Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1.C(N(C(C)C)C(C)C)C.[F:28][C:29]([F:47])([F:46])[C:30]1[CH:31]=[C:32]([C:40]([CH3:45])([CH3:44])[C:41](Cl)=[O:42])[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1.[OH-].[Na+]>C(Cl)Cl>[F:28][C:29]([F:47])([F:46])[C:30]1[CH:31]=[C:32]([C:40]([CH3:45])([CH3:44])[C:41]([N:2]([CH3:1])[C:3]2[C:4]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=2)=[O:42])[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1
Reactant: CNc1cnc(SC)nc1Oc1ccccc1C
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSc1ncc(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(Oc2ccccc2C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.6 %

Procedure:
To a solution of 1.10 g (4.21 mol) methyl-(2-methylsulfanyl-4-o-tolyloxy-pyrimidin-5-yl)-amine and 1.44 ml (8.42 mmol) N-ethyldiisopropylamine in 30 ml CH2Cl2 a solution of 1.87 g (5.89 mmol) 2-(3,5-bis-trifluormethyl-phenyl)-2-methyl-propionyl chloride in 5 ml CH2Cl2 was added and the reaction mixture stirred for 12 hrs at RT. The reaction mixture was poured into 50 ml 0.5 N NaOH-solution. The phases were separated and the aqueous phase three times extracted with 80 ml CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, hexane/ ethyl acetate 2:1) to give 2.10 g (92%) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-methylsulfanyl-4-o-tolyloxy-pyrimidin-5-yl)-isobutyramide as a white foam, MS (ISP): 544.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH:32]([CH3:34])[CH3:33])[CH:27]=2)[CH:21]=1)=O)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH:32]([CH3:33])[CH3:34])[CH:27]=4)[CH:21]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: CC(C)c1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Solvent: Cc1ccccc1C
Product: CC(C)c1cc(-c2cccc(C3=Nc4cc(Cl)c(Cl)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from commercially available 4,5-dichloro-1,2-phenylendiamine (133 mg, 0.75 mmol) and 3-[3-(2-isopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K39) (255 mg, 0.75 mmol) in xylene (15 ml) under reflux conditions for 1.5 h according to the general procedure M. Obtained as a light red solid (220 mg, 69%).
Reaction SMILES: [CH3:1][C:2]([NH2:12])([CH3:11])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.ClC(Cl)(Cl)C1O[N:16]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C(Cl)Cl>[CH3:11][C:2]([NH:12][NH:16][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1
Reactant: Cc1ccc(CC(C)(C)N)cc1
Reactant: CC(C)(C)OC(=O)N1OC1C(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(CC(C)(C)NNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C

Procedure:
2.40 g (14.7 mmol) of separately prepared 2-methyl-1-p-tolylpropan-2-amine was dissolved in 20 mL of methylene chloride, and 2.60 g (10.0 mmol) of separately prepared t-butyl 3-(trichloromethyl)-1,2-oxaziridine-2-carboxylate in 10 mL of methylene chloride was added under cooling with ice. The reaction solution was stirred under cooling with ice for 30 minutes and at room temperature for 1 hour, and the methylene chloride was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography using hexane-ethyl acetate (100:0 to 0:100) as the eluent to give 1.61 g of the desired product as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[C:5](=O)[C:6]2[CH:12]=[CH:11][S:10][C:7]=2[NH:8][CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[C:7]2[S:10][CH:11]=[CH:12][C:6]=12
Reactant: O=c1c([N+](=O)[O-])c[nH]c2sccc12
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc2sccc2c1Cl
Temperature: 115 °C
Yield: 94 %

Procedure:
A mixture of 3.4 g of 5-nitrothieno[2,3-b]pyridin-4(7H)-one 6 and 34 ml of phosphorus oxychloride is heated at 115° C. (bath temperature) for 1 hour and evaporated to dryness in vacuo. The residue is taken up in chloroform and washed with water. The organic phase is dried over magnesium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel. Elution with dichloromethane-ether (50:1 v/v) affords 3.51 g (94%) of Compound 7 as crystals melting at 110°-113° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](O)=[C:8]([CH3:14])[C:9]([CH3:13])=[N:10]2)=[CH:5][C:4]=1[CH3:16].O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([CH3:16])[CH:5]=2)[N:10]=[C:9]([CH3:13])[C:8]=1[CH3:14]
Reactant: COc1cc2nc(C)c(C)c(O)c2cc1C
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2nc(C)c(C)c(Cl)c2cc1C

