Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH:14]=[C:13]2[C:7]([CH2:8][N:9]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:11]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:12]=32)=[CH:6]1)=[O:4].ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]([N:5]1[CH:14]=[C:13]2[C:7]([CH2:8][N+:9]([O-:35])=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:11]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:12]=32)=[CH:6]1)=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)n1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Solvent: ClCCl
Product: COC(=O)n1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=[N+]([O-])C2
Reaction time: 2.5 h

Procedure:
A mixture of 4.2 g (11 mmol) of 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-carboxylic acid methyl ester and 3.15 g (14.5 mmol) of m-chloroperbenzoic acid in 100 ml of methylene chloride was stirred at 0° for 2.5 hr. The mixture was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue was crystallized from ether to give a white solid, mp 224°-226°. Recrystallization from a mixture of ether and methylene chloride gave colorless prisms, mp 226°-227°.
Reaction SMILES: [O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:28])[NH:11][CH:12]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:13]([OH:20])[CH2:14][NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1.C(=O)(O)[O-].[Na+].[O:34]=[C:35]1[CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([S:44](Cl)(=[O:46])=[O:45])[CH:41]=2)[NH:36]1>C(Cl)Cl.C(OCC)(=O)C>[O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:28])[NH:11][CH:12]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:13]([OH:20])[CH2:14][N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[S:44]([C:40]2[CH:41]=[C:42]3[C:37](=[CH:38][CH:39]=2)[NH:36][C:35](=[O:34])[CH2:43]3)(=[O:45])=[O:46])[CH2:2]1
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Reactant: CC(C)CNCC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of (1-benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester 19 (59 mg, 0.15 mmol) in CH2Cl2 (1.6 ml) was added saturated aqueous sodium bicarbonate (0.4 ml), solid sodium bicarbonate (16 mg, 0.19 mmol), and then 2-oxo-2,3-dihydro-1H-indole-5-sulfonyl chloride 14 (42 mg, 0.18 mmol). The mixture was stirred overnight, diluted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to provide the title product as a white solid, (79 mg, 90%). TLC: Rf 0.33 (Ethyl acetate). MS m/z 588 (MH)+. 1H NMR (CDCl3) is consistent with the structure.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH:15]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])=[O:29]>O.CCOC(C)=O>[Cl:33][C:32]([Cl:35])([Cl:34])[CH2:31][O:30][C:28](=[O:29])[NH:10][C:8]1[N:7]([C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH:15]=2)[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=1
Reactant: CC(C)(C)c1cc(N)n(-c2cnn(CCOC3CCCCO3)c2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cnn(CCOC3CCCCO3)c2)n1
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To a mixture of Intermediate 108a (1.29 g, 3.87 mmol) in water (5 mL) and EtOAc (13 mL) was added NaOH (310 mg, 7.74 mmol). After 10 min stirring, 2,2,2-trichloroethyl chloroformate (640 μL, 4.65 mmol) was added and the reaction mixture was stirred at RT for 1 h. The aqueous layer was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-75% EtOAc in cyclohexane, to afford the title compound (1.24 g, 63%). LCMS (Method 4): Rt 3.92 min, m/z 508, 510 [MH+].
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6]P(=O)(OCC)OCC)=[O:5])[CH3:2].[H-].[Na+].O1CCCC1.O=[C:23]1[C:31]2[CH:30]=[CH:29][S:28][C:27]=2[CH2:26][CH2:25][CH2:24]1>C(OCC)(=O)C.O>[CH2:1]([O:3][C:4]([CH:6]=[C:23]1[C:31]2[CH:30]=[CH:29][S:28][C:27]=2[CH2:26][CH2:25][CH2:24]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=C1CCCc2sccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CCCc2sccc21
Reaction time: 0.5 h

Procedure:
Diethyl ethoxycarbonylmethylphosphonate (8.47 ml) was dropwise added to a mixture of sodium hydride (60%, 1.71 g) and tetrahydrofuran (THF) (50 ml) at room temperature (r.t.) under nitrogen atmosphere, and the mixture was stirred under the same condition for 30 minutes. To the reaction mixture was added 4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene (5.00 g) in a portion, and the whole mixture was stirred at r.t. for 3 hours. The reaction mixture was poured into a mixture of water and ethyl acetate (AcOEt). The separated organic layer was washed with water and brine, and dried over magnesium sulfate (MgSO4), and dried in vacuo to precipitate. The resulting precipitate was washed with isopropyl ether (iPE) to give 4-ethoxycarbonylmethylidene-4,5,6,7-tetrahydrobenzo[b]thiophene (5.91 g).
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OC)=O.CCCCCC.[C:46]([O:49]CC)(=[O:48])[CH3:47]>C(Cl)Cl>[C:46]([OH:49])(=[O:48])/[CH:47]=[CH:1]/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCOC(C)=O
Reactant: CCCCCCCCCCC/C=C/C=O
Agent: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCCCCCCCC/C=C/C=C/C(=O)O
Reaction time: 2 h

