Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][S:10]2(=[O:19])=[O:18])[CH:5]=[CH:6][C:7]=1[F:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])[CH2:44][CH2:43]3)[S:10]2(=[O:18])=[O:19])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=S1(=O)Nc2ccccc2N1c1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCN2c3ccccc3N(c3ccc(F)c(F)c3)S2(=O)=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
A solution of 1-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.29 g, 1.0 mmol) in tetrahydrofuran (10 mL) was cooled to 0° C., treated with triphenylphosphine (0.41 g, 1.5 mmol), tert-Butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (0.47 g, 2.1 mmol) were added followed by diisopropylazodicarboxylate (0.3 mL, 1.5 mmol). The reaction mixture stirred for 2 hours at ambient temperature and then was evaporated. The crude reaction product was purified by flash chromatography (SiO2, 3-70% ethyl acetate/hexane) to provide tert-butyl 4-{2-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}piperazine-1-carboxylate (0.39 g, 76%) as a pink solid:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH:13][CH2:14][C:15]3[CH:16]=[C:17]4[CH:23]=[C:22]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[NH:21][C:18]4=[N:19][CH:20]=3)[CH:7]=2)[CH2:3][CH2:2]1.NC1C(F)=CC([F:44])=C(C=1)C(NC1CC1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(O)(=O)C.ClCCl>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:7]=[C:8]([NH:13][CH2:14][C:15]3[CH:16]=[C:17]4[CH:23]=[C:22]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[NH:21][C:18]4=[N:19][CH:20]=3)[C:9]([F:12])=[CH:10][C:11]=2[F:44])[CH2:3][CH2:2]1
Reactant: O=C(NC1CC1)c1ccc(F)c(NCc2cnc3[nH]c(-c4ccccc4)cc3c2)c1
Reactant: Nc1cc(C(=O)NC2CC2)c(F)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(NC1CC1)c1cc(NCc2cnc3[nH]c(-c4ccccc4)cc3c2)c(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.5 %

Procedure:
To a solution of compound D of Example 1 (22 mg, 0.1 mmol), in a mixture of acetic acid and dichloromethane (1:1, 1 mL) were added 5-amino-N-cyclopropyl-2,4-difluorobenzamide (30 mg, 0.15 mmol) and NaBH(OAc)3 (30 mg, 0.2 mmol). The mixture was stirred at RT for 1 h. The reaction mixture was concentrated and the residue was purified by preparative RP HPLC. The appropriate fractions were collected and concentrated to remove methanol and saturated solution of NaHCO3 was added to precipitate out the desired product. The solid was filtered and dried in vacuo to give the title compound (6.5 mg) as a solid. LC/MS; (M+H)+=419.2
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:25]=[CH:24][C:10]([NH:11][CH:12]=[C:13]([C:19]([O:21]CC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=2)[CH2:5][CH2:4][O:3]1.C1(OC2C=CC=CC=2)C=CC=CC=1>C(OCC)C>[OH:21][C:19]1[C:24]2[C:10](=[CH:9][CH:8]=[C:7]([N:6]3[CH2:5][CH2:4][O:3][C:2]3=[O:1])[CH:25]=2)[N:11]=[CH:12][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(=CNc1ccc(N2CCOC2=O)cc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Product: CCOC(=O)c1cnc2ccc(N3CCOC3=O)cc2c1O
Temperature: 235 °C
Yield: 42.6 %

