Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=2)=[CH:5][CH:4]=1.[C@@H:19]1([NH2:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1>>[C@@H:19]1([NH:29][CH2:15][C:11]2[CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:18])([F:17])[F:1])=[CH:4][CH:5]=3)[CH:14]=[CH:13][CH:12]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: O=Cc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: N[C@H]1CCCc2ccccc21
Product: FC(F)(F)c1ccc(-c2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1

Procedure:
4′-(Trifluoromethyl)[1,1′-biphenyl]-3-carbaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22](I)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#[N:27]>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([C:31]5[CH:32]=[CH:33][C:28]([C:26]#[N:27])=[CH:29][CH:30]=5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccc(I)cc32)n1)c1ccccc1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: C[C@H](Nc1nccc(-n2cnc3ccc(-c4ccc(C#N)cc4)cc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 416, starting from 2-[(S)-1-Phenylethylamino]-4-[6-iodobenzimidazol-1-yl]pyrimidine and 4-cyanophenylboronic acid. Mass spectrum (ESI) 417.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[C:12]([F:18])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].O>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([F:18])[CH:11]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)c2ccc(Br)cc2)cc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: O
Product: O=C(c1ccc(Br)cc1)c1ccc(O)c(F)c1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
A mixture of 81 (1.28 g, 4.34 mmol) and AlCl3 (3.50 g, 26.2 mmol) were refluxed in benzene (50 mL) for 3 h and cooled to RT. Water (100 mL) was cautiously added dropwise, and the mixture was extracted with ether (3×100 mL). The combined ethereal extracts were washed with water (200 mL), brine (200 mL), and dried over MgSO4. Concentration afforded 1.19 g (98%) of 82 that was used without further purification. 1H NMR (400 MHz, CDCl3): δ 5.80 (br s, 1H), 7.09 (t, J=8.4 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.61-7.64 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:15][CH:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=O.O>C1(C)C=CC=CC=1>[CH3:15][C:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]=1[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Reactant: CC1C(=O)CCC1=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=C(Nc2ccc(C3=NNC(=O)CC3)cc2)CCC1=O

Procedure:
3.4 g of 4,5-dihydro-6-(4-aminophenyl)-3(2H)-pyridazinone and 2.0 of 2-methylcyclopentane-1,3-dione were suspended in 30 ml of toluene, to which a catalytic amount of p-toluene sulfonate-hydrate was add while the resulting suspension was heated to reflux with stirring for 8 hours, with removal of water as an azcotropic mexture. After cooled, deposited crude crystal was collected by filtrating, and purified by silica gel column chromatography (eluting solvent: chloroform:methanol=10:1), 4.7 g of the title compound was obtained. m.p. 284°-285° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[S:16])[O-])=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:30]2[CH2:29][CH2:28][N:27]([C:21]3[CH:20]=[C:19]([O:18][CH3:17])[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=3)[CH2:32][CH2:31]2)=[S:16])=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: COc1nc2c(cc1NC([O-])=S)CCCC2
Product: COc1cc(OC)cc(N2CCN(C(=S)Nc3cc4c(nc3OC)CCCC4)CC2)c1
Yield: 56 %

