Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:6]2[N:5]=1)=O.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:22][CH2:21]1.COCC(O)C.C(N(CC)C(C)C)(C)C>>[CH3:19][N:20]1[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:31]=[CH:32][C:33]([NH:36][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=5)[N:6]4[N:5]=3)=[CH:34][CH:35]=2)[CH2:24][CH2:25]1
Reactant: CS(=O)c1ncc2ccc(-c3cccnc3)n2n1
Reactant: CN1CCN(CCCOc2ccc(N)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: CN1CCN(CCCOc2ccc(Nc3ncc4ccc(-c5cccnc5)n4n3)cc2)CC1

Procedure:
Into a Microwave vial, 2-Methanesulfinyl-7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazine (0.104 g, 0.000404 mol), 4-[3-(4-Methyl-piperazin-1-yl)-propoxy]-phenylamine (0.221 g, 0.000888 mol), 1-Methoxy-2-propanol (0.971 mL, 0.00993 mol) and N,N-Diisopropylethylamine (0.155 mL, 0.000888 mol) were added. The reaction was microwaved on 300 watts, 170° C. for 50 minutes. The solvent was removed under vacuum. The desired product was isolated via ISCO column chromatography with DCM and methanol as eluant (0 to 15% methanol). The collected fractions afforded {4-[3-(4-Methyl-piperazin-1-yl)-propoxy]-phenyl}-(7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-amine as a yellow solid (25 mg, 14%). MP 135-139° C. LCMS (E/I+) 444.8 (M+H). NMR 1H (DSMO-d6)-9.38-9.46 (m, 2H), 9.03 (s, 1H), 8.66 (d, 1H, J=8.08 Hz), 8.61 (d, 1H, J=4.67 Hz), 7.60-7.70 (m, 3H), 7.32 (d, 1H, J=4.81 Hz), 6.98 (d, 1H, J=4.80 Hz), 6.93 (d, 2H, J=9.00 Hz), 4.03 (t, 2H, J=5.26 Hz), 2.30-3.60 (m, 13H), 1.95-2.10 (bm, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10](=[O:12])(=[O:11])[N:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:8](=[O:23])[N:7]([CH3:24])[C:6]=2[CH:25]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:33]([CH3:35])[CH3:34]>CN(C)C=O>[F:22][C:19]([F:20])([F:21])[C:16]1[CH:15]=[CH:14][C:13]([N:9]2[C:8](=[O:23])[N:7]([CH3:24])[C:6]3[CH:25]=[C:2]([O:1][CH:33]([CH3:35])[CH3:34])[CH:3]=[CH:4][C:5]=3[S:10]2(=[O:12])=[O:11])=[CH:18][CH:17]=1
Reactant: CC(C)I
Reactant: CN1C(=O)N(c2ccc(C(F)(F)F)cc2)S(=O)(=O)c2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2c(c1)N(C)C(=O)N(c1ccc(C(F)(F)F)cc1)S2(=O)=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
A suspension of 6-hydroxy-4-methyl-2-(4-trifluoromethylphenyl)-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (124 mg), potassium carbonate (55 mg) and 2-iodopropane (68 mg) in N,N-dimethyl formamide (1 ml) was stirred for 2 hours at 60° C. The mixture was poured into ice water. The separated solid was collected by filtration, dried, and recrystallized from ethanol to yield 2-(4-trifluoromethylphenyl)-4-methyl-6-isopropoxy-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (78 mg).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH2:13]([N:21]=[C:22]=S)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[Cl:8][C:6]1[S:5][C:4]2[S:9](=[O:10])(=[O:11])[N:12]=[C:22]([NH:21][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[NH:2][C:3]=2[CH:7]=1
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Reactant: CCCCCCCCN=C=S
Agent: Cl
Product: CCCCCCCCNC1=NS(=O)(=O)c2sc(Cl)cc2N1

