Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([O:14]CC)(=[O:13])[CH3:12].[O:17]=[C:18]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]1>>[C:25]([O:24][C:22]([N:20]1[CH2:21][C:18]([CH2:12][C:11]([OH:14])=[O:13])([OH:17])[CH2:19]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CC(C)(C)OC(=O)N1CC(O)(CC(=O)O)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 15.9 %

Procedure:
LHMDS (6.43 mL of 1N solution in THF) was cooled to −78° C. Ethyl acetate (0.63 mL, 6.43 mmol) was added and the reaction mixture was stirred for 10 minutes. tert-Butyl 3-oxoazetidine-1-carboxylate (1 g, 5.84 mmol) was added to the mixture and the reaction was stirred for 15 minutes. The reaction mixture was warmed to 0° C. and was then quenched with water (25 mL). The reaction mixture was extracted with ether. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The remaining oil was dissolved in MeOH (25 mL) and 1N NaOH (15 mL) was added and the mixture was stirred at room temperature overnight. This was concentrated in vacuo to remove MeOH and then to the remaining aqueous solution was added 1N HCl (100 mL). This mixture was extracted with CH2Cl2 (100 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to afford the title intermediate (215 mg) as an oil.
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[S-:15][C:16]#[N:17].[Na+]>O1CCCC1>[C:11]([N:3]1[CH:4]=[CH:5][N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[SiH:2]1[N:17]=[C:16]=[S:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: N#C[S-]
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1N=C=S
Temperature: 25 °C
Reaction time: 14 h
Yield: 90 %

Procedure:
In an argon atmosphere, 6.10 g (26.2 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 20 mL of tetrahydrofuran and after adding 2.15 g (purity: 99%, 26.3 mmol) of sodium thiocyanate, the mixture was stirred at room temperature for 14 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 108° C./3.3×102 Pa) to obtain 1,3-di-tert-butyl-2-thioisocyanato-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)NCS) as a pale yellow liquid (yielded amount: 6.05 g, yield: 90%).
Reaction SMILES: C([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH3:18])[N:14]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:13]=2[CH:12]=[C:11]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[CH:10]=1)C1C=CC=CC=1>[Pd].O1CCCC1>[OH:8][C:9]1[C:17]2[N:16]=[C:15]([CH3:18])[N:14]([S:19]([C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)(=[O:21])=[O:20])[C:13]=2[CH:12]=[C:11]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(C)nc3c(OCc4ccccc4)cc(C(=O)N(C)C)cc32)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(C)nc3c(O)cc(C(=O)N(C)C)cc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.4 %

Procedure:
A mixture of 4-(benzyloxy)-N,N,2-trimethyl-1-[(4-methylphenyl)sulfonyl]-1H-benzimidazole-6-carboxamide (29.0 g, 62.6 mmol, Step 3) and 10% palladium on carbon (6.0 g) in tetrahydrofuran (200 mL) was stirred under hydrogen gas (1 atm) at room temperature for 24 hours. Another 4.0 g of 10% palladium on carbon was added, and the mixture was stirred under hydrogen gas (1 atm) at room temperature for additional 6 hours. The resulted mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to afford the title compound as a white solid (23.0 g, 98%).
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:6]=2[C:5]1=[O:16])[CH:2]=[CH2:3].[N:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]OS(C1C(C)=CC=CC=1)(=O)=O)=[N+:18]=[N-:19].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH2:1]([N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[CH:12][C:13]([O:15][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][N:17]=[N+:18]=[N-:19])=[CH:14][C:6]=2[C:5]1=[O:16])[CH:2]=[CH2:3]
Reactant: C=CCN1CCCc2ccc(O)cc2C1=O
Reactant: Cc1ccccc1S(=O)(=O)OCCCCCCCCN=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCN1CCCc2ccc(OCCCCCCCCN=[N+]=[N-])cc2C1=O
Temperature: 65 °C
Yield: 50.7 %

