Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].[CH2:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20](=O)[CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25].N1CCCC1>C1(C)C=CC=CC=1>[CH2:21]([C:20]1([CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15])[CH2:13][C:11](=[O:12])[C:8]2[CH:7]=[CH:6][C:5]([OH:14])=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=2[O:10]1)[CH2:22][CH2:23][CH:24]=[CH2:25]
Reactant: C=CCCCC(=O)CCCC=C
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: C=CCCCC1(CCCC=C)CC(=O)c2ccc(O)c(CCC)c2O1
Yield: 84.6 %

Procedure:
A mixture of 3.93 g (20.2 mmol) of 2,4-dihydroxy-3-propylacetophenone, 3.36 g (20.2 mmol) of the title product of Example 68, 1.44 g (20.2 mmol) of pyrrolidine, and 23.5 ml of toluene was stirred at reflux under a water separator containing 3A molecular sieves for 5 hours. The mixture was then permitted to cool, and the solvent was removed under reduced pressure. Chromatography of the residue over silica gel using 25% ethyl acetate/hexane as eluant gave the title compound (5.85 g) as a dark red oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([CH:11]=[O:12])=[CH:5][C:4]=1[CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][C:15]([O:17]C)=[O:16]>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([CH:11]=[O:12])=[CH:5][C:4]=1[CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][C:15]([OH:17])=[O:16]
Reactant: CCCCCC(CC(=O)OC)c1cc(C=O)c(OC)cc1OC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCC(CC(=O)O)c1cc(C=O)c(OC)cc1OC

Procedure:
Methyl 3-(2,4-dimethoxy-5-formylphenyl)octanoate [prepared as described in step (ii) above] was hydrolyzed in a similar manner to that described in Preparation 7 to give the title compound as crystals, melting at 110-111.5° C. (from ethyl acetate-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:7]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH2:24][C:25]([OH:27])=[O:26])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:15])=[O:16])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1-c1ccc(S(=O)(=O)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)COc1ccc(Cl)cc1-c1ccc(S(=O)(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared from the product of step (iii) (0.6 g) which was stirred in TFA/DCM (1:1, 10 ml) overnight. The mixture was concentrated under reduced pressure to give an oil. The residue was purified by reverse phase HPLC, yield 0.31 g.
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=N)[O:17][CH3:18])[N:11]=2)[N:9]=1)[NH2:3].Cl.C(=O)([O-])[O-:22].[K+].[K+]>O1CCCC1>[NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:17][CH3:18])=[O:22])[N:11]=2)[N:9]=1)[NH2:3]
Reactant: O=C([O-])[O-]
Reactant: COC(=N)c1cccc(-c2csc(N=C(N)N)n2)n1
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(-c2csc(N=C(N)N)n2)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 2-(diaminomethyleneamino)-4-[6-[(imino)(methoxy)methyl]pyridin-2-yl]thiazole (0.9 g) in 50% aqueous tetrahydrofuran (60 ml) was adjusted to pH 1.0 with 6N-hydrochloric acid and stirred for 5 minutes at ambient temperature. The mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate and the mixture was extracted with ethyl acetate. The extract layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of methanol, dioxane and diisopropyl ether to give 2-(diaminomethyleneamino)-4-(6-methoxycarbonylpyridin-2yl)thiazole (0.54 g).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[N:6]([CH2:16][C:15]2[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: Nc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc2ccccc2n1Cc1ccc(Cl)cc1
Temperature: 50 °C

