Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7](N)=[CH:6][CH:5]=1.N([O-])=O.[Na+].[CH:15](=[O:21])[C:16]1[O:20][CH:19]=[CH:18][CH:17]=1>O>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:19]2[O:20][C:16]([CH:15]=[O:21])=[CH:17][CH:18]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc(N)cc1
Reactant: O=Cc1ccco1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(-c2ccc(C=O)o2)cc1
Temperature: 25 °C
Yield: 23.1 %

Procedure:
A 5l. three-necked flask equipped with stirrer, thermometer and dropping funnel was charged with water (150ml), concentrated HCl (400 ml) was introduced, followed by p-anisidine (185 g, 1.5 moles). A solution of sodium nitrite (108 g, 1.56 moles) in water (300 ml) was introduced dropwise maintaining -10° to -5°C. Furfural (184 g, 1.92 moles) was introduced followed by a solution of CuCl2.2H2O (46 g) in water (300 ml). The reaction mixture was heated to 53° with hot water maintaining 53°-68° for 2.5 hours. After cooling to room temperature overnight, the reaction mixture was extracted with ether (1800 ml). The dried (MgSO4) extract was evaporated in a rotary evaporator, and the residue was distilled under reduced pressure to give 70 g of black semi-solid product (b.p. 160°-190° at 2-5 mm).
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][C@@H:4]1[C@H:6]([C:7](Cl)=[O:8])[C:5]1([CH3:11])[CH3:10].[C:13]1([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH:22]([OH:28])[CH2:23]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]([Cl:12])=[CH:3][C@@H:4]1[C@H:6]([C:7]([O:28][CH:22]2[CH2:21][C:20]3[C:24](=[CH:25][CH:26]=[CH:27][C:19]=3[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:23]2)=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Reactant: OC1Cc2cccc(-c3ccccc3)c2C1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)OC1Cc2cccc(-c3ccccc3)c2C1
Yield: 65.5 %

Procedure:
In a manner similar to Example 12A, the reaction of 1.54 g (0.007 mole) of (±)-cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride and 1.5 g (0.007 mole) of (+)-4-phenyl-2-indanol (EE≥95%) in the presence of 0.7 g (0.009 mole) of pyridine and 20 ml of toluene gave 1.84 g of (+)-4-phenyl-2-indanyl(±)-cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate as an oil, EE≥95% (alcohol moiety). The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15]([N:19]5[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:26])[C:6]([C:27]([O:29]CC)=[O:28])=[CH:5]2)[CH2:3][CH2:2]1.C(O)(=O)C>C(O)C.[OH-].[K+].O>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15]([N:19]5[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:26])[C:6]([C:27]([OH:29])=[O:28])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc3cc(N4CCN(C)CC4)c(F)cc3cc2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CN1CCN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C2CC2)CC1
Yield: 50.4 %

