Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:13]=[C:12](Cl)[N:11]=[C:10]([CH:15]2[CH2:17][CH2:16]2)[N:9]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[Cl:7][C:8]1[N:9]=[C:10]([CH:15]2[CH2:17][CH2:16]2)[N:11]=[C:12]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:13]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)nc(C2CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Clc1nc(C2CC2)nc(N2CCOCC2)n1
Temperature: 5 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
A solution of 2.61 g (0.03 mole) of morpholine in 20 ml of chloroform is added in the course of 30 minutes to a solution of 5.7 g (0.03 mole) of 2,4-dichloro-6-cyclopropyl-1,3,5-triazine in 50 ml of chloroform, cooled to between 3° and 5° C. The temperature of the mixture is allowed to return to about 10° C., then the mixture is cooled again to 5° C. and a solution of 4.14 g (0.03 mole) of potassium carbonate in 15 ml of water is added dropwise. The mixture is then stirred at room temperature for two hours. 30 ml of water are added and the organic phase is separated off. The solution is washed with water and dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by chromatography on silica (eluent: 96.5:3.5 (v/v) dichloromethane-ethylacetate) and then recrystallized from hexane. 5.5 g of 2-chloro-4-cyclopropyl-6-morpholino-1,3,5-triazine are thus obtained. Yield: 76.2%. M.P.: 99°-100° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[O:11])=[C:4](/[N:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:3]=1.[CH3:21][N:22]1[C:26]([CH:27]=O)=[N:25][CH:24]=[N:23]1.[CH3:29][CH2:30][O-:31].[Na+]>C(OCC)(=O)CC>[F:1][C:2]1[CH:10]=[C:9]([C:8]([O:7][CH2:6][CH3:5])=[O:11])[C:29]2[C:30](=[O:31])[CH:27]([C:26]3[N:22]([CH3:21])[N:23]=[CH:24][N:25]=3)[CH:13]([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[NH:12][C:4]=2[CH:3]=1
Reactant: CC[O-]
Reactant: O=C1OCc2c(/N=C/c3ccc(F)cc3)cc(F)cc21
Reactant: Cn1ncnc1C=O
Agent: [Na+]
Solvent: CCOC(=O)CC
Product: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1ncnn1C)C(c1ccc(F)cc1)N2
Temperature: 40 °C
Reaction time: 6 h
Yield: 16.9 %

