Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[C@@H:16]([CH3:17])[CH2:15][CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[C:23]3[C:28]([CH:29]=[CH:30][C:20]=2[N:19]=1)=[CH:27][C:26]1[C:31]2[C:36]([CH2:37][O:38][C:25]=1[CH:24]=3)=[CH:35][C:34]([C:39]1[NH:43][C:42]([C@@H:44]3[CH2:48][C@H:47]([CH3:49])[CH2:46][N:45]3C(OC(C)(C)C)=O)=[N:41][CH:40]=1)=[CH:33][CH:32]=2)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].[CH3:57][O:58][C:59]([NH:61][C@@H:62]([CH:66]([CH3:68])[CH3:67])[C:63](O)=[O:64])=[O:60].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>Cl.CCO.CN(C=O)C>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@@H:6]([CH:7]([CH3:9])[CH3:8])[C:10]([N:12]1[C@@H:16]([CH3:17])[CH2:15][CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[C:23]3[C:28]([CH:29]=[CH:30][C:20]=2[N:19]=1)=[CH:27][C:26]1[C:31]2[C:36]([CH2:37][O:38][C:25]=1[CH:24]=3)=[CH:35][C:34]([C:39]1[NH:43][C:42]([C@@H:44]3[CH2:48][C@H:47]([CH3:49])[CH2:46][N:45]3[C:63](=[O:64])[C@@H:62]([NH:61][C:59]([O:58][CH3:57])=[O:60])[CH:66]([CH3:68])[CH3:67])=[N:41][CH:40]=1)=[CH:33][CH:32]=2)=[O:11]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1c1nc2ccc3cc4c(cc3c2[nH]1)OCc1cc(-c2cnc([C@@H]3C[C@H](C)CN3C(=O)OC(C)(C)C)[nH]2)ccc1-4)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1ncc(-c2ccc3c(c2)COc2cc4c(ccc5nc([C@@H]6CC[C@H](C)N6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c54)cc2-3)[nH]1)C(C)C
Reaction time: 3 h
Yield: 51 %

Procedure:
tert-butyl(2S,4S)-2-[5-(2-{(2S,5 S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate (60 mg, 0.079 mmol) in 1.25 N HCl in EtOH (2 mL) was heated to 50° C. for 3 h and then concentrated under reduced pressure. The crude residue was treated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (21 mg, 0.12 mmol), HATU (36 mg, 0.095 mmol) and DMF (1.5 mL), then N-methylmorpholine (0.027 mL, 0.24 mmol) was added dropwise. After 3 h, the mixture was quenched with 1N HCl (0.100 mL) and then purified by HPLC to afford methyl{(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (33 mg, 51%).
Reaction SMILES: [CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH2:18][C:19]([OH:21])=O)[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1N=NN(CC(O)=O)N=1)CCCCCCCCC.[CH3:41][O:42][C:43]1[CH:49]=[C:48]([O:50][CH3:51])[CH:47]=[C:46]([O:52][CH3:53])[C:44]=1[NH2:45].C(C1C=CC=C(C(C)C)C=1N)(C)C>>[CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH2:18][C:19]([NH:45][C:44]2[C:46]([O:52][CH3:53])=[CH:47][C:48]([O:50][CH3:51])=[CH:49][C:43]=2[O:42][CH3:41])=[O:21])[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: COc1cc(OC)c(N)c(OC)c1
Reactant: CCCCCCCCCCCCc1nnn(CC(=O)O)n1
Agent: CC(C)c1cccc(C(C)C)c1N
Agent: CCCCCCCCCCc1nnn(CC(=O)O)n1
Product: CCCCCCCCCCCCc1nnn(CC(=O)Nc2c(OC)cc(OC)cc2OC)n1

Procedure:
When in the general procedure of Example 88 an appropriate amount of 5-dodecyl-2H-tetrazole-2-acetic acid was substituted for 5-decyl-2H-tetrazole-2-acetic acid and 2,4,6-trimethoxyaniline was substituted for 2,6-diisopropylaniline, the title compound was obtained, mp 144°-146° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].C(N(CC)C(C)C)(C)C.[C:56]1([S:62](Cl)(=[O:64])=[O:63])[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>CN(C)C=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][N:43]([S:62]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)(=[O:64])=[O:63])[CH2:42][CH2:41]1)=[O:39]
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCN(S(=O)(=O)c2ccccc2)CC1
Yield: 18 %

