Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20](CN)[CH:21]=4)[CH:16]=[CH:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:27][N:28]([CH3:32])[C:29](Cl)=[O:30].[CH2:33](N(CC)CC)[CH3:34]>C(#N)C>[F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:27][N:28]5[CH2:32][CH2:34][CH2:33][C:29]5=[O:30])[CH:21]=4)[CH:16]=[CH:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: CCN(CC)CC
Reactant: NCc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Solvent: CC#N
Product: O=C1CCCN1Cc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Yield: 72.6 %

Procedure:
1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-aminomethylindole (150 mg) obtained in Example 322-3), dimethylcarbamyl chloride (54 mg), triethylamine (50 mg) and acetonitrile (5 ml) were treated as in Example 373 to give the title compound (130 mg) as a white powder (yield: 72%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:12]([C:14]1[CH:26]=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][C:16]=2[CH:15]=1)[CH3:13].Cl>ClC(Cl)C>[C:1]([C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[C:16](=[CH:15][C:14]([CH2:12][CH3:13])=[CH:26][CH:25]=3)[CH2:17][C:18]=2[CH:19]=1)(=[O:3])[CH3:2]
Reactant: CCc1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCc1ccc2c(c1)Cc1cc(C(C)=O)ccc1-2

Procedure:
Acetic anhydride (2.67 g.) in dichloroethane (10 ml.) was added dropwise to a stirred, cooled (0°) suspension of aluminum chloride (6.95 g.) in dichloroethane (20 ml.). Cooling and stirring were continued during the dropwise addition of a solution of 2-ethylfluorene (4.61 g.) in dichloroethane (50 ml.). The mixture was stirred for one hour at room temperature and then decomposed by the dropwise addition of 2N-hydrochloric acid (40 ml.) to the cooled solution. The organic layer was separated, washed with water and with aqueous sodium bicarbonate, dried over anhydrous sodium sulphate, filtered, and evaporated under reduced pressure. The residue was recrystallised from light petroleum (ca 250 ml., b.p. 60°-80°) to give 2-acetyl-7-ethylfluorene m.p. 120°-122°.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:22])[CH2:14][C@@H:15]1[CH3:21])[CH2:10][CH2:9]3.[C:23]([O:26]C(=O)C)(=[O:25])[CH3:24].O>N1C=CC=CC=1>[C:23]([OH:26])(=[O:25])[CH3:24].[C:23]([OH:26])(=[O:25])[CH3:24].[OH:22][C:13]1[CH2:14][C@H:15]([CH3:21])[C@@:16]2([CH3:17])[C:11](=[CH:10][CH2:9][C@@H:8]3[C@@H:18]2[CH2:19][CH2:20][C@@:3]2([CH3:4])[C@H:5]3[CH2:6][CH2:7][C@@H:2]2[OH:1])[CH:12]=1
Reactant: C[C@H]1CC(=O)C=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21C
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)O
Product: C[C@H]1CC(O)=CC2=CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21C
Yield: 93 %

