Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([CH3:12])[CH:6]=[C:7]([CH3:11])[CH:8]=2)[C:3]1=O.[BH4-].[Na+].Cl>O1CCCC1.CO>[CH3:1][C:2]1[CH2:10][C:9]2[C:4]([CH:3]=1)=[C:5]([CH3:12])[CH:6]=[C:7]([CH3:11])[CH:8]=2
Reactant: Cc1cc(C)c2c(c1)CC(C)C2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1=Cc2c(C)cc(C)cc2C1
Yield: 95.6 %

Procedure:
20.4 g (117 mmol) of 2,5,7-trimethyl-1-indanone (1) were dissolved in 300 ml of a mixture of tetrahydrofuran/methanol (2:1), and 6.6 g (175 mmol) of NaBH4 were added at room temperature. The mixture was stirred for a further hour, 50 ml of half-concentrated HCl were added and the mixture was extracted with ether. The combined organic phases were dried over sodium sulfate and freed from the solvent. The residue was transferred to a distillation apparatus, and 13 g of magnesium sulfate were added. A vacuum of about 10 mbar was applied and the mixture was heated up until the product distilled over (130°-150° C.). Distillation gave 17.7 g of the indene 2 as a colorless oil. The yield was 96%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15]([C:17]1[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=1)=O)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][C:17]1[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1C(=O)c1cccc2ccccc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1[nH]c2ccccc2c1Cc1cccc2ccccc12
Reaction time: 21 h

Procedure:
2. To a solution of 3-(naphthalene-1-carbonyl)-1H-indole-2-carboxylic acid ethyl ester (0.81 g) in trifluoroacetic acid (3.6 ml) was added triethylsilane (1.5 ml) and stirring was continued at 22° C. for 21 h. The suspension was filtered, the residue washed with n-heptane and dried to give 3-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester as a white solid. MS: 328.1 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1.Br[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:18][CH:19]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3)cc12
Reactant: COC(=O)CCCBr
Product: COC(=O)CCCOc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1

Procedure:
Methyl 4-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenoxy)butanoate was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenol (from Example 170) following the procedure described for the preparation of Example 139, but using methyl 4-bromobutanoate. 1H NMR (Acetone-d6): δ 8.74 (s, 1H), 8.67 (s, 1H), 8.24 (d, 1H), 7.39 (s, 1H), 7.09-7.19 (m, 3H), 6.82 (d, 2H), 6.53 (br, 2H), 3.97 (t, 2H), 3.60 (s, 3H), 3.19 (t, 2H), 3.04 (t, 2H), 2.48 (t, 2H), 2.44 (s, 3H), 0.84-0.91 (m, 2H). LRMS [M+H]=430.2.
Reaction SMILES: O1[CH2:5][CH2:4][N:3]=C1.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2C=[CH:20][CH:19]=[CH:18][C:14]=2C(O)=O)=[CH:9][CH:8]=1.C(O)(=O)C1C=CC=CC=1.C1(C)C=CC([Mg]Br)=CC=1>C(#N)C1C=CC=CC=1>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:18][CH:19]=[CH:20][C:5]=2[C:4]#[N:3])=[CH:9][CH:8]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: C1=NCCO1
Agent: Cc1ccc([Mg]Br)cc1
Agent: O=C(O)c1ccccc1
Solvent: N#Cc1ccccc1
Product: Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
Carini et al., J. Med. Chem., vol. 34 (1991), 2525-2547 disclose the application of the Meyers oxazoline method to the preparation of 2-(4'-methylphenyl) benzonitrile by the following steps: 1) 2-methoxybenzoic acid is reacted with thionyl chloride; 2) the acyl chloride formed is treated with 2-amino-2-methyl-1-propanol, which provides an amide in the crude form; 3) this amide is subjected to the action of thionyl chloride, forming 4,4-dimethyl-2-(2-methoxyphenyl)-oxazoline (yield 88% from the acid chloride); 4) this oxazoline derivative is reacted with p-tolyl-magnesium bromide and the complex formed is hydrolyzed, which gives 4,4-dimethyl-2-(4'-methylbiphenyl-2'-yl)-oxazoline (yield 91%); and 5) the oxazoline derivative formed is then treated with phosphorus oxychloride, which finally provides 2-(4'-methylphenyl)benzonitrile (yield 96%). The overall yield is 77% but this process has the disadvantage of requiring the use of 5 steps, starting from