Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]2[C:16]3[O:17][CH:18]=[CH:19][C:15]=3[CH2:14][N:13]3[CH:20]=[CH:21][CH:22]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.NN>C(O)C.[Pd]>[NH2:1][C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]2[C:16]3[O:17][CH:18]=[CH:19][C:15]=3[CH2:14][N:13]3[CH:20]=[CH:21][CH:22]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2cccn2Cc2ccoc21
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccoc32)cc1

Procedure:
To a solution of 1 mmol of 9,10-dihydro-10-(4-nitrobenzoyl)-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepine in 20 ml of ethyl alcohol is added 0.2 g of 10% Pd/C and 2.5 mmol of hydrazine followed by stirring and heating under reflux for 3 hours. The room temperature reaction mixture is filtered through diatomaceous earth and the filtrate concentrated in vacuo. The residue is dissolved in methylene chloride and passed through a thin pad of hydrous magnesium silicate. The filtrate is concentrated in vacuo to give the desired product which is purified by flash chromatography on silica gel to give the desired product as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH:10]=2)=[CH:5][CH:4]=1.[H][H].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.FC(F)(F)C([O-])=O.[NH+]1C=CC=CC=1>CO.ClCCl.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2=CC(=O)CCC2)cc1
Reactant: [H][H]
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Pd]
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(C2CCCC(=O)C2)cc1

Procedure:
1.5 g of 5% palladium on active carbon are added to 15.15 g of 3-(4-methoxyphenyl)-2-cyclohexen-1-one in 400 ml of methanol and stirring is carried out in a hydrogen atmosphere for 4 hours. The catalyst is filtered off and the reaction mixture is concentrated. The mixture so obtained is dissolved in 200 ml of dichloromethane and stirred with 26.9 g of pyridinium dichromate and 2.1 g of pyridinium trifluoroacetate at room temperature for 6 hours. The reaction mixture is decanted, concentrated and purified over silica gel. 3-(4-Methoxyphenyl)cyclohexanone is obtained in the form of a colourless oil.
Reaction SMILES: NC1C=CC(C#N)=C(Cl)C=1.CC1(C)C(=O)N(C2C=C(C3C=CC(F)=CC=3)C(C#N)=CC=2)C(=O)N1.Br[C:36]1[CH:66]=[C:65]([F:67])[CH:64]=[CH:63][C:37]=1[CH2:38][N:39]1[C:43]([CH3:45])([CH3:44])[C:42](=[O:46])[N:41]([C:47]2[CH:52]=[C:51]([C:53]3[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=3)[C:50]([C:60]#[N:61])=[CH:49][CH:48]=2)[C:40]1=[O:62].[F:68][C:69]1[CH:74]=[C:73]([F:75])[CH:72]=[CH:71][C:70]=1[NH2:76]>>[F:68][C:69]1[CH:74]=[C:73]([F:75])[CH:72]=[CH:71][C:70]=1[NH:76][C:36]1[CH:66]=[C:65]([F:67])[CH:64]=[CH:63][C:37]=1[CH2:38][N:39]1[C:43]([CH3:45])([CH3:44])[C:42](=[O:46])[N:41]([C:47]2[CH:52]=[C:51]([C:53]3[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=3)[C:50]([C:60]#[N:61])=[CH:49][CH:48]=2)[C:40]1=[O:62]
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(-c3ccc(F)cc3)c2)C(=O)N1Cc1ccc(F)cc1Br
Reactant: Nc1ccc(F)cc1F
Agent: CC1(C)NC(=O)N(c2ccc(C#N)c(-c3ccc(F)cc3)c2)C1=O
Agent: N#Cc1ccc(N)cc1Cl
Product: CC1(C)C(=O)N(c2ccc(C#N)c(-c3ccc(F)cc3)c2)C(=O)N1Cc1ccc(F)cc1Nc1ccc(F)cc1F