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and n-octyl isothiocyanate by a procedure analogous to the procedure described in example 3Bc-d; mp >190° C. decomp.; 1H-NMR (DMSO-d6): δ 0.85 (t, 3H), 1.28 (m, 10H), 1.50 (m, 2H), 3.18 (q, 2H), 7.03 (s, 1H), 7.25 (br. s, 1H), 10.2 (br. s, 1H).
Reaction SMILES: CS([Cl:5])(=O)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=[C:15]([CH3:23])[N+:14]=2[O-])=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=[C:15]([CH2:23][Cl:5])[N:14]=2)=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(C)[n+]([O-])c1-c1ccc(F)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CCl)nc1-c1ccc(F)cc1

Procedure:
Methane sulfonyl chloride (7.11 ml) was added to a stirred solution of 2-(4-fluorophenyl)-3-(methoxycarbonyl)-6-methylpyridine-1-oxide (12.0 g) in toluene (300 ml) and the mixture heated at reflux under an inert atmosphere for 16 hours. The solution was partially concentrated under reduced pressure and then applied directly to a silica flash column and eluted with ethyl acetate/iso-hexane (1:5) to give methyl 2-(4-fluorophenyl)-6-chloromethylpyridin-3-carboxylate as a white crystalline solid (13.6 g).
Reaction SMILES: S(C1C=CC=CC=1C(NC1[N:11]([C@H:15]([CH2:19][CH2:20][CH2:21]CCC)[C:16]([OH:18])=[O:17])C=CN=1)=O)(O)(=O)=O.O[C:30]1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[CH3:30][O:18][C:16](=[O:17])[C@@H:15]1[CH2:19][CH2:20][CH2:21][NH:11]1
Reactant: Oc1cccc2[nH]nnc12
Reactant: CCCCCC[C@H](C(=O)O)n1ccnc1NC(=O)c1ccccc1S(=O)(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCCN1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
To a solution of the above amine in 10 mL of anhydrous DMF was added (R)-[(2-sulfobenzoyl)amino-1H-imidazol-1-yl]-octanoic acid (1.00 g, 2.45 mmol) and hydroxybenzotriazole (0.37 g, 2.77 mmol). This mixture was cooled to 0° C., and then treated with dicyclohexylcarbodiimide (0.56 g, 2.70 mmol). The resulting solution was warmed to room temperature and stirred for 48 hours. After removal of dicyclohexylurea by filtration, the filtrate was diluted with 100 mL of ethyl acetate and washed several times with H2O. The organic was then dried (Na2SO4) and concentrated in vacuo to an oil. Chromatography (SiO2, 5% methanol/CHCl3) provided 0.84 g (34%) of (R)-1-[1-oxo-2-[4-(2-sulfobenzoyl)amino-1H-imidazol-1-yl]octyl]-4-(cis)-methanesulfonamido))-phenoxy]-L-proline methyl ester as a white solid. M.Pt. 150° C. (dec).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=O)[CH:8]=2)[CH:3]=[CH:2]1.[CH3:12][CH:13]([CH3:29])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:18]=1)=[O:15]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][N:26]3[CH2:27][CH2:28][CH:23]([C:19]4[CH:18]=[C:17]([NH:16][C:14](=[O:15])[CH:13]([CH3:12])[CH3:29])[CH:22]=[CH:21][CH:20]=4)[CH2:24][CH2:25]3)[CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=Cc1ccc2cc[nH]c2c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4cc[nH]c4c3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 1H-indole-6-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 376.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[C:11](O)=[O:12])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[CH3:37][NH:38][CH2:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH3:9])[C@@H:10]([C:11](=[O:12])[N:38]([CH3:37])[CH2:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNCCCc1ccccc1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(CCCc1ccccc1)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 46.3 %

