Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH:7]([CH3:8])[CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([S:13]([NH2:16])(=[O:15])=[O:14])[C:4]=2[O:3]1.N12CCCN=C1CCCCC2.[CH3:29][O:30][C:31]1[CH:36]=[C:35]([CH3:37])[N:34]=[C:33]([N:38](C2C=CC=CC=2)[C:39](=O)[O-:40])[N:32]=1>O1CCOCC1>[O:17]=[S:2]1(=[O:1])[CH:7]([CH3:8])[CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([S:13]([NH:16][C:39]([NH:38][C:33]3[N:32]=[C:31]([O:30][CH3:29])[CH:36]=[C:35]([CH3:37])[N:34]=3)=[O:40])(=[O:14])=[O:15])[C:4]=2[O:3]1
Reactant: COc1cc(C)nc(N(C(=O)[O-])c2ccccc2)n1
Reactant: CC1Cc2cccc(S(N)(=O)=O)c2OS1(=O)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc3c2OS(=O)(=O)C(C)C3)n1
Reaction time: 0.75 h
Yield: 93.4 %

Procedure:
A mixture of 3.33 g of 3,4-dihydro-2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonamide, 1.84 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene, 3.2 g of N-(4-methoxy-6-methylpyrimidin-2-yl)phenylcarbamate and 35 ml of absolute dioxan is stirred for 45 minutes at a temperature in the range from 20° to 25° C. The mixture is concentrated and the oily residue is triturated with ether and 14 ml of 1N hydrochloric acid. The crystalline precipitate obtained is isolated, washed with water and dried, affording 4.96 g of N-(3,4-dihydro-2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonyl)-N'-(4-methoxy-6-methylpyrimidin-2-yl)urea of m.p. 215°-218° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:15][C:16]1[CH:17]=[C:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:20][CH:21]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(#N)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C:12]([NH:15][C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH:19]=[CH:20][CH:21]=2)=[O:14])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Reactant: O=C(O)CCc1cccc([N+](=O)[O-])c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1cccc(NC(=O)CCc2cccc([N+](=O)[O-])c2)c1
Reaction time: 16 h

Procedure:
A solution of 3-(3-nitrophenyl)propanoic acid (0.43 g, 2.2 mmol) and tert-butyl (3-aminophenyl)carbamate (0.50 g, 2.4 mmol) in acetonitrile (16 mL) was treated with O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.2 g, 3.3 mmol) followed by N,N-diisopropylethylamine (0.57 mL, 3.3 mmol) and stirred for 16 h. The reaction mixture was concentrated and diluted with brine (80 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product as a crude residue. This material was purified by flash column chromatography to give the desired product (0.87 g, 98%) as an off-white foam. LCMS for C16H16N3O5 ([M-(t-Bu)+H]+H)+: m/z=330.0.
Reaction SMILES: C(O[C:4](=[O:20])[NH:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[N:9]=[CH:8][N:7]=1)C.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C1(C)C=CC=CC=1>O>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:4]([NH:5][C:6]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])[N:9]=[CH:8][N:7]=2)=[O:20])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)Nc1cc(-c2ccccc2OC)ncn1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccccc1-c1cc(NC(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ncn1
Reaction time: 0.17 h
Yield: 53.2 %

Procedure:
A mixture of [6-(2-methoxy-phenyl)-pyrimidin-4-yl]-carbamic acid ethyl ester (XL) (0.30 g, 1.1 mmol), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.23 g, 1.1 mmol) and toluene (4 ml) was subjected to microwave conditions at 120° C. and 100 psi pressure for 10 minutes. The reaction was monitored by TLC. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to provide 0.250 g of 4-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-ureido}-piperidine-1-carboxylic acid tert-butyl ester (XLIV).
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[NH2:10][CH:11]([CH2:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1)[CH2:12][OH:13].[C:21]([N:25]=[C:26]=[S:27])([CH3:24])([CH3:23])[CH3:22]>C(O)C>[C:21]([NH:25][C:26]([NH:10][CH:11]([CH2:12][OH:13])[CH2:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1)=[S:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)N=C=S
Reactant: NC(CO)Cc1cnccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)NC(=S)NC(CO)Cc1cnccn1
Temperature: 50 °C

