Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][S:14][C:13]([CH3:18])([CH3:17])[C@@H:12]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:26](O)[C:27]#[CH:28]>>[CH3:18][C:13]1([CH3:17])[S:14][CH2:15][CH2:16][N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:28][C:27]#[CH:26])=[CH:3][CH:4]=2)(=[O:9])=[O:10])[C@H:12]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: CC(C)(C)OC(=O)[C@@H]1N(S(=O)(=O)c2ccc(O)cc2)CCSC1(C)C
Reactant: C#CCO
Product: C#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)OC(C)(C)C)cc1
Yield: 95 %

Procedure:
According to the procedure of Step 2 of Example 248, Mitsunobu coupling of 0.30 g (0.775 mmoL) of tert-butyl (3S)-4-[(4-hydroxyphenyl)sulfonyl]-2,2-dimethyl-3-thiomorpholinecarboxylate and 0.054 mL (0.93 mmol) of propargyl alcohol gave 0.313 g of tert-butyl (3S)-2,2-dimethyl-4-{[4-(2-propynyloxy)phenyl]sulfonyl}-3-thiomorpholine carboxylate as a white solid. Electrospray Mass Spec 426.4 (M+H)+
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.C([Li])CCC.[Br:15][C:16]1[CH:17]=[CH:18][C:19]([F:24])=[C:20]([CH:23]=1)[CH:21]=[O:22]>O.O1CCCC1.CCCCCC>[S:1]1[C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[C:5]1[CH:21]([C:20]1[CH:23]=[C:16]([Br:15])[CH:17]=[CH:18][C:19]=1[F:24])[OH:22]
Reactant: c1ccc2sccc2c1
Reactant: O=Cc1cc(Br)ccc1F
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1cc2ccccc2s1)c1cc(Br)ccc1F
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 83.6 %

Procedure:
Into a tetrahydrofuran (20 ml) solution of benzo[b]thiophene (5.0 g) was dropwise added a n-hexane solution (25 ml) of n-butyl lithium (1.58 M) at −78° C. in an argon atmosphere, followed by stirring at −78° C. for 10 minutes. Into this solution was dropwise added a tetrahydrofuran (80 ml) solution of 5-bromo-2-fluorobenzaldehyde (8.0 g), followed by stirring at −78° C. for 2.5 hours. The temperature of the reaction mixture was elevated to room temperature. Water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 1-benzothien-2-yl(5-bromo-2-fluorophenyl)methanol (10.5 g, yield: 83.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([CH3:11])[C:4]=1[C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16].OS(O)(=O)=O.[CH3:24]O>>[CH3:24][O:16][C:15](=[O:17])[CH2:14][CH2:13][C:12]([C:4]1[C:5]([CH3:11])=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1])=[O:18]
Reactant: CO
Reactant: COc1cc(C)c(C(=O)CCC(=O)O)c(OC)c1
Agent: O=S(=O)(O)O
Product: COC(=O)CCC(=O)c1c(C)cc(OC)cc1OC
Temperature: 75 °C

Procedure:
A mixture of 4-(2,4-dimethoxy-6-methyl-phenyl)-4-oxo-butyric acid (3.70 g, 14.68 mmol) and concentrated H2SO4 (0.2 mL) in MeOH (50 mL) was heated at 75° C. for 1 hour and concentrated in vacuo. The residue was purified by silica gel flash column chromatography to give 4-(2,4-dimethoxy-6-methyl-phenyl)-4-oxo-butyric acid methyl ester (3.86 g, quant.). 1H NMR (400 MHz, CDCl3) δ 6.70 (s, 1H), 6.50 (s, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.65 (s, 3H), 3.10 (t, J=8.1 Hz, 2H), 2.65 (t, J=8.1 Hz, 2H), 2.20 (s, 3H).
Reaction SMILES: Br.Br[CH2:3][C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15].[NH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.C(=O)(O)[O-]>CN(C)C(=O)C>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][NH:16][CH2:3][C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15]
Reactant: Nc1nc(N)c2nc(CBr)cnc2n1
Reactant: NCc1ccccn1
Agent: Br
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2nc(CNCc3ccccn3)cnc2n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
To a solution of 6-bromomethyl-2,4-pteridinediamine hydrobromide (51 mg, 0.2 mmol) in anhydrous N,N dimethylacetamide was added 2-(aminomethyl) pyridine (22.48 ul, 0.22 mmol). The reaction mixture was stirred at 50° C. overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative HPLC. 32.3 mg product was obtained. Yield: 57%; 1H NMR (500 MHz, DMSO-d6): δ 3.93801 (s, 2H), 4.05772(s, 2H), 7.5758–7.6003 (m, 1H), 7.97993–8.00181 (m, 1H), 8.49332–8.50942 (d, J=8.05 Hz, 1H), 8.62592–8.64301 (d, J=8.545 Hz, 1H), 8.9938(s, 1H); ESI-MS: 283 (M++1)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Br)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.5 %

