Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
To a solution of 1 g (4.69 mmol) of 4-oxo-azepane-1-carboxylic acid tert-butyl ester), in 2 mL of Methanol and 8 mL of THF, is added at 0° C. (ice bath) sodium tetrahydroborate (0.18 g, 4.69 mmol). The resulting mixture is stirred at 0° C. for 1 h. To the reaction mixture is added at 0° C. (ice bath), a solution of HCl (1N) (2 mL), then solvent is removed and the resulting slurry is diluted with water and extracted with EtOAc (250 mL). The organic layers are combined, dried (Na2SO4), filtered and concentrated to afford the title compound as a colorless oil (0.95 g, 94%). MS (m/e): 216 (M+1).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.Cl[S:16]([OH:19])(=[O:18])=[O:17]>C(Cl)Cl>[F:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][C:4]2[CH:3]=[CH:2][C:1]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:6][CH:5]=2)=[CH:13][CH:12]=1
Reactant: O=S(=O)(O)Cl
Reactant: Fc1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: O=S(=O)(O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 4-fluorodiphenyl ether 1b (1.00 g, 5.31 mmol) in dry CH2Cl2 (30 mL) under an argon atmosphere at 0° C., was added chlorosulphonic acid (0.35 mL, 5.31 mmol). The reaction mixture was stirred for 2 h at 0° C. The solvent was evaporated at room temperature and the residue dried overnight under vacuum to give the corresponding 4-(4-fluorophenoxy)benzenesulphonic acid (2b) as a pale-pink hygroscopic solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH3:26])=[O:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:46]1([CH:52](O)[CH2:53][CH3:54])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1.N(C(OCC)=O)=NC(OCC)=O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:54][CH2:53][CH2:52][N:46]4[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH3:26])=[O:24]
Reactant: CNC(=O)Nc1ccc(Oc2ncnc3cc(O)c(OC)cc23)cc1Cl
Reactant: CCC(O)N1CCCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CNC(=O)Nc1ccc(Oc2ncnc3cc(OCCCN4CCCCC4)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.4 %

Procedure:
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinaz-olinyl)oxy]phenyl}-N′-methylurea (2.0 g) was dissolved in N,N-dimethylformamide (50 ml), and triphenylphosphine (2.8 g), piperidinopropanol (0.9 g), and diethyl azodicarboxylate (1.9 g) were added to the solution. The mixture was stirred at room temperature for 2 hr. Triphenylphosphine (2.8 g), piperidinopropanol (0.6 g), and diethyl azodicarboxylate (1.9 g) were then again added to the reaction solution, followed by stirring at room temperature for additional 10 hr. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol (20/1) to give 650 mg (yield 25%) of the title compound.
Reaction SMILES: [I-].[CH2:2]([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([Zn+])=[CH:9][CH:8]=1)=[O:6])[CH3:3].[CH3:14][C:15]([CH3:20])([CH3:19])[C:16](Cl)=[O:17].Cl>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][C:15]([CH3:20])([CH3:19])[C:16]([C:10]1[CH:11]=[CH:12][C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])=[CH:8][CH:9]=1)=[O:17]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)c1ccc([Zn+])cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [I-]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(=O)C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4-(Ethoxycarbonyl)phenyl-zinc iodide (50.0 mL of a 0.5 M solution in THF, 25.0 mmol) was added slowly via cannula to a stirred solution of dichlorobis(triphenylphosphine)palladium(II) (484 mg, 0.690 mmol) in THF (50 mL) at 0° C. After 15 min, trimethylacetyl chloride (2.80 mL, 22.7 mmol) was added and the resulting mixture was stirred at 0° C. for 1.5 h. The reaction mixture was poured into 1 N HCl and extracted three times with EtOAc. The combined organic extracts were washed with water, brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0-10% EtOAc/hexanes as eluent) afforded the title compound i-1a. 1HNMR (500 MHz, CDCl3): δ 8.08 (d, 2H, J=8.5 Hz), 7.67 (d, 2H, J=8.5 Hz), 4.42 (q, 2H, J=7.2 Hz), 1.42 (t, 3H, J=7.2 Hz), 1.36 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[F:13].Cl[Si](C)(C)C.[CH2:19](O)[CH3:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:19][CH3:20])=[O:11])=[CH:4][C:3]=1[F:13]
Reactant: O=C(O)/C=C/c1ccc(Cl)c(F)c1
Reactant: CCO
Agent: C[Si](C)(C)Cl
Product: CCOC(=O)/C=C/c1ccc(Cl)c(F)c1
Reaction time: 20 h
Yield: 99.65 %