Procedure:
Prepared according to procedure S using 7-methoxy-2,3,6-trimethylquinolin-4-ol (444.7 mg, 2.0 mmol) and POCl3 (2.0 mL, 21.5 mmol) to give 4-chloro-7-methoxy-2,3,6-trimethylquinoline. Mass Spectrum (ESI), m/e=236.1 (M+1).
Reaction SMILES: CS[C:3]1[N:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:6]2[CH2:15][CH2:16][CH2:17][CH2:18][C@H:5]2[N:4]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:11]([O:10][C:8]([N:7]1[C@H:6]2[CH2:15][CH2:16][CH2:17][CH2:18][C@H:5]2[N:4]=[C:3]1[NH:26][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CSC1=N[C@@H]2CCCC[C@@H]2N1C(=O)OC(C)(C)C
Reactant: NCc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(NCc2ccccc2)=N[C@@H]2CCCC[C@@H]21
Temperature: 100 °C
Yield: 84.9 %

Procedure:
A mixture of intermediate 76 (200 mg, 0.0.740 mmol), benzylamine (0.5 mL, 4.6 mmol) is heated at 100° C. (reaction block) overnight. The reaction mixture is cooled to RT. The reaction mixture is diluted with dichloromethane, washed with 0.1N HCl, and brine. The solvent is evaporated, and the residue triturated with EtOAc, and the insoluble material filtered to give 207 mg of the product 189. 1H NMR (CDCl3) δ 8.56 (s, 1 H), 7.50-7.20 (m, 5 H), 5.15-4.95 (m, 2 H), 4.35-4.05 (m, 2 H), 2.85-2.55 (m, 1 H), 2.25-2.05 (m, 1 H), 1.90-1.05 (m, 15 H); MS: m/z 330 (M++1).
Reaction SMILES: [C:1]([NH2:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].I[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2>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.CN(C=O)C.CCN(CC)CC>[CH3:26][O:25][C:24]1[CH:23]=[CH:22][NH:21][C:20]=1/[CH:19]=[C:11]1\[C:12](=[O:18])[NH:13][C:14]2[C:10]\1=[C:9]([C:5]#[C:4][CH2:3][CH2:2][C:1]([NH2:7])=[O:6])[CH:17]=[CH:16][CH:15]=2
Reactant: C#CCCC(N)=O
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCC(N)=O)c21

Procedure:
Using Method C above, 4-pentynamide (49 mg, 0.5 mmol) (prepared from 4-pentyonic acid according to Method G above) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 2 supra) (120 mg, 0.32 mmol) using (Ph3P)2PdCl2 (12 mg) and Cul (6 mg) as catalyst in DMF (1 mL) and Et3N (1 mL) as solvent at 70° C. for 22 h to yield (Z)-5-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-4-pentynamide. (Yield 45 mg, 42%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([CH2:21][CH2:22][CH2:23][CH3:24])(=[O:20])=[O:19])[CH2:12][C:13]([O:15]CC)=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:25][NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[NH:35])[NH2:34])=[CH:29][CH:28]=1.[OH-].[Na+]>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([CH2:21][CH2:22][CH2:23][CH3:24])(=[O:20])=[O:19])[CH2:12][C:13]([OH:15])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:25][NH:26][C:27]1[CH:28]=[CH:29][C:30]([C:33](=[NH:34])[NH2:35])=[CH:31][CH:32]=1
Reactant: CCCCS(=O)(=O)N(CC(=O)OCC)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C
Agent: [Na+]
Agent: [OH-]
Product: CCCCS(=O)(=O)N(CC(=O)O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C

