Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Br)(Br)([Br:3])=O.O[C:7]1[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.[Cl-].[Na+]>>[Br:3][C:7]1[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: O=C(O)c1cc(O)nc2ccccc12
Reactant: O=P(Br)(Br)Br
Agent: [Cl-]
Agent: [Na+]
Product: O=C(O)c1cc(Br)nc2ccccc12
Temperature: 90 °C
Reaction time: 4 h

Procedure:
Phosphorus oxybromide (5.00 g, 17.4 mmol) was added to commercially available 2-hydroxy-4-quinolinecarboxylic acid (1.00 g, 5.29 mmol), and the mixture was heated with stirring at 90° C. for 4 hours. The reaction solution was added to ice water. To the mixture, sodium chloride was added, and the deposited crystal was collected by filtration, washed with water, and dried to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:23][CH3:24])=[CH:6][C:7]2[O:12][C:11](=[O:13])[C:10]([CH2:14][CH2:15]OS(C)(=O)=O)=[C:9]([CH3:21])[C:8]=2[CH:22]=1)[CH3:2].[C:25]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)(C)C>[CH2:1]([O:3][C:4]1[C:5]([O:23][CH3:24])=[CH:6][C:7]2[O:12][C:11](=[O:13])[C:10]([CH2:14][CH2:15][N:34]3[CH2:35][CH2:36][N:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:32][CH2:33]3)=[C:9]([CH3:21])[C:8]=2[CH:22]=1)[CH3:2]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCOc1cc2c(C)c(CCOS(C)(=O)=O)c(=O)oc2cc1OC
Solvent: CC(C)O
Product: CCOc1cc2c(C)c(CCN3CCN(c4ccccc4)CC3)c(=O)oc2cc1OC
Yield: 70 %

Procedure:
Process B; starting materials: 6-ethoxy-3-[2-(methanesulphonyloxy)ethyl]-7-methoxy-4-methyl -2H-1-benzopyran-2-one (Example 29) and 1-phenylpiperazine; yield 70%; m.p. 164°-165° C. (from isopropanol).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([Cl:9])=[CH:5][C:6]=1[CH:7]=[O:8].[Cl:10][C:11]1[CH:12]=[C:13]([Mg]Br)[CH:14]=[CH:15][CH:16]=1>C1COCC1.CCOCC>[Br:1][C:2]1[S:3][C:4]([Cl:9])=[CH:5][C:6]=1[CH:7]([C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:10])[CH:16]=1)[OH:8]
Reactant: Clc1cccc([Mg]Br)c1
Reactant: O=Cc1cc(Cl)sc1Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1cccc(Cl)c1)c1cc(Cl)sc1Br
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-bromo-5-chlorothiophene-3-carbaldehyde from Example 1, Step 3 (2.50 g, 11.1 mmol) in THF/ether at −78° C. was added 3-chlorophenylmagnesium bromide (26.6 mL, 0.5M in THF) in 2 min. and the mixture was stirred at −78° C. for 5 min., quenched with saturated NH4Cl/water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by flash chromatography (10-20% EtOAc/hexanes) to give the desired product.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:5]1[CH:6]=[N:7][C:8]([C:14]([F:17])([F:16])[F:15])=[C:9]([CH:13]=1)C(O)=O)[CH3:4]>[Cu].C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH3:1][S:2][CH:3]([C:5]1[CH:13]=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[N:7][CH:6]=1)[CH3:4]
Reactant: CSC(C)c1cnc(C(F)(F)F)c(C(=O)O)c1
Agent: [Cu]
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CSC(C)c1ccc(C(F)(F)F)nc1
Temperature: 240 °C
Yield: 44.5 %

Procedure:
To a dry 50 mL round bottom flask equipped with magnetic stirrer, nitrogen inlet, thermometer, and reflux condenser was charged 0.35 g (0.00132 moles) of 5-(1-methylthioethyl)-2-trifluoromethylnicotinic acid, 0.17 g (0.00264 moles) of copper powder and 10 mL of DowTherm A. The reaction was heated at 240° C. for 1 hour, then cooled to room temperature. The reaction mixture was extracted with 3 aliquots of 50 mL of ethyl acetate, and washed with 50 mL of water and 50 mL of saturated aqueous sodium chloride solution. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum on a rotary evaporator. The crude product thus obtained was chromatographed on silica gel with a gradient of 100% hexane to 50% ethyl acetate, 50% hexane. The pure fractions were combined, and concentrated under vacuum on a rotary evaporator to afford 0.13 g of the title compound as a pale yellow oil. 1H NMR (CDCl3): δ 1.62 (d, 3H), 1.94 (s, 3H), 3.93 (q, 1H), 7.68 (d, 1H), 7.90 (d, 1H), and 8.66 (s, 1H).