commercially available products, due to the prior formation of the dimethyloxazolinyl group and its subsequent conversion to the cyano group. U.S. Pat. No. 5,128,355 (to Carini et al.) similarly exemplifies the application of the multistep Meyers oxazoline method to the preparation of 2-(4'-methylphenyl)benzoic acid (Example 85), and the conversion of this benzoic acid to the benzonitrile (Example 89). Implicitly, these references illustrate that when an aryl magnesium reagent (in this case, p-tolyl magnesium bromide) is used directly to provide the aryl group in an arylbenzonitrile (in this case, 2-(4'-methylphenyl)benzonitrile) the nitrile group cannot be present in the substrate that is treated with the aryl magnesium reagent. It must be in a protected precursor form during the coupling process (in this case, as the dimethyloxazolinyl group).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])[CH2:4][CH2:3]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:46][C:47]1[CH:48]=[C:49]([C:54]2[CH:63]=[C:62]3[C:57]([CH:58]=[C:59]([NH:64][C:65]([CH:67]4[CH2:69][CH2:68]4)=[O:66])[N:60]=[CH:61]3)=[CH:56][CH:55]=2)[C:50]([CH3:53])=[N:51][CH:52]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C.O>[CH:67]1([C:65]([NH:64][C:59]2[N:60]=[CH:61][C:62]3[C:57]([CH:58]=2)=[CH:56][CH:55]=[C:54]([C:49]2[CH:48]=[C:47]([NH:46][C:13](=[O:14])[C:12]4[CH:16]=[CH:17][C:9]([CH2:8][N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)=[C:10]([C:18]([F:21])([F:19])[F:20])[CH:11]=4)[CH:52]=[N:51][C:50]=2[CH3:53])[CH:63]=3)=[O:66])[CH2:68][CH2:69]1
Reactant: CN1CCN(Cc2ccc(C(=O)O)cc2C(F)(F)F)CC1
Reactant: Cc1ncc(N)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ncc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 1.1 %

Procedure:
To a solution of 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzoic acid (302 mg, 1.0 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (570 mg) at 0° C. A solution of N-(7-(5-amino-2-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide (318 mg, 1.0 mmol) in anhydrous N,N-dimethylformamide (5 mL) was mixed with N,N-diisopropylethylamine (387 mg, 3.0 mmol) and immediately added to the reaction at 0° C. It was stirred at 0° C. for 10 minutes and then at room temperature for 4-5 hours. The reaction was diluted with ethyl acetate (15 mL) and water (10 mL) and the aqueous layer was extracted with ethyl acetate (3×15 mL). The combined organic layers were dried, concentrated, and purified by prep-HPLC to give the product (6.4 mg, 1.1%). LCMS (ESI): RT (min)=0.760, M+H+=603.4, method=A; 1H NMR: (MeOH-d4, 400 MHz): δ 9.40 (d, J=2.0 Hz, 1H), 9.18 (s, 1H), 8.59 (d, J=2.0 Hz, 1H), 8.51 (s, 1H), 8.37 (s, 1H), 8.29 (d, J=4.4 Hz, 1H), 8.19 (s, 1H), 8.07-01 (m, 2H), 7.83 (d, J=1.6 Hz, 1H), 3.88 (s, 2H), 3.51 (d, J=12.4 Hz, 2H), 3.31 (t, J=1.6 Hz, 2H), 3.22 (t, J=1.6 Hz, 2H), 3.06 (d, J=12.4 Hz, 2H), 2.92 (s, 3H), 2.72 (s, 3H), 2.51 (t, J=1.6 Hz, 2H), 2.02-1.97 (m, 1H), 1.05-1.04 (m, 2H), 0.95-093 (m, 2H).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3I)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:22]1(B(O)O)[CH2:24][CH2:23]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:22]1([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:18]=2[CH:19]=[CH:20][C:11]([NH:10][C@H:1]2[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]2)=[N:12]3)[CH2:24][CH2:23]1
Reactant: Ic1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)CC[C@H]2Nc1ccc2c(C3CC3)cccc2n1

Procedure:
(R)-Indan-1-yl-(5-iodo-quinolin-2-yl)-amine (example 1, step A, 2000 mg, 0.52 mmol) was dissolved in 5 mL toluene and 0.15 mL water. Cyclopropylboronic acid (89 mg, 1.04 mmol) was added. Argon was bubbled through the solution for 2 minutes to remove oxygen. Tri(cyclohexyl)-phosphine (30 mg, 0.11 mmol), palladium acetate (12 mg, 0.05 mmol) and tri-potassium phosphate (385 mg, 1.8 mmol) were added. The reaction mixture was evaporated. The residue was purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0→75:25 gradient). The title compound was obtained as a white gum (114 mg, 73%), MS: m/e=301.3 (M+H+).
