Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:9]=1[OH:10])[CH:5]=O.[C:15](#[N:19])[CH2:16][C:17]#[N:18]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:9]=1[OH:10])[CH:5]=[C:16]([C:15]#[N:19])[C:17]#[N:18]
Reactant: N#CCC#N
Reactant: CC(C)(C)c1cc(C=O)cc(Br)c1O
Product: CC(C)(C)c1cc(C=C(C#N)C#N)cc(Br)c1O

Procedure:
In a similar manner as described in Example 2 reaction of 3-bromo-5-tert-butyl-4-hydroxybenzaldehyde and malononitrile gave 3-bromo-5-tert-butyl-4-hydroxybenzylidenemalononitrile as pale yellow needles from alcohol m.p. 185°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4]O.[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[N:14]=[C:15]=[S:16]>O1CCCC1>[CH3:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([CH3:6])[C:8]=1[NH:14][C:15]1[S:16][CH2:4][CH2:3][CH2:2][N:1]=1
Reactant: NCCCO
Reactant: Cc1cccc(C)c1N=C=S
Solvent: C1CCOC1
Product: Cc1cccc(C)c1NC1=NCCCS1
Temperature: 50 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
380 ml (373 grams, 4.97 moles) of 3-amino-1-propanol and 450 ml of tetrahydrofuran ("THF") were added to a 5-L flask fitted with a mechanical stirrer, teflon clad thermol-couple and an addition funnel. Then with rapid stirring, 749 grams (4.59 moles) of the 2,6-dimethylphenylisothiocyanate were added dropwise over a 2 hour period. The temperature was kept below 45° C. by controlling the rate of addition and by the use of a cooling bath. The cooling bath was removed, and replaced with a heating mantle. The temperature was raised to 50° C. followed by the addition of 435 ml. concentrated hydrochloric acid. The addition funnel was removed and a distillation head was placed on the flask. Heating was continued with the distillation of THF and water until the internal temperature had reached 95° C., which took about 2 hours. The reaction mixture was then diluted with 2 liters of water and the stirred solution was allowed to cool to room temperature. The aqueous solution was filtered through a 0.2 microfilter. The reaction mixture was made basic by the careful addition of 10% sodium hydroxide. The addition was continued until the pH of the solution was greater than or equal to 12. A solid was collected by filtration, washed with water and partially dryed in the funnel. The solid was then transferred into a flask fitted with a mechanical stirrer and 1 liter of acetone was added. The slurry was stirred for 1 hour using an ice bath to chill the mixture. The product was isolated by filtration, and air dryed to give 750 grams of crude xylazine. The product had a purity of 99% by GC analysis and gave a IR spectrum that was virtually identical to that of a standard sample of xylazine. The 80 MHz 1HNMR spectrum (CDCl3) produced the following results: delta 7.15 (bs, 3, ArH), 4.5 (t, 2, CH2), 3.15 (t, 2, CH2), 2.9-2.0 (m, 8, CH2 and CH3) was in complete agreement with a spectrum of a standard xylazine sample. Furthermore, the mixed melting point of the xylazine sample and a standard showed no depression.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:5][CH:4]=1.O1CCCC1>[Pd].C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:7][CH:8]=1
Reactant: COc1ccc(C=C2SC(=O)NC2=O)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 96.5 %

Procedure:
