Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[CH2:33][CH:34]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH:28]2[CH2:33][CH:34]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: CCOC(=O)C(CC1COCCN1)C(=O)OCC
Product: CCOC(=O)C1=C(CN2CCOCC2CC(C(=O)OCC)C(=O)OCC)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 30.7 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.77 g, 1.53 mmol) was reacted with diethyl 2-(morpholin-3-ylmethyl)malonate (0.4 g, 1.53 mmol) according to the procedure as described in Example 24 to give the title compound as a pale yellow solid (0.32 g, 47%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH:11]([NH:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[NH:26][C:25]4=[O:34])[CH2:20][CH2:19]3)=[O:17])[C:12](O)=[O:13])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C(N(CC)C(C)C)(C)C.[O:44]1[C:48]2([CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[O:47][CH2:46][CH2:45]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O.C(Cl)Cl>[O:44]1[C:48]2([CH2:53][CH2:52][N:51]([C:12](=[O:13])[CH:11]([NH:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[NH:26][C:25]4=[O:34])[CH2:20][CH2:19]3)=[O:17])[CH2:10][C:6]3[CH:7]=[C:8]4[C:3](=[CH:4][CH:5]=3)[NH:2][N:1]=[CH:9]4)[CH2:50][CH2:49]2)[O:47][CH2:46][CH2:45]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=C(O)C(Cc1ccc2[nH]ncc2c1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NC(Cc1ccc2[nH]ncc2c1)C(=O)N1CCC2(CC1)OCCO2)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.3 %

Procedure:
To a solution of the 3-(1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid (95 mg, 0.21 mmol) and N,N-diisopropylethylamine (0.14 mL, 0.82 mmol) in dimethylformamide (5 mL) was added a solution of 1,4-dioxa-8-azaspiro[4,5]decane (32 mg, 0.23 mmol) and PyBOP® (107 mg, 0.21 mmol) in methylene chloride (5 mL). The reaction mixture was stirred for 16 h at room temperature. All solvent was removed using high vacuum. The residue was subjected to flash column chromatography using methylene chloride/methanol/triethylamine (93:5:2) to give the title compound as a white solid (67 mg, 56% yield). 1H-NMR (CDCl3, 500 MHz) δ 10.52 (s, 1H), 7.97 (s, 1H), 7.54 (s, 1H), 7.37 (d, J=8.6 Hz, 1H), 7.20 (d, J=10.7 Hz, 1H), 7.16 (t, J=7.2 Hz, 1H), 7.04 (d, J=7.6 Hz, 1H), 7.01 (s, 1H), 6.94 (t, J=8.6 Hz, 1H), 6.67 (d, J=7.6 Hz, 1H), 5.64 (d, J=7.9 Hz, 1H), 5.16 (dd, J=15.0, 6.7 Hz, 1H), 4.56-4.49 (m, 1H), 4.25 (s, 2H), 4.11 (br t, J=15.6 Hz, 2H), 3.92-3.84 (m, 4H), 3.73-3.69 (m, 1H), 3.60-3.56 (m, 1H), 3.48-3.43 (m, 1H), 3.22-3.17 (m, 1H), 3.11 (d, J=6.7 Hz, 2H), 2.90-2.85 (m, 2H), 2.68-2.60 (m, 4H), 1.67-1.61 (m, 2H), 1.54-1.49 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([O:13]C)=[CH:4][C:5]([O:11]C)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.C[O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([O:30]C)[CH:24]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[F:29][C:26]1[C:25]([OH:30])=[CH:24][C:23]([OH:22])=[C:28]([CH:27]=1)[C:7]([C:6]1[CH:10]=[C:2]([F:1])[C:3]([OH:13])=[CH:4][C:5]=1[OH:11])=[O:9]
Reactant: COc1ccc(F)c(OC)c1
Reactant: COc1cc(OC)c(C(=O)O)cc1F
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1cc(F)c(O)cc1O)c1cc(F)c(O)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
2,4-dimethoxy-5-fluorobenzoic acid 6 (5.4 g, 27 mmol) in dry CH2Cl2 (100 mL) was treated with 10.6 mL of oxalyl chloride under an Ar atmosphere and stirred at room temperature overnight. The excess reagent and solvent were removed under reduced pressure. The residue, 2,4-dimethoxy-5-fluorobenzoyl chloride, was redissolved in anhydrous CH2Cl2 (125 mL). 1,3-dimethoxy-4-fluorobenzene 3 (3.29 mL, 26 mmol) and AlCl3 (10.8 g, 81 mmol) were added at 0° C. After stirring at 0° C. for 1 h, the reaction mixture was allowed to warm to room temperature for 67 h, the mixture was then hydrolyzed with 1M HCl (300 mL) at 0° C. and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography, eluting with 30%-40% EtOAc in hexane to yield 7 (3.3 g, 44%) as a yellow solid. 1H NMR (300 MHz, MeOH-d4) 7.14 (d, 2H, J=11.5 Hz), 6.46 (d, 2H, J=7.4 Hz); 13C NMR (75 MHz, MeOH-d4) δ 199.1, 159.0, 152.9, 152.7, 147.7, 144.5, 119.2, 118.9, 114.2, 114.1, 106.1, 106.0; 19F NMR (282 MHz, MeOH-d4). δ −149.8 (dd, 2F).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[S:15][C:16]([C:18](O)=[O:19])=[CH:17][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.[F:24][C:25]1([F:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[F:24][C:25]1([F:31])[CH2:30][CH2:29][N:28]([C:18]([C:16]2[S:15][C:14]3[CH:21]=[CH:22][C:11]([O:10][CH:7]4[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]4)=[CH:12][C:13]=3[CH:17]=2)=[O:19])[CH2:27][CH2:26]1
Reactant: FC1(F)CCNCC1
Reactant: CC(C)N1CCC(Oc2ccc3sc(C(=O)O)cc3c2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)N1CCC(Oc2ccc3sc(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Yield: 64.7 %