Procedure:
17β-Hydroxy-1α-methylandrost-4-en-3-one (1α-methyltestosterone, 1.0 g, 3.3 mmol) was dissolved in pyridine (10 ml) and acetic anhydride (10 ml) and stirred at room temperature under a drying tube for 18 hours. The mixture was poured into cold water and the precipitate collected and washed with additional cold water. After drying, the solid was chromatographed on flash SiO2 and eluted with 5% ether--95% hexane. There was obtained 1.18 g (93%) of 3,17β-dihydroxy-1α-methylandrosta-3,5-diene diactate 51, which was recrystallized from methanol-water: mp 111°-112° C.; NMR (CDCl3) δ 5.65 (d, J=3 Hz, 1H, H-4), 5.52 (br s, 1H, H-6), 4.64 (t, 1H, H-17), 2.10 (s, 3H, Ac), 2.02 (s, 3H, Ac), 1.05 (s, 3H, C-18 Me), 0.83 (s, 3H, C-19 Me), 0.86 (d, 3H, C-1 Me); IR (KBr) 2910, 1745, 1730, 1360, 1245, 1215; MS 386 (M+, 4), 358(1), 344(100), 329(2), 315 M* (344-329), 301(1), 151(1), 43(13); Anal. Calcd for C24H34 O4 : C, 74.57; H, 8.86. Found: C, 74-39; H, 8.62.
Reaction SMILES: [C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]4[CH2:27][CH2:26][C:25]5[C:20](=[CH:21][C:22]([O:28][CH3:29])=[CH:23][CH:24]=5)[C@H:19]4O)[CH2:13][CH2:12]3)[C:10](=[O:31])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C.CCOCC>[CH3:29][O:28][C:22]1[CH:21]=[C:20]2[C:25]([CH2:26][CH2:27][C:18]([CH2:17][N:14]3[CH2:15][CH2:16][C:11]4([N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH2:8][NH:9][C:10]4=[O:31])[CH2:12][CH2:13]3)=[CH:19]2)=[CH:24][CH:23]=1
Reactant: COc1ccc2c(c1)[C@@H](O)[C@H](CN1CCC3(CC1)C(=O)NCN3c1ccccc1)CC2
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2c(c1)C=C(CN1CCC3(CC1)C(=O)NCN3c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.7 %

Procedure:
trans-1-Phenyl-8-[(1,2,3,4-tetrahydro-1-hydroxy-7-methoxy-2-naphthalenyl)methyl]-1,3,8-traizaspiro[4.5]decan-4-one (5.0 g, see example 196) is added in portions to 25 ml of 20% v/v sulfuric acid/acetic acid. The resulting mixture is stirred for 16 hours at room temperature protected from moisture by a drying tube. The reaction mixture is warmed on a steam bath for 5 minutes, cooled, poured onto ice, basified with solid sodium bicarbonate, and extracted with methylene chloride. The dried methylene chloride solution is concentrated to give a crude solid. Trituration with 1:1 absolute ethanol/ether yields 3.0 g of the title compound, melting point 184°-186° C.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O.N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[C:3]([C:2](=[O:1])[CH2:9][CH2:10][CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: O=Cc1ccccc1Cl
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCCC(=O)C(=Cc1ccccc1Cl)C(=O)OCC

Procedure:
A solution of ethyl 3-ketohexanoate (7.5 g), 2-chlorobenzaldehyde (6.6 g), piperidine (1.2 g) and acetic acid (2.25 g) in benzene (50 ml) was heated under reflux for 5 hours, and the reaction mixture was dehydrated using a Dean-Stark condenser. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent (hexane-ethyl acetate (3:1)) to give ethyl 2-(2-chlorophenyl)methylen-3-oxohexanoate ((E)/(Z)=1:1 mixture) as a yellow oil. A solution of ethyl 2-(2-chlorophenyl)methylene-3-oxohexanoate ((E)/(Z)=1:1 mixture, 2.8 g), 3-amino-1-methylpyrazole (0.25 g) and p-toluenesulfonic acid (25 mg) in toluene (5 mL) and dimethylsulfoxide (0.5 mL) was heated under reflux for one day. The solvent was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate (10 mL) and washed with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent (ethyl acetate-methanol (10:1))) to give the title compound as colorless crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1.[N+:11]([CH:14]=[C:15](SC)[S:16][CH3:17])([O-:13])=[O:12]>C(#N)C>[N+:11]([CH:14]=[C:15]([S:16][CH3:17])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)([O-:13])=[O:12]
Reactant: NCCCCc1c[nH]cn1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CC#N
Product: CSC(=C[N+](=O)[O-])NCCCCc1c[nH]cn1

