Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([C:12]1[CH:25]=[CH:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:14]=2[CH:13]=1)(=[O:11])[CH3:10]>>[CH:13]1[C:14]2[CH:15]=[CH:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]=2[CH:24]=[CH:25][C:12]=1[C:9](=[O:11])[CH:10]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1ccc2c(ccc3ccccc32)c1
Product: O=C(C=Cc1ccccc1)c1ccc2c(ccc3ccccc32)c1

Procedure:
By a procedure similar to that of example 1.59.1, starting from benzaldehyde and commercial 2-acetylphenanthrene, 1-(2-phenanthrenyl)-3-phenylprop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]3[CH:11]=[C:12]([C:16]#[N:17])[N+:13]([O-])=[CH:14][C:8]=3[N:7]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:6]=2[N:5]=[CH:4][CH:3]=1.P(Cl)(Cl)Cl>ClCCl>[Cl:1][C:2]1[C:10]2[C:9]3[CH:11]=[C:12]([C:16]#[N:17])[N:13]=[CH:14][C:8]=3[N:7]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1c2c[n+]([O-])c(C#N)cc2c2c(Cl)ccnc21
Solvent: ClCCl
Solvent: ClP(Cl)Cl
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(Cl)ccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A solution of 4-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile-7-oxide (1.3 g, 3.52 mmol) in dichloromethane (11 mL) was treated with phosphorus trichloride (2N solution in dichloromethane, 1.9 mL, 3.9 mmol) and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica, 40 g, ISCO, 0-40% ethyl acetate in heptane) to afford the title compound as a white solid (1.2 g, 93%). 1H NMR (400 MHz, CDCl3) δ 9.20 (d, J=0.9, 1H), 8.74 (d, J=0.9, 1H), 8.60 (d, J=5.3, 1H), 7.39 (d, J=5.3, 1H), 6.02 (s, 2H), 3.60 (t, J=8.0, 2H), 0.94 (t, J=8.0, 2H), −0.08 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14](=[S:16])[NH2:15])=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.Br[CH2:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21]>C(#N)C>[Br:1][C:2]1[C:3]([C:14]2[S:16][CH2:18][C:19]([OH:24])([C:20]([F:23])([F:22])[F:21])[N:15]=2)=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1
Reactant: CCNC(=O)Nc1cc(C(N)=S)c(Br)cn1
Reactant: O=C(CBr)C(F)(F)F
Solvent: CC#N
Product: CCNC(=O)Nc1cc(C2=NC(O)(C(F)(F)F)CS2)c(Br)cn1
Temperature: 80 °C
Yield: 96 %

Procedure:
A suspension of 5-bromo-2-(3-ethylureido)pyridine-4-carbothioamide (Intermediate 6, 160 g, 510 mmol), 3-bromo-1,1,1-trifluoroacetone (200 g, 1.02 mol) in acetonitrile (3 L) was heated at 80° C. for 20 h. The solution was then cooled down and concentrated. 2:1 Acetonitrile: methyl tert-butyl ether (2.4 L) was added, and the solution thus obtained was placed on a rotovap, and the volume of solvent was reduced by half. The precipitate that formed was filtered and dried in a vacuum oven at 40° C. After letting the filtrate sit, more solid precipitated out and an additional two crops of precipitate were collected and dried in the vacuum oven at 40° C. resulting in a combined collection of 202.4 g (92%) of 1-(5-bromo-4-(4-hydroxy-4-(trifluoromethyl)-4,5-dihydrothiazol-2-yl)pyridin-2-yl)-3-ethylurea as pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[C:10](O)[C:9]2[C:4](=[C:5]([C:14]([F:17])([F:16])[F:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:10]1[C:9]2[C:4](=[C:5]([C:14]([F:17])([F:16])[F:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[C:11]=1[CH3:12]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2c(C(F)(F)F)cccc2c(O)c1C
Product: Cc1nc2c(C(F)(F)F)cccc2c(Cl)c1C