Procedure:
(2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3(2-naphthyl)propionic acid (2.21 g, 6.70 mmol) was dissolved in N,N-dimethylformamide (3 ml) and dichloromethane (6 ml). 1-Hydroxy-7-azabenzotrazole (0.91 g, 6.70 mmol) was added. The solution was cooled to 0° C. N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.28 g, 6.70 mmol) was added. The reaction mixture was stirred for 15 min at 0° C. A solution of N-methyl-N-(3-phenylpropyl)amine (1.0 g, 6.7 mmol) in dichloromethane (3 ml) was added. Ethyldiisopropylamine (1.2 ml, 6.7 mmol) was added. The reaction mixture was stirred for 16 h, while it was slowly warming up to room temperature. The solution was diluted with ethyl acetate (100 ml). It was washed with 1 N hydrochloric acid (100 ml). The aqueous phase was extracted with ethyl acetate (100 ml). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (100 ml) and dried over magnesium sulfate. Thesolvent was removed in vacuo. The crude product was purified by flash chromatography on silica (400 g), using ethyl acetateiheptane (1:3) as eluent to give 1.43 g of N-methyl-N-((1R)-1-(N-methyl-N-(3-phenylpropyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butyl ester.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36])(OCC)=O>C(#N)C.O>[C:27]1(=[O:36])[N:1]([CH:2]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[CH2:3][C:4]([OH:6])=[O:5])[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]12
Reactant: COc1ccc(C(N)CC(=O)O)cc1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a stirred mixture of 3-amino-3-(4-methoxyphenyl)propionic acid (1.95 g, 10.0 mmol) and sodium carbonate (1.11 g, 10.5 mmol) in 200 mL of acetonitrile-water 1:1 is added N-carboethoxyphthalimide (2.26 g, 10.0 mmol). After 1 hour, the reaction slurry is filtered. The filtrate is concentrated to remove the acetonitrile and the pH adjusted to 1-2 with 4 N hydrochloric acid and stirred over night. The resulting slurry is filtered and the solid washed with water. The solid is dried in vacuo (60 C, <1 mm) to afford 2.82 g (87%) of the 3-phthalimido-3-(4-methoxyphenyl)propionic acid as a white powder: mp 160°-164° C.; 1H NMR (dmso-d6, 250 MHz) δ 12.5 (br s, 1H), 7.95-7.80 (m, 4 H), 7.36 (d, 2 H, J=8.7), 6.92 (d, 2 H, J=8.4 Hz), 5.18-5.10 (m, 1 H), 3.70-3.15 (m, 2 H); 13C NMR (dmso-d6) δ 171.7, 167.6, 158.6, 134.6, 131.0, 130.8, 128.3, 123.1, 113.9, 55.0, 49.6, 35.9. Anal. Calculated for C18H15NO5. Theoretical: C, 66.46; H, 4.63; N, 4.31. Found: C, 66.25; H, 4.65; N, 4.28.
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:12]=[C:11]([Cl:13])[CH:10]=[C:9](Cl)[N:8]=1)C.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20][NH2:21].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:13][C:11]1[CH:10]=[C:9]([NH:21][CH2:20][C:19]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:17]([Cl:16])[CH:18]=2)[N:8]=[C:7]([S:6][CH2:5][C:4]([OH:3])=[O:15])[N:12]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)CSc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CSc1nc(Cl)cc(NCc2ccc(Cl)c(Cl)c2)n1

Procedure:
A stirred mixture of 8.0 g of (4,6-dichloro-2-pyrimidinylthio)acetic acid ethyl ester, 5.3 g of 3,4-dichlorobenzylamine and 3.2 g of sodium carbonate in 200 ml. of ethanol was heated under reflux for 6 hr. The reaction mixture was filtered and water was added to the filtrate to the cloudy point. The mixture was cooled in ice and the resulting precipitate which formed was removed by filtration and recrystallized from 70% aqueous ethanol. The product amounted to 4.8 g, mp. 64°-69°C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:18]=[CH:17][C:16]([OH:19])=[C:11]([C:12]([O:14]C)=O)[C:10]=1[C:20]([O:22]C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:25][CH:26]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:27]1=[O:33]>N1C=CC=CC=1>[O:33]=[C:27]1[CH:26]([N:25]2[C:20](=[O:22])[C:10]3[C:11](=[C:16]([OH:19])[CH:17]=[CH:18][C:9]=3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:12]2=[O:14])[CH2:31][CH2:30][C:29](=[O:32])[NH:28]1
Reactant: COC(=O)c1c(O)ccc(NC(=O)OC(C)(C)C)c1C(=O)OC
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1ccc(O)c2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 73.2 %