Procedure:
A mixture of 2-amino benzimidazole (6.66 g, 50 mmol), 4-chlorobenzylchloride (8.86 g, 55 mmol), and potassium carbonate (13.8 g, 100 mmol) in DMF (150 ml) was heated to 50° C. overnight. After dilution with water the product was filtered off. Recrystallization from water/ethanol 1:2 gave pure product. Yield 5.6 g (46%) mp 196°-197° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13](=[C:14]([CH3:16])[CH:15]=1)[S:12][CH2:11][CH2:10][C:9]2=[O:17])=[O:5])[CH3:2].[Br:19]Br>C(O)C>[Br:19][CH:10]1[C:9](=[O:17])[C:8]2[C:13](=[C:14]([CH3:16])[CH:15]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:7]=2[CH3:18])[S:12][CH2:11]1
Reactant: CCOC(=O)c1cc(C)c2c(c1C)C(=O)CCS2
Reactant: BrBr
Solvent: CCO
Product: CCOC(=O)c1cc(C)c2c(c1C)C(=O)C(Br)CS2
Reaction time: 1 h
Yield: 97.1 %

Procedure:
1.9 Grams (7.2 mmol) of 6-ethoxycarbonyl-5,8-dimethylthiochroman-4-one was dissolved in 28 ml of ethanol. Then, 1.2 g (7.5 mmol) of bromine was dropwise added with an ice bath cooling, and the mixture was stirred at the same temperature for 1 hour, then the ice bath was removed and further stirred for 1 hour. Water was added to the reaction mixture, and the reaction mixture was extracted with chloroform three times. An organic layer was washed with a saturated sodium chloride aqueous solution three times, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 2.4 g (yield 97%) of the titled compound.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].[CH2:22]([C:24]([C:42]1[CH:47]=[CH:46][C:45](O)=[C:44]([CH3:49])[CH:43]=1)([C:27]1[CH:32]=[CH:31][C:30]([C:33]#[C:34][C:35]2([OH:40])[CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:29]([CH3:41])[CH:28]=1)[CH2:25][CH3:26])[CH3:23].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:22]([C:24]([C:42]1[CH:47]=[CH:46][C:45]([O:12][S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10])=[C:44]([CH3:49])[CH:43]=1)([C:27]1[CH:32]=[CH:31][C:30]([C:33]#[C:34][C:35]2([OH:40])[CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:29]([CH3:41])[CH:28]=1)[CH2:25][CH3:26])[CH3:23]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(C#CC2(O)CCCC2)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(CC)(c1ccc(C#CC2(O)CCCC2)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Reaction time: 0.17 h
Yield: 51.1 %

Procedure:
Pyridine (0.97 mL, 12 mmol) and trifluoromethanesulfonic anhydride (1.3 mL, 7.7 mmol) were added to a solution of 4-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (Example 32-(1); 3 g, 8 mmol) in dichloromethane (30 mL) at −10° C., and the mixture was stirred at the same temperature for 10 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane only to hexane/ethyl acetate=4/1) to give the title compound (2 g, 49%).
Reaction SMILES: NN.C1(=O)[N:7]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:19][C@H:18]3[C@H:13]([CH2:14][C:15]4[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=4[CH2:17]3)[CH2:12]2)C(=O)C2=CC=CC=C12.C(OCC)C>C(O)C>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:19][C@H:18]2[C@H:13]([CH2:14][C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[CH2:17]2)[CH2:12]1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1C[C@H]2Cc3ccccc3C[C@H]2C1
Agent: NN
Solvent: CCOCC
Solvent: CCO
Product: NCCCN1C[C@H]2Cc3ccccc3C[C@H]2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
Hydrazine (9 mg, 0.28 mmol) was added to a solution of 2-(3-Phthalimido-n-prop-1-yl)-cis-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindole (50 mg, 0.14 mmol) in 1 mL of ethanol, and the mixture was refluxed for 6 hours. The mixture was cooled to room temperature, and 5 mL of diethyl ether was added with stirring. After 30 minutes, a white solid had precipitated. The solid was collected by filtration, rinsed with diethyl ether, then stirred in 10 mL of chloroform. The solids were filtered and washed with chloroform. The filtrate was concentrated to yield 20 mg of a colorless oil as product. Yield=63%. NMR (300 MHz, CD3OD) δ7.09-7.05 (m, 4H), 3.03-2.97 (m, 2H), 2.77-2.70 (dd, 2H, J=6 Hz, 14 Hz), 2.68-2.58 (m, 4H), 2.50-2.44 (dd, 2H, J=5 Hz, 14 Hz), 2.30 (t, 2H, J=7 Hz), 1.82 (t, 2H, J=7 Hz), 1.61 (tt, 2H, J=7 Hz, 8 Hz, 7 Hz).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[C:8]3[NH:16][N:15]=[N:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)=[CH:4][CH:3]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][CH2:27][CH:28]2[CH2:32][CH2:31][O:30][CH2:29]2)[N:20]=1>>[O:30]1[CH2:31][CH2:32][CH:28]([CH2:27][O:26][CH2:25][C:21]2[N:20]=[C:19]([CH2:18][N:14]3[C:9]4[N:10]=[C:11]([NH2:13])[N:12]=[C:7]([C:5]5[O:6][C:2]([CH3:1])=[CH:3][CH:4]=5)[C:8]=4[N:16]=[N:15]3)[CH:24]=[CH:23][CH:22]=2)[CH2:29]1
Reactant: Cc1ccc(-c2nc(N)nc3nn[nH]c23)o1
Reactant: BrCc1cccc(COCC2CCOC2)n1
Product: Cc1ccc(-c2nc(N)nc3c2nnn3Cc2cccc(COCC3CCOC3)n2)o1

