Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([OH:17])=[O:16])=[CH:12][CH:13]=2)[NH:8][C:7]=1[CH2:18][CH2:19][CH3:20])(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH2:21](O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.CN(C)C1C=CN=CC=1>[C:1]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([O:17][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:16])=[CH:12][CH:13]=2)[NH:8][C:7]=1[CH2:18][CH2:19][CH3:20])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: OCc1ccccc1
Reactant: CCCc1[nH]c2cc(C(=O)O)ccc2c1C(=O)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCc1[nH]c2cc(C(=O)OCc3ccccc3)ccc2c1C(=O)C(C)C
Temperature: 20 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-isobutyryl-2-propylindole-6-carboxylic acid (331 mg) in tetrahydrofuran (5 ml) were added benzylalcohol (1.25 ml), dicyclohexylcarbodiimide (303 mg) and 4-dimethylaminopyridine (20 mg) at 20° C. The reaction mixture was stirred at 20° C. for 8 hours. The precipitated urea was filtered off and the filtrate was evaporated in vacuo. The residue was extracted with ethyl acetate and the extract was washed with water two times and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:4) to give the crystals which were recrystallized from a mixture of ethyl acetate and hexane to give benzyl 3-isobutyryl-2-propylindole-6-carboxylate (215 mg) as colorless crystals.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:10]=[C:9]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[O:19]=[C:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][CH:30]=O)=[CH:28][C:23]=2[CH2:22][O:21]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][NH:2][C:3]1[CH:10]=[C:9]([CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][N:16]([CH2:30][CH2:29][C:27]3[CH:26]=[CH:25][C:24]4[C:20](=[O:19])[O:21][CH2:22][C:23]=4[CH:28]=3)[CH2:17][CH2:18]2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: CNc1cc(CCN2CCNCC2)ccc1C#N
Reactant: O=CCc1ccc2c(c1)COC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CNc1cc(CCN2CCN(CCc3ccc4c(c3)COC4=O)CC2)ccc1C#N

Procedure:
A solution of crude 2-(methylamino)-4-(2-piperazin-1-ylethyl)benzonitrile (˜18 mg, 0.05 mmol), (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (9 mg, 0.05 mmol) and NaBH(OAc)3 (100 mg, 0.47 mmol) in 10 mL of anhydrous DCM was stirred at ambient temperature overnight. The reaction mixture was added 50 mL of DCM and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified with prep-TLC to afford 2-(methylamino)-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile. 1H-NMR (400 MHz, CDCl3) δ 7.77 (d, J=7.8, 1H), 7.22˜7.32 (m, 3H), 6.42˜6.47 (m, 2H), 5.22 (s, 2H), 4.50˜4.58 (m, 1H), 2.84˜2.91 (m, 7H), 2.72˜2.77 (m, 2H), 2.53˜2.67 (m, 10H). (0.43 μM)
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@@H:2]([C:10]([NH:12][C@@H:13]([C:26]([O:28][CH3:29])=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=1)=[O:11])[C@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[H][H]>[Pd]>[NH2:1][C@@H:2]([C:10]([NH:12][C@@H:13]([C:26]([O:28][CH3:29])=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=1)=[O:11])[C@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: COC(=O)[C@@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@H](NC(=O)OCc1ccccc1)[C@H](C)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Product: COC(=O)[C@@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@H](N)[C@H](C)OC(C)(C)C
Reaction time: 4 h
Yield: 95 %

Procedure:
4.03 g of Z-D-Thr(tBu)-D-Tyr(tBu)-OMe (7.45 mmoles) were dissolved in 250 ml of CH30H. After addition of 850 mg of 10% Pd on activated charcoal (Fluka, cat. No 75990) a hydrogen stream was blown on the solution at room temperature under shaking for 4 h. The hydrogenation reaction was monitored by TLC. After removal of the catalyst by filtration and evaporation of the filtrate, 2.88 g (7.08 mmoles, yield 95%) of H-D-Thr(tBu)-D-Tyr(tBu)-OMe were obtained in the form of pure oil (TLC).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[C:17]3[CH:18]=[C:19]4[O:24][CH2:23][O:22][C:20]4=[CH:21][C:16]=3[CH2:15][C:14]([C:25](O)=[O:26])=[N:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[N-:28]1C=CN=C1.N.O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[C:17]3[CH:18]=[C:19]4[O:24][CH2:23][O:22][C:20]4=[CH:21][C:16]=3[CH2:15][C:14]([C:25]([NH2:28])=[O:26])=[N:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(C2=NN=C(C(=O)O)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Reactant: c1c[n-]cn1
Agent: N
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C2=NN=C(C(N)=O)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.9 %