Procedure:
11.2 cm3 of triethylamine are added with stirring to a solution of 7.91 g of (2RS)-2-amino-3-(2-pyrazinyl)-1-propanol dihydrochloride in 80 cm3 of ethanol, followed by addition of 7.2 cm3 of tert-butyl isothiocyanate. The mixture is heated at a temperature in the region of 50° C. for 18 hours. After cooling, the reaction medium is concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C., taken up in 100 cm3 of water and extracted with dichloromethane. The organic phases are combined, washed with 50 cm3 of water, dried over magnesium sulphate, filtered and then concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. 7.2 g of N-(tert-butyl)-N′-[(1RS)-1-hydroxymethyl-2-(2-pyrazinyl)-ethyl]thiourea are obtained in the form of a colourless paste [mass spectrum: DCI m/z=269 MH+]
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[H-].[Na+].[CH2:10](Br)[C:11]#[CH:12].O>O1CCCC1>[CH:10]([N:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1)=[C:11]=[CH2:12]
Reactant: O=Cc1cc[nH]c1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=C=Cn1ccc(C=O)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1 g of pyrrole-3-carboxaldehyde was dissolved in 25 ml of tetrahydrofuran with stirring at the ambient temperature for 15 minutes and after cooling to 0° to 5° C., 528 mg of sodium hydride as 50% in oil were added with stirring for 10 minutes cold. The temperature was allowed to return to the ambient with stirring for 40 minutes under nitrogen and 1 ml of propargyl bromide was added with stirring for a further 2 hours at 40° to 50° C. Then, the reaction mixture was poured into 15 ml of water, and was extracted with methylene chloride. The extracts were dried and concentrated by distilling off the solvent. The residue was chromatographed over silica and eluted with a mixture of hexane and ethyl acetate (7-3) to obtain 1.166 g of 1-propadienyl-1H-pyrrole-3-carboxaldehyde.
Reaction SMILES: [F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[CH:37]1([C:40](Cl)=[O:41])[CH2:39][CH2:38]1>ClCCl>[CH:37]1([C:40]([N:34]2[CH2:35][CH2:36][N:31]([C:30]3[C:2]([F:1])=[CH:3][C:4]4[N:8]=[C:7]([CH2:9][O:10][C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[N:6]([CH2:17][C:18]5[CH:19]=[CH:20][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:22][CH:23]=5)[C:5]=4[CH:29]=3)[CH2:32][CH2:33]2)=[O:41])[CH2:39][CH2:38]1
Reactant: O=C(Cl)C1CC1
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(OC(F)(F)F)cc3)c2cc1N1CCNCC1
Solvent: ClCCl
Product: O=C(C1CC1)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
80 mg of 5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole (0.16 mmol) and 0.033 ml TEA (0.24 mmol) were dissolved in 1.5 ml dichloromethane and treated with 0.019 ml cyclopropanecarbonyl chloride (0.2 mmol). After 2 h stirring at rt, the reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 89 mg yellow solid (98%). MS (ISP) 569.4 (M+H)+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:15]=[C:16]1[O:20][C@H:19]([C:21]([Cl:24])([Cl:23])[Cl:22])[N:18]2[CH2:25][CH2:26][CH2:27][C@@:17]12[CH:28]=O.[F:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][NH2:35].C(O)(=O)C>ClCCCl>[F:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][NH:35][CH2:28][C@@:17]12[CH2:27][CH2:26][CH2:25][N:18]1[C@@H:19]([C:21]([Cl:24])([Cl:23])[Cl:22])[O:20][C:16]2=[O:15]
Reactant: NCc1cccc(F)c1
Reactant: O=C[C@@]12CCCN1[C@@H](C(Cl)(Cl)Cl)OC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@]12CNCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium triacetoxyborohydride (544 mg, 2.57 mmol) was added to (3R,7aR)-1-oxo-3-trichloromethyl-dihydro-pyrrolo[1,2-c]oxazole-7a-carbaldehyde (obtained as described in J. Org. Chem. 2006, 71(1), 97-102, 500 mg, 1.835 mmol), 3-fluorobenzylamine (0.251 mL, 2.20 mmol) and acetic acid (0.263 mL, 4.59 mmol) in DCE (4 mL) under an argon atm. The RM was stirred at rt for 3 h, then partitioned between water and DCM, the combined organic dried over Na2SO4 and evaporated to give the title compound as a pale yellow oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[N:10][CH:9]=[CH:8][C:7]=3[C:6]=2[C:5]2[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:4]=2[N:3]=1.[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.ClCCl>[CH2:21]([O:20][C:18]1[CH:17]=[CH:16][C:5]2[C:6]3[C:7]4[CH:8]=[CH:9][N:10]=[CH:11][C:12]=4[C:13](=[O:15])[C:14]=3[C:2]([Cl:1])=[N:3][C:4]=2[CH:19]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClCc1ccccc1
Reactant: O=C1c2cnccc2-c2c1c(Cl)nc1cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1c2cnccc2-c2c1c(Cl)nc1cc(OCc3ccccc3)ccc21
Temperature: 90 °C
Reaction time: 2 h

