Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[C:2]([CH3:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH:21]([CH2:27][CH2:28][CH2:29][CH3:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23].[I-].[K+]>CC(=O)CC>[NH:1]([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH:21]([CH2:27][CH2:28][CH2:29][CH3:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:11][CH:12]=1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)NCCc1ccc(O)cc1
Reactant: CCCCC(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCC(Oc1ccc(CCNC(C)=O)cc1)C(=O)OCC

Procedure:
A mixture of 17.92 g. (0.1 mol) 4-(2-acetamino-ethyl)-phenol, 17.3 g. (0.125 mol) pulverized potassium carbonate and 150 ml. butan-2-one is stirred for 2 hours at reflux temperature, then 27.9 g. (0.125 mol) ethyl 2-bromohexanoate and a spatula tip of potassium iodide are added thereto and the reaction mixture kept at reflux temperature for a further 28 hours. The reaction mixture is then filtered with suction and the filtrate evaporated in a vacuum. The residue is taken up in diethyl ether and the ethereal phase is extracted with 2 N hydrochloric acid, water, 0.5 N aqueous sodium hydroxide solution and again with water, dried over anhydrous sodium sulphate and evaporated to give 32.1 g. (quantitative yield) ethyl 2-[4-(2-acetaminoethyl)-phenoxy]-n-hexanoate in the form of a colorless oil with a refractive index nD20 =1.5010.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>>[O:6]=[C:4]([N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:3][C:1]#[N:2]
Reactant: C1CCNC1
Reactant: CCOC(=O)CC#N
Product: N#CCC(=O)N1CCCC1
Yield: 72.4 %

Procedure:
Ethyl cyanoacetate (5.33 mL, 50 mmol) and pyrrolidine (20.87 mL, 250 mmol) were gently refluxed at 90° C. in an oil bath for 8 hours. Excess pyrrolidine was removed by concentration and the residue was triturated with diethyl ether. This was purified by silica gel column chromatography eluting with 50% acetone in n-hexane to provide the desired product (5.0 g). MS (DCI) m/e 139 (M+H)+, 156 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) δ 3.90 (s, 2H), 3.27-3.38 (m, 4H), 1.73-1.91 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1([O:5][CH2:4]1)[CH3:3].[CH3:6][C:7]1([CH3:19])[C:11]([CH3:13])([CH3:12])[O:10][B:9]([C:14]2[CH:15]=[N:16][NH:17][CH:18]=2)[O:8]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)C>[CH3:3][C:2]([OH:5])([CH3:1])[CH2:4][N:17]1[CH:18]=[C:14]([B:9]2[O:8][C:7]([CH3:19])([CH3:6])[C:11]([CH3:13])([CH3:12])[O:10]2)[CH:15]=[N:16]1
Reactant: CC1(C)CO1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 80 °C
Reaction time: 16 h
Yield: 30.1 %

Procedure:
Isobutylene oxide (101 μL, 1.13 mmol) was added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (200 mg, 1.03 mmol) and cesium carbonate (403 mg, 1.24 mmol) stirring in N,N-dimethylformamide (3.4 mL). The mixture was stirred at 80° C. for 16 h, cooled to room temperature, diluted with diethyl ether, washed with water (3×) and brine, dried over sodium sulfate, filtered, and concentrated to give 2-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-2-ol (84 mg, 0.31 mmol, 31% yield) as a yellow solid. ESI: [M+H]+ m/z 267.0.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15][CH3:16])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:22]([O:24][CH3:25])=[O:23])[S:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:33])C(=O)C1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[Br:33][C:13]1[C:14]2[N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[N:7]=[C:8]([C:17]3[CH:18]=[C:19]([C:22]([O:24][CH3:25])=[O:23])[S:20][CH:21]=3)[C:9]=2[C:10]([O:15][CH3:16])=[N:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(-c2nn(C3CCCC3)c3ccnc(OC)c23)cs1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2nn(C3CCCC3)c3c(Br)cnc(OC)c23)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
To a solution of methyl 4-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylate (103 mg) obtained in Step D of Example 12 in DMF (5 mL) was added NBS (56.4 mg) at 0° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added saturated aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (117 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[F:25][C:4]1[C:5]([CH3:24])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: C1CCNC1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCCC4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 301 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and pyrrolidine. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.79-1.95 (m, 4H) 2.33 (d, J=2.44 Hz, 3H) 3.49 (t, J=5.61 Hz, 4H) 7.42-7.82 (m, 2H) 7.84-8.76 (m, 4H). ESI-MS m/z [M+H]+392.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[OH:12].Cl.Cl[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[N:17]1([CH2:16][CH2:15][O:12][C:4]2[CH:5]=[C:6]([CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[NH2:9])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: ClCCN1CCOCC1
Reactant: COc1ccc([N+](=O)[O-])cc1O
Agent: Cl
Product: COc1ccc(N)cc1OCCN1CCOCC1

