Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][S:6][C:7]1[N:12]=[C:11]([OH:13])[CH:10]=[C:9]([NH:14][C@H:15]([CH3:18])[CH2:16][OH:17])[N:8]=1.N1C=CC=CC=1.[S-:28][C:29]#[N:30].[K+].BrBr>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][S:6][C:7]1[N:12]=[C:11]([OH:13])[C:10]([S:28][C:29]#[N:30])=[C:9]([NH:14][C@H:15]([CH3:18])[CH2:16][OH:17])[N:8]=1
Reactant: N#C[S-]
Reactant: C[C@H](CO)Nc1cc(O)nc(SCc2cccc(Cl)c2)n1
Agent: BrBr
Agent: [K+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C[C@H](CO)Nc1nc(SCc2cccc(Cl)c2)nc(O)c1SC#N
Temperature: 0 °C

Procedure:
The product of Example 3 (0.5 g), pyridine (0.21 ml) and potassium thiocyanate (0.6 g) were dissolved in DMF (10 ml) and cooled to 0° C. Bromine (74 μl) was added before the cooling bath was removed and the reaction mixture allowed to warm to room temperature. After 1 h water (50 ml) was added and the mixture extracted with EtOAc (3×30 ml). The combined extracts were dried (MgSO4), filtered, evaporated and purified by silica gel chromatography (10% methanol/DCM) to yield the title product as a white solid. Yield 0.3 g.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[I-].C[N+]1C=CN([C:19](=[O:28])[N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)C=1.C(N(CC)CC)C>C(#N)C>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=[CH:11][C:2]=1[O:1][C:19](=[O:28])[N:20]([CH3:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1cnc2ccccc2n1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C(=O)Oc1cnc2ccccc2n1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.6 %

Procedure:
A mixture of 2-hydroxyquinoxaline (0.44 g, 3.00 mmol) ), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 9, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours followed by heating at 40° C. for 24 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (30:70)) yielding the title compound (0.65 g, 77% yield) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][C:16]=2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:16]2[CH2:17][CH2:18][C:19]([CH3:21])([CH3:22])[CH2:20][C:15]=2[CH2:14][N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:24][CH:25]=1
Reactant: CC1(C)CCC(c2ccc(Cl)cc2)=C(CN2CCN(C(=O)OC(C)(C)C)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CCC(c2ccc(Cl)cc2)=C(CN2CCNCC2)C1
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of 4-[2-(4-chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazine-1-carboxylic acid tert-butyl ester (1.0 g, 2.39 mmol) in dichloromethane (20 ml) was added TFA (5 ml). The reaction was stirred for 1 h and then concentrated under reduced pressure. A saturated solution of NaHCO3 was added to adjust the pH to ˜8-9 and the mixture was extracted with dichloromethane (×2). The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to give 1-[2-(4-chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazine (0.76 g, 100%). HPLC-MS 319, 321 [M+1]+.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][C:6]1[N:11]=[C:10]([C:12](Cl)=[O:13])[CH:9]=[CH:8][CH:7]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1.Cl>>[Cl:5][C:6]1[N:11]=[C:10]([C:12](=[O:13])[C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][C:18]=2[Cl:22])[CH:9]=[CH:8][CH:7]=1
Reactant: Clc1cccc(Cl)c1
Reactant: O=C(Cl)c1cccc(Cl)n1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1cccc(Cl)n1)c1ccc(Cl)cc1Cl
Reaction time: 8 h

Procedure:
40.9 g AlCl3 is added in portions to a mixture of 26.4 g 6-chloro-2-pyridinecarboxylic acid chloride and 112 g 1,3-dichlorobenzene. The mixture is slowly heated until 130°-40° C. After standing overnight, it is added to a mixture of diluted HCl and crushed ice, basified and extracted with ethyl ether. The ethereal extracts are washed with water, dried and solvent evaporated (water pump). The residual deep green oil is crystallised from ethanol: water in the presence of decolorizing carbon. Yield: 10 g title compound, m.p. 103°-4° C.; UV (ethanol): λmax. 281 nm; ε: 14,500; Cl 37.02 (37.12).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([OH:6])[CH3:5].[CH2:7]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C1(C)C=CC=CC=1>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][CH:4]([O:6][C:25](=[O:26])[C:24]1[CH:23]=[CH:22][C:21]([C:18]2[CH:19]=[CH:20][C:15]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:16][CH:17]=2)=[CH:29][CH:28]=1)[CH3:5]
Reactant: CCCCCCCCc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Reactant: COCC(C)O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCc1ccc(-c2ccc(C(=O)OC(C)COC)cc2)cc1