Procedure:
A solution of dimethyl 3-(tert-butoxycarbonylamino)-6-hydroxyphthalate C3-3 (7.68 g, 23.6 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (7.77 g, 47.2 mmol) in pyridine (150 mL) was heated at 100° C. overnight. The solvent was removed in vacuo and the residue was purified by chromatography (silica gel, DCM:MeOH:PE) to give compound C3-4 as a yellow solid (6.73 g, yield: 73%). 1H NMR (DMSO-d6, 400 MHz) δ: 1.47 (s, 9H), 1.98-2.02 (m, 1H), 2.54-2.60 (m, 2H), 2.83-2.92 (m, 1H), 5.04 (dd, J=13.0 and 5.4 Hz, 1H), 7.22 (d, J=8.8 Hz, 1H), 8.10 (d, J=9.2 Hz, 1H), 8.68 (s, 1H), 11.01 (s, 1H), 11.11 (s, 1H); MS (ESI+): m/z 412 (M+23).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])=O.[CH2:21]([NH2:24])[CH2:22][CH3:23].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[N+:18]([C:17]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])=[CH:4][C:3]=1[CH2:1][NH:24][CH2:21][CH2:22][CH3:23])([O-:20])=[O:19]
Reactant: N#Cc1cccc(Oc2ccc([N+](=O)[O-])c(C=O)c2)c1
Reactant: CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCNCc1cc(Oc2cccc(C#N)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Under N2, a mixture of 3-(3-formyl-4-nitrophenoxy)-benzonitrile (0.056 mol) and propylamine (0.059 mol) in DCE (450 mL) was stirred at room temperature, and then NaBH(OAc)3 (0.063 mol) was added, and the reaction mixture was stirred overnight at room temperature. A saturated NaHCO3 solution was added, and the layers were separated. The organic layer was dried, filtered off and the solvent was evaporated. The residue was purified over silica gel filter (eluent: 99:1 CH2Cl2:CH3OH). The purest product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [CH3:1][C:2]([CH3:39])([CH3:38])[C@@H:3]([NH:11][C:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]3[CH:24]=[N:25][N:26]([CH2:28][CH3:29])[CH:27]=3)[N:21]=2)[N:16](COCC[Si](C)(C)C)[CH:15]=1)=[O:13])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]([CH3:38])([CH3:39])[C@@H:3]([NH:11][C:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]3[CH:24]=[N:25][N:26]([CH2:28][CH3:29])[CH:27]=3)[N:21]=2)[NH:16][CH:15]=1)=[O:13])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: CCn1cc(-c2cnc3c(n2)c(C(=O)N[C@@H](C(=O)N2CCCC2)C(C)(C)C)cn3COCC[Si](C)(C)C)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1cc(-c2cnc3[nH]cc(C(=O)N[C@@H](C(=O)N4CCCC4)C(C)(C)C)c3n2)cn1
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of 2-(1-ethyl-1H-pyrazol-4-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2,2-dimethyl-1-(pyrrolidine-1-carbonyl)-propyl]-amide in CH2Cl2 (2.25 mL) was added TFA (0.75 mL). The reaction mixture was stirred overnight and concentrated. The residue was dissolved in a mixture of ammonium hydroxide, MeOH and CH2Cl2 (1:10:60, 3.0 ml) and stirred at room temperature for 90 min. The reaction mixture was then concentrated and the residue purified by SiO2 chromatography (0-10% MeOH/CH2Cl2) to afford 85 mg (89%) of 2-(1-ethyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2,2-dimethyl-1-(pyrrolidine-1-carbonyl)-propyl]-amide as a yellow powder. MS: (M+H)+=424.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)[CH3:2].[CH3:14][O:15][CH:16]([O:19][CH3:20])[CH2:17][NH2:18].[BH4-].[Na+]>C(O)C>[CH3:14][O:15][CH:16]([O:19][CH3:20])[CH2:17][NH:18][CH2:7][C:6]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1
Reactant: COC(CN)OC
Reactant: CCOc1cc(C=O)ccc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc(CNCC(OC)OC)ccc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-ethoxy-4-methoxybenzaldehyde (3.6 g, 20 mmol) in ethanol (15 ml) is added to 2,2-dimethoxyethylamine (21 mmol) and the mixture heated at reflux for 2 hours. After cooling to room temperature, sodium borohydride (0.794 g, 21 mmol) is added and the mixture stirred at room temperature overnight. Ethanol is removed by evaporation and water added, followed by extraction with ethyl acetate. The organic extracts are combined, washed with water, brine, dried over magnesium sulfate and evaporated to give (2,2-dimethoxy-ethyl)-(3-ethoxy-4-methoxy-benzyl)-amine, [MH]+ 270. The intermediate (2.70 g, 10 mmol) is suspended in 6N HCl (50 ml), glyoxylic acid (0.88 g, 12 mmol) is added and the mixture heated for 1 hour at 100° C. After cooling to room temperature, methanol (30 ml) is added and the mixture filtered and characterised as the methyl ester M+ 276. The filtrate is treated with lithium hydroxide (10 mmol) in THF-methanol-water overnight. After evaporation of the solvents, the crude product is partitioned between water and dichloromethane. The aqueous phase is washed with dichloromethane and evaporated to dryness to afford (7-ethoxy-6-methoxy-isoquinolin-4-yl)-acetic acid lithium salt which is used for xanthine formation without further characterisation.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[SH:17].C[S:19]([CH3:21])=O>C(#N)C>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][S:19][C:21]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:10]
Reactant: CS(C)=O
Reactant: Sc1ccccc1Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC#N
Product: Clc1ccccc1SSc1ccccc1Cl

