Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:40])[C@H:10]([CH3:39])[CH2:11][C@H:12]([NH:26][C:27](=[O:38])[C:28](=[O:37])[NH:29][NH:30][C:31](=O)[C:32]([F:35])([F:34])[F:33])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)C1C=CC=CC=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[C:17]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:18]=[CH:19][C:14]([CH2:13][C@@H:12]([NH:26][C:27]([C:28]2[O:37][C:31]([C:32]([F:34])([F:35])[F:33])=[N:30][N:29]=2)=[O:38])[CH2:11][C@@H:10]([CH3:39])[C:9]([OH:8])=[O:40])=[CH:15][CH:16]=1
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)C(=O)NNC(=O)C(F)(F)F)C(=O)OCc1ccccc1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1nnc(C(F)(F)F)o1)C(=O)O
Reaction time: 0.5 h

Procedure:
To a solution of (2R,4S)-5-biphenyl-4-yl-2-methyl-4-{2-oxo-2-[N′-(2,2,2-trifluoro-acetyl)-hydrazino]-acetylamino}-pentanoic acid benzyl ester (177 mg, 0.319 mmol) in THF (10 mL) at room temperature is added Burgess reagent (304 mg, 1.274 mmol). The reaction is carried out in a microwave at 130° C. for 30 minutes. The reaction is quenched by brine and is extracted with ethyl acetate. The combined organic layer is concentrated and purified by reverse phase HPLC [70% to 85% acetonitrile-H2O (containing 0.1% TFA)] to give the benzyl ester of the title compound. The obtained benzyl ester intermediate is dissolved in MeOH (4 mL) and is hydrogenated with 10% Pd/C at room temperature for 20 minutes. The reaction mixture is purified by reverse phase HPLC [45% to 70% acetonitrile-H2O (containing 0.1% TFA)] to give (2R,4S)-5-biphenyl-4-yl-2-methyl-4-[(5-trifluoromethyl-[1,3,4]oxadiazole-2-carbonyl)-amino]-pentanoic acid. HPLC Retention time 1.38 minutes (condition D); MS 448 (M+1); 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (d, J=7.3 Hz, 3 H), 1.60-1.71 (m, 1 H), 1.84-1.95 (m, 1 H), 2.41-2.49 (m, 1 H), 2.80-2.88 (m, J=13.9, 6.1 Hz, 1 H), 2.92 (dd, J=13.6, 7.8 Hz, 1 H), 4.21-4.34 (m, 1 H), 7.27-7.37 (m, 3 H), 7.44 (t, J=7.7 Hz, 2 H), 7.58 (d, J=8.3 Hz, 2 H), 7.61-7.66 (m, 2 H), 9.50 (d, J=8.8 Hz, 1 H), 12.05 (br. s., 1 H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[C:16]1N=NC(N)=C(C2C=CC=CC=2)[CH:17]=1.C(OC(OCC)CCl)C>O.C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:5]2[N:6]([CH:16]=[CH:17][N:8]=2)[N:7]=1
Reactant: Nc1nnc(Cl)cc1-c1ccccc1
Reactant: Nc1cc(-c2ccccc2)c(Cl)nn1
Agent: CCOC(CCl)OCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1nn2ccnc2cc1-c1ccccc1
Reaction time: 6 h
Yield: 30.1 %

Procedure:
The mixture of 6-chloro-5-phenyl-pyridazin-3-yl-amine and 6-chloro-4-phenyl-pyridazin-3-yl-amine (20.2 g=0.1 mol) was suspended in 300 mL water and 30 mL THF. After addition of 32 mL (0.51 mol) chloracetaldehyde diethylacetal the reaction mixture was heated for five hours at reflux. Additional 32 mL (0.51 mol) chloracetaldehyde diethylacetal were added and heating was continued for another six hours. The reaction mixture was diluted with ethyl acetate and extracted three times. The organic phase was dried (sodium sulfate), filtrated and the solvent was removed. The residue was purified by chromatography (Biotage, eluents: ethyl acetate/hexane). 6.8 g (30.1%) of the title compound, 6-chloro-7-phenyl-imidazo[1,2-b]pyridazine, and 6.4 g (28.4%) of the regioisomer, 6-chloro-8-phenyl-imidazo[1,2-b]pyridazine, were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][O:23][CH2:24][CH3:25])[N:14]([CH2:15][CH2:16][CH2:17][O:18][CH:19]([CH3:21])[CH3:20])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:26][CH2:27][CH2:28][CH2:29][N:30]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:5][C:4]=2[N:3]=1.NN>C(O)C>[NH2:30][CH2:29][CH2:28][CH2:27][CH2:26][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[N:14]([CH2:15][CH2:16][CH2:17][O:18][CH:19]([CH3:20])[CH3:21])[C:13]([CH2:22][O:23][CH2:24][CH3:25])=[N:12][C:11]=3[C:2]([NH2:1])=[N:3][C:4]=2[CH:5]=1
Reactant: CCOCc1nc2c(N)nc3cc(CCCCN4C(=O)c5ccccc5C4=O)ccc3c2n1CCCOC(C)C
Agent: NN
Solvent: CCO
Product: CCOCc1nc2c(N)nc3cc(CCCCN)ccc3c2n1CCCOC(C)C
Temperature: 25 °C
Yield: 24.3 %