Procedure:
0.8 g of 1-methoxy-2-propanol, 3.2 g of p-(p-n-octylphenyl)-benzoic acid chloride 20 ml of toluene and 2.1 ml of pyridine are boiled under reflux for 6 hours. The pyridinium chloride is filtered off hot with suction and the filtrate is worked up in the customary manner. Optically active 1-methoxy-2-[p-(p-n-octylphenyl)-benzoyloxy]-propane is obtained
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].O.[O:7]=[C:8]1[C:17](=[O:18])[NH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([S:19](Cl)(=[O:21])=[O:20])[CH:14]=2)[NH:9]1>>[CH2:1]([NH:5][S:19]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:7])[C:17](=[O:18])[NH:16]2)(=[O:20])=[O:21])[CH2:2][CH2:3][CH3:4]
Reactant: O=c1[nH]c2ccc(S(=O)(=O)Cl)cc2[nH]c1=O
Reactant: CCCCN
Solvent: O
Product: CCCCNS(=O)(=O)c1ccc2[nH]c(=O)c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
To a solution of 7.31 g (0.1 mole) of n-butylamine in 20 ml of water 5.21 g (0.02 mole) of 1,2,3,4-tetrahydro-2,3-dioxo-6-quinoxalinesulfonyl chloride are added, and the mixture is stirred at room temperature for 5 hours. Then it is allowed to stand for 16 hours, the separated crystals are filtered off, washed with water, dried and recrystallized from acetone. Thus 4.50 g (76%) of N-(n-butyl)-1,2,3,4-tetrahydro-2,3-dioxo-6-quinoxaline sulfonamide are obtained, m.p.: 257-262° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([Cl:18])=[C:9]([S:11]([NH:14][CH:15]2[CH2:17][CH2:16]2)(=[O:13])=[O:12])[CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([Cl:18])=[C:9]([S:11]([NH:14][CH:15]2[CH2:17][CH2:16]2)(=[O:13])=[O:12])[CH:10]=1
Reactant: [N-]=[N+]=NCc1ccc(Cl)c(S(=O)(=O)NC2CC2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(Cl)c(S(=O)(=O)NC2CC2)c1
Temperature: 25 °C

Procedure:
A round bottom flask was charged with 5-(azidomethyl)-2-chloro-N-cyclopropylbenzenesulfonamide (1.40 g, 4.87 mmol), THF (40 mL), triphenylphosphine (1.6 g, 6.43 mmol) and water (0.11 mL, 6.43 mmol) at 0° C. and the reaction was stirred at room temperature over night. The solvents were removed and the residue was dissolved in MTBE and 20% HCl in dioxane was added dropwise at 0° C. The resulting salt was collected and washed with EtOAc. The salt was then neutralized with 6N NaOH and extracted with CH2Cl2. The combined organic phases were concentrated under reduced pressure to get the title product as a very thick oil. 1H NMR (400 MHz, DMSO-d6): 8.00 (s, 1H), 7.58 (s, 2H), 3.78 (s, 2H), 2.18 (m, 1H), 0.50-0.35 (m, 4H).
Reaction SMILES: CS[C:3]1[S:4][C:5]([C:9]#[N:10])=[C:6]([NH2:8])[N:7]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>CS(C)=O>[N:11]1([C:3]2[S:4][C:5]([C:9]#[N:10])=[C:6]([NH2:8])[N:7]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CSc1nc(N)c(C#N)s1
Reactant: C1CCNC1
Solvent: CS(C)=O
Product: N#Cc1sc(N2CCCC2)nc1N
Temperature: 60 °C
Yield: 91 %

