Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[C:10]([CH2:20][CH3:21])([CH2:18][CH3:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].BrN1C(=O)CCC1=O.BrBr>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:10]([CH2:18][CH3:19])([CH2:20][CH3:21])[C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])=[CH:4][CH:3]=1
Reactant: CCC(Br)(CC)C(=O)OC(C)(C)C
Reactant: Sc1ccc(Br)cc1
Agent: BrBr
Agent: O=C1CCC(=O)N1Br
Product: CCC(CC)(Sc1ccc(Br)cc1)C(=O)OC(C)(C)C

Procedure:
The synthesis was carried out similarly to Example II-1 from 4-bromothiophenol and 1,1-dimethylethyl 2-bromo-2-ethyl-butanoate [preparation, for example, similarly to Liebigs Ann. Chem. 725, 106-115 (1969); J. Am. Chem. Soc. 77, 946-947 (1955), and bromination with N-bromosuccinimide or bromine, for example similarly to Tetrahedron Lett. 1970, 3431; J. Org. Chem. 40, 3420 (1975)].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21](Br)[CH:20]=2)=[O:16])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][N:31](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:30]#[N:31])[CH:20]=2)=[O:16])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2cc(Br)cc(C(F)(F)F)c2)CC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2cc(C#N)cc(C(F)(F)F)c2)CC1
Temperature: 150 °C

Procedure:
3-Bromo-5-(trifluoromethyl)benzyl 4-((tert-butoxycarbonyl)amino)piperidine-1-carboxylate (Example 63, step 2) (214 mg, 0.445 mmol), zinc cyanide (26.1 mg, 0.222 mmol) and Pd(PPh3)4 (20.5 mg, 0.018 mmol) were dissolved in DMF (4 ml) and the vial flushed with nitrogen. The mixture was heated in the microwave at 150° C. for 10 mins, then cooled and diluted with EtOAc (30 ml). This was washed with a saturated solution of brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification by chromatography on a 4 g silica column using 0-50% EtOAC/hexanes as eluent gave the title compound.
Reaction SMILES: [C:1]([N:9]1[C@@H:13]([CH3:14])[C:12](=[O:15])OC1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([C@@H:23]([NH2:25])[CH3:24])=[CH:19][CH:18]=1.CN1CCOCC1.Cl>C(OCC)(=O)C>[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([C@@H:23]([NH:25][C:12](=[O:15])[C@H:13]([CH3:14])[NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:24])=[CH:19][CH:18]=1
Reactant: C[C@H]1C(=O)OC(=O)N1C(=O)c1ccccc1
Reactant: Cc1ccc([C@H](C)N)cc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: Cc1ccc([C@H](C)NC(=O)[C@H](C)NC(=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
(S)-3-Benzoyl-4-methyl-2,5-oxazolidinedione (N-benzoyl-L-alanine-NCA) (110 mg, 0.50 mmol) was dissolved in ethyl acetate (2.5 mL), followed by the addition of a solution of (S)-1-(p-tolyl)ethylamine (68 mg, 0.50 mmol) in ethyl acetate (2.5 mL) at 0° C. A solution of N-methylmorpholine (61 mg, 0.6 mmol) in ethyl acetate (3.0 mL) was then added, followed by stirring for 30 minutes. The reaction mixture was poured into 1 N hydrochloric acid (10 mL), followed by extraction with ethyl acetate (10 mL). The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate (10 mL) and a saturated aqueous solution of sodium chloride (10 mL), and was then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to afford the title compound (149 mg, 97%) as white crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9]1)=O)(C)(C)C.[NH2:15][C:16]1[C:25]2[C:20](=[CH:21][C:22](O)=[CH:23][CH:24]=2)[CH:19]=[CH:18][N:17]=1>>[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[C:16]([NH2:15])=[N:17][CH:18]=[CH:19]3)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Reactant: Nc1nccc2cc(O)ccc12
Product: Nc1nccc2cc(OC3CCCNC3)ccc12
Yield: 12.1 %