Procedure:
To the trans-2-tetradecenal (2.3 g) dissolved in methylene chloride (80 ml ) was added (carbomethoxymethylene) triphenylphosphorane (4.4 g), and the mixture was stirred for 2 hours. The reaction mixture was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 100:1 to 20:1) to give the methyl ester of trans,trans-2,4-hexadecadienoic acid (2.2 g). Potassium hydroxide (2.8 g) was dissolved in a mixed solvent of ethanol-water (1:1), and the methyl ester of trans,trans-2,4-hexadecadienoic acid (2.2 g). After the mixture was stirred at 60° C. for 40 minutes, it was cooled, adjusted to a weak acidic range of pH with citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give trans, trans-2,4-hexadecadienoic acid (2.0 g). The product was dissolved in N,N-dimethylformamide (DMF, 50 ml), and para-nitrophenol (1.1 g) and N,N'-dicyclohexylcarbodiimide (1.6 g) were added. The mixture was stirred for 12 hours. After the reaction, precipitates produced were removed by filtration, DMF was removed by distillation, and the residue was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 200:1 to 50:1) to give the active ester of trans,trans-2,4-hexadecadienoic acid (0.8 g). To the active ester (340 mg) dissolved in DMF (30 ml) were added 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (500 mg) and triethylamine (1.2 ml). The mixture was stirred for 12 hours. After the solvent was removed by distillation, the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK283 in the yield of 270 mg.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[CH3:12][NH2:13]>C(O)C>[C:12]([NH:5][C:4]([NH:3][CH3:2])=[N:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])#[N:13]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CN
Solvent: CCO
Product: CNC(=NCCSCc1[nH]cnc1C)NC#N
Reaction time: 4 h

Procedure:
A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]-imidazole (1.93 g.) and dimethyl-N-cyanoimidodithiocarbonate (1.65 g.) in ethanol (33 ml.) was set aside overnight at room temperature. Ethanolic methylamine (33%, 22 ml.) was added and the solution was then set aside for 4 hours. Concentration and recrystallisation from isopropyl alcohol-ether yielded N-cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine (2.0 g.), m.p. 139°-140°. (Found: C, 47.5; H, 6.5; N, 33.3; S, 12.7. C10H16N6S requires: C, 47.6; H, 6.4; N, 33.3; S, 12.7).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([O:11][CH3:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([NH:13][C:2]2[C:3]3[CH2:10][CH2:9][CH:8]([O:11][CH3:12])[C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:15][CH:16]=1)#[N:19]
Reactant: COC1CCc2c(Cl)ncnc21
Reactant: N#Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC1CCc2c(Nc3ccc(C#N)cc3)ncnc21
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 40.7 %

Procedure:
0.92 g of 4-chloro-6,7-dihydro-7-methoxy-5H-cyclopenta[d]pyrimidine [prepared as described in step (e) above] and 0.59 g of p-aminobenzonitrile were dissolved in 5 ml of ethanol, and the solution was stirred at 130° C. for 10 minutes. At the end of this time, the mixture was cooled to room temperature, and the resulting solid reaction product was pulverized. 50 ml of a 1N aqueous solution of sodium hydroxide and 200 ml of ethyl acetate were added to the resulting powder, and the ethyl acetate layer was separated, washed with water and dried over anhydrous sodium sulfate. The ethyl acetate was evaporated off under reduced pressure, and the resulting residue was purified by silica gel column chromatography, eluted with ethyl acetate, to give 0.54 g of the title compound as colorless crystals melting at 167°-169° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH3:21])[C:17]([O:19][CH3:20])=[CH:18][C:13]=2[NH:12][C:11](=S)[CH2:10][N:9]=1.C(OC(OCC)[N:27]([CH3:29])C)C.[NH2:33]N>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH3:21])[C:17]([O:19][CH3:20])=[CH:18][C:13]=2[N:12]=[C:11]2[NH:33][NH:27][CH:29]=[C:10]2[N:9]=1
Reactant: CCOC(OCC)N(C)C
Reactant: NN
Reactant: COc1cc2c(cc1C)C(c1ccccc1Cl)=NCC(=S)N2
Product: COc1cc2c(cc1C)C(c1ccccc1Cl)=NC1=CNNC1=N2

