Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([NH:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])[S:10][N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([N:13]3[C:14]([CH3:18])([CH3:17])[CH2:15][O:16][C:27]3=[O:29])[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(CO)Nc1nc(-c2ccc(Br)cc2)ns1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)COC(=O)N1c1nc(-c2ccc(Br)cc2)ns1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 85.9 %

Procedure:
2-{[3-(4-Bromophenyl)-1,2,4-thiadiazol-5-yl]amino}-2-methylpropan-1-ol (0.80 g, 2.4 mmol), prepared in the previous step, was dissolved in methylene chloride (20 mL), triethylamine (3.3 mL, 24 mmol) was added, and the mixture was cooled to 0° C. Triphosgene (1.8 g, 6.1 mmol) was added and the mixture was stirred for 2.5 h. The mixture was then diluted with methylene chloride and washed with 2N HCl, saturated NaHCO3, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (7.5% acetone/hexane) afforded the title compound (730 mg, 86%). Analytical HPLC: purity 100% at 210-370 nm, 11.0 min; 100% at 246 nm, 11.0 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.Cl.[N:13]1([CH2:18][CH2:19][NH2:20])[CH:17]=[N:16][CH:15]=[N:14]1.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:20][CH2:19][CH2:18][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)=[O:7])=[CH:4][CH:3]=1
Reactant: NCCn1cncn1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCn1cncn1)c1ccc(Br)cc1
Reaction time: 8 h

Procedure:
A mixture of about 2.2 g of 4-bromobenzoyl chloride, about 1.85 g of 1H-1,2,4-triazole-1-ethanamine dihydrochloride, about 30 ml of approximately 1N sodium hydroxide and about 75 ml of methylene chloride was stirred overnight, then about 5 ml of approximately 1N sodium hydroxide and about 75 ml of methylene chloride were added. The layers were separated and the organic layer was concentrated to remove the solvent. The crystalline residue was washed onto a filter with ether giving the desired product, mp 160°-162° C.
Reaction SMILES: [CH2:1]([C:4]1([OH:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[Na+].[I-].C[Si](C)(C)[C:22]([F:25])(F)[F:23].C1COCC1>C(Cl)Cl>[F:23][C:22]1([F:25])[CH2:3][CH:2]1[CH2:1][C:4]1([OH:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: C=CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)(CC2CC2(F)F)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a sealed tube was added tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate 11B (280 mg, 1.16 mmol), NaI (112 mg, 0.74 mmol), trimethyl(trifluoromethyl)silane (0.6 mL) and THF (10 mL), The tube was sealed, and then the mixture was stirred at 80° C. overnight. The resulting mixture was diluted with DCM, filtered, and the filtrate was concentrated in vacuo to give the crude product 11C which was used for next step without further purification. LC-MS: m/z 292.3 (M+H)+
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([O:15]C)=[O:14])[CH2:9][CH2:8]1.[OH-].[Na+].Cl.[Cl-].[Na+]>CO>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]1
Reactant: COC(=O)[C@H]1CC[C@H](N2CCCC2=O)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: O=C1CCCN1[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl trans-4-(2-oxo-pyrrolidin-1-yl)cyclohexanecarboxylate (39.15 g) obtained in Reference Example 113(3) dissolved in methanol (400 ml), and thereto is added 2 N aqueous sodium hydroxide solution (60 ml) and the mixture is stirred at room temperature for 3 hours. The reaction solution is adjusted to pH 1-2 by pouring 10% hydrochloric acid under ice-cooling, saturated with sodium chloride, and then extracted with chloroform. The organic layer is dried over sodium sulfate, and then evaporated to remove the solvent under reduced pressure. The resulting residue is suspended in a small amount of ethyl acetate, and diisopropyl ether is poured thereto, and the resulting crystals are collected by filtration. The crystals are washed with diisopropyl ether several times and dried to give the title compound (35.94 g).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][CH2:7][CH2:8]O.[Cl:10]S(Cl)=O.N#N>>[Cl:10][CH2:8][CH2:7][CH2:6][CH:2]1[CH2:3][CH2:4][CH2:5][O:1]1
Reactant: OCCCC1CCCO1
Reactant: O=S(Cl)Cl
Agent: N#N
Product: ClCCCC1CCCO1
Temperature: 25 °C

