Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]#[C:10][C:11]#[C:12][C@@H:13]2[O:15][C@H:14]2[CH:16]=[CH:17][CH2:18][OH:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:24]O)(C)(C)C>C1C=CC=CC=1.C/C(/O)=C\C(C)=O.C/C(/O)=C\C(C)=O.O=[V]>[C:1]1([C:7]#[C:8][C:9]#[C:10][C:11]#[C:12][CH:13]2[O:15][CH:14]2[C@@H:16]2[O:24][C@H:17]2[CH2:18][OH:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OO
Reactant: OCC=C[C@@H]1O[C@H]1C#CC#CC#Cc1ccccc1
Agent: O=[V]
Agent: CC(=O)/C=C(\C)O
Solvent: c1ccccc1
Product: OC[C@@H]1O[C@H]1C1OC1C#CC#CC#Cc1ccccc1
Reaction time: 4 h

Procedure:
To a stirred solution of 22 mg (0.089 mmole) of (trans)-3-[3-(6-phenyl-1,3,5-hexatriynyl)oxiranyl]-2-propen-1-ol (see example 6) in 5 ml of dry benzene was added 2 mg of vanadyl acetylacetonate and 50 μl (0.26 mmole) of a 5.43M solution of t-butylhydroperoxide in benzene. The mixture was stirred for 4 hours. The mixture was concentrated and the residue was purified via preparative thin layer chromatography (silica gel; ethyl acetate-hexane 1:1) to afford 11 mg of the title compound as an approximately 1:1 mixture of diastereomers.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Nc1cccc([N+](=O)[O-])c1)Nc1ccnc2ccccc12
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(NC(=O)Nc2ccnc3ccccc23)c1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
1-(3-Nitrophenyl)-3-quinolin-4-ylurea (0.775 g) was suspended in ethanol (150 ml) containing 10% Pd/C (0.75 g paste) and shaken under a hydrogen atmosphere (50 psi) at room temperature. After 3 h the mixture was filtered (celite pad) and the residue washed with ethanol. The combined filtrate and washings were evaporated to dryness under reduced pressure and the residue triturated with diethyl ether/hexane to give the title compound (0.54 g).
Reaction SMILES: C([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([CH3:51])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:50])[CH2:12][CH2:13][C@@:14]3([C:30]([NH:32][C@@H:33]4[CH2:36][C@H:35]([C:37]([NH:39][C@@H:40]([CH:45]([CH3:47])[CH3:46])[C:41]([O:43]C)=[O:42])=[O:38])[C:34]4([CH3:49])[CH3:48])=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:53])[CH3:52])(=O)C.[OH-].[Na+]>CO.C1COCC1>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:51])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:50])[CH2:12][CH2:13][C@@:14]3([C:30]([NH:32][C@@H:33]4[CH2:36][C@H:35]([C:37]([NH:39][C@@H:40]([CH:45]([CH3:46])[CH3:47])[C:41]([OH:43])=[O:42])=[O:38])[C:34]4([CH3:49])[CH3:48])=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:52])[CH3:53]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)N[C@H](C(=O)OC)C(C)C)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)N[C@H](C(=O)O)C(C)C)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.9 %

Procedure:
To a stirred solution of (S)-methyl 2-((1S,3R)-3-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxamido)-2,2-dimethylcyclobutanecarboxamido)-3-methylbutanoate (Example 39, 0.300 g, 0.407 mmol) in MeOH:THF (2:1) (7.5 ml) 2N NaOH (2.5 ml) was added at 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the volatile was evaporated and the reaction mixture was acidified with 1N HCl, filtered, washed with water and dried under vacuum to afford the title compound as an off white solid. Wt: 0.180 g: Yield: 64.9%; 1H NMR (300 MHz, DMSO-d6): δ 7.55 (d, 2H, J=6.6 Hz), 4.62 (s, 1H), 4.51 (s, 1H), 4.20-4.11 (m, 1H), 3.91-3.82 (m, 1H), 3.00-2.98 (m, 2H), 2.71-2.56 (m, 1H), 2.48-2.39 (m, 1H), 2.37-2.18 (m, 2H), 1.92-1.76 (m, 2H), 1.69-1.15 (m, 32H), 0.93-0.76 (m, 15H), 0.85 (s, 3H), 0.84 (s, 3H); Mass: [M+Na]+ 703 (100); IR (KBr, cm−1): 3321, 2951, 1713, 1631, 1532, 1460, 1386, 1252, 1169, 1108, 1044, 983, 882; M.R: 203.9° C.-205.0° C.; HPLC: 97.3%.
Reaction SMILES: [BH4-].[Na+].C[O:4][C:5]([C:7]1[CH:15]=[CH:14][C:10]2[N:11]=[N:12][S:13][C:9]=2[CH:8]=1)=O>CO>[OH:4][CH2:5][C:7]1[CH:15]=[CH:14][C:10]2[N:11]=[N:12][S:13][C:9]=2[CH:8]=1
Reactant: COC(=O)c1ccc2nnsc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc2nnsc2c1
Yield: 45 %