Procedure:
A suspension of 2-allyl-8-hydroxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one (1.0 g, 0.0049 mol), 8-azido-1-(toluenesulfonyloxy)octane (1.50 g, 0.0049 mol) and K2CO3 in N,N-dimethylformamide (20mL) was stirred vigorously under argon, and heated at 65° C. for 18 hours. The solution was then partitioned between ethyl acetate and brine, and the combined organic layers were washed with water, dried (K2CO3), filtered, and concentrated in vacuo. The residue was purified by chromatography over silica gel to yield 920 mg (51%) of 2-allyl-8-(8-azidooctyloxy)-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one as a colorless oil; 1H NMR(CDCl3) d7.47(s, 1H), 6.95(d, J=6 Hz, 1H), 6.84(dd, J=3, 6 Hz, 1H), 5.89(m, 1H), 5.22(m, complex, 2H), 4.20(d, J=6 Hz, 2H), 3.95(t, J=6 Hz, 2H), 3.22(t, J=6 Hz, 2H), 3.18(t, J=6 Hz, 2H), 2.66(t, J=6 Hz, 2H), 1.90(t, J=6 Hz, 2H), 1.79(t, J=6 Hz, 2H), 1.60(m, 4H), 1.35(m, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH:5]([CH:8]=O)[CH2:4][CH2:3]1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH:5]([CH2:8][NH:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][CH2:3]1
Reactant: NCc1ccccc1
Reactant: CC1(C)CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC1(C)CCC(CNCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4,4-dimethylcyclohexanecarbaldehyde (6.6 g, 0.047 mol), benzylamine (5.0 g, 0.047 mol) and acetic acid (1 mL) in methanol (60 mL) was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (10.0 g, 0.047 mol) was added in one portion and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated in vacuo and partitioned between dichloromethane and water. The organic phase was washed with brine, silica gel was added and the mixture was concentrated in vacuo. The residue was purified by flash chromatography (CH2Cl2/MeOH), affording [(4,4-dimethyl cyclohexyl)methyl](phenylmethyl)amine as a white solid. (M+H) 232, 1.76 min. (LC/MS method B).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([F:26])=[C:16]([C@@:18]4([CH3:25])[NH:23][C:22](=O)[CH2:21][O:20][CH2:19]4)[CH:17]=3)[CH2:7][CH2:8][C:9]=2[CH:10]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([F:26])=[C:16]([C@@:18]4([CH3:25])[NH:23][C:22](=[S:36])[CH2:21][O:20][CH2:19]4)[CH:17]=3)[CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C[C@@]1(c2cc(NC3CCc4cc(Cl)cnc43)ccc2F)COCC(=O)N1
Solvent: C1COCCO1
Product: C[C@@]1(c2cc(NC3CCc4cc(Cl)cnc43)ccc2F)COCC(=S)N1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A solution of (R)-5-[5-((RS)-3-chloro-6,7-dihydro-5H-[1]pyrindin-7-ylamino)-2-fluoro-phenyl]-5-methyl-morpholin-3-one (76 mg, 0.2 mmol) in dioxane (3 ml) was treated with Lawesson's reagent (53.2 mg, 0.13 mmol). The reaction mixture was stirred at 80° C. for 3 hours. For the workup, the mixture was quenched with a saturated aqueous solution of sodium hydrogen carbonate, thereafter extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate, then evaporated at reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 45:55 as the eluent. The (R)-5-[5-((RS)-3-chloro-6,7-dihydro-5H-[1]pyrindin-7-ylamino)-2-fluoro-phenyl]-5-methyl-morpholin-3-thione was obtained as a white solid (58 mg, 73%); (calculated) C19H19ClFN3OS [391.90]; (found) [M+H]+=392, [M+2+H]+=394.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([CH2:10][N:11](C(OC(C)(C)C)=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:7]=[CH:6][C:5]=1[N+:26]([O-:28])=[O:27].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH:7]=[CH:6][C:5]=1[N+:26]([O-:28])=[O:27]
Reactant: COC(=O)c1cc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(CNC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred brown solution of 5-(di-tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid methyl ester (74.18 g, 180.7 mmol) in methylene chloride (700 mL) was added trifluoroacetic acid (26.2 mL, 352.4 mmol), and the mixture was stirred at room temp overnight. Sat. sodium bicarbonate (400 mL) was added to the solution, and the mixture was stirred for 10 minutes. The organic layer was separated, dried over magnesium sulfate, and evaporated to give 5-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid methyl ester as a brown oil (52.5 g, 94% crude yield). The product was used in the next step without further purification.
Reaction SMILES: CO[C:3]1[CH:31]=CC(CS[C@@H]2CN(C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C@H](C(O)=O)C2)=C[CH:4]=1.FC(F)(F)C(O)=O.[N+](C1C=CC(COC(N=C(NC(OCC2C=CC([N+]([O-])=O)=CC=2)=O)N[C@@H:53](C)[C:54]([NH:56][C@H:57]2[CH2:61]CN[CH2:58]2)=O)=O)=CC=1)([O-])=O>C(#N)C>[CH:3]([N:56]([CH2:54][CH3:53])[CH:57]([CH3:58])[CH3:61])([CH3:31])[CH3:4]
Reactant: C[C@H](NC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)N[C@H]1CCNC1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-4-(4-methoxybenzyl)thio-1-(4-nitrobenzyloxycarbonyl)-L-proline (1.13 g) in anhydrous acetonitrile (10 ml), N,N'-carbonyldiimidazole (430 mg) was added, followed by stirring at room temperature for one hour. To the reaction mixture, N,N-diisopropylethylamine (0.42 ml) and the compound (2.26 g), which had been obtained in (2), in anhydrous tetraydrofuran (15 ml) were added. The reaction mixture was then treated in a similar manner to that described in Referential Example 16-(3), whereby the title compound (2.06 g) was obtained as an amorphous substance.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH2:23][CH3:24])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O.O>CN(C=O)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:21][S:22][CH2:23][CH3:24])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[CH:26][CH:27]=1
Reactant: [C-]#N
Reactant: CCSCc1cccc2c(C(CCOS(C)(=O)=O)c3ccc(Cl)cc3)c[nH]c12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSCc1cccc2c(C(CCC#N)c3ccc(Cl)cc3)c[nH]c12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
152 mg (2.33 mmol) of potassium cyanide were added to 510 mg (1.16 mmol) of the compound from Example 53A in 7 ml of DMF. The mixture was stirred at 80° C. for 2 h and, after cooling, water was added, the mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid). 222 mg (52% of theory) of the target compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:18]([F:21])([F:20])[F:19])=[C:15]([CH:17]=3)[NH2:16])[N:10]=2)[CH:7]=1.C(#N)C.[CH3:25][C:26]([CH3:31])([CH3:30])[C:27](Cl)=[O:28]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:18]([F:21])([F:20])[F:19])=[C:15]([NH:16][C:27](=[O:28])[C:26]([CH3:31])([CH3:30])[CH3:25])[CH:17]=3)[N:10]=2)[CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cc(-c2cn3cc(Br)ccc3n2)ccc1C(F)(F)F
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(C)C(=O)Nc1cc(-c2cn3cc(Br)ccc3n2)ccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 37 %

