Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14](/[CH:15]=[CH:16]/[C@@H:17]([OH:29])[CH2:18][C@@H:19]([OH:28])[CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])=[C:13]([CH:30]([CH3:32])[CH3:31])[N:12]=[C:11]([N:33]([CH3:38])[S:34]([CH3:37])(=[O:36])=[O:35])[N:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+].C(#[N:43])C>>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14](/[CH:15]=[CH:16]/[C@@H:17]([OH:29])[CH2:18][C@@H:19]([OH:28])[CH2:20][C:21]([OH:23])=[O:22])=[C:13]([CH:30]([CH3:32])[CH3:31])[N:12]=[C:11]([N:33]([CH3:38])[S:34]([CH3:37])(=[O:36])=[O:35])[N:10]=2)=[CH:5][CH:4]=1.[CH3:13][C:14]([NH2:43])([CH3:15])[CH3:9]
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H](O)C[C@@H](O)CC(=O)OC(C)(C)C
Reactant: CC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)N
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H](O)C[C@@H](O)CC(=O)O
Reaction time: 2 h

Procedure:
Hydrochloric acid (0.02 N; 15 mL) was added to a solution of tert-butyl (3R,5S,6E)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-(propan-2-yl)pyrimidin-5-yl]-3,5-dihydroxyhept-6-enoate (Example 3; 15 g) in acetonitrile (150 mL) at 25° C. to 30° C. and stirred at the same temperature for 2 hours. After completion of the reaction, aqueous solution of sodium hydroxide (1.55 g in 30 mL) was added to the reaction mixture at 25° C. to 30° C. and stirred for 2.0 hours at 30° C. to 35° C. Acetonitrile was recovered completely under vacuum at 40° C. to 45° C. De-ionized water (30 mL) was added to the resulting residue at room temperature. Methyl tert-butyl ether (30 mL) was added to the mixture and stirred for 10 minutes. Layers were separated; methyl tert-butyl ether (30 mL) was added to the aqueous layer and stirred for 10 minutes. Layers were separated; the aqueous layer was cooled to 0° C. to 5° C. and added acetonitrile (75 ml) and sodium chloride (25 g) adjusted pH of 3.5 to 4.0 using hydrochloric acid (2N) at 0° C. to 5° C. Organic layer was separated and cooled to 0° C. to 5° C. To this pre-cooled organic layer, tert-butyl amine (1.9 g) was slowly added in 20 minutes at 0° C. to 5° C. and stirred for 1 hour at room temperature. The resulting mixture was cooled to 5° C. to 10° C., filtered, washed with acetonitrile (30 mL) and dried under vacuum at 40° C. to 45° C. for 4 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:12]([O-])=O)[C:3]=1[OH:15]>CCO.[Pd]>[ClH:1].[Cl:1][C:2]1[C:3]([OH:15])=[C:4]([NH2:12])[C:5](=[C:9]([Cl:11])[CH:10]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1c(Cl)cc(Cl)c(O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cl
Product: Nc1c(O)c(Cl)cc(Cl)c1C(=O)O
Reaction time: 1 h
Yield: 28.1 %

Procedure:
4,6-Dichloro-3-hydroxy-2-nitrobenzoic acid (223 mg, 0.88 mmol) was dissolved in EtOH (50 mL) and Pd/C (10%, 30 mg) was added. Hydrogenation at atmospheric pressure and at room temperature for 1 h, filtration and evaporation of the solvent gave 205 mg of crude product. Purification by column chromatography (SiO2, EtOAc-HOAc 50:1) gave a residue which was recrystallized from MeOH/water (0.5/ 1.5 mL). Column chromatography (SiO2, EtOAc-HOAc 400:1) followed by dissolving the free amine in THF (0.6 mL) and precipitating the hydrochloride by adding HCl/Et2O (3M, 1 mL) and Et2O (1 mL) gave 4,6-dichloro-3-hydroxyanthranilic acid hydrochloride (32 mg). Mp: 231° C. (dec.). 1H NMR (DMSO-d6): δ 7.0 (br, 5 H), 6.68 (s, 1 H). 13C NMR (DMSO-d6): δ 167.15, 140.27, 139.05, 122.49, 121.88, 116.24, 113.99. MS (EI, 70 eV): m/z (rel.int.) 223/221 (M+, 42/65).
Reaction SMILES: [NH3:1].Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[C:5]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:24])[CH2:19][CH2:18]2)[N:4]=1>O1CCCC1>[NH2:1][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[C:5]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:24])[CH2:19][CH2:18]2)[N:4]=1
Reactant: COc1cc2nc(N3CCN(C(=O)C4CCCC4)CC3)nc(Cl)c2cc1OC
Reactant: N
Solvent: C1CCOC1
Product: COc1cc2nc(N3CCN(C(=O)C4CCCC4)CC3)nc(N)c2cc1OC