Procedure:
A mixture of 5-bromo-pyridine-2-carbaldehyde (0.5 g, 2.68 mmol) in ethanol (30 mL) was cooled in an ice bath. Sodium borohydride (0.41 g, 10.75 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated, dried, the residue dissolved in dichloromethane (30 mL) and quenched with a saturated aqueous sodium bicarbonate solution. The organic phase was separated and the aqueous phase was extracted further with dichloromethane (2×10 mL). The combined organic phase was dried over sodium sulfate and concentrated to give the product as an off-white solid (426 mg, 84%). 1H NMR (300 MHz, CDCl3): δ (ppm) 8.61 (d, 1H), 7.82 (dd, 1H), 7.23 (d, 1H), 4.73 (s, 2H), 3.92 (bs, 1H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][N:9]=[C:10]=[O:11])(=[O:5])[C:2]([CH3:4])=[CH2:3].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>O1CCOCC1>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:10](=[O:11])[NH:9][CH2:8][CH2:7][O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[CH:14][CH:15]=1
Reactant: C=C(C)C(=O)OCCN=C=O
Reactant: Nc1ccc(O)cc1
Solvent: C1COCCO1
Product: C=C(C)C(=O)OCCNC(=O)Nc1ccc(O)cc1
Reaction time: 2 h

Procedure:
Methacryloyloxyethylisocyanate and 4-aminophenol were added to dioxane solvent, and stirred for 2 hours to obtain 2-(N'-(4-hydroxyphenyl)ureido)ethylmethacrylate (hereinafter referred to simply as "Compound 1").
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[OH:9].Cl.[C:11](OC(=O)C)(=[O:13])[CH3:12]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[C:6]([C:11](=[O:13])[CH3:12])[CH:5]=[C:4]([Br:8])[C:3]=1[OH:9]
Reactant: Oc1c(Br)cccc1Br
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=S(=O)(O)O
Product: CC(=O)c1cc(Br)c(O)c(Br)c1
Temperature: 0 °C
Reaction time: 50 h

Procedure:
In 5 ml of acetic anhydride was dissolved 5.0 g of 2,6-dibromophenol and, one drop of conc. sulfuric acid was added to the solution. While sometimes manually shaking, the mixture was stirred. When generation of heat stopped, the solution was poured onto 50 ml of ice water and the precipitated crystals of acetic acid-2,6-dibromophenyl were taken by filtration. The crystals were washed with chilled water and dried under reduced pressure. Next, this acetic acid-2,6-dibromophenyl was dissolved in 20 ml of nitrobenzene and 4.0 g of powdery aluminum chloride was gradually added to the solution. The reaction was carried out at 60° to 70° C. for 50 hours to effect Fries rearrangement. After completion of the reaction, the reaction solution was poured onto 100 ml of cold dil. hydrochloric acid. After allowing to stand at 5° C. overnight, the precipitated crystals were taken out by filtration, washed with n-hexane and dried under reduced pressure to give 3.87 g of 2,6-dibromo-4-acetylphenol as crude crystals. The crystals were recrystallized from hot ethyl acetate to give 2.42 g of pure 2,6-dibromo-4-acetylphenol as light brown crystals. 2,6-Dibromo-4-acetylphenol (3,5-dibromo-4-hydroxyacetophenone): C8H6Br2O2
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:13]#[N:14])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.CCOC(C)=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:13]#[N:14])[CH2:11][CH2:12]2)=[CH:8][CH:9]=1
Reactant: N#CC1(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#CC1(c2ccc(N)cc2)CC1
Reaction time: 8 h
Yield: 23 %