Procedure:
A 20 mL vial is charged with 5-(6-bromoimidazo[1,2-a]pyridin-2-yl)-2-(trifluoromethyl)aniline (0.463 g, 0.0013 mol), acetonitrile (7 mL) and pyridine (0.210 mL). The mixture is added trimethylacetyl chloride (0.320 mL, 2.6 mmol) and stirred for 20 min at 80° C. The solution is concentrated, taken into EtOAc (10 mL) and washed once with HCl (10 mL, 1M) and NaOH (10 mL, 1M). Organics are dried, concentrated, and purified on silica (0-100% EtOAc in Hexanes) to give the title compound (212 mg, 37% yield). LCMS m/z=440.4 [M+H]+, tR=2.67 min.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1([CH3:17])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28](F)=[N:27][CH:26]=1)([CH3:22])([CH3:21])[CH3:20]>O1CCOCC1>[C:19]([O:23][C:24]([C:25]1[CH:30]=[CH:29][C:28]([N:14]2[CH2:15][CH2:16][C:11]([NH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:18])([CH3:17])[CH2:12][CH2:13]2)=[N:27][CH:26]=1)=[O:32])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC1(NC(=O)OCc2ccccc2)CCNCC1
Reactant: CC(C)(C)OC(=O)c1ccc(F)nc1
Solvent: C1COCCO1
Product: CC1(NC(=O)OCc2ccccc2)CCN(c2ccc(C(=O)OC(C)(C)C)cn2)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester (0.31 g, 1.28 mmol, Example 30B) in dioxane (5.0 mL) at room temperature was added 6-fluoro-nicotinic acid tert-butyl ester (0.21 g, 1.07 mmol). The reaction mixture was stirred at 80° C. for 18 hours, concentrated under reduced pressure and purified by flash chromatography with 10% to 30% ethyl acetate in hexane to provide 4-benzyloxycarbonylamino-4-methyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-5′-carboxylic acid tert-butyl ester. MS (CT) m/z 426 (M+1)+; 1H NMR (300 MHz, CDCl3) δ ppm 8.74 (d, 1H), 7.97 (dd, 1H), 7.35 (m, 5H), 7.26 (s, 1H), 5.07 (s, 2H), 4.68 (s, 1H), 3.97 (m, 2H), 3.37 (m, 2H), 2.08 (m, 2H), 1.66 (m, 2H), 1.56 (s, 9H), 1.42 (s, 3H).
Reaction SMILES: [OH:1][CH:2]([CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[C:3]#[N:4].[CH3:21]I.[H-].[Na+]>CN(C=O)C.O>[CH3:21][O:1][CH:2]([CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[C:3]#[N:4]
Reactant: COc1ccccc1OC(c1ccccc1)C(O)C#N
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1OC(c1ccccc1)C(C#N)OC
Yield: 68.9 %