Procedure:
The title compound was prepared from 2-methoxy-5-nitrophenol and 4-(2-chloroethyl)morpholine hydrochloride using a similar procedure to Descriptions 1 and 2 (63%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]([CH2:11][CH2:12][CH2:13][OH:14])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].CO[C:18](OC)([CH3:20])[CH3:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[OH:14][CH2:13][CH2:12][CH2:11][C@H:8]1[CH2:9][O:10][C:18]([CH3:20])([CH3:19])[N:7]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CCCO
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1[C@@H](CCCO)COC1(C)C

Procedure:
A solution of tert-butyl[(2S)-1,5-dihydroxypentan-2-yl]carbamate (9.45 g), 2,2-dimethoxypropane (48 mL) and p-toluenesulfonic acid monohydrate (0.41 g) in chloroform (100 mL) was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogen carbonate solution was added thereto, and the solvent was distilled off under reduced pressure. Ethyl acetate was added thereto, and the resulting mixture was washed with water and brine, followed by drying over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel cartridge, hexane/ethyl acetate=10:1-0:100) to afford tert-butyl (4S)-4-(3-hydroxypropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (3.05 g).
Reaction SMILES: [O:1]1[C:5]([C:6]2[O:7][C:8]([CH3:13])=[C:9]([CH2:11]Cl)[N:10]=2)=[CH:4][C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]1=2.[OH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][C:28]#[N:29])=[CH:21][CH:20]=1>>[O:1]1[C:5]([C:6]2[O:7][C:8]([CH3:13])=[C:9]([CH2:11][O:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH2:27][C:28]#[N:29])=[CH:23][CH:24]=3)[N:10]=2)=[CH:4][C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]1=2
Reactant: N#CCCCc1ccc(O)cc1
Reactant: Cc1oc(-c2cc3ccccc3o2)nc1CCl
Product: Cc1oc(-c2cc3ccccc3o2)nc1COc1ccc(CCCC#N)cc1

Procedure:
According to the method described for Reference Example 45, 2-(benzo[b]furan-2-yl)-4-chloromethyl-5-methyloxazole was allowed to react with 4-(4-hydroxyphenyl)butyronitrile to give 4-[4-[2-(benzo[b]furan-2-yl)-5-methyl-4-oxazolylmethoxy]phenyl]butyronitrile. Recrystallization from dichloromethane--isopropyl ether gave colorless prisms, m.p.118°-119° C.
Reaction SMILES: [NH2:1][C:2]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C([O-])(O)=O.[Na+].O.[C:15](=O)([O:24]N1C(=O)CCC1=O)[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH2:17]([O:16][C:15](=[O:24])[NH:1][C:2]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: NC1(CO)CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(NC1(CO)CCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-amino-1-cyclopentanemethanol (1.15 g, 10 mmol) and NaHCO3 (0.84 g, 10 mmol) in acetone (14 mL)/water (14 ml) at room temperature was added benzyl succinimidyl carbonate (2.5 g, 10 mmol). The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and purified by flash chromatography with 3% methanol:dichloromethane to provide the titled compound. MS (DCI) m/z 250 (M+H)+.
Reaction SMILES: [CH2:1]1[CH2:19][O:18][C:3]2([CH2:8][CH2:7][C:6]([C:9]3[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]([F:17])[CH:10]=3)=[CH:5][CH2:4]2)[O:2]1.[H][H]>C(O)C.[Pd]>[CH2:19]1[CH2:1][O:2][C:3]2([CH2:4][CH2:5][CH:6]([C:9]3[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]([F:17])[CH:10]=3)[CH2:7][CH2:8]2)[O:18]1
Reactant: Fc1cc(C2=CCC3(CC2)OCCO3)cc(F)c1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Fc1cc(C2CCC3(CC2)OCCO3)cc(F)c1F
Yield: 94.3 %

