Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][CH2:16][C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13](C(=O)CCl)[C:12]=2[CH:26]=1)([O:3][CH:4]([CH3:6])C)=[O:2].[CH2:27]([OH:29])[CH3:28].[CH3:30][NH2:31]>O>[C:1]([NH:7][C:8]1[CH:9]=[C:10]([C:27](=[O:29])[CH3:28])[C:11]2[CH2:17][CH2:16][C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13]([NH:31][CH:30]3[CH2:10][CH2:9][CH2:8][CH2:26][CH2:12]3)[C:12]=2[CH:26]=1)([O:3][CH2:4][CH3:6])=[O:2]
Reactant: CN
Reactant: CC(C)OC(=O)Nc1ccc2c(c1)N(C(=O)CCl)c1ccccc1CC2
Reactant: CCO
Solvent: O
Product: CCOC(=O)Nc1cc(C(C)=O)c2c(c1)N(NC1CCCCC1)c1ccccc1CC2
Temperature: 50 °C
Reaction time: 8 h

Procedure:
18 g, approximately 0.05 moles of 3-carbisopropoxyamino-5-chloroacetyl-10,11-dihydro-5H-dibenz[b,f]azepine (hereafter referred to as Startazeine 2) and 300 ml of 96% ethanol are added to a 2liter 3-neck flask. At room temperature, 100 ml of aqueous monomethylamine solution (38%=1.2 moles) are added with stirring. The reaction mixture is heated slowly by means of a water bath to 50° C., stirred for 3 hours at this temperature and then for another hour at 60° C. After cooling to 25° C.-30° C., 750 ml of cold water are added. After standing overnight, an additional 400 ml of water are added with stirring. The water-amine-alcohol mixture is decanted from the oily deposit formed and same amount of fresh water is added. After decanting the supernatant once more, the oily residue is dissolved in 80 ml of warm acetone, cleaned through a filter and induced to crystallize in the refrigerator. The yield is 11 g, or 60% of the theoretical yield. The melting point is 150° C.-152° C. The empirical formula is C21H25N3O3, and the molecular weight is 367.46.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][CH2:10][CH2:11][C:5]2=[N:4][N:3]=1.[Cl:16][C:17]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:18]=1[C:19]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)=[O:20].C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[N:9]([C:26]([C:25]3[CH:24]=[CH:23][C:22]([NH:21][C:19](=[O:20])[C:18]4[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:17]=4[Cl:16])=[CH:30][CH:29]=3)=[O:27])[CH2:10][CH2:11][C:5]2=[N:4][N:3]=1
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccc(Cl)cc2Cl)cc1
Reactant: Cc1nnc2n1-c1ccccc1NCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nnc2n1-c1ccccc1N(C(=O)c1ccc(NC(=O)c3ccc(Cl)cc3Cl)cc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5 mmol of 5,6-dihydro-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine in 20 ml of dichloromethane is added 5.5 mmol of 4-[(2,4-dichlorobenzoyl)amino]benzoyl chloride and 7.5 mmol of triethylamine. The mixture is stirred at room temperature for 8 hours and then washed with water, aqueous NaHCO3 and brine. The organic layer is dried (Na2SO4) and the solvent removed in vacuo to give a solid. The solid is purified by chromatography on silica gel to give the desired product as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[CH2:11]([CH:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:28])[C:25](O)=[O:26])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)C>[CH2:11]([CH:18]1[CH2:19][CH2:20][N:21]([C:24](=[O:28])[C:25]([NH:1][C:2]2[CH:10]=[CH:9][C:5]3[NH:6][CH:7]=[N:8][C:4]=3[CH:3]=2)=[O:26])[CH2:22][CH2:23]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Solvent: CCOCC
Product: O=C(Nc1ccc2[nH]cnc2c1)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 5-amino-benzimidazole and (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) according to the method described in Example 1c. Melting Point: 85-87° C. (diethylether)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][NH:14][CH3:15]>C(O)C>[CH3:13][N:14]([CH3:15])[C:6]1[C:5]([F:9])=[CH:4][C:3]([N+:10]([O-:12])=[O:11])=[C:2]([F:1])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: CNC
Solvent: CCO
Product: CN(C)c1cc(F)c([N+](=O)[O-])cc1F
Temperature: 80 °C