Procedure:
Hexamethyldisilazane (4.4 ml) was added to a stirred solution of 2-chlorobenzenethiol (2.0 ml) and DMSO (3.7 ml) in dry acetonitrile at room temperature. After 2 h the white precipitate was filtered and washed (cold acetonitrile) to give the sub-title compound as a white solid (2.27 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:22]([N+:23]([O-])=O)=[CH:21][C:6]2[NH:7][C:8](=[O:20])[CH2:9][N:10]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[C:11]([CH3:13])([CH3:12])[C:5]=2[CH:4]=1>[Pd].C(O)C>[NH2:23][C:22]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[N:10]([C:14](=[O:19])[C:15]([F:18])([F:16])[F:17])[CH2:9][C:8](=[O:20])[NH:7][C:6]=2[CH:21]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CN(C(=O)C(F)(F)F)C2(C)C
Agent: [Pd]
Solvent: CCO
Product: COc1cc2c(cc1N)NC(=O)CN(C(=O)C(F)(F)F)C2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a round bottom flask, 7-methoxy-5,5-dimethyl-8-nitro-4-(2,2,2-trifluoro-acetyl)-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.27 g, Ethanol (200 mL), and 10% Pd/C (50 mg) were added. The mixture was evacuated under vacuum and charged with hydrogen via balloon (3 times). The reaction was stirred at room temperature overnight under hydrogen atmosphere via a balloon. The solid was filtered and washed with ethanol. The solvent was removed under vacuum to give 8-amino-7-methoxy-5,5-dimethyl-4-(2,2,2-trifluoro-acetyl)-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one a glass solid. 1H-NMR (CDCl3, 400 MHz): δ 8.38 (bs, 1H), 7.30 (bs, 1H), 6.89 (bs, 1H), 6.30 (bs, 1H), 4.10-4.70 (bm, 2H), 3.87 (bs, 3H), 3.45 (bs, 1H), 1.88 (bs, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.F[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1
Reactant: Oc1cccc(Cl)c1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(Oc2cccc(Cl)c2)cc1
Yield: 95 %