Procedure:
Prepared according to procedure S using 2,3-dimethyl-8-(trifluoromethyl)-quinolin-4-ol (1.25 g, 5.18 mmol) in POCl3 (7 mL). The resulting precipitate was collected by filtration to give 4-chloro-2,3-dimethyl-8-(trifluoromethyl)quinoline. Mass Spectrum (ESI) m/e=260 (M+1).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40](O)=[O:41].Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:18]([CH:20]2[CH2:21][CH2:22][N:23]([C:40]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=3)=[O:41])[CH2:24][CH2:25]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C1CCNCC1)N(CCCN1CCC(Cc2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(c1ccccn1)N1CCC(C(=O)N(CCCN2CCC(Cc3ccccc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.2 %

Procedure:
To the solution of the compound obtained in Example 66 (391 mg, 0.80 mmol), picolinic acid (108 mg, 0.88 mmol) and 1-hydroxbenzotriazole (119 mg, 0.88 mmol) in DMF (8 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (307 mg, 1.60 mmol), and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and to the concentrate were added a saturated aqueous solution of sodium hydrogen carbonate (15 mL) and water (5 mL). The mixture was extracted with ethyl acetate (15 mL×5). The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate (5 mL×3), saturated sodium chloride solution (5 mL), successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 10 g, ethyl acetate/methanol=1/0 to 9/1), and the desired fraction was concentrated under reduced pressure to give the titled compound (433 mg, 0.73 mmol, Yield 91%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20]I.[C:22]([C:26]1[CH:27]=[C:28]([C:37]2[O:38][CH:39]=[C:40]([CH2:42][CH2:43]O)[N:41]=2)[CH:29]=[C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:31]=1[OH:32])([CH3:25])([CH3:24])[CH3:23].N1C=CN=C1>C(Cl)Cl>[C:22]([C:26]1[CH:27]=[C:28]([C:37]2[O:38][CH:39]=[C:40]([CH2:42][CH2:43][I:20])[N:41]=2)[CH:29]=[C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:31]=1[OH:32])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)c1cc(-c2nc(CCO)co2)cc(C(C)(C)C)c1O
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(-c2nc(CCI)co2)cc(C(C)(C)C)c1O
Yield: 96.1 %

Procedure:
A solution of triphenylphosphine (118.8 mmole, 31.12 g), in methylene chloride (460 ml) was treated with iodine (approximately 30.17 g) until a dull yellow color persisted. The reaction stirred fifteen minutes, then a solution of 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-(2-hydroxyethyl)oxazole (79.2 mmole, 25.10 g) and imidazole (158.3 g, 10.77 g) in methylene chloride (300 ml) was added over a ten minute period. At 3.0 hours the reaction was concentrated in vacuo then taken up into methylene chloride and subjected to flash silica gel filtration. Desired product was eluted with 1:1 ethyl acetate:hexane, collecting 500 ml fractions. Desired fractions were combined, washed with 1×250 ml 1N sodium thiosulfate and 1×250 ml brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 32.53 g (96%) of the title compound.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH3:9].[F:10][C:11]([F:26])([F:25])[C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[C:15](Cl)=[O:16]>CCCCCCC.CCOC(C)=O>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:9])[C:15](=[O:16])[C:14]1[CH:13]=[C:12]([C:11]([F:26])([F:25])[F:10])[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1I
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1I

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from (4-iodo-pyridin-3-yl)-methyl-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 40:60) for the chromatographic purification. Light yellow solid (18%). MS (ESI): m/z=474.9738 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2[C:6](=O)[C:7]3[N:8]([CH:9]=[CH:10][CH:11]=3)[C:4]=2[CH:3]=[CH:2]1.Cl.[NH2:14][OH:15]>N1C=CC=CC=1>[OH:15][N:14]=[C:6]1[C:5]2[S:1][CH:2]=[CH:3][C:4]=2[N:8]2[CH:9]=[CH:10][CH:11]=[C:7]12
Reactant: NO
Reactant: O=C1c2sccc2-n2cccc21
Agent: Cl
Solvent: c1ccncc1
Product: ON=C1c2sccc2-n2cccc21
Yield: 82.8 %