Procedure:
A suspension of 0.85 g of 1-cyclopropyl-3-ethoxycarbonyl-7-fluoro-8-(4-methyl-1-pip-erazinyl)-4 -oxo-1,4-dihydro-benzo[b][1,8]naphthyridine in 12 cm3 of ethanol, 5 cm3 of 2 N aqueous potassium hydroxide solution and 7 cm3 of water is heated at a temperature close to 80° C. for 1 hour. After adding 5.8 cm3 of a 10% aqueous solution of acetic acid, the precipitate obtained is drained and washed with 3 times 5 cm3 of water. After recrystallizing twice from a mixture of 7.5 cm3 of ethanol and 7.5 cm3 of dimethylformamide each time, 0.4 g of 1-cyclopropyl-7-fluoro-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a yellow solid melting at 250° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH:12]([O:15]C)OC.C([Li])CCC.Br[CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27].Cl>C1COCC1>[CH2:27]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=1[CH:12]=[O:15])[CH2:26][CH2:25][CH:24]=[CH2:23]
Reactant: C=CCCCBr
Reactant: COC(OC)c1cc(C(F)(F)F)ccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCCCc1ccc(C(F)(F)F)cc1C=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
Step AJ (2): To a solution of 1-bromo-2-(dimethoxymethyl)-4-(trifluoromethyl)benzene (1060 mg, 3.544 mmol) in THF (10 mL) at −78° C. was added 1.6N solution of n-butyl lithium in hexanes (4.43 mL, 7.088 mmol). The resulting mixture was stirred at −78° C. for 15 min. 5-Bromopent-1-ene (0.42 mL, 3.544 mmol) was added by drops. The reaction mixture was warmed to rt and stirred overnight. Aqueous hydrochloric acid solution (1N) was added and the reaction mixture was stirred at rt for 3 h. The reaction was extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to give 2-(pent-4-enyl)-5-(trifluoromethyl)benzaldehyde (858.0 mg, 100%) as a brown oil. LC-MS (M+H)+=243.09. 1H NMR (CDCl3, 500 MHz) δ 10.30 (s, 1H) 8.22-7.35 (m, 3H) 7.06 (m, 1H) 5.83 (m, 1H) 5.10-5.00 (m, 2H) 3.84 (s, 3H) 2.16 (m, 2H) 1.75 (m, 2H) 1.60 (m, 2H).
Reaction SMILES: [C:1]1([P:7]2(=[O:12])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]=[O:14].C1(C)C=CC=CC=1>C1COCC1>[C:1]1([P:7]2(=[O:12])[CH2:8][CH2:9][CH2:10][CH:11]2[CH2:13][OH:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=P1(c2ccccc2)CCCC1
Reactant: C=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=P1(c2ccccc2)CCCC1CO
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
In a 1 l round bottom 2-neck flask charged a with a magnetic stirring bar, 23.4 g 1-phenylphospholane-1-oxide (0.11 mol) was dissolved in 300 ml freshly distilled THF, and 10.4 g dry paraformaldehyde was added. The reaction flask was flushed with argon and cooled to −20° C. Subsequently 100 ml phenyllithium solution in cyclohexane/diethylether 7:3 (1.8M) was added in one portion. The resulting mixture was stirred until the temperature reached +10° C. and additionally 5 minutes at that temperature. Then 10 g NH4Cl was added. The mixture was filtered, concentrated, and the residue purified by flash chromatography (EtOAc, followed by EtOAc/methanol 10:1). Yields: 2.5 g substrate (1-phenylphospholane-1-oxide) (11%), 11.7 g (43%) trans-1-phenyl-2-phospholanemethanol-1-oxide as white crystals, m.p. 109-110° C. (toluene); 1H NMR (500 MHz) δ: 1.70-1.85 (m, 1H), 1.95-2.30 (m, 6H), 3.90-4.00 (m, 2H), 4.19 (t, 1H, J=6.1), 7.45-7.55 (m, 3H), 7.70-7.76 (m, 2H); 31P NMR (200 MHz) δ: 63.3; and 2.2 g (8%) cis-1-phenyl-2-phospholanemethanol-1-oxide, white crystals, m.p. 149-151° C. (toluene); 1H NMR (500 MHz) δ: 1.46-1.57 (m, 1H), 2.02-2.22 (m, 4H), 2.28-2.42 (m, 1H), 2.44-2.58 (m, 1H), 3.32-3.49 (m, 2H), 3.76 (t, 1H, J=5.7), 7.46-7.51 (m, 2H.), 7.52-7.57 (m, 1H), 7.67-7.73 (m, 2H); 31P NMR (200 MHz) δ: 62.7.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:35])[C:27]3[CH:32]=[CH:31][C:30]([CH2:33]Cl)=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:35])[C:27]3[CH:32]=[CH:31][C:30]([CH2:33][N:41]4[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]4)=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Oc1ccc(S(=O)(=O)CCN2CC[C@H](Cc3ccccc3)[C@H](O)C2)cc1)c1ccc(CCl)cc1
Reactant: CN1CCNCC1
Product: CN1CCN(Cc2ccc(C(=O)Oc3ccc(S(=O)(=O)CCN4CC[C@H](Cc5ccccc5)[C@H](O)C4)cc3)cc2)CC1
Yield: 27 %

Procedure:
The title compound was prepared from 4-chloromethyl-benzoic acid (3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl ester and 4-methylpiperazin in 27% yield as a colorless oil.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1>ClCCl.C(#N)C>[Br:1][C:12]1[CH:11]=[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[CH:5]=2)[CH:15]=[CH:14][C:13]=1[OH:16]
Reactant: Oc1ccc(-c2cccc(F)c2)cc1
Reactant: BrBr
Solvent: CC#N
Solvent: ClCCl
Product: Oc1ccc(-c2cccc(F)c2)cc1Br
Reaction time: 17 h
Yield: 105.2 %