Procedure:
Phenyl N-[(2-methoxy-5,6,7,8-tetrahydroquinolin-3-yl)thiocarbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([N:47]4[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]4)=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: C1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CCCCC2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with piperidine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C41H52Cl2N5O3 [(M+H)+] 732.3442, observed 732.3440.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:9]([C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)[CH3:10])=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[C:9]([C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)[CH2:10][Br:24])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1nnnc1C(CBr)=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
A slurry of 1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-1-propene (61.46 g, 0.197 mole) [prepared in Step C], N-bromosuccinimide (35.06 g, 0.197 mole) and catalytic amount of azobis isobutyronitrile or benzoyl peroxide in carbon tetrachloride (1.2 liters) was heated to reflux in an inert atmosphere for a period of 2 hours. The reaction mixture was cooled to ambient temperature and the solid from the reaction was filtered. The filtrate was concentrated under reduced pressure and the solid obtained was recrystallized from toluene-hexane to give 72 g (93%) of the title compound as white crystals; m.p.=159°-160° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:8][C:9]=1[NH:10][CH2:11][C:12]1[O:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[CH:15][CH:16]=1)=[O:4].[Cl:33][C:34]1[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37]>ClCCl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C:36](=[O:37])[C:35]1[CH:39]=[CH:40][C:41]([Cl:43])=[CH:42][C:34]=1[Cl:33])[CH2:11][C:12]1[O:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:24])[F:26])[CH:18]=2)=[CH:15][CH:16]=1)=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NCc1ccc(-c2cccc(C(F)(F)F)c2)o1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1sc(-c2ccccc2)cc1N(Cc1ccc(-c2cccc(C(F)(F)F)c2)o1)C(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a stirred solution of 5-Phenyl-3-{[5-(3-trifluoromethyl-phenyl)-furan-2-ylmethyl]-amino}-thiophene-2-carboxylic acid methylester (65 mg 0.142 mmol) in dichloromethane (3 ml) and saturated NaHCO3 solution (3 ml) was added a solution of 2,4-dichloro-benzoyl chloride (36 mg, 1.2 eq.) in dichloromethane (0.9 ml). The reaction mixture was stirred vigorously at room temperature for overnight. The organic phase was collected and the aqueous phase was extracted twice with methylene chloride (2×15 ml). The organic layers were combined, washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed and residue was purified on silica gel using Hexane:EtOAc 9:1 as eluant to give the desired product in 78% yield (70 mg). The proton NMR indicated the presence of rotamers.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Br:11]N1C(=O)CCC1=O>>[Br:11][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1ccc(O)cc1
Product: CC(C)c1ccc(O)c(Br)c1
Yield: 65.4 %

Procedure:
To a solution of 4-isopropylphenol (13.38 g, 98.0 mmol) with N-bromosuccinimide (17.5 g, 98 mmol) generally according to the procedure described for Example 305 afforded 13.78 g (65%) of 2-bromo-4-isopropylphenol. Treatment of 2-bromo-4-isopropylphenol (13.74 g, 41.0 mmol) with potassium carbonate (22.0 g, 160 mmol) and allyl bromide (9.23 g, 76.8 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-6-bromo-4-isopropylphenol. Treatment of 2-allyl-6-bromo-4-isopropylphenol (6.85 g, 27.0 mmol) with 3-chloroperoxybenzoic acid (7.72 g, 27.0 mmol, 77%) followed by potassium carbonate (9.3 g, 67.5.0 mmol) generally according to the procedure described for Intermediate 9 afforded 1.12 g, (17%) of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methanol (1.12 g, 4.6 mmol) with p-toluenesulfonyl chloride (1.32 g, 6.9 mmol) generally according to the procedure described for Intermediate 10 gave 1.90 g (97%) of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.4 g, 0.94 mmol) and 2-methylphenylboronic acid (0.38 g, 2.82 mmol) generally according to the procedure described for Intermediate 35 afforded 0.19 g, (46%) of (5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.141 g, 2.17 mmol) generally according to the procedure described for Intermediate 98 afforded 0.11 g (83%) of (±)-2-(azidomethyl)-5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.188 g, 0.716 mmol) according to the procedure described in Example 154 afforded 0.055 g (48%) of (±)-[(5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine as a white solid, hydrochloride salt. mp 221-222° C. (dec).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[NH:4][N:3]=1.[F:13][C:14]([F:28])([F:27])[C:15]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:16]=1[CH2:17]Br>>[F:13][C:14]([F:27])([F:28])[C:15]1[CH:22]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:20]=[CH:19][C:16]=1[CH2:17][N:4]1[C:5]2[C:10](=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=2)[C:2]([I:1])=[N:3]1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: O=Cc1ccc2[nH]nc(I)c2c1
Product: O=Cc1ccc2c(c1)c(I)nn2Cc1ccc(C(F)(F)F)cc1C(F)(F)F