Procedure:
A mixture of anhydrous ammonia and 4-chloro-2-[4-(cyclopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline in 100 ml. of tetrahydrofuran is heated at 100° C. for a period of 16 to 24 hours and the product isolated according to the procedure of Example 1(a) to provide 4-amino-2-[4-(cyclopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7]([Br:10])[S:8][CH:9]=1)(=[O:3])[CH3:2].S(C1C=CC(C)=CC=1)(O[CH3:15])(=O)=O.[H-].[Na+]>C(#N)C>[Br:10][C:7]1[S:8][CH:9]=[C:5]([N:4]([CH3:15])[C:1](=[O:3])[CH3:2])[N:6]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CC(=O)Nc1csc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)N(C)c1csc(Br)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 32 %

Procedure:
A solution of 4-acetamido-2-bromothiazole (prepared as described in Example 1) and methyl tosylate (4.65 g, 25 mM) in dry acetonitrile (125 ml) was treated with a 60% dispersion of sodium hydride in oil (1 g, 25 mM) and the mixture stirred 72 hours at ambient temperature. The reaction mixture was filtered and the filtrate evaporated under reduced pressure. The residue was chromatographed on silica (Woelm grade, 1, 150 g) using 2% methanol in chloroform as eluant. Evaporation of the appropriate fractions followed by recrystallisation from hexane gave the title compound (1.9 g, 32%) mp 84° C. Found: C, 30.55; H, 2.95; N, 11.8%. C6H7N2BrOS requires C, 30.7; H, 3.0; N, 11.9%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17]([CH3:22])([CH3:21])[O:16][C:15]3([CH3:24])[CH3:23])=[CH:7][CH:6]=1)[CH3:2].C([BH3-])#N.[Na+].[CH:30](=O)[CH2:31][CH3:32]>C(O)(=O)C.O1CCCC1>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:30][CH2:31][CH3:32])[C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17]([CH3:22])([CH3:21])[O:16][C:15]3([CH3:24])[CH3:23])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Nc2ccc3c(c2)C(C)(C)OC3(C)C)cc1
Reactant: CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCN(c1ccc(C(=O)OCC)cc1)c1ccc2c(c1)C(C)(C)OC2(C)C
Yield: 90.1 %

Procedure:
Following general procedure Q and using 4-[(1,1,3,3-tetramethyl-1,3-dihydro-isobenzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 79, 0.2 g, 0.64 mmol), sodiumcyanoborohydride (0,121 g, 1.92 mmol) and propionaldehyde (1 mL, 13.7 mmol) in 5 mL of acetic acid and 5 mL of tetrahydrofuran, the title compound (0.22 g, 90%) was obtained as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.85 (d, 2H, J=9.0 Hz), 7.08 (s, 2H), 6.90 (s, 1H), 6.67 (d, 2H, J=8.9 Hz), 4.31 (q, 2H, J=7.1 Hz), 3.66 (t, 2H, J=7.8 Hz), 1.77-1.64 (m, 2H) 1.54 (s, 6H), 1.50 (s, 6H), 1.34 (t, 3H, J=7.1 Hz), 0.94 (t, 3H, J=7.4 Hz).
Reaction SMILES: [P:1]([O-:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:19]=[O:20].C(N(CC)CC)C>>[CH2:3]([O:2][P:1]([CH2:19][OH:20])(=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: C=O
Solvent: CCN(CC)CC
Product: O=P(CO)(OCc1ccccc1)OCc1ccccc1
Yield: 42.5 %

