Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][NH2:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[C:28]([OH:29])=[CH:27][CH:26]=[CH:25][C:24]=2[O:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)[N:3]=1.C(N(CC)CC)C.[C:42](OC(=O)C)(=[O:44])[CH3:43]>O1CCCC1>[C:42]([NH:9][CH2:8][C:7]1[C:2]([NH2:1])=[N:3][C:4]([C:23]2[C:28]([OH:29])=[CH:27][CH:26]=[CH:25][C:24]=2[O:30][CH2:31][CH:32]2[CH2:33][CH2:34]2)=[CH:5][C:6]=1[CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1)(=[O:44])[CH3:43]
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3c(O)cccc3OCC3CC3)nc(N)c2CN)C1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCc1c(C2CCCN(C(=O)OC(C)(C)C)C2)cc(-c2c(O)cccc2OCC2CC2)nc1N
Temperature: 0 °C
Reaction time: 4 h
Yield: 54.6 %

Procedure:
To a cold (0° C.) solution of tert-butyl 3-{2-amino-3-(aminomethyl)-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-pyridinyl}-1-piperidinecarboxylate (1.9 g, 4.055 mmol) and triethylamine (1.13 mL, 8.109 mmol) in tetrahydrofuran (40.0 mL) was added acetic anhydride (0.457 mL, 4.865 mmol). The mixture was stirred at 0° C. for 4 hrs. After quenched by water, the mixture was extracted with ethyl acetate and water. The separated organic phase was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue (yellow solid) was purified by recrystallization from ethyl acetate/diisopropyl ether to give tert-butyl 3-{3-(acetylamino-methyl)-2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-pyridinyl}-1-piperidinecarboxylate (1.13 g, yield; 55%).
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][NH:7][C:6]2=[O:15].C1C=CC2N=CNC(=O)C=2C=1.[Cl:27][CH2:28][CH2:29][CH2:30][CH2:31]I.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:27][CH2:28][CH2:29][CH2:30][CH2:31][N:7]1[C:6](=[O:15])[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8]1
Reactant: ClCCCCI
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC
Agent: O=C([O-])[O-]
Agent: O=c1[nH]cnc2ccccc12
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncn(CCCCCl)c(=O)c2cc1OC

Procedure:
3-(4-chlorobutyl)-6,7-dimethoxy-4(3H)-quinazolinone was prepared starting from 6,7-dimethoxy-4(3H)-quinazolinone (1.65 g, 8 mmol). The quinazolinone was combined with 1-chloro-4-iodobutane (1.08 mL, 8.8 mmol), an excess of potassium carbonate (10 g) and stirred in 30 mL DMF overnight. The salts were filtered off and the reaction mixture was dilluted with water. The solid that formed was collected via vacuum filtration, washed with water and dried, 1.55 g (65%); gray solid; m.p. 117° C., MS: 296.8 (M+H)+
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1S(O)(=O)=[O:10].[C:14]1([S:20]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)=[NH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CO.I([O-])(=O)(=O)=O.[Na+]>O>[C:14]1([S:20]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[NH:21])=[O:10])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N=S(c1ccccc1)c1cccs1
Reactant: Cc1cc(C)c(S(=O)(=O)O)c(C)c1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: O
Product: N=S(=O)(c1ccccc1)c1cccs1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10 g. Phenyl-(2-thienyl)-sulphimide mesitylene-sulphonate are dissolved in 200 ml. methanol. A solution of 7 g. sodium periodate in 150 ml. water are added dropwise thereto, whereafter the reaction mixture is stirred for 24 hours at ambient temperature. The reaction mixture is then rendered alkaline and evaporated on a rotary evaporator. The residue obtained is partitioned between water and dichloromethane and the organic phase is evaporated. There are obtained 3.7 g. phenyl-(2-thienyl)-sulphoximide which, after recrystallisation from ethyl acetate/isopropanol, melts at 133° C.
Reaction SMILES: [C:1](=[O:40])([O:36][CH:37](I)[CH3:38])[O:2][CH:3]([CH2:20][O:21][C:22](=[O:35])[C@H:23]([CH:32]([CH3:34])[CH3:33])[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:4][O:5][C:6](=[O:19])[C@H:7]([CH:16]([CH3:18])[CH3:17])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[CH3:41][C:42]([O:44][CH2:45][C:46]1[CH2:67][S:66][C@@H:49]2[C@H:50]([NH:53][C:54](/[C:56](/[C:60]3[N:64]=[C:63]([NH2:65])[S:62][CH:61]=3)=[N:57]\[O:58][CH3:59])=[O:55])[C:51](=[O:52])[N:48]2[C:47]=1[C:68]([O-:70])=[O:69])=[O:43].[Na+]>CN(C=O)C>[C:42]([O:44][CH2:45][C:46]1[CH2:67][S:66][C@@H:49]2[C@H:50]([NH:53][C:54](=[O:55])/[C:56](/[C:60]3[N:64]=[C:63]([NH2:65])[S:62][CH:61]=3)=[N:57]\[O:58][CH3:59])[C:51](=[O:52])[N:48]2[C:47]=1[C:68]([O:70][CH:37]([O:36][C:1]([O:2][CH:3]([CH2:20][O:21][C:22](=[O:35])[C@H:23]([CH:32]([CH3:34])[CH3:33])[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:4][O:5][C:6](=[O:19])[C@H:7]([CH:16]([CH3:18])[CH3:17])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:40])[CH3:38])=[O:69])(=[O:43])[CH3:41]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Reactant: CC(I)OC(=O)OC(COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)OC(=O)OC(COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1

