Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH3:21][NH2:22]>C1COCC1>[CH3:21][NH:22][S:2]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CN
Reactant: O=C(OCc1ccccc1)N1CCC(S(=O)(=O)Cl)CC1
Solvent: C1CCOC1
Product: CNS(=O)(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A solution of 190 mg (0.6 mmol) of benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate in 10 mL THF was treated with a 10-fold excess of 40% aq. methylamine and the mixture was stirred at room temperature for 2 hrs. The THF was removed under vacuum. After dilution with water, the resulting solid was collected and dried to give 260 mg (83% yield) of benzyl 4-[(methylamino)sulfonyl]-1-piperidinecarboxylate: mp (aq. MeOH) 124-126° C.; 1H NMR (CDCl3) δ 7.40-7.30 (m, 5H), 5.13 (s, 2H), 4.34 (m, 2H), 4.01 (dd, J=10.2, 5.0 Hz, 1H), 3.05 (tt, J=11.9, 3.7 Hz, 1H), 2.87-2.77 (m, 5H), 2.11 (br d, J=12.9 Hz, 2H), 1.75 (dq, J=12.6, 4.5 Hz, 2H). Anal. Calcd. for C14H20N2O4S: C, 53.8; H, 6.45; N, 9.0. Found: C, 53.75; H, 6.5; N, 9.0%.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1.[CH:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:14]([C:5]1[CH:4]=[C:3]([CH2:2][N:26]2[CH2:27][CH2:28][N:23]([C:20]3[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=3)[CH2:24][CH2:25]2)[CH:8]=[CH:7][C:6]=1[CH2:9][NH:10][C:11](=[O:13])[CH3:12])([O-:16])=[O:15]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CC(=O)NCc1ccc(CCl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc(CN2CCN(c3ccccc3)CC2)cc1[N+](=O)[O-]

Procedure:
A solution of N-(4-chloromethyl-2-nitrophenylmethyl)acetamide (1.4 g), phenylpiperazine (0.8 ml) and potassium carbonate (0.6 g) in dimethylformamide (20 ml) was stirred at 60° C. for 4 hr. The reaction mixture was poured into water (150 ml) and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a pale-yellow solid. The obtained pale-yellow solid was crystallized from ethyl acetate to give the title compound (1.3 g) as pale-yellow white crystals, m.p.=135-136° C.
Reaction SMILES: [CH3:1][C:2]([CH:4]([OH:23])[CH2:5][CH2:6]/[C:7](/[CH3:22])=[CH:8]/[CH2:9][CH2:10]/[C:11](/[CH3:21])=[CH:12]\[CH2:13][O:14]C1CCCCO1)=[CH2:3]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[OH:14][CH2:13]/[CH:12]=[C:11](/[CH3:21])\[CH2:10][CH2:9]/[CH:8]=[C:7](\[CH3:22])/[CH2:6][CH2:5][C:4](=[O:23])[C:2]([CH3:3])=[CH2:1]
Reactant: C=C(C)C(O)CC/C(C)=C/CC/C(C)=C\COC1CCCCO1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: C=C(C)C(=O)CC/C(C)=C/CC/C(C)=C\CO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 0.5 g (0.0016 mol) of (6E,10Z)-2,6,10-trimethyl-12-[(tetrahydro-2H-pyran-2-yl)oxy]-1,6,10-dodecatrien-3-ol dissolved in 15 ml of methylene chloride is treated with 10 g of manganese dioxide. The suspension is stirred at room temperature for 18 hours under argon. After filtration and removal of the solvent the residue is chromatographed on silica gel with ether-hexane 10:1. The product, containing (6E,10Z)-2,6,10-trimethyl-12-[(tetrahydro-2H-pyran-2-yl)oxy]-1,6,10-dodecatrien-3-one, is dissolved in 10 ml of tetrahydrofuran and 2.6 ml of water and treated with 118 mg of pyridinium p-toluenesulfonate. The solution is boiled at reflux for 17 hours. After cooling 100 ml of water and 200 ml of ether are added thereto. The organic phase is neutralized with sodium bicarbonate solution. After drying and removing the solvent the residue is chromatographed on silica gel with ether-hexane 1:1. There is obtained (6E,10Z)-12-hydroxy-2,6,10-trimethyl- 1,6,10-dodecatrien-3-one which exhibits the following absorption bands in the IR spectrum: 3390 cm-1, 1678 cm-1, 1625 cm-1, 1415 cm-1, 1380 cm-1, 945 cm-1.
Reaction SMILES: [NH2:1][C@@H:2]1[C:23](=[O:24])[N:4]2[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]3[N:15]([NH:16][C:17](=[O:19])[CH3:18])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.C(N(CC)CC)C.[C:32]([NH:51][C:52]1[S:53][CH:54]=[C:55](/[C:57](=[N:70]/[O:71][CH3:72])/[C:58](ON2C3C=CC=CC=3N=N2)=[O:59])[N:56]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[C:32]([NH:51][C:52]1[S:53][CH:54]=[C:55](/[C:57](=[N:70]/[O:71][CH3:72])/[C:58]([NH:1][C@@H:2]2[C:23](=[O:24])[N:4]3[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]4[N:15]([NH:16][C:17](=[O:19])[CH3:18])[N:14]=[N:13][N:12]=4)[CH2:7][S:8][C@H:3]23)=[O:59])[N:56]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(=O)Nn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CO/N=C(\C(=O)On1nnc2ccccc21)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3NC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.9 %