Procedure:
3-Chlorophenol (0.52 g, 4 mmol), 4-fluorobenzaldehyde (0.50 g, 4 mmol), and potassium carbonate (0.56 g, 4 mmol) were stirred in DMF (5 mL) at 80° C. for 48 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over Na2SO4, filtered and evaporated to give the title compound in 95% yield. 1H NMR (CDCl3, 300 MHz) δ 6.95-7.40 (m, 9H), 7.85-8.31 (m, 4H), 9.94 (s, 1H). MS m/e 233 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:17].[C:18]1([CH2:24][C:25](=[NH:29])OCC)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[ClH:17].[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:25](=[NH:29])[CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1ccccc1F
Reactant: CCOC(=N)Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: N=C(Cc1ccccc1)Nc1ncccc1OCc1ccccc1F
Yield: 4.8 %

Procedure:
A mixture of 2-amino-3-(2-fluorobenzyloxy)pyridine (4.36 g, 20 mmol) and ethyl phenylacetimidate hydrochloride (4.39 g, 22 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was purified by flash chromatography (chloroform/methanol) and recrystallisation from ethanol/ether to obtain the product (0.36 g), m.p. 160°-165° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[NH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C>ClCCl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: CCOC(=O)CCCN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCCNc1c([N+](=O)[O-])cnc2ccccc12
Yield: 88.4 %

Procedure:
The general method described in Step 1 of Example 15 was used to react 4-chloro-3-nitroquinoline (49.6 g, 238 mmol), ethyl 4-aminobutyrate hydrochloride (43.8 g, 262 mmol), and triethylamine (36.1 g, 357 mmol) in dichloromethane for 15 hours to provide ethyl 4-(3-nitroquinolin-4-ylamino)butyrate (63.8 g) as a yellow solid that was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]=[C:20]([C:22]#[N:23])[S:21][C:14]=12>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][C:13]1[CH:18]=[CH:17][N:16]=[C:15]3[CH:19]=[C:20]([C:22]#[N:23])[S:21][C:14]=13)=[CH:6][CH:5]=2
Reactant: N#Cc1cc2nccc(Cl)c2s1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C#N)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-chloro-thieno[3,2-b]pyridine-2-carbonitrile by a procedure analogous to Example 1C. MS: 305 (MH+), HPLC Rf: 4.86 min.; HPLC purity: 85%.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:8][C:9](=[O:31])[CH:10]([S:29][CH3:30])[O:11][C:12]1[CH:13]=[C:14]2[C:19](=[C:20]([CH3:22])[CH:21]=1)[N:18]=[CH:17][C:16]([C:23]#[C:24][Si](C)(C)C)=[CH:15]2)([CH2:5][O:6][CH3:7])[CH3:4].C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[C:23]([C:16]1[CH:17]=[N:18][C:19]2[C:14]([CH:15]=1)=[CH:13][C:12]([O:11][CH:10]([S:29][CH3:30])[C:9]([NH:8][C:3]([CH2:5][O:6][CH3:7])([CH3:4])[CH2:2][OH:1])=[O:31])=[CH:21][C:20]=2[CH3:22])#[CH:24]
Reactant: COCC(C)(CO)NC(=O)C(Oc1cc(C)c2ncc(C#C[Si](C)(C)C)cc2c1)SC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1cnc2c(C)cc(OC(SC)C(=O)NC(C)(CO)COC)cc2c1
Reaction time: 1 h
Yield: 87.6 %

Procedure:
A solution of N-(2-hydroxy-1-methoxymethyl-1-methyl-ethyl)-2-methylsulfanyl-2-(8-methyl-3-trimethylsilanylethynyl-quinolin-6-yloxy)-acetamide (650 mg) in methanol (16 ml) was treated with potassium carbonate (97 mg) at room temperature. The reaction mixture was stirred for 1 h. The reaction mixture was diluted with ethyl acetate and washed with sat. aq. sodium hydrogen carbonate. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography (cyclohexane/ethyl acetate/dichloromethane 2:2:1) to give 2-(3-ethynyl-8-methyl-quinolin-6-yloxy)-N-(2-hydroxy-1-methoxymethyl-1-methyl-ethyl)-2-methylsulfanyl-acetamide (480 mg) as a white solid as mixture of diastereoisomers.