Procedure:
Prepared analogously to Example 3 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-5-[N-(ethoxycarbonylmethyl)-n-butanesulphonylamino]-benzimidazole and sodium hydroxide solution.
Reaction SMILES: [CH2:1]([O:4][N:5]([CH:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH2:31][O:32][Si](C(C)(C)C)(C)C)[CH:20]=[C:19]1[CH2:40][C:41]([NH2:43])=[O:42])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C(ON([C@H]1CN(C(OC(C)(C)C)=O)[C@H](CO)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:4][N:5]([CH:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[C@H:21]([CH2:31][OH:32])[CH:20]=[C:19]1[CH2:40][C:41]([NH2:43])=[O:42])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:7])=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCON(C1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1CC(N)=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON(C1CN(C(=O)OC(C)(C)C)[C@H](CO)C=C1CC(N)=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (2S)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-4-(2-amino-2-oxoethyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 173, crude, 5.78 mmol) following the procedure described for Intermediate 18. Silica column eluting with 0-100% ethyl acetate/hexanes gave a pale yellow solid. 2.61 g, 86%.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9](I)=[C:10]([Cl:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH:15]([Sn](CCCC)(CCCC)CCCC)=[CH2:16]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:15]=[CH2:16])=[C:10]([Cl:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(=O)N1CCc2cc(I)c(Cl)cc21
Product: C=Cc1cc2c(cc1Cl)N(C(C)=O)CC2

Procedure:
1-Acetyl-6-chloro-5-iodoindoline (D60) (0.19 g, 0.6 mmol) was treated with vinyl tributyltin as in the method developed by Stille (A. M. Echavarren and J. K. Stille, J. Am. Chem. Soc., 1987, 109, 5478) to give the title compound (0.13 g) as a brown oil which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][NH:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1.[CH2:31](O)[CH3:32].O.Cl[CH2:36][C:37]1[NH:38][C:39]2[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=2[N:41]=1>C(O)C>[NH:41]1[C:40]2[CH:42]=[CH:43][CH:44]=[CH:45][C:39]=2[N:38]=[C:37]1[CH2:36][N:10]([CH2:11][C:12]1[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=1)[CH2:9][CH2:8][N:7]([CH2:36][C:37]1[NH:38][C:39]2[CH:40]=[CH:42][CH:43]=[CH:31][C:32]=2[N:41]=1)[CH2:6][C:5]1[CH:24]=[C:25]([O:29][CH3:30])[C:26]([O:27][CH3:28])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(CNCCNCc2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: CCO
Solvent: O
Product: COc1cc(CN(CCN(Cc2cc(OC)c(OC)c(OC)c2)Cc2nc3ccccc3[nH]2)Cc2nc3ccccc3[nH]2)cc(OC)c1OC
Temperature: 45 °C