Procedure:
Prepared from 7-(5-methyl-2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine and 2-bromomethyl-6-(tetrahydrofuran-3-ylmethoxymethyl)pyridine by the alkylation method described for Example 36.
Reaction SMILES: N.C([N:5](CC)C(C)C)(C)C.[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][N:13]=1>ClCCl>[Cl:11][C:12]1[N:17]=[C:16]([NH2:5])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][N:13]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: N
Solvent: ClCCl
Product: Nc1nc(Cl)ncc1[N+](=O)[O-]
Yield: 90.1 %

Procedure:
Aqueous ammonia (8.0 ml) and N,N-diisopropylethylamine (13.2 ml) were dissolved into 150 ml dichloromethane. The mixture was added dropwise to a solution of 2,4-dichloro-5-nitropyrimidine (10.0 g) in dichloromethane (30 ml) at 0° C. After the completion of the dropwise addition, the mixture was kept at the same temperature to react for 1 hour. The precipitate was filtered off. The filter cake was recrystallized to obtain a yellow solid (8.1 g) in a yield of 90.1%. 1H NMR (400 MHz, DMSO-d6): δ 9.20 (s, 1H), 9.02 (s, 1H), 8.60 (s, 1H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[NH2:13])[C:6]([O:8][CH3:9])=[O:7].[Br:14]Br>CO.C(O)(=O)C>[Br:14][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:12]=1[NH2:13])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(N)c(OC)c1
Reactant: BrBr
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)c(N)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 115.3 %