Procedure:
4.17 g (10.0 millimoles) of 5-(3-methyl-4-nitro-phenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine-8-carboxylic acid-imidazolide are suspended in a mixture of 85 ml dichloro methane and 15 ml of a 15% aqueous methanolic ammonia solution. The reaction mixture is sealed and stirred at room temperature for 6 hours. The mixture is cooled with icecold water. The precipitated product is filtered and washed with 20 ml of diethyl ether. Thus 3.11 g of the desired compound are obtained, yield 85%, mp.: 266–268° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:10]1([N:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>O1CCCC1>[C:10]1([N:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: NN(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C(=NN(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 500 parts of tetrahydrofuran were dissolved 23.8 parts of 4- 5-(5H-dibenzo b,f!azepinyl)!benzaldehyde and 26.5 parts of N,N-diphenylhydrazine hydrochloride. This solution was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into 2,000 parts of water, and the crystals precipitated were taken out by filtration. The crystals obtained were washed with ethyl alcohol and then dried at reduced pressure. The crystals dried were dissolved in 100 parts of ethyl acetate, and this solution was poured into 1,000 parts of methyl alcohol to recrystallize the reaction product. Thus, 28.9 parts (yield, 77.9%) of 4- 5-(5H-dibenzo b,f!azepinyl)!benzaldehyde N,N-diphenylhydrazone was obtained. This compound had a melting point of 178.0° to 179.0° C. The results of elemental analysis are shown in Table 4 below, together with calculated values for C33H25N3.
Reaction SMILES: N[C:2]1O[N:5]=[C:4]([C:7]([CH3:10])(C)C)[CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][C:13]=1[C:21]([F:24])([F:23])[F:22].[CH2:25]([Cl:27])Cl>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:20])[NH:5][C:4]2[CH:7]=[CH:10][C:25]([Cl:27])=[C:2]([C:21]([F:24])([F:23])[F:22])[CH:3]=2)=[CH:14][C:13]=1[C:21]([F:22])([F:23])[F:24]
Reactant: ClCCl
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)(C)c1cc(N)on1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 85 °C
Reaction time: 72 h

Procedure:
To a solution of 5-amino-3-tert-butylisoxazole (0.100 g) in anh toluene (5 mL) was added 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.395 g). The reaction vessel was sealed, heated at 85° C. for 24 h, and cooled to room temp. The reaction mixture was added to a slurry of Dowex® 50WX2-100 resin (0.5 g) in CH2Cl2 (40 mL), and the resulting mixture was stirred vigorously for 72 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (gradient form 100% CH2Cl2 to 5% MeOH/95% CH2Cl2) to give bis(4-chloro-3-(trifluoromethyl)phenyl)urea followed by N-(3-tert-butyl-5-isoxazolyl)-N′-(4-chloro-3-(trifluoromethyl)phenyl)urea. The residue from the symmetrical urea fractions was triturated (Et2O/hexane) to give the urea as a white solid (0.110 g): TLC (3% MeOH/97% CH2Cl2) Rf 0.55; FAB-MS m/z 417 ((M+H)+). C. Urea Interconversions and Misc. Reactions C1. General Method for Alkylation of Hydroxyphenyl Ureas
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH:11]1[CH2:15][C@@H:14]([C:16]([OH:18])=O)[C@H:13]([CH2:19][O:20][CH3:21])[CH2:12]1)(=[O:10])=[O:9].[CH2:22]1[C:24]([NH2:27])([C:25]#[N:26])[CH2:23]1.Cl>>[C:25]([C:24]1([NH:27][C:16]([C@@H:14]2[CH2:15][CH:11]([S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:9])=[O:10])[CH2:12][C@H:13]2[CH2:19][O:20][CH3:21])=[O:18])[CH2:22][CH2:23]1)#[N:26]
Reactant: N#CC1(N)CC1
Reactant: COC[C@@H]1CC(S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)O
Agent: Cl
Product: COC[C@@H]1CC(S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
The title compound was synthesized in analogy to Example 68/69, Step 11, from (1R,2R)-4-(2-Chloro-benzenesulfonyl)-2-methoxymethyl-cyclopentanecarboxylic acid (epimeric mixture) and 1-amino-cyclopropyl cyanic hydrochloride to afford the desired product as a yellow foam. MS (EI): 397.0 (M+H)+.
Reaction SMILES: O1[C@H:11]2[C@:2]1([OH:17])[C:3]([CH3:16])([CH3:15])[O:4][C:5]1[C:10]2=[CH:9][CH:8]=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1.Cl([O-])(=O)(=O)=O.[Li+].[F:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30][NH2:31])=[CH:27][CH:26]=1.C(O)(=O)/C=C\C(O)=O>O1CCOCC1.C(OCC)(=O)C.C(O)C>[F:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30][NH:31][C@H:11]2[C:10]3[C:5](=[CH:6][C:7]([N+:12]([O-:14])=[O:13])=[CH:8][CH:9]=3)[O:4][C:3]([CH3:15])([CH3:16])[C@@H:2]2[OH:17])=[CH:27][CH:26]=1
Reactant: CC1(C)Oc2cc([N+](=O)[O-])ccc2[C@H]2O[C@]21O
Reactant: NCCc1ccc(F)cc1
Agent: O=C(O)/C=C\C(=O)O
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC1(C)Oc2cc([N+](=O)[O-])ccc2[C@H](NCCc2ccc(F)cc2)[C@H]1O
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 81 %