Procedure:
Charged an Emrys 5 mL process vial with 2.0 g (7.63 mmol) dibenzyl phosphite, 229 mg (7.63 mmol) paraformaldehyde powder, and 0.11 mL (0.76 mmol) triethylamine. The white mixture was heated in a microwave (Personal Chemistry) at 130° for 5 minutes. The crude oil was purified on silica gel, eluting with 50-100% ethyl acetate in hexane to provide 947 mg (42% yield) of the title compound, a colorless oil. MS (ESI) m/z: 181.1, 293.0 [M+H]+ 1H NMR (DMSO-d6) δ: 3.83 (m, 2H), 5.02 (d, 4H), 5.50 (m, 1H), 7.37 (m, 10H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.S([NH:19][NH2:20])(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+].[CH:23](N1C=CN=C1)=[CH2:24]>CCO.O.CCOC(C)=O>[NH:19]1[CH:24]=[CH:23][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[N:20]1
Reactant: C=Cn1ccnc1
Reactant: O=Cc1cccnc1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: c1cncc(-c2cc[nH]n2)c1
Yield: 56.2 %

Procedure:
(See FIG. 10.) To a solution of nicotinaldehyde (2.0 mL, 21.2 mmol) in 95% EtOH (20 mL) was added 2-tosylhydrazine (3.95 g, 21.2 mmol) and the resultant solution was stirred at room temperature for 2 h. To the solution was added aqueous sodium hydroxide (5 N, 4.2 mL, 21.2 mmol) and the solution was stirred for twenty minutes. To the solution was added 1-vinylimidazole (9.6 mL, 106 mmol) and the resultant solution was warmed to 50° C. and stirred under an argon atmosphere for 96 h. The solution was poured into a water/EtOAc mixture (1:1, 100 mL), the organic fraction was collected and the aqueous fraction was extracted with EtOAc (2×50 mL). The combined organic fractions were dried (Na2SO4), filtered and the solvent was removed in vacuo. The crude material was chromatographed on silica gel (EtOAc/Hex, 50/50, Rf=0.08) to afford the title compound 27 (1.73 g, 56% yield) as a pale white oil: 1H NMR (CDCl3) δ 9.03 (m, 1H), 8.52 (m, 1H), 8.06 (m, 1H), 7.59 (d, J=2.2 Hz, 1H), 7.29 (m, 1H); 6.61 (d, J=2.5 Hz, 1H); LRMS (ESI) m/z calcd for C8H8N3 [M+H]+ 146. found 146.
Reaction SMILES: [I-].[Na+].[In].Br[CH2:5][CH:6]=[C:7]([CH3:9])[CH3:8].[CH3:10][O:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=2[F:28])=[C:16]([CH:29]=[O:30])[CH:15]=1)=[O:13]>CN(C=O)C.CCOC(C)=O.O>[CH3:10][O:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=2[F:28])=[C:16]([CH:29]([OH:30])[C:7]([CH3:9])([CH3:8])[CH:6]=[CH2:5])[CH:15]=1)=[O:13]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C=O)c1
Reactant: CC(C)=CCBr
Agent: [I-]
Agent: [In]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CC(C)(C)C(O)c1cc(C(=O)OC)ccc1-c1cc(OC)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
To a mixed solution of sodium iodide (2080 mg, 13876 μmol), indium (2000 mg, 6938 μmol) and 1-bromo-3-methylbut-2-ene (1616 μL, 13876 μmol) in DMF (30 mL), was added T30.3 (1593 mg, 13876 μmol). The mixture was stirred at room temperature for 1 hour, and then was diluted with EtOAc and water. The organic phase was washed with water and brine and then dried over anhydrous sodium sulfate. After filtration, the organic solvent was removed in vacuo to give a residue which was purified by chromatography to give the product as an oil (2.30 g, 92%). MS ESI m/e: 376.1 (M+18)+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:29]1[C:38]2[C:37]3[CH2:39][NH:40][CH2:41][CH2:42][C:36]=3[CH:35]=[CH:34][C:33]=2[NH:32][C:31](=[O:43])[C:30]1=[O:44].C(N(CC)CC)C>O1CCCC1.CN(C)C=O>[O:44]=[C:30]1[NH:29][C:38]2[C:37]3[CH2:39][N:40]([C:14]([CH:11]4[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:13][CH2:12]4)=[O:16])[CH2:41][CH2:42][C:36]=3[CH:35]=[CH:34][C:33]=2[NH:32][C:31]1=[O:43]
Reactant: O=c1[nH]c2ccc3c(c2[nH]c1=O)CNCC3
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCc3ccc4[nH]c(=O)c(=O)[nH]c4c3C2)CC1
Temperature: 70 °C
Reaction time: 19 h
Yield: 72.6 %