Procedure:
In a flask were mixed together the above prepared 5-(1-isopropyl-piperidin-4-yloxy)-benzo[b]thiophene-2-carboxylic acid (0.128 g, 0.333 mmol, corrected for purity), 4,4-difluoropiperidine hydrochloride (0.063 g, 1.2 eq.), (benzotriazol-1-yloxy)-tris-(dimethylamino)phosphonium hexafluorophosphate (0.181 g, 1.23 eq.) and 2.4 eq. of N-ethyldiisopropylamine (0.225 mL) in 1.3 mL of abs. THF and allowed to react during one night at ambient temperature. Pouring onto crashed ice/AcOEt/NH4Cl-solution, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, NEt3/AcOEt=4/96) produced 0.091 g of the title compound as light yellow solid.
Reaction SMILES: [Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:26]=[C:27]1[CH:33]=[CH:32][C:31]2[CH:34]=[C:35]([C:38](O)=[O:39])[CH:36]=[CH:37][C:30]=2[O:29][CH2:28]1>CO>[CH2:26]=[C:27]1[CH:33]=[CH:32][C:31]2[CH:34]=[C:35]([C:38]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:39])[CH:36]=[CH:37][C:30]=2[O:29][CH2:28]1
Reactant: C=C1C=Cc2cc(C(=O)O)ccc2OC1
Reactant: Nc1ccccc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: C=C1C=Cc2cc(C(=O)Nc3ccccc3)ccc2OC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 18 %

Procedure:
1.12 g (4.07 mmol) of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride and then 0.379 g (4.07 mmol) of aniline are successively added to 0.75 g (3.7 mmol) of 3-methylene-2,3-dihydro-1-benzoxepin-7-carboxylic acid, prepared according to example 40, in solution in 25 ml of methanol. The medium is stirred at ambient temperature for 24 h. After evaporating the methanol, the crude reaction product is purified by chromatography on silica gel (ethyl acetate/heptane 40/60) to give 185 mg (49%) of 3-methylene-N-phenyl-2,3-dihydro-1-benzoxepin-7-carboxamide in the form of a pink solid; M.p.=139° C.
Reaction SMILES: [NH:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:2]([C:4]([NH:6][C@H:7]([C:9]([OH:11])=O)[CH3:8])=[O:5])[CH3:3].CN1CCOCC1.Br.[NH2:27][CH2:28][CH2:29][CH2:30][Br:31].CN(C=O)C>C1COCC1>[NH:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:2]([C:4]([NH:6][C@H:7]([C:9]([NH:27][CH2:28][CH2:29][CH2:30][Br:31])=[O:11])[CH3:8])=[O:5])[CH3:3]
Reactant: NCCCBr
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)O
Agent: Br
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)NCCCBr
Temperature: 25 °C

