Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][NH2:3].[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([CH:19]=O)=[CH:17][N:18]=3)[CH:15]=2)[CH:5]=1.[CH2:21]([N:28]=[C:29]=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([NH:28][C:29]([N:2]([CH3:1])/[N:3]=[CH:19]/[C:16]1[N:14]2[CH:15]=[C:10]([C:6]3[CH:5]=[N:4][CH:9]=[CH:8][CH:7]=3)[CH:11]=[CH:12][C:13]2=[N:18][CH:17]=1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CNN
Reactant: O=Cc1cnc2ccc(-c3cccnc3)cn12
Reactant: O=C=NCc1ccccc1
Product: CN(/N=C/c1cnc2ccc(-c3cccnc3)cn12)C(=O)NCc1ccccc1
Temperature: 85 °C
Yield: 41 %

Procedure:
Methyl hydrazine (41.25 mg, 0.8968 mmoles) was added to ethanolic solution of 6-(pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbaldehyde (100 mg, 0.4484 mmoles) at RT. The reaction mixture was heated at 85° C. for 1.5 hours. The solvent was then evaporated. The residue was dissolved in ethanol (5 ml), followed by addition of benzyl isocyanate (140.58 mg, 0.6726 mmoles). The reaction mixture was refluxed for 2 hours, then the solvent was evaporated. Water was poured into the residue and the aqueous solution was extracted with chloroform. Organic layer was separated, washed with water and brine and dried over sodium sulfate. The crude product was purified by column chromatography (100-200 mesh size silica gel, 1.5% methanol in chloroform). Yield: 41%; 1HNMR (DMSO-d6; 300 MHz): δ 9.48 (s, 1H), 9.05 (s, 1H), 8.58 (s, 1H), 8.21 (m, 3H), 7.98 (s, 1H), 7.80 (s, 2H), 7.29 (m, 6H), 4.39 (d, 2H, J=4.2 Hz), 3.35 (s, 3H); MS: m/z 384 (M+1)+.
Reaction SMILES: [C:1]([N:9]([C:18]1[N:22]([C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[N:28]([CH3:32])[CH:27]=[CH:26]3)[C:21]([C:33]2[CH:38]=[C:37]([CH:39]([CH3:41])[CH3:40])[C:36]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:35][C:34]=2[O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[N:20][N:19]=1)C(=O)C1C=CC=CC=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:51]([O:50][C:34]1[CH:35]=[C:36]([O:42][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:37]([CH:39]([CH3:41])[CH3:40])=[CH:38][C:33]=1[C:21]1[N:22]([C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[N:28]([CH3:32])[CH:27]=[CH:26]3)[C:18]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:19][N:20]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: CC(C)c1cc(-c2nnc(N(C(=O)c3ccccc3)C(=O)c3ccccc3)n2-c2ccc3c(ccn3C)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)c1cc(-c2nnc(NC(=O)c3ccccc3)n2-c2ccc3c(ccn3C)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 16 h