Procedure:
A solution of 1,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propyl 1-iodoethyl carbonate (0.156 mmol) and cefotaxime sodium (67.8 mg, 0.142 mmol) in 3.2 mL dry N,N′-dimethylformamide was stirred under argon for 22 h. The reaction mixture was concentrated and subjected to column chromatography (silica, 2/1 petroleum ether—ethyl acetate, and then 20/1 CH2Cl2-methanol) to yield an oil enriched in the desired product. The oil was dissolved in 10 mL ethyl acetate, washed with water, dried, and concentrated. A second chromatography (silica, 40/1 CH2Cl2-methanol) gave the title compound (59.7 mg) as cream-colored solids.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[C:6]([C:16]([F:19])([F:18])[F:17])=[CH:5][C:3]=1[NH2:4].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[C:24]([Cl:34])=[CH:23][N:22]=1.Cl.C([O-])(O)=O.[Na+]>CC(O)C>[Cl:34][C:24]1[C:25]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)=[N:26][C:21]([NH:4][C:3]2[CH:5]=[C:6]([C:16]([F:17])([F:18])[F:19])[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)=[CH:8][C:2]=2[F:1])=[N:22][CH:23]=1
Reactant: CN1CCN(c2cc(F)c(N)cc2C(F)(F)F)CC1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1cc(Nc2nc(Nc3cc(C(F)(F)F)c(N4CCN(C)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 130 °C

Procedure:
To a mixture of 2-fluoro-4-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)aniline (37 mg, 0.133 mmol) and 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (36 mg, 0.147 mmol) in iPrOH (1 mL) was added HCl (100 uL, 4N in dioxane). The reaction vessel was then sealed and heated to 130° C. for 4 hr. After cooling to room temperature, the mixture was treated with saturated NaHCO3 aqueous solution (5 mL) and extracted with EtOAc (3×5 mL). The organic layers were combined and concentrated. The residue was purified by preparative thin layer chromatography (silica gel, 8% MeOH/CH2Cl2), to provide 5-chloro-N2-(2-fluoro-4-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine. ESMS m/z 485.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.Cl[C:12]1[C:16]2[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=2[S:14](=[O:23])(=[O:22])[N:13]=1>>[F:21][C:19]1[CH:18]=[CH:17][C:16]2[C:12]([C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[NH:3][C:2]=3[CH3:1])=[N:13][S:14](=[O:23])(=[O:22])[C:15]=2[CH:20]=1
Reactant: O=S1(=O)N=C(Cl)c2ccc(F)cc21
Reactant: Cc1cc2ccccc2[nH]1
Product: Cc1[nH]c2ccccc2c1C1=NS(=O)(=O)c2cc(F)ccc21

Procedure:
The sub-title compound was prepared as described for example 1, step b) using 2-methyl indole and the product from step b). The product did not crystallize upon quenching, and was instead purified by partitioning between DCM and water.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([O:11][CH2:12][CH2:13][CH2:14][OH:15])=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[S:24]([O:15][CH2:14][CH2:13][CH2:12][O:11][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][CH:3]=1)(=[O:26])(=[O:25])[CH3:23]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCOc1ccnc2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCOc1ccnc2ccccc12
Yield: 53 %