Procedure:
1,1-Ethylenedioxy-4-(3,4',5'-trifluorophenyl)-3-cyclohexen (100 g) was dissolved in ethanol (1 l), followed by adding Pd/C (5%) (40 g), stirring the mixture in a hydrogen gas atmosphere to carry out a catalytic reduction, filtering off the catalyst after the reaction, and distilling off the organic layer under reduced pressure, to obtain 1,1-ethylenedioxy4-(3',4',5'-trifluorophenyl)-cyclohexane (95 g).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[N:14]=[CH:13][CH2:12][C:11]2=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:3][C:11]1[C:10]2[C:15](=[CH:16][C:17]([O:18][CH3:19])=[C:8]([O:7][CH3:6])[CH:9]=2)[N:14]=[CH:13][CH:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2c(cc1OC)C(=O)CC=N2
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Cl)c2cc1OC
Reaction time: 1 h
Yield: 80.6 %

Procedure:
Toluene (3 L) and phosphorus oxychloride (1300 g) were added to 6,7-dimethoxy-4-quinolone (1056 g), and the mixture was heated under reflux with stirring for one hr. The reaction solution was neutralized with an aqueous sodium hydroxide solution at 0° C. The resultant precipitate was collected by filtration and was slurried in water (10 L) for washing. The slurry was filtered, and the filtered product was then dried under the reduced pressure to give 4-chloro-6,7-dimethoxyquinoline (928 g, yield 87.6%).
Reaction SMILES: [CH3:1][C:2]1(O)[C:6]([CH3:8])([CH3:7])[CH2:5][CH2:4][C:3]1([CH3:10])[CH3:9].S(Cl)(Cl)=O>N1C=CC=CC=1>[CH2:1]=[C:2]1[C:6]([CH3:8])([CH3:7])[CH2:5][CH2:4][C:3]1([CH3:10])[CH3:9]
Reactant: CC1(C)CCC(C)(C)C1(C)O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: C=C1C(C)(C)CCC1(C)C
Reaction time: 8 h
Yield: 40.7 %

Procedure:
30 g of 1,2,2,5,5-pentamethylcyclopentanol was dissolved in 150 ml of pyridine, and 20 ml of thionyl chloride was added dropwise thereto with ice cooling. The reaction mixture was stirred overnight and subjected to filtration. Ether and water were added to the filtrate, and the resulting layers were separated. The organic layer was washed twice with 200 ml of water, and then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, whereby 10.8 g of 1-methylene-2,2,5,5-tetramethylcyclopentane was obtained (b.p. 137°-140° C./760 mmHg).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([C:10]1[NH:11][C:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=1)[CH2:8][CH3:9].[C:25]([N:44]1[C:48]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[C:55]2[CH:62]=[CH:61][C:58]([CH2:59]Br)=[CH:57][CH:56]=2)=[N:47][N:46]=[N:45]1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C(=O)C.O>[CH2:7]([C:10]1[N:14]([CH2:59][C:58]2[CH:57]=[CH:56][C:55]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=3[C:48]3[N:44]([C:25]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:45]=[N:46][N:47]=3)=[CH:62][CH:61]=2)[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:11]=1)[CH2:8][CH3:9]
Reactant: CCCc1nc(C(=O)OCC)c(C(=O)OCC)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCc1nc(C(=O)OCC)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
0.441 g of potassium t-butoxide was added to a solution of 1.00 g of diethyl 2-propylimidazole-4,5-dicarboxylate (prepared as described in Preparation 12) in 15 ml of N,N-dimethylacetamide, and the resulting mixture was stirred at room temperature for 30 minutes. A solution of 2.19 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide in 15 ml of N,N-dimethylacetamide was then added dropwise to the reaction mixture at room temperature, and the reaction mixture was stirred at room temperature for 3 hours. At the end of this time, it was diluted with water and then extracting with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then freed from the solvent by distillation. The residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 2.24 g of the title compound as an amorphous solid.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][N:21]([CH2:42][CH2:43][O:44][Si:45]([C:58]([CH3:61])([CH3:60])[CH3:59])([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:22]1[S:23][C:24]([C:27]2[CH:32]=[C:31]([N+:33]([O-])=O)[CH:30]=[C:29]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH:28]=2)=[CH:25][N:26]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[NH2:33][C:31]1[CH:32]=[C:27]([C:24]2[S:23][C:22]([N:21]([CH2:42][CH2:43][O:44][Si:45]([C:58]([CH3:61])([CH3:60])[CH3:59])([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:26][CH:25]=2)[CH:28]=[C:29]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[CH:30]=1
Reactant: CC(C)(C)[Si](OCCN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ncc(-c2cc(N3CCOCC3)cc([N+](=O)[O-])c2)s1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)[Si](OCCN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ncc(-c2cc(N)cc(N3CCOCC3)c2)s1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a solution of N,N-bis(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-[3-(morpholin-4-yl)-5-nitrophenyl]-1,3-thiazol-2-amine (999 mg, 1.147 mmol) in ethyl acetate (10 mL) and acetic acid (1.000 mL) at R.T., under nitrogen, was added palladium on carbon (122 mg, 0.115 mmol). The mixture was purged 3 times alternating between vacuum and H2. The reaction mixture was stirred under 1 atm H2 for 2 h. The system was evacuated with vacuum and purged 3 times alternating between vacuum and N2, and 3 mL DCM were added. The mixture was filtered through a pad of celite. The pad was rinsed with ethyl acetate and the filtrate concentrated. Residual AcOH was azeotroped with toluene (3×) to give 5-[3-amino-5-(morpholin-4-yl)phenyl]-N,N-bis(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-1,3-thiazol-2-amine as a yellow gum (958 mg, 1.139 mmol, 99%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]([Cl:20])([Cl:19])[C:8]([N:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)=[O:9]>>[Cl:20][C:7]([Cl:6])([Cl:19])[C:8]([N:10]1[CH2:11][C:12]2[C:17](=[CH:16][CH:15]=[C:14]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:13]=2)[CH2:18]1)=[O:9]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(N1Cc2ccccc2C1)C(Cl)(Cl)Cl
Product: O=C(N1Cc2ccc(S(=O)(=O)Cl)cc2C1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Chlorosulfonic acid (5.22 mL, 78.5 mmol) was cooled to −78° C. and 2,2,2-trichloro-1-(1,3-dihydro-2 H-isoindol-2-yl)ethanone (1.32 g, 5.00 mmol) was added thereto. The reaction mixture was warmed to room temperature and stirred for 30 min. The reaction mixture was poured into ice water and the mixture was extracted three times with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was powdered with hexane and collected by filtration to afford 2-(trichloroacetyl)-2,3-dihydro-1 H-isoindole-5-sulfonyl chloride as a pale green powder (1.38 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([OH:13])=[CH:11][C:10]([C:14]([OH:16])=[O:15])=[N:9]1.C(=O)([O-])[O-].[Cs+].[Cs+].[N:23]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([O:13][C:28]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:29])=[CH:11][C:10]([C:14]([OH:16])=[O:15])=[N:9]1
Reactant: O=C(Cl)N1CCCC1
Reactant: O=C(O)c1cc(O)n(-c2ccccc2F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(OC(=O)N2CCCC2)n(-c2ccccc2F)n1
Temperature: 50 °C