Procedure:
Add sodium borohydride (1.35 g, 36 mmol) in five portions over 4 h to a solution of benzo[1,2,3]thiadiazole-6-carboxylic acid methyl ester (0.35 g, 1.8 mmol, prepared by following the procedure described in J. Heterocyclic Chem. 1972, 1149) in methanol (18 mL) at 0° C. Add acetone to quench and evaporate the mixture onto silica gel. Purify the residue by chromatography on silica gel eluting with hexane/EtOAc (1:0 to 2:3 gradient) to give the desired intermediate (133 mg, 45%). MS (GCMS) m/z: 166 M+.
Reaction SMILES: [CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH:15]([NH2:22])[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:25][C:26]([CH3:28])=O.C(O)(=O)C.C([BH3-])#N.[Na+]>C(Cl)Cl>[CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH:15]([NH:22][CH:26]([CH3:28])[CH3:25])[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CC(C)=O
Reactant: Cc1ccc2c(c1)c1c(n2CC(N)c2ccncc2)CCN(C)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(NC(C)C)c2ccncc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
2-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethylamine (200 mg, 0.62 mmol) was dissolved in 15 mL DCM, acetone (108 mg, 1.87 mmol), acetic acid (0.5 mL) was added and the reaction mixture was stirred at RT overnight. Sodiumcyanoborohydride (117 mg, 1.87 mmol) was added and stirred at for 1 h. The reaction mixture was diluted with DCM (300 mL) and washed with saturated bicarbonate solution (200 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by reverse phase chromatography to obtain 120 mg of [2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethyl]-isopropyl-amine as the TFA salt. 1H NMR (CD3OD, TFA salt): δ (ppm): 8.52 (m, 2H), 7.42 b (s, 2H), 7.30 b (s, 1H), 7.22 (s, 1H), 7.02 (m, 1H), 4.8 (m, 1H), 4.58 (m, 2H), 4.23 (t, 1H), 3.72 (m, 1H), 3.4 (m, 3H), 3.13 (m, 2H), 2.99 (d, 3H), 2.39 (s, 3H), 1.43 (d, 3H), 1.34 (d, 3H). Chiral HPLC separates the racemate into enantiomers II-10a-b.
Reaction SMILES: C(OC(=O)[N:7]([CH2:30][CH2:31][CH2:32][CH2:33][N:34]([CH2:38][CH2:39][CH3:40])[CH2:35][CH2:36][CH3:37])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH2:24][C:25]2[NH:26][CH:27]=[CH:28][N:29]=2)[CH2:17][C:18]2[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=2)=[CH:11][CH:10]=1)(C)(C)C.Cl.CO>CO>[NH:29]1[CH:28]=[CH:27][N:26]=[C:25]1[CH2:24][N:16]([CH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][NH:7][CH2:30][CH2:31][CH2:32][CH2:33][N:34]([CH2:35][CH2:36][CH3:37])[CH2:38][CH2:39][CH3:40])=[CH:10][CH:11]=1)[CH2:17][C:18]1[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=1
Reactant: CCCN(CCC)CCCCN(Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CCCN(CCC)CCCCNCc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
The compound (197 mg) obtained in Example 1-7 was dissolved in methanol (1.0 ml) and added with a 10% hydrogen chloride/methanol solution (3.0 ml) and the whole was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off and a hydrochloride (159 mg) of the subject compound was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([OH:18])=O)=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1.[K].C(N(C(C)C)C(C)C)C.ON1C2C=CC=CC=2N=N1.[CH2:39]([C:41]1[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][CH3:49])[C:42]=1[NH2:43])[CH3:40]>CN(C)C=O.O>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([NH:43][C:42]4[C:44]([CH2:48][CH3:49])=[CH:45][CH:46]=[CH:47][C:41]=4[CH2:39][CH3:40])=[O:18])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1
Reactant: CCc1cccc(CC)c1N
Reactant: Cn1nc(C(=O)O)c2c1-c1nc(N)ncc1CC2
Agent: On1nnc2ccccc21
Agent: [K]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(N)nc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
A suspension of potassium 8-amino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid (180 mg, 0.73 mmol) in anhydrous dimethylformamide (5.0 mL) was treated with N-ethyl-N,N-diisopropylamine (0.258 mL, 1.47 mmol) and N-ethyl-N′,N′-diisopropyl carbodiimide hydrochloride (EDCI) (280 mg, 1.47 mmol) and 1-hydroxybenzotriazole (200 mg, 1.47 mmol). The mixture was then treated with 2,6-diethylaniline (0.170 mL, 1.1 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with water and the resulting precipitate was collected by filtration to afford the title compound (190 mg, 70% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][C@@H:6]1[C:18]2[N:17]([C@H](C3C=CC(Cl)=CC=3)C)[C:16]3[C:11](=[CH:12][C:13]([F:32])=[CH:14][C:15]=3[S:28]([CH3:31])(=[O:30])=[O:29])[C:10]=2[CH2:9][CH2:8][CH2:7]1)C.C1COCC1.CO.[Li+].[OH-]>CC(O)=O>[CH3:1][O:3][C:4](=[O:33])[CH2:5][C@@H:6]1[C:18]2[NH:17][C:16]3[C:11](=[CH:12][C:13]([F:32])=[CH:14][C:15]=3[S:28]([CH3:31])(=[O:30])=[O:29])[C:10]=2[CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)C[C@H]1CCCc2c1n([C@@H](C)c1ccc(Cl)cc1)c1c(S(C)(=O)=O)cc(F)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C[C@H]1CCCc2c1[nH]c1c(S(C)(=O)=O)cc(F)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the compound of Step 5 in a 2:1 mixture of THF and methanol (0.1M) was added 1N aqueous LiOH (3 eq). The mixture was stirred at room temperature for 2 hr, AcOH was added and the solvent was removed by evaporation. The residue was taken up in EtOAc/H2O and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was swished in 30% EtOAc in hexane, and the product was suspended in diethyl ether and sonicated for 45 min, filtered, and dried under high vacuum at 50° C. for 24 hr to give the title compound as a white solid. MS (−APCI) m/z 462.1 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23]Cl)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(OCCCCl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(OCCCN3CCCCC3)cc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 4-[4-(3-chloro-propoxy)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (D9) (4.0 g; 11.3 mM), piperidine (2.23 ml; 2 eq), potassium carbonate (3.73 g; 2.4 eq) and potassium iodide (3.74 g; 2 eq) in butan-2-one (100 ml) was heated at reflux for 3 days. The mixture was allowed to cool to room temperature, filtered and evaporated to give the title compound as a pale yellow solid (4.6 g)
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][O:5][C:4]1=[O:8].[BrH:9]>CC(O)=O>[BrH:9].[NH2:2][C@@H:3]([CH2:7][CH2:6][Br:9])[C:4]([OH:5])=[O:8]
Reactant: N[C@H]1CCOC1=O
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Product: N[C@@H](CCBr)C(=O)O
Reaction time: 0.5 h
Yield: 98 %