Procedure:
A solution of 4-(4-aminobutyl)imidazole (from the dihydrobromide 3.6 g) and 1-nitro-2,2-bis-methylthioethylene (2.0 g) in acetonitrile (50 ml) is set aside at room temperature for 3 days. The product is chromatographed on a column of silica gel with elution by ethyl acetate to give 1-nitro-2-methylthio-2-[4-(4-imidazolyl)butylamino]ethylene. Reaction of this methylthio compound with hydrazine hydrate in the procedure of Example 3 results in the production of 1-nitro-2-[4-(4-imidazolyl)butylamino]-2-hydrazinoethylene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:12][CH2:13][CH3:14])[C:10]#[N:11].[CH2:15]([O:17][C:18]([NH:20]N)=[O:19])[CH3:16].C(O)(=O)C.[H][H]>[Ni].CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:12][CH2:13][CH3:14])[CH:10]=[N:11][NH:20][C:18]([O:17][CH2:15][CH3:16])=[O:19]
Reactant: [H][H]
Reactant: CCOC(=O)NN
Reactant: CCCC(C#N)c1ccc(Cl)cc1Cl
Agent: [Ni]
Solvent: CO
Solvent: CC(=O)O
Product: CCCC(C=NNC(=O)OCC)c1ccc(Cl)cc1Cl

Procedure:
22.8 g (0.1 mol) of 2-(2,4-dichlorophenyl)-valeronitrile, 10.4 g (0.1 mol) of hydrazinecarboxylic acid ethyl ester and 6.0 g (0.1 mol) of acetic acid are hydrogenated with 11.0 g of Raney nickel in 100 ml of 95% aqueous methanol at room temperature under a normal pressure of hydrogen for 4.5 hours. Filtration and crystallisation yield 22.1 g (70% of theory) of the above product; m.p. 127°-129° C.:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][NH:11][CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH2:12]([N:11]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH3:10])[CH3:13]
Reactant: O=Cc1ccc(F)cc1
Reactant: CCNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCN(C)c1ccc(C=O)cc1
Yield: 89 %

Procedure:
To a solution of 4-fluorobenzaldehyde (1.5 g) and methylethylamine (1.56 mL) in dimethylsulfoxide (9 mL) was added potassium carbonate (2.17 g) and the mixture was stirred by using a microwave synthesizer (Biotage LTD.) at 120° C. for 2 hours. Thereto was added water and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated in vacuo. The resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=95:5→80:20) to give 4-(N-ethyl-N-methylamino)benzaldehyde (1.89 g, yield: 89%).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(Cl)(=O)C(Cl)=O.O[C:26]1[CH:61]=[CH:60][C:29]([CH2:30][N:31]([CH2:52][C:53]([O:55]C(C)(C)C)=[O:54])[C:32](=[O:51])[C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:40](=[O:50])[CH2:41][C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=3)=[CH:35][CH:34]=2)=[CH:28][CH:27]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CN(C=O)C>[CH3:49][O:48][C:45]1[CH:44]=[CH:43][C:42]([CH2:41][C:40]([NH:39][C:36]2[CH:35]=[CH:34][C:33]([C:32]([N:31]([CH2:52][C:53]([OH:55])=[O:54])[CH2:30][C:29]3[CH:28]=[CH:27][C:26]([O:15][C:14](=[O:16])[C:13]4[CH:12]=[CH:11][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:18][CH:17]=4)=[CH:61][CH:60]=3)=[O:51])=[CH:38][CH:37]=2)=[O:50])=[CH:47][CH:46]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(O)cc3)cc2)cc1
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)O)C(=O)c3ccc(NC(=O)Cc4ccc(OC)cc4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14 %