Procedure:
A solution of N-Boc-4-piperidinecarboxylic acid (158 mg, 0.69 mmol) and carbonyldiimidazole (119 mg, 0.69 mmol) in tetrahydrofuran (3 mL) under a nitrogen atmosphere was reluxed for 15 min. This solution was then added to suspension of the quinoxalinedione from Example 30 (100 mg, 0.46 mmol) in anhydrous dimethylformamide (3 mL). After stirring for 15 min (nitrogen atmosphere), triethylamine (0.96 mL, 0.69 mmol) was added and the reaction was stirred at 70° C. for 19 h. The mixture was concentrated to dryness and the residue triturated with water and collected by filtration. A beige solid (143 mg, 73% yield) was obtained. mp=283-286° C. CHN calc'd for C22H28N4O5 within ±0.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[C:11]1([C:17]2[O:18][CH2:19][CH:20]([OH:29])[CH:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:22]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([O:29][CH:20]2[CH2:19][O:18][C:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:22][CH:21]2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: OC1COC(c2ccccc2)=NC1c1ccccc1
Solvent: ClCCCl
Product: O=C(Nc1ccc(Cl)cc1)OC1COC(c2ccccc2)=NC1c1ccccc1
Yield: 57.1 %

Procedure:
4-Chlorophenyl isocyanate (1 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (4RS, 5RS)-2,4-diphenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (1.2 g) in 1,2-dichloroethane (20 cc). The solution obtained is heated to reflux for 7 hours 30 minutes and then concentrated to dryness under reduced pressure (2.7 kPa). After two successive recrystallizations in acetonitrile, (4RS, 5RS)-5-(4-chlorophenylcarbamoyloxy)-2,4-diphenyl-5,6-dihydro-4H-1,3-oxazine (1.1 g), m.p. 200° C., is obtained.
Reaction SMILES: [O-][CH2:2]C.[Na+].[C:5]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:6][SH:7].Cl[C:13]1[N:17](C)[C:16]([CH2:19][O:20][CH3:21])=[N:15][C:14]=1[CH:22]=O>C(O)C>[CH3:2][N:15]1[C:14]2[CH:22]=[C:6]([C:5]([O:9][CH2:10][CH3:11])=[O:8])[S:7][C:13]=2[N:17]=[C:16]1[CH2:19][O:20][CH3:21]
Reactant: CC[O-]
Reactant: COCc1nc(C=O)c(Cl)n1C
Reactant: CCOC(=O)CS
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc2c(nc(COC)n2C)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a freshly prepared sodium ethoxide solution (from 391 mg, 17 mmol of sodium) in 15 mL of ethanol were added dropwise 1.9 mL (2.1 g, 17 mmol) of ethyl thioglycolate. After 1 hour stirring at ambient temperature, 1.6 g (8.5 mmol) of 5-chloro-4-formyl-2-methoxymethyl-1-methylimidazole in 20 mL of absolute ethanol were added and the mixture was heated to 80° C. (analogously to B. Iddon et al., J. Chem. Soc. Perkin Trans. I, 1987, 1457). After 5 hours, the solvent was distilled off, the residue was taken up in 50 mL of methylene chloride and washed with 20 mL of water. The aqueous phase was washed again with 20 mL of methylene chloride and then the combined organic phases were dried with sodium sulfate. After removal of the solvent in vacuo, the crude product obtained was purified by column chromatography (aluminium oxide; methylene chloride). Yield: 1.0 g (46% of theory), C11H14N2O3S (254.31); Rf value: 0.48 (silica gel; methylene chloride/ethanol=50:1); EKA mass spectrum: (M+H)+=255; (M+Na)+=277.
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][C@H:22]1[CH2:26][CH2:25][S:24](=[O:28])(=[O:27])[NH:23]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH2:30][CH2:31][CH2:32][C:33]1[S:37][C:36]([C:38]([O:40][CH3:41])=[O:39])=[CH:35][CH:34]=1>CN(C=O)C>[Si:3]([O:20][CH2:21][C@H:22]1[CH2:26][CH2:25][S:24](=[O:28])(=[O:27])[N:23]1[CH2:30][CH2:31][CH2:32][C:33]1[S:37][C:36]([C:38]([O:40][CH3:41])=[O:39])=[CH:35][CH:34]=1)([C:16]([CH3:17])([CH3:18])[CH3:19])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)[Si](OC[C@H]1CCS(=O)(=O)N1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(CCCI)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCCN2[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CCS2(=O)=O)s1
Temperature: 0 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
To a mixture of sodium hydride (37 mg, 1.54 mmol) in DMF (3.0 mL) cooled to 0° C. was added dioxide 8 (554 mg, 1.42 mmol). After 0.5 h a solution methyl 5-(3-iodopropyl)thiophene-2-carboxylate (485 mg, 1.56 mmol) in DMF (4.5 mL). The reaction was allowed to warm to room temperature on its own accord and stirred for 16 h. The reaction was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic portion was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 20% EtOAc/hex) afforded 751 mg (91%) of ester 9.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH:11][C@@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1.C(N(CC)CC)C>C1COCC1>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[N:14]1[CH2:15][CH2:16][CH:12]([OH:11])[CH2:13]1
Reactant: Clc1nc2ccccc2o1
Reactant: O[C@@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OC1CCN(c2nc3ccccc3o2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.1 %