Procedure:
A mixture of 7β-amino-3-[(1-acetamido-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (0.450 g, 1.21 mmol), triethylamine (0.245 mg, 2.42 mmol) and dichloromethane (10 ml) was stirred at room temperature for 10 minutes. To the mixture was added 1-benzotriazolyl 2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetate (0.678 g, 1.21 mmol) and allowed to react at 5° C. for 17 hours. The dichloromethane was removed by evaporation. Water (10 ml) and triethylamine (0.5 ml) were added to the residue. The aqueous layer was separated, washed with ethyl acetate (5 ml) and adjusted to pH 3.5 with citric acid. Precipitated substance was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated. The residue was treated with ether and filtered to give pale yellow powder of 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-[(1-acetamido-1H-tetrazol-5-yl)thiomethyl]-3-cephem- 4-carboxylic acid (0.790 g, 92%), mp 167°-170° C. (decomposition).
Reaction SMILES: [CH:1]1([C:6]2[C:7]([OH:20])=[CH:8][C:9]([N+:17]([O-])=O)=[C:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O>C(O)(=O)C.CO.[Zn]>[NH2:17][C:9]1[CH:8]=[C:7]([OH:20])[C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:11][C:10]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)Cc1cc(C2CCCC2)c(O)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COC(=O)Cc1cc(C2CCCC2)c(O)cc1N
Reaction time: 2 h
Yield: 93.4 %

Procedure:
Methyl 2-(5-cyclopentyl-4-hydroxy-2-nitro-phenyl)acetate (30 mg, 0.11° mmol) was dissolved in acetic acid (1 mL) and water (0.5 mL) and treated with Zn dust (7 mg, 0.98 μL, 0.11 mmol) at room temperature. The mixture was stirred for 2 h then diluted with methanol (5 mL) and filtered. The filtrate was diluted with ethyl acetate, washed with 50% saturated NaHCO3 (2×20 mL), water, and brine. The solution was dried over Na2SO4, filtered, and dried down to provide methyl 2-(2-amino-5-cyclopentyl-4-hydroxyphenyl)acetate as an amber colored oil (25 mg, 93% yield). LC/MS m/z 249.8 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:4]=2[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[OH:41])O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:2]1[C:3]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:4]=2[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=1
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Reactant: O=c1ccc2c(Cl)nc(NC(CO)CO)nc2n1-c1c(F)cccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=c1ccc2c(-c3ccccc3O)nc(NC(CO)CO)nc2n1-c1c(F)cccc1F
Temperature: 150 °C
Yield: 82 %