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13](Cl)[C:12]([Cl:19])=[N:11]2)=[O:7]>CO>[CH3:4][O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([NH:2][NH2:3])[C:12]([Cl:19])=[N:11]2)=[O:7]
Reactant: NN
Reactant: COC(=O)c1ccc2nc(Cl)c(Cl)nc2c1
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc2nc(NN)c(Cl)nc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Hydrazine monohydrate (0.26 mL) was added dropwise to a suspension of 2,3-dichloro-quinoxaline-6-carboxylic acid methyl ester (1.2 g) in methanol (10 mL) at −10° C. After three hrs. at this temperature, an additional portion of hydrazine monohydrate (0.26 mL) was added, and the resulting mixture was stirred at 0° C. for three hrs., and then for one hr. at 23° C. The suspension was filtered, and the solids were washed with MeOH. Flash column chromatography provided a residue that was recrystallized from MeOH to provide 3-chloro-2-hydrazino-quinoxaline-6-carboxylic acid methyl ester as a yellow solid. MS (M+H)+=253.2.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[NH2:17][CH2:18][C:19]1[C:20]([N:29]([CH2:32][CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:30][CH3:31])=[N:21][C:22]2[CH2:23][CH2:24][CH2:25][CH2:26][C:27]=2[CH:28]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH:17][CH2:18][C:19]1[C:20]([N:29]([CH2:32][CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:30][CH3:31])=[N:21][C:22]2[CH2:23][CH2:24][CH2:25][CH2:26][C:27]=2[CH:28]=1
Reactant: CCN(CC1CCCC1)c1nc2c(cc1CN)CCCC2
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCN(CC1CCCC1)c1nc2c(cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a solution of 3,5-bis-trifluoromethyl benzaldehyde (0.185 g, 0.76 mmol) in MeOH (3 mL) was added (3-aminomethyl-5,6,7,8-tetrahydro-quinoline-2-yl)-cyclopentylmethyl-ethylamine (0.2 g, 0.69 mmol), followed by the addition of acetic acid (0.08 mL, 1.39 mmol). This reaction mixture was stirred at RT for 1 h, after which time sodium cyanoborohydride (0.172 g, 2.78 mmol) was added, and stirring was continued for another 8 h. The solvent was then evaporated under vacuum and water was added, followed by extraction of the product with ethyl acetate. The organic layer was washed with saturated sodium bisulfite solution, the organic layer was separated and dried over sodium sulfate, and the solvent was evaporated to give the {3-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-5,6,7,8-tetrahydro-quinolin-2-yl}-cyclopentylmethyl-ethylamine (0.250 g, yield: 70%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[S-:7][C:8]#[N:9].[Na+].BrBr.[NH4+].[OH-]>CO.[Na+].[Br-]>[S:7]([C:4]1[S:3][C:2]([NH2:1])=[N:6][CH:5]=1)[C:8]#[N:9]
Reactant: Nc1nccs1
Reactant: N#C[S-]
Agent: BrBr
Agent: [Br-]
Agent: [NH4+]
Solvent: CO
Product: N#CSc1cnc(N)s1
Temperature: 0 °C
Yield: 54.5 %

Procedure:
2-Aminothiazole (35 g, 350 mmol) and sodium thiocyanate (89 g, 1.08 mol) in MeOH (400 mL) was stirred at −10° C. Bromine (18.0 mL, 350 mmol) dissolved in MeOH (100 mL) saturated with NaBr was slowly added keeping the internal temperature between −10 and 0° C. After the addition the mixture was stirred at 0° C. for 3H and the reaction mixture was poured into ice water (1500 mL). Aqueous NH4OH was added to pH ca 8.5 causing precipitation of light yellow crystals which were isolated by filtration, washed with ice water and dried in a vacuum oven to give 30 g (55%) 5-thiocyanato-thiazol-2-ylamine as light yellow crystals.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[NH2:31][C@@H:32]1[CH2:41][CH2:40][C:39]2[C:34](=[C:35]([N:44]3[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]3)[CH:36]=[CH:37][C:38]=2[O:42][CH3:43])[CH2:33]1>CN(C)C=O>[CH3:43][O:42][C:38]1[CH:37]=[CH:36][C:35]([N:44]2[CH2:45][CH2:46][N:47]([CH3:50])[CH2:48][CH2:49]2)=[C:34]2[C:39]=1[CH2:40][CH2:41][C@@H:32]([NH:31][C:11](=[O:13])[C:10]1[CH:9]=[CH:8][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:15][CH:14]=1)[CH2:33]2
