Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:13][C:14]1[CH:15]=[C:16]2[C:21]3=[C:22]([CH2:24][CH2:25][N:20]3[CH2:19][C@@H:18]3[CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][C@H:17]23)[CH:23]=1>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]([F:12])([F:11])[F:10])=[CH:3][C:2]=1[NH:13][C:14]1[CH:15]=[C:16]2[C:21]3=[C:22]([CH2:24][CH2:25][N:20]3[CH2:19][C@@H:18]3[CH2:26][NH:27][CH2:28][C@H:17]23)[CH:23]=1
Reactant: FC(F)(F)c1ccc(Cl)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN3CCc4cc(N)cc(c43)[C@H]2C1
Product: FC(F)(F)c1ccc(Cl)c(Nc2cc3c4c(c2)[C@H]2CNC[C@H]2CN4CC3)c1

Procedure:
Using 3-bromo-4-chlorobenzotrifluoride and following the procedures described in EXAMPLE 17, Parts B and C, (±)-cis tert-butyl 2-amino-4,5,7a,8,10,10a-hexahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinoline-9(7H)-carboxylate was converted into (±) -cis-N-[2-chloro-5-(trifluoromethyl)phenyl]-4,5,7,7a,8,9,10,10a-octahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinolin-2-amine, bis-trifluoroacetic acid salt, after HPLC purification (c18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA). This material was free-based with aq ammonium hydroxide, extracted with chloroform, washed with brine, dried (K2CO3) and concentrated to the title compound of EXAMPLE 114 as the free base. LRMS (ES)+: 394.4 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2)([O-:3])=[O:2].[H-].[Na+].[CH2:20](I)[CH2:21][CH3:22].O>CS(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:20][CH2:21][CH3:22])[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2)([O-:3])=[O:2]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCn1c(C(=O)OCC)cc2cc([N+](=O)[O-])ccc21
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Under argon, 937 mg (4.00 mmol) of ethyl 5-nitro-1H-indole-2-carboxylate (A. Guy, J. -P. Guetté, Synthesis 1980, 222–223) are initially charged in 12 ml of dimethyl sulphoxide. 4.40 mmol of sodium hydride (176 mg of a 60% dispersion in paraffin) are added a little at a time, and the mixture is stirred at 50° C. for 30 min. After cooling to RT, 170 mg (4.40 mmol) of propyl iodide are added, and the mixture is stirred at RT for another 3 h. The reaction mixture is poured into 30 ml of water and extracted with ethyl acetate (6×30 ml). The combined organic phases are washed with 50 ml of sat. sodium chloride sol., dried over sodium sulphate and freed from the solvent using a rotary evaporator. The resulting brown crude product is purified by column chromatography (silica gel 60, mobile phase gradient cyclohexane→cyclohexane-ethyl acetate 3:1), giving the product as second fraction.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14](B(O)O)=[CH:13][C:12]=1[CH3:21])(C(C)(C)C)(C)C.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29]([N:33]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[N:28][CH:27]=[CH:26]2.O.[C:49]([OH:53])(=[O:52])[CH:50]=O>>[C:44]([O:43][C:41]([N:33]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[C:29]1[C:30]2[C:25](=[CH:24][C:23]([NH:22][CH:50]([C:14]3[CH:13]=[C:12]([CH3:21])[C:11]([CH2:10][CH2:9][OH:8])=[C:16]([CH3:17])[CH:15]=3)[C:49]([OH:53])=[O:52])=[CH:32][CH:31]=2)[CH:26]=[CH:27][N:28]=1)=[O:42])([CH3:47])([CH3:46])[CH3:45]
Reactant: O=CC(=O)O
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Reactant: Cc1cc(B(O)O)cc(C)c1CCO[Si](C)(C)C(C)(C)C
Solvent: O
Product: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)O)cc(C)c1CCO
Yield: 39 %

Procedure:
Using a procedure analogous to that used to prepare 2D, 50B (1.43 g, 4.6 mmol) was reacted with Intermediate 1 and glyoxylic acid monohydrate to afford 50C (1.1 g, 39%) as an orange solid. MS (ESI) m/z 566.6 (M+H)+.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]#[C:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][C:20]2([CH3:26])[CH3:25])[CH2:11][C@H:10]1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([CH3:35])[CH:29]=1)=O)(C)(C)C>C(OCC)(=O)C.C(O)C>[ClH:1].[ClH:1].[ClH:1].[CH3:35][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][C:31]=1[CH3:34])[CH2:27][C@H:10]1[NH:9][CH2:14][CH2:13][N:12]([CH2:15][C:16]#[C:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][C:20]2([CH3:26])[CH3:25])[CH2:11]1
Reactant: Cc1ccc(C[C@@H]2CN(CC#CCN3CCOCC3(C)C)CCN2C(=O)OC(C)(C)C)cc1C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(C[C@@H]2CN(CC#CCN3CCOCC3(C)C)CCN2)cc1C
Reaction time: 12 h

Procedure:
A solution of 4N hydrogen chloride in ethyl acetate was added to a solution of (2R)-1-tert-butoxycarbonyl-2-(3,4-dimethylbenzyl)-4-[4-(3,3-dimethylmorpholino)-2-butynyl]piperazine (40.0 g) in ethanol (120 ml) at room temperature and the whole was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (500 ml) and potassium carbonate solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (300 ml). The combined extract was dried over sodium sulfate and evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel using a mixed solvent of n-hexane and ethyl acetate (3:1). The fractions containing the objective compound were collected and evaporated under reduced pressure, and treated with 4N hydrogen chloride in ethyl acetate to give (3R)-3-(3,4-dimethylbenzyl)-1-[4-(3,3-dimethylmorpholino)-2-butynyl]piperazine trihydrochloride (37.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:11]2[CH:12]([C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[C:13]([CH3:16])([CH3:15])[S:14][C@H:10]12)=[O:7])=[O:4].[C:25](=[S:27])=[S:26].[H-].[Na+].Br[CH:31](Br)[CH3:32]>CN(C)C=O.C1(C)C=CC=CC=1>[S:26]1[CH2:32][CH2:31][S:27][C:25]1=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:11]2[CH:12]([C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[C:13]([CH3:16])([CH3:15])[S:14][C@H:10]12)=[O:7]
Reactant: C=CCOC(=O)C1N2C(=O)[C@@H](NC(=O)CC(=O)OC)[C@H]2SC1(C)C
Reactant: CC(Br)Br
Reactant: S=C=S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C=CCOC(=O)C1N2C(=O)[C@@H](NC(=O)C(C(=O)OC)=C3SCCS3)[C@H]2SC1(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
To a stirred solution of allyl 6β-[(methoxycarbonyl)acetamido]-2,2-dimethylpenam-3-carboxylate (713 mg, 2 mmol) in 2 mL of sieve-dried dimethylformamide at 0° C. was added carbon disulfide (1 mL), then sodium hydride, 60% (160 mg, 4 mmol), portionwise. The reaction mixture was stirred at 0° C. for 10 min under a nitrogen atmosphere, and treated with dibromoethane (413 mg, 2.2 mmol). The mixture was stirred at 0° C. for 30 min, diluted with toluene, washed with water and saturated NaCl solution, and dried over Na2SO4. The solution was concentrated to give a brown oil, which was chromatographed on silica gel eluting with chloroform-ethyl acetate (95:5) to yield the title compound (811 mg, 88%) as a yellow foam: IR (CHCl3) 1790, 1750, 1685 cm-1; 1 H NMR (CDCl3) δ 1.50 and 1.67 (each 3H, s, C2-(CH 3)2), 3.33 (4H, s, SCH2CH2S), 3.88 (3H, s, CO2CH3), 4.48 (1H, s, C3 -H), 4.64-4.68 (2H, m, OCH2CH=CH2), 5.25-5.42 (2H, m, OCH2CH=CH2), 5.58 (1H, d, J=4Hz, C5 -H), 5.83 (1H, dd, J=4 and 9Hz, C6 -H), 5.85-6.00 (1H, m, OCH2CH=CH2), 8.97 (1H, d, J=9Hz, NH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:18]#[N:19])[C:7]=1[C:8]1[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=1[F:17].O.O.[Sn](Cl)Cl>O1CCCC1.C(O)C>[NH2:14][C:12]1[CH:11]=[CH:10][C:9]([F:17])=[C:8]([C:7]2[C:6]([C:18]#[N:19])=[CH:5][CH:4]=[CH:3][C:2]=2[F:1])[CH:13]=1