Procedure:
The compound of Example 253 (5-{3-[2-(2,4-difluorophenylamino)-4-fluorobenzyl]-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl}-4′-fluorobiphenyl-2-carbonitrile, molecular weight 558.16 (C31H22F4N4O2); retention time Rt=2.38 min. [B]; MS (ESI): 559.15 (MH+)) was obtained similarly to the manner described for the preparation of the compound of Example 223 via the sequence of 4-amino-2-chlorobenzonitrile→5-amino-4′-fluorobiphenyl-2-carbonitrile (253.3, 1H NMR: 7.54-7.49, m, 3H, 7.31, t, 2H, 6.61, m, 2H, 6.25, s, 2H)→5-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-4′-fluorobiphenyl-2-carbonitrile (253.1, 1H NMR: 8.73, s, 1H; 8.09, d, 1H, 7.74, s, 1H, 7.65, m, 3H, 7.41, m, 2H, 1.42, s, 6H)→5-[3-(2-bromo-4-fluorobenzyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-4′-fluorobiphenyl-2-carbonitrile (253.2, 1H NMR: 8.1, d, 1H, 7.8, s, 1H, 7.75, d, 1H, 7.69-7.59, m, 4H; 7.41, t, 1H, 4.61, s, 2H, 1.4, s, 6H) δ 253 (from 253.2 by reaction with 2,4-difluorophenylamine).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:16]([O:18][C:19]([C:21]1([CH2:36]I)[CH2:25][CH2:24][N:23]([C:26](=[O:35])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:22]1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1([CH2:36][O:1][C:2]2[CH:7]=[N:6][C:5]([C:8]3[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)[CH2:25][CH2:24][N:23]([C:26](=[O:35])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:22]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccccc2OC)C1
Reactant: N#Cc1ccc(-c2ccc(O)cn2)cc1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(C#N)cc3)nc2)CCN(C(=O)c2ccccc2OC)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4-(5-hydroxy-pyridin-2-yl)-benzonitrile (Preparation 22) and 3-iodomethyl-1-(2-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 15) to afford the racemate as a white solid (149 mg, 85.2%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:23][C:24]([O:26]C)=[O:25])=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:15][CH:14]=2)[S:11][CH:12]=1.[OH-].[Na+].Cl>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:23][C:24]([OH:26])=[O:25])=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:15][CH:14]=2)[S:11][CH:12]=1
Reactant: CCCOc1ccc(-c2scc(-c3ccccc3Cl)c2CC(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCOc1ccc(-c2scc(-c3ccccc3Cl)c2CC(=O)O)cc1
Yield: 93.4 %

Procedure:
Methyl [4-(2-chlorophenyl)-2-(4-propoxyphenyl)thien-3-yl]acetate (0.290 g, 0.725 mmol) was dissolved in EtOH (6 mL). NaOH (2.17 mL, 1N, 2.17 mmol) was added and the solution heated to reflux for 5 h. HCl (2.17 mL, 2N, 4.34 mmol) was added and the solvent removed. The mixture was partioned between EtOAc and H2O. The EtOAc layer was dried (MgSO4) and the solvent removed to yield [4-(2-chlorophenyl)-2-(4-propoxyphenyl)thien-3-yl]acetic acid (0.262 g) as a clear oil. 1H NMR (500 MHz, DMSO-d6) δ: 0.95 (t, 3H, J=7.44 Hz), 1.70 (m, 2H), 3.30 (s, 2H), 3.93 (t, 2H, J=6.47 Hz), 6.99 (d, 2H, J=8.78 Hz), 7.28 (dd, 1H, J=1.71 and 7.20 Hz), 7.38 (m, 5H), 7.51 (dd, 1H, J=1.71 and 7.44 Hz), 12.11 (bs, 1H). MS (ES) m/z 387.0 ([M+H]+). MS (ES) m/z 404.1 ([M+NH4]+).
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[F:16][C:17]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:18]=1[NH2:19]>>[F:16][C:17]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:18]=1[NH:19][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1cnc2ccnn2c1O
Reactant: Cc1ccc(F)c(N)c1
Product: CCOC(=O)c1cnc2ccnn2c1Nc1cc(C)ccc1F
Yield: 62.6 %