5-[(4-Methoxyphenyl)methylidene]thiazolidine-2,4-dione (6.00 g, 25.5 mmol), 10% palladium on carbon (6.00 g) and a mixed solvent of tetrahydrofuran and ethanol (2:1 v/v, 300 mL) were mixed, and hydrogenation was performed at room temperature and at an initial pressure of 294 kPa. After completion of the reaction, catalyst was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (eluate n-hexane: ethyl acetate=2:1 v/v) to obtain 5.84 g (97%) of the title compound as colorless powder.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([O-:4])=[O:3].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl.C(Cl)(Cl)Cl>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:11][CH:12]=1)([O-:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: NCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 84.3 %

Procedure:
To a solution of 25.0 g (133 mmol, 1.0 equiv.) of 4-nitro benzylamine hydrochloride in 500 mL of methylene chloride at 0° C. was added 46.4 mL (331 mmol, 2.5 equiv.) of triethylamine followed by 11.3 mL (146 mmol, 1.1 equiv.) of methanesulfonyl chloride dropwise. The reaction was stirred for thirty minutes at 0° C. then diluted with 500 mL of chloroform. The organic layer was washed with 150 mL portions of 1N HCl and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated to give 25.8 g (85%) of N-[(4-nitrophenyl)methyl]methanesulfonamide.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([C@H:13]([NH2:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:21]([OH:23])=[O:22].[K].[C:26](=[O:34])([O:31][CH2:32][CH3:33])[O:27][CH:28](Br)[CH3:29].C(=O)(O)[O-].[Na+]>C(#N)C>[CH3:29][CH2:28][O:27][C:26]([O:31][CH:32]([O:22][C:21]([C@@H:3]1[N:4]2[C:8]([C@@H:7]([NH:10][C:11]([C@H:13]([NH2:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[C@H:5]2[S:6][C:2]1([CH3:24])[CH3:1])=[O:9])=[O:23])[CH3:33])=[O:34]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: CCOC(=O)OC(C)Br
Agent: O=C([O-])O
Agent: [K]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)OC(C)OC(=O)[C@@H]1N2C(=O)[C@@H](NC(=O)[C@H](N)c3ccccc3)[C@H]2SC1(C)C
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A mixture of ampicillin Dane potassium salt (45.6 g), 1-bromoethyl ethyl carbonate (36.0 g), sodium bicarbonate (38.4 g) and acetonitrile (260 ml) is stirred for 3 hours at 40° C. The mixture is filtered and the cake is washed with acetonitrile (2×20 ml). Water (20 ml) is added and the mixture is stirred for 1 hour. Most of the solvent is removed by evaporation at 35°-40° C., under reduced pressure. Acetone (70 ml) and water (4.5 ml) are added. A mixture of concentrated hydrochloric acid (6.85 ml) and water (2.3 ml) is added slowly in order to keep the pH at 2-2.5. If, at the end, the pH is not stable, a small additional amount of 1:1 hydrochloric acid is added until a stable pH in the range 2-2.5 is obtained. The solution is dried and filtered. Butyl acetate (180 ml) and the solution is distilled under reduced pressure to a volume of ca. 40 ml. More butyl acetate (270 ml) is added and the product is allowed to crystallize at ca. 5° C. The mixture is filtered to give 32.5 g bacampicillin.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH:32]([CH3:34])[CH3:33])[C:13](=[O:31])[C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][NH:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH:17]=[C:16]([Cl:30])[CH:15]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37].C(N(CC)CC)C>C(#N)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:30][C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([O:20][CH2:21][CH2:22][NH:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH:17]=1)[C:13]([N:12]([CH:32]([CH3:34])[CH3:33])[CH2:11][CH2:10][CH2:9][NH:8][S:36]([CH3:35])(=[O:38])=[O:37])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)N(CCCN)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(C)N(CCCNS(C)(=O)=O)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1