Procedure:
Prepared using General Procedures 2 and 8: To a stirring solution of 4-(octyloxy)benzoic acid (30 mg, 0.119 mmol) in DCM (0.5 mL) were added DMF (1 drop) and oxalyl chloride (0.011 mL, 0.127 mmol). The reaction mixture was stirred at room temperature for 30 min. To this mixture was added a solution of tert-butyl 2-(N-(4-hydroxybenzyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)acetate INT-7 (40 mg, 0.079 mmol) and TEA (0.022 mL, 0.159 mmol) in DCM (1 mL). The reaction was stirred at room temperature for 2 h then TFA (1 mL) was added. After stirring for 2 h, the solvent was concentrated and the product was purified by preparative HPLC to afford 7.6 mg (14%) of 2-(4-(2-(4-methoxyphenyl)acetamido)-N-(4-((4-(octyloxy)benzoyl)oxy)benzyl)benzamido)acetic acid 17. LCMS-ESI (m/z) calculated for C40H44N2O8: 680; found 679 [M−H]−, tR=9.96 min (Method 4).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].[C:17]([O-:20])([O-])=[O:18].[Cs+].[Cs+].[NH4+:23].[Cl-]>CN(C=O)C>[C:6]([O:20][C:17]([NH:23][CH2:8][CH2:9][CH2:10][O:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[C@H:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:16])[CH2:7][CH2:8]2)=[O:18])([CH3:14])([CH3:7])[CH3:5]
Reactant: [NH4+]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCNC(=O)OC(C)(C)C)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
To a solution of ethyl [(1S-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6, 1 g, 4.54 mmol) and (3-Boc-amino)propyl bromide (1.51 g, 6.36 mmol) in DMF (40 mL) was added Cs2CO3 (2.96 g, 9.08 mmol). The mixture was stirred at rt for 18 h, and diluted with a saturated solution of NH4Cl. The mixture was extracted with Et2O and the combined ether extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. The product (2.15 g, 94%) was isolated by silica gel column chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD2Cl2) δ 7.05 (d, 1H), 6.77 (s, 1H), 6.69 (dd, 1H), 4.16 (q, 2H), 3.99 (t, 2H), 3.48 (qt, 1H), 3.34-3.25 (m, 2H), 2.95-2.78 (m, 2H), 2.71 (dd, 1H), 2.45-2.33 (m, 2H), 1.95 (qt, 2H), 1.80-1.72 (m, 1H), 1.44 (s, 9H), 1.28 (t, 3H).
Reaction SMILES: [OH-].[Na+].[I:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([OH:12])[CH:7]=[C:6]([I:13])[N:5]=1.I[CH2:15][CH2:16][CH2:17][O:18][CH3:19].O>CN(C)C=O.C(OCC)(=O)C>[I:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH2:15][CH2:16][CH2:17][O:18][CH3:19])[CH:7]=[C:6]([I:13])[N:5]=1
Reactant: COCCCI
Reactant: COc1c(O)cc(I)nc1I
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COCCCOc1cc(I)nc(I)c1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 60 mmol NaOH in 50 ml N,N-dimethyl formamide is progressively added 50 mmol 2,6-diiodo-3-methoxy-pyridin-4-ol [437709-87-0]. The reaction mixture is stirred for 30 minutes and then cooled to 0° C. 60 mmol 1-iodo-3-methoxy-propane [61542-10-7] are added and the mixture is stirred for 15 minutes at room temperature. Water and ethyl acetate are added to the mixture, the layers are separated and the aqueous layer is extracted with ethyl acetate (3×). The combined organic layers are dried over sodium sulphate, filtered and concentrated. The title compound is obtained from the residue by means of flash chromatography (SiO2 60 F) and identified based on its Rf value,
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N+:19]([O-])=O.[NH4+].[Cl-]>[Fe].CCO>[NH2:19][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:2]=1[F:1])[CH2:6][NH:7][C:8]([C:10]1([C:13]([F:14])([F:15])[F:16])[CH2:11][CH2:12]1)=[O:9]
Reactant: O=C(NCc1ccc(F)c([N+](=O)[O-])c1)C1(C(F)(F)F)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1cc(CNC(=O)C2(C(F)(F)F)CC2)ccc1F