Procedure:
1-[2,4-Bis(trifluoromethyl)benzyl]-3-iodo-1H-indazol-5-carbaldehyde was prepared from 3-iodo-1H-indazol-5-carbaldehyde (from Example 367) and 2,4-bis-(trifluoromethyl)benzyl bromide following General Procedure A.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH3:23][C@H:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:31][C@H:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:23])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](Nc1c([N+](=O)[O-])c(Cl)nc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
The method described in Part A of Example 1 was used to treat 2,4-dichloro-3-nitroquinoline (19.4 g, 78.5 mmol) in DMF (100 mL) with triethylamine (32 mL, 0.235 mol) and (S)-(−)-α-methylbenzylamine (11.5 g, 94.2 mmol) with the modification that the reaction was allowed to warm to room temperature and stirred for two hours. After the isolated precipitate was washed with water, it was dried under high vacuum overnight to provide 25.1 g of 2-chloro-3-nitro-N-[(1S)-1-phenylethyl]quinolin-4-amine as an orange solid.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14])([O:3][CH2:4][CH3:5])=[O:2].[C:15](OC(=O)C)(=[O:17])[CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:15]([O:14][C:10]1[CH2:11][CH2:12][CH2:13][C:9]=1[CH2:8][CH2:7][CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:17])[CH3:16]
Reactant: CCOC(=O)CCCC1CCCC1=O
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)CCCC1=C(OC(C)=O)CCC1

Procedure:
In the manner described in Example 20, treatment of 2-(3-carbethoxypropyl)cyclopentan-1-one (Example 6) with acetic anhydride and p-toluenesulfonic acid monohydrate gives a yellow oil, b.p. 98°-103°C. (0.35 mm).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH:14]=[O:15])([O-:3])=[O:2].[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19](I)[CH:18]=1>>[Br:16][C:17]1[CH:18]=[C:19]([CH:14]([C:5]2[CH:6]=[CH:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:4]=2[N+:1]([O-:3])=[O:2])[OH:15])[CH:20]=[CH:21][CH:22]=1
Reactant: Brc1cccc(I)c1
Reactant: O=Cc1ccc2ccccc2c1[N+](=O)[O-]
Product: O=[N+]([O-])c1c(C(O)c2cccc(Br)c2)ccc2ccccc12

Procedure:
The titled compound was prepared from 1-nitro-2-naphthaldehyde and 1-bromo-3-iodobenzene in a procedure similar to that of example 1 (1).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([CH2:20][CH2:21][C:22](OCC)=[O:23])=[CH:11][NH:12]2>C1COCC1>[CH3:7][C:8]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([CH2:20][CH2:21][CH2:22][OH:23])=[CH:11][NH:12]2
Reactant: CCOC(=O)CCc1c[nH]c2ccc([N+](=O)[O-])c(C)c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c([N+](=O)[O-])ccc2[nH]cc(CCCO)c12
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
To a suspension of 95% LiAlH4 (0.378 g, 9.44 mmol) in 10 mL of dry THF was added a solution of ethyl 4-methyl-5-nitro-3-indolepropionate (0.650 g, 2.36 mmol) in 2 mL of dry THF, at 0° C. under Ar. After 5 min the cooling bath was removed and stirring was continued at room temperature for 30 min. The reaction was then quenched by the sequential addition of 0.4 mL of water, 0.4 mL of 15% aqueous NaOH and finally 1.2 mL of water. The resulting suspension was diluted with ethyl acetate and then it was filtered and the filtercake was washed with additional ethyl acetate. The filtrate was evaporated and the residue was chromatographed (SiO2 /dichloromethane-ethyl acetate, 2:1) to give the title compound (0.458 g, 83%) as a solid. An analytical sample was crystallized from ethyl acetate-hexane to give yellow-orange needles, mp 129°-130° C.: IR (KBr) 3543, 3210, 1616, 1520, 1330 cm-1 ; 1H NMR (DMSO-d6, 200 MHz) δ11.43 (br s, 1H), 7.63 (d, J=8.9 Hz, 1H), 7.30 (d, J=8.7 Hz, 1H), 7.29 (s, 1H), 4.51 (t, J=5.2 Hz, 1H), 5.20 (dt, J=6.2, 5.4 Hz, 2H), 2.91 (t, J=7.7 Hz, 2H), 2.78 (s, 3H), 1.78 (m, 2H). Anal. Calcd for C12H14N2O3 : C, 61.52; H, 6.02; N, 11.96. Found: C, 61.23; H, 5.85; N, 11.90.
Reaction SMILES: [CH3:1][N:2]([CH3:37])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:36]=[CH:35][C:13]3[N:14]([C:17]4[CH:18]=[C:19]([NH:31]C(=O)C)[CH:20]=[C:21]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=5[F:30])[CH:22]=4)[CH:15]=[N:16][C:12]=3[CH:11]=2)[N:7]=[N:6]1.[CH:38]1([S:41](Cl)(=[O:43])=[O:42])[CH2:40][CH2:39]1>>[CH3:37][N:2]([CH3:1])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:36]=[CH:35][C:13]3[N:14]([C:17]4[CH:18]=[C:19]([NH:31][S:41]([CH:38]5[CH2:40][CH2:39]5)(=[O:43])=[O:42])[CH:20]=[C:21]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=5[F:30])[CH:22]=4)[CH:15]=[N:16][C:12]=3[CH:11]=2)[N:7]=[N:6]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(CCN(C)C)nn4)ccc32)c1
Product: CN(C)CCn1cc(-c2ccc3c(c2)ncn3-c2cc(NS(=O)(=O)C3CC3)cc(-c3ccc(F)cc3F)c2)nn1

