Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.[C:23]([O:27][C:28](=[O:33])[NH:29][CH2:30][CH2:31]Br)([CH3:26])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C>C1COCC1>[C:23]([O:27][C:28](=[O:33])[NH:29][CH2:30][CH2:31][N:8]1[CH2:9][CH2:10][C:11]2[C:16](=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH:7]1[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:22][CH:21]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(F)cc1)NCC2
Reactant: CC(C)(C)OC(=O)NCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)C(Cc1ccc(F)cc1)N(CCNC(=O)OC(C)(C)C)CC2
Temperature: 70 °C
Reaction time: 120 h

Procedure:
To a solution of 1-(4-fluorobenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline (example A31, 1.05 g, 3.5 mmol) in THF (40 mL) is added (2-bromo-ethyl)-carbamic acid tert-butyl ester (example B1, 0.94 g, 4.2 mmol) and DIPEA. The reaction mixture is stirred at 70° C. in a sealed flask for 5 days. After cooling to rt, the reaction mixture is evaporated to dryness, and the residue is purified by preparative HPLC to provide the title compound.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.ClC(OC)=O.[N:32]1([CH2:37][C:38]2[CH:39]=[C:40]([CH:42]=[CH:43][CH:44]=2)[NH2:41])[CH:36]=[N:35][CH:34]=[N:33]1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:41][C:40]3[CH:42]=[CH:43][CH:44]=[C:38]([CH2:37][N:32]4[CH:36]=[N:35][CH:34]=[N:33]4)[CH:39]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Nc1cccc(Cn2cncn2)c1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Agent: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2cccc(Cn3cncn3)c2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclopropylmethyl(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 112 mg; 0.45 mmol) in DCM was treated with diisopropylethylamine (78.4 mL; 0.52 mmol) and methyl chloroformate (36.2 mL; 0.47 mmol). After stirring at 0° C. for 15 minutes, 3-(1H-1,2,4-triazol-1-ylmethyl)aniline (Maybridge, 117 mg; 0.67 mmol) was added and the mixture stirred for 72 hours. The solvent was evaporated and the compound purified by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:4]=1[CH:5]=O.[NH2:17][C:18]1[CH:19]=[C:20]2[C:24]3=[C:25]([CH2:27][S:28][CH2:29][CH2:30][N:23]3[C@H:22]3[CH2:31][CH2:32][N:33](C(OC(C)(C)C)=O)[CH2:34][C@@H:21]23)[CH:26]=1>>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:4]=1[CH2:5][NH:17][C:18]1[CH:19]=[C:20]2[C:24]3=[C:25]([CH2:27][S:28][CH2:29][CH2:30][N:23]3[C@H:22]3[CH2:31][CH2:32][NH:33][CH2:34][C@@H:21]23)[CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Reactant: O=Cc1c(C(F)(F)F)cccc1C(F)(F)F
Product: FC(F)(F)c1cccc(C(F)(F)F)c1CNc1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2

Procedure:
Using 2,6-bis(trifluoromethyl)benzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 152. LRMS (ES)+: 488.4 (M+H)+.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.ON.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C@H:19]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]=C(C3C=CC=CC=3)C3C=CC=CC=3)[CH:24]=2)[CH2:18][C@@H:17]1[CH3:43])=[O:15])([CH3:12])([CH3:11])[CH3:10]>>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C@H:19]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=2)[CH2:18][C@@H:17]1[CH3:43])=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: C[C@H]1C[C@@H](Oc2cccc(N=C(c3ccccc3)c3ccccc3)c2)CCN1C(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Product: C[C@H]1C[C@@H](Oc2cccc(N)c2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add sodium acetate (0.309 g) and hydroxyamine hydrochloride (0.197 g) to 4-[3-(benzhydrylidene-amino)-phenoxy]-cis-2-methyl-piperidine-1-carboxylic acid tert-butyl ester isomer 2 (preparation 37) and stir at room temperature. After 1 hr., partition between ethyl acetate and saturated aqueous NaCl, dry over anhydrous sodium sulfate and evaporate. Purify on a silica gel column (35 g, solvent: dichloromethane-2M NH3 in methanol, gradient) to give the title compound (0.290 g). Mass spectrum (electrospray) m/z=251 (M-57+1), 207 (M-BOC+1); 1H NMR (CDCl3): 7.04 (t, 1H), 6.37 (d, 1H), 6.35 (d, 1H), 6.32 (t, 1H), 4.61 (m, 1H), 4.33 (m, 3H), 3.86 (m, 1H), 3.25 (m, 1H), 1.93 (m, 2H), 1.86 (m, 1H), 1.70 (m, 1H), 1.46 (s, 9H), 1.29 (d, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(N1C2C(=CC=C(OCCCNC(N)=N)C=2)C=C(CC(O)=O)C1=O)C.FC(F)(F)C(O)=O.[CH2:40]([N:42]1[C:51]2[C:46](=[CH:47][CH:48]=[C:49]([O:52][CH2:53][CH2:54][CH2:55][CH2:56][NH:57][C:58]([NH2:60])=[NH:59])[CH:50]=2)[CH:45]=[C:44]([CH2:61][C:62]([OH:64])=[O:63])[C:43]1=[O:65])[CH3:41]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:40]([N:42]1[C:51]2[C:46](=[CH:47][CH:48]=[C:49]([O:52][CH2:53][CH2:54][CH2:55][CH2:56][NH:57][C:58]([NH2:60])=[NH:59])[CH:50]=2)[CH2:45][CH:44]([CH2:61][C:62]([OH:64])=[O:63])[C:43]1=[O:65])[CH3:41]
Reactant: CCn1c(=O)c(CC(=O)O)cc2ccc(OCCCCNC(=N)N)cc21
Agent: CCn1c(=O)c(CC(=O)O)cc2ccc(OCCCNC(=N)N)cc21
Solvent: O=C(O)C(F)(F)F
Product: CCN1C(=O)C(CC(=O)O)Cc2ccc(OCCCCNC(=N)N)cc21

Procedure:
The title compound is prepared using the procedure of Example 158 except that [1-ethyl-7-(3-guanidino-propoxy)-2-oxo-1,2-dihydro-quinolin-3-yl]acetic acid trifluoroacetate is replaced with [1-ethyl-7-(4-guanidino-butoxy)-2-oxo-1,2-dihydro-quinolin-3-yl]acetic acid trifluoroacetate.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH3:12])[CH:6]=1)=O.O.[NH2:14][NH2:15]>C(O)C>[CH3:12][N:7]1[C:8](=[O:11])[CH:9]=[CH:10][C:5]([C:3]([NH:14][NH2:15])=[O:2])=[CH:6]1
Reactant: NN
Reactant: COC(=O)c1ccc(=O)n(C)c1
Solvent: CCO
Solvent: O
Product: Cn1cc(C(=O)NN)ccc1=O
Temperature: 78 °C
Reaction time: 8 h

Procedure:
The title compound of Example 27 (775 mg, 4.64 mmol) was dissolved in ethanol (10 mL) and heated to 78° C. Hydrazine hydrate (1.12 mL, 23.2 mmol) was added and the reaction was stirred at 78° C. overnight. The reaction was then cooled to room temperature and the product (white solid) was filtered off (590 mg, 76%).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Br[C:8]1[N:13]=[C:12]([CH2:14][N:15]([CH3:52])[C:16]([C:18]2[CH:51]=[CH:50][C:21]([CH2:22][C@H:23]3[CH2:27][CH2:26][C@@H:25]([C@H:28]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:24]3[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[CH:20][CH:19]=2)=[O:17])[CH:11]=[CH:10][CH:9]=1.CC(CC(C)=O)=O.[OH-].[NH4+:61]>[Cu]I.CN(C=O)C>[NH2:61][C:8]1[N:13]=[C:12]([CH2:14][N:15]([CH3:52])[C:16]([C:18]2[CH:51]=[CH:50][C:21]([CH2:22][C@H:23]3[CH2:27][CH2:26][C@@H:25]([C@H:28]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:24]3[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[CH:20][CH:19]=2)=[O:17])[CH:11]=[CH:10][CH:9]=1