Procedure:
To a solution of 2,4,5-trifluoronitrobenzene (8.9 g, 50 mmol) in 100 mL ethanol is bubbled dimethylamine gas (6.8 g, 150 mmol). The solution is heated at 80° C. in a Parr pressure reactor for 6 hours. After evaporation of the solvent the product is chromatographed on silica gel/methylene chloride to give Compound 18.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:30])[CH:16]=[C:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)=[CH:11][CH:10]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C[O-].[Na+].CO>C(Cl)(Cl)Cl>[CH2:23]([N:20]1[CH2:21][CH2:22][C:17](=[CH:16][C:15]([C:12]2[CH:11]=[CH:10][C:9]([NH2:8])=[CH:14][CH:13]=2)=[O:30])[CH2:18][CH2:19]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)C=C2CCN(Cc3ccccc3)CC2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Nc1ccc(C(=O)C=C2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
4.12 g of N-t-butoxycarbonyl-4-[(1-benzyl-4-piperidinyliden)acetyl]aniline was added to 50 ml of chloroform, and then 10 ml of trifluoroacetic acid was added thereto. The mixture was stirred at room temperature for 4 hours. After the reaction, the reaction mixture was condensed under reduced pressure, and the residue was dissolved in chloroform. Then, the solution was neutralized by adding a 28% sodium methylate·methanol solution thereto. The residue obtained by condensation under reduced pressure was applied to silica gel column chromatography to obtain 2.33 g of the title compound as bluish green powder.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[O:11][CH2:12][CH2:13][OH:14]>C(OCC)C>[S:1]([O:14][CH2:13][CH2:12][O:11][C:10]1[CH:15]=[CH:16][CH:17]=[C:8]([O:7][CH3:6])[CH:9]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)Cl
Reactant: COc1cccc(OCCO)c1
Solvent: CCOCC
Product: COc1cccc(OCCOS(N)(=O)=O)c1

Procedure:
The title compound was prepared by procedures of Example 12 from sulfamoyl chloride and 2-(3-methoxyphenoxy)ethanol through the first evaporation step to give a brown, viscous, oily residue. The oil was dissolved in 300 ml of ethyl ether. The organic solution was washed with two 300 ml portions of water, dried over magnesium sulfate and the solvent evaporated under reduced pressure to give a viscous, oily residue for the second time. The oil was purified by chromatography using silica gel and methylene chlorideacetone in 90:1 ratio as eluting agent. Fractions containing the title compound were combined and solvents evaporated under reduced pressure to give a viscous oil which solidified on standing. The solid was recrystallized from ethyl-petroleum ether (bp range 30°-60° C.) to give the title compound as white solid, mp 78°-82° C., in 46% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[C:13]([N:21]=[C:22]([S-])[S-:23](C)[CH3:24])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[CH3:24][S:23][C:22]([N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1)=[N:21][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[S-](C)C([S-])=NC(=O)c1ccccc1
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: ClCCl
Product: CSC(=NC(=O)c1ccccc1)N1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.2 %