Procedure:
A solution of the 3-(quinolin-4-yloxy)propan-1-ol obtained in step a) (0.5298 g, 2.6 mmol) was treated with triethylamine (0.60 mL) and methanesulfonyl chloride (0.55 g, 4.8 mmol) in dichloromethane (5 mL). After the starting material was consumed, the reaction was diluted with dichloromethane, washed with water, aq NaHCO3 and evaporated. The residue was purified by column chromatography on SiO2 and eluted with ethyl acetate. The product was obtained as a light yellow solid (0.3868 g, 53%). 1H NMR (400 MHz, CDCl3): 2.43 (2H, m), 3.00 (3H, s), 4.38 (2H, t, J=5.8 Hz), 4.55 (2H, t, J=5.8 Hz), 6.80 (1H, d, J=5.5 Hz), 7.55 (1H, t, J=8.0 Hz), 7.75 (1H, ddd, J=1.2, 7.0, 8.2 Hz), 8.20 (1H, d, J=8.4 Hz), 8.13 (1H, d, J=8.4 Hz), 8.77 (1H, d, J=5.3 Hz).
Reaction SMILES: N[C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N([O-])=O.[Na+].[ClH:20]>O.CC(C)=O>[Cl:20][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: Cl
Reactant: COC(=O)c1cc(N)c(OC)cc1OC
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cc(Cl)c(OC)cc1OC
Temperature: 25 °C

Procedure:
A 0.65 g portion of methyl 5-amino-2,4-dimethoxybenzoate was dissolved in a mixture solvent of 1.5 ml of water and 10 ml of acetone, and 1.3 ml of concentrated hydrochloric acid was added thereto, followed by dropwise addition of 0.23 g of sodium nitrite dissolved in 1 ml of water under ice-cooling and subsequent stirring for a while. Next, 0.35 g of cuprous chloride was added and the mixture was warmed up to room temperature. After completion of the reaction, insoluble matter was filtered and the resulting residue was mixed with water, extracted with ethyl acetate and then washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=500:1-40:1) to give 0.56 g of methyl 5-chloro-2,4-dimethoxybenzoate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:19](=[O:20])[NH:18][C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=2)=[C:6]([Cl:21])[CH:5]=[CH:4][C:3]=1[NH:22][C:23](=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1.[H-].[Na+].I[CH3:38]>CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]2[C:19](=[O:20])[N:18]([CH3:38])[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=2)=[C:6]([Cl:21])[CH:5]=[CH:4][C:3]=1[NH:22][C:23](=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=1
Reactant: CI
Reactant: CSc1ncc2cc(-c3c(Cl)ccc(NC(=O)c4cccc(C(F)(F)F)c4)c3Cl)c(=O)[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ncc2cc(-c3c(Cl)ccc(NC(=O)c4cccc(C(F)(F)F)c4)c3Cl)c(=O)n(C)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
To a solution of N-[2,4-dichloro-3-(2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-phenyl]-3-trifluoromethyl-benzamide (1.14 g, 2.17 mmol) in DMF (35 mL) is slowly added NaH (117.2 mg, 60%, 2.93 mmol) with stirring for 30 minutes a 0° C. Iodomethane (369 mg, 2.60 mmol) is added to above solution with stirring for 40 minutes at 0° C. The solvents are evaporated and diluted with EtOAc and washed with saturated K2CO3, brine and water. The organic layer is dried, filtered and concentrated to give crude product, which is purified by flash silica gel column, eluting with CH2Cl2 (100%) gradient to CH2Cl2/MeOH(NH3, 2N)(93/7), to give the title intermediate as a solid (1.14 g, 98.0%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH2:11][C:10](=[O:12])[CH:9]=[CH:8][CH2:7]1)(=[O:3])[CH3:2].C(O[CH2:18][N:19]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:20][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>ClCCl.FC(F)(F)C(O)=O>[C:1]([O:4][CH2:5][CH:6]1[CH2:7][CH:8]2[CH:9]([CH2:18][N:19]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:20]2)[C:10](=[O:12])[CH2:11]1)(=[O:3])[CH3:2]
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CC(=O)OCC1CC=CC(=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCC1CC(=O)C2CN(Cc3ccccc3)CC2C1
Reaction time: 1 h