Reactant: N#Cc1cccc(F)c1-c1cc([N+](=O)[O-])ccc1F
Agent: Cl[Sn]Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1cccc(F)c1-c1cc(N)ccc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6,2′-Difluoro-5′-nitrobiphenyl-2-carbonitrile (3.25 g, 12.5 mmol) in tetrahydrofuran (20 mL) and ethanol (20 mL) was treated with tin(II) chloride dihydrate (9.86 g, 43.8 mmol) and the mixture left to stir at ambient temperature for 18 h. The solvent was evaporated and the residue stirred with 2 N sodium hydroxide solution (40 mL) for 2 h. The resulting suspension was diluted with water (100 mL) and extracted with dichloromethane (3×200 mL). The combined organics were washed with water (200 mL), brine (200 mL), dried over anhydrous sodium sulfate, filtered and evaporated to give 5′-amino-6,2′-difluorobiphenyl-2-carbonitrile as a brown oil (2.87 9,100%): δH (360 MHz, CDCl3) 3.74 (2H, s), 6.68 (1H, m), 6.73-6.77 (1H, m), 7.02 (1H, dd, J 9 and 9), 7.37-7.49 (2H, m), 7.56-7.65 (1H, m).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH:7]2[CH:8]3[CH2:22][CH2:21][CH:20]=[CH:19][C:9]3=[C:10]3[C:18]([CH2:17][C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]3=4)=[C:6]2[C:5](C)([CH3:23])[C:4]([CH3:26])([CH3:25])[C:3]1([CH3:28])[CH3:27].[CH2:30]([Li])CCC.[C:35]([C:39]1[CH:44]=[CH:43][C:42]([C:45]([C:51]2[CH:56]=[CH:55][C:54]([C:57]([CH3:60])([CH3:59])[CH3:58])=[CH:53][CH:52]=2)=[C:46]2[CH:50]=[CH:49][CH:48]=[CH:47]2)=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36].[Cl-].[NH4+]>O1CCCC1.C(OCC)C.CCCCCC>[C:57]([C:54]1[CH:55]=[CH:56][C:51]([C:45]([C:42]2[CH:43]=[CH:44][C:39]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:40][CH:41]=2)([CH:46]2[CH:50]=[CH:49][CH:48]=[CH:47]2)[C:7]2([CH3:30])[C:6]3[C:5]([CH3:23])([CH:12]4[CH2:13][CH2:14][CH:15]=[CH:16][C:11]4=[C:10]4[C:18]=3[CH2:17][C:19]3[CH:20]=[CH:21][CH:22]=[CH:8][C:9]4=3)[C:4]([CH3:26])([CH3:25])[C:3]([CH3:28])([CH3:27])[C:2]2([CH3:1])[CH3:29])=[CH:52][CH:53]=1)([CH3:60])([CH3:59])[CH3:58]
Reactant: CC1(C)C2=C3Cc4ccccc4C3=C3C=CCCC3C2C(C)(C)C(C)(C)C1(C)C
Reactant: [Li]CCCC
Reactant: CC(C)(C)c1ccc(C(=C2C=CC=C2)c2ccc(C(C)(C)C)cc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(C(c2ccc(C(C)(C)C)cc2)(C2C=CC=C2)C2(C)C3=C4Cc5ccccc5C4=C4C=CCCC4C3(C)C(C)(C)C(C)(C)C2(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.1 %

Procedure:
A 300 ml two-necked flask equipped with a magnetic stirrer, a three-way cock and a dropping funnel, was purged thoroughly with nitrogen. Into the flask, octamethyloctahydrodibenzofluorene 2.01 g (5.21 mmol) and dehydrated tetrahydrofuran 40 ml were introduced. With cooling in an ice bath, 1.56 mol/L n-hexane solution of n-butyllithium, 3.5 ml (5.5 mmol), was dropwise added. The contents were stirred at room temperature in a nitrogen atmosphere for 1 day. With the flask cooled in a dry ice/methanol bath, a solution of 6,6-bis(4-tert-butylphenyl)fulvene 1.78 9 (5.20 mmol) in 20 ml of tetrahydrofuran, was dropwise added to the solution by means of the dropping funnel over a period of 20 minutes. The liquid temperature was then slowly raised to room temperature, and the solution was stirred in a nitrogen atmosphere at the temperature for 3 days. Then, a saturated aqueous solution of ammonium chloride 100 ml and diethyl ether 100 ml were gradually added to the solution in this order. The resulting two-phase solution was poured into a 300 ml separation funnel, and the funnel was shaken several timessothatthewaterphasewasremoved. Theobtainedorganic phase was washed three times