Procedure:
A flask was charged with [5-(5-Isopropyl-2,4-dibenzyloxy-phenyl)-4-(1-methyl-1H-indol-5-yl)-4H-[1,2,4]triazol-3-yl]-phenyl-amine (0.33 mmol, 183 mg.), dichloromethane (10 mL), diisopropylethylamine (3 eq., 0.2 mmol), and benzoyl chloride (2 eq., 70 mg.), and the reaction was stirred for 16 hours. The organic solution was washed with saturated ammonium chloride (2×5 mL), dried and the product was purified by column chromatography to give N-(5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)benzamide and also N-benzoyl-N-(5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)benzamide. The N-benzoyl-N-(5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)benzamide was dissolved in methanol (5 mL), and 10% aqueous potassium carbonate (1 mL) was added, and the reaction was stirred for 16 hours. The solvent was then evaporated, and the solid was dissolved in ethyl acetate (10 mL), washed with water (2×5 mL), dried and evaporated to give more N-(5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)benzamide. The N-(5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)benzamide was hydrogenolyzed in a fashion analogous to N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)acetamide (Compound 4) to give N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)benzamide. MS: expected ion=467.2; observed ion=467.3.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:24])[CH:16]2[C:7]([CH3:22])([C:8]3[C:9](=[O:21])[CH:10]=[C:11]([CH:18]([CH3:20])[CH3:19])[C:12](=[O:17])[C:13]=3[CH2:14][CH2:15]2)[CH2:6][CH2:5][C:4]1=[O:23].[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([O:1][CH2:2][C:3]1([CH3:24])[CH:16]2[C:7]([CH3:22])([C:8]3[C:9](=[O:21])[CH:10]=[C:11]([CH:18]([CH3:20])[CH3:19])[C:12](=[O:17])[C:13]=3[CH2:14][CH2:15]2)[CH2:6][CH2:5][C:4]1=[O:23])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)C1=CC(=O)C2=C(CCC3C(C)(CO)C(=O)CCC23C)C1=O
Solvent: c1ccncc1
Product: CC(=O)OCC1(C)C(=O)CCC2(C)C3=C(CCC12)C(=O)C(C(C)C)=CC3=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture consisting of 60 mg of the 5,6,8,8a,9,10-hexahydro-8-hydroxymethyl-4b,8-dimethyl-2-(1-methylethyl)-1,4,7(4bH)-phenanthrenetrione obtained in Example 2, 0.1 ml of acetic anhydride and 1 ml of pyridine was stirred at room temperature for 2.5 hours. The reaction mixture was poured into ice water, and extracted with ether. The organic layer was washed with an aqueous saturated with sodium chloride, dried with anhydrous magnesium sulfate, and concentrated. The resulting crude product was purified by a silica gel column chromatography (eluant: ether/n-hexane=1/2) to obtain 41 mg of 8-(acetoxymethyl)-5,6,8,8a,9,10-hexahydro-4b,8-dimethyl-2-(1-methylethyl)-1,4,7(4bH)-phenanthrenetrione.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:18][CH2:19][N:20]([CH2:25][CH2:26]Cl)[S:21]([CH3:24])(=[O:23])=[O:22].O>C(N(CC)C(C)C)(C)C>[C:13]([O:12][C:10]([NH:9][CH2:8][C@@H:3]([N:2]1[CH2:26][CH2:25][N:20]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:19][CH2:18]1)[C:4]([O:6][CH3:7])=[O:5])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)[C@H](N)CNC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)N(CCCl)CCCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)[C@@H](CNC(=O)OC(C)(C)C)N1CCN(S(C)(=O)=O)CC1
Reaction time: 18 h
Yield: 44.1 %

Procedure:
A solution of 6 g (23.6 mmol) of methyl (R)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride and 5.2 g (23.6 mmol) of N,N-bis(2-chloroethyl)methanesulphonamide in 80 ml of N,N-diisopropylethylamine is heated at 125° C. with vigorous stirring for 18 h. After addition of water, the product is extracted with ethyl acetate. The organic phases are combined, washed with water, dried over magnesium sulphate, filtered and concentrated under vacuum. The crude product obtained is purified by chromatography over silica gel eluted with a 5/5 heptane/ethyl acetate mixture. 3.8 g (44%) of methyl (R)-3-tert-butoxycarbonylamino-2-(4-methanesulphonylpiperazin-1-yl)propanoate are obtained in the form of a white solid.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1.CI.[C:19]([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:19][S:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCc2ccc(S)cc2O1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CCOC(=O)C1CCc2ccc(SC)cc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
A mixture of ethyl 7-mercaptochromane-2-carboxylate (3.4 g, 14.3 mmol), Methyliodide (3.03 g, 21.4 mmol) and K2CO3 (7.88 g, 57 mmol) in ACN (100 ml) was stirred for 2 h at RT. Filtration and evaporation of solvents gave the title compound (3.28 g). MS m/z (rel. intensity, 70 eV) 252 (M+, bp), 179 (94), 177 (40), 132 (55), 131 (63).
Reaction SMILES: [C:1]1([N:7]2[C:15]([NH2:16])=[C:14]3[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]1([N:7]2[C:15]([N:16]=[CH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:14]3[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]3)=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1c2ccccc2nn1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: C(=Nc1c2ccccc2nn1-c1ccccc1)c1ccccc1
Yield: 107.1 %