Procedure:
A solution of bromine (887 mg, 5.55 mmol) in dichloromethane (10 mL) was added dropwise to a solution of 4-(3-fluorophenyl)phenol [purchased from Combi-Blocks] (1.044 g, 5.55 mmol) in dichloromethane (10 mL) and acetonitrile (5 mL) at 0° C. under nitrogen. The reaction mixture was then stirred at 0° C. to room temperature for 17 hours. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium hydrogen carbonate solution (100 mL) containing 10% aqueous sodium thiosulfate solution (10 mL). The organic phase was separated, washed with water (100 mL) and saturated brine (100 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give an orange oil. The crude product was purified by chromatography on silica eluting with a solvent gradient of 0 to 15% ethyl acetate (containing 2% methanol) in hexanes to give 3-bromo-3′-fluoro-[1,1′-biphenyl]-4-ol (1.56 g, quant.) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].[F:16][C:17]1[CH:23]=[C:22]([S:24][CH3:25])[CH:21]=[CH:20][C:18]=1[NH2:19]>>[F:16][C:17]1[CH:23]=[C:22]([S:24][CH3:25])[CH:21]=[CH:20][C:18]=1[NH:19][C:2]1[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: CCOC(=O)c1nn(C)c(=O)c(C)c1Cl
Reactant: CSc1ccc(N)c(F)c1
Product: CCOC(=O)c1nn(C)c(=O)c(C)c1Nc1ccc(SC)cc1F
Yield: 81 %

Procedure:
The title compound was prepared in 81% yield by the procedure described in Example 166 (step H) using ethyl 4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylat (500 mg, 2.17 mmol) and 2-fluoro-4-methylthioaniline (375 mg, 2.38 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:26].[CH2:27]([NH:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH3:30]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:31]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:27][CH2:28][CH2:29][CH3:30])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:26]
Reactant: O=C1c2c(ccc(F)c2Cl)-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Reactant: CCCCNCCCC
Solvent: CN(C)C=O
Product: CCCCN(CCCC)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c-3ccc(F)c2Cl)no1
Yield: 36.1 %

Procedure:
1 g (2.5 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one was stirred at room temperature overnight with 0.98 g (7.5 mmol) of dibutylamine and 10 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there was obtained 0.44 g (36%) of (S)-8-chloro-1-(5-dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride (amorphous).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH:10]([C:14](=[O:26])[CH:15]=[CH:16][C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)[C:9](=[O:27])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>O1CCCC1.[C].[Pd]>[C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH:10]([C:14](=[O:26])[CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)[C:9](=[O:27])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(C=Cc1ccc2c(c1)OCO2)C1C(=O)CC(c2ccccc2)CC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(CCc1ccc2c(c1)OCO2)C1C(=O)CC(c2ccccc2)CC1=O

Procedure:
In 200 ml of tetrahydrofuran was dissolved 10.8 g of 5-phenyl-2-[3-(3,4-methylenedioxyphenyl)-propenoyl]cyclohexane-1,3-dione prepared in step (1) above, and 2 g of a 5% palladium-carbon catalyst was added to the solution and catalytic reduction was carried out for 7 hours with hydrogen under atmospheric pressure. The catalyst was removed by filtration and tetrahydrofuran was removed by distillation. Recrystallization from isopropyl alcohol have 7.5 g (the yield being 70%) of the desired 5-phenyl-2-[3-(3,4-methylenedioxyphenyl)propionyl]-cyclohexane-1,3-dione.
Reaction SMILES: Br[CH:2]([C:4]1[C:12]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)[CH3:3].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:21]([CH:2]([C:4]1[C:12]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)[CH3:3])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(Br)c1nn2ccccc2c1-c1cc(F)cc(F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(N=[N+]=[N-])c1nn2ccccc2c1-c1cc(F)cc(F)c1
Yield: 72.1 %

Procedure:
2-(1-Bromoethyl)-3-(3,5-difluorophenyl)pyrazolo[1,5-a]pyridine (0.63 g, 1.9 mmol) and sodium azide (0.12 g, 1.9 mmol) were stirred in N,N-dimethylformamide (20 mL) for 1 hour at 20° C. The mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered, concentrated and purified on silica gel with ethyl acetate in hexanes (0-35%) to give the desired compound (0.41 g, 73%). LCMS for C15H12F2N5 (M+H)+: m/z=299.9. 1H NMR (300 MHz, DMSO-d6): δ 8.80 (m, 1 H), 7.72 (m, 1 H), 7.38 (m, 1 H), 7.22 (m, 3 H), 7.02 (m, 1 H), 4.92 (m, 1 H), 1.62 (m, 3 H).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([NH:20][C:21](=[O:25])[C:22]([OH:24])=O)[CH:9]=1)(=[O:3])[CH3:2].CN(C(ON1N=N[C:36]2[CH:37]=[CH:38][CH:39]=[N:40][C:35]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.N1CCCCC1>CN1C(=O)CCC1>[C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:11]=[C:10]([NH:20][C:21](=[O:25])[C:22](=[O:24])[N:40]2[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(=O)NCCNc1cc(NC(=O)C(=O)O)nc(-c2ccccc2)n1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCNc1cc(NC(=O)C(=O)N2CCCCC2)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 18.2 %