Procedure:
2-{4-[4-amino-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinolin-7-yl]butyl}-1H-isoindole-1,3(2H)-dione (1.15 g, 2.1 mmol) was dissolved in ethanol (36 mL. Hydrazine (0.372 mL, 11.4 mmol) was added and the solution was heated at reflux temperature for 1 hour. The resulting white slurry was cooled to ambient temperature and filtered. The solid showed 40% product by NMR. The solid was saved and used in Part E. The filtrate was concentrated under reduced pressure and purified using a HORIZON HPFC system (silica cartridge, eluting with a linear gradient of 2-20% CMA in chloroform) to provide 0.211 g of 7-(4-aminobutyl)-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:19]([O-])=O)=[C:13]([S:15]([NH2:18])(=[O:17])=[O:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>CO.O.[Fe]>[NH2:19][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][C:13]=1[S:15]([NH2:18])(=[O:16])=[O:17]
Reactant: NS(=O)(=O)c1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1ccc(OCc2ccccc2)cc1S(N)(=O)=O
Yield: 97.1 %

Procedure:
A suspension of the product of Example 2C (7.26 g, 23.57 mmol), ammonium chloride (8.27 g, 155 mmol), and iron powder (8.11 g, 145 mmol) in methanol (188 mL) and water (94 mL) was stirred at reflux for 2 hours. The mixture was filtered while hot through Celite®, and the filter cake was washed with hot methanol (200 mL). The filtrate was concentrated to an approximate volume of 100 mL and then extracted with ethyl acetate (400 mL). The organic layer was washed with water and saturated sodium chloride solution, dried (Na2SO4), filtered through Celite® and concentrated in vacuo to afford the title compound (6.37 g, 97%). 1H NMR (300 MHz, DMSO-d6): δ 7.38 (m, 7 H), 7.22 (m, 2 H), 7.01 (dd, J=8.82, 2.94 Hz, 1 H), 6.76 (d, J=8.82 Hz, 1 H), 5.46 (s, 2 H), 4.98 (s, 2 H).
Reaction SMILES: CN.[CH3:3][O:4][C:5]([C:7]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11]([C:20]([O:22][CH3:23])=[O:21])=[C:10]([CH3:24])[NH:9][C:8]=1[CH2:25][O:26][CH2:27][CH2:28][N:29]1C(=O)C2C(=CC=CC=2)C1=O)=[O:6]>O>[CH3:3][O:4][C:5]([C:7]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11]([C:20]([O:22][CH3:23])=[O:21])=[C:10]([CH3:24])[NH:9][C:8]=1[CH2:25][O:26][CH2:27][CH2:28][NH2:29])=[O:6]
Reactant: COC(=O)C1=C(C)NC(COCCN2C(=O)c3ccccc3C2=O)=C(C(=O)OC)C1c1ccccc1Cl
Agent: CN
Solvent: O
Product: COC(=O)C1=C(C)NC(COCCN)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
To a stirred solution of methylamine (40 wt % in water, 125 mL, 1.45 mol) at ambient temperature was added 4-(2-chloro-phenyl)-2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethoxymethyl]-6-methyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid dimethyl ester (dimethylamlodipine phthalimide) (4, 6.30 g, 12.0 mmol). The reaction mixture was stirred at ambient temperature for 18 hours, then diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with saturated brine (100 mL), dried over MgSO4 and concentrated under reduced pressure to give 5 a yellow oil (4.0 g, 84% yield, 90% pure by LCMS and 1H NMR), 1H NMR (400 MHz; CDCl3): δ 7.15 (m, 1H); 7.02–7.00 (m, 3H); 4.43 (m, 1H); 4.04 (s, 2H); 3.76 (singlets, 6H total); 3.63 (m, 2H); 2.82 (m, 2H); 1.71 (s, 3H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C@@H:12]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[C:28]([C:35]([NH:37][C:38]1[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][C:39]=1[O:53][CH3:54])=[O:36])[N:29]2[CH3:34]>>[CH3:21][N:20]([CH3:22])[C:18](=[O:19])[CH2:17][N:14]1[CH2:15][CH2:16][C@@H:12]([C:4]2[N:5]3[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]3=[C:2]([C:41]3[CH:42]=[CH:43][C:38]([NH:37][C:35]([C:28]4[N:29]([CH3:34])[C:30]5[C:26]([CH:27]=4)=[C:25]([O:24][CH3:23])[CH:33]=[CH:32][CH:31]=5)=[O:36])=[C:39]([O:53][CH3:54])[CH:40]=3)[N:3]=2)[CH2:13]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2c(OC)cccc2n1C
Reactant: Cc1nccn2c([C@@H]3CCN(CC(=O)N(C)C)C3)nc(Br)c12
Product: COc1cc(-c2nc([C@@H]3CCN(CC(=O)N(C)C)C3)n3ccnc(C)c23)ccc1NC(=O)c1cc2c(OC)cccc2n1C
Yield: 91.1 %