Procedure:
To a solution of 2-phenyl-2H-indazol-3-amine (300 mg, 1.4 mmol; Shirtcliff, Laura D.; Rivers, Jazmin; Haley, Michael M, Journal of Organic Chemistry (2006), 71(17), 6619-6622) in CH2Cl2 (16 ml) was added benzaldehyde (730 μl, 7.2 mmol; [100-52-7]), acetic acid (220 ul, 4.3 mmol) and sodium triacetoxyborohydride (912 mg, 4.3 mmol) at ambient temperature under an argon atmosphere. The reaction mixture was heated under reflux conditions for 64 h, poured onto ice water/aqueous NaHCO3 solution 1/1 and extracted two times with CH2Cl2. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure, the resulting yellow oil was purified by column chromatography (silica gel, iPrOAc/heptane) to give the title compound (470 mg, 1.5 mmol; quant.) as yellow solid. MS: m/e=298.1 [M+H+].
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH2:22])=[CH:18][CH:17]=1.[CH3:23][O:24][C:25]1[C:30]([CH:31]=O)=[CH:29][CH:28]=[CH:27][N:26]=1>>[CH3:23][O:24][C:25]1[C:30]([CH2:31][NH:1][C:4]2[C:5]3[CH:6]=[CH:7][C:8]([NH:22][CH2:21][C:19]4[O:20][C:16]([CH3:15])=[CH:17][CH:18]=4)=[N:9][C:10]=3[CH:11]=[CH:12][CH:13]=2)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: Cc1ccc(CN)o1
Reactant: COc1ncccc1C=O
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: COc1ncccc1CNc1cccc2nc(NCc3ccc(C)o3)ccc12

Procedure:
The title compound, MS: m/e=375.1 (M+H+), was prepared from 5-nitro-2-chloroquinoline, 5-methyl-2-furanmethanamine and 2-methoxy-3-pyridinecarboxaldehyde as described in example 26.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]([CH:11]=[CH2:12])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S([CH2:23][N+:24]#[C-:25])(C1C=CC(C)=CC=1)(=O)=O.[OH2:26]>C(OCC)C.CS(C)=O>[C:9]([C:11]1[CH:12]=[CH:25][NH:24][CH:23]=1)(=[O:26])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O
Reactant: C=CC(=O)c1ccccc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: O=C(c1ccccc1)c1cc[nH]c1

Procedure:
To a stirred suspension of sodium hydride (8.0 g) in 200 ml of dry ethyl ether was added dropwise a solution of phenylvinylketone (13.22 g) and tosylmethyl isocyanide (19.52) in 150 ml of dry methyl sulfoxide and 300 ml of dry ethyl ether at such a rate that the ether refluxed gently. After complete addition, the suspension was stirred at room temperature for 30 minutes and subsequently hydrolyzed by dropwise addition of 200 ml of water. The ether layer was separated and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with water, 0. 1N sulfuric acid, and again with water. The organic phase was dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel, DCM/ethyl acetate, 5:1). The desired fractions were concentrated and the residual oil was crystallized from DCM/hexane, affording the product as crystals (7.11 g), m.p. 98°-99° C. (lit* m.p. 6°-97° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[N:10]1>CCOC(C)=O.CCO.O=[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]1
Reactant: COc1cccc(OCCn2cc([N+](=O)[O-])cn2)c1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cccc(OCCn2cc(N)cn2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(2-(3-methoxyphenoxy)ethyl)-4-nitro-1H-pyrazole (533 mg, 1.90 mmol), in EtOAc (2 mL, degassed) and EtOH (6 mL, degassed), PtO2 (42 mg, 0.19 mmol) was added and the reaction mixture was stirred at rt under a H2-atmosphere for 3 h. The mixture was diluted with EtOH, filtered over celite and the filter cake was rinsed with EtOH. The filtrate was concentrated to obtain the title compound as a pale brown oil. LC-MS conditions A: tR=0.53 min, [M+H]+=234.41.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:26]4[CH:31]=[CH:30][C:29](CCCCCCCCBr)=[CH:28][CH:27]=4)[C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][C:15]([C:20]2[S:21][C:22]([CH3:25])=[CH:23][CH:24]=2)=[CH:14][CH:13]=4)=[CH:4][CH:3]=1.[C:41]([O-:44])(=[S:43])[CH3:42].[K+].[OH2:46]>O1CCCC1.C(O)C>[C:41]([O:44][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:7][CH2:19][CH2:18][O:46][C:29]1[CH:30]=[CH:31][C:26]([N:11]2[C:12]3[CH:13]=[CH:14][C:15]([C:20]4[S:21][C:22]([CH3:25])=[CH:23][CH:24]=4)=[CH:16][C:17]=3[C:18]3[C:10]2=[CH:9][CH:8]=[C:7]([C:5]2[S:6][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:19]=3)=[CH:27][CH:28]=1)(=[S:43])[CH3:42]
Reactant: Cc1ccc(-c2ccc3c(c2)c2cc(-c4ccc(C)s4)ccc2n3-c2ccc(CCCCCCCCBr)cc2)s1
Reactant: O
Reactant: CC([O-])=S
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=S)OCCCCCCCCOc1ccc(-n2c3ccc(-c4ccc(C)s4)cc3c3cc(-c4ccc(C)s4)ccc32)cc1
Temperature: 25 °C