Procedure:
This compound was prepared from racemic 3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (207 mg, 1.02 mmol) and 1-amino-6-hydroxyisoquinoline (198 mg, 1.23 mmol) by the Mitsunobu procedure described in 3C, subsequent Boc deprotection according to procedure described in 3D gave racemic 6-(piperidin-3-yloxy)-isoquinolin-1-ylamine (30 mg), El-MS: m/z=244.4 [M+H]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)(=O)=O.[CH:15]1([SH:20])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[Br:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][S:20][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:13][CH:12]=1
Reactant: SC1CCCC1
Reactant: CS(=O)(=O)OCCc1ccc(Br)cc1
Product: Brc1ccc(CCSC2CCCC2)cc1

Procedure:
Obtained by working as in Example 1a, starting with 2-(4-bromophenyl)ethyl methanesulfonate (Carbohydr. Res. (2003) 338, 29) and cyclopentanethiol.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([F:19])([F:18])[CH2:13]1)(C(C)(C)C)(C)C>C1COCC1>[F:19][C:14]1([F:18])[CH2:15][CH2:16][CH2:17][N:12]([CH2:11][CH2:10][CH2:9][OH:8])[CH2:13]1
Reactant: CC(C)(C)[Si](C)(C)OCCCN1CCCC(F)(F)C1
Solvent: C1CCOC1
Product: OCCCN1CCCC(F)(F)C1
Temperature: 50 °C

Procedure:
To a solution of the product of Step 1 (612 mg) in THF (20 mL) was added HF-TEA (13.58 mL) at room temperature. The solution was heated to 50° C. for 45 minutes. The reaction mixture was concentrated to remove THF and then diluted with ethyl acetate (100 mL) and water was added (100 mL). To that mixture was added Na2CO3 (14.4 g) portion wise at 0° C. When the quench was complete, the layers were separated. The organic layer was washed with 10% Na2CO3, water and brine. The aqueous layer was re-extracted with ethyl acetate (2×). The combined organics were dried over magnesium sulfate, filtered and concentrated. The crude product (350 mg) was used directly in the next step. HRMS (ES+) m/z 180.1202 (M+H)+.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH3:15])[N:11]=[C:10]([C:16]2[CH:23]=[C:22]([S:24][CH3:25])[C:19]([C:20]#[N:21])=[C:18](F)[CH:17]=2)[CH:9]=1)[CH3:2].CCN(C(C)C)C(C)C.[NH2:36][NH2:37]>CCO>[CH2:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH3:15])[N:11]=[C:10]([C:16]2[CH:17]=[C:18]3[C:19]([C:20]([NH2:21])=[N:36][NH:37]3)=[C:22]([S:24][CH3:25])[CH:23]=2)[CH:9]=1)[CH3:2]
Reactant: NN
Reactant: CC[C@@H]1CCCN1c1cc(-c2cc(F)c(C#N)c(SC)c2)nc(NC)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H]1CCCN1c1cc(-c2cc(SC)c3c(N)n[nH]c3c2)nc(NC)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
In a microwave tube, 4-[6-[(2R)-2-ethyl-1-pyrrolidinyl]-2-(methylamino)-4-pyrimidinyl]-2-fluoro-6-(methylthio)benzonitrile (136 mg, 0.366 mmol), 5 mL of EtOH, Hunig's base (0.064 mL, 0.366 mmol), and hydrazine anhydrous (0.069 mL, 2.197 mmol) were added. The yellow suspension mixture was heated to 100° C. in an oil bath overnight. When the temperature of the reaction reached 100° C., the solid in the mixture was all dissolved. After overnight, there was a white colored solid formed. LCMS showed no more starting material. The reaction was cooled to room temperature, then the white solid was filtered from the yellow solution, washed by CH3CN (2 mL), dried under reduced pressure to afford the title compound (90 mg). LC-MS (ES) m/z=370 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.91 (t, J=7.3 Hz, 3H), 1.36 (m, 1H), 1.80 (m, 2H), 1.93 (m, 3H), 2.59 (s, 3H), 2.83 (d, J=4.6 Hz, 3H), 3.53 (m, 1H), 4.06 (m, 1H), 5.08 (s, 2H), 6.22 (s, 1H), 6.44 (s, 1H), 7.38 (s, 1H), 7.71 (s, 1H), 11.75 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([O:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][NH:16][C:17](=[O:23])[CH2:18][S:19][CH2:20][CH2:21][OH:22])[CH:6]=1)[CH3:3].[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([O:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][NH:16][C:17](=[O:23])[CH2:18][S:19][CH2:20][CH2:21][O:22][C:24](=[O:26])[CH3:25])[CH:6]=1)[CH3:3]
Reactant: CN(C)Cc1ccnc(OC/C=C\CNC(=O)CSCCO)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCCSCC(=O)NC/C=C\COc1cc(CN(C)C)ccn1
Yield: 58 %

