Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[CH:27]=[C:26](Cl)[N:25]=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:34]1[O:35][C:36]([CH:39]2[O:43][CH2:42][CH2:41][O:40]2)=[CH:37][CH:38]=1)CCC>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[CH:27]=[C:26]([C:34]5[O:35][C:36]([CH:39]6[O:43][CH2:42][CH2:41][O:40]6)=[CH:37][CH:38]=5)[N:25]=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc2c(Nc3ccc4c(cnn4Cc4ccccc4)c3)ncnc2cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: c1ccc(Cn2ncc3cc(Nc4ncnc5cnc(-c6ccc(C7OCCO7)o6)cc45)ccc32)cc1

Procedure:
(1-Benzyl-1H-indazol-5-yl)-(6-chloropyrido[3,4-d]pyrimidin-4-yl)-amine (4.28 g), 2-(tributylstannyl)-5-(1,3-dioxolan-2-yl)-furan (J. Chem Soc., Chem. Commun., (1988), p 560) (10 g) and 1,4-bis(diphenylphosphino)butane palladium (II) chloride (1 g) were heated at reflux in dioxane (150 ml) for 24 hr (Procedure B). The solvent was removed in vacuo and the residue chromatographed on silica. Subsequent trituration gave the title compound as a yellow solid; □□ [2H6]-DMSO 10.46 (1H, s), 9.17 (1H, s), 8.74 (1H, s), 8.52 (1H, s), 8.23 (1H, s), 8.18 (1H, s), 7.80–7.68 (2H, m), 7.41–7.22 (5H, m), 7.17 (1H, d), 6.80 (1H, d), 6.06 (1H, s), 5.71 (2H, s), 4.20–3.96 (4H, m).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18](S(C)=O)=[N:19][CH:20]=2)[N:15]([CH2:26][CH3:27])[C:14]1=[O:28].[NH2:29][CH2:30][C@H:31]([OH:36])[C@@H:32]([OH:35])[CH2:33][NH2:34]>>[NH2:29][CH2:30][CH:31]([OH:36])[CH:32]([OH:35])[CH2:33][NH:34][C:18]1[N:17]=[C:16]2[N:15]([CH2:26][CH3:27])[C:14](=[O:28])[N:13]([C:3]3[C:2]([F:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=3[F:12])[CH2:22][C:21]2=[CH:20][N:19]=1
Reactant: NC[C@H](O)[C@@H](O)CN
Reactant: CCN1C(=O)N(c2c(F)c(OC)cc(OC)c2F)Cc2cnc(S(C)=O)nc21
Product: CCN1C(=O)N(c2c(F)c(OC)cc(OC)c2F)Cc2cnc(NCC(O)C(O)CN)nc21
Yield: 42.7 %

Procedure:
7-(4-Amino-2,3-dihydroxy-butylamino)-3-(2,6-difluoro-3,5-dimethoxy-phenyl)-1-ethyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one was prepared as in Example 2 using 0.5 g (1.2 mmol) 3-(2,6-difluoro-3,5-dimethoxy-phenyl)-1-ethyl-7-methanesulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 0.433 g (3.6 mmol) (S,S)-1,4-diamino-butane-2,3-diol. The final product was purified by column chromatography (40:6:1 dichloromethane/methanol/sat. aqueous ammonium hydroxide solution) which gave 0.24 g (43%) of the final product as a white solid: mp 115° C. (dec.); MS (APCI) m/z 469.1, 470.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH2:22][CH2:23][N:24]([C:26]([NH2:28])=[O:27])[OH:25])[CH:17]=3)[C:12]2=[O:29])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38].Cl>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH2:22][CH2:23][N:24]([C:26]([NH2:28])=[O:27])[O:25][C:37](=[O:39])[CH3:38])[CH:17]=3)[C:12]2=[O:29])=[CH:4][CH:3]=1
Reactant: NC(=O)N(O)CCOc1ccc2c(c1)CCN(CCCc1ccc(F)cc1)C2=O
Reactant: CC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)ON(CCOc1ccc2c(c1)CCN(CCCc1ccc(F)cc1)C2=O)C(N)=O
Reaction time: 2 h