Procedure:
N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) (10.0 mg, 0.018 mmol) was stirred in N,N-dimethylformamide (1.0 mL) with N,N-diisopropylethylamine (16 μL, 0.089 mmol), and benzenesulfonyl chloride (2.5 μL, 0.020 mmol) was added. Purification by preparative LCMS (pH 2) gave the desired compound (18%). LCMS for C30H30ClN6O3S (M+H)+: m/z=589.2.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11])[CH3:2].[CH3:12]I>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:12])[C:10]#[N:11])[CH3:2]
Reactant: CI
Reactant: CCc1ccccc1CC#N
Product: CCc1ccccc1C(C)C#N

Procedure:
rac-2-(2-Ethyl-phenyl)-propionitrile was prepared from (2-ethyl-phenyl)-acetonitrile and methyl iodide in analogy to Example 65a): light-yellow liquid; MS (EI): 159.1 (M+.).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(Cl)CCl.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([OH:29])=O)=[CH:21][CH:20]=1>>[CH3:5][O:4][N:3]([CH3:2])[C:27](=[O:29])[CH2:26][CH2:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=1
Reactant: CNOC
Reactant: COc1ccc(CCC(=O)O)cc1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCC(=O)N(C)OC)cc1
Reaction time: 15 h
Yield: 85.5 %

Procedure:
N,O-dimethylhydroxylamine hydrochloride (5.41 g, 55.5 mmol), EDC (12.77 g, 66.6 mmol), followed by triethylamine (17 mL, 122 mmol) were added to a cooled 0° C. solution of 3-(4-methoxyphenyl)propionic acid (10 g, 55.5 mmol). The reaction mixture was stirred for 15 h under N2 and then concentrated. The residue was partitioned between 1 N HCl and EtOAc. The organic layers were washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to an oil. The oil was purified by silica gel chromatography (40% EtOAc in hexanes) to give a clear oil (10.6 g, 85%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][S:20]([CH2:23][CH2:24][NH2:25])(=[O:22])=[O:21])[CH2:15][CH2:14]1)([CH3:12])[CH3:11]>>[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][S:20]([CH2:23][CH2:24][NH:25][C:7]([C:5]2[S:6][C:2]([CH3:1])=[CH:3][CH:4]=2)=[O:9])(=[O:21])=[O:22])[CH2:15][CH2:14]1)([CH3:12])[CH3:11]
Reactant: Cc1ccc(C(=O)O)s1
Reactant: CC(C)N1CCC(NS(=O)(=O)CCN)CC1
Product: Cc1ccc(C(=O)NCCS(=O)(=O)NC2CCN(C(C)C)CC2)s1

Procedure:
5-Methyl-thiophene-2-carboxylic acid [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide was prepared by an analogous procedure as described in example 9 starting from 94 mg (1.1 equiv.) 5-methyl-thiophene-2-carboxylic acid and 150 mg (0.60 mmol) 2-amino-ethanesulfonic acid (1-isopropyl-piperidin-4-yl)-amide. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 5-methyl-thiophene-2-carboxylic acid [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material, which turned out to be hygroscopic with time.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[N:30][CH:31]=1.[I-].[K+]>CN(C)C=O.O.C(Cl)Cl.CCOCC>[CH3:32][C:29]1[N:30]=[CH:31][C:26]([CH2:25][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]3)=[CH:27][CH:28]=1
Reactant: Cc1ccc(CCl)cn1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(O)cc2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(COc2ccc3c(c2)C[C@@H](NS(=O)(=O)C(C)C)C3)cn1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
In a 250 ml round-bottomed flask at room temperature under nitrogen, N-[(2S)-5-hydroxy-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (5.31 g, 20.80 mmol, Description 3) was dissolved in N,N-dimethylformamide (25 ml) to give a colourless solution. Cesium carbonate (10.16 g, 31.2 mmol) was then added, followed by 5-(chloromethyl)-2-methylpyridine (4.26 g, 30.1 mmol, Description 6) dissolved in dry N,N-dimethylformamide (20 ml), and potassium iodide (0.863 g, 5.20 mmol). This resulting brown mixture was then allowed to stir at room temperature for the weekend. The mixture was brought to 0° C. and was diluted with water (100 ml) and DCM (150 ml) (exothermic reaction). Phases were separated and the aqueous phase was back extracted with DCM (2×100 ml). The combined organic phases were dried over Na2SO4, filtered and concentrated to give an oily residue, which was diluted in Et2O (250 ml) and washed with water (2×100 ml). The organic was dried again over Na2SO4, filtered and concentrated to give 8.8 g as a brown foam, which was purified by flash-chromatography (100 g SiO2 cartridge, eluting with cyclohexane/EtOAc=60/40, 1/1 and 40/60) to give N-((2S)-5-{[(6-methyl-3-pyridinyl)methyl]oxy}-2,3-dihydro-1H-inden-2-yl)-2-propanesulfonamide (free base) as a pale-yellow solid (3.43 g).
Reaction SMILES: [C:1]([C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])(=[O:3])[NH2:2]>COC(OC)N(C)C>[CH3:4][N:5]([CH:9]=[N:2][C:1]([C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=[O:3])[CH3:6]
Reactant: NC(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: COC(OC)N(C)C
Product: CN(C)C=NC(=O)[C@H]1CCCN1C(=O)OCc1ccccc1