Procedure:
Using ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate (5.0 g, 24.1 mmol) and 2-fluoro-5-methylaniline (2.43 g, 19.3 mmol) instead of 4-fluoro-2-methylaniline, and in the same manner as in Example 1 step 1, the title compound (3.80 g, 50%) was obtained.
Reaction SMILES: [CH:1]1[C:6](N)=[CH:5][CH:4]=[C:3]([NH2:8])[CH:2]=1.[C:9]([O:12][C:13](=[O:15])[CH3:14])(=[O:11])[CH3:10]>>[CH:1]1[C:13]([CH2:14][C:6]2[CH:1]=[CH:2][C:3]([NH2:8])=[CH:4][CH:5]=2)=[CH:5][CH:4]=[C:3]([NH2:8])[CH:2]=1.[C:9]([O:12][C:13](=[O:15])[CH3:14])(=[O:11])[CH3:10]
Reactant: Nc1ccc(N)cc1
Solvent: CC(=O)OC(C)=O
Product: Nc1ccc(Cc2ccc(N)cc2)cc1

Procedure:
In a similar manner, if one substitutes for the reaction product of p-phenylene diamine and acetic anhydride in the above reaction, the compound resulting from the reaction of 4,4'-diaminodiphenylmethane and acetic anhydride, i.e., ##STR43## a polyamide imide is obtained having the formula ##STR44##
Reaction SMILES: Cl[C:2]1[CH:25]=[N:24][C:5]2=[N:6][C:7]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[N:9]=[C:4]2[CH:3]=1.[Na].[CH3:27][OH:28]>C(Cl)Cl>[CH3:27][O:28][C:2]1[CH:25]=[N:24][C:5]2=[N:6][C:7]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[N:9]=[C:4]2[CH:3]=1
Reactant: CO
Reactant: Cc1ccc(-c2nc3cc(Cl)cnc3nc2-c2ccc(C)cc2)cc1
Agent: [Na]
Solvent: ClCCl
Product: COc1cnc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2c1
Temperature: 25 °C