Reaction SMILES: C1(S(CC2C(C(OC)=O)=C3C(C4C=COC=4C(C)O3)=CC=2)(=O)=O)C=CC=CC=1.[NH2:29][C:30]1[C:35]([C:36]([O:38][CH3:39])=[O:37])=[C:34](O)[C:33]([C:41]2[CH:45]=[CH:44][O:43][C:42]=2[CH2:46][CH2:47][OH:48])=[CH:32][CH:31]=1>>[NH2:29][C:30]1[CH:31]=[CH:32][C:33]2[C:41]3[CH:45]=[CH:44][O:43][C:42]=3[CH2:46][CH2:47][O:48][C:34]=2[C:35]=1[C:36]([O:38][CH3:39])=[O:37]
Reactant: COC(=O)c1c(N)ccc(-c2ccoc2CCO)c1O
Agent: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc2c1OC(C)c1occc1-2
Product: COC(=O)c1c(N)ccc2c1OCCc1occc1-2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 14 starting from methyl 6-amino-2-hydroxy-3-[2-(2-hydroxyethyl)-furan-3-yl]-benzoate (Intermediate 25).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][N:7]([CH2:9][C:10]([OH:12])=O)[CH3:8])=[O:5])[CH3:2].[NH2:13][C@@H:14]([CH3:38])[C:15]([N:17]([C@@H:29]([CH3:37])[CH:30]([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[N:27]=[CH:26][CH:25]=[CH:24]2)=[O:16]>>[CH2:32]([O:31][CH:30]([O:34][CH2:35][CH3:36])[C@@H:29]([N:17]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[N:27]=[CH:26][CH:25]=[CH:24]2)[C:15](=[O:16])[C@@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:7]([CH3:8])[NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH3:38])[CH3:37])[CH3:33]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)N
Reactant: CCNC(=O)NN(C)CC(=O)O
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](C)C(=O)N(Cc1cccc2cccnc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(ethylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-9) 73 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-11) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)([O-:3])=[O:2].Br[C:19]1[S:20][CH:21]=[CH:22][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>O>[N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[NH:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: Nc1ccc(Nc2ccccc2[N+](=O)[O-])cc1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccccc1Nc1ccc(Nc2nccs2)cc1

Procedure:
2-Nitro-N-(4-aminophenyl)aniline (5.0 g, 21.8 mmol), 2-bromothiazole (3.58 g, 21.8 mmol) and potassium carbonate (3.01 g, 21.8 mmol) was stirred at 150° C. for 24 h. Water (250 ml) was added and the mixture was extracted with ethyl acetate (250 ml). The crude extract was purified by chromatography using silica gel and a mixture of ethanol (4%) and dichloromethane as eluent. The product was isolated as the free base. Yield 1.47 g, 22%. M.p. 195-197° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11](F)[C:12]=3[F:14])[C:7](=[O:16])[CH:6]([C:17]([OH:19])=[O:18])[CH2:5]2)[CH2:3][CH2:2]1.[CH:20]12[CH2:27][NH:26][CH2:25][CH:24]1[CH2:23][CH2:22][NH:21]2>CS(C)=O>[CH:20]12[CH2:27][N:26]([C:11]3[C:12]([F:14])=[C:13]4[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]4[CH:1]4[CH2:3][CH2:2]4)=[CH:9][CH:10]=3)[CH2:25][CH:24]1[CH2:23][CH2:22][NH:21]2