Procedure:
A solution of the amide from Example 33 (1.56 g, 6.28 mmol) in 10 mL of dimethylformamide dimethyl acetal was heated to 120° C. for 2 h. After cooling, the solvent was evaporated under high vacuum and the residue was taken to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[C:6]([O:8][CH2:9][C:10]([N:19](C(OC(OC(=O)C(C)C)C)=O)[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:11][CH3:12])=[O:7].[OH2:39]>>[CH3:38][O:37][C:33]1[CH:32]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:34]=1[O:35][CH3:36])[C:6]([O:8][CH2:9][C:10]([NH:19][CH2:20][C:9]([O:8][CH2:6][C:5]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[CH:3][CH:4]=1)=[O:39])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:11][CH3:12])=[O:7]
Reactant: CCC(COC(=O)c1cc(OC)c(OC)c(OC)c1)(c1ccccc1)N(C)C(=O)OC(C)OC(=O)C(C)C
Reactant: O
Product: CCC(COC(=O)c1cc(OC)c(OC)c(OC)c1)(NCC(=O)OCc1ccc(OC)cc1)c1ccccc1

Procedure:
10 ml water is added to the mixture. The product is extracted with ethyl acetate (3 times 10 mL) then the organic phase is washed successively with water and a saturated solution of sodium chloride (15 mL). The organic phases are dried over Na2SO4, filtered then concentrated to dryness in order to produce a brown oil. The oil is purified by flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate: 85/15) in order to produce 105 mg of the expected product (S) 2-[(1-isobutyryloxy-ethoxycarbonyl)-methyl-amino]-2-phenyl-n-butyl 3,4,5-trimethoxy-benzoate in the form of a colourless oil (yield=15%).
Reaction SMILES: [C:1]1([C:7](=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[SH:18])[C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.II.C(N(CC)CC)C>C(Cl)Cl>[C:1]1([C:7]2[C:8](=[O:9])[N:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:18][C:17]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccccc1)C(=C(S)c1ccccc1)c1ccccc1
Agent: II
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1c(-c2ccccc2)c(-c2ccccc2)sn1-c1ccccc1
Temperature: 25 °C
Yield: 72.7 %

Procedure:
A mixture of 150 mg (0.450 mmol) 2,3,N-triphenyl-3-mercaptopropenamide and 25 mL methylene chloride was stirred at room temperature. Added was 115 mg (1 equiv.) of iodine followed by 116 mg (1 equiv.) of triethylamine and the mixture stirred for one hour. Solvent was evaporated and 50 mL ethyl acetate added and the mixture poured into 50 mL water. The organic layer was separated and washed with three 50 mL portions of water. The organic layer was dried, filtered and solvent was evaporated from the filtrate. The resulting solid was recrystallized from ethanol/water to provide 108 mg (0.327 mmol, 73%) 4,5,N-triphenyl-4-isothiazolin-3-one as a tan solid, mp=175°-176° C. NMR (CDCl3 /TMS): 7.30-7.72 (m, 15H). IR (KBr): 1656. Mass spectrum (CI): M/z=330 (M+H)+. Anal. calcd. for C21H15NOS: C 76.57, H 4.59, N 4.25, S 9.73; Found: C 76.25, H 4.40, N 4.19, S 9.81.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[CH2:4][CH2:5][NH:6][C:7](=[O:39])[C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:21]2[CH:22]=[C:23]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)[C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:40])[CH2:4][CH2:5][NH:6][C:7](=[O:39])[C:8]1[CH:9]=[CH:10][C:11]([CH:14]([C:21]2[CH:22]=[C:23]([C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:34]=3)[C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:13]=1
Reactant: CCCCCC=C(c1ccc(C(=O)NCCC(=O)OC)cc1)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCC(c1ccc(C(=O)NCCC(=O)OC)cc1)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.6 %

