Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C(N(CC)CC)C.Br[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C:21](=[O:24])[NH:20][C:19]=2[CH:25]=1>CN(C)C=O>[CH2:1]([NH:4][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C:21](=[O:24])[NH:20][C:19]=2[CH:25]=1)[CH2:2][CH3:3]
Reactant: CCCN
Reactant: O=C1COc2ccc(CCBr)cc2N1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCNCCc1ccc2c(c1)NC(=O)CO2

Procedure:
In a round-bottomed flask equipped with a mechanical stirrer and a calcium chloride guard tube, 0.01 mol of n-propylamine and 0.015 mol of triethylamine are added to a solution of 6-(2-bromoethyl)-3-oxo-2,3-dihydro-1,4-benzoxazine in 40 cm3 of dimethylformamide. The mixture is heated to reflux for 15 hours and the precipitate formed is drained in the heated state. The residue is evaporated under vacuum and the product is recrystallized.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4](OC)=[O:5].[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][NH2:15]>>[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][NH:15][C:4](=[O:5])[CH:3]([O:8][CH3:9])[O:2][CH3:1]
Reactant: COC(=O)C(OC)OC
Reactant: NCc1cccc(F)c1
Product: COC(OC)C(=O)NCc1cccc(F)c1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
Into a sealable tube were added methyl dimethoxyacetate (0.98 g, 7.3 mmol) and 3-fluorobenzylamine (0.91 g, 7.3 mmol); this mixture was stirred at 60° C. for 2 days. The compound was purified by chromatography on silica gel (10 g/70 mL prepacked column, eluting with 5% EtOAc in hexanes→5% MeOH in hexanes), affording the title compound. HPLC: tR=2.59 min. (ZQ2, polar—5 min.). MS (ES+): m/z=249.92 (29) [MNa+], 227.91 (100) [MH+].
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]([N:15]1[CH2:20][CH2:19][N:18]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][CH2:16]1)[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.[ClH:25]>CO.C(O)(C)C.C(OCC)C>[ClH:25].[ClH:25].[NH2:8][CH2:9][C@H:10]([N:15]1[CH2:20][CH2:19][N:18]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][CH2:16]1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCN(S(C)(=O)=O)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: CC(C)O
Product: COC(=O)[C@H](CN)N1CCN(S(C)(=O)=O)CC1
Temperature: 40 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
A solution of 4 g (11 mmol) of methyl (S)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propanoate (prepared as described in example 2.4) in 40 ml of methanol and 20 ml of a solution of hydrochloric acid in isopropanol, having a concentration of 5 or 6M, is stirred at 40° C. for 18 h and then concentrated under vacuum. The residue obtained is taken up in 200 ml of diethyl ether, filtered, and then dried under vacuum. 3.5 g (94%) of methyl (S)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoate dihydrochloride are obtained in the form of a beige solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:30])[N:14]([N:23]=[C:24]3[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25]3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:31]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:30])[N:14]([NH:23][CH:24]3[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25]3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: CC1CCC(=Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3ccccc32)C1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1CCC(Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3ccccc32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 236A (0.068 g, 0.16 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.010 mL, 0.28 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.100 mL, 0.20 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water, and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with dichloromethane to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03 (m, 3 H) 1.35 (m, 1 H) 1.78 (m, 4 H) 2.56 (m, J=5.52 Hz, 2 H) 3.69 (m, 1 H) 5.78 (m, 1 H) 7.05 (m, 1 H) 7.27 (m, 2 H) 7.52 (m, 2 H) 7.69 (m, 2 H) 8.06 (dd, J=7.72, 1.47 Hz, 1 H) 16.28 (s, 1 H). MS (ESI−) m/z 437 (M−H)−.
Reaction SMILES: [F:1][C:2]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([N:21](C)[C:22](=O)C)=[CH:20][C:7]=2[N:6]=1)([F:4])[CH3:3].[OH-].[Na+]>Cl>[F:4][C:2]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:8]2[CH:17]=[CH:18][C:19]([NH:21][CH3:22])=[CH:20][C:7]=2[N:6]=1)([F:1])[CH3:3]
Reactant: CC(=O)N(C)c1ccc2c(c1)nc(C(C)(F)F)n2CC1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CNc1ccc2c(c1)nc(C(C)(F)F)n2CC1CCOCC1
Temperature: 0 °C