Procedure:
To a stirred solution of [(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)amino](oxo)acetic acid (50 mg) in NMP (2.5 ml) were added HATU (51 mg) and N,N-diisopropylethylamine (25 μl). The mixture was stirred at room temperature for 15 min then piperidine (90 μl) added and the solution left for 16 hrs. After this time, the solvent was removed in vacuo. Purification via flash chromatography on silica gel using ethyl acetate as the eluent furnished the correct material (10 mg).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])[CH2:23][CH2:22][C:21]([C:34]([O:36]C)=[O:35])=[CH:20][C:19]=3[CH:38]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])[CH2:23][CH2:22][C:21]([C:34]([OH:36])=[O:35])=[CH:20][C:19]=3[CH:38]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccccc2OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccccc2OC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.6 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-(2-methoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylate (391 mg) in a mixture of tetrahydrofuran (24 ml) and methanol (24 ml) was added 1N sodium hydroxide solution (8 ml), and the mixture was stirred at room temperature for 1 day. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to make acidic (pH=4), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting solid was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-(2-methoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (257 mg) as yellow crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][CH:18]3[CH2:20][CH2:19]3)=[CH:12][CH:11]=2)[CH:3]=1.[Li][CH2:22]CCC.C[Si](C)(C)[O:28][C@@H:29]1[C@@H:34]([O:35][Si](C)(C)C)[C@H:33]([O:40][Si](C)(C)C)[C@@H:32]([CH2:45][O:46][Si](C)(C)C)[O:31][C:30]1=[O:51].CS(O)(=O)=O>C1(C)C=CC=CC=1.C1COCC1.C1(C)C=CC=CC=1.CO>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:30]2([O:51][CH3:22])[C@H:29]([OH:28])[C@@H:34]([OH:35])[C@H:33]([OH:40])[C@@H:32]([CH2:45][OH:46])[O:31]2)=[CH:3][C:4]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][CH:18]2[CH2:20][CH2:19]2)=[CH:12][CH:11]=1
Reactant: [Li]CCCC
Reactant: Clc1ccc(Br)cc1Cc1ccc(COC2CC2)cc1
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Agent: CS(=O)(=O)O
Solvent: CO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC1(c2ccc(Cl)c(Cc3ccc(COC4CC4)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: -65 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-1-chloro-2-(4-(2-cyclopropoxymethyl)benzyl)benzene (0.6 g, 1.71 mmol) in anhydrous toluene/THF (6 mL, v/v=2:1) was added dropwise n-BuLi (2.5 M in hexane, 0.82 mL) at −65° C., and the mixture was stirred for 30 min at −65 ° C. Then a −65° C. solution of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one (0.87 g, 1.88 mmol) in toluene (6 mL) was added dropwise over 15 min. The mixture was stirred at −65° C. for 3.5 h until starting material was consumed. The reaction was quenched with methanesulfonic acid (0.23 mL, 3.58 mmol) in methanol (6 mL), and the mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated sodium bicarbonate, the organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated bicarbonate, then with water, and then with brine, and dried over sodium sulfate. Removal of the volatiles afforded a residue (0.75 g), which was used in the next step without further purification.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.C([O:22][C:23](=O)[C:24](=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)C>C(O)C>[OH:33][C:24]1[C:23](=[O:22])[N:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:16]([C:15]2[CH:18]=[CH:19][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[C:25]=1[C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CCOC(=O)C(=O)Cc1ccc(O)cc1
Reactant: NCCCn1ccnc1
Solvent: CCO
Product: COc1ccc(C2C(c3ccc(O)cc3)=C(O)C(=O)N2CCCn2ccnc2)cc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
3-Imidazol-1-yl-propylamine (1 mmol) and 4-Methoxy-benzaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 2-Oxo-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[C:16]([F:17])=[C:15]([F:18])[CH:14]=[C:13]([F:19])[C:12]=3[F:20])[N:9]=[CH:10][C:3]=12.[O:21]1CC[O:23][BH:22]1.C([O-])(=O)C.[K+].C(Cl)Cl>CS(C)=O>[F:20][C:12]1[C:13]([F:19])=[CH:14][C:15]([F:18])=[C:16]([F:17])[C:11]=1[N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([B:22]([OH:23])[OH:21])=[C:3]2[CH:10]=[N:9]1
Reactant: Fc1cc(F)c(F)c(-n2ncc3c(I)ccnc32)c1F
Reactant: B1OCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: OB(O)c1ccnc2c1cnn2-c1c(F)c(F)cc(F)c1F
Temperature: 105 °C