Procedure:
(S)-3-aminodihydrofuran-2(3H)-one hydrochloride (10.30 g, 74.87 mmol) in 58 mL of 30% w/w HBr in HOAc was stirred at 65° C. for 30 hrs. The solvent was removed under reduced pressure and the resulted solid was suspended in MTBE (200 mL) and stirred for 30 min. The solid was collected by filtration and washed with MTBE (200 mL) and dried to give (S)-2-amino-4-bromobutanoic acid hydrobromide as white solid (19.33 g, 98%). 1H NMR (400 MHz, d6-DMSO) δ8.37 (s, 3H), 4.01 (m, 1H), 3.65 (m, 2H), 2.33 (m, 2H).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][C:11]=1[C@@H:19]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:20][CH2:21][N:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.COCCO[AlH2-]OCCOC.[Na+].Cl>C1(C)C=CC=CC=1>[CH2:2]([O:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][OH:15])=[CH:12][C:11]=1[C@@H:19]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:20][CH2:21][N:22]([CH:23]([CH3:24])[CH3:25])[CH:26]([CH3:27])[CH3:28])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(C(=O)O)ccc1OCc1ccccc1)C(C)C
Agent: COCCO[AlH2-]OCCOC
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CO)ccc1OCc1ccccc1)C(C)C

