Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([CH3:13])[CH:3]=1.[H-].[Na+].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.CCOC(C)=O>[C:16]1([S:22]([N:8]2[C:9]3[C:5](=[C:4]([CH3:13])[CH:3]=[C:2]([Cl:1])[C:10]=3[O:11][CH3:12])[CH:6]=[N:7]2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1c(Cl)cc(C)c2cn[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1c(Cl)cc(C)c2cnn(S(=O)(=O)c3ccccc3)c12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
6-Chloro-7-methoxy-4-methyl-1H-indazole (1.55 g, 9.2 mmol) is dissolved in THF (50 mL) and cooled to 0° C. Sodium hydride (60% in mineral oil, 0.40 g, 10 mmol) is added and the reaction is stirred 10 min. Benzenesulfonyl chloride (1.2 mL, 9.7 mmol) is added and the reaction is stirred 20 min. The reaction is diluted with EtOAc, washed with a solution of NH4Cl, water, brine and dried with MgSO4. The solution is concentrated and triturated with hexane to provide 1-benzenesulfonyl-6-chloro-7-methoxy-4-methyl-1H-indazole which is used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:27])=[C:4]2[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:8]([C:24]#[N:25])[CH:7]=[N:6][N:5]2[CH:26]=1.[O:28](S(C(F)(F)F)(=O)=O)[S:29]([C:32]([F:35])([F:34])[F:33])(=O)=[O:30]>C(Cl)Cl.CCOC(C)=O>[C:24]([C:8]1[CH:7]=[N:6][N:5]2[CH:26]=[C:2]([O:1][S:29]([C:32]([F:35])([F:34])[F:33])(=[O:30])=[O:28])[C:3]([CH3:27])=[C:4]2[C:9]=1[NH:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)#[N:25]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1c(O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1c(OS(=O)(=O)C(F)(F)F)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reaction time: 0.08 h
Yield: 95.5 %

Procedure:
To a solution of 397A (32 mg, 0.090 mmol) in CH2Cl2 (1 ml) was added Tf2O (18 μl, 0.099 mmol) at −10° C. The reaction mixture was stirred for 5 min, diluted with EtOAc, washed with brine, dried and concentrated to give 397 (42 mg, 95%) LCMS Found: (M+H)+=489.0
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[C:15]1(=[O:21])[CH2:20][CH2:19][CH2:18][CH:17]=[CH:16]1.FC(F)(F)S([O-])(=O)=O.[Bi+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C>[O:21]=[C:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:16]1
Reactant: O=C1C=CCCC1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Bi+3]
Solvent: CC#N
Product: CCOC(=O)c1[nH]c2ccccc2c1C1CCCC(=O)C1
Temperature: 65 °C

Procedure:
Ethyl 1H-indole-2-carboxylate (2.953 g) and cyclohex-2-enone (1.004 mL) were added to acetonitrile (50 mL). Bismuth (III) trifluoromethanesulfonate (341 mg) was added, and the solution was heated at 65° C. for two days. The solution was cooled, concentrated, and purified by flash column chromatography on silica gel with 10% increasing to 20% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: [C:1]([O:5]C)(=O)[CH2:2][CH3:3].[CH3:7][NH:8][NH2:9].[C:10]1(C)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:7][N:8]1[CH:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:2][C:1](=[O:5])[NH:9]1
Reactant: CNN
Reactant: Cc1ccccc1
Reactant: CCC(=O)OC
Product: CN1NC(=O)CC1c1ccccc1
Reaction time: 12 h

Procedure:
20.5 g methyl propionate were dissolved in 150 ml toluene and 6.7 ml methyl hydrazine were added to the solution under ice cooling. After standing for 12 hours, the solution was evaporated. The residue was a mixture of 1-methyl-5-phenylpyrazolin-3-one and 2-methyl-5-phenylpyrazolin-3-one. This crude isomeric mixture was chromatographed on silica gel. Ether was used as elution agent, to which increasing quantities of methanol were added. From the eluate the non-polar 1-methyl-5-phenylpyrazolin-3-one was isolated. Melting point: 160°-161° C.; yield 6.3 g.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)[O:3][CH2:2]1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C1CCCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:3]1[C:4]2([CH2:9][CH2:8][C:7]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:6][CH2:5]2)[O:11][CH2:1][CH2:2]1
Reactant: C1CCNC1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: O
Product: C1=C(N2CCCC2)CCC2(C1)OCCO2
Yield: 30.2 %