Procedure:
40 parts of 2-methylmercapto-4-amino-5-cyanothiazole are dissolved in 200 parts of dimethylsulfoxide and 45 parts of pyrrolidine are added. The mixture is heated for 6 hours at 60° C. and the product is filtered off. 41.5 parts of 2-pyrrolidino-4-amino-5-cyano-thiazole (91% of theory) of melting point 305°-308° C. are obtained.
Reaction SMILES: [ClH:1].[C:2]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:7][CH2:6]1)(O)=[O:3].S(Cl)([Cl:32])=O>CCOCC>[ClH:32].[Cl:1][C:2]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:7][CH2:6]1)=[O:3]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CCN(CCCCOc2ccccc2CCc2ccccc2)CC1
Agent: Cl
Solvent: CCOCC
Product: O=C(Cl)C1CCN(CCCCOc2ccccc2CCc2ccccc2)CC1

Procedure:
To 6.0 g of 2-[4-(4-carboxypiperidino)butoxy]bibenzyl hydrochloride was added dropwise 15 ml of thionyl chloride with stirring. The reaction mixture was stirred at room temperature for 3 hours. As the reaction proceeded the reaction mixture became homogenous. Upon completion of the reaction, anhydrous ether was added and the resultant oily product was washed well twice or three times with anhydrous ether. To the washed oil was added anhydrous ether and the mixture was allowed to stand yielding crystalline 2-[4-(4-chlorocarbonylpiperidino)butoxy]bibenzyl hydrochloride which was sufficiently dried for use in the subsequent reaction. To a solution of 10 ml of 50% aqueous dimethylamine solution and 10 ml of tetrahydrofuran cooled in an ice-salt bath was quickly added 1.5 g of crystalline 2-[4-(4-chlorocarbonylpiperidino)butoxy]bibenzyl hydrochloride with stirring. The mixture was allowed to react for 1.5 hours and then concentrated. To the concentrate was added 2N-NaOH aqueous solution and the product was extracted with ether. The extract from ether was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. To the ether solution was added 20% ethanolic hydrogen chloride to yield a precipitate. Recrystallization from etherethanol gave 1.2 g (78% yield) of 2-[4-(4-dimethylcarbamoylpiperidino)butoxy]bibenzyl hydrochloride, m. p. 139°-160° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([NH:12]C(=O)OC(C)(C)C)[CH2:10][OH:11].ClS([N:24]=[C:25]=[O:26])(=O)=O.O.C(=O)([O-])O.[Na+]>C(#N)C>[C:25](=[O:26])([O:11][CH2:10][CH:9]([NH2:12])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1])[NH2:24]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(CO)c1cccc(Cl)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: NC(=O)OCC(N)c1cccc(Cl)c1Cl
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Of the compound from Example 182A, 290 mg (about 0.95 mmol) were introduced in 5 ml of acetonitrile under argon. At −15° C., 115 μl (1.33 mmol) of chlorosulphonyl isocyanate were added dropwise. After 30 min, the reaction solution was admixed with 20 ml of water and heated at 60° C. overnight. The reaction mixture was cooled and introduced into saturated aqueous sodium hydrogen carbonate solution. It was extracted with twice 20 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and freed from the solvent on a rotary evaporator. Drying in an HV gave 176 mg (66% of theory) of the title compound in 89% purity.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12](O)=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][C:2]1[C:3]([CH2:12][OH:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Cc1cc2ccccc2cc1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc2ccccc2cc1CO
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 99.3 %