Procedure:
To a mixture of 1-(2-pyridyl)piperazine (10 ml, 64.37 mmol) in dichloromethane (200 ml) was added N-benzoyidimethyldithioimidocarbonate (14.64 g, 65.01 mmol) and the reaction mixture was stirred for 18 h at room temperature. The volatiles were evaporated in vacuo and the residue crystallised from a mixture of heptane/diethyl ether 9:1. The solid was filtered off, washed with a mixture of heptaneldiethyl ether 1:1 and dried in vacuo affording 20.86 g of N-[methylsulfanyl-(4-(pyridin-2-yl)piperazin-1-yl)methylene]-benzamide as a solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]=12.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=1>>[N:8]1([C:6]2[N:5]=[C:4]3[CH2:13][CH2:14][CH2:15][C:3]3=[C:2]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:21][CH:22]=3)[CH:7]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Clc1cc(N2CCCC2)nc2c1CCC2
Reactant: CCOC(=O)Cc1ccc(N)cc1
Product: CCOC(=O)Cc1ccc(Nc2cc(N3CCCC3)nc3c2CCC3)cc1
Yield: 91.2 %

Procedure:
Following general procedure B1, 4-chloro-2-(pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.068 g, 0.30 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate (0.080 g, 0.45 mmol) to afford the title compound (0.100 g, 90%) as a brown oil. MW=365.47. APCI MS m/z 366 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH3:16])=[O:6].[NH:18]1C=CN=[CH:19]1>>[N:2]1([CH2:3][CH2:4][C:5]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH3:16])=[O:6])[CH:1]=[CH:19][N:18]=[CH:17]1
Reactant: c1c[nH]cn1
Reactant: Cc1[nH]c2ccccc2c1C(=O)CCN(C)C
Product: Cc1[nH]c2ccccc2c1C(=O)CCn1ccnc1

Procedure:
3-(Dimethylamino)-1-(2-methyl-1H-indol-3-yl)-1-propanone was converted to the methiodide (1.50 g) which was then reacted with imidazole (2.67 g) to give a solid which was crystallised from methanol to give the title compound (0.65 g), m.p. 196°-197°; λmax (EtOH) 244 (ε12,920), λmax 268.5 nm (ε10,460), λmax 302.5 (ε11,400).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)=[O:14])[CH2:5][C:6]#[CH:7].[C:28]([O:32][C:33](=[O:42])[NH:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][C:36]=1I)([CH3:31])([CH3:30])[CH3:29].C(N(CC)CC)C>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.[Cu](I)I.CN(C=O)C>[CH3:1][O:2][C:3](=[O:27])[CH:4]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:19][CH:20]=1)=[O:14])[CH2:5][C:6]#[C:7][C:40]1[CH:39]=[N:38][CH:37]=[CH:36][C:35]=1[NH:34][C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:42]
Reactant: CC(C)(C)OC(=O)Nc1ccncc1I
Reactant: C#CCC(C(=O)OC)C1CCCN1C(=O)c1ccc(-c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(CC#Cc1cnccc1NC(=O)OC(C)(C)C)C1CCCN1C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 90 °C

