Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:27][NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)(=[O:31])=[O:30].C(=O)(O)[O-].[Na+].O>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:35]2[CH:34]=[CH:33][C:32]([S:29]([NH:28][CH3:27])(=[O:30])=[O:31])=[CH:37][CH:36]=2)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CNS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: CNS(=O)(=O)c1ccc(-c2cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c3cnn(C(C)C)c3n2)cc1
Temperature: 150 °C
Yield: 28.5 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (75 mg, 0.2 mmol), {4-[(methylamino)sulfonyl]phenyl}boronic acid (69 mg, 0.32 mmol) in DME/water (3 ml:1 ml). PdCl2(dppf)-CH2Cl2 adduct (8.2 mg, 0.01 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (50.6 mg, 0.6 mmol) was added, the vessel was sealed, and the insoluble mixture was heated in a microwave at 150° C. for 30 min. After cooling, 2 mL of water was added to the mixture and solids that precipitated were filtered. DCM/MeOH (1:1) was added and the solution was filtered through a pad of silica gel and the filtrate was evaporated. The residue was purified by silica gel chromatography (eluent: gradient of 0 to 90:10 DCM/MeOH) and the isolated solid triturated in EtOAc. The solids were filtered and dried to afford the title compound (29 mg, 28%) as an off-white solid. LCMS E-S (M+H)=509.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.58 (br. s., 1H), 8.99 (t, J=4.93 Hz, 1H), 8.47 (m, J=8.59 Hz, 2H), 8.43 (s, 1H), 8.25 (s, 1H), 7.95 (m, J=8.59 Hz, 2H), 7.60 (br. s., 1H), 5.91 (s, 1H), 5.36 (quin, J=6.69 Hz, 1H), 4.42 (d, J=4.80 Hz, 2H), 2.46 (s, 3H), 2.23 (s, 3H), 2.13 (s, 3H), 1.56 (d, J=6.82 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[CH2:3][CH2:4][CH:5]([C:16]1[CH:17]=[N:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[CH:20][CH:21]=1)[O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1.ClC1C(OC)=NN=NC=1OC.CN1CCOCC1.[CH3:52][O:53][C:54](=[O:59])[CH2:55][CH:56]([NH2:58])[CH3:57]>C(Cl)Cl.O>[CH3:52][O:53][C:54](=[O:59])[CH2:55][CH:56]([NH:58][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:7]([O:6][CH:5]([C:16]2[CH:17]=[N:18][C:19]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[CH2:4][CH2:3][C:2]([CH3:1])([CH3:33])[CH3:32])=[CH:15][CH:14]=1)[CH3:57]
Reactant: CC(C)(C)CCC(Oc1ccc(C(=O)O)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Reactant: COC(=O)CC(C)N
Agent: COc1nnnc(OC)c1Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: COC(=O)CC(C)NC(=O)c1ccc(OC(CCC(C)(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 4-{4,4-Dimethyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-pentyloxy}-benzoic acid (95 mg, 0.21 mmol), chloro-dimethoxy-triazine (CDMT) (37 mg, 0.21 mmol), and 4-methylmorpholine (25 uL, 0.23 mmol) are combined in anhydrous DCM under nitrogen. The reaction is allowed to stir under nitrogen at room temperature overnight. 3-Amino-butyric acid methyl ester (26 mg, 0.23 mmol) and 4-methylmorpholine (50 uL, 0.47 mmol) is then added to the reaction mixture, and allowed to stir at room temperature. Some water (<10% volume) is added to help solubility. The reaction is monitored by HPLC, and upon complete consumption of the acid, the reaction is diluted with DCM and water and rinsed with 1N HCl. The organic layer is washed with water and brine, dried over anhydrous sodium sulfate, then filtered and concentrated. The 3-(4-{4,4-dimethyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-pentyloxy}-benzoylamino)-butyric acid methyl ester is isolated after column chromatography.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[CH3:18][N:19]([CH3:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([N:19]([CH3:29])[CH3:18])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: CN(C)c1ccc(B(O)O)cc1
Product: Cc1c2n(c3c(-c4ccc(N(C)C)cc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (31 mg, 35%), MS (ISP) m/z=354.5 [(M+H)+], mp 227° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 4-dimethylamino-phenylboronic acid (53.6 mg, 0.325 mmol).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].CC(C)([O-])C.[K+].[CH3:34][O:35][C:36]1[CH:45]=[CH:44][CH:43]=[C:42]2[C:37]=1[CH2:38][CH2:39][CH2:40][C:41]2=O.[Cl-].[NH4+]>O1CCCC1>[CH3:34][O:35][C:36]1[CH:45]=[CH:44][CH:43]=[C:42]2[C:37]=1[CH2:38][CH2:39][CH2:40][C:41]2=[CH:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3]
Reactant: COc1cccc2c1CCCC2=O
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1cccc2c1CCCC2=CCCCC(=O)O