Procedure:
To 3-(tetrahydrofuran-2-yl)propan-1-ol (3.90 g, 30.0 mmol) was added dichlorosulfoxide (15 mL) dropwise under N2 and the mixture was refluxed for 3.5 h. It was then cooled to rt and concentrated in vacuo. To the residue was added water (30 mL) and the resulting mixture was extracted with DCM (30 mL×4). The combined organic layers were washed with brine (40 mL×2), dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as yellow liquid, which was used for next step without further purification.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[C:7]([Cl:11])=[C:8]([Cl:10])[CH:9]=1)(=O)[CH3:2].C(O)C.[BH4-].[Na+].[NH3:30]>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[NH2:30][CH:1]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[C:7]([Cl:11])=[C:8]([Cl:10])[CH:9]=1)[CH3:2]
Reactant: COc1c(C(C)=O)cc(Cl)c(Cl)c1C1CN(C(=O)OC(C)(C)C)C1
Reactant: N
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Product: COc1c(C(C)N)cc(Cl)c(Cl)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A solution of tert-butyl 3-(3-acetyl-5,6-dichloro-2-methoxyphenyl)azetidine-1-carboxylate (1.0 g, 2.7 mmol) in 2.0 M ammonia in ethanol (13 mL, 27 mmol) at 0° C. was treated with titanium tetraisopropoxide (1.6 mL, 5.3 mmol) and stirred at 60° C. overnight. The reaction mixture was treated with sodium tetrahydroborate (0.15 g, 4.0 mmol) at 0° C. and the solution was stirred at room temperature for another 1 hour. The reaction mixture was quenched with 2 M ammonia in water and filtered. The solid was washed with acetonitrile. The filtrate was concentrated and the residue was diluted with dichloromethane, washed with water, dried with magnesium sulfate, filtered, and concentrated to give the desired product (1.0 g, 97%) that was used without further purification. LCMS for C13H14Cl2NO3 (M−[NH2]-[t-Bu]+H)+: m/z=302.0, 304.0. Found: 301.9, 304.0.
Reaction SMILES: [OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([C:10]([OH:12])=O)[CH:6]=1)([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:43][C@@H:44]([CH3:60])[CH2:45][N:46]1[CH:50]=[CH:49][C:48]([C:51]2[CH:58]=[CH:57][C:54]([C:55]#[N:56])=[C:53]([Cl:59])[CH:52]=2)=[N:47]1>C(Cl)Cl.CN(C=O)C>[Cl:59][C:53]1[CH:52]=[C:51]([C:48]2[CH:49]=[CH:50][N:46]([CH2:45][C@@H:44]([NH:43][C:10]([C:7]3[CH:6]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[O:9][N:8]=3)=[O:12])[CH3:60])[N:47]=2)[CH:58]=[CH:57][C:54]=1[C:55]#[N:56]
Reactant: CC(C)(O)c1cc(C(=O)O)no1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(C(C)(C)O)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
5-(2-hydroxypropan-2-yl)isoxazole-3-carboxylic acid (0.088 g, 0.515 mmol) and DIPEA (0.090 ml, 0.515 mmol) were dissolved in 5 ml of dry DCM. Anhydrous HOBt (0.070 g, 0.515 mmol), and EDCI (0.099 g, 0.515 mmol) were added. After stirring at RT for 30 min the (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.112 g, 0.430 mmol) dissolved in 1 ml of dry DMF was added to the reaction mixture. After overnight stirring at RT a mixture of 5-(2-hydroxypropan-2-yl)isoxazole-3-carboxylic acid (0.088 g, 0.515 mmol), DIPEA (0.090 ml, 0.515 mmol), anhydrous HOBt (0.070 g, 0.515 mmol) and EDCI (0.099 g, 0.515 mmol) dissolved in 5 ml of dry DCM was added to the reaction mixture. After 3 h the solvents were evaporated and the residue was purified by CombiFlash using MeOH in DCM as an eluent. Product fractions were combined and evaporated to give 58 mg of the product. 1H-NMR (400 MHz; CDCl3): δ 1.23 (d, 3H), 1.65 (s, 6H), 4.26 (m, 1H), 4.43 (m, 1H), 4.58 (m, 1H), 6.60 (s, 1H), 6.63 (d, 1H), 7.49 (d, 1H), 7.68 (d, 1H), 7.83 (d, 1H), 7.90 (d, 1H), 8.07 (d, 1H).
Reaction SMILES: [C:1]([C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])=CN(C)C)(=[O:3])[CH3:2].O>O1CCOCC1>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:4][C:1](=[O:3])[CH3:2])([O-:17])=[O:16]
Reactant: CC(=O)C(=CN(C)C)c1ccccc1[N+](=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Cc1ccccc1[N+](=O)[O-]