Procedure:
The sub-title compound was prepared in accordance with the procedure in Example 2, step (b) using N-(4-fluoro-3-nitrobenzyl)-1-(trifluoromethyl)-cyclopropanecarboxamide (3.77 g; 12.3 mmol), Fe (3.45 g; 61.6 mmol), NH4Cl (aq, sat, 30 mL) and EtOH (30 mL). Yield: 3.2 g (76%).
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:5]1[N:10]2[CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[N:13]=[C:9]2[C:8]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[N:7][CH:6]=1)\[NH2:4].[C:32](N1C=CN=C1)(N1C=CN=C1)=[O:33].N12CCCN=C1CCCCC2>C(#N)C.CCOC(C)=O>[O:29]1[CH2:30][CH2:31][N:26]([C:8]2[C:9]3[N:10]([CH:11]=[C:12]([CH2:14][O:15][C:16]4[CH:25]=[CH:24][C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[N:17]=4)[N:13]=3)[C:5]([C:3]3[N:4]=[C:32]([OH:33])[O:1][N:2]=3)=[CH:6][N:7]=2)[CH2:27][CH2:28]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N/C(=N\O)c1cnc(N2CCOCC2)c2nc(COc3ccc4ccccc4n3)cn12
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: Oc1nc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)no1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of compound 55b (70.0 mg, 0.170 mmol), 1,1′-carbonyldiimidazole (40.6 mg, 0.250 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.099 mL, 0.670 mmol) in acetonitrile (2 mL) was stirred at rt for 12 h. The residue was diluted with EtOAc (2×50 mL) and washed with 1N HCl (30 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with MeOH, collected by filtration, and dried to give the title compound 75 as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 3.79-3.96 (m, 4H), 4.49 (br. s., 4H), 5.66-5.76 (m, 2H), 6.99 (d, J=8.8 Hz, 1H), 7.36-7.47 (m, 1H), 7.66 (td, J=7.7, 1.2 Hz, 1H), 7.74 (d, J=8.1 Hz, 1H), 7.81 (s, 1H), 7.91 (d, J=8.3 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 8.76 (s, 1H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C22H19N7O4: 446.2 [M+H]. found 446.2.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[NH:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=2[C:8]=1[C:17]([O:19][CH3:20])=[O:18])([O-])=O.[H][H]>C(OCC)(=O)C>[NH2:1][C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[NH:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=2[C:8]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: [H][H]
Reactant: COC(=O)c1c(Nc2ccccc2[N+](=O)[O-])sc2ccc(C)cc12
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Nc2ccccc2N)sc2ccc(C)cc12

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using methyl 2-(2-nitroanilino)-5-methylbenzo[b]thiophene-3-carboxylate, ethyl acetate, 10%/opalladium-carbon and hydrogen (60 atm kg/cm2), methyl 2-(2-aminoanilino)-5-methylbenzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[N:11]=[CH:10][NH:9][C:8]=2[C:7](=[O:13])[NH:6][C:5]1=[O:14])[CH2:2][CH3:3].[Cl:15]N1C(=O)CCC1=O>CN(C=O)C>[Cl:15][C:10]1[NH:9][C:8]2[C:7](=[O:13])[NH:6][C:5](=[O:14])[N:4]([CH2:1][CH2:2][CH3:3])[C:12]=2[N:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCn1c(=O)[nH]c(=O)c2[nH]cnc21
Solvent: CN(C)C=O
Product: CCCn1c(=O)[nH]c(=O)c2[nH]c(Cl)nc21
Reaction time: 5 h
Yield: 43.2 %

Procedure:
3-Propyl-3,7-dihydro-1H-purine-2,6-dione (J.Med.Chem, 1993, 36 (10), 1380-6) (0.3 g, 1.5 mmol) and N-chlorosuccinimide (0.21 g, 1.5 mmol) were dissolved in DMF (5 ml) and the solution stirred for 5 h. The solution was concentrated and the solid residues washed with methanol and filtered to provide the product as a white solid (0.148 g, 42%). NMR; δH (400 MHz, d6-DMSO) 0.85 (t, 3H, J=7 Hz), 1.65 (m, 2H), 3.8 (t, 2H, J=7 Hz), 11.2 (s, 1H), one exchangeable not observed to δH 13; m/z 229[MH+]
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C@H:10]1[F:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.CO>ClCCl>[CH2:1]([NH:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[F:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccccc2)[C@H](F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: F[C@@H]1CNCC[C@@H]1NCc1ccccc1
Temperature: 25 °C
Reaction time: 2.33 h
Yield: 93.7 %