Procedure:
A solution of 3-methyl-2-naphthoic acid (5.0 g, 26.9 mmol) in anhydrous THF (75 mL) was cooled to 0° C. and treated with lithium aluminum hydride (1M in THF, 26.9 mL, 26.9 mmol) added dropwise. After the addition was complete, the resulting mixture was stirred 5 minutes at 0° C., the ice bath was removed, the mixture warmed to room temperature and stirred a total of 20 hours. The mixture was cooled to 0° C. and quenched by dropwise addition of water (1.02 mL), followed by 15% NaOH (1.02 mL), and more water (3 mL). The resulting mixture was stirred 1 hour and the granular precipitate removed by filtration through a plug of Florosil and anhydrous magnesium sulfate. The filtrate was concentrated in vacuo, to give the desired product (4.6 g, 99%) as a white crystalline solid of sufficient purity for use in the subsequent reaction.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][CH:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([O:54][CH3:55])[C:40]=1[OH:56]>>[NH2:30][CH:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:43]5[CH:42]=[C:41]([O:54][CH3:55])[C:40]([OH:56])=[C:39]([Cl:38])[CH:44]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(Nc4ccc(N5CCCC(N)C5)nc4)c3c2)cc(Cl)c1O
Yield: 39.8 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinoline-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (100 mg, 0.18 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (77 mg, 0.27 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (39 mg, 40% over 2 steps) as a yellow-orange solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.39 (s, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 8.05 (s, 1H), 7.77 (s, 1H), 7.21 (s, 1H), 7.02 (s, 1H), 6.87 (s, 1H), 4.49 (s, 1H), 4.02 (s, 1H), 3.93 (s, 3H), 2.84 (s, 1H), 2.22 (s, 1H), 1.97 (s, 1H), 1.75 (s, 2H), 1.23 (s, 4H); ESI MS m/z 544 [C30H30ClN5O3+H]+; HPLC 99.7% (AUC), tR=10.68 min.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C@@:11]([CH3:31])([OH:30])[CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+]>C1COCC1>[F:27][C:26]([F:29])([F:28])[O:25][C:22]1[CH:23]=[CH:24][C:19]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][C@:11]3([CH3:31])[O:30][C:2]4=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]4[CH2:10]3)[CH2:14][CH2:15]2)=[CH:20][CH:21]=1
Reactant: C[C@](O)(CN1CCN(c2ccc(OC(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@]1(CN2CCN(c3ccc(OC(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Yield: 47.9 %

Procedure:
To a solution of (S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-trifluoromethoxyphenyl)piperazin-1-yl]propan-2-ol prepared in Example 369 (5.85 g, 12.61 mmol) in THF (150 ml), sodium hydride (0.66 g, 18.92 mmol) was added with cooling on ice-bath followed by stirring under reflux for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was added water and ethyl acetate. The precipitates were filtered off, purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1) and recrystallized from isopropanol to afford (S)-2-[4-(4-trifluoromethoxyphenyl)piperazin-1-yl]methyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (2.58 g, yield 48%) as a light yellow solid.
Reaction SMILES: [NH2-].[Na+].Cl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1>O1CCCC1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:11]([C:8]2[CH:9]=[CH:10][C:5]([F:4])=[CH:6][CH:7]=2)[NH2:12])=[CH:16][CH:17]=1
Reactant: NNc1ccc(F)cc1
Reactant: Clc1ccc(CBr)cc1
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NN(Cc1ccc(Cl)cc1)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A flask containing tetrahydrofuran (2.0 mL) was charged with sodium amide (202 mg, 4.92 mmol; Aldrich) and chilled to 0° C. (4-Fluorophenyl)hydrazine hydrochloride (400 mg, 2.46 mmol; Aldrich) was added in portions. After 5 minutes the solid had completely dissolved and the ice bath was removed. Stirring was continued for 1 hour, then the solution was chilled again in an ice bath and 1-(bromomethyl)-4-chlorobenzene (556 mg, 2.7 mmol; Aldrich) was added dropwise. After 30 minutes, the ice bath was removed and the reaction was heated to 50° C. overnight. The mixture was diluted with water (5 mL) and extracted with dichloromethane (2×10 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title product which was carried on without further purification: LC/MS (DCI/NH3) m/z 234 (M+H−NH3)+.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([N+:29]([O-])=O)[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].CC(O)=O>CCOC(C)=O.[Fe]>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:29])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc([N+](=O)[O-])c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.1 %

Procedure:
A mixture of 4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (11.2 mg, 0.026 mmol), AcOH (73.3 μL) and iron powder (14.4 mg, 0.26 mmol) was stirred at room temperature for 3 h. The reaction mixture was diluted with EtOAc, filtered and washed with more EtOAc. The filtrate was concentrated under vacuum, and the residue was diluted with EtOAc and neutralized with Na2CO3 solution. The mixture was stirred at room temperature for 30 min. The organic layer was separated, dried over Na2SO4, filtered and concentrated under vacuum to give the sub-title compound as a yellowish solid (10.0 mg, 96%). LCMS calc. for C21H33N4O4 (M+H)+: m/z=405.2. Found: 405.1.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[N:9]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]1=[O:29])C.[OH-].[Na+]>CO>[C:16]([C:13]1[CH:14]=[CH:15][C:10]2[N:9]([CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)[C:8](=[O:29])[N:7]([CH2:6][CH2:5][C:4]([OH:30])=[O:3])[C:11]=2[CH:12]=1)#[N:17]
Reactant: CCOC(=O)CCn1c(=O)n(Cc2cccc3ccccc23)c2ccc(C#N)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc2c(c1)n(CCC(=O)O)c(=O)n2Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.5 %