Procedure:
5-(2-chlorophenyl)-1,2-dihydro-8-methoxy-7-methyl-pyrazolo[3,4-b][1,4]benzodiazepine (XXIIz) was prepared by reacting 0.003 moles of 5-(2-chlorophenyl)-1,3-dihydro-8-methoxy-7-methyl-2H-1,4-benzodiazepin-2-thione (IIz) with 1,1-diethoxy-N,N-dimethyl-methanamine and then hydrazine in a manner analogous to Example 90. Recrystallization from ethyl acetate-methanol provided 5-(2-chlorophenyl)-1,2-dihydro-8-methoxy-7-methyl-pyrazolo[3,4-b][1,4]benzodiazepine as a light red solid, mp 275-276° C.
Reaction SMILES: Br[C:2]1[C:3]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)=[CH:13][CH:12]=2)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[F:25][C:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[F:25][C:26]1[CH:31]=[C:30]([C:2]2[C:3]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=4)=[CH:13][CH:12]=3)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=2)[CH:29]=[CH:28][N:27]=1
Reactant: COc1cnc(Oc2ccc(Nc3ccc(C)cn3)cc2)c(Br)c1
Reactant: OB(O)c1ccnc(F)c1
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: O
Solvent: C1COCCO1
Product: COc1cnc(Oc2ccc(Nc3ccc(C)cn3)cc2)c(-c2ccnc(F)c2)c1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
N-(4-(3-bromo-5-methoxypyridin-2-yloxy)phenyl)-5-methylpyridin-2-amine (0.076 g, 0.20 mmol), 2-fluoropyridine-4-boronic acid (0.056 g, 0.39 mmol), and tetrakis(triphenylphosphine)palladium (0.023 g, 0.020 mmol) were mixed in dioxane (0.8 mL) under an argon atmosphere. Sodium carbonate (0.30 mL, 0.59 mmol, 2.0 M in water) was added via syringe, and the reaction mixture was stirred at 80° C. for 20 h before being warmed to 90° C. and stirred for 24 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was separated, washed with sat. sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel chromatography to give N-(4-(2′-fluoro-5-methoxy-3,4′-bipyridin-2-yloxy)phenyl)-5-methylpyridin-2-amine. MS (ESI, pos. ion) m/z: 403.2 (M+1). IC50 (uM) 0.004.
Reaction SMILES: CC[Mg+].[Br-].Br[C:6]1[S:7][CH:8]=[CH:9][C:10]=1[CH3:11].[O:12]=[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.Cl>C1COCC1.CCOC(C)=O>[OH:12][C:13]1([C:6]2[S:7][CH:8]=[CH:9][C:10]=2[CH3:11])[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: Cc1ccsc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC[Mg+]
Agent: Cl
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccsc1C1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.5 %

Procedure:
To a solution of EtMgBr (300 mL of 1.0M, 300 mmol) in THF (400 mL) at RT was added 2-bromo-3-methylthiophene (48.28 g, 272.7 mmol) dropwise. The mixture was stirred at RT for 72 hours. To the reaction mixture was added a solution of tert-butyl 4-oxopiperidine-1-carboxylate (54.33 g, 272.7 mmol) in THF at RT. The reaction was stirred for 3 hours and 2 N HCl was added to quench the reaction. The mixture was extracted with EtOAc and the combined organics washed with water, satd' NaHCO3 solution, and dried over MgSO4. Removal of the volatiles in vacuo gave a gummy product, to which was added EtOAc. After shaking for 10 min a white precipitate appeared, which was collected by filtration and washed with EtOAc. The filtrate was evaporated again and the precipitation step repeated to obtain additional product, which was combined with the solid previously collected to yield tert-Butyl 4-hydroxy-4-(3-methylthiophen-2-yl)piperidine-1-carboxylate (Compound 1052, 58 g, 71.5% yield; 1H NMR (300 MHz, DMSO-d6): δ 7.17 (d, J=5.0 Hz, 1H), 6.79 (d, J=5.1 Hz, 1H), 5.47 (s, 1H), 3.82 (brd, 2H), 3.09 (brs, 2H), 2.26 (s, 3H), 1.84-1.79 (m, 4H) and 1.41 (s, 9H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:18][CH:17]=2)=[CH:14][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: Brc1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Yield: 85.7 %