Reactant: O=C(O)C1CN(C2CC2)c2c(ccc(F)c2F)C1=O
Reactant: C1CC2CNCC2N1
Solvent: CS(C)=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4CCNC4C3)ccc2c1=O

Procedure:
620 mg (2.3 mmol) of 1-cyclopropyl-7,8-difluoro-1,3-dihydro-4-oxo-3-quinolinecarboxylic acid together with 315 mg (2.8 mmol) of 2,7-diazabicyclo[3.3.0]octane and 0.51 g (4.6 mmol) of 1,4-diazabicyclo[2.2.21]octane are heated for two hours at 120° C. in 23 ml of dimethyl sulphoxide. All volatile components are removed under a high vacuum, and the residue is stirred thoroughly with acetonitrile and dried at approximately 100° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[N:4][CH:3]=1.[F:13][C:14]1[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[CH:17][C:15]=1[NH2:16]>CC(O)CCC.Cl>[ClH:1].[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[N:4][CH:3]=[C:2]2[NH:16][C:15]1[CH:17]=[C:18]([OH:22])[C:19]([CH3:21])=[CH:20][C:14]=1[F:13]
Reactant: Clc1ccc2nncc(Cl)c2c1
Reactant: Cc1cc(F)c(N)cc1O
Agent: Cl
Solvent: CCCC(C)O
Product: Cc1cc(F)c(Nc2cnnc3ccc(Cl)cc23)cc1O
Yield: 95.8 %

Procedure:
A solution of 4,6-dichlorocinnoline (200 mg, 1 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (169 mg, 1.2 mmol), (prepared as described for the starting material in Example 11), in 2-pentanol (4 ml) containing 7M isopropanolic hydrogen chloride (2 drops) was heated at reflux for 45 minutes. After cooling the solid was filtered off, washed with isopropanol followed by ether to give 6-chloro-4-(2-fluoro-5-hydroxy-4-methylanilino)cinnoline hydrochloride (326 mg, 95%).
Reaction SMILES: Br[CH2:2][C:3]1[O:7][C:6]([CH:8]=[O:9])=[CH:5][CH:4]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>O1CCOCC1>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:2][C:3]2[O:7][C:6]([CH:8]=[O:9])=[CH:5][CH:4]=2)[CH2:13][CH2:12]1
Reactant: O=Cc1ccc(CBr)o1
Reactant: CN1CCNCC1
Solvent: C1COCCO1
Product: CN1CCN(Cc2ccc(C=O)o2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
To a solution of 0.20 g (1.1 mmol) of 5-(bromomethyl)furan-2-carboxaldehyde in anhydrous dioxane (10 ml) are added 261 μL (0.24 g, 2.3 mmol) of 1-methylpiperazine. The mixture is stirred at room temperature for 30 min. The precipitate formed is filtered and rinsed with dioxane. The filtrate is concentrated, dissolved in dichloromethane, and washed in water. The organic phase is dried over magnesium sulfate, filtered, and concentrated. The residue obtained is purified by chromatography on silica (eluent: 7N NH4OH in MeOH/CH2Cl2, 5:95) to yield 0.12 g (55%) of 5-((4-methylpiperazine-1-yl)methyl)furan-2-carboxaldehyde in the form of an orange solid.