Procedure:
To a solution of N-(3-amino-propyl)-3-chloro-N-isopropyl-5-[2-(pyridin-4-ylamino)-ethoxy]-benzamide trifluoroacetate (0.02 g) in dry acetonitrile (1 ml) was added a mixture of methanesulfonyl chloride (0.005 g) and triethylamine (0.017 ml) in acetonitrile (1 ml). The resultant mixture was stirred at room temperature for 15 h, and then concentrated under reduced pressure. The residue was stored in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (2 ml) for 4 h, and then concentrated under reduced pressure. The residue was then subjected to preparative hplc and the title compound obtained as a colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: FC1[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)[C:8]2=[O:22])=CC=1.C1(CN2CCN(C3C=C(C=CN=3)C(OC)=O)C2=O)CC1.[N:45]1[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51][NH2:52])[CH:46]=1>>[CH:5]1([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]([NH:52][CH2:51][C:47]3[CH:46]=[N:45][CH:50]=[CH:49][CH:48]=3)=[O:17])[C:8]2=[O:22])[CH2:23][CH2:24]1
Reactant: NCc1cccnc1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Agent: COC(=O)c1ccnc(N2CCN(CC3CC3)C2=O)c1
Product: O=C(NCc1cccnc1)c1ccnc(N2CCN(CC3CC3)C2=O)c1
Yield: 46 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate with methyl 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)isonicotinate to react with pyridin-3-ylmethanamine, 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-N-(pyridin-3-ylmethyl)isonicotinamide was obtained as a colorless solid in 46% yield: mp 122-123° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.28 (t, J=9.0 Hz, 1H), 8.54-8.50 (m, 2H), 8.43-8.41 (m, 1H), 8.36 (d, J=3.0 Hz, 1H), 7.70-7.67 (m, 1H), 7.35-7.29 (m, 2H), 4.45 (d, J=5.7 Hz, 2H), 3.93 (t, J=9.0 Hz, 2H), 3.56 (t, J=9.0 Hz, 2H), 3.06 (d, J=9.0 Hz, 2H), 0.96-0.85 (m, 1H), 0.48-0.42 (m, 2H), 0.21-0.15 (m, 2H); MS (ES+) m/z 352.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][NH:13][CH2:14][C:15]1[S:16][CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:13]([CH2:14][C:15]2[S:16][CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=2)[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CCOC(=O)c1csc(CNC)n1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1csc(CN(C)S(=O)(=O)c2ccc(Br)cc2)n1
Reaction time: 18 h
Yield: 66.8 %

Procedure:
4-Bromobenzenesulfonyl chloride (2.1 g, 8.2 mmol) was added to a solution of ethyl 2-(methylaminomethyl)thiazole-4-carboxylate (1.5 g, 7.5 mmol) and triethylamine (2.1 ml, 1.5 g, 15 mmol) in dichloromethane (30 ml) and the mixture was stirred for 18 h. The mixture was diluted with ethyl acetate and washed with 1N potassium hydrogen sulphate, water and brine, dried and reduced. Chromatography (35% EtOAc/65% hexanes) afforded ethyl 2-(N-(4-bromobenzenesulphonyl)-N-methylaminomethyl)thiazole-4-carboxylate (2.1 g, 67%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].[CH3:19][C:20]1[CH:21]=[C:22]([OH:27])[CH:23]=[C:24]([CH3:26])[CH:25]=1>C1COCC1>[CH3:19][C:20]1[CH:21]=[C:22]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[O:27][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Cc1cc(C)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(Oc2ccc(C#N)cc2[N+](=O)[O-])c1