Reactant: COc1ccc(N2CCN(C)CC2)c2c1CC[C@@H](N)C2
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(C)CC2)c2c1CC[C@@H](NC(=O)c1ccc(N3CCOCC3)cc1)C2
Temperature: 75 °C
Reaction time: 48 h
Yield: 53 %

Procedure:
To a solution of 4-morpholinobenzoic acid (0.92 g, 4.5 mmol; described in: Degutis, J.;Rasteikiene, L.; Degutiene, A. Zh. Org. Khim. 1978, 14(10), 2060-2064) in anhydrous N,N-dimethylformarnride (75 mL) was added 1,1′-carbonyldiimidazole (0.76 g, 4.8 mrnol) and the reaction was heated at 75° C. When the carbon dioxide evolution had ceased (after 45 min), the reaction was cooled to room temperature and a solution of (R)-2-arnino-5-methoxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (1.2 g, 4.2 mmol) dissolved in anhydrous N,N-dimethylformamide (20 mL) was added. The reaction was allowed to stir at ambient temperature for 48 h and the solvent was evaporated in vacuo. Purification on a silica gel column using chloroform/methanol/concentrated ammonium hydroxide (180:5:0.5) as the eluent followed by recrystallization from ethyl acetate and a few drops of methanol gave 1.0 g (53% yield) of white crystals: mp 237-238° C. [α]21D+40° (c=1,1chloroform); EIMS (70 eV) m/z (relative intensity) 464 (5, M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:7](Br)=[N:6]1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[C:24]([O:31][CH3:32])[CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>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>[CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:7]([C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][C:24]=2[O:31][CH3:32])=[N:6]1
Reactant: COc1cc(Cl)ccc1B(O)O
Reactant: COC(=O)Cn1nc(Br)n(Cc2cccc(F)c2)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Product: COC(=O)Cn1nc(-c2ccc(Cl)cc2OC)n(Cc2cccc(F)c2)c1=O
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Under argon, 250 mg (0.73 mmol) of the compound from Example 146A and 190 mg (1.07 mmol) of 4-chloro-2-methoxyphenylboronic acid are dissolved in 7 ml degassed DMF. A previously degassed solution of sodium carbonate (2 N in water, 1.09 ml, 2.18 mmol) and 42 mg of tetrakis(triphenylphosphine)palladium (0.036 mmol) are added. The resulting mixture is heated and stirred for 8 hrs at 90° C. After cooling to RT it is acidified with 10% hydrochloric acid and the mixture filtered. The filtrate is purified by preparative HPLC (Method 20). 159 mg (54% of theory) of the title compound and 54 mg (18% of theory) of the corresponding acid formed by hydrolysis (see also Example 148A) are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH3:38])[CH2:12][P:13]([CH2:20][CH:21]([CH2:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[C:22]([O:24]C(C)(C)C)=[O:23])([O:15]C(C)(C)C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]([CH:11]([CH3:38])[CH2:12][P:13]([CH2:20][CH:21]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:22]([OH:24])=[O:23])([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(CP(=O)(CC(CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(CP(=O)(O)CC(CCC(=O)O)C(=O)O)C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 71.7 %