Procedure:
6-Chloro-3-hydroxy-5,9-diaza-benzo[c]fluoren-7-one (Example 34a) (27 mg) was dissolved in DMF (2 ml). To the solution were added benzyl chloride (0.016 ml) and potassium carbonate (29 mg). The mixture was stirred at 90° C. for 2 hours. The reaction mixture was dissolved in dichloromethane and the mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography developed by dichloromethane and dichloromethane-MeOH=50:1. The desired product (12 mg) was obtained as a light yellow solid. EI−MS: m/z 372 (M+); 1H-NMR (CDCl3): δ5.25 (2H, s), 7.30-7.55 (7H, m), 8.00 (1H, dd, J=5 Hz, 1 Hz), 8.36 (1H, d, J=9Hz), 8.95 (1H, d, 5 Hz), 9.03 (1H, d, J=1 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=1.O.[NH2:17][NH2:18]>O>[NH:17]([C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=1)[NH2:18]
Reactant: NN
Reactant: Clc1cc(OCc2cccnc2)ccn1
Solvent: O
Product: NNc1cc(OCc2cccnc2)ccn1
Temperature: 80 °C
Yield: 40.1 %

Procedure:
A mixture of 0.5 g (2.27 mmol) of 2-chloro-4-(pyridin-3-ylmethoxy)pyridine and 2 mL (40.5 mmol) of hydrazine hydrate is heated at 80° C. for 12 hours. The reaction medium is then taken up in 30 mL of water and extracted with EtOAc (3×30 mL). The organic phases are combined, washed with brine (20 mL) and then dried over Na2SO4, filtered, concentrated under reduced pressure and purified on silica gel, eluting with a 95/5 DCM/MeOH mixture. 197 mg of 2-hydrazinyl-4-(pyridin-3-ylmethoxy)pyridine are obtained in the form of a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[N:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[N:3]=1.O.[NH2:30][NH2:31]>C(Cl)(Cl)Cl>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:4]2[N:3]=[C:2]([NH:30][NH2:31])[N:7]([CH3:8])[C:6](=[N:9][C:10]3[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[CH3:18])[CH:5]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: NN
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(Cl)n2)cc1OC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(NN)n2)cc1OC

Procedure:
To a suspension of 2-chloro-3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)pyrimidine (10.0 g) in chloroform (100 ml) was added hydrazine hydrate (3.66 ml). The mixture was refluxed for 6 hours. The reaction mixture was evaporated in vacuo. The residue was chromatographed on silica gel using chloroform to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-2-hydrazino-3-methyl-4-(2,4,6-trimethylphenylimino)pyrimidine (3.46 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([NH:16][S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])(=[O:10])=[O:9])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccccc1F
Product: CC(C)(C)NS(=O)(=O)c1ccccc1F

Procedure:
30 g (0.13 mol) of (N-tert-butyl)-2-fluorobenzenesulfonamide, obtained from the reaction of 2-fluorobenzenesulfonyl chloride with N-tert-butylamine in analogy to example A1, are introduced in 300 ml of dry tetrahydrofuran. The solution is cooled to −70° C. and a solution of 18.28 g (0.285 mol) of n-butyllithium (2.5 molar in tetrahydrofuran) is added dropwise. Thereafter the reaction solution is warmed to −30° C. over 30 min, after which it is cooled again to −70° C. Then 36.21 g (0.143 mol) of iodine in 200 ml of dry tetrahydrofuran are added dropwise. Following the addition the reaction solution is warmed slowly to room temperature and stirred for 12 h. Thereafter it is washed with 50% strength aqueous sodium thiosulfate solution and water. The organic phase is dried and evaporated. This gives 40.8 g (88% of theory) of N-(tert-butyl)-2-fluoro-6-iodobenzenesulfonamide.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31]([OH:33])=O)[C:20]([CH3:34])=[C:19]1[CH3:35])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C(O[N:40]([C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(=O)N)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[C@H:21]([C:31](=[O:33])[NH2:40])[C:20]([CH3:34])=[C:19]1[CH3:35])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C(C)=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C(C)=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 95 %