Procedure:
To a solution of (3R*,4R*)-3,4-epoxy-2,2-dimethyl-7-nitro-3-chromanol (2.07 g, 9.37 mmol) in dioxane (4 mL), lithium perchlorate (997 mg, 9.37 mmol) and 4-fluorophenethyl amine (1.47 mL, 11.3 mmol) were added, and the resulting solution was stirred at 70° C. for 3.5 hours under nitrogen atmosphere. The reaction solution was diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution. Then, the organic phase was dried over magnesium sulfate and concentrated under a reduced pressure. The resulting residue was diluted with ethanol, and a solution of maleic acid (1.20 g, 10.3 mmol) in ethanol was added dropwise thereto. The resulting solid was filtered off, and washed with ethyl acetate. The resulting solid was suspended in ethyl acetate, the resulting suspension was neutralized with 1 mol/L sodium hydroxide aqueous solution and washed with saturated sodium chloride solution. After drying the organic phase over magnesium sulfate, it was dried under a reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain (3R*,4S*)-4-{[2-(4-fluorophenyl)ethyl]amino}-2,2-dimethyl-7-nitro-3-chromanol (yield: 81%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=2)[CH2:7]1)[CH3:3].[H-].[Na+].Cl[CH2:20][C:21]1[O:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[CH:25]=1>CN(C=O)C.C1COCC1.O>[O:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[CH:25]=[C:21]1[CH2:20][O:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])[CH2:15][CH2:14]2
Reactant: CN(C)CCC1CCc2cc(O)ccc2C1
Reactant: ClCc1cc2ccccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCC1CCc2cc(OCc3cc4ccccc4o3)ccc2C1
Temperature: 50 °C
Reaction time: 1 h
Yield: 4.9 %

Procedure:
To a solution of (+)-2-[2-(N,N-dimethylamino)ethyl]-6-hydroxytetralin (0.217 g) in DMF (5 ml) was added sodium hydride (60% in oil, 0.052 g) at room temperature. The reaction mixture was stirred at 50° C. for one hr and cooled to 0° C. A solution of 2-chloromethylbenzofuran (0.187 g) in THF (5 ml) was added to the solution. The reaction mixture was stirred at 0° C. for one hr, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by alumina column chromatography (eluent:ethyl acetate:hexane=1:4) and recrystallized from ethyl acetate-hexane to obtain the titled compound (17 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:15])[CH2:13][CH3:14].[Br:17]N1C(C)(C)C(=O)N(Br)C1=O>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([CH2:10][Br:17])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:15])[CH2:13][CH3:14]
Reactant: CCC(=O)Nc1ccc(C)cc1C(=O)OC
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCC(=O)Nc1ccc(CBr)cc1C(=O)OC
Yield: 106.6 %

Procedure:
The radical bromination was performed as described by Patil et al. 1989: 5-Methyl-2-propionylamino-benzoic acid methyl ester (8.85 g, 40 mmol) and 1,3-dibromo-5,5-dimethyl hydantoin (DDH) (5,72 g, 20 mmol) in a mixture of CHCl3 (500 mL) and CCl4 (500 mL) was heated to reflux. Every 60 minutes 50 mg of dibenzoyl peroxide was added for six hours and then the reaction mixture was left at reflux over night. It was then allowed to reach room temperature and the solvents were removed by evaporation. Chromatography using silica gel 60 and heptane/ethyl acetate (18:2 ->17:3 ->16:4) as eluent afforded the pure title compound (6.40 g, 53%).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:49]([O:53][C:54]([N:56]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=[C:57]1[C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([NH2:71])[CH:66]=1)=[O:55])([CH3:52])([CH3:51])[CH3:50]>CN(C=O)C>[C:49]([O:53][C:54]([N:56]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=[C:57]1[C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([NH:71][C:22]([C:17]2[C:18](=[O:21])[O:19][C:20]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[OH:10])=[O:24])[CH:66]=1)=[O:55])([CH3:52])([CH3:50])[CH3:51]
Reactant: CC(C)(C)OC(=O)n1c(-c2cccc(N)c2)cc2ccccc21
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)n1c(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cc2ccccc21
Temperature: 25 °C
Yield: 62 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2-(3-Amino-phenyl)-indole-1-carboxylic acid tert-butyl ester (0.02 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.02 g of product in 64% yield: LCMS (ESI) m/z 497 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:4]=1)#[N:2].Cl>CO.[Pd]>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:4]=1
Reactant: CS(=O)(=O)Nc1cc(C#N)ccn1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)Nc1cc(CN)ccn1
Reaction time: 12 h
Yield: 98.1 %