Procedure:
N-[2-(1,1-Difluoroethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-methylacetamide (0.48 g, 1.37 mmol) was heated to 80° C. overnight in concentrated HCl (80 mL). The reaction mixture was cool to 0° C. and brought to slightly basic pH using NaOH solution. The compound was extracted with EtOAc (3×) and the combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was concentrated giving the title compound that was used for the next step without further purification. Yield: 0.42 g (98%); MS (ESI) (M+H)+: 310.2.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:27]=[CH:26][C:16]([CH:17](Cl)[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1.[Cl-].[Na+]>CN(C)C=O>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:2]2[N:3]=[N:4][CH:5]=[N:1]2)=[CH:26][CH:27]=1
Reactant: Clc1ccc(C(Cl)c2ccc(Cl)cc2)cc1
Reactant: c1nnn[nH]1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc(C(c2ccc(Cl)cc2)n2ncnn2)cc1
Yield: 107.7 %

Procedure:
A mixture of 3.12 g of tetrazole, 26.2 g of potassium carbonate, and 10 g of 4,4'-dichlorobenzhydryl chloride from above in 150 ml of dimethylformamide was heated under a nitrogen atmosphere for 2.5 hours at 85°-90° C. and then overnight at 60°-65° C. The reaction mixture was poured into 1 liter of a saturated aqueous sodium chloride solution which was then extracted twice with 200 ml portions of ethyl acetate. The combined organic extracts were washed three times with a saturated sodium chloride solution, dried over magnesium sulfate, and evaporated to dryness to provide 12.1 g of the crude product as a pale yellow oil. The residue was purified by high pressure liquid chromatography. The primary product which was recovered was 1.1 g of the 2-tetrazole derivative as white crystals when recrystallized from methanol, m.p. 91°-92° C. Mass spectral analysis confirmed that the product had the correct molecular formula (M+ =305) and 13C and 1H NMR NOE experiments confirmed that the primary product was 2-[bis(4-chlorophenyl)methyl]-2H-tetrazole.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[Na+].Cl[CH2:30][CH:31]([OH:34])[CH2:32][OH:33]>CN(C)P(N(C)C)(N(C)C)=O.O.CCOCC>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:30][CH:31]([OH:34])[CH2:32][OH:33])=[O:23])=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: OCC(O)CCl
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1
Temperature: 140 °C

Procedure:
A solution of 7.35 g of 4-(n-hexadecylamino)benzoic acid in 50 ml of hexamethylphosphoramide is treated with 4.80 g of 25% aqueous sodium hydroxide followed by 11.0 g of 3-chloro-1,2-propanediol and then is heated at 140° C. for 6 hours. The mixture is diluted with water and ether and filtered to yield a white solid. Recrystallization from acetonitrile and then from carbon tetrachloride affords analytically pure 2,3-dihydroxypropyl 4-(n-hexadecylamino)benzoate, mp 112°-113° C.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:31]=[CH:30][C:29]([S:32]([NH:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])(=[O:34])=[O:33])=[CH:28][CH:27]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CN(C)CCNS(=O)(=O)c1ccc(Br)cc1
Product: CN(C)CCNS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 4-bromo-N-(2-dimethylamino-ethyl)-benzenesulfonamide (example B.30) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (260 mg, 45%). MS (ISP) 564.3 [(M+H)+]; mp 157-159° C.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])=CC=1)([O-])=O.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH:34]=1>O1CCCC1>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][C:35]1[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=1)=[O:10]
Reactant: COc1ccccc1C(=C/C=C/C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccccc1OC
Reactant: NCCCCc1cccnc1
Solvent: C1CCOC1
Product: COc1ccccc1C(=C/C=C/C(=O)NCCCCc1cccnc1)c1ccccc1OC
Yield: 83.6 %