Procedure:
To a solution of (E)-6-fluoro-4-(4-fluorobenzylideneamino)isobenzofuran-1(3H)-one (4 g, 14.6 mmol) and 1-methyl-1H-1,2,4-triazole-5-carbaldehyde (4.1 g, 36.9 mmol) in ethyl propionate (220 mL) was added EtONa ((sodium 940 mg, 40.9 mmol), in 70 mL ethanol) at 37° C., then the mixture was stirred at 40° C. for 6 hr. The resulting mixture was evaporated under reduced pressure and extracted with ethyl acetate (100 mL×4). The extract was concentrated to dryness to give a crude product, which was purified by column chromatography (silica gel, dichloromethane:methanol=200:1 to 100:1) to obtain a green solid (1.02 g, yield 14%). LC-MS (ESI) m/z: 413 (M+1)+.
Reaction SMILES: [CH2:1]=O.[N:3]1([C:9]([S:11][CH3:12])=[S:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:16]=1[OH:23]>C(O)C>[CH3:22][O:21][C:17]1[CH:18]=[C:19]([CH:20]=[C:15]([O:14][CH3:13])[C:16]=1[OH:23])[CH2:1][N:6]1[CH2:7][CH2:8][N:3]([C:9]([S:11][CH3:12])=[S:10])[CH2:4][CH2:5]1
Reactant: CSC(=S)N1CCNCC1
Reactant: COc1cccc(OC)c1O
Reactant: C=O
Solvent: CCO
Product: COc1cc(CN2CCN(C(=S)SC)CC2)cc(OC)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
In 10 ml of ethanol was dissolved 0.86 g of 35% formaline. To the solution was dropwise added under chilling with ice a solution of 2.35 g of methyl 1-piperazinecarbodithioate in 4 ml of ethanol. The resulting mixture was then stirred for 30 min. at room temperature. Under chilling with ice, a solution of 1.54 g of 2,6-dimethoxyphenol in 4 ml of ethanol was to the stirred mixture. The resulting mixture was stirred for one hour at room temperature, and then refluxed under heating for 38 hours. The refluxed mixture was then cooled to room temperature. Precipitated crystals were collected by filtration and then washed with ethanol to give 1.94 g of thedesired compound a whilte crystalline product, yield 56.7%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][N:8]=[C:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][C:16]=3[F:25])[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.[CH3:26][N:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH:32]=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:26][N:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH2:32][N:1]1[CH2:6][CH2:5][CH:4]([O:7][N:8]=[C:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:17][C:16]=3[F:25])[CH2:11][CH2:10]2)[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(N2CCC(=NOC3CCNCC3)CC2)c(F)c1
Reactant: Cn1cccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cccc1CN1CCC(ON=C2CCN(c3ccc(S(C)(=O)=O)cc3F)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 63a (24 mg, 0.065 mmol) in 1 mL of DCM, was added 1-methyl-1H-pyrrole-2-carbaldehyde (10.6 g, 0.098 mmol), triethylamine (27 μL, 0.19 mmol) and sodium triacetoxyborohydride (27.6 mg, 0.13 mmol). The mixture was stirred overnight at room temperature, concentrated and purified on preparative HPLC to give 66-1: LC-MS 463.0 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2([C:19]#[N:20])[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].N1CCOCC1.O1CCCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[OH:18][CH:15]1[CH2:14][CH2:13][C:12]([C:5]2[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=2)([C:19]#[N:20])[CH2:17][CH2:16]1
Reactant: COc1cc(C2(C#N)CCC(=O)CC2)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: COc1cc(C2(C#N)CCC(O)CC2)ccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
Into a 8-dram vial, 1-(3-Methoxy-4-nitro-phenyl)-4-oxo-cyclohexanecarbonitrile (0.450 g, 1.64 mmol), Morpholine (0.429 g, 4.92 mmol), Tetrahydrofuran (8.00 mL, 98.6 mmol) was added and stirred at 50° C. for 1 hour. Sodium triacetoxyborohydride (0.695 g, 3.28 mmol) was added and continued to heat at 50° C. overnight. The reaction was cooled to room temperature. The reaction was partitioned with saturated NaHCO3 and EtOAc. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with hexane and EtOAc as eluant. The collected fractions afforded trans-1-(3-methoxy-4-nitrophenyl)-4-(morpholin-4-yl)cyclohexanecarbonitrile (0.38 g, 67%) and 4-Hydroxy-1-(3-methoxy-4-nitro-phenyl)-cyclohexanecarbonitrile (0.05 g, 10%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[CH:8]=[CH:9][O:10]C.Cl.CCOC(C)=O.CCCCCC>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]=[O:10]
Reactant: COC=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=CCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1F
Temperature: 25 °C
Yield: 89.3 %

Procedure:
To a 0° C. solution of 3-fluoro-4-(2-methoxy-vinyl)-4′-trifluoromethyl-biphenyl (458 mg, 1.54 mmol) in THF (15 mL) is added dropwise concentrated hydrochloric acid (2.75 mL) and the reaction is warmed to room temperature. After 1 h TLC (30% EtOAc/hexane) indicates complete consumption of starting material. The reaction mixture was diluted with water and the pH is adjusted to 8 with solid NaHCO3. The reaction mixture is concentrated and the aqueous layer extracted with EtOAc (3×50 mL). The combined organic layers are washed with brine, dried (MgSO4), filtered, concentrated and chromatographed (40 g SiO2, 5% EtOAc/Hexanes) to yield the title compound (388 mg, 89%). 1NMR (400 MHz, CDCl3) δ ppm: 9.82 (s, 1H), 7.69 (q, 4H, J=8.4 Hz), 7.39 (dd, 1H, J=7.9, 1.3 Hz), 7.35 (dd, 1H, J=10.4, 1.5 Hz), 7.30 (t, 1H, J=7.7 Hz), 3.82 (s, 2H).
Reaction SMILES: [CH2:1]([NH:5][S:6]([C:9]([F:12])([F:11])[F:10])(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21]>CO>[CH2:21]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[S:6]([C:9]([F:12])([F:10])[F:11])(=[O:7])=[O:8])[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: CCCCNS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C=CCN(CCCC)S(=O)(=O)C(F)(F)F
Reaction time: 2 h