Procedure:
To a solution of di-tert-butyl 2-[[[2-(benzylcarboxy)propyl]tert-butoxyphosphinyl]methyl]pentane-1,5-dioate (1.6 g, 2.89 mmol) in dichloromethane (10 ml) under nitrogen was added trifluoroacetic acid (10 ml). The reaction mixture was stirred for two hours and then concentrated under reduced pressure. Additional dichloromethane was added to the reaction residue and removed under reduced pressure. The product was dissolved in ethyl acetate and washed with water, then the organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure leaving a clear oil (800 mg, 72%). 1H NMR (D2O): δ1.2 (m, 3H), 1.6-1.8 (m, 4H), 2.1 (m, 2H), 2.2 (m, 2H), 2.6 (m, 1H), 2.8 (m, 1H), 5.0 (m, 2H), 7.3 (m, 5H). Analysis calculated for C17H23PO8 1.0H2O: C, 50.50; H, 6.23. Found: C, 50.52; H, 5.92.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH:11]([C@@H:13]1[CH2:17][S:16][CH2:15][N:14]1[C:18]([C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:19])[OH:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[C@@]12[C@@H]([C@@](O)([C@H](O)CCC(O)(C)C)C)CC[C@@]1(O)C1=CC([C@@H]3C[C@@H](O)[C@@H](O)C[C@]3(C)[C@H]1CC2)=O>>[Si:1]([O:8][CH2:9][CH2:10][C:11]([C@@H:13]1[CH2:17][S:16][CH2:15][N:14]1[C:18]([C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])=[O:19])=[O:12])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCC(O)[C@@H]1CSCN1C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CC(C)(O)CC[C@@H](O)[C@](C)(O)[C@H]1CC[C@@]2(O)C3=CC(=O)[C@@H]4C[C@@H](O)[C@@H](O)C[C@]4(C)[C@H]3CC[C@]12C
Product: CC(C)(C)[Si](C)(C)OCCC(=O)[C@@H]1CSCN1C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Yield: 48.9 %

Procedure:
(R)-4-[3-(tert-Butyldimethylsilyloxy)-1-hydroxypropyl]-3[[(S)-1-(phenylmethyloxycarbonyl)-2-pyrrolidinyl]carbonyl]thiazolidine (1.44 g) was subjected to the same reaction as in Example 20-e) to give the title compound (701 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7].C(N1C=CN=C1)(N1C=CN=C1)=O.CN(CCN)C.[Cl:40]C1C=CC(N2CCNCC2)=CC=1>O1CCCC1>[Cl:40][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:21])[CH3:1])=[O:7])[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: CN(C)CCNC(=O)N1CCN(c2ccc(F)cc2)CC1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: CN(C)CCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Yield: 66 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 11. A mixture of 4.9 g (0.03 mole) of 1,1'-carbonyldiimidazole, 2.6 g (0.03 mole) of unsym-dimethylethylenediamine, and 5.9 g (0.03 mole) of 1-(4-chlorophenyl)piperazine in a total of 200 ml of tetrahydrofuran gave an oil which solidified when triturated with petroleum ether (30°-60° C.). The collected solid was recrystallized from 2-propanol-isopropyl ether to yield 6.1 g (66%) of the title compound as a white, crystalline solid, m.p. 125°-128° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH3:12])[NH:8][N:7]=1)=[O:5])C.[OH-].[Na+].Cl>O1CCCC1>[CH3:12][O:11][C:9]1[NH:8][N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1
Reactant: CCOC(=O)c1cc(OC)[nH]n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)n[nH]1
Temperature: 25 °C
Yield: 85.2 %

Procedure:
5-Methoxy-1H-pyrazole-3-carboxylic acid ethyl ester (120 mg, 0.71 mmol) was dissolved in tetrahydrofuran (THF) (2 mL). After addition of sodium hydroxide (2M in water; 1 mL) the mixture was stirred under reflux for 2 h. The reaction mixture was cooled to room temperature and acidified (pH 3) by addition of hydrochloric acid and extracted with ethyl acetate (3×20 ml). The extract was dried over sodium sulfate and evaporated to yield 86 mg (86%) of a white solid.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Br:15][C:16]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:17]=1[CH:18]=O.[Cl:28][C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1.CC(O)=O>CCOC(C)=O.ClCCCl>[Br:15][C:16]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:17]=1[CH2:18][NH:42][C:39]1[CH:38]=[CH:37][C:36]([C:30]2[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:29]=2[Cl:28])=[CH:41][CH:40]=1
Reactant: Nc1ccc(-c2ccc(Cl)cc2Cl)cc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(CNc2ccc(-c3ccc(Cl)cc3Cl)cc2)c(Br)c1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (39 mg, 1.9 mmol) was added to a DCE solution (3 mL) of 2-bromo-4-(trifluoromethyl)benzaldehyde (235 mg, 0.9 mmol), 2′,4′-dichloro-[1,1-biphenyl]-4-amine (233 g, 1.0 mmol), and AcOH (0.21 mL, 3.7 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture diluted with EtOAc washed with water and brine, dried (Na2SO4), dry-packed onto silica gel and purified via column chromatography to yield the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[CH2:14][C:13](/[CH:15]=[CH:16]/[CH3:17])=[CH:12][N:11]1[C:18]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][Si:29]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])=[CH:22][C:21]=1[NH:39][C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][C:47]([NH:50][C:51](=[O:68])[C@@H:52]([NH:54][C:55](=[O:67])[C@@H:56]([NH:60][C:61](=[O:66])[O:62][CH2:63][CH:64]=[CH2:65])[CH:57]([CH3:59])[CH3:58])[CH3:53])=[CH:46][CH:45]=1)=[O:41])=[O:19])(C(C)(C)C)(C)C>C(O)(=O)C.CO.O1CCCC1.O.CCOC(C)=O>[OH:8][CH2:9][C@@H:10]1[CH2:14][C:13](/[CH:15]=[CH:16]/[CH3:17])=[CH:12][N:11]1[C:18]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][Si:29]([CH:36]([CH3:37])[CH3:38])([CH:33]([CH3:34])[CH3:35])[CH:30]([CH3:32])[CH3:31])=[CH:22][C:21]=1[NH:39][C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][C:47]([NH:50][C:51](=[O:68])[C@@H:52]([NH:54][C:55](=[O:67])[C@@H:56]([NH:60][C:61](=[O:66])[O:62][CH2:63][CH:64]=[CH2:65])[CH:57]([CH3:58])[CH3:59])[CH3:53])=[CH:46][CH:45]=1)=[O:41])=[O:19]
Reactant: C=CCOC(=O)N[C@H](C(=O)N[C@@H](C)C(=O)Nc1ccc(COC(=O)Nc2cc(O[Si](C(C)C)(C(C)C)C(C)C)c(OC)cc2C(=O)N2C=C(/C=C/C)C[C@H]2CO[Si](C)(C)C(C)(C)C)cc1)C(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C=CCOC(=O)N[C@H](C(=O)N[C@@H](C)C(=O)Nc1ccc(COC(=O)Nc2cc(O[Si](C(C)C)(C(C)C)C(C)C)c(OC)cc2C(=O)N2C=C(/C=C/C)C[C@H]2CO)cc1)C(C)C
Temperature: 25 °C
Yield: 91.4 %

Procedure:
The silyl ether 14 (1.49 g, 1.52 mmol, 1.0 eq) was dissolved in a 7:1:1:2 mixture of acetic acid/methanol/tetrahydrofuran/water (14:2:2:4 mL) and allowed to stir at room temperature. After 2 hours the reaction was diluted with EtOAc (100 mL), washed sequentially with water, aq. sodium bicarbonate then brine. The organic phase was then dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 100/0 then 99/1 to 92/8 v/v DCM/MeOH) to afford the product as an orange solid (1.2 g, 92%). LC/MS (3.649 min (ES+)), m/z: 865.44 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 8.35 (s, 1H), 7.69 (br s, 1H), 7.53 (d, 2H, J=8.7 Hz), 7.32 (d, 2H, J=8.3 Hz), 6.78 (s, 1H), 6.56 (m, 2H), 6.32 (br s, 1H), 6.05 (d, 1H, J=14.9 Hz), 5.90 (m, 1H), 5.56 (m, 1H), 5.30 (m, 2H), 5.22 (m, 1H), 5.10 (d, 2H, J=3.1 Hz), 4.73 (m, 1H), 4.64 (m, 1H), 4.57 (d, 2H, J=5.8 Hz), 4.01 (m, 1H), 3.79 (m, 2H), 3.76 (s, 3H), 2.98 (dd, 1H, J=16.3, 10.2 Hz), 2.38 (dd, 1H, J=16.6, 4.1 Hz), 2.16 (m, 1H), 1.78 (dd, 3H, J=6.8, 0.9 Hz), 1.46 (d, 3H, J=7.1 Hz), 1.29 (m, 3H), 1.11 (d, 18H, J=7.4 Hz), 0.97 (d, 3H, J=6.7 Hz), 0.92 (d, 3H, J=6.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]([CH3:14])[CH2:8][O:9][N:10]=C(C)C)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH3:14])[CH2:8][O:9][NH2:10])=[CH:15][CH:16]=1