Temperature: 25 °C
Yield: 85.2 %

Procedure:
To a solution of 4-chloro-3-nitrobenzonitrile (12.00 g, 65.75 mmol) in THF was added potassium carbonate (45.58 g, 328.70 mmol) and 3,5-dimethylphenol (9.658 g, 78.88 mmol). The reaction mixture was refluxed for 17 hrs, whereupon the starting material was consumed (TLC, 25% EtOAc in hexanes). The reaction mixture was then cooled to room temperature, and potassium carbonate was filtered and washed with copious amounts of EtOAc. The filtrate was washed sequentially with saturated sodium bicarbonate solution, water, and saturated sodium chloride solution, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give the crude product as a yellow solid. The solid was triturated with hexanes and filtered to afford compound 21 as a whitish-yellow powder. (15.022 g, 85.2% yield, 100% HPLC purity). 1H NMR (500 MHz, DMSO-d6): δ 8.65 (d, J=2 Hz, 1H), 8.06 (dd, J1=9 Hz, J2=2 Hz, 1H), 7.12 (d, J=9 Hz, 1H), 6.97 (s, 1H), 6.84 (s, 2H), 2.29 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:4][N:3]=1.[CH3:17][C:18](=O)[CH2:19][C:20](=O)[CH3:21]>CC(O)=O>[CH2:10]([S:9][C:5]1[C:6]([C:7]#[N:8])=[C:2]2[N:1]=[C:18]([CH3:17])[CH:19]=[C:20]([CH3:21])[N:3]2[N:4]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1c(N)n[nH]c1SCc1ccccc1
Reactant: CC(=O)CC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(C)n2nc(SCc3ccccc3)c(C#N)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
A slurry of 0.5 g (2.2 mmole) of 3-amino-5-benzylthio-4-cyanopyrazole in 15 ml glacial HOAc was stirred at room temperature as 0.44 g (4.4 mmole) of 2,4-pentanedione was added. The mixture was stirred at room temperature for 3 hours. The white solid was collected by filtration, washed with HOAc, and dried to give 0.62 g (95.4 percent) of product as a white powder, m.p. 140° C. The analytical sample was recrystallized from 2-propanol. 1H NMR (DMSO-d-6): 7.5 (m, 2H, benzene), 7.3 (m, 3H, benzene), 7.1 (s, 1H, pyrazolopyrimidinyl H-6), 4.5 (s, 2H, CH ), 2.7 (s, 3H, CH ), 2.5 (s obscured by DMSO, 3H, CH3). 13C NMR (DMSO-d-6): 163.3, 155.3, 150.5, 146.7, 137.0, 129.1, 128.3, 127.3 112.8, 111.1, 79.0, 34.5, 24.1, 16.3. IR (KBr): 2220, 1615, 1550 cm-1. Analysis: Calculated for C16H14N4S: C, 65.28; H, 4.79; N, 19.03; S, 10.89. Found: C, 65.11; H, 4.64; N, 18.95; S, 11.03.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)=O.[OH-].[K+].O.NN.Cl>C(O)CO>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1
Reactant: Cc1[nH]cnc1C(=O)c1ccc2cccnc2c1
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: OCCO
Solvent: O
Product: Cc1[nH]cnc1Cc1ccc2cccnc2c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
A mixture of (9) (0.53 g, 2.23 mmol), potassium hydroxide (0.50 g, 8.91 mol), and hydrazine hydrate (0.45 mL, 14.4 mmol) in ethylene glycol was heated at 120° C. for 1 h, then kept at 165° C. overnight. The reaction mixture was cooled to room temperature and acidified with 2 M HCl (aq) to pH˜4. The aqueous layer was washed with chloroform/isoprpanol (3:1, 200 ml). The aqueous layer was basified to pH˜7, and extracted with chloroform/isopropanol (3:1, 200 mL). The pooled organic layers were dried over magnesium sulfate. The mixture was filtered, and the solvents were removed under vacuum. The residue was purified by chromatography on silica gel with 3% saturated ammonia methanol in dichloromethane to give 7-((5-methyl-1H-imidazol-4-yl)methyl)quinoline (10) as a yellow foam (0.32 mg, 1.45 mmol, 65% yield).