Procedure:
A flask is charged with 2-[1-(Biphenyl-4-carbonyl)-pyrrolidin-2-yl]-pent-4-ynoic acid methyl ester (0.58 g, 1.62 mmol), (3-iodopyridin-4-yl)-carbamic acid tert-butyl ester (0.52 g, 1.62 mmol), bis(triphenylphosphine)-palladium(II) chloride (0.057 g, 0.081 mmol), copper iodide (0.0104 g, 0.055 mmol), triethylamine (0.90 mL, 6.5 mmol) and DMF (7.3 mL) and heated at 90° C. for 2 h. The reaction is cooled to RT and partitioned between EtOAc (200 mL) and saturated sodium bicarbonate (75 mL). The organic layer is washed with saturated sodium bicarbonate (2×75 mL), brine (50 mL), dried over MgSO4 and concentrated. The residue is subjected to flash chromatography (1:1/EtOAc:hexanes) to give 2-[1-(biphenyl-4-carbonyl)-pyrrolidin-2-yl]-5-(4-tert-butoxycarbonylamino-pyridin-3-yl)-pent-4-ynoic acid methyl ester as an impure mixture (0.35 g, three components) which is used without further purification. This material (0.35 g, 0.63 mmol estimated), DBU (0.19 g, 1.26 mmol) and acetonitrile (7 mL) is stirred at 50° C. for 6 h. The reaction mixture is concentrated and purified by flash chromatography (0.5% MeOH/CH2Cl2) to (2.0% MeOH/CH2Cl2) to give the title compound (0.18 g, 0.325 mmol). 1H NMR (CDCl3, 300 MHz) 8.83(s, 1H), 8.41(m, 1H), 8.25(d, 1H), 7.65-7.53(m, 6H), 7.52-7.32(m, 3H), 6.80(s, 1H), 4.84-4.68(m, 1H), 3.73, 3.68(two s, 3H), 3.67-3.35(m, 6H), 2.21-1.91(m, 4H), 1.67(s, 9H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[N:15]([CH2:16][C:17]([OH:19])=O)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:32]([NH:35][CH2:36][CH2:37][CH3:38])[CH2:33][CH3:34]>O1CCCC1.C(O)(C)C>[CH3:1][C:2]1[S:6][C:5]([C:7]2[N:15]([CH2:16][C:17]([N:35]([CH2:36][CH2:37][CH3:38])[CH2:32][CH2:33][CH3:34])=[O:19])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCCNCCC
Reactant: Cc1ccc(-c2nc3cccnc3n2CC(=O)O)s1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)Cn1c(-c2ccc(C)s2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
A solution of 2-(5-methyl-2-thienyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0183 mole) and 1,1'-carbonyl-diimidazole (2.97 g, 0.0183 mole) in tetrahydrofuran (100 ml) was stirred at room temperature for 3 hours with a stream of nitrogen bubbling through it. A solution of dipropylamine (5.56 g, 0.055 mole) in tetrahydrofuran (7 ml) was added and the reaction mixture was stirred overnight at room temperature. The solvents were evaporated and the residue was partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed twice with water, twice with a 5% potassium hydroxide solution, and twice again with water. The organic layer was dried over magnesium sulfate, treated with charcoal, filtered, and evaporated to give a solid which was dissolved in hot isopropyl alcohol and filtered while hot. Addition of water and cooling caused a solid to precipitate. The solid was dissolved again in hot isopropyl alcohol with charcoal, filtered while hot and brought to the cloud point by addition of water. Upon cooling, solid precipitated which was collected by filtration, rinsed with water, and dried under high vacuum at 50° C. overnight to give 2.28 g (35%) of title compound, mp 125°-127° C.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:18][CH2:19][C:20](Br)=[O:21]>Cl>[Br:18][CH2:19][C:20]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:21]
Reactant: O=C(Br)CBr
Reactant: CC(C)Nc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)N(C(=O)CBr)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
Isopropyl aniline (8.00 g, 59.2 mmol) and triethylamine (8.26 mL, 59.2 mmol) are combined in anhydrousDCM (75 mL) under nitrogen and cooled to 0°-5° C. with an ice-water bath. Bromoacetyl bromide (5.16 mL, 59.2 mmol) is added dropwise over approximately 10 min. and the reaction is allowed to stir to ambient temperature overnight. The mixture is combined with aqueous HCl (50 mL 1N) and transferred to a separatory funnel. The organic layer is separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to provide the title compound as a brown solid (15.13 g, 59.1 mmol). 1H NMR (300 MHz, CDCl3) δ=1.08 (d, J=6.8 Hz, 6H); 3.53 (s, 2H); 4.92-5.01 (m, 1H); 7.18-7.54 (m, 5H). TLC Rf=0.22 (3:17 ethyl acetate: hexane).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16](C(O)=O)[C:17](C)=[N:18][CH:19]=2)=[CH:10][CH:9]=1>C(Cl)Cl>[ClH:4].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[C:1]([C:2]([Cl:4])=[O:3])[C:17]([CH3:16])=[N:18][CH:19]=2)=[CH:12][CH:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ncc(-c2ccc(Cl)cc2)cc1C(=O)O
Solvent: ClCCl
Product: Cc1ncc(-c2ccc(Cl)cc2)cc1C(=O)Cl
Product: Cl
Reaction time: 1 h
Yield: 97.8 %