Reaction SMILES: Br[C:2]1[C:3](=[O:41])[N:4]([CH3:40])[C:5](=[O:39])[C:6]=1[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[NH:22][C:23]2[C:28]([C:29]=1[C:30]1[C:31](=[O:38])[N:32]([CH3:37])[C:33](=[O:36])[C:34]=1Br)=[CH:27][CH:26]=[CH:25][CH:24]=2.[NH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1>>[CH3:40][N:4]1[C:5](=[O:39])[C:6]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[NH:22][C:23]3[C:28]([C:29]=2[C:30]2[C:31](=[O:38])[N:32]([CH3:37])[C:33](=[O:36])[C:34]=2[N:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:2]([N:4]2[CH2:5][CH2:6][CH2:2][CH2:3]2)[C:3]1=[O:41]
Reactant: C1CCNC1
Reactant: CN1C(=O)C(Br)=C(c2c(CCCCCc3[nH]c4ccccc4c3C3=C(Br)C(=O)N(C)C3=O)[nH]c3ccccc23)C1=O
Product: CN1C(=O)C(c2c(CCCCCc3[nH]c4ccccc4c3C3=C(N4CCCC4)C(=O)N(C)C3=O)[nH]c3ccccc23)=C(N2CCCC2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.0 g (1.5 mmol) of 3-bromo-4-(2-(5-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione is dissolved in 5 ml (60.6 mmol) of pyrrolidine and stirred overnight at room temp. Excess pyrrolidine is then distilled off. The residue is completely freed from solvent residues in an oil-pump vacuum and then purified by column chromatography (SiO2, CH2Cl2/ethyl acetate 95:5). Yield: 480 mg (49%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH2:14][O:15][CH3:16])[C:11](=[O:17])[N:10]([CH2:18][C:19]([OH:21])=O)[N:9]=2)=[CH:4][CH:3]=1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:13][CH2:14][O:15][CH3:16])[C:11](=[O:17])[N:10]([CH2:18][C:19]([NH:28][CH2:27][C:26]3[CH:29]=[CH:30][CH:31]=[C:24]([C:23]([F:22])([F:32])[F:33])[CH:25]=3)=[O:21])[N:9]=2)=[CH:6][CH:7]=1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: COCCn1c(-c2ccc(Cl)cc2)nn(CC(=O)O)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1c(-c2ccc(Cl)cc2)nn(CC(=O)NCc2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50.0 mg (0.160 mmol) of 2-[3-(4-chlorophenyl)-4-(2-methoxyethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid from Example 90A, 30.9 mg (0.176 mmol) of 3-trifluoromethylbenzyl-amine and 40.0 mg (0.209 mmol) of HOBt are placed in 2 ml of dimethylformamide and treated with 26.0 mg (0.192 mmol) of EDC hydrochloride. This is stirred overnight at room temperature, then stirred with 15 ml of water and the resulting precipitate recovered by filtration. The crude product is washed with water and dried in vacuo. 66.9 mg (89% of theory) of the target compound are thus obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([O:16]CC)=[O:15])[N:11]([CH3:19])[N:10]=2)=[CH:5][CH:4]=1)#[N:2].[Li+].[OH-].O.Cl>C1COCC1.CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[N:11]([CH3:19])[N:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)c1cc(-c2ccc(C#N)cc2)nn1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nc(-c2ccc(C#N)cc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a solution of ethyl 3-(4-cyanophenyl)-1-methyl-1H-pyrazole-5-carboxylate (70 mg, 274 μmol, Eq: 1.00) in THF (5 ml) and MeOH (1.00 ml) was added LiOH 1M (548 μl, 548 μmol, Eq: 2). The mixture was stirred for ca. 8 h at rt., then treated with water and HCl 1N (pH:3). The mixture was extracted two times with ethyl acetate. The resulting organic layers were combined, washed with Brine and dried over MgSO4, filtered and concentrated to give the desired compound (55 mg, 88.3%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([CH:11]([OH:15])[CH2:12][CH2:13][CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH3:16].[NH:18]1[CH:22]=[CH:21][N:20]=[N:19]1>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]([CH:11]([OH:15])[CH2:12][CH2:13][CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([N:19]1[N:20]=[CH:21][CH:22]=[N:18]1)[N:6]2[CH3:16]
Reactant: c1c[nH]nn1
Reactant: CCCC(O)c1nc(N)c2nc(Br)n(C)c2n1
Solvent: CN(C)C=O