Procedure:
Reflux a solution of 1,4-cyclohexanedione mono-ethylene ketal (10.4 g, 66.5 mmol) and pyrrolidine (4.96 g, 69.8 mmol) and p-toluenesulfonic acid monohydrate (0.13 g, 0.66 mmol) in 50 mL cyclohexane overnight with a Dean-Stark trap and drying tube. Filter the mixture, wash with Et2O and concentrate the brown filtrate to afford 4.20 g of 1-(1,4-dioxa-spiro[4.5]dec-7-en-8-yl)-pyrrolidine as brown oil
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[CH:11]=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=2[C:6]2[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:5]1=2)[CH:2]=[CH2:3].Br[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:13][C:9]1[CH:10]=[CH:11][C:12]2[N:4]([CH2:1]/[CH:2]=[CH:3]/[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[C:5]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][C:6]=3[C:7]=2[CH:8]=1
Reactant: Brc1ccncc1
Reactant: C=CCn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCc2c(c3cc(Cl)ccc3n2C/C=C/c2ccncc2)C1
Temperature: 25 °C

Procedure:
5-Allyl-8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (400 mg, 1.52 mmol, 1 equiv.) and 4-bromopyridine (240 mg, 1.52 mmol, 1 equiv.) were heated to 100° C. with palladium acetate (10 mg, 0.046 mmol), triphenyl phosphine (24 mg, 0.092 mmol) and triethyl amine (0.44 mL, 2 equiv.) in 10 mL of THF for 14 h. The reaction mixture was cooled to RT and diluted with THF (10 mL), filtered over a Celite bed and concentrated. The concentrate was dissolved in EtOAc (40 mL) and washed with water (10 mL) followed by brine. The organic layer was dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain crude product that was purified by HPLC. 1H NMR (DMSO-d6) δ (ppm): 0.64 (bs, 1H), 8.68-8.66 (d, 2H), 7.79-7.77 (d, 2H), 7.6-7.56 (m, 2H), 7.2-7.1 (d, 1H), 7.0-6.9 (m, 1H), 6.5-6.4 (d, 1H), 5.15-5.03 (m, 2H), 4.64-4.60 (d, 1H), 4.3-4.25 (m, 1H), 3.79-3.76 (m, 1H), 3.52-3.50 (m, 1H), 3.17 (bs, 2H), 2.98 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[CH3:16][Mg+].[Br-].[NH4+].[Cl-]>C1COCC1>[OH:1][C:2]1([CH3:16])[CH2:3][CH2:4][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Reactant: C[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(O)CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.3 %

Procedure:
To a stirred solution of tert-butyl 4-oxocyclohexylcarbamate (2 g, 9.3 mmol) in THF (40 mL) at −78° C. was added dropwise MeMgBr (10 mL of 3M/THF, 30 mmol). The reaction mixture was allowed to warm to room temperature. After stirring at room temperature for 18 h, the reaction was treated with saturated NH4Cl aqueous solution. The solution was concentrated, taken up into CH2Cl2, washed with H2O by aid of citric acid. The organic phase was washed with saturated NaHCO3 aqueous solution, H2O, brine, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography to give tert-butyl 4-hydroxy-4-methylcyclohexylcarbamate 2 as oil (1.2 g, 56%). 1H NMR (300 MHz, CDCl3) δ 1.20 (s, 3H), 1.45 (s, overlapped 9H), 1.5˜1.8 (set of m, 10H), 3.40 (br, 1H), 4.40 (br, 1H).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH2:20]([N:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][NH2:26])[CH3:21]>>[ClH:19].[CH2:20]([N:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][NH:26][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17])[CH3:21]
Reactant: CCN(CC)CCCN
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCCN(CC)CC)s2)c(C)[nH]c1=O
Product: Cl
Yield: 50 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with N,N-diethyl-propane-1,3-diamine as described in Steps 5 and 6, Example 24 to give the title compound as an orange solid (50% yield). LC/MS: RT: 2.03 min; m/e 412 (M+H); 1H NMR (δ, ppm): 11.86 (1H, s), 10.07 (1H, s), 8.05 (1H, t), 7.56 (1H, d), 7.34 (1H, s), 7.19 (1H, d), 2.93-3.58 (8H, m), 2.40 (2H, q), 2.32 (3H, s), 1.82 (2H, m), 1.19 (6H, t), 1.10 (3H, t).
Reaction SMILES: [CH:1]1([N:7]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8](=[O:23])[NH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]=2[OH:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:31](OC(=O)C)(=[O:33])[CH3:32].C(N(CC)CC)C>ClCCl>[C:31]([O:22][C:11]1[C:12]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:10]=1[NH:9][C:8]([N:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:23])(=[O:33])[CH3:32]
Reactant: COc1cc(NC(=O)N(Cc2ccccc2)C2CCCCC2)c(O)c(C(C)(C)C)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(NC(=O)N(Cc2ccccc2)C2CCCCC2)c(OC(C)=O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 4.00 g of 2-(3-cyclohexyl-3-phenylmethylureido)-4-methoxy-6-tert-butylphenol, 2.0 ml of acetic anhydride, 3.2 ml of triethylamine and 80 ml of dichloromethane was stirred at room temperature for 24 hours. The reaction mixture was washed and dried, and the solvent was removed under reduced pressure. The residue was applied to silica gel column chromatography (solvent; chloroform:ethyl acetate=9:1) to give 735 mg of O-acetyl-2-(3-cyclohexyl-3-phenylmethylureido)-4-methoxy-6-tert-butylphenol (Rf=0.75, melting point: 129°-132° C. (recrystallized from hexane)).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:6]2.[CH2:17]([CH:19]1[O:21][CH2:20]1)Cl>N1CCCCC1>[O:21]1[CH2:20][CH:19]1[CH2:17][O:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:6]2
Reactant: ClCC1CO1
Reactant: CCOC(=O)c1cc2c(O)cc(C)cc2[nH]1
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2c(OCC3CO3)cc(C)cc2[nH]1
Reaction time: 3.5 h
Yield: 64 %