with water 100 ml and once with a saturated salt solution 100 ml, and dried over anhydrous magnesium sulfate. The solution was filtered to remove solids, and the solvent of the filtrate was distilled away. The residual solid was washed with n-hexane to give 2.664 g of bis(4-tert-butylphenyl)cyclopentadienyl(octamethyloctahydrodibenzofluorenyl)methane as a white solid (3.65 mmol, 70.1% yield). Identification of the bis(4-tert-butylphenyl)cyclopentadienyl(octamethyloctahydrodibenzofluorenyl)methane was made by 1H NMR and the FD-mass spectrometric analysis, the results being given below:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH3:32][O:33][C:34]1[CH:46]=[CH:45][C:37]([CH2:38][N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:42]4[CH2:41][CH2:40][N:39]([CH2:38][C:37]5[CH:45]=[CH:46][C:34]([O:33][CH3:32])=[CH:35][CH:36]=5)[CH2:44][CH2:43]4)=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: COc1ccc(CN2CCNCC2)cc1
Product: COc1ccc(CN2CCN(C(=O)c3ccc(-c4cnc5c(c4)N(Cc4cc(Cl)ccc4C(F)(F)F)CCN5)cc3)CC2)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(4-methoxybenzyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=636.02 (M+H+); retention time=0.61 minutes.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.C[C@H]1CC[C@H](N)CC1.[Cl:22][C:23]1[CH:60]=[CH:59][C:26]([C:27]2[C:32]([C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[C:38]([C:43]5[N:47](CC)[C:46]6[CH:50]=[CH:51][C:52]([C:54](O)=O)=[CH:53][C:45]=6N=5)[CH:39]=4)[N:34]=3)=[CH:31][C:30]([O:57][CH3:58])=[CH:29][CH:28]=2)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:60]=[CH:59][C:26]([C:27]2[C:32]([C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[C:38]([C:43]5[N:47]([CH:46]6[CH2:45][CH2:53][CH:52]([CH3:54])[CH2:51][CH2:50]6)[C:2]6[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=6[N:11]=5)[CH:39]=4)[N:34]=3)=[CH:31][C:30]([O:57][CH3:58])=[CH:29][CH:28]=2)=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCn1c(-c2ccc3nc(-c4cc(OC)ccc4-c4ccc(Cl)cc4)ccc3c2)nc2cc(C(=O)O)ccc21
Agent: C[C@H]1CC[C@H](N)CC1
Product: COc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCC(C)CC4)ccc3n2)c1

Procedure:
The title compound was prepared from Resin 534a and a mixture of cis and trans 4-methylcyclohexyl-amine according to the procedure described in the preparation of Compound 534.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[O:9])=[CH:3][CH:2]=1.Br.[NH2:12][CH2:13][C:14]([NH:16][C:17]1[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20])=[O:15].C(N(CC)CC)C.Cl>O1CCCC1.O>[C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:9])[NH:12][CH2:13][C:14]([NH:16][C:17]2[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=2[C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:20])=[O:15])=[CH:3][CH:2]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: NCC(=O)Nc1ccccc1C(=O)c1ccccc1
Agent: Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(NC(=O)NCC(=O)Nc2ccccc2C(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
A solution of p-tolylisocyanate (655 mg, 4.92 mmol) in tetrahydrofuran (8 ml) is added to a solution of the salt 3a (1.341 g, 4 mmol) prepared in Preparation 3 in tetrahydrofuran (50 ml). Triethylamine (558 μl, 4 mmol) is added at 0° C., and the mixture is stirred at 0° C. for 30 minutes, and then at room temperature overnight. Water and then 10% hydrochloric acid are added, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried (sodium sulfate), and then the solvent is distilled off under reduced pressure. The residue is recrystallized from dichloromethane/diisopropylether to obtain the objective compound 6z (1.31 1 g, 85%).