Procedure:
Reaction of (R)-2-(3-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)pyrrolidin-1-yl)-N,N-dimethylacetamide (22 mg) and 4-methoxy-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H-indole-2-carboxamide (23 mg) according to the procedure described in example 4 step 4c and purification using prep-HPLC (column Luna C18(2); gradient acetonitrile/water with constant 0.003M trifluoroacetic acid) gave (R)—N-(4-(3-(1-(2-(dimethylamino)-2-oxoethyl)pyrrolidin-3-yl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide (28.6 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][N:19]4[CH:23]=[C:22]([C@:24]([OH:31])([C:27]([F:30])([F:29])[F:28])[CH2:25][CH3:26])[N:21]=[N:20]4)=[CH:15][CH:16]=3)[N:11]=[C:10]([C:32](=[O:34])[CH3:33])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:35][Mg]Br.CCOCC>C1COCC1>[F:28][C:27]([F:29])([F:30])[C@:24]([C:22]1[N:21]=[N:20][N:19]([CH2:18][C:14]2[CH:13]=[C:12]3[C:17]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[CH:9][C:10]([C:32]([OH:34])([CH3:35])[CH3:33])=[N:11]3)=[CH:16][CH:15]=2)[CH:23]=1)([OH:31])[CH2:25][CH3:26]
Reactant: C[Mg]Br
Reactant: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(C(C)=O)nc3c2)nn1)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(C(C)(C)O)nc3c2)nn1)C(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of (S)-1-[4-(4-fluorophenyl)-7-({4-[1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)quinolin-2-yl]ethanone (100 mg, 0.21 mmol) in THF (5 mL) at −78° C. was added methylmagnesium bromide 3M in ether (210 μL, 0.63 mmole). The reaction was warmed up to rt over 2 h and quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. Purification on silica gel (eluting with acetone/dichloromethane, 2:8) gave the title compound. MS (+ESI): 490 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[Br-].[O:14]1CCO[CH:15]1[CH2:19][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOCCN(CCOCCOC)CCOCCOC>ClCCl.C([O-])([O-])=O.[K+].[K+]>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[CH:19][CH:15]=[O:14])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1
Reactant: c1ccc([P+](CC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccc2nccnc2c1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: ClCCl
Product: O=CC=Cc1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
A mixture of 6-quinoxalinecarboxaldehyde (0.62 g, 3.92 mmol, prepared as described in Photochem. Photobiol. 1991, 54, 7), (1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide (2.50 g, 5.82 mmol), and TDA-1 (1.20 mL, 3.75 mmol) in dichloromethane (20 mL) and sat. aq. K2CO3 (20 mL) was heated to reflux for 4 h. The layers were separated and the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (Na2SO4), and concentrated. THF (10 mL) and 10% HCl (10 mL) were added and the mixture was stirred for 1 h at rt. The mixture was cooled to 0° C., the precipitated solids were removed by filtration, washed with water and dried in vacuo to give 0.47 g (65%) of the title compound as a tan solid. MS 185 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][C@H:9]1[CH2:19][OH:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:10][C@H:9]1[CH2:19][O:20][S:29]([CH3:28])(=[O:31])=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](c2ccccc2)C[C@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](c2ccccc2)C[C@H]1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.2 %