Procedure:
2.69 g of 2-hydroxy-3-phenyl-3-(2-methoxy-phenoxy)-propionitrile dissolved in 25 ml of anhydrous DMF and 7.1 g of methyl iodide were stirred at 0° C. Addition was made, in portions, of 2.18 g of 55% NaH. After the addition, the whole was stirred at 0°-5° C. for 1 and a half hours. Under an atmosphere of nitrogen the whole was then decomposed cautiously with water, diluted with plentiful water, extracted with ethyl acetate and washed with water. The organic phase was dried over Na2SO4 and evaporated to dryness, in this way obtaining 1.95 g of 2-methoxy-3-phenyl-3-(2-methoxy-phenoxy)-propionitrile as an oil. Yield=69%.
Reaction SMILES: [CH:1]1([CH2:7][S:8][C:9]2[CH:22]=[CH:21][C:12]3[NH:13][C:14]([NH:16][C:17](=[O:20])[O:18][CH3:19])=[N:15][C:11]=3[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26]CO.O>C1(C)C=CC=CC=1>[CH:5]1[CH2:4][CH2:3][CH2:2][CH:1]([CH2:7][S:8][C:9]2[CH:22]=[CH:21][C:12]3[NH:13][C:14]([NH:16][C:17](=[O:20])[O:18][CH2:19][CH2:26][CH2:25][N:24]([CH3:29])[CH3:23])=[N:15][C:11]=3[CH:10]=2)[CH:6]=1
Reactant: CN(C)CCCO
Reactant: COC(=O)Nc1nc2cc(SCC3CCCCC3)ccc2[nH]1
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)CCCOC(=O)Nc1nc2cc(SCC3C=CCCC3)ccc2[nH]1

Procedure:
A mixture of 0.01 mole of the methyl ester of Example 4 and 0.02 mole of 3-dimethylamino-1-propanol is refluxed in 20 ml of toluene until all the H2O present has been azeotroped off. The heating mantle is removed and 0.25 g of aluminum isopropoxide is added. The mixture is then refluxed overnight. After cooling the solid present is filtered off, washed with water and crystallized.
Reaction SMILES: N[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([O:22][CH2:23][CH3:24])[N:3]=1.N(OCCC(C)C)=O.[ClH:33]>C(#N)C.[Cu](Cl)Cl>[Cl:33][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([O:22][CH2:23][CH3:24])[N:3]=1
Reactant: Cl
Reactant: CCOc1nc(N)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: CCOc1nc(Cl)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Temperature: 60 °C
Reaction time: 3 h

Procedure:
14.8 g (45.631 mmol) of 2-amino-6-ethoxy-4-[4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrile are initially charged in 830 ml of acetonitrile, 32.07 g (273.785 mmol) of isoamyl nitrite and 36.81 g (273.785 mmol) of copper(II) chloride are added and the mixture is stirred at 60° C. for 3 hours. 800 ml of 1N hydrochloric acid are added, and the reaction mixture is extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated. The residue is triturated with ethanol, and the solid is filtered off, washed with ethanol and dried under high vacuum. As the mother liquor still contains product, it is adsorbed onto 35 g of silica gel and purified on a silica gel column (mobile phase: cyclohexane/ethyl acetate 2:1→1:1). This gives a total of 11.9 g (72% of theory) of the target compound.
Reaction SMILES: [C:1]1([NH:7][N:8]=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2F)[N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].O>O1CCCC1>[C:1]1([N:7]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN1CCN(C(=NNc2ccccc2)c2ccccc2F)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(c2nn(-c3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
To a stirred solution, under nitrogen of 12.4 g of 1-[(phenylhydrazono)(2-fluorophenyl)methyl]-4-methylpiperazine in 100 ml of a solution of tetrahydrofuran was added dropwise, 5.3 g of potassium t-butoxide in 50 ml of tetrahydrofuran. Following the addition, the reaction mixture was stirred at ambient temperature for 1 hour, poured into water, and extracted with dichloromethane. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated to an oil. The oil was purified on a Water's Model 500 Preparative High Pressure Liquid Chromatograph utilizing two silica gel columns and dichloromethane/methanol (4%) as the eluent. Concentration of the appropriate fractions gave 7.0 g (61%) of 1-phenyl-3-(4-methyl-1-piperazinyl)-1H indazole. Treatment of 3.1 g of the indazole with ethereal hydrogen chloride produced the hydrochloride salt. Recrystallization from ethanol gave 2.8 g of 1-phenyl-3-(4-methyl-1-piperazinyl)-1H-indazole hydrochloride, mp 244°-246°.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH2:20][CH3:21])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:22]>CO>[NH2:22][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH2:20][CH3:21])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N
Reactant: CC[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(Cl)ncnc21
Solvent: CO
Product: CC[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(N)ncnc21
Temperature: 75 °C
Reaction time: 72 h