Procedure:
Heat at reflux for 90 minutes a solution of 0.011 mol of 8H-thieno[2,3-d]pyrrolo[1,2-a]pyrrol-8-one (Preparation 28) and 0.0132 mol of hydroxylamine hydrochloride in 50 ml of pyridine. After cooling and after removal of the pyridine under reduced pressure, the residue is taken up in 150 ml of water and extracted with diethyl ether. The ethereal solution is dried over magnesium sulfate and then concentrated under reduced pressure to yield the title compound in the form of a mixture comprising 70% of the Z form, 30% of the E form.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13](F)[C:12]([F:16])=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[Cl:17][C:18]1[CH:19]=[C:20]([OH:32])[CH:21]=[N:22][C:23]=1[O:24][CH2:25][CH:26]1[CH2:29][C:28]([F:31])([F:30])[CH2:27]1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CS(C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([O:32][C:13]2[C:12]([F:16])=[CH:11][C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[C:2]([F:1])[CH:14]=2)[CH:21]=[N:22][C:23]=1[O:24][CH2:25][CH:26]1[CH2:27][C:28]([F:30])([F:31])[CH2:29]1
Reactant: Oc1cnc(OCC2CC(F)(F)C2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(F)c(Oc2cnc(OCC3CC(F)(F)C3)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.7 %

Procedure:
tert-Butyl 2,4,5-trifluorobenzoate (Preparation 6, 0.200 g, 0.86 mmol), 5-chloro-6-[(3,3-difluorocyclobutyl)methoxy]pyridin-3-ol (Preparation 5, 0.258 g, 1.03 mmol) and potassium carbonate (0.178 g, 1.29 mmol) were suspended in DMSO (5.0 mL). The mixture was stirred at room temperature under nitrogen for 16 hours. EtOAc (50 mL) was added and the mixture was washed with water (3×150 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (0.400 g, 101%):
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[NH:23][C:22]3[C:17]2=[N:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[N:20][C:21]=3[NH2:26])=[CH:7][CH:6]=1.Cl.[CH3:34][N:35]([CH3:40])[CH2:36][C:37](Cl)=[O:38].C(N(CC)CC)C>CC#N>[CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[NH:23][C:22]3[C:17]2=[N:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[N:20][C:21]=3[NH2:26])[C:37](=[O:38])[CH2:36][N:35]([CH3:40])[CH3:34])=[CH:7][CH:6]=1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCc3ccc(CC(=O)OC)cc3)c2n1
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3ccc(CC(=O)OC)cc3)C(=O)CN(C)C)c2n1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
The product of example 1, step (ix) (200 mg) was suspended in MeCN. N,N-dimethylglycyl chloride hydrochloride (110 mg) and triethylamine (0.19 ml) were added and the mixture stirred at rt for 10 h. The mixture was purified by RPHPLC. Yield 100 mg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:18](=[O:48])[C:19]2[C:24]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][C:22]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:21][C:20]=2[O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:55](Br)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1.O>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:10]([C:18]([C:19]2[C:20]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:21][C:22]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:23][C:24]=2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:48])=[C:11]([C:12]([O:14][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[O:13])[CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c(C(=O)c2c(OCc3ccccc3)cccc2C(=O)O)c(OCc2ccccc2)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c(C(=O)c2c(OCc3ccccc3)cccc2C(=O)OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 73 %