Procedure:
In a flask, 25 g of benzyl bromide, 36.4 g of 4-bromo-4'-hydroxybiphenyl, 40.4 g of potassium carbonate, and 300 ml of 2-butanone were placed, and stirred under reflux for 6 hours. The reaction solution was poured into water, and an organic layer was extracted with toluene. After the toluene layer was washed with water and dried over sodium sulfate anhydrous, the solvent was distilled away. The residue was recrystallized from acetone to give 42.5 g of 4-bromo-4'-benzyloxybiphenyl (Y: 85.8%). The purity of the compound thus obtained was 99.0% by GC.
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][CH2:7][NH:8][CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([O-:14])=[O:13]>C(Cl)Cl>[CH3:10][CH:9]([N:8]([CH2:7][CH2:6][CH2:5][NH:4][CH:1]([CH3:3])[CH3:2])[S:21]([C:18]1[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:20][CH:19]=1)(=[O:22])=[O:23])[CH3:11]
Reactant: CC(C)NCCCNC(C)C
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: CC(C)NCCCN(C(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 56.8 %

Procedure:
To N,N'-diisopropyl propane-1,3-diamine (23.43 g) in methylene chloride was added p-nitrobenzenesulfonyl chloride (11.08 g, 0.05 mole) dropwise and the reaction stirred 2 hours. The reaction was filtered, stripped, the residue dissolved in diethyl ether, refiltered after washing with water and the contents of the filtrate chromatographed on dry column silica gel with ethyl acetate to provide 9.75 g of clear product as the free base. Preparation of hydrochloride salt gave 8.22 g, m.r. 183°-185° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([NH2:12])=[N:6][NH:7]2.CC(N(CC1C=CC(CN2C3C(=C(OC)C=CC=3)C(NS(C3SC(Cl)=CC=3)(=O)=O)=N2)=CC=1)C(=O)[O-])(C)C.[OH-].[K+].Cl[CH2:53][C:54]1[CH:62]=[CH:61][C:57]([C:58]([NH2:60])=[O:59])=[CH:56][CH:55]=1>CS(C)=O.O>[NH2:12][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])[N:7]([CH2:53][C:54]2[CH:62]=[CH:61][C:57]([C:58]([NH2:60])=[O:59])=[CH:56][CH:55]=2)[N:6]=1
Reactant: NC(=O)c1ccc(CCl)cc1
Reactant: COc1cccc2[nH]nc(N)c12
Agent: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1ccc(CN(C(=O)[O-])C(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1cccc2c1c(N)nn2Cc1ccc(C(N)=O)cc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of 4-(methyloxy)-1H-indazol-3-amine (for a preparation see Intermediate 1) (0.816 g, 5 mmol) in DMSO (50 mL) at room temperature under nitrogen was added potassium hydroxide (0.561 g, 10.0 mmol). After stirring the resulting deep red solution for 25 min 4-(chloromethyl)benzamide (0.848 g, 5.00 mmol) was added in one portion. The reaction mixture was stirred for a further 30 min and then poured into water (250 mL), forming an emulsion. The reaction mixture was extracted using chloroform (3×250 mL). The combined organic solutions were washed with water (250 mL) and passed through hydrophobic frit. The solvent was removed in vacuo and the residue was loaded in dichloromethane to a silica (100 g) cartridge and purified by chromatography on Flashmaster eluting with 0-100% ethyl acetate-cyclohexane+0-20% methanol-ethyl acetate over 60 min. The appropriate fractions were combined and evaporated in vacuo to give the title compound (1.18 g, 80%). LCMS: (System A) RT=0.69 min, ES+ve m/z 297 (M+H)+.
Reaction SMILES: [N:1]([CH:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][C:9]=2[CH:10]=1)[CH3:5])=[N+]=[N-].C1C[O:23][CH2:22][CH2:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(=O)C)(=O)C>C(OCC)(=O)C.O>[C:22]([NH:1][CH:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][C:9]=2[CH:10]=1)[CH3:5])(=[O:23])[CH3:21]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1ccc2oc(C(C)N=[N+]=[N-])cc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1ccc2oc(C(C)NC(C)=O)cc2c1
Yield: 53 %