Procedure:
To a solution of 3-{4-[1-(6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-hept-1-enyl]-benzoylamino}-propionic acid methyl ester (330 mg) in ethanol (10 mL) is added Pd/C (5%, 20 mg). The system is purged with N2, filled with H2 (30 PSI), stirred at room temperature for 5 h. Then the mixture is filtered through celites, and the filtrate is concentrated to give 3-{4-[1-(6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-heptyl]-benzoylamino}-propionic acid methyl ester (290 mg), hydrolyze by 5N NaOH (0.5 mL) to afford the titled compound. MS (ES): 540.3 [M+H]−.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:19][CH2:18][C:13]3(OCC[O:14]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Cl.O>C(O)C>[F:21][C:2]([F:1])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][C:13](=[O:14])[CH2:18][CH2:19]2)=[CH:6][CH:5]=1
Reactant: FC(F)(F)Oc1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C1CCN(c2ccc(OC(F)(F)F)cc2)CC1
Yield: 80.6 %

Procedure:
A mixture of 8-(4-trifluoromethoxyphenyl)-1,4-dioxa-8-azaspiro[4.5]decane (1.23 g, 4.06 mmol) prepared in Reference Example 21, concentrated hydrochloric acid (5 ml), water (10 ml), and ethanol (30 ml) was heated under reflux for 5 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. To the residue, 10% sodium hydroxide aqueous solution was added, and the mixture was extracted with methylene chloride. The extract was washed with water and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1) to afford 1-(4-trifluoromethoxyphenyl)piperidin-4-one (848 mg, yield 81%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][CH:11]([C:13](O)=[O:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([O:8][CH:9]1[CH2:12][CH:11]([CH2:13][OH:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CC(OCc2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCC1CC(OCc2ccccc2)C1
Yield: 93.8 %

Procedure:
3-benzyloxy-cyclobutanecarboxylic acid (1.67 g) in dry tetrahydrofuran (100 mL) was treated with borane-dimethylsulfide complex (1.3 mL) at 50° C. for 16 hours. Water (4 mL) and saturated sodium hydrogen carbonate (3 mL) were added and the mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate in cyclohexane (0 to 1:1 by volume) to give the title compound (1.46 g). 1H NMR (400 MHz, CHCl3-d): δ 7.29 (d, 5H), 4.36 (d, 2H), 4.08 (t, 1H), 3.91-3.82 (m, 1H), 3.53 (t, 2H), 2.39-2.30 (m, 1H), 2.33-2.22 (m, 1H), 2.10-2.02 (m, 2H), 1.72-1.63 (m, 1H).
Reaction SMILES: [CH2:1]([O:7][C:8]1[C:9](=[O:20])[O:10][C:11]2[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[CH:22]([CH3:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:1]([O:7][C:8]1[C:9](=[O:20])[O:10][C:11]2[C:18]([O:19][CH2:29][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1c(O)c2cccc(O)c2oc1=O
Reactant: CCOC(=O)CC(C)Br
Product: CCCCCCOc1c(O)c2cccc(OCCCC(=O)OCC)c2oc1=O

Procedure:
In the same manner as in Reference Example 3, except that an equimolar amount of 3-hexyloxy-4,8-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-hexyloxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and ethyl 3-bromobutanoate was used in place of ethyl bromoacetate in Reference Example 3, 3-hexyloxy-4-hydroxy-8-(3-ethoxycarbonylpropyloxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: [O-:1]Cl.[Na+].[Cl:4][C:5]1[N:6]=[C:7]2[N:11]([C:12]=1[CH:13]=[O:14])[CH:10]=[CH:9][S:8]2>O.C(O)(C)(C)C>[Cl:4][C:5]1[N:6]=[C:7]2[N:11]([C:12]=1[C:13]([OH:1])=[O:14])[CH:10]=[CH:9][S:8]2
Reactant: O=Cc1c(Cl)nc2sccn12
Reactant: [O-]Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1c(Cl)nc2sccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of NaOCl (230 mmol) and NaH2PO4 (176 mmol) in water (195 mL) is added dropwise to a solution of 6-chloro-imidazo[2,1-b]thiazole-5-carbaldehyde (26.8 mmol) in tert.-butanol (195 mL) and the mixture is stirred for 8 h at RT. The solvents are partially removed in vacuo and the obtained precipitate is filtered off. The filtrate is made acidic and the obtained precipitate is filtered off to give the desired product as a white solid. LC-MS: tR=0.67 min; [M+H]+=202.9.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([OH:13])=[C:5]([C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][C:8]=1[OH:9])[CH3:2].[CH2:14]([O:16][C:17](=[O:20])[CH2:18]Br)[CH3:15]>>[CH2:14]([O:16][C:17](=[O:20])[CH2:18][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:10](=[O:12])[CH3:11])=[C:4]([OH:13])[C:3]=1[CH2:1][CH3:2])[CH3:15]
Reactant: CCOC(=O)CBr
Reactant: CCc1c(O)ccc(C(C)=O)c1O
Product: CCOC(=O)COc1ccc(C(C)=O)c(O)c1CC