Procedure:
Following a procedure similar to that described in Example 67(c), but using N-[4-(4-dimethylaminomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide [prepared as described in step (a) above] and acetic anhydride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a 58% yield.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:13])(=[O:3])[CH3:2].[CH2:14]([O:16][C:17](=O)[CH3:18])[CH3:15]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:14]([O:16][CH2:17][CH3:18])[C:15]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:5]1=[O:13])(=[O:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(=O)N1C(=O)Cc2ccccc21
Product: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1

Procedure:
Yield: about 67% of theory, the product contains about 25 to 34% of 1-acetyl-2-indolinone. Melting point: 123-129° C. (with an amount of 34% of 1-acetyl-2-indolinone). An insoluble fraction is isolated from the above mixture by combining with ethylacetate, extracting with dilute aqueous sodium carbonate solution and with water and by filtering, this fraction being the pure product. Melting point: 187-189° C.; C19H17NO3 ; Calc.: C, 74.25; H, 5.57; N, 4.56; Found: 73.95; 5.57; 4.53.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:35])([C:29]2[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=2)[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=[C:13]3[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[CH:5][CH:4]=1.[CH3:36][CH2:37][O-:38].[Na+].CCO.O>C(O)C>[Cl:28][C:24]1[CH:23]=[C:22]([C:13]2[C:12]3[C:17](=[CH:18][CH:19]=[C:10]([C:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:2][O:38][CH2:37][CH3:36])=[CH:4][CH:5]=4)([OH:35])[C:29]4[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=4)[CH:11]=3)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC[O-]
Reactant: Cn1cncc1C(O)(c1ccc(CCl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOCc1ccc(C(O)(c2ccc3c(c2)c(-c2cccc(Cl)c2)cc(=O)n3C)c2cncn2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.1 %

Procedure:
A mixture of (±)-6-[[4-(chloromethyl)phenyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (0.0002 mol), obtained in Example B14, and EtONa/EtOH (0.0005 mol) in ethanol (1 ml) was stirred at room temperature for 18 hours, poured out into water and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (0.1 g) was purified by column chromatography over kromasil 10 μm (eluent: CH2Cl2/CH3OH; 90/10). The pure fractions were collected and the solvent was evaporated, yielding 0.034 g (33%) of 4-(3-chlorophenyl)-6-[[4-(ethoxymethyl)phenyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone, as a white foam, MS (ESI) m/z:514, 516 (MH+).
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[N:8]=2)=[N:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CS(C)=O>[N:26]1([C:2]2[S:6][C:5]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]4[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=4)[N:8]=3)=[N:4][CH:3]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: C1CNCCN1
Reactant: COc1cc(Nc2nccc(-c3ncc(Cl)s3)n2)cc(OC)c1OC
Solvent: CS(C)=O
Product: COc1cc(Nc2nccc(-c3ncc(N4CCNCC4)s3)n2)cc(OC)c1OC
Temperature: 100 °C
Yield: 23.6 %