Procedure:
Using ethyl 2-(1-azidoethyl)-1-benzofuran-5-carboxylate (4.34 g, 16.7 mmol) obtained in Reference Example 88, THF (17 mL), water (1.7 mL); triphenylphosphine (6.58 g, 25.1 mmol), ethyl acetate (5 mL) and acetic anhydride (2.4 mL, 25.1 mmol), an operation in the same manner as in Reference Example 37 was performed to give the title compound (2.42 g, yield 53%).
Reaction SMILES: [S:1](Br)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].N1C=CC=CC=1.[C:18]([C:22]1[C:23]([SH:30])=[CH:24][C:25]([CH3:29])=[C:26]([OH:28])[CH:27]=1)([CH3:21])([CH3:20])[CH3:19]>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[C:18]([C:22]1[CH:27]=[C:26]([OH:28])[C:25]([CH3:29])=[CH:24][C:23]=1[S:30][S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1ccc(S(=O)(=O)Br)cc1
Reactant: Cc1cc(S)c(C(C)(C)C)cc1O
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)Sc2cc(C)c(O)cc2C(C)(C)C)cc1
Temperature: 0 °C

Procedure:
To a round bottom flask equipped with a magnetic stirrer and addition funnel were added tosyl bromide (30.6 g, 130 mmol), CCl4 (150 mL), and pyridine (10.51 mL, 130 mmol), respectively. This slurry was cooled to 0° C. and treated dropwise a solution of 24.3 g (124 mmol) of 5-tert-butyl-4-mercapto-2-methyl-phenol (prepared in Example QQQ) in CCl4 (150 mL). The mixture was diluted with CHCl3, washed with brine, and dried (MgSO4). The solvent was evaporated to give a solid which was washed and filtered with hexanes:Et2O (4:1) to give the title compound. 1H NMR (CDCl3) δ 1.22 (s, 9 H), 2.11 (s, 3 H), 2.42 (s, 3 H), 6.87 (s, 1 H), 7.16 (s, 1 H) 7.26 (d, 2 H), 7.49 (d, 2 H).
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]#[N:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:5]=[CH:4][N:3]=1.[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20][NH2:21].C(N(C(C)C)C(C)C)C.CC1C=CC(S(O)(=O)=O)=CC=1>CN1C(=O)CCC1.CO>[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20][NH:21][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]#[N:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1ccc2c(c1)[nH]c1ncnc(Cl)c12
Reactant: CN(C)CCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNc1ncnc2[nH]c3cc(C#N)ccc3c12
Temperature: 140 °C
Yield: 18.2 %

Procedure:
A mixture of 4-chloro-9H-pyrimido[4,5-b]indole-7-carbonitrile (23 mg, 0.10 mmol), 2-dimethylaminoethylamine (27 mg, 0.3 mmol) and N-ethyldiisopropylamine (88 μL, 0.50 mmol) in 1 ml of NMP was heated at 140° C. for 20 minutes using microwave irradiation. The reaction mixture was diluted with 5 mL methanol and applied to a 500 mg MP-TsOH SPE cartridge. After washing the cartridge, the product was eluted using 2 N ammonia in methanol. The eluent was concentrated in vacuo and the residue purified by prep HPLC to give 5.1 mg of the title compound as a white solid. 1H NMR (DMSO, δ, ppm) δ 2.3 (6H, s), 2.65 (2H, t, J=6.8 Hz), 3.7-3.8 (2H, m), 7.45 (1H, t, J=6.1 Hz), 7.7 (1H, d, J=8.1 Hz), 7.9 (1H, s), 8.2 (1H, s), 8.4 (1H, s), 8.5 (1H, d, J=8.1 Hz), 12.4 (1H, br s); LC-MS (2) Rt 2.03 min; m/z (ES+) 281.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][N:21]=3)[C:15]([O:17]C)=[O:16])[C:8]2=[O:22])=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][N:21]=3)[C:15]([OH:17])=[O:16])[C:8]2=[O:22])=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Yield: 94.7 %

Procedure:
A solution of methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate (4.57 g, 13.90 mmol) and lithium hydroxide monohydrate (4.05 g, 96.52 mmol) in tetrahydrofuran (170 mL) and water (85 mL) was stirred for 19 hours. The organic solvent was removed in vacuo. The aqueous solution was acidified with 12 M hydrochloric acid solution until pH 3. The solid was filtered, washed with water (30 mL), hexanes (20 mL) and dried in vacuo to give 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinic acid as a colorless solid (4.15 g, 95%). 1H NMR (300 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.40 (d, J=5.1 Hz, 1H), 7.37-7.31 (m, 3H), 7.18-7.13 (m, 2H), 4.39 (s, 2H), 3.94 (t, J=8.1 Hz, 2H), 3.35 (t, J=8.1 Hz, 2H); MS (ES+) m/z 316.2 (M+1).