Procedure:
1-(3-Ethyl-2,4-dihydroxy-phenyl)-ethanone was treated with 2-bromo-acetic acid ethyl ester and processed as described in the synthesis of example 20a. Yield, 96.89%; mp, 74-75° C.; MS (CI): 267 (M++1).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4].[C-:22]#[N:23].[Na+].O>CCO>[C:22]([CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4])#[N:23]
Reactant: [C-]#N
Reactant: O=C(CCl)Nc1cccc(-c2cnc3ccccc3n2)c1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCC(=O)Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 10.1 %

Procedure:
To a solution of 2-chloro-N-(3-quinoxalin-2-ylphenyl)acetamide (276 mg, 0.93 mmol) in EtOH (8 mL), NaCN (50 mg, 1.02 mmol) was added and the reaction mixture was heated at reflux for 21 hrs. After cooling to room temperature, water (10 mL) was added and the reaction mixture was extracted with ethyl acetate (20 mL). The organic phase was washed with brine (20 mL), dried over MgSO4, and the residue was purified by flash chromatography (Flash Master, 5 g Isolute Silica column, gradient 0 to 5 min hexane, then ethyl acetate up to 50% over 20 min). The isolated solid was triturated with Et2O (10 mL) and filtered to afford 2-cyano-N-[3-(quinoxalin-2-yl)phenyl]acetamide as a light-yellow solid (27 mg, 10% yield). LCMS calculated for C17H12N4O (M+H): 289.30. found 289.00. 1H-NMR (DMSO-d6, 400 Mhz) δH: 10.55 (1H, br. S), 9.52 (1H, s), 8.48 (1H, m), 8.20-8.12 (2H, m), 8.10 (1H, d, J=7 Hz), 7.98-7.80 (3H, m), 7.58 (1H, m), 3.95 (2H, s).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[C:9]([C:10]([OH:12])=[O:11])[C:8]([NH2:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:17]=1[C:18](Cl)=O.FC1C=CC=C(F)C=1C1OC(=O)C2C=C([N+]([O-])=O)C=CC=2N=1.Cl>C(N(CC)CC)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]=[C:18]([C:17]3[C:16]([F:15])=[CH:24][CH:23]=[CH:22][C:21]=3[F:25])[O:11][C:10](=[O:12])[C:9]=2[CH:13]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CC(=O)Nc1ccc(N)c(C(=O)O)c1
Agent: Cl
Agent: O=c1oc(-c2c(F)cccc2F)nc2ccc([N+](=O)[O-])cc12
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc2nc(-c3c(F)cccc3F)oc(=O)c2c1
Yield: 94 %

Procedure:
5-Acetamidoanthranilic acid (0.64g) and 2,6-difluorobenzoyl chloride (1.3 g) were reacted in triethyl amine/toluene (1/1) (20 mL) like described for compound (9), reaction time 1 h. Ethyl acetate (50 mL) and HCl-solution (1 mL 4N in 50 mL water) were added resulting in the formation of a precipitate.The mixture was filtered and the residue dissolved in THF followed by evaporation to dryness, subsequent dissolution in hot dioxane followed by precipitation with hexane resulted in colourless crystals of 6-acetamido-(2,6-difluoro-phenyl)-benzo[d][1,3]oxazin-4-one (0.98 g), mp.246 C, MS m/e.: 316 M+.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH2:38][CH3:39])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:41]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:42]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH2:38][CH3:39])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:41]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:42])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCOC(=O)Cl
Reactant: CCCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCCC)c4ccccc4)ccc3n2C)cc1
Yield: 31 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-n-propyloxycarbonylethyl)-amide-hydrochloride and n-hexyl chloroformate. Yield: 31% of theory, C36H44N6O5 (640.8) Rf value: 0.42 (silica gel; dichloromethane/ethanol=19:1) ##EQU69##