Procedure:
The obtained 3,6-bis(5-methylthiophen-2-yl)-9-[4-(8-bromooctyl)phenyl]carbazole (1.50 g, 2.3 mmol) was dissolved in a solvent mixture of tetrahydrofuran (THF) (20 mL) and ethanol (20 mL). Under nitrogen flow, potassium thioacetate (0.40 g, 3.5 mmol) was added to the resultant solution, and the mixture was refluxed for 5 hours and left to cool to room temperature. Next, the resultant mixture was poured to water, followed by extraction with methylene chloride. In addition, the mixture was washed with water and dried and the solvent was evaporated, to thereby a pale yellowish-white solid. The obtained solid was purified through silica gel column chromatography using as an eluent a solvent mixture of methylene chloride/hexane (13/7 by volume), to thereby obtain 1.22 g of 8-{4-[3,6-bis(5-methylthiophen-2-yl)carbazol-9-yl]phenoxy}octyl thioacetate.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([CH:11]1[CH2:15][S:14][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH2:23][CH2:24][O:25][N+:26]([O-:28])=[O:27])[NH:12]1)([OH:10])=[O:9].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[C:1]([N:12]1[CH:11]([C:8]([OH:10])=[O:9])[CH2:15][S:14][CH:13]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH2:23][CH2:24][O:25][N+:26]([O-:28])=[O:27])(=[O:3])[CH3:2]
Reactant: O=C(O)C1CSC(c2ccccc2OCCO[N+](=O)[O-])N1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1C(C(=O)O)CSC1c1ccccc1OCCO[N+](=O)[O-]
Reaction time: 1 h
Yield: 60 %

Procedure:
A solution of 0.9 ml of acetic anhydride in THF was added slowly at 0° C. to a solution of 2 g of the compound from Example XVI and 2.1 g of potassium carbonate in H2O. The resulting solution was stirred for 1 hour, after which 1.0 g of potassium carbonate was added to the reaction mixture, followed by the addition of 1 ml of acetic anhydride. The reaction mixture was stirred for one and a half hours, after which a further 1.0 g of potassium carbonate and 1 ml of acetic anhydride were added. After finally stirring for a further 30 minutes, the solution was concentrated under vacuum and cooled in ice. The addition of dilute sulphuric acid gave a precipitate. This precipitate was filtered off, dried and recrystallised from methanol/ether. Yield 60%. Empirical formula C14H16N2O7S. Molecular weight 356. Melting point 159°-162° C. TLC system: ethyl acetate:methanol/1:1. Rf 0.50.
Reaction SMILES: [SiH:1]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:2][CH3:3].[C:8]([O:11][CH:12]=[CH2:13])(=[O:10])[CH3:9].CCOC(C)=O>C1(C)C=CC=CC=1.C1CCCCC1>[CH2:2]([Si:1]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:13][CH2:12][O:11][C:8](=[O:10])[CH3:9])[CH3:3]
Reactant: C=COC(C)=O
Reactant: CC[SiH](CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CC[Si](CC)(CC)CCOC(C)=O
Reaction time: 0.08 h