Procedure:
A solution of 4-Chloro-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,6-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one (50 mg, 0.13 mmol) in dioxane/H2O (3:1, 4.8 mL) was mixed with 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (44.0 mg, 0.20 mmol) and K2CO3 (71.9 mg, 0.52 mmol). The resultant mixture was bubbled with argon for 5 minutes, and added by Pd(PPh3)4 (3.0 mg, 0.0026 mmol). The reaction tube was sealed and heated with “Smith Creator” (microwave, 150° C.) for 15 minutes. The mixture was concentrated under vaco. Flash chromatography (EtOAc/Hexane, 3:1) then afforded the title compound (82%): MS (ES) m/z 441 (M+H)+; 1H-NMR(CDCl3) δ 1.65 (s, br, 2H), 3.80 (m, br, 5H), 6.05 (m, br, 1H), 6.54 (m, 1H), 7.15 (m, 4H), 7.48 (m, 3H), 7.98 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[CH:7][C:8]2[N:9]=[CH:10][N:11]=[C:12](O)[C:13]=2[N:14]=1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:18])=O>>[C:1]([C:5]1[N:6]=[CH:7][C:8]2[N:9]=[CH:10][N:11]=[C:12]([Cl:18])[C:13]=2[N:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)c1ncc2ncnc(O)c2n1
Product: CC(C)(C)c1ncc2ncnc(Cl)c2n1
Reaction time: 0.17 h

Procedure:
6-tert-Butyl-pyrimido[5,4-d]pyrimidin-4-ol (210 mg, 1.03 mMol) was dissolved in phosphorous oxychloride (10 mL), and the mixture was heated at reflux for 4 hours. The solution was concentrated in-vacuo, then stripped from methylene chloride (3×50 mL) to remove excess phosphorous oxychloride. The residue was stirred for 10 minutes in saturated sodium bicarbonate (50 mL), then extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with water (30 mL), followed by brine (30 mL), dried over sodium sulfate, then concentrated in-vacuo. The residue was purified over silica gel, eluting with 50% ethyl acetate/heptane, to yield 150 mg of a white solid as product. NMR (500 MHz, CDCl3) δ 9.61 (s, 1H), 9.15 (S, 1H), 1.52 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][CH2:13][CH2:14][CH2:15][SH:16].[OH-].[K+]>C1COCC1>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[S:16][CH2:15][CH2:14][CH2:13][Cl:12]
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Reactant: SCCCCl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(Cl)c1SCCCCl
Temperature: 23 °C
Reaction time: 3.5 h
Yield: 99.1 %

Procedure:
To a dry THF (Aldrich anhydrous grade, 70 mL) solution of 2,3-dichloronitrobenzene (9.61 g, 50.1 mmol) and 3-chloropropanethiol (5.0 g, 45.5 mmol) was added in one portion at 23° C. KOH pellets. The resulting mixture was vigorously stirred at 23° C. for 3.5 h. The reaction mixture was filtered through a Celite plug to remove remaining KOH. The plug was washed with THF (2×50 mL). The filtrate was concentrated in vacuo to give crude 1-chloro-2-[(3-chloropropyl)sulfanyl]-3-nitrobenzene (12 g, ˜100%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:16])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:15])[C@H:12]([CH3:14])[NH2:13])[CH3:3].C(N(CC)CC)C.[OH:24][C:25]1[N:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>O1CCOCC1.C(Cl)(Cl)Cl>[CH2:2]([O:4][C:5](=[O:16])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:15])[C@H:12]([CH3:14])[NH:13][C:27]([C:26]1[C:25](=[O:24])[NH:33][CH:32]=[CH:31][CH:30]=1)=[O:28])[CH3:3]
Reactant: O=C(Cl)c1cccnc1O
Reactant: CCOC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)c1ccc[nH]c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.4 %