Reactant: CN(Cc1cccc(Br)n1)C(=O)c1ccc(C[C@H]2CC[C@@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccccc3)N2C(=O)OC(C)(C)C)cc1
Reactant: [NH4+]
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC(=O)CC(C)=O
Product: CN(Cc1cccc(N)n1)C(=O)c1ccc(C[C@H]2CC[C@@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccccc3)N2C(=O)OC(C)(C)C)cc1
Temperature: 90 °C
Yield: 105.2 %

Procedure:
In a round bottom flask was added CuI (0.54 mg, 2.8 μmol, 0.1 equivalents), Cs2CO3 (18.3 mg, 0.056 mmol, 2 equivalents), and tert-butyl (2R,5S)-2-(4-{[(6-bromopyridin-2-yl)methyl](methyl)carbamoyl}benzyl)-5-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]-pyrrolidine-1-carboxylate (20 mg, 0.028 mmol). The flask was evacuated and backfilled with nitrogen (3×) and then 2,4-pentadione (1.69 mg, 0.017 mmol, 0.6 equivalents), DMF (141 μL) and ammonium hydroxide (19.6 μL, 0.141 mmol, 5 equivalents) was added. The contents were transferred to a sealed tube under positive nitrogen pressure. The reaction was stirred and heated at 90° C. for 16 hours. The reaction was cooled and filtered over celite and washed with EtOAc. The EtOAc was washed with water and the aqueous layer was extracted with. EtOAc (3×). The organic extracts were then dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude product (19 mg) that was taken directly onto the next step. LC-MS=646.3 (M+H)+.
Reaction SMILES: [C:1]([NH:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([NH:18][CH:19]([CH2:20][OH:21])[CH2:22][OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)NC(CO)CO
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCNC(CO)CO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.0 g. of the resulted 2-(hexadecanoylamino)propane-1,3-diol were transferred to a three necks round bottom flask equipped with a dropping funnel, a cooling bath, and a magnetic stirrer, under an air stream. The compound was dissolved in 200 ml dry THF and the solution wad cooled to 0° C. 1.2 g of LiAlH4 were added in small portions with strong stirring during 1 hour and then the mixture was left to react for another 2 hours at 0° C. The cooling bath was removed and the reaction was left to stir overnight. The next day, 2 ml of ethyl acetate followed by 10 ml of methanol and 10 ml of HCl 1N, were added very slowly and the solution was evaporated to approximately 20 ml. The mixture was transferred to a separatory funnel and 100 ml water, 100 ml dichloromethane and 50 ml methanol were added. Following shaking, the lower phase was collected and the upper, acidic-aqueous-methanolic phase was extracted twice with 50 ml CH2Cl2:MeOH, 3:1. The combined organic phases were washed with 100 ml HCl 0.1 N and then with 100 ml H2O, dried for 2 hours over MgSO4, filtered and evaporated to dryness. The resulted product was crystallized from ethanol: H2O. Yield: 0.5 g.