Procedure:
As before in Example 134, a solution of (E)-5,5-bis(2-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (2.1 g)and 3-pyridinebutanamine (0.9 g) in tetrahydrofuran (20 mL) was stirred overnight at room temperature and then worked up in the normal manner. The crude was purified by HPLC (ethyl acetate) and then crystallized from ether to yield 1.8 g of (E)-5,5-bis(2-methoxyphenyl)-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide, mp 103.5°-104.5° C.
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].N1C=CN=C1.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][CH2:17][C@@H:18]([OH:21])[CH2:19][CH3:20]>ClCCl>[CH2:19]([C@@H:18]1[O:21][S:1](=[O:2])[N:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=2)[CH2:17]1)[CH3:20]
Reactant: CC[C@H](O)CNc1ccccn1
Reactant: O=S(Cl)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC[C@H]1CN(c2ccccn2)S(=O)O1

Procedure:
Thionyl chloride (18.98 millimoles) in dichloromethane (20 ml) is added dropwise to imidazole (4.7 g, 69 millimoles) in dichloromethane (50 ml) under argon. Then after 15 minutes the title compound of part (a) (17.26 millimoles) in 25 ml of dichloromethane was added slowly at a temperature maintained below 5° C. After an hour at a temperature range of 0° to 5° the temperature was allowed to warm up to room temperature. After 1 hour, water was added The organic layer was separated and the aqueous layer was subjected to extraction with dichloromethane. The combined organic portions were washed twice with water, dried (sodium sulphate) and evaporated to give the title compound as an orange oil (3.325 g, 15.66 millimoles), NMR data δ(400 MHz; CDCl3) 1.11 (1.5 H, t,J 8 Hz), 1.12 (1.5 H, t,J 8 Hz), 1.88-2.05 (1.5 H, m), 2.11-2.22 (0.5 H, m), 3.32 (0.5 H, dd, J 10 and 8 Hz), 3.74 (0.5 H, dd, J 10 and 7 Hz), 3.93-4.02 (1 H, m) 4.84-4.91 (0.5 H, m), 5.35-5.42 (0.5 H, m), 6.63 (0.5 H, d, J 8 Hz), 6.73 (0.5 H, d, j 8 Hz), 6.88-6.94 (1 H, m), 7.59-7.65 (1 H, m) and 8.25-8.30 (1 H, m).
Reaction SMILES: [PH2:1]([OH:3])=[O:2].[OH-].[CH2:5]([N+:9]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH3:8].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[PH2:1]([O-:3])=[O:2].[CH2:18]([N+:9]([CH2:5][CH2:6][CH2:7][CH3:8])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:19][CH2:20][CH3:21]
Reactant: O=[PH2]O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=[PH2][O-]

Procedure:
A mixture of 50% aqueous hypophosphorous acid (6.6 g, 50 mmol) and toluene (30 mL) was cooled in ice and treated with tetrabutyl-ammonium hydroxide solution (32.4 g of 40% solution in water). The pH was adjusted to 7.00 by the addition of sodium bicarbonate. Toluene and the remaining water were removed under reduced pressure. The residue was dissolved in methyl ethyl ketone, filtered, and evaporated. The residue was triturated with diethyl ether and dried to afford a hygroscopic crystalline solid, 15.5 g.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[N:6]1.Cl[C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][N:23]=1>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:18]([NH:19][C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][N:23]=3)=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[N:6]1
Reactant: COCCn1ccc(NC(=O)c2nc(C)ccc2N)n1
Reactant: Fc1ccnc(Cl)c1
Product: COCCn1ccc(NC(=O)c2nc(C)ccc2Nc2cc(F)ccn2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid [1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-amide in accordance with the general method of example) step using 2-Chloro-4-fluoropyridine instead of 3-bromopyridineto yield the final compound as a off-white solid, MS (ISP): m/e=371.4 (M+H+).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][C:23]([O:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[CH:22][CH:21]=2)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[N:30]1([CH2:29][CH2:28][O:27][C:23]2[CH:24]=[C:25]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18]([C:12]2[C:11]4[C:15](=[CH:16][CH:17]=[C:9]([OH:8])[CH:10]=4)[NH:14][N:13]=2)=[CH:26]3)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: c1ccc(COc2ccc3[nH]nc(-c4cc5cc(OCCN6CCCCC6)ccc5[nH]4)c3c2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Oc1ccc2[nH]nc(-c3cc4cc(OCCN5CCCCC5)ccc4[nH]3)c2c1
Yield: 66.4 %