Procedure:
To a solution of 6.5 g of 5-acetoxymethyl-2-cyclohexen-1-one [J. Am. Chem. Soc., 110, 2919 (1988)]and 14 g of N-butoxymethyl-N-trimethylsilylmethylbenzylamine in 60 cm3 of dry dichloromethane are added 2 drops of trifluoroacetic acid. The reaction mixture reaches reflux and is maintained at the same temperature for 30 minutes and is then left at 20° C. for one hour. After addition of 1.0 g of potassium carbonate, the suspension obtained is filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The oily residue obtained is chromatographed on a column of silica gel (particle size 0.06-0.2 mm, height 42 cm) in a mixture of cyclohexane and ethyl acetate (40/60 by volume) and then in ethyl acetate. 8.2 g of (3aRS,6SR,7aSR)-6-acetoxymethyl-2-benzyl-4-perhydroisoindolone are obtained in the form of a yellowish oil.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[CH:21]([C:23]1[C:24]([O:32][CH3:33])=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)=[O:22].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=3)[NH:3][C:2]=2[C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([CH:21]=[O:22])[C:24]=2[O:32][CH3:33])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: COc1c(C=O)cccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccc(C=O)c3OC)[nH]c2c1
Temperature: 110 °C
Yield: 77 %

Procedure:
Methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (prepared as in International patent application WO 2004/087714), (3-formyl-2-methoxyphenyl) boronic acid (1.5 eq) and Pd(PPh3)2Cl2 (0.1 eq) were dissolved in dioxane (0.08M). The solution was degassed and flushed with Ar. 2M Na2CO3 solution (1 eq) was added and the mixture was heated to 110° C. for 2 h. All volatiles were evaporated in vacuo and the residual material was dissolved in EtOAc, filtered over Celite and evaporated in vacuo. The residual material was filtered over a plug of silica gel eluting with (PE/EtOAc 1:1). After evaporation of the fractions containing product and trituration with Et2O methyl 3-cyclohexyl-2-(3-formyl-2-methoxyphenyl)-1H-indole-6-carboxylate was obtained as off-white solid (77%). (ES+) m/z 392 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[CH:10]=[N:9][N:8]([CH:11]3[CH2:14][O:13][CH2:12]3)[C:6]=2[N:7]=1.[CH3:28][C:29]1([CH3:46])[CH2:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][C:31]([CH3:45])([CH3:44])[NH:30]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][C:24]1[CH:23]=[C:22]([CH3:26])[NH:21][C:20](=[O:27])[C:19]=1[CH2:18][NH:17][C:15]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]3[CH2:14][O:13][CH2:12]3)[C:6]=2[N:7]=[C:2]([C:33]2[CH2:32][C:31]([CH3:45])([CH3:44])[NH:30][C:29]([CH3:46])([CH3:28])[CH:34]=2)[CH:3]=1)=[O:16]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C2COC2)c(=O)[nH]1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CC(C)(C)NC(C)(C)C3)nc3c2cnn3C2COC2)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(oxetan-3-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.), 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane was purged with argon for 10 min. Then, 2 M Na2CO3 (3.6 equiv.) solution was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (44% yield). LCMS: 491.50 (M+1)+; HPLC: 98.99% (@ 254 nm) (Rt; 4.678); 1H NMR (DMSO-d6, 400 MHz) δ 11.54 (bs, 1H), 8.93 (t, 1H), 8.43 (s, 1H), 7.83 (s, 1H), 6.84 (s, 1H), 6.21-6.14 (m, 1H), 5.89 (s, 1H), 5.08-5.02 (m, 4H), 4.38 (d, 2H, J=4.4 Hz), 2.42 (s, 2H), 2.23 (s, 3H), 2.12 (s, 3H), 1.24 (s, 6H), 1.14 (s, 6H).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.Cl[C:22]1[O:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1.N12CCCN=C1CCCCC2>O1CCOCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:22]4[O:23][C:24]5[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=5[N:26]=4)[CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: Clc1nc2ccccc2o1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(c3nc4ccccc4o3)CC2)nn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
To the 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (0.080 g, 0.290 mmol) in dioxane (7 mL) was added 2-chlorobenzooxazole (0.053 g, 0.34 mmol) followed by the addition of 1,8-diazabicyclo[5,4,0]undec-7-ene (0.132 mL, 0.87 mmol) and tetra-n-butylammonium iodide (3 mg). The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate, then washed with citric acid, sodium bicarbonate and brine solution. The organic layer was separated, and dried over anhydrous Na2SO4, and evaporated. The residue was purified by recrystallization from n-hexane to yield the title compound as a white powder in 44% yield (0.050 g). 1H NMR (300 MHz, CDCl3) δ 8.07 (d, J=9.5 Hz, 1H), 7.99 (t, J=5.3 Hz, 1H), 7.39 (d, J=7.4 Hz, 1H), 7.28 (d, J=7.8 Hz, 1H), 7.19 (m, 1H), 7.05 (m, 2H), 3.92 (m, 8H), 3.55 (m, 2H), 1.48 (m, 2H), 0.79 (m, 1H), 0.46 (m, 2H), 0.07 (m, 2H). MS (ES+) m/z 393 (M+1).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1([C:13]#[N:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-:15].[Na+]>>[NH2:6][C:7]1([C:13]([NH2:14])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: N#CC1(N)CCCCC1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)C1(N)CCCCC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To 20 g concentrated sulfuric acid at 5° C is added with stirring 10 g of 1-aminocyclohexanecarbonitrile. After the addition, the mixture is heated with stirring at 100° C for 1 hour. The hot solution is then poured onto ice, the solution made strongly basic with 50% aqueous sodium hydroxide solution, and extracted three times with chloroform. The extract is washed with water, saturated NaHCO3 solution, dried, and the solvent removed in vacuo to leave the product, 1-aminocyclohexanecarboxamide, as a crystalline residue, melting point 99°-102° . This can be recrystallized from either benzene or ether or give a pure product, melting point 101°-102° C.
Reaction SMILES: C(O[CH:6]([N:29]=[C:30]=[O:31])[CH2:7][CH2:8][NH:9][C:10](=[O:28])[NH:11][C:12]1[CH:13]=[C:14]([CH:25]=[CH:26][CH:27]=1)[C:15]([NH:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[O:16])(C)(C)C.[OH-:32].[Na+]>C(O)C>[C:14]([O:32][C:30]([NH:29][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:28])[NH:11][C:12]1[CH:13]=[C:14]([CH:25]=[CH:26][CH:27]=1)[C:15]([NH:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:16])=[O:31])([CH3:25])([CH3:15])[CH3:13]
Reactant: [OH-]
Reactant: CCOC(=O)CCNC(=O)c1cccc(NC(=O)NCCC(N=C=O)OC(C)(C)C)c1
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCNC(=O)Nc1cccc(C(=O)NCCC(=O)O)c1
Reaction time: 25 h