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To an anhydrous tetrahydrofuran (200 ml) solution of (4-carboxybutyl)triphenylphosphonium bromide (25.0 g), potassium t-butoxide (12.7 g) was added, followed by stirring at 30° C. for 1 hour. To the reaction mixture, a tetrahydrofuran (20 ml) solution of 5-methoxy-1-tetralone (5.0 g) was added, followed by stirring at room temperature overnight. The reaction mixture was added to a mixture of saturated aqueous ammonium chloride solution and ice, followed by extracting with ethyl acetate. The extract was concentrated to thereby obtain the crude title compound having the following physical data. The obtained compound was used without purification in the subsequent reaction.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][C:9](CCCC(O)=O)=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].CCN=C=NCCCN(C)C.Cl.C(CCN)CCC(O)=O.C(O)C(N)(CO)CO>C1N(CCS(O)(=O)=O)CCOC1>[N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2]
Reactant: Cn1c(=O)c2[nH]c(CCCC(=O)O)nc2n(C)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC(CO)(CO)CO
Product: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1 mg of theophylline-8-butanoic acid (Sigma) was dissolved in 2 ml of a 0.1 M MES buffer solution. Thereafter, 3.6 mg of WSC hydrochloride and 2.5 mg of NHS were added thereto, and the mixture was stirred at room temperature for 15 minutes. Thereafter, 2.0 mg of ε Amino Caproic Acid (Sigma) was dissolved in 200 μl of 0.1 M MES, and the obtained solution was added to the above reaction product. The obtained mixture was reacted at room temperature for 2 hours. 100 μl of 1M Tris buffer solution (pH 7.5) was added to the mixture, and the reaction was terminated. Thereafter, the obtained reaction product was adsorbed to a column filled with 8 g of ODS silica (YMC-ODS-AQ 120A), followed by elution with a 30% methanol aqueous solution. The eluant was concentrated and then purified by medium-pressure separation chromatography (YAMAZEN Ultrapack ODS-S-4OB).
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH2:12])=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19]Br)[CH3:16]>CN(C)C=O>[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][NH:12][C:11]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[N:9][N:10]=1)[CH3:16]
Reactant: Nc1nnnn1-c1ccccc1
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(CNc1nnnn1-c1ccccc1)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
A solution of 1-phenyl-5-amino-1H-tetrazole (10 g.) in dried dimethylformamide (50 ml.) was dropwise added to a suspension of 50% sodium hydride (5.1g.) in dried dimethylformamide (5 ml.) over 15 minutes under ice-cooling, and the mixture was stirred for 30 minutes at ambient temperature. To the resultant mixture was added a solution of bromoacetaldehyde diethyl acetal (13.5 g.) in dried dimethylformamide (15 ml.). The mixture was stirred for 1 hour at ambient temperature and for 2 hours and 20 minutes at 60° C. The reaction mixture was cooled to at ambient temperature, ice-water was added thereto and the mixture was extracted 3 times with ethyl acetate. The extract was washed with water and a saturated sodium chloride aqueous solution, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained oil was purified by column chromatography on silica gel (250 g.) using chloroform as developing solvent to give (1-phenyl-1H-tetrazol-5-yl)aminoacetaldehyde diethyl acetal (11 g.), oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].C([N-]C(C)C)(C)C.[Li+].[CH3:17][Si:18](Cl)([CH3:20])[CH3:19]>O1CCCC1>[CH3:17][Si:18]([CH3:20])([CH3:19])[O:8][C:3]1[CH:2]([CH3:1])[CH2:7][CH2:6][CH2:5][CH:4]=1
Reactant: C[Si](C)(C)Cl
Reactant: CC1CCCCC1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1CCCC=C1O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
Under nitrogen atmosphere, a solution of 2-methylcyclohexanone (0.5 g, 4.46 mmol) in anhydrous tetrahydrofuran (1 mL) was added dropwise to a solution of lithium diisopropylamide 2.0M in tetrahydrofuran (2.45 mL, 4.90 mmol) in anhydrous tetrahydrofuran (10 mL), previously cooled at −78° C. After stirring for 30 minutes at the same temperature, trimethylsilyl chloride (0.96 mL, 7.58 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour before being quenched with a saturated solution of ammonium chloride (10 mL) at 0° C. Diethyl ether (20 mL) was added and the mixture was allowed to reach room temperature. Layers were separated and the organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane) to provide trimethyl[(6-methylcyclohex-1-en-1-yl)oxy]silane (18a) (660 mg, 3.58 mmol, 80%)
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][N:5]=[N:4]1.[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>S1(CCCC1)(=O)=O>[CH2:13]([N:3]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][N:5]=[N:4]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)c1nnn[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Product: CCOC(=O)c1nnnn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 117.2 %