Procedure:
The title compound was prepared from (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-1-(tert-butoxycarbonyl)-3,4-dimethyl-1,2,5,6-tetrahydropyridine-2-carboxylic acid (Intermediate 194, 1.48 g, 2.89 mmol) following the procedure described for Intermediate 20. Silica gel chromatography (0%-80% ethyl acetate/hexanes) afforded the desired product as a light yellow foamy solid (1.41 g, 95%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[CH3:12][NH:13][O:14][CH3:15].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:13]([O:14][CH3:15])[CH3:12])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CNOC
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3-bromophenyl)acetic acid (4.4 g, 20.56 mmol) in N,N-dimethylformamide (125 ml) was successively added N,O-dimethylhydroxyamine (4.5 g, 46.26 mmol), triethylamine (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.9 g, 46.26 mmol) and 1-hydroxybenzotriazole (6.24 g, 46.26 mmol). The reaction mixture was stirred at room temperature overnight, and partitioned between ethyl acetate and brine. The organic phase was washed with brine, and concentrated. The residue was purified by flash chromatography on silica gel (50% ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 258 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[N:6][C:7]=1[Cl:8].C([Mg]Cl)(C)C.C([Li])(C)(C)C.CN(C)[CH:30]=[O:31]>O1CCCC1.O>[Cl:8][C:7]1[C:2]([CH:30]=[O:31])=[CH:3][CH:4]=[C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:6]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc(CNc2ccc(Br)c(Cl)n2)cc1
Agent: CC(C)[Mg]Cl
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(NCc2ccc(Cl)cc2)nc1Cl
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To (5-bromo-6-chloro-pyridin-2-yl)-(4-chloro-benzyl)-amine (539, 2.60 g, 7.83 mmol) in tetrahydrofuran (60.0 mL) under an atmosphere of nitrogen at −78° C., isopropylmagnesium chloride (2.00 M in tetrahydrofuran, 4.20 mL) was added over 10 minutes. The reaction was stirred at −78° C. for 20 minutes, then allowed to warm to room temperature for 10 minutes. The reaction was cooled to −78° C. tert-Butyllithium (1.70 M in hexane, 10.2 mL) was added to the reaction over 10 minutes. After 40 minutes, N,N-dimethylformamide (1.80 mL, 0.0232 mol) was added to the reaction. The reaction was stirred at −78° C. for 40 minutes, then allowed to warm to room temperature for another 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 35% to 100% ethyl acetate in hexane to give a light yellow solid (540, 1.0 g, 45.4%). MS (ESI) [M−H+]−=279.0.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]3[NH:15][N:16]=[C:17]([NH2:18])[C:12]3=[N:11][CH:10]=2)=[CH:5][CH:4]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=1[S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl.N1C=CC=CC=1>[NH2:18][C:17]1[C:12]2[C:13](=[N:14][C:9]([C:6]3[CH:7]=[CH:8][C:3]([NH:2][S:27]([C:21]4[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=4[F:19])(=[O:28])=[O:29])=[CH:4][CH:5]=3)=[CH:10][N:11]=2)[NH:15][N:16]=1
Reactant: Nc1ccc(-c2cnc3c(N)n[nH]c3n2)cc1
Reactant: Cc1ccc(F)c(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(F)c(S(=O)(=O)Nc2ccc(-c3cnc4c(N)n[nH]c4n3)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 500 mg of 6-(4-amino-phenyl)-1H-pyrazolo[3,4-b]pyrazin-3-ylamine hydrochloride and 397 mg of 2-fluoro-5-methyl-benzenesulfonyl chloride in 4 ml DCM, 0.16 ml pyridine were added and the reaction mixture was stirred for 16 h at RT. Then, the solvents were removed under reduced pressure and the crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/EtOAc. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 220 mg.
Reaction SMILES: [N:1]1([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=O)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[CH2:24]([NH2:27])[CH2:25][CH3:26]>C1COCC1>[N:1]1([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([NH:27][CH2:24][CH2:25][CH3:26])=[O:21])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)CCCCCn1cnc2cnc3ccccc3c21
Reactant: CCCN
Solvent: C1CCOC1
Product: CCCNC(=O)CCCCCn1cnc2cnc3ccccc3c21
Yield: 95.9 %