Procedure:
To a cold (−15° C.) solution of Boc-Ala-Ala-OH (908 mg, 3.5 mmol) and NMM (570 μl, 5.23 mmols) in THF (15 ml) was added ECF (341 μl, 3.6 mmols) under N2 atmosphere and vigorously stirred. After 2 min of stirring, a solution of 1-amino-3-propylbromide hydrobromide (976 mg, 4.90 mmols) in a mixture of THF:DMF (4 mL: 3 mL) was added to the mixture followed by NMM (951 μl, 8.73 mmols) and stirred. After 10 min the mixture was warmed to 25° C. and stirred for further 8 h. THF was removed under reduced pressure and the resulting viscous solution was diluted with water (10 mL) and thoroughly extracted with ethyl acetate. The combined organic extracts were washed with 5 ml saturated citric acid, 5 ml saturated NaHCO3 and dried over by Na2SO4 and concentrated to give a residue, which was purified by silica gel flash column chromatograph (EtOAc:Hexane—3:7) to give the desired product as a solid (m.p. 146° C.) in good yields (1.022 g, 78%). (TLC:EtOAc—Rf—0.39).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:16][CH2:15][C:14]3[C:9](=[C:10]([C:17]([O:19][CH3:20])=[O:18])[CH:11]=[CH:12][CH:13]=3)[NH:8]2)[CH:2]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:16]=[CH:15][C:14]3[C:9](=[C:10]([C:17]([O:19][CH3:20])=[O:18])[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=1
Reactant: COC(=O)c1cccc2c1NC(c1cccnc1)NC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: COC(=O)c1cccc2cnc(-c3cccnc3)nc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.2 %

Procedure:
A mixture of methyl 2-(pyridin-3-yl)-1,2,3,4-tetrahydroquinazoline-8-carboxylate (4.0 g, 14.8 mmol) and DDQ (5.0 g, 22.2 mmol) in CH2Cl2 (50 mL) was stirred at room temperature for 24 hours. The solvent was removed in vacuo, and the residue was purified by silica gel column chromatography (5% methanol in CH2Cl2) to obtain methyl 2-(pyridin-3-yl)quinazoline-8-carboxylate (3.5 g, 89% yield).
Reaction SMILES: [O:1]=[C:2]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)[CH2:3][C:4]([O-:6])=[O:5].[Li+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].ClCCl>[O:1]=[C:2]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=1)[CH2:3][C:4]([O:6][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:5]
Reactant: O=C([O-])CC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: BrCc1ccccc1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: O
Product: O=C(CC(=O)OCc1ccccc1)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of lithium 3-oxo-3-{[3-(trifluoromethyl)phenyl]amino}propanoate (2.0 g, 7.9 mmol) (Example 2A) in water (15 ml) is added a solution of Aliquat 336® (3.1 g) and benzyl bromide (1.35 g, 7.5 mmol) in dichloromethane (15 ml). The reaction mixture is stirred for two days at room temperature, then extracted with dichloromethane (500 ml). The organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography over silica gel 60 with cyclohexane/ethyl acetate mixtures as eluent.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:20])=[C:4]([C:11]2(O)[CH2:16][CH2:15][CH:14]([CH:17]=[CH2:18])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([F:20])=[C:4]([C:11]2[CH2:16][CH2:15][CH:14]([CH:17]=[CH2:18])[CH2:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10]
Reactant: C=CC1CCC(O)(c2ccc(OCC)c(Cl)c2F)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=CC1CC=C(c2ccc(OCC)c(Cl)c2F)CC1
Yield: 34 %

Procedure:
16.0 g of the compound (24), 0.3 g of p-toluenesulfonic acid and 80 mL of toluene were mixed, and the mixture was refluxed under heating for 1 hour while water distilled out was removed. After cooling the resulting reaction mixture to 25° C., 100 mL of water and 100 mL of toluene were added to and mixed with the reaction mixture. Thereafter, the mixture was separated into an organic layer and an aqueous layer by standing still, so as to attain extraction to the organic layer. The resulting organic layer was fractionated and washed with a 2N sodium hydroxide aqueous solution, a saturated sodium bicarbonate aqueous solution and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain a residue. The resulting residue was purified by silica gel column chromatography using a mixed solvent of heptane and toluene (heptane/toluene=2/1 by volume) as eluent, and then further purified by recrystallization from ethanol to obtain 5.11 g of 2-chloro-1-ethoxy-3-fluoro-4-(4-vinylcyclohexa-1-enyl)benzene (No. 286) in white color. The yield based on the compound (23) was 45.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8]O)[S:5][C:6]=1[Cl:7].[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.N(C(OCC)=O)=NC(OCC)=O.O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:14]2[C:10](=[O:20])[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:13]2=[O:15])[S:5][C:6]=1[Cl:7]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1cc(Cl)c(Cl)s1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: O
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1cc(Cl)c(Cl)s1
Temperature: 25 °C
Yield: 68.7 %