Procedure:
10.5 Grams (55 mmole) of methyl 3-methoxy-4-aminobenzoate was dissolved in 80 ml methanol, and 3.0 ml bromine (55 mmole) in 20 ml acetic acid was added dropwise at room temperature. The solution was stirred for three hours at room temperature and the solvents were evaporated under reduced pressure. The residue was treated with sodium bicarbonate solution and the product was filtered and air-dried to yield 16.5 grams of methyl 3-bromo-5-methoxy-4-aminobenzoate.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[NH:18]2)=[C:9]1[CH3:28])(C)(C)C.[F:30][C:31]([F:41])([F:40])[C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br>>[O:26]=[S:19]1(=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][C:6]([OH:5])=[O:29])[C:9]=2[CH3:28])[N:18]1[CH2:35][C:34]1[CH:37]=[CH:38][CH:39]=[C:32]([C:31]([F:30])([F:40])[F:41])[CH:33]=1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2ccccc2n1CC(=O)OC(C)(C)C
Product: Cc1c(C2c3ccccc3S(=O)(=O)N2Cc2cccc(C(F)(F)F)c2)c2ccccc2n1CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 3, step c) and 3-trifluoromethyl-benzyl bromide. MS: ESI (negative): 513 (M−H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9](=[O:25])[CH:10]([NH:18][C:19](=O)[CH2:20][CH2:21][S:22][CH3:23])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>ClCCl>[CH3:7][O:8][C:9]([CH:10]1[CH2:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:19]([CH2:20][CH2:21][S:22][CH3:23])=[N:18]1)=[O:25]
Reactant: COC(=O)C(Cc1ccccc1)NC(=O)CCSC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)C1Cc2ccccc2C(CCSC)=N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
0.882 mL (10.07 mmol) of oxalyl chloride was added dropwise to a solution of 2-(3-methylsulfanyl-propionylamino)-3-phenyl-propionic acid methyl ester (from previous step) in 30 mL of dichloromethane and stirred at room temperature for 1 h. This reaction mixture was then cooled to −10° C. and treated with 1.82 g (11 mmol) of FeCl3 at this temperature in portions. This reaction mixture was allowed to warm up to room temperature overnight. 30 mL of 2 N aq. HCl was added slowly while stirring for 1 h. 20 mL of dichloromethane was added and separated, washed again with water (50 mL), and dried over sodium sulfate. The organic solvents were evaporated in vacuo. The residual red solid was mixed with 30 mL of methanol and 1.5 mL of conc. H2SO4 and heated under reflux overnight. Water was added to the reaction mixture and the methanol was evaporated under reduced pressure. Ammonium hydroxide was added to adjust pH to basic. The aqueous layer (˜50 mL) was extracted with dichloromethane (2×50 mL). The combined organic layers were dried over sodium sulfate and evaporated. Purification by column chromatography on silica gel gave 923 mg (38%) of 1-(2-methylsulfanyl-ethyl)-3,4-dihydro-isoquinoline-3-carboxylic acid methyl ester. LCMS: 264 (M+1)+.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([C:26]4[S:27][C:28]([Cl:31])=[CH:29][CH:30]=4)[CH:23]=[C:22]([C:32]([F:35])([F:34])[F:33])[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:31][C:28]1[S:27][C:26]([C:24]2[CH:23]=[C:22]([C:32]([F:33])([F:34])[F:35])[N:21]=[C:20]([C:16]3[CH:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[CH:19]=[CH:18][CH:17]=3)[N:25]=2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(Cl)s4)cc(C(F)(F)F)n3)c2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(Cl)s4)cc(C(F)(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 40.6 %

Procedure:
To a cooled and stirred solution of 5-{3-[4-(5-chloro-thiophen-2-yl)-6-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid tert-butylamide (0.23 g) in dichloromethane (5 ml) was added TFA (5 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated, and purified by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (MeOH, dichloromethane, hexane) yielded the title compound as a light yellow solid (0.084 g, 23%). MS (ISP) 502.0 [(M+H)+]; mp 233° C.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:6][CH2:7][OH:8])[CH3:5].N#N.F[C:12]1[CH:17]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:22]1[C:26]2=[N:27][CH:28]=[N:29][C:30]([OH:31])=[C:25]2[CH:24]=[N:23]1>O1CCOCC1>[CH3:3][N:4]([CH3:5])[CH2:6][CH2:7][O:8][C:12]1[CH:17]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:22]1[C:26]2=[N:27][CH:28]=[N:29][C:30]([OH:31])=[C:25]2[CH:24]=[N:23]1
Reactant: CN(C)CCO
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(O)ncnc32)c(F)c1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(C)CCOc1cc(S(C)(=O)=O)ccc1-n1ncc2c(O)ncnc21
Temperature: 70 °C