Procedure:
To a 48 mL pressure bottle under N2 was added the compound from Intermediate 69A (1.1 g, 2.8 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane (1.17 g, 4.61 mmol), potassium acetate (1.15 g, 11.72 mmol), and anhydrous DMSO (8 mL). Argon was bubbled into the reaction mixture for 5 min and then PdCl2(dppf).CH2Cl2 (71 mg, 0.097 mmol) was added. The reaction mixture was flushed with argon, securely capped, and heated at 105° C. for 75 min. After adding 30 mg more palladium catalyst and 60 mg more 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane, the reaction mixture was heated at 115° C. in an oil bath for an additional 75 min to give the desired intermediate. LC/MS (Condition B): ret. T=3.2 min, (M+H)+ 312.03.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([C:14]2[CH:15]=[CH:16][C:17]([S:20][CH3:21])=[N:18][CH:19]=2)=[CH2:13])[CH2:11][O:10]1.C(=O)([O-])[O-].[K+].[K+].[NH:28]1[CH:32]=[N:31][CH:30]=[N:29]1.C(OCC)(=O)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([C:12]([C:14]1[CH:15]=[CH:16][C:17]([S:20][CH3:21])=[N:18][CH:19]=1)=[CH2:13])[CH2:11][N:28]1[CH:32]=[N:31][CH:30]=[N:29]1
Reactant: c1nc[nH]n1
Reactant: C=C(c1ccc(SC)nc1)C1(c2ccc(F)cc2F)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(c1ccc(SC)nc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 50 °C
Reaction time: 20 h
Yield: 71.9 %

Procedure:
A solution of the product of part (vi) (3.6 g, 13 mmol) in DMF (30 ml) was added to potassium carbonate (2.0 g, 15 mmol) and 1H-1,2,4-triazole (1.0 g, 15 mmol). The mixture was stirred at 50° C. for 20 hours then poured into ethyl acetate (200 ml) and washed with water (2×100 ml). The organic phase was dried (MgSO4) and evaporated under reduced pressure. Flash chromatography of the residue on silica by elution with ethyl acetate gave the title compound as an oil, (3.5 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH:6]=[CH:7][CH:8]=[N:9][NH:10][C:11]([NH2:13])=[S:12].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=O>>[F:28][C:27]([F:29])([F:30])[C:24]1[CH:23]=[CH:22][C:21]([C:19]2[N:13]=[C:11]([NH:10][N:9]=[CH:8]/[CH:7]=[CH:6]/[C:5]3[CH:4]=[C:3]([CH2:2][OH:1])[CH:16]=[CH:15][CH:14]=3)[S:12][CH:18]=2)=[CH:26][CH:25]=1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Reactant: NC(=S)NN=CC=Cc1cccc(CO)c1
Product: OCc1cccc(/C=C/C=NNc2nc(-c3ccc(C(F)(F)F)cc3)cs2)c1
Yield: 37 %

Procedure:
The compound is prepared according to the method described in example 1B from 3-hydroxymethylcinnamaldehyde thiosemicarbazone (0.4 mmoles) prepared in step 28A and from 2-bromo-4′-trifluoromethylacetophenone (0.4 mmoles). Yield 37%.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C[C:5]1[C:10]([C:11]([C:13]2[C:14]([CH2:19][C:20]3C=C[C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])=NC=CC=2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1.[C:33]1([CH3:43])C=CC(S(O)(=O)=O)=C[CH:34]=1.[OH2:44].[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[Cl:26][C:23]1[CH:22]=[C:21]([Cl:27])[CH:20]=[CH:19][C:14]=1[CH2:13][C:11]1([C:10]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[O:12][CH:33]([CH3:43])[CH2:34][O:44]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O
Reactant: O=C(c1cccnc1Cc1ccc(Cl)cc1Cl)c1cccnc1Cc1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CC1COC(Cc2ccc(Cl)cc2Cl)(c2cccnc2)O1
Temperature: 25 °C

Procedure:
13.3 g of 2,4-dichlorobenzyl-3-pyridyl ketone, 7.6 g of propanediol-1,2 and 13.0 g of p-toluenesulfonic acid are boiled in 150 ml of xylene for 32 h in a water separator. After cooling to RT, the reaction mixture is poured into 600 ml of 2N sodium hydroxide solution, and extracted 3 times with 200 ml of ether each time. The combined organic phases are washed with 250 ml of water, dried over sodium sulfate and filtered. The solvent is evaporated off and the oily crude product is purified by column chromatography (eluant: ether). The compound is obtained as clear colourless oil; nD22.5 :1.5676.