Procedure:
A mixture of N-butyltrifluoromethanesulfonamide (62.0 g, 0.302 mole), potassium carbonate (45.54 g, 0.330 mole) and methanol (250 ml) was refluxed with stirring for two hours. Allyl bromide (39.93 g, 0.330 mole) was then added and this mixture stirred under reflux for 24 hours, cooled, filtered, and the solvent evaporated in vacuo. The residue was fractionally distilled yielding 37.0 g (b.p. of 53°-58° C. at 0.07 torr) of the desired compound, N-allyl-N-butyltrifluoromethylsulfonamide.
Reaction SMILES: Cl.[C:2]([OH:9])(=O)[CH2:3]/[CH:4]=[CH:5]/[CH2:6][CH3:7].[NH2:10][C@@H:11]([CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=[O:13]>>[CH2:31]([O:30][CH2:29][C@H:11]([NH:10][C:2](=[O:9])[CH2:3]/[CH:4]=[CH:5]/[CH2:6][CH3:7])[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=[O:13])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC/C=C/CC(=O)O
Agent: Cl
Product: CC/C=C/CC(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 52.5 %

Procedure:
Proceeding as in Example 1, but substituting (E)-hex-3-enoic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 232, (S,E)-N-(3-(benzyloxy)-1-(4-(4-fluorophenoxy)phenylamino)-1-oxopropan-2-yl)hex-3-enamide (3 mg, 52.5%). MS (EI) for C28H29FN2O4. found 477.5 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[CH3:14][C:15]([NH2:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18]>C(#N)C>[C:10]([C@@H:9]1[N:5]([C:3](=[O:4])[CH2:2][NH:22][C:15]([CH3:21])([CH3:14])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:6]([C:12]#[N:13])[CH2:7][CH2:8]1)#[CH:11]
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Reactant: CC(C)(C)CC(C)(C)N
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC(C)(C)CC(C)(C)C
Reaction time: 48 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.04 g, 0.20 mmol, Example 8D) in acetonitrile (3 mL) at room temperature under nitrogen was added 1,1,3,3-tetramethylbutylamine (0.066 g, 0.406 mmol). The reaction mixture was stirred for two days and then concentrated under reduced pressure. The residue was flash chromatographed with 2% MeOH/CH2Cl2 to provide the titled compound. MS (DCI) m/z 290 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 1.5-2.02 (10H, m), 2.07-2.21 (2H, m), 2.45-2.50 (2H, m), 3.03-3.5 (6 Hs), 3.76 (1H, d), 3.78-4.53 (2H, m), 4.53-4.55 (1H, t), 5.06 (1H, m), 5.1 (1H, m).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[H-].[Na+].Cl[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:15]=[C:14]2[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=1.[I-].[Na+]>O1CCCC1.O>[F:45][C:41]1[CH:40]=[C:39]([C:14]2[C:13]3[C:17](=[CH:18][CH:19]=[C:11]([CH2:10][O:1][C@H:2]4[CH2:6][CH2:5][O:4][CH2:3]4)[CH:12]=3)[N:16]([C:20]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:15]=2)[CH:44]=[CH:43][CH:42]=1
Reactant: Fc1cccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(CCl)cc23)c1
Reactant: O[C@H]1CCOC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1cccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(CO[C@H]4CCOC4)cc23)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.8 %

Procedure:
To a solution of 40 mg of (S)-3-hydroxytetrahydrofuran in tetrahydrofuran was added 15 mg of 60% sodium hydride (oily) in an atmosphere of nitrogen gas, and the mixture was stirred at room temperature for 15 minute. To the reaction mixture were added 150 mg of 5-(chloromethyl)-3-(3-fluorophenyl)-1-trityl-1H-indazole produced in Production Example I-32 and 45 mg of sodium iodide, followed by stirring at room temperature for five days. After adding water to the reaction mixture, it was extracted with 20 ml of ethyl acetate. The organic layer was sequentially washed with half-saturated aqueous sodium chloride solution and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The resulting crude product was purified and separated by silica gel column chromatography (ethyl acetate:toluene=0:1 to 1:9), to give 84 mg of the title compound as a white amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][C:10]2=O)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.CN.[C:23]([BH3-])#[N:24].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH:10]2[NH:24][CH3:23])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CCc2ccccc2C1c1ccc(Cl)c(Cl)c1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNC1CCc2ccccc2C1c1ccc(Cl)c(Cl)c1
Reaction time: 20 h
Yield: 66 %