Procedure:
The product of Example 8, i.e., α-acetyl-β-dimethylamino-2-nitrostyrene was refluxed with a mixture of 8 ml. of water and 25 ml. of dioxane for 24 hours. After cooling, the mixture was concentrated in vacuo and the residue partitioned between methylene chloride and water. The organic phase was washed with brine, dried and concentrated. The crude product was chromatographed on silica gel using benzene, followed by methylene chloride as the eluent to give 926 mg. (26 percent based on β-dimethylamino-2-nitrostyrene) of 1-o-nitrophenyl-2-propanone as an oil. A small amount was recrystallized from hexane to give pale yellow plates of 1-o-nitrophenyl-2-propanone, having a melting point of 24°-25°. The nmr spectrum was in agreement with the proposed structure.
Reaction SMILES: C([O:5][C:6]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:15]=1[S:16][C:17]1[S:18][C:19]([NH2:22])=[N:20][N:21]=1)[C@H:11]([NH:23][C:24](=[O:57])[C:25]([C:31]1[N:32]=[C:33]([NH:37]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:34][C:35]=1[Cl:36])=[N:26][O:27][CH2:28][CH2:29][F:30])[C:10]2=[O:58])=[O:7])(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[NH2:37][C:33]1[S:34][C:35]([Cl:36])=[C:31]([C:25](=[N:26][O:27][CH2:28][CH2:29][F:30])[C:24]([NH:23][C@@H:11]2[C:10](=[O:58])[N:9]3[CH:12]2[S:13][CH2:14][C:15]([S:16][C:17]2[S:18][C:19]([NH2:22])=[N:20][N:21]=2)=[C:8]3[C:6]([OH:7])=[O:5])=[O:57])[N:32]=1
Reactant: CC(C)(C)OC(=O)C1=C(Sc2nnc(N)s2)CSC2[C@H](NC(=O)C(=NOCCF)c3nc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)sc3Cl)C(=O)N12
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(SC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=NOCCF)c4nc(N)sc4Cl)C3SC2)s1

Procedure:
To a solution of (7R)-7-[2-[5-chloro-2-(tritylamino)-thiazol-4-yl]-2-(2-fluoro-ethoxyimino)-acetylamino]-3-(5-amino-[1,3,4]thiadiazol-2-ylsulfanyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid t-butyl ester (8 mg, 0.009 mmol) in dichloromethane (0.16 mL) was added triethylsilane (0.04 mL), followed by trifluoroacetic acid (0.16 mL). After 3 hr at room temperature the reaction mixture was concentrated under vacuum and disopropyl ether was added to the oily residue. The title compound precipitated and was filtered, washed with additional diisopropyl ether and dried under vacuum (3 mg, 32%).
Reaction SMILES: [OH-].[K+].[CH2:3]1[O:11][C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=2)[O:4]1.[CH2:18]([OH:24])[CH2:19][O:20][CH2:21]CO>>[N+:12]([C:8]1[C:7]([N+:15]([O-:17])=[O:16])=[CH:6][C:5]([OH:4])=[C:10]([O:11][CH2:3][CH2:21][O:20][CH2:19][CH2:18][OH:24])[CH:9]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OCO2
Reactant: OCCOCCO
Agent: [K+]
Agent: [OH-]
Product: O=[N+]([O-])c1cc(O)c(OCCOCCO)cc1[N+](=O)[O-]