Procedure:
To solution of [4-(5-Chloro-thiazol-2-yl)-pyrimidin-2-yl]-(3,4,5-trimethoxy-phenyl)-amine (150 mg) in dimethylsulfoxide (2 ml) was added piperazine (300 mg). The mixture was heated to 100° C. for 5 hours then allowed to cool and concentrated under high vacuum to an oil. The residue was purified by HPLC with 0.1% TFA/water acetonitrile as eluant to afford the sub-titled compound as an yellow solid (40 mg, 25%); IR (solid) 1567, 1504, 1432, 1411 cm−1; 1H NMR (400 Mhz, CDCl3) δ 1.3-1.5 (1H, br s), 3.1 (4H, s), 3.25 (4H, s), 3.85 (3H, s), 3.95 (6H, s), 7.05 (1H, s), 7.15 (1H, s), 7.19 (1H, s), 7.40 (1H, m), 8.6 (1H, d); MS (ES+) 429.3 (M+1), (ES−) 427.3 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9](Cl)(=[O:11])=[O:10].C(N(CC)CC)C.[CH2:20]([P:22]([CH2:28][OH:29])(=[O:27])[O:23][CH:24]([CH3:26])[CH3:25])[CH3:21]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:20]([P:22]([CH2:28][O:29][S:9]([C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:11])=[O:10])(=[O:27])[O:23][CH:24]([CH3:26])[CH3:25])[CH3:21]
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: CCP(=O)(CO)OC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCP(=O)(COS(=O)(=O)c1c(Cl)cccc1Cl)OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
A solution of 19.6 g of 2,6-dichlorobenzenesulfonyl chloride dissolved in 70 ml of methylene chloride was added dropwise over 40 minutes to a mixture of 25 ml of methylene chloride, 15.0 ml of triethylamine, 1.0 g of DMAP, and 16.5 g of O-isopropyl P-ethyl(hydroxymethyl)phosphinate, (Example 22, Method A). The addition caused a mild exotherm and the reaction was allowed to stir at room temperature overnight. The reaction mixture was then washed with two 50 ml portions of water, the phases separated, the organic phase dried with magnesium sulfate, filtered, and concentrated to yield 19.6 g of the desired product as a yellow oil. The crude product was diluted with 10 ml of methylene chloride and flash chromatographed using blends of ethyl acetate and hexanes. Similar fractions were combined and rechromatographed to yield 0.95 g of the desired product.
Reaction SMILES: [CH2:1]([O:8][C@@:9]1([C:36]([F:39])([F:38])[F:37])[CH2:33][C@H:13]2[CH2:14][CH2:15][CH2:16][C:17]3[C:18](=[CH:19][C:20]4[CH:21]=[N:22][N:23]([C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)[C:24]=4[CH:25]=3)[C@:12]2([CH2:34][NH2:35])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH2:1]([O:8][C@@:9]1([C:36]([F:38])([F:39])[F:37])[CH2:33][C@H:13]2[CH2:14][CH2:15][CH2:16][C:17]3[C:18](=[CH:19][C:20]4[CH:21]=[N:22][N:23]([C:26]5[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=5)[C:24]=4[CH:25]=3)[C@:12]2([CH2:34][NH:35][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC[C@@]12CC[C@](OCc3ccccc3)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)NC[C@@]12CC[C@](OCc3ccccc3)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Crude ((3R,4aR,12bS)-3-(benzyloxy)-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-12b-yl)methan amine (34, R1=4-Fluorophenyl, R3=Trifluoromethyl, R4═H, R3=Benzyl) (0.135 mmol) was dissolved in DCM (3 mL) and methanesulfonyl chloride (0.026 mL, 0.334 mmol) and TEA (0.023 mL, 0.167 mmol) were added at rt. The reaction was stirred at rt for about 30 min, then diluted with DCM (10 mL) and concentrated with silica gel (3 g). The residue was purified on silica gel using a gradient of 0-10% EtOAc in DCM. Product fractions were combined and concentrated to yield N-(((3R,4aR,12bS)-3-(benzyloxy)-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-12b-yl)methyl)methanesulfonamide (35, R1=4-Fluorophenyl, R3=Trifluoromethyl, R4=Methanesulfonyl, R3=Benzyl) (40 mg, 39%) as a clear glass; LC/MS, method 3, Rt=2.95 min, MS m/z 616 (M+H)+.) The residue was used in step #4 without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[C:12]([O:11][CH3:10])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COc1cccc(N)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cccc(NCc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
4-Chlorobenzaldehyde (3.41 g, 27.5 mmol) was added to a cooled stirred solution of 3-methoxy aniline (3.38 g, 27.5 mmol) in anhydrous dichloromethane (120 ml). Sodium triacetoxy borohydride (8.16 g, 38.5 mmol) and acetic acid (1.57 ml, 27.5 mmol) were added and the reaction stirred under nitrogen at room temperature overnight. The reaction was quenched by the addition of 2 N sodium hydroxide (aq) and the resulting solution was extracted with dichloromethane (3×100 ml). The organic extracts were combined, washed with water (100 ml), brine (100 ml) and then concentrated in vacuo to obtain crude product. The residues were purified by flash chromatography (SiO2) eluting with petrol/dichloromethane 3:1 to afford the title compound (4.4 g, 64% yield). HPLC retention time 8.4 min Mass spectrum (ES+) m/z 248 (M+H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:52][C:53]1[S:54][CH:55]=[N:56][N:57]=1>CN(C)C=O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:52][C:53]2[S:54][CH:55]=[N:56][N:57]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nncs1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nncs1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Yield: 76.1 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared from Example 38, 200.0 mg, 0.70 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (316.9 mg, 0.84 mmol), N,N-diisopropylethylamine (365 mL, 2.09 mmol), and 2-amino-1,3,4-thiadiazole (140.8 mg, 1.39 mmol) in dry N,N-dimethylformamide (2 mL) was stirred at 25° C. under nitrogen for 20 h. The reaction mixture was concentrated in vacuo to remove N,N-dimethylformamide. The resulting residue was diluted with ethyl acetate (100 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×50 mL), a 10% aqueous hydrochloric acid solution (1×100 mL), and a saturated aqueous sodium chloride solution (1×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-[1,3,4]thiadiazol-2-yl-propionamide (197.3 mg, 77%) as a white foam: mp 90-91° C.; EI-HRMS m/e calcd for C16H17Cl2N3OS (M+) 369.0469, found 369.0476.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[CH:12][C:13]([Cl:16])([Cl:15])[Cl:14]>C1C=CC=CC=1>[C:1]([NH:9][N:10]=[CH:12][C:13]([Cl:16])([Cl:15])[Cl:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC(Cl)(Cl)Cl
Reactant: NNC(=O)c1ccccc1
Solvent: c1ccccc1
Product: O=C(NN=CC(Cl)(Cl)Cl)c1ccccc1