Procedure:
In a reaction vial was placed a stir bar and NaH (60% in oil, 90 mg). Dimethylaminoethanol (200 mg) was dissolved in dioxane (1.5 mL) and added to the reaction vial under N2. The mixture was stirred at room temperature for 1 hour before 1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (50 mg) was added. The reaction mixture was heated at 70° C. for 60 hours. The resulting solution was concentrated under vacuum and 1-[2-(2-dimethylamino-ethoxy)-4-methanesulfonyl-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-ol was purified by preparative HPLC. 1H NMR (DMSO-d6, 400 MHz) δ 2.68 (s, 6H), 3.36 (s, 3H), 3.40 (m, 2H), 4.54 (m, 2H), 7.74 (m, 1H), 7.78 (m, 1H), 7.85 (m, 1H), 8.10 (s, 1H), 8.37 (s, 1H), 9.75 (s, 1H), 12.5 (s, 1H). Exact mass calculated for C16H19N5O4S 377.12, found 377.9 (MH+).
Reaction SMILES: F[C:2]([F:13])(F)[C:3]([O:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])=O.[F:14][C:15]1[C:20]([F:21])=CC(F)=[C:17]([F:23])[C:16]=1O.B(F)(F)F.CCOCC>>[F:10][C:7]([F:8])([F:9])[C:6]([O:5][C:3]1[C:2]([F:13])=[C:17]([F:23])[CH:16]=[C:15]([F:14])[C:20]=1[F:21])=[O:11]
Reactant: Oc1c(F)c(F)cc(F)c1F
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: FB(F)F
Solvent: CCOCC
Product: O=C(Oc1c(F)c(F)cc(F)c1F)C(F)(F)F
Yield: 61.4 %

Procedure:
Trifluoroacetic anhydride (28 mL, 0.2 mol) was added dropwise with stirring to 27.1 g (0,163 mol) of 2,3,5,6tetrafluorophenol. Boron trifluoride etherate (0.2 mL) was added and the mixture was refluxed overnight. The residual solution was distilled at atmospheric pressure to remove trifluoroacetic anhydride and trifluoroacetic acid. The desired product 18 (32.2 g; 75% yield) was collected at 45° C. (18mm) as a colorless liquid:
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48](O)=[O:49])[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(C(C)C)C(C)C)C.[NH2:60][CH:61]([C:68]1[CH:73]=[CH:72][C:71]([Cl:74])=[CH:70][CH:69]=1)[CH2:62][NH:63][S:64]([CH3:67])(=[O:66])=[O:65]>CN1C(=O)CCC1>[Cl:74][C:71]1[CH:70]=[CH:69][C:68]([CH:61]([NH:60][C:48]([C:33]2([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:28])[CH3:26])[CH2:34][CH2:35][N:36]([C:39]3[C:40]4[CH:47]=[CH:46][NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)[CH2:37][CH2:38]2)=[O:49])[CH2:62][NH:63][S:64]([CH3:67])(=[O:66])=[O:65])=[CH:73][CH:72]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: CS(=O)(=O)NCC(N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(CNS(C)(=O)=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 65 h
Yield: 79.1 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (88 mg, 0.23 mmol) was added in one portion to a stirred solution of 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (79 mg, 0.22 mmol) and N-ethyldiisopropylamine (0.046 mL, 0.26 mmol) in NMP (3 mL). The mixture was treated with N-(2-amino-2-(4-chlorophenyl)ethyl)methanesulfonamide (Intermediate 75) (60 mg, 0.24 mmol). The solution was stirred for 65 hours at room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed twice with water. The organic solution was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica using gradient elution (1% methanol/DCM to 15% methanol/DCM). Product containing fractions were combined to give tert-butyl 4-(1-(4-chlorophenyl)-2-(methylsulfonamido)ethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (103 mg, 79%) as colourless solid.
Reaction SMILES: [Cl-].Cl[CH2:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][NH+:5]=1.[SH:14][C:15]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])=[CH:23][C:17]=2[N:16]=1>C(O)C.O.[OH-].[Na+]>[CH3:11][O:10][C:9]1[C:4]([CH2:3][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])=[CH:23][C:17]=3[N:16]=2)=[N:5][CH:6]=[CH:7][C:8]=1[O:12][CH3:13]
Reactant: COc1cc[nH+]c(CCl)c1OC
Reactant: FC(F)C(F)(F)Oc1ccc2[nH]c(S)nc2c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccnc(CSc2nc3cc(OC(F)(F)C(F)F)ccc3[nH]2)c1OC
Temperature: 20 °C
Reaction time: 1 h