Procedure:
7.8 g of the thus obtained 4-hydroxy-2-ethoxycarbonyl-6-methylindole are dissolved in 100 ml epichlorohydrine and the solution is heated subsequent to the addition of 5 to 6 drops of piperidine, to boiling. After about 3 to 4 hours, the solution is evaporated in vacuum and the residue is recrystallized from isopropanol. There is obtained 6.4 g (~64% of theory) 4-(2,3-epoxypropoxy)-2-ethoxycarbonyl-6-methyl indole; m.p. 173°-175° C.
Reaction SMILES: [CH:1]1([C:6]([OH:8])=O)[CH2:5][CH:4]=[CH:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:21][NH:22][O:23][CH3:24].O>ClCCl>[CH3:21][N:22]([O:23][CH3:24])[C:6]([CH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1)=[O:8]
Reactant: O=C(O)C1CC=CC1
Reactant: CNOC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)C1CC=CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106 %

Procedure:
To a solution of cyclopent-3-ene-1-carboxylic acid (80.0 g, 0.71 mol) in dichloromethane (300 ml) was added 1,1′-carbonyldiimidazole (127.5 g, 0.78 mol) slowly and the reaction mixture was stirred at room temperature for 1 h. N,O-dimethylhydroxylamine (76.7 g, 0.78 mol) was added and stirred for 18 h at room temperature. The reaction mixture was poured into water (300 ml) and extracted with dichloromethane (100 ml). The organic extracts were washed with hydrochloric acid (1N, 2×200 ml) and then with brine before filtering through cotton wool, drying and concentrating. The product was purified by flash chromatography using silica gel eluting with dichloromethane to give the title compound (116.78 g, 95%).
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH:3]=[O:4].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1>CCOCC>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:3]([OH:4])[C:2]([CH3:6])([CH3:5])[CH3:1])=[CH:10][CH:9]=1
Reactant: CC(C)(C)C=O
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: CCOCC
Product: CC(C)(C)C(O)c1ccc(Cl)cc1