Procedure:
To the compound from Step C (50 mg, 0.16 mmol) was added saturated ammonia in methanol (4 mL). The mixture was stirred at 75° C. for 72 h in a closed container, cooled and evaporated in vacuo. The crude mixture was purified on silica gel using methanol/dichloromethane (1:9) as eluent. Fractions containing the product were pooled and evaporated in vacuo to give the desired product (29 mg) as a colorless powder.
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[C:18]([CH2:21]O)[CH:19]=[CH:20][C:13]=3[S:12][C:11]=2[CH:23]=1)#[N:6]>CCOCC>[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[C:18]([CH2:21][Br:2])[CH:19]=[CH:20][C:13]=3[S:12][C:11]=2[CH:23]=1)#[N:6]
Reactant: N#Cc1ccc2c(c1)Sc1ccc(CO)cc1CC2
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: N#Cc1ccc2c(c1)Sc1ccc(CBr)cc1CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Phosphorous tribromide (0.2 ml) was added to a suspension of 3-cyano-8-hydroxymethyl-10,11-dihydrodibenzo[b,f]thiepin (500 mg; 1.87 mmole) in ether (7 ml). The reaction mixture was stirred at room temperature for one hour, then poured onto ice, extracted with ether (3×50 ml), dried over Na2SO4 and evaporated to afford 581 mg (95%) of 3-cyano-8-bromomethyl-10,11-dihydrodibenzo[b,f]thiepin as an oil.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@@H:7]([C:18]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[O:19])[CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][C:38]([N:41]=[C:42]=[O:43])=[CH:37][CH:36]=1>ClCCl>[CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@@H:7]([C:18]([N:20]3[CH2:21][CH2:22][N:23]([C:42]([NH:41][C:38]4[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:44])[F:45])=[CH:40][CH:39]=4)=[O:43])[CH2:24][CH2:25]3)=[O:19])[CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCC2)C[C@@H]1C(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C2CCC2)C[C@@H]1C(=O)N1CCN(C(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Reaction time: 8 h

Procedure:
tert-Butyl (2R)-4-cyclobutyl-2-(piperazin-1-ylcarbonyl)piperazine-1-carboxylate (350 mg) was stirred at room temperature in dichloromethane (15 ml). Triethylamine (0.14 ml) was added followed by 4-(trifluoromethyl)phenyl isocyanate (0.14 ml) and the solution stirred overnight. The solvent was removed in vacuo and the residue adsorbed onto silica for purification by chromatography eluting with 0-7.5% methanol/dichloromethane. This gave tert-butyl (2R)-4-cyclobutyl-2-{[4-({[4-(trifluoromethyl)phenyl]amino}carbonyl)piperazin-1-yl]carbonyl}piperazine-1-carboxylate as a white glass (370 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:23][CH2:22][N:12]2[C:13]3[C:18]([NH:19][C:20](=[O:21])[CH:11]2[CH2:10]1)=[CH:17][CH:16]=[CH:15][CH:14]=3.O.Cl.[H][H]>O=[Pt]=O.C(O)C>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][N:9]1[CH2:23][CH2:22][N:12]2[C:13]3[C:18]([NH:19][C:20](=[O:21])[CH:11]2[CH2:10]1)=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: O=C1Nc2ccccc2N2CCN(CCc3ccccn3)CC12
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C1Nc2ccccc2N2CCN(CCC3CCCCN3)CC12

Procedure:
A solution of 2,3,4,4a-tetrahydro-3-[2-(2-pyridinyl)-ethyl]-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one in 120 ml. water and 60 ml. ethanol containing 14 ml. conc. hydrochloric acid, was shaken with 1.2 g. of PtO2 under 45 psi. hydrogen pressure. Solution was filtered, concentrated under vacuum, and residue crystallized once from ethanol and then from methanol. After filtration and drying the dihydrochloride salt of the title compound had a m.p. of 268°-271° C. (dec.); yield: 3.5 g.