Procedure:
To a flask containing diethyl 2-{[4-(2-oxo-1,3-oxazolidin-3-yl)anilino]-methylene}-malonate (0.46 g) is added diphenyl ether (6 mL). The reaction mixture is heated from room temperature to 235° C. over 2 hours under a flow of argon gas. After 1 hour at 235° C. the reaction is cooled to room temperature, diluted with diethyl ether and filtered. The collected precipitate is washed repeatedly with diethyl ether then dried in vacuo to give 0.17 g of ethyl 4-hydroxy-6-(2-oxo-1,3-oxazolidin-3-yl)-3-quinolinecarboxylate as a tan solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([CH3:19])[C:4]=1[NH2:20])[CH3:2].N1C=CC=CC=1.S(=[N:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34])=O>ClCCl>[NH2:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33]([NH:20][C:4]1[C:5]([CH3:19])=[CH:6][C:7]([C:9]([F:18])([C:10]([F:11])([F:12])[F:13])[C:14]([F:15])([F:16])[F:17])=[CH:8][C:3]=1[CH2:1][CH3:2])=[O:34]
Reactant: O=S=Nc1cccc(C(=O)Cl)c1
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 2-ethyl-6-methyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenylamine (2.09 g, 6.9 mmol) (prepared according to EP 1,006,102) in dichloromethane (30 ml) under stirring at 25° C., was added sequentially pyridine (0.8 ml, 9.9 mmol) and a solution of 3-sulfinylamino-benzoyl chloride (1.39 g, 6.9 mmol) (Example 1.1) in dichloromethane (7 ml). The reaction mixture was stirred at ambient temperature for 6 hours. The reaction mixture was quenched by addition of aqueous hydrochloric acid (2N) (4 ml) and stirred vigorously for 20 minutes. The mixture was diluted with water (20 ml) and the phases separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed successively with aqueous sodium hydrogen carbonate (saturated) and brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/cyclohexane 1:4 to 3:2). After evaporation of the solvents, the yellow oil was triturated with hexane, where it crystallized. The desired compound was isolated as white crystals. M.p. 143-145° C. 1H-NMR as described for Example 3.1.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[O:8][CH2:9][C:10]3([CH2:12][CH2:11]3)[C:6]=2[C:5]([O:13][C:14]2[N:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=2)=[CH:4][CH:3]=1.O.[Cl-].[NH4+]>O1CCCC1>[CH3:1][C:2]1[C:7]2[O:8][CH2:9][C:10]3([CH2:12][CH2:11]3)[C:6]=2[C:5]([O:13][C:14]2[N:15]=[CH:16][C:17]([NH2:20])=[CH:18][N:19]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Oc2ncc([N+](=O)[O-])cn2)c2c1OCC21CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ncc(N)cn2)c2c1OCC21CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 22.7 %

Procedure:
To a solution of 2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxy-5-nitro-pyrimidine (Intermediate 18, 255 mg) in tetrahydrofuran (5 ml)/water (2.5 ml) iron (234 mg, 4.25 mmol) and then ammonium chloride (227 mg, 4.25 mmol) were added and the reaction mixture was stirred for 48 hours at room temperature. The catalyst was filtered off and the residue was diluted with an aqueous saturated solution of NaHCO3 (5 ml) and extracted with ethyl acetate (3×10 ml). The organic layer was dried over sodium sulphate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 8:2 to cyclohexane/ethyl acetate 4:6 as eluents affording the title compound (52 mg) as a light orange solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][CH:12]([CH3:14])[CH3:13])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:15]Br.OS(O)(=O)=O>CC(O)=O.CO>[Br:15][C:7]1[C:3]([C:4]([OH:6])=[O:5])=[C:2]([CH3:1])[C:10]([O:11][CH:12]([CH3:14])[CH3:13])=[CH:9][CH:8]=1
Reactant: Cc1c(OC(C)C)cccc1C(=O)O
Reactant: BrBr
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c(OC(C)C)ccc(Br)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
To a solution of 2-methyl-3-(propan-2-yloxy)benzoic acid (Cpd NN, 1.08 g, 5.56 mmol) in AcOH (5 mL) was added Br2 (888 mg, 5.56 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum to give an oil. The crude oil was dissolved in MeOH (20 mL) then H2SO4 was added and the resulting mixture was heated at 65° C. for 2 hours. The reaction mixture was concentrated under vacuum and the residue dissolved in EtOAc. The organic layer was washed with water and brine, dried with Na2SO4, and concentrated under vacuum to give 6-bromo-2-methyl-3-(propan-2-yloxy)benzoic acid (Cpd OO, 1.3 g, 86%) as an oil which solidified to a tan solid upon standing.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[C:6]1(=[O:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C(OCC)C>[CH2:3]([C:6]1([OH:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH:2]=[CH2:1]
Reactant: C=CC[Mg]Br
Reactant: O=C1CCCCC1
Solvent: CCOCC
Product: C=CCC1(O)CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of allyl magnesium bromide in diethyl ether (1 M, 53 mL, 53 mmol) was added dropwise to a solution of cyclohexanone (5.00 mL, 48.2 mmol) in diethyl ether at 0° C. The cloudy white reaction mixture was allowed to stir at rt overnight. The reaction was quenched with saturated aqueous NH4Cl (100 mL) and diluted with water (20 mL) and diethyl ether (50 mL). The mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with diethyl ether (2×50 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated to afford a 1-allylcyclohexanol as a colorless oil (6.97, 103%) that contained a small amount of diethyl ether.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH:5]=1)[CH3:2].O.[Sn](Cl)(Cl)(Cl)Cl>C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1cccc(Oc2ccc(N)cc2)c1
Yield: 82 %