Procedure:
0.61 g (1.33 mmol) of ethyl 3-(3-(3-(3-tert-butyloxy-carbonylaminopropyl)ureido)benzoylamino)propionate is dissolved in 50 ml of ethanol and treated with 0.73 ml of 2N NaOH. After 25 h at room temperature, the solvent is removed in vacuo and the residue is treated with 20 ml of water and 20 ml of ethyl acetate and acidified with citric acid. The phases are separated and the aqueous phase is extracted a further two times with 20 ml of ethyl acetate each time. After drying (MgSO4), the solvent is removed in vacuo and the residue (0.62 g) is employed without further purification.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[CH2:19]([NH2:22])[CH2:20][NH2:21]>O>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:21][CH2:20][CH2:19][NH2:22])[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reactant: NCCN
Solvent: O
Product: C=CCNc1nc(NCCN)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
A mixture of 230 mg (0.87 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 899 mg (14.96 mmol) of ethylenediamine was stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 200 mg (yield: 79.9%) of the title compound.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[OH:8][C@@H:9]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:25]2[C:24](=[O:30])[CH2:23][C@@:22]2([CH3:31])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C:19](=[O:21])[CH3:20])[CH2:10]1.N1C=CC=CC=1>O1CCCC1>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([O:8][C@@H:9]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:25]2[C:24](=[O:30])[CH2:23][C@@:22]2([CH3:31])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C:19](=[O:21])[CH3:20])[CH2:10]1)=[O:4]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(=O)C(Cl)(Cl)Cl)CC[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
A solution of trichloroacetyl chloride (0.5 ml.) in dry tetrahydrofuran (8 ml.) was added dropwise to a cooled (-80°) and stirred solution of 3α-hydroxy-5α-pregnane-11,20-dione (0.75 g.) and pyridine (0.35 ml.) in dry tetrahydrofuran (15 ml.). After 30 min. the mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with 2N-hydrochloric acid, aqueous sodium hydrogen carbonate, then water. The solution was dried and concentrated to leave a residue which was crystallised from benzene then benzene-petrol to afford the title compound (0.21 g.), m.p. 126°-127°, [α]D + 86°.