Procedure:
150 mg (0.675 mmol) of 1-(2-fluoro-phenyl)-5-hydroxy-1H-pyrazole-3-carboxylic acid were dissolved in 5 ml of THF. 440 mg (1.35 mmol) of cesium carbonate and 90.2 mg (0.675 mmol) of pyrrolidine-1-carbonyl chloride were added and the mixture was heated to 50° C. for 4 h. Then the mixture was filtrated and the filtrate containing the title compound directly used in the next step.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=4)[N:23](C(OC(C)(C)C)=O)[CH:22]=3)[CH:18]=[N:17][CH:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.CO.Cl>>[N+:30]([C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[C:21]2[C:19]1[N:20]=[C:15]([N:12]2[CH2:11][CH2:10][CH:9]([NH2:8])[CH2:14][CH2:13]2)[CH:16]=[N:17][CH:18]=1)([O-:32])=[O:31]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3cn(C(=O)OC(C)(C)C)c4ccc([N+](=O)[O-])cc34)n2)CC1
Agent: Cl
Solvent: CO
Product: NC1CCN(c2cncc(-c3c[nH]c4ccc([N+](=O)[O-])cc34)n2)CC1
Temperature: 60 °C
Yield: 23.1 %

Procedure:
To tert-butyl 3-(6-(4-(tert-butoxycarbonylamino)piperidin-1-yl)pyrazin-2-yl)-5-nitro-1H-indole-1-carboxylate (170 mg, 0.32 mmol) was added 3N MeOH—HCl (3.5 mL) and then heated at 60° C. overnight. The reaction mixture was quenched with water and neutralized with K2CO3. The resulting precipitate was filtered, washed with water and dried to obtain the crude compound. This crude compound was re-crystallized in ethanol to obtain the title compound as a pale yellow solid (25 mg). MS (ESI, pos. ion) m/z: 339.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[N:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][CH2:7][NH:8][C:9](=O)[C:10](F)(F)F)[CH3:2].[Br:22][C:23]1[N:27]2[N:28]=C(F)C=[CH:31][C:26]2=[N:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC>[CH2:1]([O:3][C:4](=[O:21])[N:5]([CH2:6][CH2:7][NH:8][C:9]1[CH:10]=[CH:31][C:26]2[N:27]([C:23]([Br:22])=[CH:24][N:25]=2)[N:28]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:2]
Reactant: Fc1ccc2ncc(Br)n2n1
Reactant: CCOC(=O)N(CCNC(=O)C(F)(F)F)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)N(CCNc1ccc2ncc(Br)n2n1)c1ccccc1
Temperature: 85 °C
Yield: 52.1 %