Procedure:
To a solution of 1-(4-nitro-phenyl)-cyclopropanecarbonitrile (500 mg, 2.65 mmol, Journal of the American Chemical Society, 71, 2031-5; 1949) in 7 mL of EtOH-2.5 mL of EtOAc was added 350 mg 5% Pd—C. The mixture was stirred under 1 atm of H2 overnight. The reaction was filtered, concentrated in vacuo and then purified using preparative thin layer chromatography (CHCl3) to afford the title compound as an oil (96 mg, 23%). Mass spectrum (ESI, m/z): Cald. C10H10N2, 159.0, found 159.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:11]([CH2:15][C:16](=O)[CH3:17])[C:12]([CH3:14])=O.C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH3:17][C:16]1[N:1]([C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([OH:7])=[O:6])[C:12]([CH3:14])=[CH:11][CH:15]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C)n1-c1cccc(C(=O)O)c1
Yield: 89.7 %

Procedure:
In a reaction vessel equipped with a Dean-Stark trap was placed 13.7 grams (0.10 mole) of 3-aminobenzoic acid, 11.4 grams (0.10 mole) of acetonylacetone, 0.10 gram of p-toluenesulfonic acid and 150 ml of toluene. The stirred reaction mixture was heated under reflux for 15.5 hours during which time the theoretical amount of by-product water was collected in the Dean-Stark trap. The reaction mixture was cooled and placed in a separatory funnel where it was washed with two portions of 50 ml each of aqueous 2N sodium hydroxide. The combined base washes were backwashed with 50 ml of toluene then acidified with aqueous 2 N hydrochloric acid. A solid precipitate was collected by filtration and recrystallized from heptane to give 19.3 grams of 3-(2,5-dimethylpyrrol-1-yl)benzoic acid; mp 148°-150° C.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([OH:23])=O.[OH:24][C:25]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:26]=1[NH2:27]>ClCCl.O>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([NH:27][C:26]1[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:25]=1[OH:24])=[O:23]
Reactant: Nc1cc(Cl)ccc1O
Reactant: O=C(O)Cc1ccccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1ccccc1Cl)Nc1cc(Cl)ccc1O
Reaction time: 1.5 h

Procedure:
To a mixture of 1,1′-carbonyl diimidazole (66.5 g, 0.41 mol) and dichloromethane (300 ml) was added 2-chlorophenylacetic acid (67.0 g, 0.39 mol) dissolved in dichloromethane (200 ml). The mixture was stirred for 1.5 hours and 2-hydroxy-5-chloroaniline (56.4 g, 0.39 mol) was added in one portion. After stirring overnight, the reaction mixture was diluted with water and the mixture was filtered to give the desired amide. The dichloromethane was separated and washed with water. Evaporation of the dichloromethane under reduced pressure afforded additional product which was triturated with a small amount of dichloromethane and combined with the material collected previously to give 108.5 g of the title compound.
Reaction SMILES: CC1(C)[N:6]2[C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH2:9][C@H:5]2[CH2:4][O:3]1.Cl.N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CO>[Si:20]([O:3][CH2:4][C@H:5]1[NH:6][C:7](=[O:12])[C:8]([CH3:10])([CH3:11])[CH2:9]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1(C)C[C@H]2COC(C)(C)N2C1=O
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CO
Product: CC1(C)C[C@@H](CO[Si](C)(C)C(C)(C)C)NC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
To a solution of (S)-3,3,6,6-tetramethyl-dihydropyrrolo[1,2-c]oxazol-5(1H,3H,6H)-one in methanol (20 mL) was added HCl (4 N in 1,4-dioxane, 10 mL, 40 mmol). The reaction mixture was stirred at RT for 30 min, concentrated to dryness, and re-dissolved in DCM (50 mL). To the resulting solution were added imidazole (1.5 g, 22 mmol) and TBS-Cl (2.8 g, 18.6 mmol) respectively. The mixture was stirred at RT overnight and filtered. The filtrate was concentrated and the residue was purified on silica gel column using a mixture of EtOAc and hexanes to give (S)-5-((tert-butyldimethylsilyloxy)methyl)-3,3-dimethylpyrrolidin-2-one (3.1 g, 71.2%). LRMS (M+H+) m/z 258.3.
Reaction SMILES: N[C@@H](C(O)=O)CC1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.O[C:17]1[C:25]2N=N[NH:22][C:21]=2[CH:20]=[CH:19][CH:18]=1>>[CH:21]1([N:22]=[C:5]=[N:6][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[CH2:25][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: Oc1cccc2[nH]nnc12
Product: C(=NC1CCCCC1)=NC1CCCCC1