Procedure:
A solution of 2-[3-(4-fluorophenyl)-propyl]-6-[2-(N-aminocarbonyl-N-hydroxyamino)-ethoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline (500 mg, 1.2 mmol) and triethylamine (0.2 mL, 1.4 mmol) are dissolved in THF (25 mL) and acetyl chloride (0.1 mL, 1.4 mmol) is added. The reaction mixture is stirred for 2 hours and subsequently poured into 2N HCl. The aqueous phase is extracted with EtOAc (3×100 mL) and the combined organics washed with 2N HCl (2×100 mL) H2O (2×100 mL), saturated NaHCO3 solution (2×100 mL), saturated NaCl solution (2×100 mL), dried over MgSO4 and concentrated in vacuo. The residue is triturated with hexanes and chromatographed (silica gel, 1:1 EtOAc/hexane). The resulting material is crystallized from cold CH2Cl2 /Et2O and dried in vacuo to give 2-[3-(4-fluorophenyl)-propyl]-6-{2-[N-(aminocarbonyl)-N-(acetyloxy)amino]-ethoxy}-1-oxo-1,2,3,4-tetrahydroisoquinoline, m.p. 113°-114°.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.Br[C:22]1[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][CH:23]=1>>[CH3:29][S:28][C:25]1[CH:26]=[CH:27][C:22]([N:16]2[CH2:15][CH2:14][N:13]([C:8]3[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]4[O:3][C:2]([CH3:20])([CH3:1])[CH2:6][C:5]=4[C:7]=3[CH3:19])[CH2:18][CH2:17]2)=[CH:23][CH:24]=1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Reactant: CSc1ccc(Br)cc1
Product: CSc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(C)O4)CC2)cc1
Yield: 60.5 %

Procedure:
By using 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (1.37 g, 5.0 mmol) synthesized in Reference example 61 and 4-bromothioanisole (1.52 g, 7.5 mmol), the reaction was carried out in the same manner as Example 23 to synthesize the title compound 1.2 g (yield 60%). Melting point was 211 to 213° C. (ethanol).
Reaction SMILES: [C:1]([N:7]1[C:15]2[C:10](=[C:11]([CH3:22])[C:12]([O:18]C(=O)C)=[C:13]([CH3:17])[C:14]=2[CH3:16])[C:9]([CH3:24])([CH3:23])[CH2:8]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(N1C2C(=C(C)C(OC(=O)C)=C(C)C=2C)C(C)C1)(=O)C>>[C:1]([N:7]1[C:15]2[C:10](=[C:11]([CH3:22])[C:12]([OH:18])=[C:13]([CH3:17])[C:14]=2[CH3:16])[C:9]([CH3:24])([CH3:23])[CH2:8]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)C(C)(C)CN2C(=O)C(C)(C)C
Agent: CC(=O)Oc1c(C)c(C)c2c(c1C)C(C)CN2C(C)=O
Product: Cc1c(C)c2c(c(C)c1O)C(C)(C)CN2C(=O)C(C)(C)C

Procedure:
Deacetylation of 31a was achieved as in the case of 29a. Product 31b was obtained as a white solid (79% yield), mp 164°-165° C. Spectral data: 1H NMR (CD3SOCD3): δ 1.25 (s, 6H), 1.90 (br s, 3H), 2.10 (s, 3H), 2.20 (s, 3H), 3.65 (br s, 2H), 7.85 (br s, 1H); 13C NMR (CD3SOCD3): δ 11.85, 12.75, 17.24, 23.41, 24.68, 42.57, 64.86, 117.90, 122.01, 124.93, 133.86, 137.71, 150.64, 168.32; CI-MS: m/z 248 (MH+, base), 230, 205, 190, 167; CI-HRMS (M+H+): Calcd. for C15H22NO2 248.1650, fnd. 248.1644. Anal: calcd. for C15H21NO2C, 72.7, H, 8.50, N, 5.70, fnd. C, 72.86, H, 8.46, N, 5.59.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([OH:11])[C@H:5]([OH:12])[C@H:4]1[OH:13].[C:14]([C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=1[OH:27])[C:21](Cl)=[O:22])([CH3:17])([CH3:16])[CH3:15]>N1C=CC=CC=1>[C:14]([C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=1[OH:27])[C:21]([O:13][C@@H:4]1[C@@H:5]([O:12][C:21](=[O:22])[C:20]2[CH:19]=[C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:26]([OH:27])=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:24]=2)[C@H:6]([O:11][C:21](=[O:22])[C:20]2[CH:19]=[C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:26]([OH:27])=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:24]=2)[C@@H:7]([CH2:9][O:10][C:21](=[O:22])[C:20]2[CH:24]=[C:25]([C:28]([CH3:29])([CH3:30])[CH3:31])[C:26]([OH:27])=[C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:19]=2)[O:8][C@@H:3]1[O:2][CH3:1])=[O:22])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Solvent: c1ccncc1
Product: CO[C@H]1O[C@H](COC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)[C@@H](OC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)[C@H](OC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)[C@H]1OC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 13.4 %