Procedure:
A suspension of 360 mg of 5-benzyloxy-3-[5-(2-piperidin-1-ylethoxy)-1H-indol-2-yl]-1H-indazole, 916 mg of ammonium formate and 120 mg of palladium in 10 ml of ethanol is placed in a reactor that is irradiated in a microwave field (Synthwave 402) at a temperature of 90° C. for 30 minutes and the reaction mixture is then filtered through a bed of celite. The filtrate is evaporated under reduced pressure and the residue is then-taken up in a mixture of ethyl acetate (150 ml) and of water (50 ml). A 30% ammonium hydroxide solution is added so as to bring the pH to 10. After separation by settling out and extraction with ethyl acetate (1×50 ml), the organic extracts are combined, dried over magnesium sulfate and then evaporated under reduced pressure. 193 mg of 3-[5-(2-piperidin-1-ylethoxy)-1H-indol-2-yl]-1H-indazol-5-ol are isolated and characterized.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]1[O:24][C:23]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=2[O:14]1.Cl.[CH3:26][NH:27][O:28][CH3:29].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.C(N(CC)CC)C>[CH3:29][O:28][N:27]([CH3:26])[C:18]([C:17]1[CH:21]=[CH:22][C:23]2[O:24][CH2:13][O:14][C:15]=2[CH:16]=1)=[O:20]
Reactant: CNOC
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
1,1'-Carbonyl-diimidazole (48.8 g) was added portionwise within 30 minutes under argon and while stirring to a suspension of 50.0 g of 3,4-methylenedioxy-benzoic acid in 500 ml of methylene chloride. The resulting clear solution was stirred at room temperature for 2 hours and added dropwise within 30 minutes to 42 ml of triethylamine. Thereafter, 29.4 g of N,O-dimethylhydroxylamine hydrochloride were added and the mixture was stirred at room temperature overnight. After the addition of 800 ml of 30% citric acid solution the mixture was extracted twice with 300 ml of methylene chloride each time. The organic phases were washed in succession with 300 ml of 30% citric acid solution, 500 ml of saturated sodium hydrogen carbonate solution and 300 ml of saturated sodium hydrogen carbonate solution. The organic phases were combined, dried with MgSO4 and freed from solvent. 60.9 g (97%) of N-methoxy-N-methyl-1,3-benzodioxol-5-carboxamide were isolated as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32]>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)(=[O:33])=[O:32])[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: O=S(=O)(c1ccccc1)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)c3ccccc3)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 1-bromo-2-(phenylsulfonyl)benzene. MS (ESI): mass calcd. for C22H16FN3O2S, 405.09; m/z found, 406.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.29 (dd, J=6.7, 2.5, 1H), 8.03 (d, J=1.4, 1H), 7.80-7.66 (m, 3H), 7.58 (m, 1H), 7.41-7.28 (m, 5H), 6.84 (dd, J=8.0, 1.6, 1H), 6.78-6.66 (m, 3H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH2:9][NH2:10])=[CH:3][CH:2]=1.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C([O-])([O-])=O.[Cs+].[Cs+].C(N(CC)CC)C>CCOC(C)=O.O>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7][CH2:8][CH2:9][NH:10][C:13](=[O:14])[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(SCCN)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(SCCNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of compound 24 (1.60 g) in EtOAc (100 mL) was added benzyl chloroformate (2.0 g, 1.2 eq.) and Cs2CO3 (3.2 g, 3 eq.). The reaction mixture was stirred at r.t. for 5 h. Triethylamine (2 mL) was added and the reaction was stirred for 3 h. After addition of H2O (30 mL), the organic phase was separated and washed with 1N HCl (2×30 mL), and sat. NaHCO3 (2×30 mL). The solvent was removed by evaporation under reduced pressure to give product 25 as white solid. Yield: 2.4 g, 79.7%.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.OO.[C:9]([OH:12])(=[O:11])[CH3:10]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:9]([O:12][CH:1]1[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1)(=[O:11])[CH3:10]
Reactant: C1=CCCCC1
Reactant: CC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: OO
Product: CC(=O)OC1C=CCCC1
Yield: 50 %