Procedure:
This is followed by coupling of the first D-tryptophan by the active ester technique with hydroxybenzotriazole (HOBt) obtained "in situ" by means of dicyclohexylcarbodiimide (DCC). 1.5 milliequivalents (3-fold excess with respect to the amine groups of the resin) of Fmoc-D-tryptophan (0.639 g) and 2 milliequivalents of HOBt (0.310 g) are dissolved in 12 ml of 2:1 DCM/DMF, transferred into the reactor of the apparatus and, after pre-equilibration for 2 minutes with stirring, 1.5 ml of 1 M DCC in 2:1 DCM/DMF (equal to 1.5 milliequivalents) are added, thus initiating the automatic coupling cycle (line 9 in Table 2). At the end of the cycle described in the table, the Kaiser test is carried out on an aliquot of resin; if the degree of incorporation of the amino acid is greater than 99%, the automatic protective group removal from the amine group is carried out; otherwise, the coupling is repeated. For the successive couplings, always according to the plan in Table 2, the following amino acids were used in the quantities indicated: Fmoc-DTrp (0.639 g for each of the 3 further couplings), Fmoc-valine (0.509 g), Fmoc-tyro-sine t-butyl ether (0.689 g) and Fmoc-t-butyl aspartate (0.617 g). After the last coupling, the protective group removal cycle is repeated, the resin is taken out of the reactor and dried in vacuo over potash, giving 1.650 g of product. This is then followed by the detachment of the peptide from the resin and simultaneous protective group removal from the side chains by trifluoroacetic acid (TFA). 1.5 g of peptide-resin are placed into a small flask containing 30 ml of a solution consisting of 27:1.5:1.5 (volume/volume) TFA/ethanedithiol/p-cresol and the mixture is maintained for 2 hours in a water bath at 35° C. with magnetic stirring. To precipitate the crude product, 10 volumes of ethyl ether and 5 volumes of petroleum ether, both cooled to 0° C., are added. The mixture is kept overnight at -78° C. and filtered over a porous funnel-shaped filter , giving 350 mg of crude crystalline product. For the purification by high-pres-sure liquid chromatography, the procedure of Example 1 is followed, giving 12 mg of product; characterization by HPLC analysis (conditions as described in Example 1): Rt=12.6 minutes, HPLC purity=98%.
Reaction SMILES: O[C:2]1([OH:9])[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.C(Cl)Cl.CN(C=O)C.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:30]1([N:34]2[CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH2:33][CH2:32][CH2:31]1>C(Cl)Cl>[CH:30]1([N:34]2[CH2:40][CH2:39][CH2:38][N:37]([C:6]([CH:4]3[CH2:3][C:2](=[O:9])[CH2:5]3)=[O:8])[CH2:36][CH2:35]2)[CH2:33][CH2:32][CH2:31]1
Reactant: O=C(O)C1CC(O)(O)C1
Reactant: C1CC(N2CCCNCC2)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CC(C(=O)N2CCCN(C3CCC3)CC2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55 %