Reactant: CC(C)=NOCC(C)Oc1ccc(Cl)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(CON)Oc1ccc(Cl)cc1
Yield: 768.5 %

Procedure:
10 g (4.13 mmol) of acetone O-[2-(4-chloro-phenoxy)-propyl]-oxime and 31 g of 30% strength aqueous trifluoroacetic acid solution were heated for 83/4 hours at 80° C. at a reduced pressure of 430 mbar, similarly to experiment 3b, 100 g of water being continuously added dropwise to the reaction mixture and a water/acetone mixture being distilled off. The working up similarly to 3b) gave 6.4 g of 2-(4-chlorophenoxy)-propoxyamine in this case. Yield: 76%.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH:11]=[O:12])[CH:4]=[CH:3]1.[BH4-].[Na+]>C(O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][OH:12])[CH:4]=[CH:3]1
Reactant: Cn1ccc2cccc(C=O)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cn1ccc2cccc(CO)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10.8 g 1-methyl-1H-indole-7-carbaldehyde are dissolved in 150 ml of ethanol, cooled to 0° C. and combined batchwise with 1.3 g sodium borohydride. After the addition has ended the cooling bath is removed and the mixture is stirred for another 2 hours at ambient temperature. Then 68 ml 1 M sodium hydroxide solution are added, the mixture is stirred for 10 minutes and then most of the ethanol is eliminated in vacuo. The residue is divided between water and ethyl acetate and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with saturated aqueous sodium chloride solution and dried on magnesium sulphate. Then the solvents are eliminated in vacuo and the residue is dried in vacuo.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[O:21]=[C:22]1[CH:27]=[C:26]([C:28](=[O:31])[CH2:29][CH3:30])[CH:25]=[CH:24][NH:23]1>O1CCCC1.O>[C:17]([O:16][C:13](=[O:15])[CH2:14][C:28]([OH:31])([C:26]1[CH:25]=[CH:24][NH:23][C:22](=[O:21])[CH:27]=1)[CH2:29][CH3:30])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCC(=O)c1cc[nH]c(=O)c1
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCC(O)(CC(=O)OC(C)(C)C)c1cc[nH]c(=O)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of diisopropylamine (35 ml, 250 mmol) in anhydrous tetrahydrofuran (275 ml) is treated dropwise at 0° C., under argon, with n-butyllithium (2.5 M in hexane, 100 ml, 250 mmol). The resulting mixture is agitated at 0° C. for 15 min, then cooled down to −78° C. and treated with tert-butyl acetate (33.8 ml, 250 mmol). After agitation at −78° C. for 15 min, the resulting lithiated reagent is added dropwise, over 1 hour, using a transfer canula, to a solution of 1-(2-oxo-1,2-dihydro-4-pyridinyl)-1-propanone (obtained according to 1.g, 15.2 g, 100 mmol) at −78° C. in anhydrous tetrahydrofuran (330 ml) and the resulting mixture is maintained at −78° C. for 15 min, then allowed to return to 0° C. for 1 hour. The reaction medium is hydrolyzed by the addition of water (60 ml) then the volatiles are evaporated off under reduced pressure. The residue is taken up in ethyl acetate and the resulting solution is washed with water, dried and concentrated. The residue is suspended in diethyl ether and filtered in order to produce after drying 21.5 g (80%) of a white solid, m.p. 167° C.