Procedure:
A solution of 1-(ethyloxy)-3-[(4-nitrophenyl)oxy]benzene (Intermediate 3, 4 g) and tin chloride monohydrate (28.8 g, 139 mmol) in ethyl acetate (200 mL) was heated at reflux overnight (15 hours). The reaction mixture was cooled down. It was then diluted with ethyl acetate (50 mL), washed with saturated NaHCO3 (100 mL), brine (100 mL) and dried over sodium sulphate. After evaporation of the volatiles, the residue was purified by an SCX (wash of the column with methanol, adsorption of the compound, wash with methanol (3CV), desorption with 2N methanolic ammonia (3CV)). Evaporation afforded the title compound (2.9 g).
Reaction SMILES: [Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[CH2:14](O)[CH2:15][OH:16].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:15]1[O:16][CH:6]([C:5]2[CH:8]=[C:9]([O:10][CH3:11])[C:2]([Br:1])=[C:3]([O:12][CH3:13])[CH:4]=2)[O:7][CH2:14]1
Reactant: OCCO
Reactant: COc1cc(C=O)cc(OC)c1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cc(C2OCCO2)cc(OC)c1Br

Procedure:
4-bromo-3,5-dimethoxybenzaldehyde (3 g) was dissolved in toluene (50 mL) and ethylene glycol (6.8 mL) and a catalytic amount of p-TSA were added. The mixture was refluxed overnight using a Dean Stark apparatus and evaporated. The residue was purified by column chromatography (silica gel; eluent hexane/AcOEt 5:1 to 2:1) to give 4-bromo-3,5-dimethoxybenzaldehyde ethylene acetal (2.63 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[C:38]([C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1)#[N:39]>>[CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[CH:26]=[C:25]([C:33]([F:34])([F:36])[F:35])[CH:24]=2)[CH:12]=[C:13]([C:44]2[CH:43]=[CH:42][CH:41]=[C:40]([C:38]#[N:39])[CH:45]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: N#Cc1cccc(B(O)O)c1
Product: COC(=O)C(CC(C)C)c1cc(-c2cccc(C#N)c2)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 48 %

Procedure:
The title compound was prepared in 48% yield from 4-methyl-2-(5-trifluoromethanesulfonyloxy-3′,5′-bis-trifluoromethyl-biphenyl-3-yl)-pentanoic acid methyl ester (prepared in Intermediate A) and 3-cyanophenylboronic acid under the conditions described in Example 26, step (d).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([O:11][C:12]1[N:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]([NH2:29])[CH3:28])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)([CH3:10])[CH3:9].[C:30](O)(=[O:33])[CH2:31][OH:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[OH:33][CH2:30][C:31]([NH:29][CH:27]([CH3:28])[CH2:26][CH2:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][C:15]2[CH:16]=[N:17][C:12]([O:11][CH:8]([CH3:10])[CH3:9])=[CH:13][CH:14]=2)=[CH:24][CH:23]=1)=[O:32]
Reactant: O=C(O)CO
Reactant: CC(N)CCc1ccc(Oc2ccc(OC(C)C)nc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC(CCc1ccc(Oc2ccc(OC(C)C)nc2)cc1)NC(=O)CO