Procedure:
1.5 g N,N'-bis-(3,4,5-trimethoxybenzyl) ethylenediamine dichlorhydrate were solubilized in 30 ml 1:1 ethanol/water mixture. The pH of the solution was brought to 11 using a soda solution. A solution of 1.1 g 2-chloromethyl benzimidazole in solution in 30 ml ethanol was added all at once. The mixture was heated for 5 hours at 45° C. while keeping the pH at between 10 and 11 by adding a soda solution. After cooling, the ethanol was evaporated in a vacuum, and the medium was cooled to 0° C. The precipitate formed was filtered and washed with water. The solid was taken up in 15 ml water +0.5 ml concentrated HCl, then filtered and washed in water. The solid was then recrystallized in 10 ml of a 98:2 water/ethanol mixture. 350 mg of a white powder having a melting point of 150° C. (dec.) were obtained, whose proton NMR spectrum (400 MHZ) and ultimate analysis matched the expected structure (in the form of dichlorhydrate).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[NH:8][C:5]2=[N:6][CH:7]=1.[CH:14]([C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][CH:30]=1)[C:19]([NH:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:20])=O.[BH3-]C#N.[Na+]>CO.CC(O)=O>[C:11]([C:9]1[NH:8][C:5]2=[N:6][CH:7]=[C:2]([NH:1][CH2:14][C:16]3[CH:17]=[C:18]([CH:28]=[CH:29][CH:30]=3)[C:19]([NH:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[O:20])[CH:3]=[C:4]2[CH:10]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)c1cc2cc(N)cnc2[nH]1
Reactant: O=Cc1cccc(C(=O)Nc2cccnc2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)c1cc2cc(NCc3cccc(C(=O)Nc4cccnc4)c3)cnc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(5-Amino-1H-pyrrolo[2,3-b]pyridin-2-yl)-ethanone (1 eq) and 3-Formyl-N-pyridin-3-yl-benzamide (1.1 eq) were stirred in a mixture of MeOH/AcOH (10/1; 0.06M) for 2 h. Then NaBH3CN (1.2 eq) was slowly added and the mixture was stirred under argon at RT overnight. The reaction was quenched by addition of saturated NaHCO3 solution until neutrality. MeOH and acetic acid were evaporated. The crude was filtered and washed with water and Et2O before being purified on reverse phase (H2O 1% TFA/MeCN 1% TFA 100/0, 0/100). MeCN was evaporated. The product was suspended in H2O and basified with saturated NaHCO3 solution until pH=8-9. The aqueous layer was extracted three times with AcOEt. The organic layer was dried over Na2SO4, filtered and concentrated to give the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:9][CH2:10][N:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[CH:4][CH:3]=1.[C:25]([NH:27][C:28](=[N:36][CH2:37][CH2:38][CH2:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)[CH:42]=1)OC1C=CC=CC=1)#[N:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:28]([NH:27][C:25]#[N:26])=[N:36][CH2:37][CH2:38][CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:48]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)[CH:42]=2)[CH3:18])=[CH:4][CH:3]=1
Reactant: CN(CCCCCN)CCC(c1ccc(Cl)cc1)c1ccccn1
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Product: CN(CCCCCNC(=NCCCOc1cccc(CN2CCCCC2)c1)NC#N)CCC(c1ccc(Cl)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 1.09 g (3.15 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,5-pentanediamine and 1.23 g (3.1 mmol) of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; IR (KBr): 2163 cm-1 (C≡N).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([CH3:24])[CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=2)O1>>[CH3:8][C:6]1[CH:7]=[C:2]([C:33]2[CH:34]=[N:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=2)[CH:3]=[C:4]([CH3:24])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10]
Reactant: CC1(C)OB(c2cncc(C(F)(F)F)c2)OC1(C)C
Reactant: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCC(O)CC2)CC1
Product: Cc1cc(-c2cncc(C(F)(F)F)c2)cc(C)c1C(=O)N1CCC(N2CCC(O)CC2)CC1

Procedure:
In analogy to the procedure described for example 1, (4-bromo-2,6-dimethyl-phenyl)-(4-hydroxy-[1,4′]bipiperidinyl-1′-yl)-methanone (example 22) was reacted with 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-pyridine (intermediate 6) to give the title compound as light yellow oil. MS: 462.2 (MH+).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1.Cl[C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1>>[N:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:33]=[CH:34][C:25]=1[NH:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: NC(=O)c1cccc2c(NCc3cccc(N)c3)ncnc12
Agent: Cl
Product: NC(=O)c1cccc2c(NCc3cccc(Nc4ccc5ccccc5n4)c3)ncnc12

Procedure:
The title compound was prepared according to Example 684 starting 4-(3-Amino-benzylamino)-quinazoline-8-carboxylic acid amide hydrochloride and 2-Chloro-quinoline at 120° C.:
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:13](=[O:14])[C@H:12]3[CH2:15][CH2:16][CH2:17][C@H:11]3[N:10]([C:18](=[O:31])[CH2:19][N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])[C:9]3[CH:32]=[CH:33][CH:34]=[CH:35][C:8]2=3)=[CH:4][CH:3]=1.[C:38]1([C@@H:44]([N:46]=[C:47]=[O:48])[CH3:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(OCC)(=O)C.C(OCC)C>[C:38]1([C@@H:44]([NH:46][C:47](=[O:48])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:7]3[C:13](=[O:14])[C@H:12]4[CH2:15][CH2:16][CH2:17][C@H:11]4[N:10]([C:18](=[O:31])[CH2:19][N:20]4[C:21](=[O:30])[C:22]5=[CH:29][CH:28]=[CH:27][CH:26]=[C:23]5[C:24]4=[O:25])[C:9]4[CH:32]=[CH:33][CH:34]=[CH:35][C:8]3=4)=[CH:36][CH:37]=2)[CH3:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1
Reactant: C[C@H](N=C=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C[C@H](NC(=O)Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1)c1ccccc1
Yield: 53 %