Procedure:
The compound was prepared from the compound of Example 20 using the procedures of Example 39 and cyclopropane sulfonyl chloride. 1H NMR (400 MHz, CD3OD): δ 8.93 (s, 1H), 8.53 (s, 1H), 8.32 (s, 1H), 7.80 (d, 1H), 7.82 (d, 1H), 7.68-7.58 (m, 4H), 7.17-7.10 (m, 2H), 4.95 (t, 2H), 3.85 (t, 2H), 3.02 (s, 6H), 2.78-2.71 (m, 1H), 1.16-1.09 (m, 2H), 1.05-1.01 (m, 2H); LC-MS (ESI): Calculated mass: 563.62; Observed mass: 564.2 [M+H]+ (rt: 0.412 min).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[C:8]([NH2:10])[CH:9]=1)([O-:3])=[O:2].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[NH2:10][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:24])[CH2:15][CH2:16]1
Reactant: Nc1cc([N+](=O)[O-])ccc1N1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1cc([N+](=O)[O-])ccc1N1CCN(C(=O)c2ccccc2)CC1
Yield: 85.9 %

Procedure:
A solution of 5-nitro-2-(piperazin-1-yl)benzenamine (2.4 g, 10.7 mmol), benzoyl chloride (1.2 ml, 12.8 mmol) and triethylamine (6.0 ml, 42.7 mmol) in 40 ml DCM was stirred at 0° C. for 2 hours. The mixture was washed with water (2×10 ml) and dried over anhydrous sodium sulfate before removing the solvents. (4-(2-Amino-4-nitrophenyl)piperazin-1-yl)(phenyl)methanone (3.0 g, 86%) was obtained by flash column chromatograph (40% ethyl acetate in hexanes). A solution of (4-(2-amino-4-nitrophenyl)piperazin-1-yl)(phenyl)methanone (0.3 g, 0.9 mmol), acetyl chloride (0.065 ml, 0.9 mmol) and sodium hydroxide (0.037 g, 0.9 mmol) in 20 ml THF was stirred at 0° C. for 2 hours. The mixture was concentrated. N-(2-(4-benzoylpiperazin-1-yl)-5-nitrophenyl)acetamide (0.11 g, 32%) was obtained by flash column chromatograph (65% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 2.29 (s, 3H), 3.00 (s, br, 4H), 3.84 (s, br, 4H), 7.23 (d, J=8.8 Hz, 1H), 7.47-7.51 (m, 5H), 8.00 (dd, J=8.6, 2.6 Hz, 1H), 8.16 (s, br, 1H), 9.24 (s, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 25.3, 52.3, 116.0, 119.9, 120.8, 127.6, 129.2, 130.7, 135.6, 171.2.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH:21][CH:22]([CH2:26][CH2:27][CH3:28])[C:23](O)=[O:24])=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:1]([C:8]1[NH:13][C:12]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)=[CH:11][N:10]2[C:23](=[O:24])[C:22]([CH2:26][CH2:27][CH3:28])=[N:21][C:9]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(Nc1ncc(-c2ccc(O)cc2)nc1Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1nc2c(Cc3ccccc3)[nH]c(-c3ccc(O)cc3)cn-2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
2-((3-benzyl-5-(4-hydroxyphenyl)pyrazin-2-yl)amino)pentanoic acid (49 mg, 0.13 mmol) was dissolved in DCM (10 mL). Pyridine (0.5 mL) was added followed by N,N′-Dicyclohexylcarbodiimide (54 mg, 0.26 mmol). The reaction mixture was slowly stirred at room temperature for 1 hr. The solvent was evaporated, and the residue purified by flash chromatography (eluting solvent: EtOAc to DCM to 10% methanol in DCM) to give the product as a yellow powder (40 mg, 86%). NMR (300 MHz, CD3OD, δ): 7.35 (m, 8H), 6.88 (d, J=9.0 Hz, 2H), 4.40 (s, 2H), 2.81 (t, J=7.5 Hz, 2H), 1.81 (m, 2H), 1.02 (t, J=7.5 Hz, 3H); MS (ESI) m/z 359.0.
Reaction SMILES: C[N:2](C)[CH:3]=[N:4][C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][CH3:13])[CH:7]=1.O.[NH2:17]N>C(O)(=O)C>[CH3:13][S:12][C:8]1[CH:7]=[C:6]([C:5]2[N:4]=[CH:3][NH:2][N:17]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: NN
Reactant: CSc1cccc(C(=O)N=CN(C)C)c1
Solvent: CC(=O)O
Solvent: O
Product: CSc1cccc(-c2nc[nH]n2)c1
Temperature: 90 °C