Procedure:
Crude phenyl-[2-(2,2,2-trifluoro-acetylamino)-ethyl]-carbamic acid ethyl ester (2.2 g, 7.3 mmol) was combine with 3-bromo-6-fluoro-imidazo[1,2-b]pyridazine (892.5 mg, 4.1 mmol) and potassium carbonate [584-08-7] (2.9 g, 20.6 mmol) in a 20% (v/v) solution of water in 1,2-dimethoxyethane (25 mL) and heated to 85° C. for 5 d. The reaction mixture was then partitioned between water and ethyl acetate and the extract flash chromatographed (silica gel eluted with 100% ethyl acetate) to yield 863.1 mg of white crystalline powder, mp. 160-161° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08 (t, J=7.06 Hz, 2H) 2.51 (dt, J=3.58, 1.85 Hz, 1H) 3.35 (s, 1H) 3.46 (q, J=6.39 Hz, 2H) 3.90 (t, J=6.50 Hz, 2H) 4.04 (q, J=7.06 Hz, 2H) 6.65 (d, J=9.70 Hz, 1H) 7.19-7.25 (m, 1H) 7.31-7.39 (m, 4H) 7.48 (s, 1H) 7.69 (d, J=9.70 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 14.16, 38.85, 47.84, 60.82, 98.79, 112.62, 125.31, 125.99, 126.79, 128.63, 130.18, 136.35, 141.81, 153.79, 154.64. LRMS (ESI) m/z 403.9/405.9 [(M+H)]+, calc'd for C17H18BrN6O2: 404.27.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[C@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15]Br)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N-:26]=[N+:27]=[N-:28].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[C@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15][N:26]=[N+:27]=[N-:28])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C[C@H](CCCBr)N(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](CCCN=[N+]=[N-])N(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 240 h
Yield: 97.9 %

Procedure:
To a solution of 4-chloro-N-(2,5-difluorophenyl)-N-[(R)-1-methyl-4-bromobutyl]-benzenesulfonamide (0.505 g, 1.12 mmol) in THF/H2O (8/2, 10 mL) was added sodium azide (0.363 g, 5.58 mmol) at 22° C. The resulting mixture was allowed to stir at 22° C. for 10 days. The mixture was extracted with ether (3×20 mL). The combined organic extracts were washed with sat. NaHCO3, dried over MgSO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:9 ethyl acetate:hexanes) of the concentrate afforded 0.455 g of 4-chloro-N-(2,5-difluorophenyl)-N-[(R)-1-methyl-4-azidobutyl]benzenesulfonamide as a colorless oil in 98% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:6][CH:7]=1.[C:17]([O-])(O)=O.[Na+]>C(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:9][CH2:10][N:11]3[CH2:12][CH2:13][CH2:14][CH2:15]3)[CH:17]=[N:16][C:4]=2[CH:3]=1
Reactant: Nc1cc(Br)ccc1NCCN1CCCC1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: Brc1ccc2c(c1)ncn2CCN1CCCC1

Procedure:
A solution of 904 mg (3.18 mmol) 4-bromo-N1-(2-pyrrolidin-1-yl-ethyl)-benzene-1,2-diamine in 5 mL formic acid is refluxed for 1.5 h. It is made alkaline with semisaturated NaHCO3 solution and extracted twice with 70 mL EtOAc. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac.
Reaction SMILES: [O:1]([CH2:8][CH2:9]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:11]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)([O-:14])(=[O:13])=[S:12].[K+]>CN(C=O)C>[O:1]([CH2:8][CH2:9][O:14][S:11]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[S:12])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)([O-])=S)cc1
Reactant: BrCCOc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=S)OCCOc2ccccc2)cc1

Procedure:
The title compound was prepared as described in General Method 2 using 2-phenoxyethyl bromide (0.025 mmol), potassium thiotosylate (0.025 mmol) and DMF (100 mL) to give a solid. 1H NMR (CDCl3) δ 2.45 (s, 3 H), 3.34 (t, 2 H), 4.14 (t, 2 H), 6.80 (d, 2 H), 6.95 (t, 1 H), 7.26 (t, 2 H), 7.35 (d, 2 H), 7.82 (d, 2 H).