Reaction SMILES: C(OC([N:8]1[CH2:19][C@@H:18]([Cl:20])[CH2:17][C@H:9]1[C:10]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=O)(C)(C)C.Cl>O1CCOCC1>[ClH:20].[C:13]([NH:12][C:10](=[O:11])[C@@H:9]1[CH2:17][C@H:18]([Cl:20])[CH2:19][NH:8]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1

Procedure:
680 mg (2.23 mmol) of (4S)-1-t-butoxycarbonyl-N-t-butyl-4-chloro-L-prolinamide (prepared as described in Preparation 2) were treated with 10 ml of a 4N solution of hydrogen chloride in dioxane, in order to eliminate the t-butoxycarbonyl group and give (4S)-N-t-butyl-4-chloro-L-prolinamide hydrochloride. The whole of the hydrochloride thus obtained and 880 mg (1.99 mmol) of (2S,3S)-3-(N2 -benzyloxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyric acid (prepared as described in Preparation 1) were dissolved in 5 ml of dimethylformamide, and the solution was cooled with ice. 420 mg (2.58 mmol) of diethyl cyanophosphate, followed by 640 mg (6.40 mmol) of triethylamine, were then added to the ice-cooled mixture, and the mixture was stirred for 3 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was mixed with a 10% w/v aqueous solution of citric acid and then extracted with ethyl acetate. The organic extract was washed with a 10% w/v aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by preparative thin layer chromatography using a 10:1 by volume mixture of methylene chloride and methanol as the developing solvent, to give 850 mg of the title compound as a colorless powder, melting at 107°-109° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:30]([F:33])([F:32])[F:31])[N:10]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21](=O)[O:22]C4C=CC=CC=4)=[CH:14][CH:13]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41]([NH2:44])(=[O:43])=[O:42]>>[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41]([NH:44][C:21]([NH:20][CH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([N:10]2[CH:11]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[C:9]2[C:30]([F:31])([F:32])[F:33])=[CH:17][CH:16]=1)=[O:22])(=[O:43])=[O:42]
Reactant: O=C(NCCc1ccc(-n2cc(-c3ccccc3)nc2C(F)(F)F)cc1)Oc1ccccc1
Reactant: NS(=O)(=O)c1ccccc1Cl
Product: O=C(NCCc1ccc(-n2cc(-c3ccccc3)nc2C(F)(F)F)cc1)NS(=O)(=O)c1ccccc1Cl

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-{4-[4-phenyl-2-(trifluoromethyl)-1H-imidazol-1-yl]phenyl}ethylcarbamate and 2-chlorobenzenesulfonamide. MS (ESI) m/z 549 [M+H]+, 547 [M−H]−, 1H-NMR (CDCl3) δ 2.86 (2H, t, J=7.3 Hz), 3.48-3.55 (2H, m), 6.58 (1H, br), 7.25-7.28 (1H, m), 7.31-7.36 (3H, m), 7.25-7.28 (1H, m), 7.39-7.47 (4H, m), 7.58-7.61 (2H, m), 7.82 (2H, dd, J=8.4, 1.4 Hz), 8.00 (2H, d, J=7.5 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[C:8]2[CH2:7][CH:6]([CH2:17][CH2:18][CH3:19])[C:5](=[O:20])[C:4]=2[C:3]=1[CH3:21]>C(=O)(O)[O-].[Na+].[Na].[Hg]>[CH3:1][C:2]1[C:10]2[O:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13][C:9]=2[C:8]2[CH2:7][CH:6]([CH2:17][CH2:18][CH3:19])[CH:5]([OH:20])[C:4]=2[C:3]=1[CH3:21]
Reactant: CCCC1Cc2c(c(C)c(C)c3oc(C(=O)O)cc23)C1=O
Agent: O=C([O-])O
Agent: [Hg]
Agent: [Na+]
Product: CCCC1Cc2c3c(c(C)c(C)c2C1O)OC(C(=O)O)C3
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4,5-dimethyl-6-oxo-7-propyl-7,8-dihydro-6H-indeno[5,4-b]furan-2-carboxylic acid (2.0 g., 0.007 mole) in aqueous sodium bicarbonate (40 ml.) is treated with 1% sodium amalgam (120 g.) and stirred at 25°C. for 18 hours. The mercury is separated and the aqueous phase is acidified with hydrochloric acid affording 2.0 g. (99%) of 4,5-dimethyl-6-hydroxy-7-propyl-1,2,7,8-tetrahydro-6H-indeno[5,4-b]furan-2-carboxylic acid which melts at 161°C. after recrystallization from nitromethane.