Procedure:
To a stirred solution of 4.0 g (0.016 mol) of L-alanyl-L-proline ethyl ester hydrochloride and 8 ml triethylamine in 200 ml dioxane, maintained at room temperature, a suspension of 3.0 g (0.019 mol) 2-hydroxynicotinoyl chloride in 200 ml anhydrous dioxane is added dropwise over 1 hour. After stirring for a further 3 hours at room temperature, the solvent is distilled off under reduced pressure. The crude product thus obtained is dissolved in 500 ml of chloroform and the solution washed twice with 100 ml of 5% aqueous sodium carbonate. After drying the organic layer over anhydrous magnesium sulfate, the solvent is removed on a rotary evaporator. The solid crystallizes from methylene chloride/isopropyl ether to give 3.4 g of the title compound as a white microcrystalline solid (yield: 64%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[C:10]=1I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25](N(CC)CC)C.C[Sn](C)(C)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[C:10]=1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(I)c(OCc2ccccc2)ccn1Cc1cccc(F)c1
Reactant: CCN(CC)CC
Agent: C[Sn](C)(C)C
Solvent: CN(C)C=O
Product: Cc1c(OCc2ccccc2)ccn(Cc2cccc(F)c2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
To a degassed solution of 4-(benzyloxy)-1-(3-fluorobenzyl)-3-iodopyridin-2(1H)-one (1.03 g, 2.36 mmol) in anhydrous DMF (15 mL) under argon atmosphere was added triethylamine (1.11 g, 11 mmol). The reaction mixture was chilled in an ice bath for 15 minutes before adding tetramethyl tin (2.10 g, 11.75 mmol) followed by bistriphenylphosphine-palladium chloride (0.166 g, 0.24 mmol). The reaction was stirred at room temperature for 30 minutes before heating at 95° C. under an atmosphere of argon for 3 hours. The reaction mixture was filtered through a bed of celite and the filtrate was concentrated under reduced pressure. The dark brown residue was diluted with ethyl acetate (100 mL) and washed with water. The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The dark brown residue was purified by flash chromatography (30% ethyl acetate in hexane). The appropriate fractions were combined and concentrated under reduced pressure to afford the desired product (0.1758 g, 22%) as a light yellow solid. The product was further purified by reverse phase HPLC using a 10-90% acetonitrile/water (30 minute gradient) at a 100 mL/min flow rate, to afford a cleaner product as a light yellow solid (0.0975 g, 8%). 1H-NMR (CD3OD, 400 MHz) δ7.58 (d, 1H, J=7.6 Hz)), 7.35 (m, 6H), 6.98 (m, 3H), 6.46 (d, 1H, J=7.6 Hz), 5.19 (s, 2H), 5.15 (s, 2H), 2.0 (s, 3H); ES-HRMS m/z 324.1366 (M+H calculated for C20H19NO2F requires 324.1394).
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([N:10]2[C:18]3[C:13](=[C:14]([O:19][CH2:20][CH2:21][CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)[CH:7]=[CH:6][N:5]=1)=O.[CH2:27]([O:29][C:30]([CH:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)=[O:31])[CH3:28]>O1CCOCC1.O>[CH2:27]([O:29][C:30]([CH:32]1[CH2:37][CH2:36][CH:35]([NH:38][C:4]2[N:9]=[C:8]([N:10]3[C:18]4[C:13](=[C:14]([O:19][CH2:20][CH2:21][CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:15]=[CH:16][CH:17]=4)[CH:12]=[CH:11]3)[CH:7]=[CH:6][N:5]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1CCC(N)CC1
Reactant: CS(=O)c1nccc(-n2ccc3c(OCCCS(C)(=O)=O)cccc32)n1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C1CCC(Nc2nccc(-n3ccc4c(OCCCS(C)(=O)=O)cccc43)n2)CC1
Temperature: 110 °C
Yield: 99.7 %