Procedure:
To a stirring solution of 5.1 mL (44.6 mmol) of 2-chlorobenzoxazole in 35 mL of THF at 0° C. was added 4.28 g (49.0 mmol, 1.1 equiv.) of (R)-3-hydroxypyrrolidine and 4.42 mL (32 mmol, 0.72 equiv.) of triethylamine. The resulting solution was stirred 12 h at RT, the precipitate was filtered, washed with THF (3×5 mL), and the filtrate concentrated in vacuo. Purification by silica gel flash column chromatography using hexane/EtOAc 1/1 to EtOAc as eluent afforded 3.74 g of the title compound: low resolution MS (ESP) m/e 205 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:25])([CH3:24])[C:18]=3[CH:26]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:27]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:24])([CH3:25])[C:18]=3[CH:26]=2)=[O:27])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCSc3ccc(Cl)c(Cl)c3)cc21
Reactant: OO
Product: CC1(C)OC(=O)Nc2ccc(OCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[3-(3,4-dichloro-phenylmercapto)-propoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]([CH2:12][CH3:13])[CH2:9][CH:10]=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH:15]([Mg]Cl)=[CH2:16]>C1COCC1>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]([CH2:12][CH3:13])[CH2:9][C@H:10]([OH:11])[CH:15]=[CH2:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@H](CC=O)NC(=O)OC(C)(C)C
Reactant: C=C[Mg]Cl
Solvent: C1CCOC1
Product: C=C[C@@H](O)C[C@@H](CC)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
To a solution of ((R)-1-ethyl-3-oxo-propyl)carbamic acid tert-butyl ester (2.9 mmol; 584 mg) in THF (20 mL) is added a 1.44 M THF solution (11.6 mmol; 8.1 mL) of vinylmagnesium chloride under nitrogen at −78° C. After stirring for 30 minutes, the reaction mixture is warmed to room temperature and stirred for an additional 1.5 hours. Another 1.44 M THF solution (2.9 mmol; 2 mL) of vinylmagnesium chloride is added to the reaction mixture at room temperature. After stirring for additional 15 minutes, the solution is quenched by saturated aqueous ammonium chloride solution and extracted three times with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent; n-hexane/EtOAc) to give ((1R,3S)-1-ethyl-3-hydroxy-pent-4-enyl)-carbamic acid tert-butyl ester (130 mg, 20%); ESI-MS m/z: 174 [M+−tBu+2], Retention time 4.13 min (condition B).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:20][C:21]1[C:30]2[C:25](=[C:26]([S:31](Cl)(=[O:33])=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][N:22]=1.Cl.ClC1C2C(=C(S(Cl)(=O)=O)C=CC=2)C=CN=1>ClCCl>[C:1]([O:5][C:6]([NH:7][CH2:8][CH2:9][CH2:10][NH:11][S:31]([C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[CH:24]=[CH:23][N:22]=[C:21]2[Cl:20])(=[O:33])=[O:32])=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=S(=O)(Cl)c1cccc2c(Cl)nccc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCNS(=O)(=O)c1cccc2c(Cl)nccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
According to the method of Example 1, Step A, a solution of N-(3-aminopropyl)carbamic acid tert-butyl ester (383 mg) and triethylamine (335 μl) in dichloromethane (3 ml) was added with a solution of (1-chloro-5-isoquinolyl)sulfonyl chloride (524 mg, prepared from (1-chloro-5-isoquinolyl)sulfonyl chloride hydrochloride according to the method of Japanese Patent Unexamined Publication (Kokai) No. 63-2980) in dichloromethane (3 ml) with stirring and ice cooling and stirred at room temperature for 20 hours. The reaction mixture was successively washed with saturated aqueous sodium hydrogencarbonate twice and with saturated brine. The organic layer was dried over anhydrous sodium sulfate (Wako Pure Chemical Industries), and then the solvent was evaporated under reduced pressure. Then, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to obtain the title compound (640 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])[C:5]2=[O:13].N1C2C(=CC=CC=2)C(=O)C1=O.[F:25][CH:26]([F:36])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1I>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])[C:5]2([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[O:28][CH2:27][CH:26]([F:25])[F:36])[OH:13]
Reactant: O=C1Nc2cc(F)c(Cl)cc2C1=O
Reactant: FC(F)COc1ccccc1I
Agent: O=C1Nc2ccccc2C1=O
Product: O=C1Nc2cc(F)c(Cl)cc2C1(O)c1ccccc1OCC(F)F