Procedure:
(E)-3-(4-Chloro-3-fluorophenyl)acrylic acid (17.3 g, 86.24 mmol) was suspended in ethanol (200 mL), and chlorotrimethylsilane (24.00 mL, 189.7 mmol) was added. The mixture was then agitated for 20 hours and evaporated, to give (E)-ethyl 3-(4-chloro-3-fluorophenyl)acrylate (19.65 g, 85.94 mmol, 99.65% yield) as an oil, which solidified later.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1I.[CH2:11]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH3:20])[CH2:12][C:13]#[CH:14].C(#N)C.C(NC(C)C)(C)C>CC([O-])=O.CC([O-])=O.[Pd+2].[Cu](I)I>[CH3:20][C@@H:16]1[CH2:17][CH2:18][CH2:19][N:15]1[CH2:11][CH2:12][C:13]1[O:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH:14]=1
Reactant: N#Cc1ccc(O)c(I)c1
Reactant: C#CCCN1CCC[C@H]1C
Agent: I[Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CC(C)NC(C)C
Product: C[C@@H]1CCCN1CCc1cc2cc(C#N)ccc2o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24.6 %

Procedure:
The product from Example 87A (10.0 g, 40.81 mmol) was sequentially treated with 0.1M (2R)-1-(3-butynyl)-2-methylpyrrolidine in acetonitrile (490 mL, 48.9 mmol), Pd(OAc)2 (0.275 g, 1.22 mmol), Ptol3 (0.747 g, 2.44 mmol), and copper iodide (1.16 g, 6.122 mmol). After stirring at 25° C. for 10 min, diisopropyl amine (43.0 mL) was added and the reaction mixture was heated at 60° C. in an inert atmosphere for 16 h. The reaction mixture was cooled, filtered through celite, concentrated under reduced pressure, and purified on silica gel using 95% DCM, 9.5% MeOH, 0.1% NH4OH to provide the title compound as a brown semi-solid (2.56 g, 24.6% yield). 1HNMR (300 MHz, CD3OD) δ 1.09 (d, 3H, J=6.1 Hz), 1.46 (m, 1H), 1.81 (m, 2H), 2.02-2.38 (m, 2H), 2.59 (m, 2H) 3.08 (m, 2H), 3.28 (m, 2H), 6.70 (s, 1H), 7.58 (s, 1H), 7.97 (s, 1H); MS (ESI) m/e 255 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH2:7])=[NH:6].[Cl:12][C:13]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:14]=1[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18]>>[NH2:20][CH2:19][C:16]1[C:17]([NH2:18])=[N:6][C:5]([C:4]2[CH:8]=[CH:9][C:10]([F:11])=[C:2]([F:1])[CH:3]=2)=[N:7][C:15]=1[C:14]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:13]=1[Cl:12]
Reactant: N=C(N)c1ccc(F)c(F)c1
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: NCc1c(N)nc(-c2ccc(F)c(F)c2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=381.3 (M+H+), was prepared from 3,4-difluoro-benzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12](B2OC(C)(C)C(C)(C)O2)[CH:11]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=2)[CH:11]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC1(C)OB(c2cc(F)ccc2C#N)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(F)cc1-c1cccc(Br)n1
Temperature: 80 °C
Yield: 37.9 %