Procedure:
A mixture comprising 7-chloro-2,3-dip-tolylpyrido[2,3-b]pyrazine (836 mg, 2.417 mmol) in dry MeOH (10 ml) and DCM (5 ml) bubbled through with nitrogen was treated portionwise with sodium (278 mg, 12.09 mmol). The resulting mixture was heated at reflux overnight. A further portion of sodium (278 mg, 12.09 mmol) was added and refluxing continued overnight. After cooling to RT, the solvent was removed in vacuo and the resulting residue was added to water. The mixture was extracted with DCM (×3) and the combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by chromatography on silica eluting with 10-40% EtOAc/iso-hexane afforded the title compound;
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C>O1CCCC1>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([B:19]([OH:24])[OH:20])[CH:13]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC1(C)CCCC(C)(C)N1
Solvent: C1CCOC1
Product: OB(O)c1cc(Br)ccc1F
Temperature: -78 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
A cooled (−20° C.) solution of 2,2,6,6-tetramethylpiperidine (28 ml, 165 mmol) in tetrahydrofuran (400 ml) was treated with m-butyllithium (63 ml of a 2.5M solution in hexanes, 157.5 mmol). This mixture was then cooled to −78° C. 1-Bromo-4-fluorobenzene (16.5 ml, 150 mmol) was then added neat and dropwise over 10 min and stirring at −78° C. was continued for 3 h. Triisopropyl borate (40 ml, 172.5 mmol) was then added and stirring at −78° C. continued for 30 min before removing the cooling bath. When the internal temperature of the reaction reached −4° C., 5N hydrochloric acid (75 ml) was added and the mixture was stirred to ambient temperature. After stirring at ambient temp for 1 h the majority of the tetrahydrofuran was removed and the mixture partitioned between ether (500 ml) and 1N hydrochloric acid (500 ml). The organics were then extracted with 2N sodium hydroxide (400 ml) and the organics were discarded. The aqueous was cooled in an ice-water bath and 5N hydrochloric acid (150 ml) was added dropwise over 15 min. The resulting white solid was collected and dried under vacuum to afford 5-bromo-2-fluorobenzeneboronic acid (25 g, 76%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH2:13]([O:16][C:17]([N:19]1[C@H:23]([CH2:24][C:25]2[N:32]3[C:28]([S:29][CH:30]=[CH:31]3)=[CH:27][N:26]=2)[CH2:22][C@@H:21](O)[CH2:20]1)=[O:18])[CH:14]=[CH2:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:53]([OH:61])(=[S:60])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>C1COCC1>[CH2:13]([O:16][C:17]([N:19]1[C@H:23]([CH2:24][C:25]2[N:32]3[C:28]([S:29][CH:30]=[CH:31]3)=[CH:27][N:26]=2)[CH2:22][C@H:21]([S:60][C:53](=[O:61])[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH2:20]1)=[O:18])[CH:14]=[CH2:15]
Reactant: OC(=S)c1ccccc1
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1Cc1ncc2sccn12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@@H](SC(=O)c2ccccc2)C[C@H]1Cc1ncc2sccn12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Diethyl azodicarboxylate (0.105 ml) is added to a solution of 102 mg of (3R,5R)-1-allyloxycarbonyl-3-hydroxy-5-(imidazo[5,1-b]thiazol-5-yl)methylpyrrolidine and 174 mg of triphenylphosphine in 1.7 ml of anhydrous THF at −11 to −10° C., the mixture is stirred in this state for 15 min, 0.130 ml of thiobenzoic acid (90%) is added thereto, and the mixture is stirred for 14 hr while raising the temperature this state to room temperature. The solvent and the excess reagent are removed by evaporation under reduced pressure to give a yellow oil which is then successively purified by column chromatography on Sephadex LH-20 (chloroform:methanol=1:1) and on silica gel (first, n-hexane:ethyl acetate=1:1) to give 87 mg of the title compound as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=O)=[CH:5][CH:4]=1)#[N:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:25]1([N:35]([CH3:47])[C:36]([C:38]2[CH:39]=[CH:40][C:41]([NH:45][CH3:46])=[C:42]([CH:44]=2)[NH2:43])=[O:37])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>O1CCCC1>[CH3:47][N:35]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[C:36]([C:38]1[CH:39]=[CH:40][C:41]2[N:45]([CH3:46])[C:10]([CH2:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)=[N:43][C:42]=2[CH:44]=1)=[O:37]
Reactant: N#Cc1ccc(CC(=O)O)cc1
Reactant: CNc1ccc(C(=O)N(C)c2cccc3ccccc23)cc1N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C(=O)c1ccc2c(c1)nc(Cc1ccc(C#N)cc1)n2C)c1cccc2ccccc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
483 mg (3.0 mmol) of 4-cyanophenylacetic acid and 486 mg (3.0 mmol) of carbonyldiimidazole are dissolved in 20 ml tetrahydrofuran and stirred for 1 hour at 50° C. Then 916 mg 5-(naphthalen-1-yl-methylaminocarbonyl)-2-methylamino-aniline are added thereto and stirring is continued for a further 3 hours at 50° C. The solvent is concentrated by evaporation, the residue is combined with 30 ml glacial acetic acid and refluxed for 1 hour. After evaporation of the solvent the filtrate is chromatographed on silica gel, eluting with methylene chloride/ethanol 99:1, 98:1 and 97:1. The desired fractions are concentrated by evaporation, the residue is triturated with acetone/ether, suction filtered and dried.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[CH2:14]([S:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=O)[CH2:15][CH3:16].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>O.N1C=CC=CC=1>[CH3:1][N:2]1[C:3]2=[N:4][CH:5]=[C:6]([C:10]([F:13])([F:11])[F:12])[CH:7]=[C:8]2[N:9]=[C:20]1[C:19]1[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=1[S:17][CH2:14][CH2:15][CH3:16]
Reactant: CNc1ncc(C(F)(F)F)cc1N
Reactant: CCCSc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: CCCSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 120 °C
Yield: 13 %