Procedure:
A mixture of 0.97 g (0.005 moles) methyl α-D-glucoside and 7.10 g (0.025 moles) 3,5-di-tert-butyl-4hydroxybenzoyl chloride in 50 ml dry pyridine was stirred and heated under a nitrogen atmosphere at 65°-70° C. for 21 hours. After a work-up in the same manner as that described in Example 1, 0.75 g (14% yield) of a light yellow solid, mp 163°-166° C., was isolated. This product was identified as the above-titled compound by IR and NMR analysis and by elemental analysis: Anal. Calc. for C67H94O14 : C, 71.63; H, 8.43.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([CH:8]([CH3:10])[CH3:9])=[N:5][CH:4]=1.BrCC1CCCCO1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2([C:31]3=[CH:32][C:33]4[O:37][CH2:36][O:35][C:34]=4[CH:38]=[C:30]3[O:29][CH2:28]2)[C:20]1=[O:39].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[CH:8]([C:6]1[O:7][C:3]([CH2:2][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]3([C:31]4=[CH:32][C:33]5[O:37][CH2:36][O:35][C:34]=5[CH:38]=[C:30]4[O:29][CH2:28]3)[C:20]2=[O:39])=[CH:4][N:5]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1ncc(CCl)o1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: CC(C)c1ncc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)o1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 5-chloromethyl-2-isopropyloxazole to replace 2-(bromomethyl)tetrahydro-2H-pyran, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 1′-[(2-isopropyl-1,3-oxazol-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (11%) as a colorless solid: mp 75-77° C.; 1H NMR (300 MHz, CDCl3) δ7.42 (s, 1H), 7.26 (dd, J=7.4, 7.4 Hz, 1H), 7.15 (d, J=7.3 Hz, 1H), 7.07-7.00 (m, 2H), 6.48 (s, 1H), 6.15 (s, 1H), 5.83 (d, J=4.2 Hz, 2H), 4.83 (ABq, 2H), 4.78 (ABq, 2H), 3.10-2.95 (m, 1H), 1.30 (d, J=7.0 Hz, 6H); 13C NMR (75 MHz, DMSO-d6) δ177.3, 169.4, 155.8, 148.9, 142.3, 141.8, 135.3, 135.1, 132.2, 128.9, 123.8, 123.5, 119.5, 109.6, 103.1, 101.5, 93.6, 80.3, 58.2, 36.6, 28.5, 20.4, 20.3; MS (ES+) m/z 405.4 (M+1).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[C:25]2[C:26]3=[C:27]4[C:22](=[CH:23][CH:24]=2)[CH:21]=[CH:20][CH:19]=[C:18]4[CH:17]=[CH:16][C:15]3=[CH:14][CH:13]=1)=[O:5])C.[S:28](=[O:32])(=[O:31])([OH:30])O>>[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[C:14]([S:28]([OH:32])(=[O:31])=[O:30])[C:15]2[CH:16]=[CH:17][C:18]3[C:27]4[C:26]=2[C:25]=1[CH:24]=[CH:23][C:22]=4[C:21]([S:28]([OH:30])(=[O:32])=[O:31])=[CH:20][C:19]=3[S:28]([OH:30])(=[O:32])=[O:31])([OH:3])=[O:5]
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)CCCCCNc1ccc2ccc3cccc4ccc1c2c34
Product: O=C(O)CCCCCNc1cc(S(=O)(=O)O)c2ccc3c(S(=O)(=O)O)cc(S(=O)(=O)O)c4ccc1c2c43
Temperature: -30 °C
Reaction time: 5 h