Procedure:
To 2.5 g of (2S,4S)-2-Hydroxymethyl-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester (9.01 mmol) in 70 ml dichloromethane were added 1.92 g of triethylamine (18.02 mmol) and 1.03 g of methanesulfonylchloride (9.01 mmol), dissolved in 5 ml dichloromethane. The reaction was stirred for 16 h at room temperature and yielded 3.4 g of product after standard workup.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:16])[CH:8]=[C:9]([O:14][CH3:15])[C:10]=2[O:12][CH3:13])[N:5]=[C:4](Cl)[N:3]=1.[NH2:18][NH2:19]>CO>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:16])[CH:8]=[C:9]([O:14][CH3:15])[C:10]=2[O:12][CH3:13])[N:5]=[C:4]([NH:18][NH2:19])[N:3]=1
Reactant: COc1cc(Cl)c2nc(Cl)nc(N)c2c1OC
Reactant: NN
Solvent: CO
Product: COc1cc(Cl)c2nc(NN)nc(N)c2c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.9 %

Procedure:
A mixture of 4-amino-2,8-dichloro-5,6-dimethoxyquinazoline (1.5 g, 0.0054 moles), anhydrous hydrazine (5 ml, 0.16 moles) and methanol (100 ml) was heated at reflux for 8 hours and stirred at room temperature for 16 hours. The mixture was cooled to 0° C. and the precipitate which formed was collected by filtration. Recrystallization of the solid from methanol followed by drying under vacuum at 55° C. afforded the product (1.12 g), mp 168°-169° C.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C#[N:14]>CC(OC)(C)C>[OH:12][CH:10]([CH2:9][CH2:8][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:11]#[N:14]
Reactant: C#N
Reactant: CC(=O)CCSc1ccccc1
Solvent: COC(C)(C)C
Product: N#CC(O)CCSc1ccccc1

Procedure:
9.01 g (50 mmol) of 4-phenylthio-2-butanone were dissolved in 30 ml of MTBE and treated with 1.0 g of ion exchanger Amberlyst A-21. After this, 9.8 ml (250 mmol) of HCN were added with stirring and the mixture was stirred at room temperature for 2 hours. The ion exchanger was filtered off and 0.05 g of citric acid was added to the solution. The solvent and HCN were stripped off in vacuo at 40° C. on a rotary evaporator. 9.5 g of (R/S)-2-hydroxy-4-phenylthiobutyronitrile (91.7% of theory) were found.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[OH:11])[CH:2]=[CH2:3].[SH:12][CH:13]([CH3:17])[CH:14]([OH:16])[CH3:15]>>[OH:16][CH:14]([CH3:15])[CH:13]([CH3:17])[S:12][CH2:3][CH2:2][CH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[OH:11]
Reactant: C=CCc1cccc(C)c1O
Reactant: CC(O)C(C)S
Product: Cc1cccc(CCCSC(C)C(C)O)c1O

Procedure:
In the same manner as in Synthetic example 1, 2-allyl-6-methylphenol and 3-mercapto-2-butanol were reacted to obtain 2-[3-(2-hydroxy-1-methylpropylthio)propyl]-6-methylphenol.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[N:10]2[C:18]3[CH:17]=[CH:16][C:15]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:14][C:13]=3[C:12]3[CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([C:11]2=3)[CH2:27][CH2:26]4)=[CH:4][CH:3]=1>CO.[Pt]=O>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:18]3[CH:17]=[CH:16][C:15]([O:19][C:20]([F:22])([F:23])[F:21])=[CH:14][C:13]=3[C:12]3[CH2:24][N:25]4[CH2:26][CH2:27][CH:28]([C:11]2=3)[CH2:29][CH2:30]4)=[CH:4][CH:3]=1
Reactant: Cc1ccc(/C=C\n2c3c(c4cc(OC(F)(F)F)ccc42)CN2CCC3CC2)cn1
Agent: O=[Pt]
Solvent: CO
Product: Cc1ccc(CCn2c3c(c4cc(OC(F)(F)F)ccc42)CN2CCC3CC2)cn1