Reaction SMILES: CI.[CH:3]1[C:8]2=[C:9]3[C:17](=[CH:18][CH:19]=[C:7]2[CH:6]=[CH:5][CH:4]=1)[C:16]1C(=[CH:12][CH:13]=[C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]2=1)C3.[CH3:24][C:25]([CH3:28])([O-])[CH3:26].[K+].CS(C)=O>O>[CH3:24][C:25]1([CH3:28])[C:9]2[C:17](=[CH:18][CH:19]=[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:8]3=2)[C:16]2[C:26]1=[CH:12][CH:13]=[C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]1=2
Reactant: c1ccc2c3c(ccc2c1)-c1c(ccc2ccccc12)C3
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CI
Product: CC1(C)c2ccc3ccccc3c2-c2ccc3ccccc3c21
Reaction time: 8 h
Yield: 50.1 %

Procedure:
Methyl iodide 13.45 g (94.74 mmol) was dropwise added to a mixed solution of 8.41 g (31.58 mmol) of 13H-dibenzo[a,g]fluorene, 15.95 g (142.11 mmol) of potassium t-butoxide and 100 ml of dimethylsulfoxide at 20° C. in 20 minutes, and the solution was stirred for 8 hours. After left standing overnight, 13.45 g (94.74 mmol) of methyl iodide was further dropwise added and stirred for 11 hours. Water was dropwise added to the reaction mixture, and the solution was extracted twice with dichloromethane. After separating the solution, the organic phase was concentrated and refined by flash chromatograph (silica gel: hexane/dichloromethane=5/1) to obtain 4.66 g (yield: 50.1%) of 13,13-dimethyl-13H-dibenzo[a,g]fluorene.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:19]([Cl:20])=[CH:18][C:10]3[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[O:13][C:9]=3[CH:8]=2)[N:5]=[C:4]([C:21]#[N:22])[CH:3]=1.[F:23][C:24]([F:29])([F:28])[S:25]([O-])=O.[Na+].S(C1C=CC(C)=CC=1)(O)(=O)=O.CNC.S(Cl)(Cl)=O>C1(C)C=CC=CC=1.O>[NH2:1][C:2]1[N:6]([C:7]2[C:19]([Cl:20])=[CH:18][C:10]3[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[O:13][C:9]=3[CH:8]=2)[N:5]=[C:4]([C:21]#[N:22])[C:3]=1[S:25][C:24]([F:29])([F:28])[F:23]
Reactant: N#Cc1cc(N)n(-c2cc3c(cc2Cl)C(F)(F)C(F)(F)O3)n1
Reactant: O=S([O-])C(F)(F)F
Agent: CNC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: N#Cc1nn(-c2cc3c(cc2Cl)C(F)(F)C(F)(F)O3)c(N)c1SC(F)(F)F
Temperature: 55 °C
Reaction time: 0.17 h
Yield: 23.1 %

Procedure:
To a suspension wherein 5-amino-1-(5-chloro-2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-6-yl)-3-cyanopyrazole (665 mg, 2.00 mmol), sodium trifluoromethanesulfinate (624 mg, 4.00 mmol) and dimethylamine tosylate (1.086 g, 5.00 mmol) are in toluene (5 ml), thionyl chloride (476 mg, 2.00 mmol) was added dropwise under ice cooling over a period of about 10 minutes and stirred at 50 to 60° C. for 10 minutes. After allowing time to cool, the reaction solution was poured into water, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography to give 200 mg of 5-amino-1-(5-chloro-2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-6-yl)-3-cyano-4-trifluoromethylsulfenylpyrazole.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[CH3:30][C:31]1[N:35]([C@@H:36]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]2)[C:34]2[CH:48]=[C:49](B3OC(C)(C)C(C)(C)O3)[CH:50]=[CH:51][C:33]=2[N:32]=1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.