Procedure:
Grignard reaction of trimethylacetaldehyde (240.0 mg; 2.8 mmol) with 4-chlorophenyhnagnesium bromide in anhydrous ether afforded 0.58 grams of 1-(4-chlorophenyl)-2,2-dimethylpropanol.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][NH:10][CH2:9][CH:8]2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](Cl)(=[O:22])[CH3:21].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:20]([N:10]1[CH2:11][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:9]1)(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CNCC1c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CC(NC(=O)OC(C)(C)C)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice cooled stirred solution of tert-butyl (4-phenylpyrrolidin-3-yl)carbamate (prepared as described in J. Med. Chem. 1993, 36, 4139 starting from (2E)-3-phenylprop-2-enoic acid) (1.0 eq.) in dry DCM (0.1M) were slowly added acetyl chloride (4.0 eq.) and DIPEA (4.0 eq.). The reaction mixture was stirred for 1 h at RT, then diluted with DCM, washed with sat. aq. NaHCO3 sol., water and brine. The solution was dried (Na2SO4), filtered and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography eluting with 5-100% EtOAc/petroleum ether, then eluting with 0-10% MeOH/EtOAc affording the titled compound as yellow oil. MS (ES) C17H24N2O3 requires: 304, found: 305 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:31])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([C:20]5[CH:21]=[N:22][N:23]([CH:25]6[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]6)[CH:24]=5)[CH:18]=4)[NH:13][CH:12]=3)=[CH:10][C:4]=2[O:3]1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[F:31][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([C:20]5[CH:21]=[N:22][N:23]([CH:25]6[CH2:26][CH2:27][N:28]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:29][CH2:30]6)[CH:24]=5)[CH:18]=4)[NH:13][CH:12]=3)=[CH:10][C:4]=2[O:3]1
Reactant: FC1(F)Oc2ccc(-c3c[nH]c4ncc(-c5cnn(C6CCNCC6)c5)cc34)cc2O1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(n2cc(-c3cnc4[nH]cc(-c5ccc6c(c5)OC(F)(F)O6)c4c3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 324 (50 mg, 0.1182 mmol) in DCM was added triethylamine (17.9 mg, 0.1773 mmol). Methane sulfonyl chloride 342 (13.5 mg, 0.1182 mmol) was added to the reaction and stirred for 2 h at rt. The reaction mixture was diluted with dichloromethane and washed with water twice. The organic layer was dried over sodium sulphate and concentrated to get the crude, which was purified by flash column using 100-200 mesh silica gel. The compound was eluted at 2% methanol in chloroform as off white coloured solid 3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-5-(1-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine 343. 1H NMR (400 MHz, DMSO) δ: 11.94 (s, 1H), 8.55 (d, 1H), 8.39 (m, 2H), 8.03 (s, 1H), 7.88 (d, 1H), 7.78 (d, 1H), 7.58 (m, 1H), 7.44 (d, 1H), 4.31 (m, 1H), 3.66 (m, 2H), 2.95 (s, 3H), 2.16 (m, 2H), 2.01 (m, 2H) and MS ES+502.1.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[NH2:5][CH2:6][C:7]1[O:11][C:10]([C:12]2[N:13]=[C:14]([NH:17][C:18]([NH2:20])=[S:19])[S:15][CH:16]=2)=[CH:9][CH:8]=1.Cl>O.CN(C)C=O>[NH:17]([C:14]1[S:15][CH:16]=[C:12]([C:10]2[O:11][C:7]([CH2:6][NH:5][C:2]([NH2:3])=[O:1])=[CH:8][CH:9]=2)[N:13]=1)[C:18]([NH2:20])=[S:19]
Reactant: NCc1ccc(-c2csc(NC(N)=S)n2)o1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)NCc1ccc(-c2csc(NC(N)=S)n2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.9 %

Procedure:
A solution of potassium cyanate (9.6 g) in water (50 ml) was added to a mixture of 4-(5-aminomethylfuran-2-yl)-2-thioureidothiazole (10.0 g) in N,N-dimethylformamide (80 ml) and 1N-hydrochloric acid (78.6 ml), and the mixture was stirred for 16 hours at ambient temperature. To the reaction mixture was added a water (100 ml) and isolated precipitate was collected by filtration to give 2-thioureido-4-(5-ureidomethylfuran-2-yl)thiazole (10.74 g).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH:7]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:18]=C([CH:23]=[CH:24][CH:25]=2)C(O)=O)[CH2:12][CH2:11]1)([CH3:9])[CH3:8]>CN(C=O)C.C(Cl)Cl>[CH:7]([N:10]1[CH2:11][CH2:12][CH:13]([O:16][C:17]2[CH:18]=[C:1]([CH:23]=[CH:24][CH:25]=2)[C:2]([Cl:4])=[O:3])[CH2:14][CH2:15]1)([CH3:9])[CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)N1CCC(Oc2cccc(C(=O)O)c2)CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)N1CCC(Oc2cccc(C(=O)Cl)c2)CC1