Reaction SMILES: C1(C2CCC3C(=CC=C(O)C=3)O2)C=CC=CC=1.[CH3:18][O:19][C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][CH:25]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:26]2=O)=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:28]=[C:27]2[C:23](=[CH:22][CH:21]=1)[CH2:24][CH:25]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:26]2
Reactant: COc1ccc2c(c1)C(=O)C(c1ccccc1)C2
Agent: Oc1ccc2c(c1)CCC(c1ccccc1)O2
Product: COc1ccc2c(c1)CC(c1ccccc1)C2

Procedure:
5-Methoxy-2-phenylindane was prepared as described for 2-phenylchroman-6-ol in Example 1(a) using 600 mg of 6-methoxy-2-phenylindan-1-one. 1H-NMR (400 MHz, d6-DMSO): 7.32-7.27 (m, 4H), 7.21-7.18 (m, 1H), 7.13 (d, 1H, J 8.2 Hz), 6.83 (d, 1H, J 2.4 Hz), 6.72 (dd, 1H, J 2.4, 8.2 Hz), 3.72 (s, 3H), 3.64 (k, 1H, J 8.5 Hz), 3.23 (dt, 2H, J 8.5, 15.9 Hz), 2.92 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=1.CCCCCC.C([Li])CCC.[CH:23]1[N:27]=[CH:26][N:25]2[CH2:28][CH2:29][C:30](=[O:31])[C:24]=12>C1COCC1.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]2[S:7][C:8]([C:30]3([OH:31])[C:24]4[N:25]([CH:26]=[N:27][CH:23]=4)[CH2:28][CH2:29]3)=[CH:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2sccc2c1
Reactant: O=C1CCn2cncc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc2sc(C3(O)CCn4cncc43)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
A solution of 5-methoxybenzo[b]thiophene (0.33 g) in THF (8 ml) was cooled to −78° C., and an n-butyl lithium hexane solution (1.6 M; 1.4 ml) was added dropwise to this solution. The mixture was stirred for 1 h at the same temperature, and a solution of 5,6-dihydro-7H-pyrrolo[1,2-c]imidazol-7-one (0.18 g) in THF (3 ml) was added to this solution. The reaction mixture was stirred for 1 h at the same temperature, and saturated brine was added. The mixture was warmed to room temperature and the organic layer was separated. The organic layer was diluted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was suspended in ethyl acetate and filtrated to give the title compound (0.24 g) as pale brown crystals. The crystals were recrystallized from THF to give the title compound (0.13 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[C:3]([C:16]2[S:20][C:19]3[C:21]([C:25]4[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=4[CH:27]=O)=[CH:22][CH:23]=[CH:24][C:18]=3[CH:17]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[N:12]2)=[N:6][CH:7]=1.[C:33]([BH3-])#[N:34].CC(C)(C)C(O)=O.CN>O1CCOCC1.C(Cl)(Cl)Cl.CC(O)C>[N:11]1([CH2:10][CH2:9][NH:8][C:5]2[N:4]=[C:3]([C:16]3[S:20][C:19]4[C:21]([C:25]5[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=5[CH2:27][NH:34][CH3:33])=[CH:22][CH:23]=[CH:24][C:18]=4[CH:17]=3)[C:2]([F:1])=[CH:7][N:6]=2)[CH:15]=[CH:14][N:13]=[N:12]1
Reactant: [BH3-]C#N
Reactant: O=Cc1ccccc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Agent: CC(C)(C)C(=O)O
Agent: CN
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CNCc1ccccc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Temperature: 100 °C
Yield: 51.4 %

Procedure:
Combine 2-{2-[5-fluoro-2-(2-[1,2,3]triazol-1-yl-ethylamino)-pyrimidin-4-yl]-benzo[b]thiophen-7-yl}-benzaldehyde (800 mg, 1.8 mmol), cyanoborohydride (silica supported, 1 mmol/g, 2.7 g, 2.7 mmol), trimethylacetic acid (0.55 g, 4.7 mmol), and mono-methylamine (0.42 g, 5.4 mmol) in 12 mL of dioxane. Heat the reaction mixture at 100° C. for 20 min in microwave reactor. Cool it to RT. Dilute with chloroform/IPA (3:1, v/v), 50 mL. Wash with water, aqueous saturated sodium chloride, and dry over magnesium sulfate. Remove the organic solvent. Purify the residue by column chromatography [chloroform/methanol/ammonium hydroxide (35% in water), 7/3/0.05] to give the title compound (425 mg, 38%). MS (ES) m/z 460 [M+1]+.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH2:6]([NH:13][CH2:14][CH2:15][C:16]1[CH:31]=[CH:30][C:19]([O:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=2)=[CH:18][CH:17]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN(C=O)C>O>[CH2:6]([N:13]([CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:14][CH2:15][C:16]1[CH:31]=[CH:30][C:19]([O:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=2)=[CH:18][CH:17]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: BrCCc1ccccc1
Reactant: NC(=O)c1ccc(Oc2ccc(CCNCc3ccccc3)cc2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc(CCN(CCc3ccccc3)Cc3ccccc3)cc2)nc1
Temperature: 25 °C
Yield: 386.6 %

Procedure:
Add sodium bicarbonate (0.0823 g, 0.0980 mmol) to a stirred solution of 6-[4-(2-benzylamino-ethyl)-phenoxy]-nicotinamide (0.3061 g, 0.0881 mmol), (2-bromoethyl)benzene (0.135 mL, 0.988 mmol), and DMF (5 mL). Heat the reaction to reflux for 3 h under nitrogen and then cool to room temperature. Pour the reaction into water (50 mL) and extract with diethyl ether (3×50 mL). Dry the diethyl ether extracts over magnesium sulfate and then filter off the magnesium sulfate. Concentrate on a rotary evaporator and purify the crude product by flash chromatography on silica gel eluting with 90% ethyl acetate/hexanes to yield 0.1538 g (39%) of 6-{4-[2-(benzyl-phenethyl-amino)-ethyl]-phenoxy}-nicotinamide: mass spectrum (ion spray): m/z=452.1 (M+1); 1H NMR (CDCl3): 8.55 (d, 1H), 8.13 (dd, 1H), 7.29-7.11 (m, 14H), 7.01 (d, 2H), 6.92 (d, 1H), 3.71 (s, 1H), 2.94-2.77 (m, 9H).