Procedure:
1-(5-ethoxycarbonylpentyl)aminopyrene (1 g) was added in small portion to a stirred solution of 30% fuming sulfuric acid (8 mL) cooled to −30° C. After the addition, the solution was slowly warmed to room temperature and stirring continued at room temperature for 5 hours. The reaction mixture was poured over ice and the resulting precipitate was collected by suction filtration. The crude product was purified by HPLC on a C18 reverse phase column using triethylammonium acetate as the eluting buffer. The collected fractions containing the desired product were pooled and concentrated. The concentrate was acidified using HCl to precipitate out the product, which was then dried on a lyophilizer.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13])=O.[Cl-].[OH:17][NH3+:18].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]([F:15])([F:14])[C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13])=[N:18][OH:17]
Reactant: [NH3+]O
Reactant: Cc1cc(C)c(C(=O)C(F)(F)F)c(C)c1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c(C(=NO)C(F)(F)F)c(C)c1
Temperature: 0 °C
Yield: 28.3 %

Procedure:
6.3 g (0.029 mol) of 2,2,2-trifluoro-1-(2,4,6-trimethylphenyl)-ethanone are dissolved in 30 ml of ethanol at 80° C. To the solution are added dropwise 2.0 g (0.029 mol) of hydroxylammonium chloride and 4.1 g (0.050 mol) of sodium acetate dissolved in 15 ml of water. The reaction mixture is refluxed overnight, poured into ice water, and extracted with ethyl acetate. The organic phase is washed with brine, dried over MgSO4, and concentrated. The residue is purified by recrystallization from 20 ml of hexane, yielding 1.9 g of 2,2,2-trifluoro-1-(2,4,6-trimethylphenyl)-ethanone oxime in the form of white crystals, mp. 119-125° C.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10](Cl)=[CH:9][C:8]=1[NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].[C:21](=[O:23])=[O:22].[OH-].[Na+]>CCCCCC.O1CCCC1>[C:16]([C:15]1[O:20][C:9]2[C:10]([C:21]([OH:23])=[O:22])=[CH:11][CH:12]=[C:7]([Cl:6])[C:8]=2[N:14]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C=O
Reactant: CC(C)(C)C(=O)Nc1cc(Cl)ccc1Cl
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1nc2c(Cl)ccc(C(=O)O)c2o1
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
n-Butyl lithium (101.6 ml of a 2.5M solution in hexane) was added during 30 minutes to a stirred solution of 2,5-dichloro-1-(trimethylacetylamino)benzene (25.0 g) in dry tetrahydrofuran at -40° C. and the solution stirred at -20° C. for 1.5 hours and poured onto solid carbon dioxide in dry tetrahydrofuran. The mixture was allowed to reach room temperature, 2M sodium hydroxide solution added and extracted with ethylacetate. The aqueous solution was acidified (concentrated hydrochloric acid) and the precipitated solid collected and dried to give 2-t-butyl-4-chlorobenzoxazole-7-carboxylic acid (1 1.7 g) m.p. 209°-210° C.
Reaction SMILES: C(OP([C:9]([O:25][CH3:26])([O:23][CH3:24])[CH2:10][CH2:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1)(OCC)=O)C.[Li]CCCC.CCCCCC.[C:38]1([CH3:58])[CH:43]=[CH:42][C:41]([C:44]2[C:53]3[C:48](=[CH:49][CH:50]=[C:51]([CH:54]=O)[CH:52]=3)[C:47]([CH3:57])([CH3:56])[CH2:46][CH:45]=2)=[CH:40][CH:39]=1>C1COCC1>[CH3:26][O:25][CH:9]([O:23][CH3:24])[CH2:10]/[C:11](/[C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][CH:22]=1)=[CH:54]\[C:51]1[CH:52]=[C:53]2[C:48]([C:47]([CH3:57])([CH3:56])[CH2:46][CH:45]=[C:44]2[C:41]2[CH:40]=[CH:39][C:38]([CH3:58])=[CH:43][CH:42]=2)=[CH:49][CH:50]=1
Reactant: Cc1ccc(C2=CCC(C)(C)c3ccc(C=O)cc32)cc1
Reactant: CCOC(=O)c1ccc(CCC(OC)(OC)P(=O)(OCC)OCC)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(/C(=C/c2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)CC(OC)OC)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a cold (-78° C.) solution of ethyl 4-(diethoxyphosphoryl-3,3-dimethoxypropyl)benzoate (Compound D, 350 mg, 0.9 mmol, available in accordance with EPO Application No. 0 210 929 published on Feb. 4, 1987), in THF (9 mL), was added n-BuLi in hexane (1.6M solution, 0.7 mL, 1.1 mmol). The mixture was stirred for 1.5 hours. To this solution 1-(tol-4-yl)3,4-dihydro-4,4-dimethyl-7-naphthaldehyde (Compound C, 200 mg, 0.72 mmol), in THF (1 mL) was added and the mixture was gradually warmed to ambient temperature (4 h). The reaction was quenched by adding water (5 mL), and extracted with ethyl acetate (3×25 mL). The organic layer was washed with brine (10 mL), dried with MgSO4 and the solvent was removed by distillation. The crude material was purified by silicagel chromatography to afford the title compound as a colorless off.