Procedure:
0.38 g (1.7 mmol) of 2-chloromethyl-3,4-dimethoxypyridinium chloride is added to a solution of 0.46 g (1.7 mmol) of 2-mercapto-5-(1,1,2,2-tetra fluoroethoxy)-1H-benzimidazole in 10 ml of ethanol, 10 ml of water and 1.8 ml of 2N sodium hydroxide solution; after the mixture has been stirred at 20° C. for one hour, a further 10 ml of water are added dropwise. The mixture is then stirred at 20° C. for a further four hours. The solid which has precipitated out is filtered off, washed with 0.01N sodium hydroxide solution and then with water until neutral and dried to constant weight. 0.63 g (90% of theory) of the title compound is obtained as a colorless crystalline powder of m.p. 98°-102° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-])=O.CN(C)[CH:16]=[S:17].C(O)C>C1(C)C(C)=CC=CC=1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]2[S:17][CH:16]=[N:11][C:3]=2[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN(C)C=S
Solvent: CCO
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1ccc2scnc2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
A mixture of 10 g of 1-chloro-2,4-dinitrobenzene and 20.26 g of N,N-dimethylthioformamide is heated to 60° C. for 3 hours. The resulting solid is suspended in 25 mL of xylene and the mixture is heated to reflux for 4 hours. The mixture is allowed to cool to room temperature and 15 mL of ethanol are added. The resulting suspension is filtered, and the brown solid is washed with a minimum amount of ethanol. The solid is dissolved in 120 mL of ethanol, heated to boiling, and filtered hot to remove trace solids. After reduction of the volume to about 100 mL, the solution is allowed to stand overnight at room temperature. The resulting solid is filtered and washed with ethanol to provide 4.68 g of 5-nitrobenzothiazole as reddish-brown needles.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:10][OH:11])[C:7]([OH:9])=[O:8].CC(C)([O-])C.[K+].Br[C:19]([CH3:28])([CH3:27])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].Cl>CS(C)=O>[C:23]([O:22][C:20]([C:19]([O:11][N:10]=[C:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[C:7]([OH:9])=[O:8])([CH3:28])[CH3:27])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(O)C(=NO)c1ccco1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)ON=C(C(=O)O)c1ccco1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 2-(fur-2-yl)-2-hydroxyiminoacetic acid (syn isomer) (14.1 g) in dimethyl sulphoxide (100 ml) was added all at once to a magnetically stirred solution of potassium t-butoxide (22.4 g) in dimethyl sulphoxide (400 ml), the reaction mixture being maintained under an atmosphere of dry nitrogen. A gel was formed which, on stirring, become a finely divided, yellow solid. Stirring was continued for one hour, and then a solution of t-butyl 2-bromo-2-methylpropionate (24.0 g) in dimethyl sulphoxide (50 ml) was added over one hour to the reaction mixture at room temperature. After addition was complete, the resulting solution was stirred for a further hour. The reaction was poured into ice-water (1.5 liters) and acidified under ether (500 ml) to pH 1.8 with concentrated hydrochloric acid. The two layers were separated, and the aqueous layer was extracted with more ether. The combined ether extracts were washed once with water, then extracted with aqueous sodium bicarbonate solution. The combined alkaline extracts were acidified under ether to pH 1.8 with concentrated hydrochloric acid, and the acid solution was extracted further with ether. The combined ether extracts were washed (water, saturated brine), dried, and concentrated to a yellow oil, which crystallised under high vacuum (22.41 g, 83%), λmax (EtOH) 272.5 nm (ε 15,400).