Procedure:
To a solution of 3-(6-Cyano-3-naphthalen-1-ylmethyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid ethyl ester (20 mg, 0.05 mmol) in MeOH (5 mL) was added 2N NaOH (3 mL). The reaction mixture was stirred at room temperature for 16 h. When all the starting material was consumed, the reaction mixture was acidified with 1N HCl. The reaction mixture was extracted with CH2Cl2 (×2). The combined organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 10:1 CH2Cl2:MeOH as an eluent to afford 4 mg (22%) of the desired product as an off-white solid. LCMS (ESMS): m/z 372.11 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][NH2:11])[CH:8]=2)[CH:3]=[CH:2]1.[CH3:12][O:13][C:14](=[O:32])[C:15]1[CH:20]=[CH:19][C:18]([C:21](ON2C(=O)CCC2=O)=[O:22])=[CH:17][C:16]=1[Cl:31]>CN(C)C=O>[CH3:12][O:13][C:14](=[O:32])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:11][CH2:10][C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[CH:2][NH:1]3)=[CH:5][CH:6]=2)=[O:22])=[CH:17][C:16]=1[Cl:31]
Reactant: COC(=O)c1ccc(C(=O)ON2C(=O)CCC2=O)cc1Cl
Reactant: NCc1ccc2cc[nH]c2c1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NCc2ccc3cc[nH]c3c2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
1H-Indole-6-methanamine (Example 71; 0.9 g, 6.2 mmol) was added to a cooled (˜0° C.) solution of 2-chloro-4-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]benzoic acid methyl ester (Example 73; 2.20 g, 7.1 mmol) in N,N-dimethylformamide and the solution was allowed to stir at room temperature overnight. The solvent was evaporated under high vacuum and ethyl acetate was added. The solution was washed in turn with 0.5N lo hydrochloric acid solution, saturated sodium bicarbonate solution and brine, then dried (MgSO4), filtered and evaporated in vacuo to afford 2-chloro-4-[[[(1H-indol-6-yl)methyl]amino]carbonyl]benzoic acid methyl ester (2.00 g, 94% yield).
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:11]([CH3:12])[C:6]2=[N:5][CH:4]=1)#[CH:2].Br[C:24]1[CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=[N:28][CH:29]=1>>[CH3:12][C:11]1[C:6]2[N:7]([C:3]([C:1]#[C:2][C:24]3[CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=[N:28][CH:29]=3)=[CH:4][N:5]=2)[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=2)[CH:10]=1
Reactant: C#Cc1cnc2c(C)cc(-c3ccc(C(F)(F)F)cc3)cn12
Reactant: NS(=O)(=O)c1cncc(Br)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(C#Cc3cncc(S(N)(=O)=O)c3)cnc12

Procedure:
The title compound was prepared from 3-ethynyl-8-methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.20) (300 mg, 1 mmol) and 5-bromo-pyridine-3-sulfonic acid amide (example B.1) (278 mg, 0.9 mmol) according to general procedure II. Obtained as an off-white solid (290 mg, 63%). MS (ISP) 457.1 [(M+H)+]; mp 294° C.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([O:37][CH3:38])[N:36]=2)[N:33]=1.[Cl-].[Na+]>CN(C)C=O>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([CH:34]=[C:35]([O:37][CH3:38])[N:36]=4)[N:33]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1cn2nc(Cl)ccc2n1
Reactant: OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cn2nc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 45.3 %

Procedure:
758 mg of 4-(diphenylmethoxy)-1-piperidinepropanol was dissolved in 40 ml of N,N-dimethylformamide; 102 mg of a 60% sodium hydride dispersion in mineral oil was added, followed by stirring at 60° C. for 40 minutes. After cooling, 428 mg of 6-chloro-2-methoxyimidazo[1,2-b]pyridazine was added, followed by stirring at 100° C. for 2.5 hours. After cooling, ice water and sodium chloride were added, followed by extraction with ethyl acetate-tetrahydrofuran (1:2); the extract was washed with saturated saline and dried with magnesium sulfate. After the dry product was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected and concentrated; the crystal precipitated was recrystallized from ethanol to yield 499 mg of the title compound.