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:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:49]3[CH:50]=[CH:51][C:33]4[N:32]=[C:31]([CH3:30])[N:35]([C@@H:36]5[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])[CH2:37]5)[C:34]=4[CH:48]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2n1[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4nc(C)n([C@@H]5CCN(C(=O)OC(C)(C)C)C5)c4c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A microwave vial was charged with (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (53 mg, 0.11 mmol), (R)-tert-butyl 3-(2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-yl)pyrrolidine-1-carboxylate (92 mg, 0.21 mmol), then Pd(PPh3)4 (23 mg, 0.02 mmol). The vial was flushed with argon, diluted with dioxane (2 mL) and to this was added 2M aqueous K2CO3 (0.2 mL, 0.4 mmol). The vial was sealed then heated to 100° C. for 16 hours and then allowed to cool to room temperature. The mixture was diluted with EtOAc, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (0-10% MeOH/CH2Cl2 gradient) to afford the desired product. LCMS-ESI+: calc'd for C39H46ClN4O5S: 717.3 (M+H+); Found: 717.1 (M+H+).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[OH-].[K+].[CH3:19][N:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1>C1(C)C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[Br-].CCOC(C)=O.O>[CH3:19][N:20]1[CH2:25][CH2:24][CH:23]([O:26][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=2)[CH2:22][CH2:21]1
Reactant: O=[N+]([O-])c1ccc(F)cc1-c1ccccc1
Reactant: CN1CCC(O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CN1CCC(Oc2ccc([N+](=O)[O-])c(-c3ccccc3)c2)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 5-fluoro-2-nitrobiphenyl (0.86 mmol) in toluene/aq.KOH (2 mL/2 mL) are added 1-methylpiperidin-4-ol (1.1 mmol) and TBAB (0.17 mmol) at room temperature. After stirred at 70° C. overnight, the reaction mixture is diluted with AcOEt and water, and extracted with AcOEt (×2). The combined organic extracts are dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography (CH2Cl2:MeOH=10:1) to give 1-methyl-4-(6-nitrobiphenyl-3-yloxy)piperidine as a yellow solid. To a solution of 1-methyl-4-(6-nitrobiphenyl-3-yloxy)piperidine (0.63 mmol) in EtOH (5 mL) is added 5% palladium on activated carbon (50 mg) under N2 atmosphere. The reaction mixture is vigorously stirred at room temperature for 2.5 h under H2, and then filtered through celite (linsed with AcOEt). The filtrate is concentrated in vacuo to the title compound as a brown oil; 1H NMR (CDCl3), δ 1.79-1.87 (2H, m), 1.96-2.01 (2H, m), 2.25-2.31 (2H, m), 2.29 (3H, s), 2.70 (2H, brs), 3.52 (2H, m), 4.15-4.18 (1H, m), 6.70 (1H, d), 6.76-6.80 (2H, m), 7.32-7.38 (1H, m), 7.42-7.45 (4H, m).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH:17]=1)[C:10]([CH3:36])([CH3:35])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([N:25]2[CH2:24][CH2:23][N:22]([C:18]3[CH:17]=[C:16]([CH:11]4[C:10]([CH3:36])([CH3:35])[CH2:9][C:8]5[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=5)[NH:12]4)[CH:21]=[CH:20][CH:19]=3)[CH2:27][CH2:26]2)=[CH:29][CH:30]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N3CCN(c4ccc(Cl)cc4)CC3)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2CCN(c3ccc(Cl)cc3)CC2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 52.5 %

Procedure:
A mixture of 2-{3-[4-(4-chloro-phenyl)-piperazin-1-yl]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.20 g, 0.40 mmol), lithium hydroxide hydrate (167 mg, 4.0 mmol), water (0.5 mL) in methanol (1 mL) and tetrahydrofuran (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-{3-[4-(4-chloro-phenyl)-piperazin-1-yl]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 53%) as a white solid: LC/MS m/e calcd for C28H30ClN3O2 M+: 476.02, observed: 476.3.