Procedure:
A mixture of 1-(2-methanesulfinyl-pyrimidin-4-yl)-4-(3-methanesulfonyl-propoxy)-1H-indole (25 g, 64 mM) and 4-amino-cyclohexanecarboxylic acid ethyl ester (16.3 g, 95.3 mM) in dioxane (400 mL) and heated at 110° C. for approximately 5 h. The solution was concentrated in vacuo to give a white residue. The residue was suspended in H2O, filtered and washed in H2O, and dried at 60° C. in vacuo to yield 4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid ethyl ester (31.7 g, 99.7%).
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][N:16]=[C:15]([CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:14]=1I)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Cu]I>[CH3:20][O:19][C:18]1[C:13]2[N:12]=[C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[S:11][C:14]=2[C:15]([CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[N:16][CH:17]=1
Reactant: COc1cnc(C2CCOCC2)c(I)c1NC(=S)NC(=O)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COc1cnc(C2CCOCC2)c2sc(NC(=O)c3ccccc3)nc12
Temperature: 130 °C
Yield: 55.6 %

Procedure:
A stirred suspension of 760 mg (1.53 mmol) 1-benzoyl-3-[3-iodo-5-methoxy-2-(tetrahydro-pyran-4-yl)-pyridin-4-yl]-thiourea, 29 mg (0.15 mmol) copper(I) iodide, 55 mg (0.31 mmol) 1,10-phenanthroline and 1.00 g (3.06 mmol) cesium carbonate in 4 ml toluene was heated at 130° C. for 10 min in a microwave oven. The resulting mixture was then cooled to room temperature and concentrated in vacuo. The residue was resuspended in methanol, the mixture filtered, and the filtrate concentrated in vacuo. Flash chromatography (ethyl acetate/heptane) afforded 314 mg (56%) N-[7-methoxy-4-(tetrahydro-pyran-4-yl)-thiazolo[5,4-c]pyridin-2-yl]-benzamide as a white solid. ES-MS m/e (%): 370 (M+H+, 100).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O.[NH2:30][NH2:31]>C(O)C>[C:12]1([N:5]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]3[NH:30][N:31]=[C:19]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:3]=3[C:4]2=[O:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CCc1ccccc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=c1c2c(CCc3ccccc3)n[nH]c2c2cccnc2n1-c1ccccc1
Yield: 72.8 %

Procedure:
To a suspension of 4-hydroxy-3-(1-oxo-3-phenylpropyl)-1-phenyl-1,8-naphthyridin-2 (1H)-one (110 mg, 0.30 mmol, prepared in Synthetic Example 6) in ethanol (6 ml) was added hydrazine monohydrate (80%, 44 μl, 1.1 mmol, 3.7 eq.), and the mixture was treated in the same manner as in Example 1 to give 5-phenyl-3-(2-phenylethyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (80 mg, 73%).
Reaction SMILES: O.[OH-].[Li+].[NH:4]1[CH:8]=[C:7]([CH2:9][NH:10][C:11](=[O:27])[NH:12][C@@H:13]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:14]([O:16]C)=[O:15])[N:6]=[CH:5]1.C(O)(=O)C>O1CCCC1.O>[NH:4]1[CH:8]=[C:7]([CH2:9][NH:10][C:11](=[O:27])[NH:12][CH:13]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[C:14]([OH:16])=[O:15])[N:6]=[CH:5]1
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)NCc1c[nH]cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CC(NC(=O)NCc2c[nH]cn2)C(=O)O)cc1
Temperature: 100 °C
Yield: 9.8 %