Procedure:
10 g (0.073 mol) of benzoylhydrazine were suspended in benzene, 200 ml, and 18.3 g (0.124 mol) of chloral were added dropwise to the suspension which was then refluxed under agitation for 3 hours. Upon cooling, the sedimented crystals were collected by filtration and washed well with benzene. In this way, white brown crystals, 19 g, were obtained substantially quantatively. m.p. 188°-189° C. (decomposed). When recrystallized from acetone, the Compound No. 1, m.p. 194°-195° (decomposed), was obtained in white needles. Yield: 15.4 g (81% of the theoretical).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:15][C:14](=[O:16])[CH:13]2[CH:5]([C:6]3[CH2:7][CH2:8][C:9]4[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=4[C:11]=3[S:12]2)[N:4]=1.C(N(C(C)C)CC)(C)C.[NH2:30][C:31]1[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1>CN(C)C=O>[OH:37][C:33]1[CH:32]=[C:31]([NH:30][CH2:2][C:3]2[NH:15][C:14](=[O:16])[CH:13]3[CH:5]([C:6]4[CH2:7][CH2:8][C:9]5[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=5[C:11]=4[S:12]3)[N:4]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: O=C1NC(CCl)=NC2C3=C(SC12)c1ccccc1CC3
Reactant: Nc1cccc(O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1NC(CNc2cccc(O)c2)=NC2C3=C(SC12)c1ccccc1CC3
Yield: 31.4 %