Procedure:
3-[4-(6-Isopropoxypyridin-3-yloxy)phenyl]-1-methylpropylamine trifluoroacetate (89 mg, 0.23 mmol) was reacted with glycolic acid and HATU in analogy to example 44. Yield: 40 mg (52%), M+H+: 359.19.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[F:19][C:20]([F:24])([F:23])[CH2:21][NH2:22]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:22][CH2:21][C:20]([F:24])([F:23])[F:19])=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NCC(F)(F)F
Product: O=C(NCC(F)(F)F)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-(2-Fluoro-4-iodo-phenylamino)-N-(2,2,2-trifluoro-ethyl)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.30 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.45 mmol of 2,2,2-trifluoro-ethylamine. LC/MS [6.73 min; 440 (M+1)]
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=4)[N:21]=3)[CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:34][C:29]1[CH:28]=[C:27]([C:22]2[CH:23]=[C:24]([CH3:26])[N:25]=[C:20]([N:18]3[CH:19]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=4)[N:16]=[CH:17]3)[N:21]=2)[CH:32]=[CH:31][C:30]=1[Cl:33]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.8 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{1-[6-(3,4-dichloro-phenyl)-4-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.23 g) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (3 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as a white solid (0.18 g, 46%). MS (ISP) 460.1 [(M+H)+]; mp 210° C.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[C:24]([OH:26])=[O:25])=[O:15])[CH3:13])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@H:12]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[C:24]([OH:26])=[O:25])=[O:15])[CH3:13]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCCCCC[C@H]1C(=O)O
Agent: [Pd]
Solvent: CO
Product: C[C@H](N)C(=O)N1CCCCCC[C@H]1C(=O)O

Procedure:
Dissolve 1.59 g of 1-[N-benzyloxycarbonyl-(S)-alanyl]-azacyclooctane-2(S)-carboxylic acid in 100 ml of methanol. Add 0.40 g 10% palladium-on-charcoal and hydrogenate the mixture at atmospheric pressure. Filter the mixture and concentrate in vacuo to give 1-[(S)-alanyl]azacyclooctane-2(S)-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=1>>[F:32][C:31]([F:33])([F:34])[O:30][C:26]1[CH:25]=[C:24]([N:17]2[CH2:16][CH2:15][C:12]3([C:11](=[O:20])[N:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=4)[CH2:14][CH2:13]3)[CH2:19][CH2:18]2)[CH:29]=[CH:28][CH:27]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: FC(F)(F)Oc1cccc(Br)c1
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(c1cccc(OC(F)(F)F)c1)CC2

Procedure:
The title compound was prepared in analogy to example 1 step D from a mixture of 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 1 step C) and 1-bromo-3-trifluoromethoxy-benzene. Light yellow solid. MS (ESI): 475.1 (MH+)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N+:3]=1[O-:9].[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>CS(C)=O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N+:3]=1[O-:9]
Reactant: Oc1ccccc1
Reactant: [O-][n+]1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: [O-][n+]1c(Cl)cccc1Oc1ccccc1

Procedure:
The 0.82 g (0.0050 moles) of 2,6-dichloropyridine N-oxide and 0.47 g (0.0050 moles of phenol was reacted with 0.200 g (0.0050 moles) of ground sodium hydroxide in 8.2 ml of DMSO at 80° C. for 6 hours to give 2-chloro-6-phenyloxypyridine N-oxide. It was reacted with 0.600 g (0.015 moles) of ground sodium hydroxide at 80° C. for 3.5 hours to give 1-hydroxy-6-phenyoxypyridine-2-(1H)-one. After cooling, it was added 74 ml of water and was adjusted with 6N HCl to pH 3. The water solution was extracted with dichloromethane (2×25 ml) and was dried over sodium sulfate. The dichloromethane solution was stripped in vacuo to give 1.29 g which was purified with Flash Chromatography (9:1 ethyl acetate:methanol):0.82 (65%).
Reaction SMILES: [CH3:1][C:2]([NH:14]C=O)([CH3:13])[CH2:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([CH3:11])=[CH:6][C:5]=1[CH3:12].[OH-].[K+]>C(O)CO>[CH3:13][C:2]([NH2:14])([CH3:1])[CH2:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([CH3:11])=[CH:6][C:5]=1[CH3:12]
Reactant: Cc1cc(C)c(CC(C)(C)NC=O)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Product: Cc1cc(C)c(CC(C)(C)N)c(C)c1
Temperature: 0 °C