Procedure:
Using (3aR*,10aS*)-9-(4-aminobenzyl)-4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one and (S)-1-phenylethyl isocyanate, the title compound was synthesized in otherwise the same manner as Example 26. Yield 53%, m.p. 156°-160° C. (ethyl acetate-diethyl ether).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[S:7]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:7]1[CH:11]=[CH:10][C:9]([C:2]2[N:3]=[CH:4][NH:5][CH:6]=2)=[CH:8]1
Reactant: Ic1c[nH]cn1
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: c1nc(-c2ccsc2)c[nH]1
Temperature: 25 °C
Yield: 85.2 %

Procedure:
A solution of 4-iodo-1H-imidazole (0.24 g, 1.25 mmol) and Pd(PPh3)4 (72 mg, 0.06 mmol) in DME (12.5 mL) was degased by purging with argon for 10 min. Thiophene-3-boronic acid (0.32 g, 2.50 mmol) and Na2CO3 (2.5 mL of a 2M solution in water) were added. The mixture was heated to reflux for 18 h. After cooling to RT, the solvent was removed under reduced pressure. The residue was subjected to flash chromatography (4% MeOH/CH2Cl2, silica gel) to give 0.16 g of the desired product as an off-white solid. MS(ES+) m/z 151.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:18]([O-])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]1>C1COCC1.[H][H].[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][CH:14]([CH3:17])[CH2:15][CH2:16]1
Reactant: CC1CCN(CCOc2ccc([N+](=O)[O-])cc2Cl)CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: CC1CCN(CCOc2ccc(N)cc2Cl)CC1

Procedure:
6.90 g (23.1 mmol) of 3-chloro-4-[2-(4-methylpiperidin-1-yl)ethoxy]nitrobenzene (III.1.b) are dissolved in 100 mL of THF and hydrogenated for 8 hours at ambient temperature at a pressure of 20 psi with hydrogen and 3.0 g of Raney nickel as catalyst. Then the catalyst is filtered off, the solvent is eliminated, and the residue is purified through a silica gel column with a gradient of methylene chloride/methanol (33:1 to 9:1) as eluant. Yield: 3.66 g (59% of theory); Rf value: 0.50 (silica gel, methylene chloride/methanol=9:1); C14H21ClN2O; EII mass spectrum: m/z=269/271 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:26])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[C:19]([Cl:25])[CH:18]=1.I[CH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:26])[CH:16]([C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[C:19]([Cl:25])[CH:18]=1)[CH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: ICC1CCOCC1
Reactant: COC(=O)Cc1ccc(SC)c(Cl)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCOCC1)c1ccc(SC)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 60.4 %

Procedure:
A solution of diisopropylamine (0.33 mL, 2.38 mmol) in tetrahydrofuran (6 mL) cooled to −78° C. under an argon atmosphere was treated with a 2.5M solution of n-butyllithium in hexanes (0.95 mL, 2.38 mmol). The reaction mixture was stirred at −78° C. for 15 min, after which time, a solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid methyl ester (prepared as in Example 4, 500 mg, 2.17 mmol) in tetrahydrofuran (1 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.5 mL) was slowly added via a cannula. The greenish yellow solution was allowed to stir at −78° C. for 1 h, after which time, a solution of 4-iodomethyl-tetrahydro-pyran (588 mg, 2.60 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.5 mL) was added via a cannula. The reaction mixture was then allowed to warm to 25° C., where it was stirred for 16 h. The reaction mixture was then quenched by the addition of a saturated aqueous ammonium chloride solution (30 mL). This solution was extracted with ethyl acetate 3×20 mL). The combined organic layers were washed with a 10% aqueous sulfuric acid solution (2×50 mL) and a saturated aqueous sodium bicarbonate solution (2×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 75/25 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionic acid methyl ester (431 mg, 61%) as a yellow oil: EI-HRMS m/e calcd for C16H21ClO3S (M+) 328.0900. found 328.0898.