Procedure:
To a solution of cis-4-benzylamino-1-tert-butoxycarbonyl-3-fluoropiperidine (0.9087 g, 2.95 mmol) in anhydrous dichloromethane (5 mL) under argon was added trifluoroacetic acid (2.5 mL) and the solution was stirred at room temperature under argon for 140 min. Anhydrous methanol (1 mL) was added and the solvents were removed in vacuo. More methanol (2 mL) was added and removed in vacuo. The residue was partitioned between CH2Cl2 (30 mL) and dilute NaOH solution (20 mL). The aqueous layer was further extracted with CH2Cl (30 ml×2) and the combined organic extracts were washed with brine (50 mL), dried (Na2SO4) and evaporated in vacuo to give 0.5756 g (94%) of the title compound as a colourless oil. δH (250 MHz, CDCl3) 1.54 (1H, qd, J=12.0 and 4.1 Hz), 1.83 (1H, m), 2.54-2.76 (3H, m), 3.11 (1H, m), 3.88 (2H, m), 4.73 (1H, m), 7.23-7.37 (5H, m).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:20])[CH2:4][O:5][C:6]1[C:11]2[CH2:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15](=[O:17])[CH2:16][C:10]=2[CH:9]=[CH:8][CH:7]=1.C(O)(=O)C(C(C(O)=O)O)O.CCOCC.[C:36]([NH2:40])([CH3:39])([CH3:38])[CH3:37]>O1CCOCC1>[C:36]([NH:40][CH2:2][CH:3]([OH:20])[CH2:4][O:5][C:6]1[C:11]2[CH2:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15](=[O:17])[CH2:16][C:10]=2[CH:9]=[CH:8][CH:7]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)N
Reactant: CC1(C)CCc2c(cccc2OCC(O)CCl)CC1=O
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)(C)NCC(O)COc1cccc2c1CCC(C)(C)C(=O)C2

Procedure:
2,2 g crude 1-(3-chloro-2-hydroxypropoxy)-6,7,8,9-tetrahydro-7,7-dimethyl-5H-benzocyclohepten-6-one in 20 ml dioxane and 10 ml tert-butylamine are heated at 130° for 20 hours in an autoclave. The reaction mixture is divided between 10% (w/w) aqueous tartaric acid solution and ether. The aqueous phase is made alkaline and extracted with ether. Evaporation of the ether phase yields the title compound (M.pt of hydrogen maleate 186°-188° after crystallization from ethanol).
Reaction SMILES: [CH2:1]1[O:24][C:23]2[CH:22]=[CH:21][C:5]([CH2:6][CH:7]3[C:16]4[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=4[O:17][CH3:18])[CH2:10][CH2:9][NH:8]3)=[CH:4][C:3]=2[O:2]1.Br[CH2:26][C:27](Br)=[O:28].[CH3:30][O:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][NH2:35]>>[CH2:1]1[O:24][C:23]2[CH:22]=[CH:21][C:5]([CH2:6][CH:7]3[C:16]4[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=4[O:17][CH3:18])[CH2:10][CH2:9][N:8]3[CH2:26][C:27]([NH:35][CH2:34][C:33]3[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=3[O:31][CH3:30])=[O:28])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(Br)CBr
Reactant: COc1ccc(OC)c2c1CCNC2Cc1ccc2c(c1)OCO2
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNC(=O)CN1CCc2c(OC)ccc(OC)c2C1Cc1ccc2c(c1)OCO2

Procedure:
prepared by reaction of 1-(3,4-Methylenedioxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-methoxy-benzylamine
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[CH2:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][NH:32]1>>[CH2:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][N:32]1[C:26]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)=[O:25]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: c1ccc2c(c1)CNC2
Product: O=C(N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O)N1Cc2ccccc2C1

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and 2,3-dihydro-1H-isoindole. MS (ESI): 460.4 (MH+).