Procedure:
2,6-Dibromopyridine (0.94 g, 4.0 mmol), 4-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (1.48 g, 6.0 mmol) and potassium phosphate (1.70 g, 8.0 mmol) were dissolved in N,N-dimethylformamide (12 ml) and degassed with nitrogen for 15 min. Tetrakis(triphenylphosphine)palladium(0) (230 mg, 0.2 mmol) was added then the mixture heated at 80° C. for 16 h. The mixture was allowed to cool to ambient temperature, diluted with water (150 ml) and extracted into ethyl acetate (2×150 ml). The combined organics were washed with brine (100 ml), dried over anhydrous sodium sulfate and evaporated to give a yellow oil. Purification by flash column chromatography on silica eluting with isohexane on a gradient of ethyl acetate (10-15%) gave 4-fluoro-2-(6-bromopyridin-2-yl)benzonitrile (0.42 g, 38%) as a waxy solid: δH (360 MHz, CDCl3) 7.21-7.25 (1H, m), 7.59 (1H, d, J 8), 7.67 (1H, dd, J 9.3, 2.6), 7.72 (1H, t, J 7.7), 7.78-7.87 (2H, m).
Reaction SMILES: [CH2:1]([O:8][NH:9][CH2:10][C@@H:11]([C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39](OC=O)(=[O:41])C>C1COCC1>[CH2:1]([O:8][N:9]([CH2:10][C@@H:11]([C:16]([N:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH2:22][CH2:23]1)=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH:39]=[O:41])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC=O
Reactant: COc1ccc(N2CCN(C(=O)[C@H](CNOCc3ccccc3)CC(C)C)CC2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCN(C(=O)[C@@H](CC(C)C)CN(C=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 81 %

Procedure:
To a solution of (2S)—N-(benzyloxy)-2-{[4-(4-methoxyphenyl)piperazin-1-yl]carbonyl}-4-methylpentan-1-amine (122 mg; 0.29 mmol; 1.0 eq.) and triethylamine (123 μL; 0.86 mmol; 3.0 eq.) in THF (2 mL) was added formic acetic anhydride (63 mg, 0.72 mmol, 2.5 eq., prepared as described in Krimen et al., in Organic Syntheses Coll. Vol 6, p8. The solution was stirred for 4.5 h at room temperature. The solvents were evaporated and the residue purified by column chromatography (Silicagel, 1/1 EtOAc/c-Hex) to give the title product as a colorless oil (105 mg, 81%). HPLC, Rt: 3.17 min (purity: 100%). M+(LC-MS (ESI)): 454.4.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([O:26][CH2:27][CH3:28])[CH:17]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].C(=O)(O)[O-].[Na+].Cl[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36]>ClCCl>[CH2:38]([O:37][C:35]([NH:3][C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([O:26][CH2:27][CH3:28])[CH:17]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:9]=1)=[NH:2])=[O:36])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOc1cc(C(Nc2ccc(C(=N)N)cc2)C(=O)OC)ccc1OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOc1cc(C(Nc2ccc(C(=N)NC(=O)OCc3ccccc3)cc2)C(=O)OC)ccc1OC(C)C
Yield: 66.8 %