Procedure:
0.4 mol (26.4 g) of 85% pure potassium hydroxide pellets is added at 70° C. to 200 ml of diethylene glycol. 0.2 mol (42.4 g) of 4,5-methylenedioxy-1,2-dinitrobenzene is added to this solution. The heating is maintained for 31/2 hours. After dilution with ice-cold water and neutralization with 22 ml of acetic acid, the expected product precipitates. After being dried, it is recrystallized from 96° strength alcohol. It melts at 135° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][CH:8]1[CH:13]=[C:12]([CH3:14])[CH2:11][CH2:10][C:9]1([CH:17]=[CH2:18])[CH:15]=[O:16].O.[OH-].[Na+]>C(OCC)C>[CH3:7][CH:8]1[CH:13]=[C:12]([CH3:14])[CH2:11][CH2:10][C:9]1([CH2:15][OH:16])[CH:17]=[CH2:18]
Reactant: C=CC1(C=O)CCC(C)=CC1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: C=CC1(CO)CCC(C)=CC1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a suspension of LiAlH4 (0.114 g, 30 mmol) in diethylether (20 ml) was added a solution of 2,4-dimethyl-1-vinylcyclohex-3-enecarbaldehyde (56 mmol) in diethylether (10 ml) at 5° C. The mixture was stirred at room temperature for 1 h. 0.1 ml of water, 0.1 ml 16% aq. NaOH and 0.3 ml of water were carefully added dropwise. The mixture was stirred for 2 h, was then filtered and concentrated in vacuo. The residue was purified by chromatography to give (2,4-dimethyl-1-vinylcyclohex-3-enyl)methanol (76% yield).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][O:22][CH2:23][CH:24]3[CH2:26][CH2:25]3)[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:31]>O1CCOCC1>[ClH:31].[ClH:31].[CH:24]1([CH2:23][O:22][CH2:21][CH2:20][N:19]2[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=[C:15]2[N:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]2)[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCOCC2CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc2c(c1)nc(N1CCCNCC1)n2CCOCC1CC1

Procedure:
Treat a solution of 4-[1-(2-cyclopropylmethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.32 g, 0.76 mmol) and dioxane (4 mL) with 4N HCl in dioxane (2.3 mL, 12 equivalents) with stirring. After 90 minutes concentrate to remove the solvent, add 2.5 mL, of dichloromethane and then add ether dropwise with stirring. Repeat the process of concentration, dissolving in dichloromethane (2 mL) and treating the solution with ether and allowing the mixture to stir overnight until a suspension of yellow crystalline material is obtained. Collect the prpeipitate by filtration under argon, wash with ether and dry in vacuo overnight to give 1-(2-cyclopropylmethoxy-ethyl)-2-[1,4]diazepan-1-yl-1H-benzoimidazole dihydrochloride (0.22 g). Treat a slurry of 1-(2-cyclopropylmethoxy-ethyl)-2-[1,4]diazepan-1-yl-1H-benzoimidazole dihydrochloride (0.16 g, 0.42 mmol) and dichloromethane (150 mL) with saturated NaHCO3 solution. Extract the aqueous phase once with dichloromethane (100 mL). Wash the combined dichloromethane phases with water (3×200 mL) and saturated brine (100 mL), dry (MgSO4) the organic phase, filter and concentrate to afford a 1-(2-cyclopropylmethoxy-ethyl)-2-[1,4]diazepan-1-yl-1H-benzoimidazole as a yellow oil (0.10 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19](O)=[O:20])[N:12]3[N:25]=[CH:26][C:27]([CH:28]=[C:29]4[C:33](=[O:34])[NH:32][C:31](=[O:35])[NH:30]4)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N:53]1([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1.C(Cl)CCl>O.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([N:56]3[CH2:55][CH2:54][N:53]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:58][CH2:57]3)=[O:20])[N:12]3[N:25]=[CH:26][C:27]([CH:28]=[C:29]4[C:33](=[O:34])[NH:32][C:31](=[O:35])[NH:30]4)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C1NC(=O)C(=Cc2cnn3c(Nc4cccc(C(=O)O)c4)cc(Nc4cccc(Cl)c4)nc23)N1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(Nc3cc(Nc4cccc(Cl)c4)nc4c(C=C5NC(=O)NC5=O)cnn34)c2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73 %