Procedure:
N-(4-Cyano-pyridin-2-yl)-methanesulfonamide (0.15 g, 0.76 mmol) is dissolved in MeOH (4 mL) and concentrated HCl (2 mL) and is treated with Pd/C (10%, 150 mg). The mixture is stirred under H2 for 12 hours, filtered and concentrated in vacuo to afford N-(4-aminomethyl-pyridin-2-yl)-methanesulfonamide (0.15 g, 97%), which is used directly in the next step without further purification.
Reaction SMILES: [ClH:1].C(=[N:15][NH:16][C:17]1[CH:26]=[C:25]([F:27])[C:20]2[NH:21][C:22]([CH3:24])=[N:23][C:19]=2[CH:18]=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(O)C>[ClH:1].[ClH:1].[F:27][C:25]1[C:20]2[NH:21][C:22]([CH3:24])=[N:23][C:19]=2[CH:18]=[C:17]([NH:16][NH2:15])[CH:26]=1
Reactant: Cc1nc2cc(NN=C(c3ccccc3)c3ccccc3)cc(F)c2[nH]1
Agent: Cl
Solvent: CCO
Product: Cc1nc2cc(NN)cc(F)c2[nH]1
Temperature: 61.5 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
Concentrated hydrochloric acid (0.7 ml) was added to a mixture of the crude N-benzhydrylidene-N′-(7-fluoro-2-methyl-1H-benzimidazol-5-yl)-hydrazine (325 mg) and ethanol (0.7 ml). This was stirred at 59 to 64° C. for one hour, and the reaction mixture was cooled to room temperature. Then, the precipitated solid was collected by filtration and dried. Thus, 7-fluoro-2-methyl-1H-benzimidazol-5-yl-hydrazine dihydrochloride (90 mg, 80%) was obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.C([Sn](CCCC)(CCCC)[C:34]1[N:39]2[N:40]=[CH:41][N:42]=[C:38]2[CH:37]=[CH:36][CH:35]=1)CCC>C1COCC1.[Cu]I.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>[N:42]1[CH:41]=[N:40][N:39]2[C:34]([C:2]3[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]4[N:11]=[C:10]([CH2:12][N:13]5[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]5)[CH:9]=[CH:8][C:6]=4[N:7]=3)=[CH:35][CH:36]=[CH:37][C:38]=12
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc2ncnn12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(O)C1CCN(Cc2ccc3nc(-c4cccc5ncnn45)nc(N4CCOCC4)c3n2)CC1
Temperature: 140 °C

Procedure:
2-(1-((2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 (50 mg, 0.12 mmol) was dissolved in 2 mL of THF and treated with CuI (1.2 mg, 0.006 mmol) and 5-(tributylstannyl)-[1,2,4]triazolo[1,5-a]pyridine (65.4 mg, 0.16 mmol). The solution was sparged with bubbling nitrogen and tetrakis(triphenylphosphine)palladium (0) (7 mg, 0.006 mmol) was added. The mixture was heated in an Agilent microwave (140° C., 20 min). The solution was cooled to room temperature and concentrated. Purification by reverse phase HPLC gave 166 as a colorless solid. 1H NMR (400 MHz, DMSO) δ 8.52 (s, 1H), 8.21 (d, J=8.6 Hz, 1H), 7.99 (d, J=8.9 Hz, 1H), 7.91 (d, J=8.7 Hz, 1H), 7.84-7.74 (m, 1H), 7.65 (d, J=7.0 Hz, 1H), 4.51 (s, 4H), 4.03 (s, 1H), 3.83-3.77 (m, 4H), 3.75 (s, 2H), 2.93 (d, J=11.1 Hz, 2H), 2.00 (t, J=11.2 Hz, 2H), 1.67 (d, J=11.4 Hz, 2H), 1.24 (overlapping m, 3H), 1.04 (s, 6H). LCMS: 489.2
Reaction SMILES: [C:1]1(=[O:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:12]=[N+]=[N-].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O.O>[C:1]1(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:12]1
Reactant: O=C1CCCCCCCCC1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1CCCCCCCCCN1
Temperature: 0 °C
Reaction time: 1 h
Yield: 112.1 %