Procedure:
To a solution of 6.39 mL (40 mmol) of Et3SiH and 3.69 mL (40 mmol) of vinyl acetate in 40 mL of toluene is added 61.3 mg (0.16 mmol) of Rh2Cl2 (CO)4. Caution: the reaction evolves heat and gas. Within about 5 min, the reaction mixture darkens in color. Reaction is judged complete by TLC analysis (10% EtOAc in cyclohexane) after 1 h. The reaction is worked up and purified, if desired, as in example 1a.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25](C(=O)N)[CH:24]=3)=[C:18]([F:32])[CH:17]=2)[C:8]([C:10]2([C:13]([NH2:15])=[O:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[N:35]1C=CC=CC=1.O.FC(F)(F)C(=O)OI(C1C=CC=CC=1)OC(C(F)(F)F)=O>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH2:35])[CH:24]=3)=[C:18]([F:32])[CH:17]=2)[C:8]([C:10]2([C:13]([NH2:15])=[O:14])[CH2:11][CH2:12]2)=[O:9])=[CH:33][CH:34]=1
Reactant: NC(=O)c1cc(Oc2ccc(N(Cc3ccc(F)cc3)C(=O)C3(C(N)=O)CC3)cc2F)ccn1
Reactant: c1ccncc1
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)C1(C(=O)N(Cc2ccc(F)cc2)c2ccc(Oc3ccnc(N)c3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-(4-fluorobenzyl)-N-(4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenyl)cyclopropane-1,1-dicarboxamide (25 mg, 0.05 mmol) in DMF (1 mL) at room temperature was added pyridine (0.2 mL), water (0.1 mL), and [bis(trifluoroacetoxyl)-iodo]benzene (Aldrich, 34 mg, 0.08 mmol). The reaction mixture was stirred at rt for 2 h, and then quenched by adding 2 mL of methanol. The reaction mixture was purified by prep. HPLC. The desired fractions were combined, neutralized with aq. K2HPO4, concentrated and extracted with ethyl acetate. The organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was dissolved in a small amount of CH3CN/H2O and lyophillized to dryness to give the title comopound (21 mg, 90%) as a white solid. 1H NMR (DMSO-d6) δ 10.87 (br s, 1H), 8.44 (t, 1H, J=6.0 Hz), 7.91 (d, 1H, J=6.6 Hz), 7.88 (d, 1H, J=13.2 Hz), 7.37-7.29 (m, 6H), 7.13 (t, 2H, J=8.8 Hz), 4.29 (d, 2H, J=6.1 Hz), 1.38 (d, 4H, J=2.2 Hz); MS(ESI+) m/z 439.14 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH:17]2[CH2:30][C:29]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])[CH:27]=4)[N:22]=[CH:21][C:20]=3[O:19][CH:18]2[O:33]C(=O)C)[CH2:13][CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl.ClCCl>C(O)C.CO>[C:3]([O:7][C:8](=[O:9])[NH:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([CH:17]([CH2:30][C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])[CH:27]=3)[N:22]=[CH:21][C:20]=2[OH:19])[CH2:18][OH:33])[CH2:15][CH2:16]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: COc1ccc2ncc3c(c2c1)CC([C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)C(OC(C)=O)O3
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc2ncc(O)c(CC(CO)[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (920 mg, 24.2 mmol, 6.0 eq) is added at room temperature to a stirred solution of acetic acid 3-(trans-4-tert-butoxycarbonylamino-cyclohexyl)-6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-2-yl ester (1.90 g, 4.04 mmol, 1.0 eq) in ethanol (120 mL). After 1 hour stirring at room temperature, the reaction mixture is acidified with a 1N hydrochloric acid aqueous solution to pH 4. Solvent is evaporated and the residue is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 25:1 to 15:1, v/v) to afford {trans-4-[2-hydroxy-1-(3-hydroxy-6-methoxy-quinolin-4-ylmethyl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester as a white solid (1.26 g, 65% yield).
Reaction SMILES: [CH2:1]=O.[CH3:3][C:4]1[O:5][CH:6]=[CH:7][CH:8]=1.[CH3:9][S:10]([NH:13][C:14]1[CH:27]=[CH:26][C:17]([C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1)(=[O:12])=[O:11].[OH-].[Na+]>O.C(O)(=O)C>[CH3:1][C:6]1[O:5][C:4]([CH2:3][N:23]2[CH2:24][CH2:25][CH:20]([C:18](=[O:19])[C:17]3[CH:16]=[CH:15][C:14]([NH:13][S:10]([CH3:9])(=[O:11])=[O:12])=[CH:27][CH:26]=3)[CH2:21][CH2:22]2)=[CH:8][CH:7]=1
Reactant: Cc1ccco1
Reactant: C=O
Reactant: CS(=O)(=O)Nc1ccc(C(=O)C2CCNCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(CN2CCC(C(=O)c3ccc(NS(C)(=O)=O)cc3)CC2)o1
Temperature: 90 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
1.88 ml of formalin and 1.07 g of methylfuran were added to a mixture of 4.43 g (15.7 mmol) of 4-(4-methylsulfonylaminobenzoyl)piperidine in free form obtained in Example 17, 1.57 ml of glacial acetic acid and 10 ml of water and the obtained mixture was stirred at 90° C. for 2 h. After cooling, the mixture was neutralized with a 20% aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was washed with water and a saturated aqueous common salt solution, dried over magnesium sulfate and concentrated. The solid residue was recrystallized from ethanol/methanol to obtain 4.16 g (yield: 70%) of the intended compound.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]([O:13][CH3:14])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].O.CCOC(C)=O>CN(C=O)C>[CH3:15][S:16]([NH:2][C@H:3]([C:11]([O:13][CH3:14])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccccc1)NS(C)(=O)=O
Reaction time: 16 h
Yield: 49.4 %