Procedure:
To a stirred solution of 3,3-dihydroxycyclobutanecarboxylic acid (80 mg, 0.61 mmol) in 4:1 DCM/DMF (2.5 ml) was added CDI (103 mg, 0.64 mmol) at RT. The mixture was stirred for 1.5 h at RT and 1-cyclobutyl-1,4-diazepane (98 mg, 0.64 mmol) was added. The resulting solution was stirred at RT for 3 H, diluted with DCM (20 ml) and washed with 1:1 H2O/brine (20 ml). The organic layer was dried (Na2SO4), filtered and concentrated at reduced pressure. Purification by silica gel FCC (eluting with DCM/MeOH/NH3 90:10:1) provided the title compound as colourless oil (84 mg, 56%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.N#N.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.CCN(CC)CC>CO.O.[Cl-].[Zn+2].[Cl-].ClCCCl.CC(O)(C)C>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]3)=[CH:18][CH:17]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: N#N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCCl
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
Zinc chloride (1.0 M in Et2O) (1.97 mL, 1.97 mmol) was added to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (0.384 g, 1.77 mmol) in 1:1 DCE/t-BuOH (10 mL) at 0° C. under a stream of N2 gas. The mixture was stirred for 1 hour at 0° C. and then tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (I44) (0.453 g, 1.64 mmol) in 1:1 DCE/tBuOH (7 mL) was added. A solution of NEt3 (0.251 mL, 1.80 mmol) in 1:1 DCE/t-BuOH (8 mL) was next added dropwise at 0° C. The reaction mixture was vigorously stirred for a further 30 minutes at 0° C. after the final addition and then at room temperature for 24 hours. The solvent was removed in vacuo to afford a brown oily residue which was purified by column chromatography on silica gel (0-20% EtOAc in petroleum benzine 40-60° C.) to yield a pale yellow solid. The solid was suspended in MeOH (10 mL) and water (10 mL). The resulting precipitate was filtered to afford the title compound (I45) (0.658 g, 88%) as a white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.60 (s, 1H), 8.77 (d, J=0.5 Hz, 1H), 7.59 (d, J=8.5 Hz, 2H), 7.23 (d, J=8.6 Hz, 2H), 4.13-3.98 (m, 2H), 2.80 (bs, 2H), 2.69-2.61 (m, 1H), 1.74 (d, J=12.4 Hz, 2H), 1.53-1.39 (m, 11H). LCMS Method C: rt 6.81 min; m/z 401 [M−tButyl+2H]+, 357 [M-Boc+2H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:19][C:18]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]=2[CH:12]=1)=[O:10].C1([O:26][C:27](=O)[NH:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)C=CC=CC=1.CCN(CC)CC>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:19][C:18]2[CH2:17][CH2:16][N:15]([C:27]([NH:28][C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)=[O:26])[CH2:14][C:13]=2[CH:12]=1)=[O:10]
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: Nc1ccccc1NC(=O)c1cc2c(s1)CCNC2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccccc1NC(=O)c1cc2c(s1)CCN(C(=O)Nc1cccnc1)C2
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of N-(2-aminophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide (1.0 eq) obtained in step VIII in DMF was treated with Pyridin-3-yl-carbamic acid phenyl ester (1.0 eq) in presence of base like Et3N and stirred at 50° C. for 8 h Reaction was then quenched with water and extracted with ethyl acetate and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:22]2[C:21]([CH3:23])=[C:20]([CH3:24])[N:19]=[C:18]([NH2:25])[C:17]=2[N:16]=[C:15]1[CH2:26][CH2:27][CH3:28].C(N(CC)CC)C.N12CCCN=C1CCCCC2>ClCCl.C(#N)C.O>[O:6]=[S:5]1(=[O:7])[CH2:4][CH2:3][CH2:2][N:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:22]2[C:21]([CH3:23])=[C:20]([CH3:24])[N:19]=[C:18]([NH2:25])[C:17]=2[N:16]=[C:15]1[CH2:26][CH2:27][CH3:28]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CCCc1nc2c(N)nc(C)c(C)c2n1CCCCN
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: CCCc1nc2c(N)nc(C)c(C)c2n1CCCCN1CCCS1(=O)=O
Reaction time: 0.33 h
Yield: 76.7 %