Procedure:
Cyclodecanone (n=6) (1.0 g) in 10 mL concentrated sulfuric acid was cooled to 0° C. and 0.54 g of sodium azide was added. The reaction continued to stir at 0° C. for 1 h and warmed to room temperature where it was stirred for two h. The solution was diluted with cold water and treated with cold 10% NaOH solution until pH=9. Extraction with ether (2×), drying over magnesium sulfate and evaporation of solvent provided 1.23 g of 2-azacycloundecanone.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8]1[N:14]([CH3:26])[C:15](=[O:25])[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)=[CH:17][C:7]2=1)(=[O:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)C>>[Br:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]2[C:15](=[O:25])[N:14]([CH3:26])[C:8]3[N:9]([CH3:13])[C:10]4[C:6]([C:7]=3[CH:17]=2)=[CH:5][C:4]([C:1](=[O:3])[CH2:2][C:30](=[O:29])[CH2:31][O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)=[CH:12][CH:11]=4)=[CH:23][CH:22]=1
Reactant: CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Br)cc3)c(=O)n(C)c1n2C
Reactant: CCOC(=O)COC1CCCCO1
Product: Cn1c(=O)c(-c2ccc(Br)cc2)cc2c3cc(C(=O)CC(=O)COC4CCCCO4)ccc3n(C)c21

Procedure:
The process is carried out as in Example 80 above, with the compound from Example 60B above, 6-acetyl-3-(4-bromophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and (tetrahydropyran-2-yloxy)acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:11]1[CH:19]2[N:14]([CH2:15][CH2:16][C:17](=O)[CH2:18]2)[CH2:13][CH2:12]1>CC(=O)OCC>[CH2:11]1[CH:19]2[N:14]([CH2:15][CH:16]=[C:17]([C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[NH:7][CH:6]=3)[CH2:18]2)[CH2:13][CH2:12]1
Reactant: O=C1CCN2CCCC2C1
Reactant: Clc1ccc2[nH]ccc2c1
Solvent: CCOC(C)=O
Product: Clc1ccc2[nH]cc(C3=CCN4CCCC4C3)c2c1

Procedure:
5-Chloro-1H-indole (1.00 g, 6.63 mmol) and 7-octahydroindolizinone (1.39 g, 9.95 mmol) were converted to product by the procedure of Preparation 4 to give 595 mg. (33.1%). EA calculated for C16H17N2Cl: C, 70.45; H, 6.28; N, 10.27. Found: C, 70.60; H, 6.46; N, 10.28.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([CH3:18])[CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:3][CH:2]=1>C(O)(=O)C.[Pt]=O>[NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]([CH3:18])[CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH2:3][CH2:2]1
Reactant: CC(Cc1c[nH]c2ccccc12)c1ccncc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC(Cc1c[nH]c2ccccc12)C1CCNCC1
Yield: 30.5 %

Procedure:
0.8 g of 3-[2-(4-pyridyl)-2-methyl-ethyl]-indole were hydrogenated at atmospheric pressure for a period of 15 hours at 60° C. in 20 ml acetic acid in the presence of 0.4 g platinum oxide. The catalyst was eliminated by filtration and the filtrate evaporated. The residue was purified by chromatography over silica (eluant: ethanol-diethylamine: 9-1). 0.25 g 3-[2-(4-piperidyl)-2-methyl-ethyl]-indole were obtained which were converted into the hydrochloride in ethanol. 0.15 g 3-[2-(4-piperidyl)-2-methyl-ethyl]-indole hydrochloride were obtained, which melted at 210° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[ClH:1].[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:5]1[N:6]([CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:7]2[C:3]([N:4]=1)=[C:2]([N:29]1[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]1)[N:10]=[CH:9][N:8]=2
Reactant: Clc1ccccc1-c1nc2c(Cl)ncnc2n1CC1CCOCC1
Reactant: CN1CCNCC1
Product: CN1CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3CC2CCOCC2)CC1
Product: Cl

Procedure:
Displace 6-Chloro-8-(2-chloro-phenyl)-9-(tetrahydro-pyran-4-ylmethyl)-9H-purine with N-methylpiperazine and prepare hydrochloride salt using the same procedure as example 1 to give the title compound. MS (m/z): 427 (M+1)