Procedure:
A solution of ethyl 6-(1H-imidazo[4,5-c]quinolin-1-yl)hexanoate (7.0 g, 22.5 mmol) and n-propylamine (11.1 mL, 135 mmol) in THF (10 mL) was heated at 100° C. for ten days in a sealed high-pressure vessel. Additional n-propylamine (20 mL) was added after three days and again after seven days. After ten days, the reaction was concentrated under reduced pressure to provide 7.0 g of 6-(1H-imidazo[4,5-c]quinolin-1-yl)-N-propylhexanamide.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]2[C:20](=[CH:21][CH:22]=1)[O:19][C:13]1([CH2:18][CH2:17][CH2:16][O:15][CH2:14]1)[CH2:12][C:11]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C[Si]([N:35]=[C:36]=[N:37][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[O:1]([C:8]1[CH:9]=[C:10]2[C:20](=[CH:21][CH:22]=1)[O:19][C:13]1([CH2:18][CH2:17][CH2:16][O:15][CH2:14]1)[CH2:12]/[C:11]/2=[N:37]\[C:36]#[N:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: O=C1CC2(CCCOC2)Oc2ccc(Oc3ccccc3)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#C/N=C1\CC2(CCCOC2)Oc2ccc(Oc3ccccc3)cc21
Temperature: 0 °C
Yield: 25.8 %

Procedure:
To a solution of 6-phenoxy-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (500 mg, 1.27 mmol) and triethylamine (227 mg, 0.73 mmol) in dried CH2Cl2 (10 mL) was added TiCl4 (1 M solution in DCM, 1.47 mmol) dropwise within 15 minutes. The mixture was stirred forl h after addition. To this mixture was added bis-trimethylsilylcarbodiimide (300 mg, 1.16 mmol) dropwise. The resulting mixture was stirred for 18 h after addition. The reaction mixture was poured into ice-water (50 g) and extracted with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give (E)-N-(6-phenoxy-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-ylidene)cyan amide (100 mg, crude), which was used for the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[OH:14])([O-])=O.Cl[Sn]Cl>CCO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][C:5]=1[OH:14]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)cc1O
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccc(C(F)(F)F)cc1O

Procedure:
2-Amino-5-trifluoromethylphenol was prepared by treating 2-nitro-5-trifluoromethylphenol (500 mg, 2.41 mmol) with a solution of SnCl2 (3.5 g, mmol) in EtOH at 23° C. for 12 h. The mixture was concentrated to 50 mL and adjusted to pH7 using saturated sodium bicarbonate. The reaction mixture was partitioned between H2O and EtOAc. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting colorless oil(370 mg, 87%) was used without further purification. 1H NMR (CDCl3): 7.6 (s, 1H), 7.39(d, 1H, J=8.5 Hz), 7.08(d, 1H, J=8.5 Hz)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]([CH3:16])=[CH2:15])[C:6]1=[O:17].Br.[CH3:19][C:20]1[CH:21]=[C:22]([C:26](=[O:34])[CH2:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[CH3:16][C:14]([N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:5]([CH2:4][CH2:3][CH2:2][N:31]2[CH2:30][CH2:29][CH:28]([CH2:27][C:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([CH3:19])[CH:21]=3)=[O:34])[CH2:33][CH2:32]2)[C:6]1=[O:17])=[CH2:15]
Reactant: C=C(C)n1c(=O)n(CCCCl)c2ccccc21
Reactant: Cc1cccc(C(=O)CC2CCNCC2)c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: C=C(C)n1c(=O)n(CCCN2CCC(CC(=O)c3cccc(C)c3)CC2)c2ccccc21
Yield: 100 %

Procedure:
A mixture of 5.5 parts of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one, 6 parts of 1-(3-methylphenyl)-2-(4-piperidinyl)ethanone hydrobromide, 8.5 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone is stirred and refluxed overnight using a water-separator. The reaction mixture is cooled, water is added and thelayers are separated. The 4-methyl-2-pentanone-phase is dried, filtered and evaporated, yielding 8.6 parts (100%) of 1,3-dihydro-1-(1-methylethenyl)-3-[3-[4-[2-(3-methylphenyl)-2-oxoethyl]-1-piperidinyl]propyl]-2H-benzimidazol-2-one as an oily residue.