Procedure:
A mixture of N2-methyl-5-trifluoromethylpyridin-2,3-diamine (0.96 g), 2-propylsulfanylbenzoic acid (1.08 g), WSC (0.78 g), and pyridine (10 ml) was stirred with heating at 120° C. for 1.5 hours. To the reaction mixture, HOBt (0.74 g) was added, and stirred with heating for 1.5 hours. WSC (0.38 g) was added thereto, and stirred with heating for further 2 hours. Into the reaction mixture cooled to room temperature, water was poured, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.23 g of 3-methyl-2-(2-propylsulfanylphenyl)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 7).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.[NH3:20].CO>O1CCCC1>[NH2:20][C:10]1[CH2:9][N:8]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:6]2[CH:19]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[N:11]=1
Reactant: S=C1CN=C(c2ccccn2)c2cc(Br)ccc2N1
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: NC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
59.5 g of 7-bromo-5-(2-pyridyl)-3H-1,4-benzodiazepine-2(1H)-thione (J. B. Hester, jr., A. D. Rudzik & P.F . Von Voigtlander, J. Med. Chem., 1980,23, 392-402) in 800 ml of tetrahydrofuran were added to 1.0 l of 25% aqueous ammonia solution and 300 ml of methanol. The mixture was stirred at room temperature for 16 h., with the solution which formed being concentrated to about 500 ml in a vacuum. The crystals were filtered off, washed with water and dried. There were obtained 52 g of 2-amino-7-bromo-5-(2-pyridyl)-3H-1,4-benzodiazepine which was used without further purification for the next step. A sample recrystallized from dioxan melted at 213-215° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]#[N:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH:14](Br)([CH3:16])[CH3:15].[H-].[Na+]>CN(C=O)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH:11]([CH:14]([CH3:16])[CH3:15])[C:12]#[N:13])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CC(C)Br
Reactant: COc1cc(CC#N)cc(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(C(C#N)C(C)C)c1

Procedure:
This is prepared by reacting a solution of 2-(3,5-dimethoxyphenyl)-acetonitrile (4 g, 0.022 mol) in 10 cc of DMF with 2.86 g of isopropyl bromide in 5 cc of DMF, in the presence of a 50% suspension of 1.1 g of sodium hydride in 25 cc of DMF.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[N:15]=[CH:14]3)=[C:6]([CH:9]=1)[C:7]#[N:8].N#N.Cl>CO.[OH-].[OH-].[Pd+2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[N:15]=[CH:14]3)=[C:6]([CH:9]=1)[CH2:7][NH2:8]
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3C#N)ccc21
Agent: [Pd+2]
Agent: Cl
Agent: N#N
Solvent: CO
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3CN)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 107.4 %

Procedure:
To a solution of 5-fluoro-2-(1-isobutyl-1H-indazol-5-yloxy)-benzonitrile (3.05 g, 9.86 mmol) purged with N2 in MeOH (50 mL) was added concentrated HCl (1.6 mL) and Pd(OH)2/C (15% wt, 0.457 g). The mixture was stirred at room temperature for 18 hours under H2 atmosphere. The catalyst was removed by filtration and the solution was concentrated under reduced pressure to afford 3.32 g of pale yellow foam (96% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:31][O:32][CH2:33][C:34](Cl)=[O:35]>C1COCC1.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH:30][C:34](=[O:35])[CH2:33][O:32][CH3:31])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:17])([F:18])[F:19])=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COCC(=O)Cl
Reactant: NS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3cc(C(F)(F)F)ccc23)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COCC(=O)NS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3cc(C(F)(F)F)ccc23)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-[2-(3-fluoro-phenyl)-6-trifluoromethyl-pyrazolo[1,5-a]pyridin-3-yl]-benzenesulfonamide (0.15 g 0.35 mmol) in dry THF (3 ml) was added N,N-(diisopropyl)aminomethylpolystyrene (Argonaut Technologies) (0.25 g 0.9 mmol), 4-dimethylaminopyridine (Aldrich) (0.03 g 0.25 mmol) and methoxyacetyl chloride (Aldrich) (0.09 g 0.8 mmol) and the mixture was shaken at room temperature for 18 hr. Tris-(2-aminoethyl)amine polystyrene (Argonaut Technologies) (0.5 g 1.7 mmol) was added and shaking continued for 6 hr. The resins were filtered, washed with dichloromethane (5 ml) and the solvents were removed. The residue was purified by SPE chromatography eluting with cyclohexane:ethyl acetate (5:1 then 2:1) to give the title compound as a white solid. (0.07 g, 40%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[C:13]1[NH:18][C:17](=[O:19])[C:16]2=[C:20]([CH3:32])[N:21]=[C:22]([CH2:23][CH:24]([CH2:30][CH3:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[N:15]2[N:14]=1)[CH3:2].C1CCCCC1.C(OCC)(=O)C>C(O)C.[Pd]>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:13]2[NH:18][C:17](=[O:19])[C:16]3=[C:20]([CH3:32])[N:21]=[C:22]([CH2:23][CH:24]([CH2:30][CH3:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[N:15]3[N:14]=2)[CH:6]=1
Reactant: CCCCCC(CC)Cc1nc(C)c2c(=O)[nH]c(-c3cc([N+](=O)[O-])ccc3OCC)nn12
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CCCCCC(CC)Cc1nc(C)c2c(=O)[nH]c(-c3cc(N)ccc3OCC)nn12