Procedure:
To the reaction flask, 3-(5-(3-chlorophenylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)benzoic acid (30 mg, 0.06 mmol) was added to DMF (0.5 mL) along with HOBt (9.2 mg, 0.06 mmol), triethylamine (8.4 μL, 0.06 mmol) and tert-butyl piperazine-1-carboxylate (11.2 mg, 0.06 mmol). The reaction mixture was stirred at room temperature for 5 minutes then EDC (11.5 mg, 0.06 mmol) was added. The reaction was allowed to stir for an additional hour then diluted with water and filtered. The recovered solid was washed with more water followed by ethanol. The product, tert-butyl 4-(3-(5-(3-chlorophenylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)benzoyl)piperazine-1-carboxylate, was collected as a solid in 73% yield. LCMS (M+1=658)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[C:20]([C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=1)#[N:21]>CCCCCC.C(OCC)(=O)C>[O:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[CH:23][CH:24]=3)[N:3]=2)[CH2:15][CH2:16]1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: CC1(C)OB(c2ccc(C#N)cc2)OC1(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 40 %

Procedure:
Following the general procedure A, 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine was coupled with 4-cyanophenylboronic acid pinacol ester with reaction time of 15 h. Chromatography (hexane/ethyl acetate 1:1) gave the 40% of the title compound as a colorless solid.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[C@@H:13]1([C:21]([OH:23])=O)[C:15]2([CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:14]1.[OH-].[NH4+]>C(OCC)(=O)C>[C@@H:13]1([C:21]([NH2:3])=[O:23])[C:15]2([CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:14]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)[C@H]1CC12CCOCC2
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: NC(=O)[C@H]1CC12CCOCC2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
18.85 g of carbonyldiimidazole are added to a solution of 17.66 g of (S)-6-oxaspiro[2.5]-octane-1-carboxylic acid (prepared in analogy to building block FFFFa from (R)-4-benzyl-3-((S)-6-oxaspiro[2.5]-octane-1-carbonyl)oxazolidin-2-one (building block FFFFb)) in 330 ml of ethyl acetate. The reaction solution is left to stand at room temperature for 6 hours and then 330 ml of 25% ammonium hydroxide solution are added. The reaction mixture is stirred at room temperature for 16 hours, the phases are separated, and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with water until neutral, dried with sodium sulphate and evaporated. The title compound is obtained from the residue by flash chromatography (SiO2 60 F) as a yellowish oil which may crystallize if sufficiently pure. Rf=0.28 (dichloromethane-methanol-conc. ammonia 25% 200:20:1).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[OH:12])[CH:2]([CH3:4])[CH3:3].[C:13](O)(=[O:15])[CH3:14].CC([O-])=O.[Na+]>B(F)(F)F>[OH:11][C:8]1[CH:7]=[C:6]([OH:12])[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:10][C:9]=1[C:13](=[O:15])[CH3:14]
Reactant: CC(=O)O
Reactant: CC(C)Cc1ccc(O)cc1O
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Product: CC(=O)c1cc(CC(C)C)c(O)cc1O
Temperature: 90 °C
Reaction time: 4 h