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][C:6]([NH2:8])=[NH:7].BrBr.C[O-].[Na+].[S-:14][C:15]#[N:16].[K+]>CO>[CH3:2][O:3][CH2:4][CH2:5][C:6]1[N:8]=[C:15]([NH2:16])[S:14][N:7]=1
Reactant: N#C[S-]
Reactant: COCCC(=N)N
Agent: BrBr
Agent: C[O-]
Agent: Cl
Solvent: CO
Product: COCCc1nsc(N)n1
Temperature: 5 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
To a solution of 3-methoxy-propionamidine hydrochloride (4.8 g, 0.035 mol) in methanol (20 mL) at 0° C. under vigorous stirring was added dropwise bromine (1.78 mL, 0.035 mol) and a 5.4M sodium methylate solution in methanol (13 mL, 0.035 mol) simultaneously over 30 min maintaining a slight bromine excess by color. To the resulting nearly colorless suspension was added dropwise a solution of potassium thiocyanate (3.37 g, 0.035 mol) in methanol (20 mL) over 10 min at 0-10° C. The resulting mixture was stirred for 2 h at 0-10° C. and then filtered. The isolated material was washed with methanol and dried which afforded a brown solid which was purified by flash chromatography (300 g silica gel 60, 5% methanol/diethyl ether) and crystallized from diethyl ether/hexanes which afforded 3-(2-methoxy-ethyl)-[1,2,4]thiadiazol-5-ylamine (4.08 g, 74%) as a light yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:28](=[O:30])[CH3:29])[CH:22]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(F)=C(F)C=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.NC1C=C(NC(=O)C)C=CC=1.C(=O)CCCC.C(OC(=O)CSC1SC(N)=NC=1)C>>[C:28]([NH:27][C:23]1[CH:22]=[C:21]([N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:31])=[O:3])=[CH:8][N:9]=2)[CH:26]=[CH:25][CH:24]=1)(=[O:30])[CH3:29]
Reactant: CCCCCN(C(=O)Nc1ncc(SCC(=O)OCC)s1)c1cccc(NC(C)=O)c1
Agent: CC(=O)Nc1cccc(N)c1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: O=C(O)Cc1csc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2)n1
Solvent: CCCCC=O
Product: CCCCCN(C(=O)Nc1ncc(SCC(=O)O)s1)c1cccc(NC(C)=O)c1

Procedure:
The title compound was prepared via {2-[3-(3-acetylamino-phenyl)-3-pentyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using N-(3-aminophenyl)-acetamide, pentanal and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=3)[C:20]([C:28]3[N:29]=[C:30]4[C:36]([CH:37]=[O:38])=[CH:35][N:34]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:31]4=[N:32][CH:33]=3)=[N:19]2)[CH2:15]1)([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.S(=O)(=O)([OH:49])N.[O-]Cl=O.[Na+].OP([O-])(O)=O.[K+]>O1CCOCC1.O>[CH:1]([N:14]1[CH2:17][CH:16]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=3)[C:20]([C:28]3[N:29]=[C:30]4[C:36]([C:37]([OH:49])=[O:38])=[CH:35][N:34]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:31]4=[N:32][CH:33]=3)=[N:19]2)[CH2:15]1)([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
Reactant: NS(=O)(=O)O
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-c3nn(C4CN(C(c5ccccc5)c5ccccc5)C4)c4cc(F)ccc34)cnc21
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(-c3nn(C4CN(C(c5ccccc5)c5ccccc5)C4)c4cc(F)ccc34)cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
To a solution of 2-[1-(1-benzhydryl-azetidin-3-yl)-6-fluoro-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (170 mg, 0.27 mmol) in 1,4-dioxane (10 mL) and water (2 mL) at 0° C. was added sulfamic acid (157 mg, 1.61 mmol). Then added a solution of NaClO2 (43 mg, 0.37 mmol) and KH2PO4 (439 mg, 3.22 mmol) in water (4 mL) dropwise over 5 min. The ice bath was removed and the yellow cloudy reaction mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc (2×). The combined organic layers were dried over MgSO4 and concentrated. The residue was triturated with petroleum ether to isolate 45 mg (26%) of 2-[1-(1-benzhydryl-azetidin-3-yl)-6-fluoro-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[N:12]([S:21]([N:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])[CH:13]=[C:14]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:15]=2)=[O:10])=[CH:4][CH:3]=1.[NH:27]1[CH:31]=[CH:30][CH:29]=[N:28]1.C(=O)([O-])[O-].[K+].[K+].CN(C)[C@@H]1CCCC[C@H]1N>C1(C)C=CC=CC=1.[Cu]I>[CH3:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:14]1[N:15]=[C:11]([C:9](=[O:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)=[CH:3][CH:4]=2)[N:12]([S:21]([N:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])[CH:13]=1