Procedure:
A solution of 6-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-9-(trifluoromethoxy)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (65 mg, 0.157 mmol; Example 177) in methanol was treated with platinum oxide under a hydrogen atmosphere (1 atm) at 40° C. for 16 hours to afford the title compound as the major product: 1H NMR (300 MHz, methanol-d4) δ ppm 1.57-1.71 (m, 2H), 1.86-2.00 (m, 2H), 2.40 (s, 3H), 2.89-2.31 (m, 7H), 4.16 (s, 2H), 4.42 (t, J=6 Hz, 2H), 6.93 (ddd, J=9, 2, 1 Hz, 1H), 7.11 (d, J=8 Hz, 1H), 7.18 (d, J=1 Hz, 1H), 7.25 (d, J=9 Hz, 1H), 7.31 (dd, J=8, 2 Hz, 1H), 7.82 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 416 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:30][OH:31])[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19]C(=O)OCC2C=CC=CC=2)=[CH:7][CH:6]=1>CO.[Pd]>[NH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:30][OH:31])=[CH:6][CH:7]=1
Reactant: O=C(NCCCCc1ccc(OCC(O)CO)c2ccccc12)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NCCCCc1ccc(OCC(O)CO)c2ccccc12
Yield: 97.6 %

Procedure:
A solution of benzyl 4-[4-(2,3-dihydroxypropoxy)naphthalen-1-yl]butylcarbamate (22, 340 mg, 0.80 mmole) and 10% Pd/C (50 mg) in MeOH (50 mL) was subjected to hydrogenation conditions (1 atm) for 2 h at room temperature. The reaction mixture was filtered through a plug of diatomaceous earth and the plug was washed with MeOH. The filtrate was then concentrated in vacuo to afford diol 23 (226 mg, 97%) as a yellow solid: MS m/z 290 [C17H23NO3+H]+. Diol 23 was used in the next step without further purification.
Reaction SMILES: [C:1]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1COCC1.CN1CCOCC1.[CH2:29]([O:31][C:32]([C@@:34]1([NH2:39])[CH2:36][C@H:35]1[CH:37]=[CH2:38])=[O:33])[CH3:30]>>[C:4]([O:3][C:1]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10](=[O:12])[NH:39][C@:34]1([C:32]([O:31][CH2:29][CH3:30])=[O:33])[CH2:36][C@H:35]1[CH:37]=[CH2:38])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OCC
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C)C(=O)OCC
Temperature: -23 °C
Reaction time: 2.5 h

Procedure:
To a solution of 4.87 g (21.0 mmol) of Boc-(2S,4R)-hydroxyproline in 25 mL of THF 2.03 mL (20.0 mmol) of NMM was added. A suspension was formed. The mixture was cooled to −23° C. and 2.85 g (20.0 mmol) of isobutylchloroformiate was added. After stirring for 10 min additional 4.25 g (42.0 mmol) of NMM was added. To this mixture the solution of (1R,2S)-1-amino-2-vinyl-cyclopropanecarboxylic acid ethyl ester prepared in example 1 was added at a temperature of −15° C. within 5 min. The reaction mixture was stirred for 2.5 h at 0° C. Salts were filtered off and the filtrate was treated with 20 mL of aqueous HCl (0.5 N). The solvents were removed at 50° C. under reduced pressure using a rotary evaporator and the residue was extracted twice with 50 mL of EtOAc. The extract was washed with 40 mL of water and 40 mL of aqueous Na2CO3 solution (10 wt %), and dried over sodium sulfate. Finally the solvent was removed completely to give 8.19 g of (2S,4R)-2-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow oil. The product was used in the next step without further purification.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])O.[C:6]1([S:20]([OH:23])(=[O:22])=[O:21])[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([S:16]([OH:19])(=[O:18])=[O:17])[C:10]=2[CH:9]=[CH:8][CH:7]=1.[Na][Na]>>[C:6]1([S:20]([OH:23])(=[O:22])=[O:21])[C:15]2[CH:14]=[C:13]([S:1]([OH:5])(=[O:4])=[O:3])[CH:12]=[C:11]([S:16]([OH:19])(=[O:18])=[O:17])[C:10]=2[CH:9]=[C:8]([S:1]([OH:3])(=[O:5])=[O:4])[CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: O=S(=O)(O)c1cccc2c(S(=O)(=O)O)cccc12
Agent: [Na][Na]
Product: O=S(=O)(O)c1cc(S(=O)(=O)O)c2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c2c1