Procedure:
351 mg (84 mmol) of lithium hydroxide monohydrate are added to a solution of 278 mg (8.4 mmol) of methyl(S)-2-[3-(1H-imidazol-4-ylmethyl)ureido]-3-(4-methoxy-phenyl)propanoate in 5 mL of tetrahydrofuran and 1 mL of water. The reaction mixture is heated for 10 minutes at 100° C. in a microwave reactor. The reaction is stopped by adding 2 mL of water and 0.5 mL of acetic acid and is then extracted with ethyl acetate. The aqueous phase is concentrated to dryness and the residue is then chromatographed on silica gel (eluent: 7/3 dichloromethane/methanol). 261 mg of 2-[3-(1H-imidazol-4-ylmethyl)ureido]-3-(4-methoxyphenyl)propionic acid in the form of a white foam are obtained in a yield of 98%.
Reaction SMILES: [N:1]1[C:2]2[C:14](=O)[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:3]=2[NH:4][C:5](=[O:7])[CH:6]=1.Cl.[NH2:17][OH:18]>N1C=CC=CC=1>[OH:18][N:17]=[C:14]1[C:2]2[N:1]=[CH:6][C:5](=[O:7])[NH:4][C:3]=2[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]1=2
Reactant: O=C1c2ccccc2-c2[nH]c(=O)cnc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: O=c1cnc2c([nH]1)-c1ccccc1C2=NO
Temperature: 80 °C
Reaction time: 18 h
Yield: 48.8 %

Procedure:
A mixture of 9H-indeno[1,2-b]pyrazine-3,9(4H)-dione (1.0 g, 5.0 mmol), pyridine (40 ml) and hydroxylamine hydrochloride (0.42 g, 6.0 mmol) was stirred at 80° C. for 18 hours. The reaction mixture was cooled to room temperature, and the precipitate was filtered off and washed with water, acetic acid and water and dried. The crude material (0.81 g) was recrystallized from DMF to afford 0.52 g (49%) of the title compound. M.p.>300° C. 1H-NMR (DMSO-d6, δ): 7.49-7.62 (m, 2H), 7.88 (d, 1H), 7.95 (s, 1H), 8.36 (d, 1H), 12.5-13.2 (broad, 1H), 12.83 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][N:5]([CH3:13])[C:4]2[C:14](=[O:22])[O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:3]1=2>Cl.O>[O:1]=[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]([CH3:13])[C:4]2[C:14](=[O:22])[O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:3]1=2
Reactant: CCOC(=O)c1cn(C)c2c(=O)oc3ccccc3c2c1=O
Agent: Cl
Solvent: O
Product: Cn1cc(C(=O)O)c(=O)c2c3ccccc3oc(=O)c21
Yield: 81.7 %

Procedure:
A suspension of ethyl 1,5-dihydro-1,5-dioxo-4-methyl-1-benzopyrano[3,4-b]pyridine-2-carboxylate (4.5 g, 0.0158 mole) in 5 N hydrochloric acid (100 ml) is refluxed under nitrogen for 20 hours. The reaction mixture is cooled and diluted with water. The product is filtered off, washed with water and sucked dry. Recrystallization from dimethylformamide gives white crystals (3.5 g, 85%), m.p. 295-297 (dec.).
Reaction SMILES: Cl[CH2:2][C@@H:3]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:4][C:5]1[CH:27]=[CH:26][C:8]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)=[CH:7][CH:6]=1.[OH:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[I:45])[C:40]#[N:41].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([O:9][C:8]2[CH:26]=[CH:27][C:5]([CH2:4][C@H:3]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:2][O:36][C:37]3[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=3[I:45])[C:40]#[N:41])=[CH:6][CH:7]=2)[CH2:11][CH2:12]1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CCl)Cc1ccc(OC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: N#Cc1ccc(I)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](COc1cc(C#N)ccc1I)Cc1ccc(OC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 65 °C
Reaction time: 96 h

Procedure:
1.3 g (2.6 mmol) of benzyl 4-[4-[(2S)-3-chloro-2-(t-butoxycarbonylamino)propyl]phenoxy]piperidine-1-carboxylate, 686 mg (2.8 mmol) of 3-hydroxy-4-iodobenzonitrile and 390 mg (2.8 mmol) of potassium carbonate were dissolved in dimethylformamide. The solution was stirred at 65° C. for 4 days, and then treated with ethyl acetate as the extractant in an ordinary manner to obtain the title compound, which was then subjected to the subsequent reaction without further purification.