Procedure:
Oxalyl chloride (0.34 ml) was added to a stirred mixture of 3-(N-isopropylpiperidin-4-yloxy)benzoic acid (0.782 g), DMF (2 drops) and methylene chloride (20 ml) which had been cooled in an ice bath. The resultant mixture was stirred at ambient temperature for 4 hours. The mixture was evaporated and the 3-(N-isopropylpiperidin-4-yloxy)benzoyl chloride so obtained was dissolved in methylene chloride (20 ml).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.C(OC(=O)[NH:35][CH2:36][CH2:37][CH:38]=O)(C)(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C1COCC1>[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)[CH2:38][CH2:37][CH2:36][NH2:35]
Reactant: CC(C)(C)OC(=O)NCCC=O
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: NCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a stirred solution of 2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzoimidazole-1-carboxylic acid tert-butyl ester (390 mg, 0.98 mmol), (3-oxo-propyl)-carbamic acid tert-butyl ester (170 mg, 0.98 mmol) from above and THF (9.8 mL) was added NaBH(OAc)3 (623 mg, 2.94 mmol) and the resulting mixture was stirred at room temperature for 1 hour. AcOH (56 μL, 0.98 mmol) was added and the mixture stirred at room temperature overnight. The mixture was concentrated under reduced pressure, diluted with CH2Cl2 (40 mL) and washed with 1N NaOH (10 mL). The aqueous was extracted with (2×20 mL) and the combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. A solution of the resulting orange foam in CH2Cl2 (4 mL) and TFA (4 mL) was stirred at room temperature for 2.5 hours. The mixture was concentrated under reduced pressure, partially dissolved in H2O (2 mL), basified with 1N NaOH and extracted with CH2Cl2 (3×25 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel (CH2Cl2MeOH/NH4OH, 100:7:1) afforded N1-(1H-benzoimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-propane-1,3-diamine (290 mg, 75% over 3 steps) as a white foam.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]([O:30]CC)=O)[N:27]=2)[CH2:20]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.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C[Al](C)C.C(O)(=O)C.C(OCC)(=O)C>C1C=CC=CC=1>[Si:1]([O:18][CH:19]1[CH2:20][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:30])[N:27]=2)[CH2:22]1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Reactant: C1CCNCC1
Agent: C[Al](C)C
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)[Si](OC1CN(c2nc(C(=O)N3CCCCC3)cs2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (1.00 g, 2.14 mmol) (obtained as described in Reference Example 2(1)) in benzene (50 ml) was added a solution of 0.67M piperidine-trimethylaluminium in benzene (7.3 ml) at room temperature under an atmosphere of nitrogen. The mixture was heated under reflux for 5 hours. After checking the completion of the reaction, 10% aqueous acetic acid solution (50 ml) and ethyl acetate (100 ml) were added to the reaction mixture in an ice bath and the resulting mixture was stirred at room temperature for 2 hours. After adding ethyl acetate thereto, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:2) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-piperidinocarbonyl-1,3-thiazol-2-yl)azetidine (607 mg, yield 56%) as a pale brown solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH3:10])[N:3]=1.[CH2:11]([C@H:13]1[NH:18][CH2:17][C@@H:16]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[O:15][CH2:14]1)[CH3:12].CCN(C(C)C)C(C)C>CC#N.O>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][CH3:10])[N:3]=[C:2]([N:18]2[C@H:13]([CH2:11][CH3:12])[CH2:14][O:15][C@H:16]([C:19]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:17]2)[CH:7]=1
Reactant: CC[C@@H]1CO[C@H](C(=O)NCc2ccccc2)CN1
Reactant: CNc1nc(Cl)cc(Cl)n1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC[C@@H]1CO[C@H](C(=O)NCc2ccccc2)CN1c1cc(Cl)nc(NC)n1
Temperature: 100 °C
Yield: 256.5 %

Procedure:
4,6-Dichloro-N-methyl-2-pyrimidinamine (0.143 g, 0.805 mmol) was added to a 20 mL microwave vial followed by the addition of (2S,5R)-5-ethyl-N-(phenylmethyl)-2-morpholinecarboxamide (0.200 g, 0.805 mmol) in CH3CN (5 mL) and Hunig's base (0.703 mL, 4.03 mmol). The reaction was irradiated at 150° C. for 10 minutes. The reaction was left in the 20 mL sealed microwave vessel and heated to 100° C. over the weekend. The reaction mixture was diluted with water and extracted with EtOAc (2×). The organic layers were combined and dried to afford the title compound (0.805 g) as an oil. LC-MS (ES) m/z=376 [M+H]+.