Procedure:
To 240 ml. of 30-33% fuming sulfuric acid at 120° C. is added, portionwise, 60 g. of 1,5-naphthalenedisulfonic acid, disodium salt. The mixture is heated at 180°-190° C. for 23 hours. The solution is cooled, allowed to crystallize and filtered through a coarse, sintered glass funnel. The product is washed with concentrated sulfuric acid to give 1,3,5,7-naphthalenetetrasulfonic acid as an off-white pasty solid. Without further purification, the solid is added, portionwise, to 150 ml. of chlorosulfonic acid and the mixture is heated at 145°-150° C. for 1-5 hours. The mixture is cooled to room temperature and filtered. The product is washed, in order, with chlorosulfonic acid, methylene chloride, acetonitrile, water, acetonitrile and finally with ether. The product is air-dried and then dried further in an Abderhalden apparatus at 76° C. to provide 33.9 g. of the desired product as a colorless powder, mp. 263°-270° C.
Reaction SMILES: [OH-].[Na+:2].[C:3]([OH:7])(=[O:6])[CH:4]=[CH2:5].OO.[O-]S(OOS([O-])(=O)=O)(=O)=O.[Na+].[Na+].[O:22]=[C:23]1[O:29][C@H]([C@H](CO)O)[C:26](O)=[C:24]1O>O>[C:3]([OH:7])(=[O:6])[CH:4]=[CH2:5].[C:23]([O-:29])(=[O:22])[CH:24]=[CH2:26].[Na+:2]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: C=CC(=O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: OO
Solvent: O
Product: C=CC(=O)[O-]
Temperature: 30 °C

Procedure:
By continuously mixing water, 50% by weight sodium hydroxide solution and acrylic acid, a 38.8% by weight acrylic acid/sodium acrylate solution was prepared such that the degree of neutralization was 69.0 mol %. After the components had been mixed, the monomer solution was cooled continuously to a temperature of 30° C. by means of a heat exchanger and degassed with nitrogen. The polyethylenically unsaturated crosslinker used was 3-tuply ethoxylated glyceryl triacrylate (purity approx. 85% by weight). The amount used, based on the acrylic acid used, was 0.35% by weight. To initiate the free-radical polymerization, the following components were used: hydrogen peroxide (0.002% by weight of a 2.5% by weight aqueous solution), sodium peroxodisulfate (0.1% by weight of a 15% by weight aqueous solution), and ascorbic acid (0.01% by weight of a 0.5% by weight aqueous solution). The percentages by weight are based in turn on the acrylic acid used. The throughput of the monomer solution was 500 kg/h.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([O:18]C)[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1>C(O)(=O)C.Br>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc3ccc(OC)cc3s2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc(-c2nc3ccc(O)cc3s2)cc1
Temperature: 25 °C

Procedure:
20 g of 2-(p-methoxyphenyl)-6-methoxybenzothiazole are refluxed in a mixture of 100 ml of glacial acetic acid and 200 ml of concentrated aqueous HBr with stirring. After 14 hours the mixture is cooled down to room temperature and filtered with suction, and the filter residue is washed with water and recrystallized from ethanol. The yield is 17.2 g (95% of theory); melting point: 284°-286° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH2:13][C:14]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:15]=1[C:16]([NH:18][NH2:19])=[O:17]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:19][NH:18][C:16](=[O:17])[C:15]1[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:14]=1[NH2:13]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)c1cc([N+](=O)[O-])ccc1N
Solvent: CC(=O)O
Product: Nc1ccc([N+](=O)[O-])cc1C(=O)NN=C1C(=O)Nc2ccc(I)cc21
Temperature: 100 °C
Yield: 76 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 2-amino-5-nitrobenzohydrazide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 69 mg of the title compound (76%) as a yellow powder in 98.8% purity by HPLC (Rt: 4.22, gradient of 8 min, MaxPlot detection between 230 and 400 nm).