Reaction SMILES: [CH2:1]([N:4]([CH2:28][CH2:29][CH3:30])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:27])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH2:21][C:22]2[NH:23][CH:24]=[CH:25][N:26]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:2][CH3:3].[CH3:31][N:32]1[CH:36]=[CH:35][N:34]=[C:33]1[CH:37]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:28]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:27])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]([CH2:21][C:22]2[NH:26][CH:25]=[CH:24][N:23]=2)[CH2:37][C:33]2[N:32]([CH3:31])[CH:36]=[CH:35][N:34]=2)=[CH:15][CH:14]=1)(=[O:11])=[O:12])[CH2:29][CH3:30]
Reactant: CCCN(CCC)CCCCN(C)S(=O)(=O)c1ccc(CNCc2ncc[nH]2)cc1
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCN(C)S(=O)(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The compound (171.8 mg) obtained in Example 112-2 was dissolved in anhydrous methanol (7.0 ml). The solution was added with 1-methyl-2-imidazole carboxaldehyde (65.0 mg) and sodium cyanoborohydride (49.0 mg). Then, the solution was adjusted to pH 5 with acetic acid and then stirred at room temperature for 2 days. After the reaction, the solvent was distilled off. The residue was added with a 1 mol/l sodium hydroxide aqueous solution and extracted with chloroform. The extract was dried with magnesium sulfate, and the solvent was distilled off. Then, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (184.8 mg) of the subject compound as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.C1(N(C2N=C(C)ON=2)C)CC1.[CH:29]1([CH2:32][C@H:33]([NH2:40])[C:34]2[N:38]=[C:37]([CH3:39])[O:36][N:35]=2)[CH2:31]C1>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([NH:40][CH:33]([CH:32]3[CH2:29][CH2:31]3)[C:34]3[N:38]=[C:37]([CH3:39])[O:36][N:35]=3)=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: Cc1nc([C@@H](N)CC2CC2)no1
Agent: Cc1nc(N(C)C2CC2)no1
Product: Cc1nc(C(NC(=O)c2ccc(C3CC3)c(OCC3CC3)n2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methylamine (which can e.g. be prepared in a similar manner than (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 38 e)) as starting materials, MS (EI): m/e=369.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]=[CH2:11])=[CH:5][CH:4]=1.B(Br)(Br)Br.[B]>C(Cl)Cl>[CH2:9]([C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=1)[CH:10]=[CH2:11]
Reactant: C=CCc1ccc(OC)cc1
Agent: BrB(Br)Br
Agent: [B]
Solvent: ClCCl
Product: C=CCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
To 50.01 g (337.4 mmol) of 1-methoxy-4-(2-propenyl)benzene (Aldrich Chemical Company, Milwaukee, Wis.) dissolved in 300 mL of anhydrous methylene chloride was added dropwise 375 mL (375 mmol) of 1.0M boron tribromide (Aldrich) in methylene chloride. The reaction was run under nitrogen at room temperature and the mixture was stirred for 1 hour. The mixture was poured over 1000 mL of crushed ice, stirred for 5 minutes, and transferred to a separatory funnel. The organic layer was drained and saved. The boron salts were transferred to a filter containing Celite™ (Aldrich Chemical Co., Milwaukee, Wis.) and the filter containing the salts was washed with portions of methylene chloride and then water. The filtrate was transferred to a separatory funnel and the organic and aqueous layers were separated. The aqueous layer was extracted with four 100-mL portions of methylene chloride. The methylene chloride solutions were pooled, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under vacuum to yield 25.27 g (56%) of crude 4-(2-propenyl)phenol. The crude product was distilled twice at reduced pressure to yield 20.34 g (45%) of 4-(2-propenyl)phenol. The NMR data was consistent with that reported by Rajashekhar and coworkers (J. Biol. Chem. 1984, 259, 6925).
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][N:17]([CH3:35])[CH2:18][CH2:19][CH2:20][C:21]1[N:22]=[N+:23]([O-:34])[C:24]2[CH:33]=[C:32]3[C:28]([CH2:29][CH2:30][CH2:31]3)=[CH:27][C:25]=2[N:26]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[O-:34][N+:23]1[C:24]2[CH:33]=[C:32]3[C:28](=[CH:27][C:25]=2[N+:26]([O-:4])=[C:21]([CH2:20][CH2:19][CH2:18][N:17]([CH3:16])[CH3:35])[N:22]=1)[CH2:29][CH2:30][CH2:31]3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CN(C)CCCc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCCc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 41.1 %