Reaction SMILES: [N+]([C:4]1[C:5]([N+:11]([O-])=O)=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1)([O-])=O.CO[CH:16](OC)[N:17](C)C.N1CCCC1>>[NH:17]1[C:7]2[C:6](=[C:5]([NH2:11])[CH:4]=[CH:9][CH:8]=2)[CH:10]=[CH:16]1
Reactant: Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: C1CCNC1
Product: Nc1cccc2[nH]ccc12

Procedure:
Scheme 4 illustrates the production of a compound of Formula (In) in which R99 is an indole compound and R7, R8, R9, R10, R11, R12, R28, R29 and R30 are defined as above for Formula (III). A piperidin-4-one compound of Formula (XIVa) is produced as described above in Scheme 3. A dinitro-toluene compound of Formula (XVI) is reacted with N,N-dimethylformamide dimethyl acetal and pyrrolidine under conditions effective to bring about cyclization, thereby providing an indol-4-ylamine compound of Formula (XVII). The compound of Formula (XVII) is then reacted with a bis(2-chloroethyl)-benzylamine under conditions effective to produce the compound of Formula (XVIII). The compound of Formula (XVIII) is then reacted under conditions effective to remove the benzyl protecting group to produce a 4-piperazin-1-yl-indole of Formula (XIX). The piperazin-1-yl-indole compound of Formula (XIX) is then reacted with the piperidin-4-one compound of Formula (XIVa) as described above in Scheme 1 to produce the piperazine-piperidine compound of Formula (XX), which is a compound of Formula (III).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C@H:14]2[C@H:19]3[CH2:20][CH2:21][C@H:16]([CH2:17][N:18]3[S:22]([C:25]3[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=3)(=[O:24])=[O:23])[CH2:15]2)=[O:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].CCCCCC>C(O)(C)C>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([CH:14]2[CH:19]3[CH2:20][CH2:21][CH:16]([CH2:17][N:18]3[S:22]([C:25]3[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=3)(=[O:23])=[O:24])[CH2:15]2)=[O:13])=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(NC(=O)[C@@H]2C[C@@H]3CC[C@H]2N(S(=O)(=O)c2cn(C)cn2)C3)cc1
Solvent: CC(C)O
Solvent: CCCCCC
Product: CC(C)Oc1ccc(NC(=O)C2CC3CCC2N(S(=O)(=O)c2cn(C)cn2)C3)cc1
Yield: 49.3 %

Procedure:
The compound (60 mg, 0.138 mmol) synthesized in Example 26 was optically resolved using normal-phase chiral HPLC(CHIRALPAK AD 2 cm ø×25 cmL (Daicel Chemical Industries, Ltd.); mobile phase: hexane:isopropyl alcohol=60:40; flow rate: 10 ml/min; isogradient), and (1R**,4S**,6R**)-N-(4-isopropoxyphenyl)-2-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-2-azabicyclo[2.2.2]octane-6-carboxamide (retention time: 14.2 min; 26.6 mg), and (1S**,4R**,6S**)-N-(4-isopropoxyphenyl)-2-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-2-azabicyclo[2.2.2]octane-6-carboxamide (retention time: 30.7 min; 29.4 mg) were obtained.