Procedure:
10 g (R)-4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-benzoic acid hydrochloride of formula (G) was added in 10 ml toluene followed by slow addition of 3.2 g Vitride in above solution at 0° C. to 5° C. within 15 minutes. Further 20% HCl solution was added and toluene layer washed with water. Distillation of toluene layer afforded the title compound as (R)-[4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-phenyl]-methanol of formula (H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:29]([CH3:34])([C:30]([NH:32][NH2:33])=[O:31])[C:28](=[O:35])[NH:27][C:4]=2[N:5]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=3)[C:10]([CH2:18][CH2:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])=[N:9]2)[N:7]=1.[C:36](N1C=CN=C1)(=[O:38])[CH3:37]>C1COCC1>[C:36]([N:32]([C:30]([C:29]1([CH3:34])[C:3]2[C:2]([NH2:1])=[N:7][C:6]([N:8]3[C:16]4[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=4)[C:10]([CH2:18][CH2:19][C:20]([F:25])([F:26])[C:21]([F:23])([F:24])[F:22])=[N:9]3)=[N:5][C:4]=2[NH:27][C:28]1=[O:35])=[O:31])[NH2:33])(=[O:38])[CH3:37]
Reactant: CC1(C(=O)NN)C(=O)Nc2nc(-n3nc(CCC(F)(F)C(F)(F)F)c4cc(Cl)ccc43)nc(N)c21
Reactant: CC(=O)n1ccnc1
Solvent: C1CCOC1
Product: CC(=O)N(N)C(=O)C1(C)C(=O)Nc2nc(-n3nc(CCC(F)(F)C(F)(F)F)c4cc(Cl)ccc43)nc(N)c21

Procedure:
To a THF solution (3 mL) of the intermediate from Step A (100 mg, 0.193 mmol) was added 1-acetylimidazole (85 mg, 0.771 mmol). The resultant mixture was stirred at ambient temperature under a nitrogen atmosphere for 3 hours then purified by preparative TLC using 10% MeOH/1% NH4OH I DCM as eluent to give the indicated product. m/z=561.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:5]=2[CH:4]=1.C(N(CC)CC)C.Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH:33]2[CH2:35][CH2:36][CH:30]1[CH2:31][CH2:32]2>O>[CH:30]12[CH2:36][CH2:35][CH:33]([CH2:32][CH2:31]1)[CH2:34][N:29]2[CH2:28][CH2:27][N:12]1[CH2:13][CH2:14][C:9]2[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[O:16][C:15](=[O:17])[C:10]=2[CH2:11]1
Reactant: ClCCN1CC2CCC1CC2
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc2c3c(c(=O)oc2c1)CN(CCN1CC2CCC1CC2)CC3
Yield: 48 %