Procedure:
To a stirring solution of 2.51 g (20.0 mmol) of methyl L-phenylalaninate hydrochloride and 6.7 mL (48 mmol) of TEA in 50 mL of DMF was added 1.86 mL (24 mmol) of methanesulfonyl chloride. After 16 hours, the reaction mixture was added to 200 mL of H2O and 200 mL of EtOAc. The resulting layers were separated, and the organic layer was washed with 3×200 mL of H2O and dried. The resulting residue was chromatographed to yield 2.54 g (49%) of N-(methylsulfonyl)-L-phenylalanine, methyl ester (13), which was a clear colorless glass.
Reaction SMILES: Cl.[NH2:2][O:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[CH:9]1[C:18]2[N:19]3[C:23]([C:24](=O)[C:16]4[C:17]=2[C:12]([CH:13]=[CH:14][N:15]=4)=[CH:11][CH:10]=1)=[CH:22][CH:21]=[CH:20]3>O.C(O)C.N1C=CC=CC=1>[C:6]([CH2:5][CH2:4][O:3][N:2]=[C:24]1[C:16]2[C:17]3[C:12]([CH:13]=[CH:14][N:15]=2)=[CH:11][CH:10]=[CH:9][C:18]=3[N:19]2[C:23]1=[CH:22][CH:21]=[CH:20]2)([OH:8])=[O:7]
Reactant: NOCCC(=O)O
Reactant: O=c1c2nccc3cccc(c32)n2cccc12
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)CCON=c1c2nccc3cccc(c32)n2cccc12
Yield: 75.2 %

Procedure:
A solution of 3-aminooxypropionic acid hydrochloride (12 g.) in water (36 cc.) is added to a stirred boiling solution of 7H-indolizino[5,6,7-ij]isoquinolin-7-one (12 g.) in ethanol (360 cc.) and pyridine (6.64 g.). Boiling is maintained for 3 hours 10 minutes. After cooling, the yellow crystals obtained are filtered off and then washed with 90% ethanol, with absolute ethanol and finally with diethyl ether. After drying, 7-(2-carboxyethoxyimino)-7H-indolizino[5,6,7-ij]isoquinoline (12.59 g.), melting at 250° C. with decomposition, is obtained.
Reaction SMILES: C[Si]([Br:5])(C)C.[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]O)=[CH:10][C:9]=1[O:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21].C(OCC)(=O)C.CCCCCC>C(Cl)(Cl)Cl>[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][Br:5])=[CH:10][C:9]=1[O:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21]
Reactant: C[Si](C)(C)Br
Reactant: COCCCOc1cc(CO)ccc1OC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: COCCCOc1cc(CBr)ccc1OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Trimethylsilyl bromide (97 ml) is added dropwise to a solution of 4-methoxy-3-(3-methoxypropoxy)-benzyl alcohol (111.1 g) in chloroform (1.31 liters), the reaction temperature being maintained at 10°-25° C. by cooling with ice. When the addition is complete, the mixture is stirred for a further 10 minutes at room temperature and concentrated under reduced pressure. The residue is purified by FC on silica gel (ethyl acetate/hexane 1:3) and after recrystallisation from hexane the title compound (144.5 g) is obtained in the form of a white crystalline solid: m.p. 50-51° C. Rf (ethyl acetate/hexane 1:2)=0.34.