Product: CCCC(O)c1nc(N)c2nc(-n3nccn3)n(C)c2n1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To the solution of 1-(6-amino-8-bromo-9-methyl-9H-purin-2-yl)-butan-1-ol (1.4 g, 4.56 mmol) in anhydrous DMF (20 ml) were added CsCO3 (5.9 g, 18.24 mmol) and then 1H-1,2,3-triazole (1.2 g, 1.0 ml, 18.24 mmol). The mixture was stirred overnight at 90° C. The solvent was evaporated under reduced pressure to give a residue that was purified by flash chromatography (DCM/MeOH: 93/7).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH3:20][N:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[CH2:26][CH2:27][NH2:28].Cl>>[ClH:19].[CH3:20][N:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[CH2:26][CH2:27][NH:28][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CN1CCCC1CCN
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Agent: Cl
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCC3CCCN3C)s2)c(C)[nH]c1=O
Yield: 70 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with [2-(1-methylpyrrolidin-2-yl)ethyl]amine as described in Step 5, Example 24 and the resulting product is subsequently converted to hydrochloride to give the title compound as a solid (70% yield). LC/MS: RT 2.03 min; m/e 410 (M+H); 1H NMR (δ, ppm): 11.84 (1H, s), 8.05 (1H, t), 7.58 (1H, d), 7.33 (1H, s); 7.17 (1H, d), 3.37 (1H), 3.01 (4H), 2.75 (3H), 2.39 (2H, q), 2.32 (3H, s), 1.60 (6H, m), 1.10 (3H, t).
Reaction SMILES: [C:1]([NH:14][C@H:15]([CH2:45][O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[CH2:16][S:17][CH2:18][C@@H:19]([C:38]([O:40]C(C)(C)C)=[O:39])[NH:20][C:21](=[O:37])[O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(O)(C(F)(F)F)=O.C(Cl)Cl.CC(OC)(C)C>[C:1]([NH:14][C@H:15]([CH2:45][O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[CH2:16][S:17][CH2:18][C@@H:19]([C:38]([OH:40])=[O:39])[NH:20][C:21](=[O:37])[O:22][CH2:23][CH:24]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=2[C:31]2[C:36]1=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)NC(=O)CCCCCCCCCCC
Solvent: ClCCl
Solvent: COC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(=O)CCCCCCCCCCC

Procedure:
A solution of (5R,9R)-tert-butyl 9-dodecanamido-1-(9H-fluoren-9-yl)-3-oxo-2,11-dioxa-7-thia-4-azaheptacosane-5-carboxylate in 40% TFA in DCM (0.3 M) was stirred at room temperature until complete deprotection of tert-butyl group (2 hours). The reaction mixture was diluted in MTBE, washed three times with 1 M citric acid (pH 3), and once with 1:2 HCl (3 M)/brine. The organic layer was dried over anhydrous Na2SO4 and concentrated en vaccuo to give (5R,9R)-9-dodecanamido-1-(9H-fluoren-9-yl)-3-oxo-2,11-dioxa-7-thia-4-azaheptacosane-5-carboxylic acid.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22]Br)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:8]2[CH:24]=[CH:25][CH:26]=[CH:27][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:28]([NH2:32])[CH2:29][CH2:30][CH3:31].O>CS(C)=O>[CH2:1]([C:5]1[N:9]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][N:32]([CH2:5][CH2:1][CH2:2][CH3:3])[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:8]2[CH:24]=[CH:25][CH:26]=[CH:27][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccccc2n1S(=O)(=O)c1ccc(OCCCBr)cc1
Reactant: CCCCN
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1nc2ccccc2n1S(=O)(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Reaction time: 17 h

Procedure:
To a solution of 0.0017 mol of 2-n-butyl-1-(4-bromopropoxy-benzenesulphonyl)benzimidazole in 15 ml of dimethylsulphoxide was added 0.0034 mol of n-butylamine. The reaction medium was allowed to stand for 17 hours at room-temperature and then poured into 50 ml of water. After extraction, the ethereal phase was dried and evaporated to dryness. The residue so obtained was purified by chromatography on a silica column (eluent: dichloromethane/ethyl acetate) to obtain an oil which was the desired product in the form of the free base (yield: 50%). The oxalate of the base so provided was formed by dissolving the base in question into ethyl ether and adding an ethereal solution of oxalic acid.