Procedure:
Chloropropanesulfonyl chloride (0.221 mL, 1.82 mmol) was added drop wise to a chilled (0° C.) solution of 1-(4-aminobutyl)-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-4-amine (0.500 g, 1.82 mmol) in dichloromethane (10 mL). The reaction mixture was allowed to stir for 20 minutes after the addition was completed then triethylamine (0.245 mL, 2.51 mmol) was added drop wise. The reaction mixture was allowed to stir for 20 minutes after the addition was completed then it was poured into water. The layers were separated. The organic layer was washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (10 mL). 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.272 mL, 1.82 mmol) was added and the reaction mixture was allowed to stir overnight. The reaction mixture was poured into water and then extracted with chloroform (×3). The combined extracts were washed with water then with brine, dried over magnesium sulfate and then concentrated under reduced pressure to provide a yellowish oil. The oil was dissolved in acetonitrile and then concentrated under reduced pressure to provide a yellowish white solid. This material was recrystallized from isopropanol to provide 0.53 g of 1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-4-amine as a yellow orange solid, m.p. 155.1-161.2° C. Analysis: Calculated for C18H29N5O2S: % C, 56.97; % H, 7.70; % N, 18.45; Found: % C, 56.61; % H, 7.77; % N, 18.14. 1H NMR (300 MHz, DMSO-d6) δ 5.67 (s, 2H), 4.21 (apparent t, J=7.5 Hz, 2H), 3.2-3.08 (m, 4H), 2.92 (t, J=6.5 Hz, 2H), 2.77 (t, J=7.5 Hz, 2H), 2.37 (s, 3H), 2.30 (s, 3H), 2.19 (quintet, J=6.7 Hz, 2H), 1.78 (sextet, J=7.4 Hz, 2H), 1.73-1.55 (m, 4H), 1.00 (t, J=7.4 Hz, 3H); MS(CI) m/e 380.2117 (380.2120 calcd for C18H29N5O2S, M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6][CH:5]=1.C([O-])=O.[NH4+]>>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6][CH2:5]1
Reactant: O=c1c(-c2ccccc2Cl)coc2ccccc12
Agent: O=C[O-]
Agent: [NH4+]
Product: O=C1c2ccccc2OCC1c1ccccc1Cl
Temperature: 25 °C
Yield: 13.7 %

Procedure:
Compound 41 was prepared following the general procedure described by Wähälä and Hase, Heterocycles 1989, 28, (1), 183-186, herein incorporated by reference. To a 10 mL round bottom flask was added 2′-chloroisoflavone (152 mg, 0.592 mmol) and ammonium formate (149 mg, 2.37 mmol). The flask was purged with N2, followed by addition of methanol (8 mL) and 10% Pd/C (151 mg). The reaction was allowed to stir at room temperature and monitored by reverse phase HPLC. Upon consumption of starting material, the reaction mixture was passed through a pad of silica gel using EtOAc as the eluent. The solvent was concentrated in vacuo to afford crude 41. Purified by flash column chromatography (SiO2, 10% EtOAc/Hex) to afford 41 (21 mg, 14%) as an off-white solid. Analytical data for isoflavanone 41: 1H NMR (500 MHz, CDCl3) δ 7.98 (d, J=9.5 Hz, 1H), 7.53 (app t, J=9 Hz, 1H), 7.39-7.28 (m, 4H), 7.09-7.03 (m, 2H), 4.71-4.66 (m, 2H), 4.04-4.01 (app t, J=6.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 192.4, 161.8, 136.3, 133.2, 129.1, 128.9, 128.1, 128.0, 121.9, 121.3, 118.1, 71.7, 52.6; GCMS: Mass calculated for C15H11ClO2, [M]+, 259. Found 225.