Procedure:
8 g of N-[1-dimethylaminomethylidene]-3-methylsulfanyl-benzamide were dissolved in 80 ml of glacial acetic acid. 2 ml of hydrazine hydrate were added and the mixture was heated to 90° C. for 2 h. The solvent was removed in vacuo. The crude product was purified by flash chromatography (300 g of silica gel; DCM/MOH, gradient from 100:0 to 95:5). 4.5 g of the title compound were obtained as an oil.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH3:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[OH-].[Na+].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>O>[CH2:18]([O:17][C:15]([NH:2][C@@H:3]([CH3:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[C@H](N)CCCCC(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C[C@@H](CCCCC(=O)O)NC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 71.4 %

Procedure:
To 30 g (166 mmol) of (S)-6-aminoheptanoic acid hydrochloride in 57 ml of water are added 57 ml of 4N aqueous sodium hydroxide solution and thereafter dropwise simultaneously at 10° 92 ml of 4N aqueous sodium hydroxide solution and 42 ml (294 mol) of benzyl chloroformate so that the pH value always lies between 10 and 12. After the precipitation of the product the mixture is stirred at 0° for a further 2 hours. Thereafter, 300 ml of water are added and the reaction mixture is extracted with ether. The aqueous phase is then acidified with 20 ml of concentrated hydrochloric acid and extracted with methylene chloride. The methylene chloride phase is dried over magnesium sulphate and evaporated. The crystals obtained are recrystallized from chloroform/hexane, whereby there are obtained 33.1 g (72%) of (S)-6-[1-(benzyloxy)formamido]heptanoic acid, m.p. 82°-83°.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:10][C:7]1[CH:8]=[CH:9][C:2]([N:15]2[CH:16]=[C:12]([CH3:11])[N:13]=[CH:14]2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc(F)ccc1F
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cn(-c2ccc(F)cc2C#N)cn1
Yield: 41 %

Procedure:
In analogy to example 5a, 2,5-difluoro-benzonitrile was reacted with 4-methylimidazole and potassium carbonate for 20 h at 90° C. After aqueous workup and crystallization from Ethyl acetate the title compound was obtained as a white solid (yield: 41%). MS: m/e=202.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)=[C:19]=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:19]([NH:18][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)=[O:20])[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Nc1cccc(C(F)(F)F)c1

Procedure:
Example 22 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 1-isocyanato-3-(trifluoromethyl)benzene (18.8 μl) to give the title compound (0.0112 g). LC-MS (System A): Rt 2.56 mins, Mass Spectrum m/z 462 [MH+].