Procedure:
To a solution of 5.98 g (9.28 mmol) of 3-benzyloxy-2-(2,6-dibenzyloxy-4-(1,1-dimethylethoxycarbonyl)benzoyl)benzoic acid in 75 mL of dry dimethylformamide was added 3.85 g (27.9 mmol) of potassium carbonate and 1.21 mL (1.74 g, 10.2 mmol) of benzyl bromide. The solution was stirred at room temperature under a nitrogen atmosphere for 13 h. The mixture was then poured onto 800 mL of water and extracted with three 400 mL portions of ether. The organic extracts were washed twice with water and then with brine, and dried over magnesium sulfate. Evaporation of the solvent afforded 6.76 g of the crude product, which was chromatographed on silica gel, eluting with 4/1 hexane-ethyl acetate to give 4.98 g (73%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23]([OH:25])=O)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[CH3:46][O:47][CH2:48][CH2:49][CH2:50][NH2:51]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23](=[O:25])[NH:51][CH2:50][CH2:49][CH2:48][O:47][CH3:46])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)O)n2)cc1Cl
Reactant: COCCCN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COCCCNC(=O)CCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
To a solution containing 3-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid (prepared in example 9, 50 mg, 0.11 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (59 μL, 0.12 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (17 μL, 0.14 mmol) was added to the solution at 0° C. After 1 h, 3-methyoxypropylamine (12 μL, 0.11 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-{1-[2-(3-methoxy-propylcarbamoyl)-ethyl]-1H-pyrazol-3-yl}-propionamide (16 mg, 27%) as a white solid: ESI-LRMS m/e calcd for C25H35ClN4O5S [M+] 538.2, found 539.5 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.08-1.21 (m, 2H, CH2), 1.43-1.97 (m, 10H, 5×CH2), 2.17-2.28 (m, 1H, CH), 2.61 (t, J=6.3 Hz, 2H, COCH2), 3.26 (s, 3H, SO2CH3), 3.27-3.34 (m, 2H, CONCH2), 3.31 (s, 3H, OCH3), 3.41-3.46 (m, 2H, OCH2), 3.55 (t, J=7.5 Hz, 1H, CH), 4.30 (t, J=6.3 Hz, 2H, NCH2), 6.19 (brm, 1H, NH), 6.60 (d, J=2.3 Hz, 1 H, Ar), 7.29 (d, J=2.3 Hz, 1H, Ar), 7.46 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.60 (d, Jm=1.7 Hz, 1H, Ar), 8.08 (d, Jo=8.2 Hz, 1H, Ar), 8.13 (s, 1H, NH).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:14]=[CH:15][CH:16]=1)=O)(C)(C)C.[ClH:23]>C(O)C>[ClH:23].[CH2:21]([O:20][C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[CH2:10][CH2:9][NH2:8])=[O:19])[CH3:22]
Reactant: CCOC(=O)Nc1cccc(CCNC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Nc1cccc(CCN)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3-(2-t-Butoxycarbonylaminoethyl)-ethoxycarbonylaminobenzene (14.96 g, Production Example 36b) was dissolved in ethanol (15 ml), to which was then added hydrochloric acid (15 ml) under ice-cooling, followed by stirring at room temperature for 20 minutes. Hydrochloric acid (12 ml) and ethanol (15 ml) were added thereto, followed by stirring at room temperature for 20 minutes. Then, hydrochloric acid (20 ml) and ethanol (30 ml) were further added thereto, followed by stirring at room temperature for 30 minutes. After evaporating (subjecting azeotropic distillation together with toluene) the solvent, the title compound (11.99 g) was obtained as pale yellow crystals.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:40])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:39])[CH2:12][CH2:13][C@@:14]3([CH:31]([CH:33]4SCCCS4)[OH:32])[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:30])[CH3:29])=[C:15]32)[C:6]1([CH3:42])[CH3:41])(=[O:3])[CH3:2].C1C(=O)N(Br)C(=[O:46])C1>C(#N)C.O>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:40])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:39])[CH2:12][CH2:13][C@@:14]3([CH:31]([OH:32])[CH:33]=[O:46])[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:30])[CH3:29])=[C:15]32)[C:6]1([CH3:42])[CH3:41])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@H]4C5=C(C(C)C)C(=O)C[C@]5(C(O)C5SCCCS5)CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Product: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@H]4C5=C(C(C)C)C(=O)C[C@]5(C(O)C=O)CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
To a solution of 103 (1.2 g, 1.945 mmol) in acetonitrile (20 ml) and water (5.00 ml) stirred in air at rt was added NBS (1.385 g, 7.78 mmol) in one charge. The reaction mixture was stirred at rt for 0.5 h, then quenched with Na2SO3 (solid), concentrated and the residue was extracted with EtOAc. The organic phase was washed with water and saturated brine, dried over sodium sulphate and concentrated in vacuo to give (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(1-hydroxy-2-oxoethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (104) (1.09 g, 1.083 mmol, 55.7% yield) as a light yellow solid which was used without further purification.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH2:13])=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>CN(C1C=CN=CC=1)C.C1COCC1>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][C:30]([F:29])=[CH:31][CH:32]=2)=[N:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccccc2)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nc(NC(=O)c3ccc(F)cc3)sc2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a 50 ml eggplant-shaped flask were added 1.00 g (3.37 mmol) 5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 1, 0.68 g (6.75 mmol) triethylamine, 30 mg (0.25 mmol) DMAP and 25 ml THF, and then added dropwise 0.53 g (3.37 mmol) p-fluorobenzoyl chloride dissolved in 5 ml THF. The resulting mixture was stirred at room temperature for 2 hours, elevated to 35-40° C. and allowed to react for 10 hours, filtrated, washed with THF, the mother liquid was concentrated under a reduced pressure to give a pale brown oily crude product, separated with 50 ml ethyl acetate and 10 ml 1N HCl, the organic layer separated was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was recrystallized with ethyl acetate/petroleum ether (1:2) to obtain a 1.10 g product as a white solid in a yield of 78.0%, mp: 164-165 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.77 (3H, s, OCH3), 4.22 (2H, s, CH2), 6.76 (2H, d, J=7.84 Hz, ArH), 6.94 (2H, t, 3JFH=3JHH=8.40 Hz, ArH), 7.24˜7.36 (7H, m, ArH), 7.71 (2H, dd, 3JHH=7.56, 4JFH=5.32 Hz, ArH), 11.62 (1H, br, CONH); EI-MS m/e (%): 418.2 (M+, 100), 123.0 (86); HREI-MS Calcd. for C24H19FN2O2S: 418.1151. found: 418.1138. Anal. Calcd. for C24H19FN2O2S: C, 68.88; H, 4.58; N, 6.69. found: C, 68.77; H, 4.48; N, 6.84.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2[O:14][CH:15]=[CH:16][C:10]=2[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[O:14]1[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]=2[CH:16]=[CH:15]1
Reactant: c1ccc(CN2CCc3occc3C2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: c1cc2c(o1)CCNC2