Reactant: c1cn[nH]c1
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)Cc1ccc(Br)cc1
Agent: [Cu]I
Agent: CN(C)[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)Cc1ccc(-n2cccn2)cc1

Procedure:
2-[(4-bromophenyl)acetyl]-4-(2,2-dimethylpropyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (Intermediate 7) (1 g, 2.261 mmol) was added to a stirred, ambient temperature mixture of pyrazole (0.146 g, 2.148 mmol), potassium carbonate (0.656 g, 4.75 mmol), rac-trans-N,N-dimethylcyclohexane-1,2-diamine (0.064 g, 0.452 mmol) and copper (I) iodide (0.022 g, 0.113 mmol) in toluene (2.5 mL). After stirring at reflux overnight, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with saturated brine, dried (sodium sulfate), filtered and concentrated in vacuo. Chromatography over silica eluting with 0-60% EtOAc/hexane afforded 4-(2,2-dimethylpropyl)-N,N-dimethyl-2-{[4-(1H-pyrazol-1-yl)phenyl]acetyl}-1H-imidazole-1-sulfonamide.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:12][C:11]([N+:20]([O-])=O)=[CH:10][C:9]=2[CH3:23])[CH2:4][CH2:3]1.C([O-])=O.[NH4+]>CCO.[Pd]>[CH3:23][C:9]1[CH:10]=[C:11]([CH:12]=[C:13]([CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]=1[N:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)[NH2:20]
Reactant: Cc1cc([N+](=O)[O-])cc(CN2CCCC2)c1N1CCN(C)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1cc(N)cc(CN2CCCC2)c1N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104 %

Procedure:
1-Methyl-4-[2-methyl-4-nitro-6-(pyrrolidin-1-ylmethyl)phenyl]piperazine (90 mg, 0.28 mmol) was hydrogenated using ammonium formate (107 mg, 6 eq) and Pd/C (10% Pd, 15 mg, 0.05 eq) in 2 mL of EtOH. The mixture was stirred overnight at room temperature and then filtered through a celite pad. The filtrate was evaporated and the residue was dissolved in DCM and washed with a saturated aqueous solution of Na2CO3. The aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and evaporated to yield expected compound as a pale yellow oil (84 mg, quantitative yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:12].[C:13](=O)([O-:15])[O-:14].[Na+].[Na+]>O1CCOCC1.O.CC1C(P(C2C([CH2-])=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC1C(P(C2C([CH2-])=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC(O)=O.CC(O)=O.[Pd].[Pd].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo]>[CH3:12][C:5]1[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=[C:2]([C:13]([OH:15])=[O:14])[CH:3]=2)[NH:7][CH:6]=1
Reactant: Cc1c[nH]c2c(C)cc(Br)cc12
Reactant: O=C([O-])[O-]
Agent: [Mo]
Agent: [Pd]
Agent: [C-]#[O+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1COCCO1
Product: Cc1c[nH]c2c(C)cc(C(=O)O)cc12
Temperature: 165 °C
Yield: 93.4 %

Procedure:
A 25 mL microwave reaction tube was charged with 317 mg 5-bromo-3,7-dimethyl-1H-indole dissolved in 3 L dioxane. 42 mg trans-Bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II) and 187 mg molybdenum hexacarbonyl were added followed by 450 mg sodium carbonate dissolved in 6 mL water. The vial was sealed and heated in a microwave reactor for 20 minutes at 165° C. The reaction was cooled and then filtered through celite, and the filtercake washed with EtOAc. The filtrate was concentrated and the resultant oil was redissolved with water. The solution was acidified to pH 3 and the precipitate collected by filtration to yield 250.0 mg (93%) of 3,7-dimethylindole-5-carboxylic acid. LC-MS @ 188.1 (M−1)