Procedure:
To 141D (6.7 g; 13.25 mmol) in dichloromethane (80 mL) was added sodium bicarbonate (132 mL, 1 M). Benzyl chloroformate (1.89 mL, 13.25 mmol) in dichloromethane (20 mL) was then added dropwise using an addition funnel over a period of 1 h. After the addition was complete, the suspension turned to a clear orange solution. The layers were separated and the organic layer was washed with brine and dried over sodium sulfate. The solvent was removed and the crude residue was purified by flash column chromatography to give 4.6 g of 141E as a yellow solid (69% yield). LC-MS: 520.10 (M+H)+.
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]([CH:34]=[C:35]([Cl:37])[N:36]=2)[C:31]([OH:33])=[O:32])[CH2:24][CH:23]1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.Cl.C(OCC)(=O)C>O1CCOCC1>[ClH:37].[Cl:37][C:35]1[CH:34]=[C:30]([CH:29]=[C:28]([N:25]2[CH2:26][CH2:27][CH:22]([CH2:21][NH:8][C@@H:9]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][CH:12]=3)[CH3:10])[CH:23]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:24]2)[N:36]=1)[C:31]([OH:33])=[O:32]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2cc(C(=O)O)cc(Cl)n2)CC1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@@H](NCC1CCN(c2cc(C(=O)O)cc(Cl)n2)CC1c1ccccc1)c1cccc2ccccc12
Reaction time: 2 h
Yield: 95.4 %

Procedure:
To a solution of 68 mg of 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-6-chloroisonicotinic acid in 1.0 mL of 1,4-dioxane was added 1.00 mL of a 4 M hydrogen chloride/ethyl acetate solution at room temperature, followed by stirring for 2 hours. The solvent was removed by distillation under reduced pressure. The residue was washed with diisopropylether, and dried under reduced pressure to obtain 29 mg of 2-chloro-6-[4-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]isonicotinic acid hydrochloride as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([CH2:12][C:13]1([C:18](O)=[O:19])[CH2:17][CH2:16][S:15][CH2:14]1)(O)=[O:10].C(N1C=CN=C1)(N1C=CN=C1)=O>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9](=[O:10])[CH2:12][C:13]3([CH2:14][S:15][CH2:16][CH2:17]3)[C:18]2=[O:19])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=C(O)CC1(C(=O)O)CCSC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1C
Product: O=C1CC2(CCSC2)C(=O)N1c1cccc(Br)c1
Yield: 92.9 %

Procedure:
A solution of 3-bromo-phenylamine (1.0 g, 5.81 mmol) and 3-carboxymethyl-tetrahydro-thiophene-3-carboxylic acid (1.15 g, 6.05 mmol, [Rice, L. M. et al; J. Med Chem; 6; 1963; 388-402]) in xylene (10 ml) was heated for 2 hours (oil bath, 180° C.) with fitted Dean-Stark trap to remove water. The material was cooled to ambient and the xylene stripped (rotovap/pump). The material was covered with dry CH2Cl2 (10 ml). Carbonyldiimidazole (1.18 g, 7.26 mmol) was added with vigorous stirring and a homogeneous solution was rapidly obtained. After over night stirring the material was adsorbed onto silica (12 g). The crude was purified by chromatography on silica gel, eluting with a gradient of 100% CH2Cl2 to 0.12% MeOH/CH2Cl2, to afford 1.76 g of 7-(3-bromo-phenyl)-2-thia-7-aza-spiro[4.4]nonane-6,8-dione as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][C:5]2([CH3:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+].[CH3:22]I.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:22])[C:7](=[O:12])[CH2:6][C:5]2([CH3:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC1(c2ccccc2)CC(=O)Nc2ccc(Cl)cc21
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CC(C)(c2ccccc2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-chloro-1,2,3,4-tetrahydro-4-methyl-2-oxo-4-phenylquinoline (6.0 g) in DMF (50 ml) was added sodium hydride (60% in oil) (0.98 g), followed by stirring at room temperature for 30 minutes. After this mixture was cooled to 0° C., methyl iodide (3 ml) was added, followed by stirring at room temperature for further 30 minutes. After dilute hydrochloric acid was added, the mixture was extracted with ethyl acetate. The extract was washed with water and then dried, after which the solvent was distilled off, to yield 6-chloro-1,2,3,4-tetrahydro-1,4-dimethyl-2-oxo-4-phenylquinoline as colorless crystals (5.58 g).
Reaction SMILES: [CH:1]([NH:3][C:4]1(NC)[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)=O.Cl.[OH-].[Na+].C(Cl)Cl>O>[CH3:1][NH:3][C:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[S:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CNC1(NC=O)c2ccccc2SC1c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CNc1c(-c2ccccc2)sc2ccccc12