Procedure:
Prepared by the method described for Example 27 from 1,2,3,4-tetrahydro-8-methoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one (3.0 g, 0.013 moles), triethylamine (3.9 ml, 0.028 moles), and 2-(2-chloroethyl)-2-azabicyclo[2.2.2]octane hydrochloride (2.9 g, 0.014 moles). Reflux time is 3 weeks. The crude product is dissolved in water, extracted with ethyl acetate, precipitated by the addition of solid potassium carbonate, filtered off, rinsed with water, and dried to yield the final product (2.3 g), mp 112°-113° C.
Reaction SMILES: [N+:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([O-:3])=[O:2].[CH2:21]1[CH2:31][CH2:30]N2C(=NCCC2)C[CH2:22]1.C1(C=O)CC1>CN(C=O)C.O>[CH:21]1(/[CH:22]=[C:4](/[C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][CH:12]=3)=[CH:9][CH:10]=2)\[N+:1]([O-:3])=[O:2])[CH2:30][CH2:31]1
Reactant: O=[N+]([O-])Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: C1CCC2=NCCCN2CC1
Agent: O=CC1CC1
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])/C(=C\C1CC1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a room temperature solution of 4-(nitromethyl)-4′-(trifluoromethyl)biphenyl (200 mg, 0.711 mmol) and DBU (54.4 mg, 0.355 mmol) in DMF (3 ml) was added cyclopropanecarbaldehyde (99.7 mg, 1.42 mmol). The reaction mixture was stirred at room temperature overnight. The resulting mixture was diluted with water and extracted with ethyl acetate (10 mL*3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative TLC to give impure (Z)-4-(2-cyclopropyl-1-nitrovinyl)-4′-(trifluoromethyl)biphenyl (110 mg) as a colorless solid. To a solution of the impure (Z)-4-(2-cyclopropyl-1-nitrovinyl)-4′-(trifluoromethyl)biphenyl (55 mg, 0.16 mmol) in THF (3 mL) was added Raney nickel. The reaction mixture was stirred at room temperature under an atmosphere of hydrogen (40 psi) overnight. The reaction mixture was purified by preparative TLC to give 2-cyclopropyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)ethanamine (20 mg) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.62-7.60 (m, 4H), 7.49 (d, J=8.0 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 4.04-4.08 (m, 1H), 1.70-1.56 (m, 1H), 1.54-1.49 (m, 1H), 0.65-0.50 (m, 1H), 0.45-0.30 (m, 2H), 0.15-0.00 (m, 2H).
Reaction SMILES: C(O[C:6](=[O:29])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:26]=[N:25][C:24]3[C:19](=[C:20]([O:27][CH3:28])[CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:10][CH2:9]1)(C)(C)C.[O:30]=[C:31]1[NH:36][C:35]2[CH:37]=[C:38](C(O)=O)[CH:39]=[CH:40][C:34]=2[S:33][CH2:32]1>>[CH3:28][O:27][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:19]=1[N:18]=[C:17]([O:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][CH:8]([NH:7][C:6]([C:38]3[CH:39]=[CH:40][C:34]4[S:33][CH2:32][C:31](=[O:30])[NH:36][C:35]=4[CH:37]=3)=[O:29])[CH2:9][CH2:10]1)[CH:26]=[N:25]2
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: COc1cccc2ncc(OCCN3CCC(NC(=O)OC(C)(C)C)CC3)nc12
Product: COc1cccc2ncc(OCCN3CCC(NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)nc12

Procedure:
The title compound is prepared as an off-white lyophilizated powder following Scheme 1 and in analogy to Example 1 using {1-[2-(8-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=1
Reactant: O=C1CCCCc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)C(=O)CCCC2
Yield: 101.3 %

Procedure:
A mixture of 3-nitro-6,7,8,9-tetrahydrobenzocyclohepten-5-one (14.87 g), iron (14.87 g) and ammonium chloride (2.0 g) in ethanol (200 ml) and water (40 ml) was refluxed for 5 hours, and filtered. The filtrate was evaporated in vacuo to afford 3-amino-6,7,8,9-tetrahydrobenzocyclohepten-5-one (12.86 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](Cl)=O)[CH:6]=[CH:7][CH:8]=1.[Cl:13][C:14]1[CH:15]=[C:16]([NH2:22])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[Cl:13][C:14]1[CH:15]=[C:16]([N:22]([CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:3](=[O:2])[CH2:8][CH3:7])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(N)cc1Cl
Reactant: COc1cccc(CC(=O)Cl)c1
Product: CCC(=O)N(CCc1cccc(OC)c1)c1ccc(OC)c(Cl)c1

