78° C., evacuated and refilled with nitrogen for 10 cycles. To this clear solution was slowly added n-butyllithium (23.7 mL, 59.3 mmol) and stirred for 30 min. Then a mixture of 1H-Indole-6-carboxylic acid methoxy-methyl-amide (5.50 g, 26.9 mmol) in THF (40 mL) was added and stirred for 3 h at −78° C. The mixture was quenched with isopropanol (12.5 mL, 162 mmol) and added water (40 mL). It was extracted with ether (3×50 mL), washed with water (2×50 mL), dried and concentrated to an oil, which was purified by flash column chromatography (EtOAc/Hexane) to give (3,5-dimethoxy-phenyl)-(1H-indol-6-yl)-methanone as an oil (3.70 g, 49% yield). The product was used in the next step without further purification.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][N:5]=[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1)[C:7]([O:9]C)=[O:8]>CO>[CH3:3][O:4][N:5]=[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: CON=C(C(=O)OC)c1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CON=C(C(=O)O)c1cccc(O)c1
Yield: 73.5 %

Procedure:
An aqueous solution of 2N sodium hydroxide (8 ml.) was added with stirring at ambient temperature to a solution of methyl 2-methoxyimino-2-(3-hydroxyphenyl)acetate (anti isomer) (1.56 g.) in methanol (30 ml). After stirring for 3 hours at the same temperature, methanol was distilled off. To the residue was added water and the mixture was washed with ether. The aqueous layer was adjusted to pH 1 with 10% hydrochloric acid, subjected to salting-out and extracted with ether. The extract was washed with a sodium chloride aqueous solution and dried over magnesium sulfate. Ether was distilled off to give crystals of 2-methoxyimino-2-(3-hydroxyphenyl)acetic acid (anti isomer) (1.07 g.). The crystals were recrystallized from a mixture of petroleum ether and ether to give crystals (0.7 g.), mp 99° to 101° C. (dec.).