Procedure:
34.2 g (0.13 mol) of 3-formamido-3-methylamino-2-phenyl-benzo(b)thiophene are refluxed with stirring for 4 hours with 300 milliliters of HCl at 25%. After cooling, it is diluted in water, made alkaline by sodium hydroxide solution and stirred with CH2Cl2. After the organic phase has been extracted several times 2 N NaOH 7.4 g (26% of theory) of 2-phenyl-thioindole are isolated. By evaporating the solution of CH2Cl2 dried over K2CO3, the 3-methylamino-2-phenyl-benzo(b)thiophene is obtained in the form of a crude oily product. It is dissolved in a little CHCl3 and converted into the hydrochloride by hydrochloric gas: 20.2 g (57% of theory) of colourless prisms in a mixture of ethanol and ether, decomposition from 198° C. (in a sealed tube).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[C:14]([CH:16]=O)[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OP([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:34][C:35]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:36]=3[N:37]=2)=[CH:29][CH:28]=1)(OCC)=O)C.O>CN(C)C=O>[C:1]1([C:7]2[O:8][C:9]3[CH:15]=[C:14]([CH:16]=[CH:26][C:27]4[CH:28]=[CH:29][C:30]([C:33]5[O:34][C:35]6[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:36]=6[N:37]=5)=[CH:31][CH:32]=4)[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc2nc(-c3ccccc3)oc2c1
Reactant: CCOP(=O)(Cc1ccc(-c2nc3cc(Cl)ccc3o2)cc1)OCC
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc2oc(-c3ccc(C=Cc4ccc5nc(-c6ccccc6)oc5c4)cc3)nc2c1
Yield: 33.4 %

Procedure:
A solution of 4.46 g (0.02 mole) of 2-phenyl-6-formyl-benzoxazole of the formula ##STR29## (melting point: 133°-135° C.) and 7.59 g (0.02 mole) of 2-(p-diethylphosphonomethylphenyl)-5-chloro-benzoxazole of the formula ##STR30## (melting point: 96°-98°) in 80 ml of dimethyl formamide is heated to 40° C. Then 2.1 g (0.022 mole) of sodium tert.butylate are added in small amounts to the solution over the course of 30 minutes and the resultant suspension is further stirred for 4 hours at 40° C. The reaction mixture is poured into water and the precipitate is collected by filtration, washed with water and subsequently with a total amount of 110 ml of methanol. The product is recrystallised form a solvent mixture of nonane/xylene (1:1) with the addition of fuller's earth, affording 3 g (30% of theory) of 1-(2-phenylbenzoxazol-6-yl)-2-[4'-(5-chlorbenzoxazol-2-yl)-phenyl]-ethylene of the formula ##STR31## in the form of pale yellow flakes having a melting point of 241°-242° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:24])[C:9]([C:15]2[CH:16]=[CH:17][C:18](=[O:23])[N:19]([CH2:21][CH3:22])[CH:20]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:25])[CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37]>>[CH2:39]([O:38][C:36]([C:28]1[CH:29]=[C:30]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:24])[C:9]([C:15]3[CH:16]=[CH:17][C:18](=[O:23])[N:19]([CH2:21][CH3:22])[CH:20]=3)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:25])[CH:3]=2)[CH:31]=[CH:32][C:27]=1[F:26])=[O:37])[CH3:40]
Reactant: CCn1cc(C(O)(C(C)c2ccc(Br)cc2Cl)C(F)(F)F)ccc1=O
Reactant: CCOC(=O)c1cc(B(O)O)ccc1F
Product: CCOC(=O)c1cc(-c2ccc(C(C)C(O)(c3ccc(=O)n(CC)c3)C(F)(F)F)c(Cl)c2)ccc1F