Procedure:
A 500 ml three-neck flask was charged with 15 g of cyclohexene (0.18 moles), 150 g of acetic acid and 80 mg of palladium acetate (0.36 mmoles). The temperature was taken to 50°, and then 10.6 g (0.22 moles) of 70% by weight hydrogen peroxide were introduced in 8 h. The reaction was continued for 2 more hours, while keeping the temperature at 50°. The acetic acid was then distilled (35°, 20×102Pa). The residue was distilled under vacuum (64°-68°, 15×102Pa) to provide cyclohex-2-en-1-yl acetate, 90% pure (13 g, yield 50%). cyclohex-2-en-1-yl-acetate
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6](O)=O)([O-:3])=[O:2].C1(S([NH2:25])(=O)=O)C=CC=CC=1>>[N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]#[N:25])([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: NS(=O)(=O)c1ccccc1
Product: N#Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
2,4-dinitrobenzonitrile was prepared from 2,4-dinitrobenzoic acid and benzenesulfonamide by the method of Oxley, Partridge, Robson and Short, J. Chem. Soc., 1946, 763. The product was purified by chromatography on alumina, using tetrahydrofuran as a solvent: yield, 56%; m.p. 102° C.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[O:19][CH2:20][CH:21]1[CH2:23][CH2:22]1)[S:5]([CH3:8])(=[O:7])=[O:6].[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH:21]1([CH2:20][O:19][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:9]=2[N:4]([CH2:3][CH2:2][N:28]2[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]2)[S:5]([CH3:8])(=[O:7])=[O:6])[C:13]([O:15][CH3:16])=[O:14])[CH2:23][CH2:22]1
Reactant: CN1CCNCC1
Reactant: COC(=O)c1ccc(N(CCBr)S(C)(=O)=O)c(OCC2CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(N(CCN2CCN(C)CC2)S(C)(=O)=O)c(OCC2CC2)c1
Temperature: 130 °C
Yield: 79 %

Procedure:
The mixture of methyl 4-(N-(2-bromoethyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoate (630 mg, 1.551 mmol), 1-methylpiperazine (155 mg, 1.551 mmol) and K2CO3 (321 mg, 2.326 mmol) in dry CH3CN (14 ml) was heated at 130° C. under microwave irradiation for 3 hours. After cooling the inorganic salts were filtered, the solvent was evaporated and the residue was purified by flash chromatography on silica gel (eluent: DCM/MeOH/32% NH4OH 95/5/0.5) to give methyl 3-(cyclopropylmethoxy)-4-(N-(2-(4-methylpiperazin-1-yl)ethyl)-methylsulfonamido)benzoate as a light brown oil (520 mg, 1.222 mmol, 79% yield, MS/ESI+ 426.0 [MH]+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15](Br)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1.[NH2:18][C:19]1[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[CH:20]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:18][C:19]3[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[CH:20]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cc1cc(N)n(C)n1
Reactant: Cc1ccc(Br)c(C(=O)Nc2ccn(C)n2)n1
Product: Cc1ccc(Nc2cc(C)nn2C)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Bromo-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide in accordance with the general method of Example 78, step 3 using 5-Amino-1,3-dimethylpyrazole instead of 3-Amino-1-methyl-pyrazole to yield the final compound as a yellow solid, MS (ISP): m/e=326.3 (M+H+).
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@H:11]1[N:34]1[C:43](=[O:44])[C:42]2[NH:41][CH:40]=[N:39][C:38]=2[NH:37][C:35]1=[O:36])(=O)C1C=CC=CC=1>N>[C@@H:11]1([N:34]2[C:43](=[O:44])[C:42]3[NH:41][CH:40]=[N:39][C:38]=3[NH:37][C:35]2=[O:36])[O:12][C@H:13]([CH2:24][OH:25])[C@@H:14]([OH:15])[C@H:10]1[OH:9]
Reactant: O=C(OC[C@H]1O[C@@H](n2c(=O)[nH]c3nc[nH]c3c2=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: N
Product: O=c1[nH]c2nc[nH]c2c(=O)n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 83.8 %

Procedure:
A solution of compound 51 (500 mg, 0.84 mmol) in saturated methanolic ammonia (10 mL) was stirred at room temperature for 24 hr, concentrated to dryness, washed with EtOAc several times, and dried to give 52 (200 mg, 84%) as a white solid.