Procedure:
5-Benzyl-4,5,6,7-tetrahydro-furo[3,2-c]pyridine (410 mg, 1.9 mmol) was dissolved in ethanol (4 ml), and the solution was mixed with 10% palladium on activated carbon (80 mg) and stirred at room temperature for 15 hours in an atmosphere of hydrogen. The reaction solution was filtered to remove 10% palladium on activated carbon, and the solvent was removed by evaporation under a reduced pressure to obtain crude 4,5,6,7-tetrahydro-furo[3,2-c]pyridine. This compound and 2a-(4-bromobutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (590 mg, 1.9 mmol) and potassium carbonate (400 mg, 2.9 mmol) were stirred at room temperature for 18 hours in anhydrous N,N-dimethylformamide (4 ml). The reaction solution was mixed with ethyl acetate, washed with water and saturated brine and then dried with anhydrous magnesium sulfate. The solvent was removed by evaporation from the organic layer under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 94 mg (0.27 mmol, 14% in yield) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])=[CH:8][CH:7]=1)[CH3:2].[N+:24]([O-])([OH:26])=[O:25]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:23])[NH:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])=[CH:10][C:11]=1[N+:24]([O-:26])=[O:25])[CH3:2]
Reactant: CCOC(=O)Nc1ccc(N2C(=O)c3ccccc3C2=O)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCOC(=O)Nc1ccc(N2C(=O)c3ccccc3C2=O)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
(4-Phtalimido-phenyl)-carbamic acid ethyl ester (99.0 g, 0.32 mol) is suspended in glacial acetic acid (1.5 L) and heated to 90° C. Fuming nitric acid (17.2 mL, 0.41 mol) is added dropwise over 30 minutes at 90-95° C. The reaction mixture is then stirred at 100° C. for 1 hour and cooled to ambient temperature. Crystallised solids are filtered off and washed with glacial acetic acid (500 mL), water (1 L) and diethylether (1 L) on the filter, then dried in vacuo to furnish 101 g (90%) of the title compound as a yellow solid. LC/MS (m/z) 355.0 (MH+); tR=3.34 min. 1H NMR (DMSO-d6): 1.25 (t, 3H); 4.16 (q, 2H); 7.81 (m, 2H); 7.93 (ddd, 2H); 7.99 (ddd, 2H); 6.15 (dd, 1H); 9.99 (s, 1H, NH).