Procedure:
To a stirred solution of (4,5-Dichloro-thiophen-2-yl)-methanol (0.660 grams, 3.60 mmole), Phthalimide (0.636 grams, 4.32 mmole), and triphenyl phosphene (1.1 grams, 4.32 mmole) in tetrahydrofuran (20 ml) at room temperature was added diethyl azodicarboxylate (0.395 grams, 12.3 mmole) and stirred at room temperature over night. The mixture was poured into 100 ml water and extracted with diethyl ether. The combined extracts were washed with 1 N NaOH, water and brine, dried over MgSO4, filtered, and concentrated to an oil from which triphenylphosphine was crystalized out using diethyl ether/hexane. The mother liquor was concentrated to give a solid which was purified via flash chromatography on silica using 30% ethyl acetate/hexane as eluent to give a yellow solid. This was triturated in hexane to give a white solid (0.772 g). MW 312.18; MS (m/e) 313 (M++1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][NH:43]3)=[CH:38][CH:37]=2)[CH2:9]1)=O)(C)(C)C.Cl>CO>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][CH2:23][CH2:22][CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C@H:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]2[O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][NH:43]3)=[CH:38][CH:37]=2)=[CH:19][CH:18]=1
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)NCCC3)cc1
Agent: Cl
Solvent: CO
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCNC[C@@H]2OCc2ccc3c(c2)NCCC3)cc1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 77.7 %

Procedure:
2.92 g (4.73 mmol) of (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butylester were dissolved in 63 ml of abs. methanol, then 63 ml (126 mmol) of hydrochloric acid in methanol (2.0 molar) were added at room temperature. After stirring for 150 minutes at 50° C., the reaction mixture was poured into 150 ml ice-cold 5% sodium hydrogen carbonate solution and the product was extracted five times with 100 ml methylene chloride. The combined organic phases were washed twice with 50 ml distilled water, dried over magnesium sulphate, filtered and concentrated. The crude product (2.9 g, yellow oil) was chromatographed on silica gel with methylene chloride/methanol/28%ammonium hydroxide solution 14:1:0.1 v/v/v to yield 1.90 g (77.7% of theory) of (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-piperidine as a slightly yellow resin; MS: 517 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:24][C:25](=[O:30])[CH2:26][CH2:27][O:28][CH3:29])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:32])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:31])[CH:6]=[CH:5]1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[C:33]([O:19][CH2:18][C:17](=[O:20])[C@:16]1([O:24][C:25](=[O:30])[CH2:26][CH2:27][O:28][CH3:29])[C@:21]2([CH3:23])[C@H:13]([C@H:12]3[C@H:3]([C@@H:2]([OH:1])[CH2:22]2)[C@:4]2([CH3:32])[C:9](=[CH:8][C:7](=[O:31])[CH:6]=[CH:5]2)[CH2:10][CH2:11]3)[CH2:14][CH2:15]1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: COCCC(=O)O[C@]1(C(=O)CO)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Product: COCCC(=O)O[C@]1(C(=O)COC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
As described in Example 5(c), 1.0 g of 11β,21-dihydroxy-17-(3-methoxypropionyloxy)-1,4-pregnadiene-3,20-dione is reacted with acetic anhydride at room temperature, worked up, and purified, thus isolating 810 mg of 21-acetoxy-11β-hydroxy-17-(3-methoxypropionyloxy)-1,4-pregnadiene-3,20-dione.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O>>[Cl:23][CH:17]1[C:9]2[C:10](=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][C:1]=2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:11](=[O:12])[O:13]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1C(=O)c1ccccc1
Product: O=C1OC(Cl)c2c1cc([N+](=O)[O-])cc2-c1ccccc1
Reaction time: 3 h