Procedure:
In analogy to Example 150, step 2, 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-ethyl-1H-pyridin-2-one was reacted with 4-fluoro-3-ethoxycarbonylphenylboronic acid to give the title compound as a colorless foam. MS (m/e)=526.3 [M+H+].
Reaction SMILES: Cl.Cl.Cl.Cl.[NH2:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]4[CH:32]=[CH:31][C:30]([C:33]5[CH:38]=[C:37]([O:39][CH3:40])[C:36]([NH2:41])=[C:35]([O:42][CH3:43])[CH:34]=5)=[CH:29][N:28]=4)[CH2:22][CH2:21]3)=[N:18][CH:19]=2)=[CH:8][C:7]=1[O:44][CH3:45].[CH3:46][S:47](Cl)(=[O:49])=[O:48]>N1C=CC=CC=1>[CH3:46][S:47]([NH:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]4[CH:32]=[CH:31][C:30]([C:33]5[CH:38]=[C:37]([O:39][CH3:40])[C:36]([NH:41][S:47]([CH3:46])(=[O:49])=[O:48])=[C:35]([O:42][CH3:43])[CH:34]=5)=[CH:29][N:28]=4)[CH2:22][CH2:21]3)=[N:18][CH:19]=2)=[CH:8][C:7]=1[O:44][CH3:45])(=[O:49])=[O:48]
Reactant: COc1cc(-c2ccc(N3CCCN(c4ccc(-c5cc(OC)c(N)c(OC)c5)cn4)CC3)nc2)cc(OC)c1N
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc(-c2ccc(N3CCCN(c4ccc(-c5cc(OC)c(NS(C)(=O)=O)c(OC)c5)cn4)CC3)nc2)cc(OC)c1NS(C)(=O)=O
Reaction time: 0.25 h
Yield: 68.9 %

Procedure:
To a solution of 1,4-bis[5-(4-amino-3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine tetrahydrochloride (40.0 mg, 0.0570 mmol), which was synthesized in Example 34, in pyridine (1.0 mL) was added methanesulfonyl chloride (30.0 mg, 0.260 mmol). The reaction mixture was stirred for 15 minutes, and concentrated under reduced pressure. A solution of the residue in methanol-chloroform (1:10) was washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from chloroform-hexane to yield the title compound as a pale brown crystalline powder (melting point: 235.0–239.0° C.) (28.0 mg, yield: 68%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[O:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:20]C1C=CC=CC=1C=O>CCCCCCC.C(OCC)(=O)C>[Cl:20][C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[CH:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=2)[O:9]1
Reactant: O=Cc1ccccc1Cl
Reactant: O=C1CC(c2cccc(F)c2)Oc2ccc(O)cc21
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C1CC(c2ccccc2Cl)Oc2ccc(O)cc21

Procedure:
2-(2-Chlorophenyl)-6-hydroxychroman-4-one was prepared as described for 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from 3.0 g of 2 ′,5′-dihydroxyacetophenone and 2.8 g of 2-chlorobenzaldehyde. The product was passed though silica gel using heptane-ethyl acetate as an eluant and then triturated with ethanol. 1H NMR (400 MHz, d6-DMSO) δ: 9.49 (s, 1H), 7.77 (dd, 1H, J 7.7, 2.0 Hz), 7.53 (dd, 1H, J 7.6, 1.8 Hz), 7.49-7.41 (m, 2H), 7.14 (d, 1H, J 2.9 Hz), 7.06 (dd, 1H, J 8.8, 2.9 Hz), 6.93 (d, 1H, J 8.8 Hz), 5.78 (dd, 1H, J 13.6, 2.6 Hz), 3.19 (dd, 1H, J −16.9, 13.6 Hz), 2.78 (dd, 1H, J −16.9, 2.6 Hz).