Procedure:
4-Isobutyl-benzene-1,3-diol (1 eq)was taken up in BF3.Oet2 (6 eq) and aceticacid (2 eq) was added. The solution was heated for 16 hours at 90° C. than allowed to cool to room temperature. The solution was added drop wise to 10% NaOAc (aq) and allowed to stand for 4 hours, before being extracted twice with diethyl ether. The organic phases were combined and washed with sat. NaHCO3 (aq), then dried over magnesium sulfate, filtered and concentrated in vacuo to give 1-(2,4-dihydroxy-5-isobutyl-phenyl)-ethanone, which was used without additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH:8]=[C:7]([C:16]#[C:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]3)[C:6]=2[CH:28]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>>[C:29]([O:27][CH2:26][CH2:25][N:22]1[CH2:21][CH2:20][N:19]([CH2:18][C:17]#[C:16][C:7]2[C:6]3[CH:28]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH:8]=2)[CH2:24][CH2:23]1)(=[O:31])[CH3:30]
Reactant: OCCN1CCN(CC#CC2=Cc3ccccc3Sc3ccc(Cl)cc32)CC1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCCN1CCN(CC#CC2=Cc3ccccc3Sc3ccc(Cl)cc32)CC1

Procedure:
A solution of 5.0 g. of 2-{4-[3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propynyl]-1-piperazinyl}-ethanol in 50 ml. of acetic anhydride is heated for 15 minutes on a steam-bath. After evaporation of the excess acetic anhydride under greatly reduced pressure, the resulting oil is taken up in ether and washed with saturated sodium bicarbonate solution. By concentration of the ethereal phase, there is obtained 2-{4-[3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propynyl]-1-piperazinyl}-ethyl acetate which melts at 96°-99° C. after recrystallization from ethyl acetate/hexane.
Reaction SMILES: S(=O)(=O)(O)O.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:15][NH:16][CH2:17][CH:18](O)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:7]1>>[C:19]1([CH:18]2[C:7]3[NH:6][C:14]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=4[C:8]=3[CH2:15][NH:16][CH2:17]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OC(CNCc1c[nH]c2ccccc12)c1ccccc1
Agent: O=S(=O)(O)O
Product: c1ccc(C2CNCc3c2[nH]c2ccccc32)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Concentrated sulfuric acid (72 mL) was stirred and cooled to 0° C. in an ice-methanol bath. α-[(1H-indol-3-ylmethyl-amino)methyl]benzyl alcohol, 22.5 g (0.08 mol) was added in small portions to the stirred cooled sulfuric acid reaction mixture over 2 hours. The cooling bath was removed and the reaction was stirred at room temperature for 5 hours. Then the reaction mixture was poured onto crushed ice, basified with 50% aqueous sodium hydroxide solution (with ice cooling). Ethyl acetate was added and the basic mixture stirred well until two clear phases resulted. The aqueous phase was extracted several more times with ethyl acetate, the combined extracts washed with water and dried over anhydrous sodium sulfate. The extract after filtration was evaporated in vacuo and the residue dissolved in hot benzene, filtered hot and allowed to crystallize to obtain 10.0 g of 2,3,4,5-tetrahydro-4-phenyl-1H-pyrido[4,3-b]indole, m.p. 135°-155° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](Cl)=[O:11])=[CH:5][CH:4]=1.[CH3:13][NH2:14]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:14][CH3:13])=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: CN
Product: CNC(=O)Cc1ccc(OC)cc1

Procedure:
was prepared from 4-methoxyphenylacetic acid chloride and methylamine following Method B. 1H NMR (300 MHz, CDCl3) δ 7.14 (d, 2H, J=8.67 Hz), 6.86 (d, 2H, J=8.67 Hz), 3.78 (s, 3H), 3.49 (s, 2H), 2.72 (d, 3H, J=4.71 Hz). LCMS (ESI+) [M+H]/z Calc'd 180, found 180.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1.[F:11][C:12]([F:27])([F:26])[C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1>>[F:11][C:12]([F:26])([F:27])[C:13]1[CH:14]=[C:15]([C:2]2[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=2)[CH:16]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)c1cnc(Br)s1
Product: COC(=O)c1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)s1

Procedure:
Synthesized as described in Example 310D using methyl 2-bromo-1,3-thiazole-5-carboxylate and [3,5-bis(trifluoromethyl)phenyl]boronic acid: 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 8.44 (s, 2H), 7.99 (s, 1H), 3.98 (s, 3H).