Procedure:
To 20 ml of thionyl chloride was added 25 g of 2-benzoyl-5-nitrobenzoic acid. The mixture was heated and stirred for 3 hours on the oil bath kept at a temperature of 60° C. Excess thionyl chloride was distilled away under reduced pressure, and 27.5 g of 3-chloro-4-phenyl-6-nitrophthalide was obtained as a brown oily substance. Separately, 4.48 g (0.04 mol.) of potassium tert-butoxide and 5.34 g (0.03 mol.) of 1-phenyl-5-mercaptotetrazole were added to 200 ml of dried dimethylformamide, and stirred for 20 minutes at room temperature. The resulting mixture was cooled to 5° C. and thereto, was added dropwise gradually the previously prepared solution containing 9.0 g (0.03 mol.) of 3-chloro-3-phenyl 6-nitrophthalide in 75 ml of dried dimethylformamide as the mixture was maintained at 5° C. After the conclusion of the dropwise addition, the reaction mixture was stirred for 30 minutes at 5° C. and further, for 2 hours at room temperature. Thereto, 200 ml of a saturated aqueous solution of ammonium chloride was added. The reaction mixture was extracted with ethyl acetate repeatedly. The extract was washed with water, and the resulting organic layer was dried over anhydrous sodium sulfate. Sodium sulfate was filtered off with suction, and the filtrate was concentrated to yield 9.2 g of crude crystals. These crude crystals were separated and purified by flash column chromatography (silica gel: 400 g, eluate: hexane-ethyl acetate (3:1 by volume) mixture). Thus, the intended compound, 3-(1-phenyltetrazole-5-ylthio)-3-phenyl-6-nitrophthalide (4), was obtained. It was recrystallized from an ethyl acetate-hexane mixture. Yield 5.5 g, Melting Point 176° to 179° C.
Reaction SMILES: [C:1]([C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH:4]=1)#N.OS(O)(=O)=O.[OH2:17].[OH2:18]>C(O)(=O)C>[O:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:3]([C:1]([OH:18])=[O:17])=[CH:4]1
Reactant: O
Reactant: N#Cc1coc2ccccc12
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(O)c1coc2ccccc12

Procedure:
To a solution of benzofuran (75 g) in chloroform (600 ml) was added dropwise a solution of bromine (41 ml) in chloroform (150 ml) at -10° C. The temperature was slowly allowed to reach room temperature and chloroform was evaporated in vacuo, leaving the crude 2,3-dibromo-2,3-dihydrobenzofuran as a crystalline product which was used without further purification. Yield: 171 g. To the dibromoderivative (147 g) in ethanol (600 ml) was added a solution of KOH (59 g) in ethanol (200 ml). The mixture was refluxed for 2.5 hours. After cooling to room temperature the mixture was poured onto water and extracted with ethyl acetate (2×300 ml). The combined organic phases were worked-up and the 3-bromobenzofuran was subsequently purified by elution through silica gel using n-heptane as the eluent. Yield 51 g of a semicrystalline product. A solution of all of the thus obtained 3-bromobenzofuran and CuCN (33 g) in N-methyl-2-pyrrolidinone (350 ml) was heated at 190° C. under N2. With 1 hour intervals was added further CuCN (3×4.5 g). The mixture was poured into a solution of FeCl3.6H2O in water (610 ml) and concentrated hydrochloric acid (156 ml) while still hot. The resulting mixture was stirred at 60° C. for 1 hour and subsequently poured onto ice/water (5 l). Extraction with diethyl ether (3×300 ml) and working-up of the combined organic phases afforded crude, crystalline 3-cyanobenzofuran melting at 76°-82° C. Yield : 34 g. The 3-cyanobenzofuran was dissolved in a mixture of acetic acid:conc. H2SO4 :water 1:1:1 (660 ml) and refluxed for 3 hours. After cooling water was added and the 3-benzofurancarboxylic acid was finally extracted with diethyl ether (3×200 ml) and worked-up. Yield 37 g. Mp: 152°-156° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=O)[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.B.CSC>C1COCC1>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[CH2:10][N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([CH2:26][OH:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)CN2C
Temperature: 50 °C
Reaction time: 18 h

Procedure:
The title compound was synthesized by solubilizing 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (0.36 mmol) in THF (20 mL), and adding borane-dimethylsulfide (2.0M, 1.8 mL, 3.6 mmol) slowly. The solution was stirred for 18 h and then heated to 50° C. for 2 hours. The reaction mixture was then washed with water (×2), brine, and the solvent evaporated. The final compound was purified by reverse phase HPLC and basified to give the free base (8.1 mg, 5% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.37-1.96 (m, 8 H) 2.82 (s, 3 H) 3.48 (t, J=13.39 Hz, 2 H) 3.78 (t, J=12.00 Hz, 2 H) 3.86 (s, 3 H) 4.43 (d, 2 H) 4.84 (t, J=7.83 Hz, 1 H) 5.07 (t, J=5.81 Hz, 1 H) 6.82 (d, J=8.34 Hz, 1 H) 6.95 (s, 1 H) 7.31 (s, 1 H) 7.66 (s, 1 H) 8.21 (d, J=8.08 Hz, 1 H). [M+H] calculated for C21H27F2N5O2, 420; found 420.