Procedure:
To a solution of tetralone 35 (400mg, 1.374 mmol) in THF (10 mL) and methanol (15mL) was added methylamine hydrochloride (1.12 g, 10 eq). The resultant mixture was stirred at 50° C. After dissolution (10 min), sodium cyanoborohydride (6.9 mL, 1M in THF, 5 eq) was added in a single portion. After 20 hours, the organic layer was evaporated, filtered through silica and an aminopropyl cartridge. The crude oil was then diluted with sodium bicarbonate solution and extracted with MTBE to give the amine (280 mg, 66%) as a mixture of four stereoisomers (1:1:1:1).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:25][NH:26][CH3:27]>O1CCOCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:26]([CH3:27])[CH3:25])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2cccc(Cl)c2C1=O
Solvent: C1COCCO1
Product: CN(C)Cc1nc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)no1

Procedure:
7.0 g 7-Chloro-3-(5-chloromethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo-[1,5-a][1,4]benzodiazepin-6-one were suspended under stirring and argon atmosphere in 70 ml 1,4-dioxane and 25.7 ml dimethylamine (33% in ethanol) were added over 60 minutes. The reaction mixture was stirred one more hour at r.t. and then the solvents were removed under reduced pressure at 35° C. The residue was partitioned between 50 ml dichloromethane and 20 ml deionized water. The phases were separated and the organic phase was washed twice with 20 ml deionized water. The aqueous phases were extracted separately with the same portion of 25 ml dichloromethane, twice. The combined organic extracts were dried (Na2SO4) and the solvent was removed under reduced pressure. Crude product: 8.0 g as a light yellow foam.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH:6]1[CH2:10][CH2:9][O:8][CH2:7]1)(=O)=O.[CH2:18]([NH2:20])[CH3:19].[OH-].[Na+]>>[O:8]1[CH2:9][CH2:10][CH:6]([CH2:5][NH:20][CH2:18][CH3:19])[CH2:7]1
Reactant: CCN
Reactant: Cc1ccc(S(=O)(=O)OCC2CCOC2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCNCC1CCOC1
Temperature: 75 °C
Reaction time: 6 h

Procedure:
A mixture comprising 4.09g of (tetrahydro-3-furanyl)methyl tosylate, 17 ml of 70% aqueous ethylamine solution and 8.2 ml of 2N aqueous sodium hydroxide solution was stirred at 75° C. for 6 hours. The reaction fluid was concentrated under a reduced pressure to obtain crude N-{(tetrahydro-3-furanyl)methyl}-N-ethylamine. To this were added 2.00 g of 1,1-bis(methylthio)-2-nitroethylene and 20 ml of acetonitrile. The resulting mixture was refluxed for 3 hours. The reaction fluid was concentrated under a reduced pressure, and purified by silica gel column chromatography (eluent:ethyl acetate/hexane=1/2) to obtain 0.81 g of 1-[N-{(tetrahydro-3-furanyl)methyl}-N-ethylamino]-1-methylthio-2nitroethylene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])[O:44][C:45](Cl)(Cl)Cl)Cl.[Cl:51][C:52]1[CH:62]=[CH:61][CH:60]=[CH:59][C:53]=1[O:54][CH2:55][CH2:56]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:44][CH2:45][CH2:56][CH2:55][O:54][C:53]2[CH:59]=[CH:60][CH:61]=[CH:62][C:52]=2[Cl:51])=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: OCCCOc1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCCCOc4ccccc4Cl)cc3C)c2cc1OC
Temperature: 25 °C
Yield: 52.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (71 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (97 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(2-chlorophenoxy)-1-propanol (72 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (62 mg, yield 44%).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O)([O-:3])=[O:2].O.[CH3:12][NH:13][CH3:14]>CO>[CH3:12][N:13]([CH3:14])[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][N+:1]([O-:3])=[O:2]
Reactant: CNC
Reactant: COC(=O)CCC[N+](=O)[O-]
Solvent: O
Solvent: CO
Product: CN(C)C(=O)CCC[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 90.9 %