Procedure:
Analogously to the procedure of example 42A, 1.95 g (4.42 mmol) of the compound from example 49A are hydrogenated in 120 g of ethanol using 200 mg of 10% Pd/C. Chromatography on 400 ml of silica gel using cyclohexane and ethyl acetate in a gradient system from 90:10 to 40:60 gives 1.26 g (69.4% of theory).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:5][CH:4]=1)#[CH:2].[Cl:16][C:17]1[N:22]=[C:21](Cl)[CH:20]=[CH:19][N:18]=1>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:16][C:17]1[N:22]=[CH:21][C:20]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:5][CH:4]=2)=[CH:19][N:18]=1
Reactant: C#Cc1ccc(CC(C)NC(C)=O)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(=O)NC(C)Cc1ccc(C#Cc2cnc(Cl)nc2)cc1
Temperature: 25 °C

Procedure:
To 3.30 g (16.4 mmol) N-(1-(4-ethynylphenyl)propan-2-yl)acetamide (I58.3) in 40 mL THF are added 2.44 g (16.4 mmol) 2,4-dichloropyrimidine, 57.5 mg (82.0 μmol) bis(triphenyphosphine)dichloropalladium and 9.10 mL (65.7 mmol) TEA. The reaction mixture is stirred under reflux for 4 h and at r.t. over night. The reaction mixture is filtrated and the solvent is removed in vacuo. The residue is triturated with water and afterwards with diethylether.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=1.F[C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27].[NH4+].[Cl-]>C1COCC1>[F:25][C:23]1[CH:22]=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[C:19]([NH:17][C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)[CH:24]=1
Reactant: Nc1cccnc1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1Nc1cccnc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 43.5 %

Procedure:
LiHMDS (1.0M in THF, 12.6 mL, 12.6 mmol) was added dropwise to a stirred solution of pyridin-3-ylamine (621 mg, 6.60 mmol) in anhydrous THF (10 mL) under a nitrogen atmosphere at −78° C. After 45 min stirring at −78° C., a solution of 2,4-difluoro-1-nitrobenzene (690 μL, 6.29 mmol) in THF (10 mL) was added and stirring continued for 1 h. The solution was poured into an aqueous solution of NH4Cl (100 mL) and extracted with EtOAc (×3). The combined organic fractions were washed with water, followed by brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was triturated with EtOAc to afford the title compound as a dark orange solid (638 mg). The mother liquours were concentrated under reduced pressure to afford the title compound as a dark orange solid (648 mg, 87% for the combined batches). 1H NMR (CDCl3, 400 MHz): δ 9.60 (1H, br s), 8.63 (1H, s), 8.56 (1H, d, J=4.76 Hz), 8.35-8.27 (1H, m), 7.65 (1H, d, J=8.20 Hz), 7.45-7.38 (1H, m), 6.75 (1H, d, J=11.14 Hz), 6.57 (1H, t, J=8.24 Hz)