Procedure:
61 g of N-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)ethyl]formamide is refluxed with 35 g of potassium hydroxide in 155 mL ethylene glycol for 9 hours with stirring and, after the reaction has ended, the mixture is poured onto 1 kg of ice. The aqueous phase is extracted three times with diethyl ether and the solvent is distilled off under reduced pressure. The residue is fractionally distilled. Yield: 48 g (89%); bp15: 135° C.-140° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[F:26][CH:27]([CH2:30][NH2:31])[CH2:28][NH2:29]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:29][CH2:28][CH:27]([F:26])[CH2:30][NH2:31])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCC(F)CN
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(F)CN)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2-fluoropropane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 429, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J=7.83, 1.01 Hz, 1 H), 7.84 (d, J=7.58 Hz, 1 H), 7.65-7.57 (m, 2 H), 7.47-7.38 (m, 2 H), 7.29 (dd, J=8.59, 1.77 Hz, 1 H), 6.10 (s, 1 H), 5.14 (s, 2 H), 4.69 (s, 2 H), 3.64 (d, J=5.31 Hz, 1 H), 3.61-3.52 (m, 4 H), 3.04-2.91 (m, 2 H), 2.41 (s, 3 H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[O:23][CH2:24][CH2:25][OH:26].[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[NH:13]1[C:14]2[C:10](=[C:9]([C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[O:23][CH2:24][CH2:25][OH:26])[CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12]1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: OCCOc1cccc(Br)c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCCOc1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
To a mixture of 4-(4,4,5 ,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (5.49 g, 22.5 mmol) and 2-(3-bromo-phenoxy)-ethanol (4.9 g, 22.5 mmol) in THF (68 mL) was added Palladium catalyst Pd(PPh3)4 (473 mg, 0.03 eq.) and the freshly prepared sodium hydroxide solution (2.7 g in 31.5 mL of water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for overnight. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed with brine (4×), and dried over Na2SO4 and concentrated. The residue was purified on a silica gel column to give 5.4 g (95%) of 2-[3-(1H-indol-4-yl)-phenoxy]-ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH:10]=[CH:11][C:12]([CH3:22])=[CH:13][CH:14]=[CH:15][C:16]([CH3:21])=[CH:17][C:18](Cl)=[O:19])=[C:5]([CH3:23])[C:4]=1[CH3:24].[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:18](=[O:19])[CH:17]=[C:16]([CH3:21])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:22])[CH:11]=[CH:10][C:6]1[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:24])[C:5]=1[CH3:23])([CH3:27])[CH3:26]
Reactant: CC(C)N
Reactant: COc1cc(C)c(C=CC(C)=CC=CC(C)=CC(=O)Cl)c(C)c1C
Product: COc1cc(C)c(C=CC(C)=CC=CC(C)=CC(=O)NC(C)C)c(C)c1C

Procedure:
9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid chloride is reacted with isopropyl amine to produce 9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid isopropyl amide, m.p. 200° C.;
Reaction SMILES: C1([C@H]([N:9]2[CH2:15][C@H:14]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[CH2:13][O:12][CH2:11][CH2:10]2)C)C=CC=CC=1.ClC(OC(Cl)C)=O.CO>ClCCCl>[O:12]1[CH2:13][C@@H:14]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[CH2:15][NH:9][CH2:10][CH2:11]1
Reactant: C[C@H](c1ccccc1)N1CCOC[C@@H](c2ccc(C#N)cc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: CO
Product: N#Cc1ccc([C@H]2CNCCOC2)cc1
Temperature: 25 °C
Yield: 71.4 %

Procedure:
To a solution of (S)-4-(4-((R)-1-phenylethyl)-[1,4]oxazepan-6-yl)benzonitrile (0.662 g, 2.16 mmol) in 1,2-dichloroethane (3.60 ml) was added 1-chloroethyl chloroformate (0.772 g, 5.40 mmol) at room temperature. The mixture was refluxed for 8 hours. Methanol (15 ml) was added to the mixture cooled to room temperature. The mixture was refluxed again for 2 hours. The mixture was concentrated in vacuo. The residue was partitioned between aqueous sodium hydrogen carbonate and chloroform. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=96/4) to afford (S)-4-([1,4]oxazepan-6-yl)benzonitrile as pale yellow solid (312 mg, 70%).