Procedure:
To a solution of methyl 4-nitrobutyrate (1.0 g, 6.80 mmol) in methanol (10 ml) was added 40% dimethylamine water solution (12.5 ml, 102 mmol). The solution was stirred at room temperature for 48 h, concentrated by vacuum, and diluted with ethyl acetate (20 ml). The organic layer was dried and evaporated. The residue was purified by flash chromatography over silica gel (Hexane-EtOAc, 1:1) to give the title product (0.99 g, 91%). 1H NMR (CDCl3): 4.53 (t, J=6.6 Hz, 2H), 3.02-2.94 (m, 6H), 2.48-2.43 (m, 2H), 2.36-2.31 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.[NH:9]1[CH2:15][CH:14]([OH:16])[CH2:13][NH:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C>CCO>[Br:1][C:2]1[N:3]=[C:4]([N:9]2[CH2:15][CH:14]([OH:16])[CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OC1CNCCNC1
Reactant: Fc1cccc(Br)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: OC1CNCCN(c2cccc(Br)n2)C1
Temperature: 100 °C

Procedure:
To a mixture of 2-bromo-6-fluoropyridine (845 mg, 4.83 mmol) and 1,4-diazepan-6-ol (560 mg, 4.83 mmol) in EtOH (20 mL) was added DIPEA (5 mL). The reaction mixture was heated at 100° C. for 15 hours, which was monitored by LCMS. After completion of the reaction, it was concentrated under reduced pressure. The crude material was used in the next step without further purification. MS (ESI) m/z: 272 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[N:25]1([C:32](=[O:34])[CH3:33])[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>O1CCOCC1.CS(C)=O.CO>[C:32]([N:25]1[CH2:31][CH2:30][CH2:29][N:28]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:15]=[CH:16][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:18][CH:19]=3)[CH:3]=2)[CH2:27][CH2:26]1)(=[O:34])[CH3:33]
Reactant: CC(=O)N1CCCNCC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: CS(C)=O
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)N1CCCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)CC1
Temperature: 25 °C
Yield: 69.2 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 200 mg, 0.604 mmol) and 1-(1,4-diazepan-1-yl)ethanone (130 mg, 0.906 mmol) in Dioxane (6 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 5-95% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (182.5 mg, 70%). 1H NMR (METHANOL-d4) δ: 7.89-7.99 (m, 6H), 7.62-7.68 (m, 4H), 7.34 (d, J=8.6 Hz, 2H), 6.26 (t, J=2.3 Hz, 2H), 4.47 (t, J=5.7 Hz, 2H), 4.18-4.30 (m, 2H), 4.05 (dt, J=16.2, 6.0 Hz, 4H), 3.82 (dt, J=11.6, 5.8 Hz, 4H), 3.67 (dt, J=8.7, 6.0 Hz, 4H), 2.19 (t, J=5.9 Hz, 2H), 2.13 (s, 3H), 2.03-2.11 (m, 2H), 1.90 (s, 3H), 1.56 (s, 12H). ESI-MS: m/z 437.1 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23])(=[O:3])[CH3:2].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][Br:30])=[CH:27][CH:26]=1>>[Br-:30].[C:1]([C:4]1[CH:5]=[N+:6]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([Cl:24])=[CH:26][CH:27]=2)[CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23])(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)CCC(Cc1ccncc1C(C)=O)C2=O
Reactant: Clc1ccc(CBr)cc1
Product: COc1ccc2c(c1)CCC(Cc1cc[n+](Cc3ccc(Cl)cc3)cc1C(C)=O)C2=O
Product: [Br-]

Procedure:
The title compound 131 is prepared according to the procedure reported in Example 38.1 with compound 103 (120 mg, 0.387 mmol) and 4-chlorobenzyl bromide (135.5 mg, 0.66 mmol) as reactants. White solid. (Yield 176.6 mg, 90%).
Reaction SMILES: [PH:1](=[O:33])([O:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][C:15]([C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)=[O:22])=[C:14]2[OH:32])[O:2]C(C)(C)C.CCCCCC>C(O)(C(F)(F)F)=O.ClCCl>[PH:1](=[O:2])([OH:33])[O:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][C:15]([C:21]([NH:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)=[O:22])=[C:14]2[OH:32]
Reactant: CC(C)(C)O[PH](=O)OCCCc1ccc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(CCCO[PH](=O)O)cc2c1O
Yield: 103 %

Procedure:
A solution of 50.0 mg of tert-butyl 3-(3-{[(4-chlorobenzyl)amino]carbonyl}-4-hydroxy-6-quinolinyl)propyl phosphonate from Example No. 270 in 0.5 mL of 1:1 TFA-dichloromethane is stirred for 2 h, then added slowly to 20 mL of rapidly stirred hexane. The resulting solution was concentrated under reduced pressure to provide 45.6 mg of the title compound as a white crystalline solid.