Procedure:
According to synthetic methods F and G, N-(3-chloro-4-methoxy-phenyl)-N-[2-(3-methoxy-phenyl)-ethyl]-propionamide (0.753 g) was obtained from (3-methoxy-phenyl)-acetyl chloride (1.0 eq) and 3-chloro-4-methoxy-phenylamine (1.0 eq) followed by reaction with propionyl chloride (1.5 eq). MS: 348.4 (MH+); HPLC tR: 2.72 mm (method D); TLC Rf: 0.48 (ethyl acetate:hexane-1:1). According to synthetic methods H and B, the title compound (0.25 g) was obtained after purification by chromatography on silica gel (eluant: a gradient of 0 to 5% methanol in methylene chloride); MS: 304.2, 306.2 (MH+); HPLC tR: 1.80 min (method D); TLC Rf: 0.16 (2% methanol:methylene chloride).
Reaction SMILES: [OH:1][CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([CH:9]=[C:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:7][CH:6]=1.O.[BH4-].[Na+].C(O)(=O)C>C1COCC1.[OH-].[Na+].O.O.O.O.O.O.[Co](Cl)Cl.CC(=NO)C(C)=NO>[OH:1][CH:2]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][CH:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:7][CH:6]=1
Reactant: O=C1NC(=O)C(=Cc2ccc(OCC(O)c3ccccc3)cc2)S1
Agent: Cl[Co]Cl
Agent: CC(=NO)C(C)=NO
Agent: [BH4-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C1NC(=O)C(Cc2ccc(OCC(O)c3ccccc3)cc2)S1
Reaction time: 1 h
Yield: 76.3 %

Procedure:
To a mixture of 5-[4-(2-hydroxy-2-phenylethoxy)benzylidene]-1,3-thiazolidine-2,4-dione (1.50 g, 4.39 mmol) in THF (20 mL) was added H2O (20 mL), 1M NaOH (3 mL), cobalt (II) chloride hexahydrate (0.60 mg, 0.003 mmol) and dimethylglyoxime (15 mg, 0.13 mmol). A solution of sodium tetrahydroborate (240 mg, 6.33 mmol) in 0.2M NaOH (3.6 mL) was added. The reaction mixture immediately turned dark but very soon assumed a clear yellow appearance. Acetic acid was added dropwise until the solution turned dark (3 drops). After ca. one hour, the reaction lightened. Additional NaBH4, CoCl2 and HOAc were added to produce a deep blue-purple color. When that color faded, more NaBH4 was added. When HPLC analysis indicated that the reaction was complete, it was partitioned between H2O and EtOAc, and the organic phase was washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting foamy solid was chromatographed, eluting with 50% EtOAc/hexanes. Fractions containing product were combined and evaporated in vacuo to give 1.15 g (76%) of the title compound as a white solid. MS (ESI−) for C18H17NO4S m/z 342.1 (M−H)−.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[C:15]1[S:16][C:17]2[C:23](=[O:24])[CH:22]=[C:21](OC)[C:20](=[O:27])[C:18]=2[N:19]=1>C(O)C>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[C:15]1[S:16][C:17]2[C:23](=[O:24])[CH:22]=[C:21]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[C:20](=[O:27])[C:18]=2[N:19]=1
Reactant: COC1=CC(=O)c2sc(-c3c(F)cccc3F)nc2C1=O
Reactant: CN(C)CCN
Solvent: CCO
Product: CN(C)CCNC1=CC(=O)c2sc(-c3c(F)cccc3F)nc2C1=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
104 ml (0.95 mmol; 1.5 equivalents) of N,N-dimethylethylenediamine are added to 195 mg of 2-(2,6-difluorophenyl)-5-methoxy-1,3-benzothiazole-4,7-dione in solution in 20 ml of anhydrous ethanol. The reaction mixture is stirred at 70° C. for 2 hours then the solvent is evaporated off under reduced pressure. The residue is purified on a silica column (eluent: 5% methanol in dichloromethane). 130 mg (yield=57%) of expected compound is obtained in the form of a red powder.