Procedure:
Oxalyl chloride (11.52 gms) in dry methylene dichloride (10 ml) was slowly added to a suspension of 5-(p-chlorophenyl)-2-methyl-3-pyridine carboxylic acid (10 g) in dry methylene dichloride (50 ml). After standing for 1 hour at room temperature, the mixture was concentrated and the residue washed with dry diethyl ether, collected and dried to give 5-(p-chlorophenyl)-2-methyl-3-chlorocarbonylpyridine hydrochloride (11.95 g).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH2:12]([CH2:14][NH2:15])[OH:13]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:15][CH2:14][CH2:12][OH:13])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: NCCO
Product: OCCNc1ccc2ncc(Br)n2n1
Yield: 63.8 %

Procedure:
400 mg (1.72 mmol) of 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 2.0 ml (33.4 mmol) of ethanolamine were stirred at 90° C. for 16 h. After cooling, the mixture was concentrated. The resulting residue was purified by chromatography (DCM/EtOH 9:1). 282 mg of the product were obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1>[C:31]([NH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:16][S:17]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(=[O:33])[CH3:32]
Reactant: CC#CCOc1ccc(S(=O)(=O)N[C@@H](C(=O)OC)c2ccc(OCCN)cc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC#CCOc1ccc(S(=O)(=O)N[C@@H](C(=O)OC)c2ccc(OCCNC(C)=O)cc2)cc1

Procedure:
A solution of 0.219 g (0.507 mmol) of methyl(2R)-[4-(2-aminoethoxy)phenyl]({[4(2-butynyloxy)phenyl]sulfonyl}amino)ethanoate in 2.5 mL of acetic anhydride and 0.25 mL of pyridine was stirred at room temperature for 15 h and then concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:1) to provide 0.213 g of methyl (2R)-{4-[2-(acetylamino)ethoxy]phenyl}({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-ethanoate as a white foam. Electrospray Mass Spec 475.3 (M+H)+
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[CH:10][NH:11]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.I[CH2:17][CH2:18][CH:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1.C(C(C)=O)C(C)C>CN1CCCC1=O>[CH2:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:27][CH:19]1[CH2:18][CH2:17][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[CH:10][NH:11]3)[CH2:6][CH2:5]1
Reactant: ICCC1Cc2ccccc2C1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Solvent: CC(=O)CC(C)C
Solvent: CN1CCCC1=O
Product: c1ccc2c(c1)CC(CCN1CCN(c3cccc4[nH]ccc34)CC1)C2
Temperature: 25 °C
Yield: 47.3 %

Procedure:
A mixture of 4-(piperazin-1-yl)-1H-indole (1.5 g), 2-(2-iodoethyl)indane (2.0 g), K2C(3, methyl isobutyl ketone (150 ml), and N-methylpyrrolidone (10 ml ) was boiled under reflux for 3 h. The mixture was allowed to cool to room temperature, filtered, and concentrated in vacuo. The residue was purified on silica gel eluted with ethyl acetate-heptane (1:2) to give a crystalline compound, which was recrystallized (ethyl acetate) to give the title compound (1.2 g, 47%). Mp 146-147° C. 1H NMR (CDCl3) δ 1.70-1.85 (m, 2H), 2.40-2.70 (m, 5H), 2.75 (broad s, 4H), 3.00-3.15 (m, 2H), 3.30 (broad s, 4H), 6.55 (s, 1H), 6.60 (d, 1H), 7.00-7.30 (m, 711), 8.20 (broad s, 1H). MS m/z (%): 346 (MH+, 34%), 159 (88%), 145 (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:21]([N:24](CC2C=CC(OC)=CC=2OC)CC2C=CC(OC)=CC=2OC)(=[O:23])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1([F:20])[CH2:15][CH2:14][N:13]([CH:16]2[CH2:19][O:18][CH2:17]2)[CH2:12][CH2:11]1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1([F:20])[CH2:11][CH2:12][N:13]([CH:16]2[CH2:17][O:18][CH2:19]2)[CH2:14][CH2:15]1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2OC)S(=O)(=O)c2ccc(OCC3(F)CCN(C4COC4)CC3)c(Cl)c2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(OCC2(F)CCN(C3COC3)CC2)c(Cl)c1
Reaction time: 1 h