Procedure:
H2O2 (70%, 0.65 mL, 13 mmol) was added dropwise to a stirred solution of TFAA (1.8 mL, 13 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 78 (353 mg, 1.3 mmol) and TFA (0.7 mL, 9.1 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 20° C. for 8 h, diluted with dilute aqueous NH3 solution (12 mL) and extracted with DCM (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 79 (154 mg, 41%) as a red solid: 1H NMR δ 8.30 (s, 1H, H-9), 8.26 (s, 1H, H-5), 3.25-3.09 (m, 6H, H-6, H-8, CH2), 2.75 (t, J=7.3 Hz, 2H, CH2), 2.70 [s, 6H, N(CH3)2], 2.29-2.14 (m, 4H, H-7, CH2); 13C NMR δ 155.2, 153.9, 150.8, 139.1, 133.9, 115.9, 113.9, 58.0, 44.3 (2), 33.4, 32.9, 27.9, 25.6, 21.7; HRMS (FAB+) calcd for C15H21N4O2 (MH+) m/z 289.1665, found 289.1669.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:22]3[CH2:27][CH2:26][CH:25]([CH2:28]O)[CH2:24][CH2:23]3)=[O:21])[C:10]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=3[O:40][CH2:41][CH3:42])=[N:9]2)=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:44].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:22]3[CH2:27][CH2:26][CH:25]([CH2:28][Br:44])[CH2:24][CH2:23]3)=[O:21])[C:10]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=3[O:40][CH2:41][CH3:42])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCC(CO)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCC(CBr)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76.2 %

Procedure:
To a cooled (0° C.) solution of [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-hydroxy methyl-piperidin-1-yl]-methanone (60 mg, 0.096 mmol) in methylene chloride (2 mL) was added carbon tetrabromide (70 mg, 0.210 mmol) followed by triphenyl phosphine (55 mg, 0.21 mmol). The reaction mixture was stirred at ambient temperature for 2.5 h. The reaction was diluted with water and extracted with methylene chloride. The organic extracts were washed with water, brine, and dried over anhydrous sodium sulfate. Evaporation of the solvents and chromatography of the residue over silica gel using 1-5% methanol in methylene chloride gave [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-bromomethyl-piperidin-1-yl]-methanone (50 mg, 76%).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([OH:10])[N:7]=[C:6]([C:11]3[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=3)[N:5]=2)[CH2:3][CH2:2]1.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>C(Cl)Cl.O>[C:20]([NH:24][S:16]([C:14]1[S:15][C:11]([C:6]2[N:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[CH:9]=[C:8]([OH:10])[N:7]=2)=[CH:12][CH:13]=1)(=[O:18])=[O:17])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccc(-c2nc(O)cc(C3CC3)n2)s1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2nc(O)cc(C3CC3)n2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24 %

Procedure:
A mixture of crude 5-(4-cyclopropyl-6-hydroxypyrimidin-2-yl)thiophene-2-sulfonyl chloride (1.9 g, 6.0 mmol, 1.0 equiv.), t-butylamine (25 mL) and TEA (10 mL) in CH2Cl2 (500 mL) was stirred at rt for 2 h. The reaction mixture was diluted with water, the organic layer was washed (brine), dried (Na2SO4), evaporated and purified by silica gel chromatography (EA/PE 1:1) to afford N-tert-butyl-5-(4-cyclopropyl-6-hydroxypyrimidin-2-yl)thiophene-2-sulfonamide (500 mg, 24%). LC-MS (m/z)=354.1 [M+H]+