Procedure:
The title compound was prepared in analogy to example a.1 using 5-chloro-6-fluoroisatin as isatin II and 2,2-difluoroethoxyiodobenzene (to form the Grignard reagent).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][N:11]([CH3:25])[S:12]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([O:22][CH3:23])=[CH:17][C:16]=3[CH3:24])(=[O:14])=[O:13])[NH:7][C:6]=2[C:26]=1[C:27]([O:29]CC)=[O:28].[Li+].[OH-]>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][N:11]([CH3:25])[S:12]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([O:22][CH3:23])=[CH:17][C:16]=3[CH3:24])(=[O:14])=[O:13])[NH:7][C:6]=2[C:26]=1[C:27]([OH:29])=[O:28]
Reactant: CCOC(=O)c1c(F)ccc2nc(CN(C)S(=O)(=O)c3c(C)cc(OC)cc3C)[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc3ccc(F)c(C(=O)O)c3[nH]2)c(C)c1
Yield: 20 %

Procedure:
Ethyl 6-fluoro-2-((4-methoxy-N,2,6-trimethylphenylsulfonamido)methyl)-1H-benzo[d]imidazole-7-carboxylate (F-20) (2.4 mmol, 1 eq.) was hydrolysed with LiOH in THF/H2O (1:1). After the hydrolysis, the solvent was removed completely from the reaction mixture in vacuo and the residue was taken up in water and washed with ethyl acetate. The aqueous phase was adjusted to pH=4 and then extracted with ethyl acetate. The free acid 6-fluoro-2-((4-methoxy-N,2,6-trimethylphenyl-sulfonamido)methyl)-1H-benzo[d]imidazole-7-carboxylic acid (ACI-20) obtained in this way was coupled with 9-pyridin-4-Yl-3,9-diazaspiro[5.5]undecane dihydrochloride (AMN-01) under standard peptide coupling conditions. Yield: 20%
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].[Cl:11][C:12]1[NH:17][C:16](=[O:18])[N:15]([CH2:19][CH2:20][CH3:21])[C:14](=[O:22])[CH:13]=1>CN(C=O)C.C(Cl)(Cl)Cl>[Cl:11][C:12]1[N:17]([CH2:2][C:3]#[N:4])[C:16](=[O:18])[N:15]([CH2:19][CH2:20][CH3:21])[C:14](=[O:22])[CH:13]=1
Reactant: N#CCCl
Reactant: CCCn1c(=O)cc(Cl)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCn1c(=O)cc(Cl)n(CC#N)c1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Chloroactonitrile (16.5 g) and potassium carbonate (29.3 g) were added to a solution of 6-chloro-3-propylpyrimidine-2,4(1H,3H)-dione (20 g) in DMF (200 ml), and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated and evaporated to dryness to obtain a residue. A resulting residue was dissolved in chloroform and H2O, and the organic layer was washed with water and dried. The solvent was evaporated to dryness to give a syrup, which was purified by column chromatography on silica gel to give a crystalline product. Recrystalization of the crude crystals from ethyl acetate-isopropylether gave colorless prisims (21.1 g, 87%), mp. 83°-84° C.