Procedure:
To a solution of EXAMPLE 517D (0.258 g) in dichloromethane (3 mL) was added trifluoroacetic acid (2 mL) dropwise. The reaction was stirred for 1 hour then quenched by the addition of saturated NaHCO3 solution (20 mL). The reaction was extracted with dichloromethane (2×50 mL), the dichloromethane layer was concentrated, ethyl acetate (20 mL) was added and the resulting solid was filtered. The organic layer was diluted to 50 ml, washed with brine (25 mL), dried over magnesium sulfate, filtered and concentrated. The resulting oil was treated with dichloromethane and concentrated, and the solid was triturated with ethyl acetate and filtered to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2([C:13]#[N:14])[CH2:11][C:10](=[O:12])[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>C(Cl)Cl.CO>[F:1][C:2]1[C:3]([C:8]2([C:13]#[N:14])[CH2:11][CH:10]([OH:12])[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1(c2ncccc2F)CC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: N#CC1(c2ncccc2F)CC(O)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a solution of 1-(3-fluoropyridin-2-yl)-3-oxocyclobutanecarbonitrile (231 g, 1.22 mol) in a mixture of DCM (2 L) and MeOH (200 mL) was added NaBH4 portionwise at −78° C. The reaction mixture was stirred at −78° C. for 1 h and quenched with a mixture of methanol and water (1/1). The organic layer was washed with water (500 mL×3), dried over Na2SO4, and concentrated. The residue was purified on silica gel (50% EtOAc/hexanes) to provide the title compound as an amber oil (185.8 g) m/z=193.2 [M+H].
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]1(/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]([OH:25])=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.Cl.[NH2:34][CH2:35][CH2:36][S:37][CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41]>O1CCCC1>[CH3:43][O:42][C:40](=[O:41])[CH2:39][CH2:38][S:37][CH2:36][CH2:35][NH:34][C:23](=[O:25])/[CH:22]=[CH:21]/[CH:20]=[CH:19]/[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)/C=C/C=C/c1ccccc1
Reactant: COC(=O)CCSCCN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CCSCCNC(=O)/C=C/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
1,1′-Carbonyldiimidazole (0.36 g, 2.2 mmol) was added to a solution of 5-phenyl-penta-2E,4E-dienoic acid (1/1) (0.35 g, 2 mmol) in dry tetrahydrofuran (10 ml) and the obtained mixture was stirred for 1 hour at ambient temperature. To the mixture triethylamine (0.30 g 3.0 mmol) and methyl 3-(2-amino-ethylsulfanyl)-propionate hydrochloride (2e) (2.2 mmol) were added and the resultant suspension was stirred for 6 hours at ambient temperature. The solvent was removed under reduced pressure, to the residue water (15 ml) was added and the precipitate was filtered off, washed with water and dried, to give the title product. Yield 67%, m.p. 58-60° C. 1H NMR (90 MHz, DMSO-d6) δ: 2.54-2.89 (6H, m, CH2); 2.96-3.45 (2H, m, CH2); 3.61 (3H, s, CH3); 6.14 (1H, d, J=14.5 Hz, CH); 6.81-7.16 (2H, m, CH—CH); 7.11-7.69 (6H, m, C6H5, CH); 8.18 (1H, t, J=5.4 Hz, NH).