Procedure:
A solution of EXAMPLE 12E (18 mg), diisopropylethylamine and 3-aminophenol (10 mg) in N,N-dimethylformamide (0.5 mL) were heated at 70° C. for 2 hours. The mixture was cooled and purified by HPLC on a C18 column using 0-70% acetonitrile/0.1% trifluoroacetic acid in water to provide 7 mg of the title compound as the trifluoroacetate salt. 1H NMR (DMSO-d6) δ 12.29 (s, 1H), 9.01 (s, 1H), 8.17 (bs, 1H), 7.53 (m, 1H), 7.31-7.38 (m, 3H), 6.86 (t, J=7.9 Hz, 1H), 6.11 (m, 1H), 6.06 (t, J=2.1 Hz, 1H), 6.03 (dd, J=7.9, 2.1 Hz, 1H), 4.22 (s, 2H), 3.01 (m, 2H), 2.94-2.96 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10](=[O:19])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14](C)[CH:13]=2)=[C:4]([N+:20]([O-:22])=O)[CH:3]=1.ClC1C=C2C(=CC=1Cl)NC(=[O:35])C(C1C=CC(OC)=CC=1)=[N+]2[O-].[K+].[Br-]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[NH:9][C:10](=[O:19])[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:35])=[N+:20]2[O-:22]
Reactant: Cc1cccc(CC(=O)Nc2cc(Cl)c(Cl)cc2[N+](=O)[O-])c1
Reactant: COc1ccc(-c2c(=O)[nH]c3cc(Cl)c(Cl)cc3[n+]2[O-])cc1
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2[n+]([O-])c1-c1ccccc1O
Yield: 30 %

Procedure:
The title compound was prepared according to the general procedure of Example 15, except that nitrone 133 is substituted for nitrone 128. Yield: 30%; mp 266°-268° C. (from EtOH); IR (KBr) 3440, 3218, 3102, 2929, 1674, 1619, 1470, 1348, 1143 and 1112 cm-1 ; 1H NMR (in DMSO-d6) δ6.86 (m, 2H), 7.25 (m, 2H), 7.53 (s, 1H), 8.28 (s, 1H), 9.41 (br.s, 1H, O--H), 12.57 (br.s, 1H, N--H); HPLC: 99%; HRMS Calcd for C14H8N2O3Cl2 : 321.9912.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.[C:14]1([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>O1CCOCC1>[C:14]1([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[N:21]2[CH2:22][CH2:23][N:24]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=3)[CH2:25][CH2:26]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(C(c2ccccn2)N2CCNCC2)cc1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)Cc1ccc(CN2CCN(C(c3ccccc3)c3ccccn3)CC2)cc1
Yield: 51.9 %

Procedure:
Using 2.8 g of methyl 4-bromomethylphenylacetate, 2.9 g of 1-[phenyl-(2-pyridyl)methyl]piperazine, 2 ml of triethylamine, and 100 ml of dioxane, the reaction procedure of Example 1 was otherwise repeated and recrystallized from benzene-hexane to provide 2.47 g of methyl 4-[[4-[phenyl-(2-pyridyl)methyl]-1-piperazinyl]methyl]phenylacetate melting at 122° C.-123° C.