Procedure:
A suspension of sodium hydride (0.13 g) in dry sulpholane (10 ml) was treated with ethyl tetrazole-5-carboxylate (0.71 g), and the mixture stirred for 20 minutes at room temperature. Benzyl chloride (0.7 g) was then added, and the mixture was stirred at 60°-65° C. overnight. The mixture was then poured onto ice (25 g) and the resulting oil was separated off and dissolved in diethyl ether (35 ml). The aqueous layer was extracted with a further quantity of diethyl ether (10 ml) and the combined ether extracts were dried over magnesium sulphate. Removal of the ether under reduced pressure gave a mixture (1.36 g) of ethyl 1-benzyl-1H-tetrazole-5-carboxylate and ethyl 2-benzyl-2H-tetrazole-5-carboxylate, containing a little sulpholane.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:10][C:11]([F:17])([F:16])[S:12]([O-:15])(=[O:14])=[O:13].[F:18][C:19]([F:29])([F:28])C[I+]C1C=CC=CC=1>>[F:10][C:11]([F:17])([F:16])[S:12]([O-:15])(=[O:14])=[O:13].[CH3:1][N+:2]([CH3:11])([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:9][C:19]([F:29])([F:28])[F:18]
Reactant: CN(C)c1ccccc1
Reactant: FC(F)(F)C[I+]c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Product: C[N+](C)(CC(F)(F)F)c1ccccc1
Reaction time: 0.5 h
Yield: 177.8 %

Procedure:
61 mg (0.50 mmol) of N,N-dimethylaniline was added to a solution of 218 mg (0.50 mmol) of (2,2,2-trifluoroethyl)phenyliodonium trifluoromethanesulfonate in an argon atmosphere at room temperature, and the mixture was stirred for 30 minutes. After completion of the reaction, the reaction mixture was concentrated and purified by silica gel thin-layer chromatography to obtain 157 mg (89%) of N,N-dimethyl-N-phenyl-N-2,2,2-trifluoroethylammonium trifluoromethanesulfonate.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C@@H:7]([CH2:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)[C:8]([OH:10])=[O:9])=[O:5])#[N:2].[Na].N>C(O)C.[Rh]>[CH:16]1[N:15]=[CH:14][NH:13][C:12]=1[CH2:11][C@H:7]([NH:6][C:4]([CH2:3][CH2:1][NH2:2])=[O:5])[C:8]([OH:10])=[O:9]
Reactant: N#CCC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: [Rh]
Agent: N
Agent: [Na]
Solvent: CCO
Product: NCCC(=O)N[C@@H](Cc1cnc[nH]1)C(=O)O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
0.3 g of rhodium/activated carbon (5% Rh) was added to a solution of 1.90 g (7.8 mmol) of (S)-2-(cyanoacetyl-amino)-3-(1H-imidazol-4-yl)propionic acid, sodium salt (prepared according to Example 1) in 50 ml of ethanol/conc. ammonia solution (V:V=4:1). The mixture was hydrogenated at 110° C. and 45 bar for 1 h. This was followed by filtering off the catalyst and adjusting the filtrate to a pH of 8.2 with formic acid. After concentrating the solution under reduced pressure, the residue was suspended in 200 ml of ethanol and heated at 60° C. for 30 min. The product was filtered off, washed successively with ethanol, ethyl acetate and diethyl ether and finally dried.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C(OC([N:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH2:24][Cl:25])[CH2:19][CH2:18]1)=O)(C)(C)C.C(=O)([O-])O.[Cs+].Cl>CN1C(=O)CCC1.O1CCOCC1>[ClH:25].[C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O:6][CH2:24][C:23](=[O:26])[N:20]1[CH2:19][CH2:18][NH:17][CH2:22][CH2:21]1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1
Reactant: COC(=O)/C=C/C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: COC(=O)/C=C/C(=O)OCC(=O)N1CCNCC1
Yield: 41.4 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (MHF) (1.00 g, 7.68 mmol) dissolved in NMP was reacted at ca. 55° C. with 1-(tert-butyloxycarbonyl)-4-chloroacetyl piperazine (2.42 g, 9.22 mmol) in the presence of CsHCO3 (1.78 g, 9.22 mmol). After work-up and removal of the solvent, the crude material was obtained as a white solid. The solid was reacted at room temperature with 15 mL of a 4 molar (4 M) solution of hydrogen chloride (HCl) in 1,4-dioxane. After removal of the solvents, the solid hydrochloride salt was further purified by mass-guided preparative HPLC to provide 0.93 g (41% yield) of the title compound (14) as a white solid after lyophilization of the solvents in the presence of an excess of aqueous 1 normal (1 N) hydrochloric acid. 1H NMR (D2O, 400 MHz): δ 6.93-6.86 (m, 2H), 4.92 (s, 2H), 3.70-3.63 (m, 7H), 3.23 (t, J=5.2 Hz, 2H), 3.17 (t, J=6 Hz, 2H). MS (ESI): m/z 257.13 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[C:10]([F:29])[C:11]([O:18][CH2:19][CH:20]4[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21]4)=[CH:12][CH:13]=3)[CH:8]([OH:30])[CH:7]([OH:31])[C:6]=2[C:5]=1[F:32])[CH3:2]>CS(C)=O>[CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[C:10]([F:29])[C:11]([O:18][CH2:19][CH:20]4[CH2:21][CH2:22][CH:23]([CH2:26][CH2:27][CH3:28])[CH2:24][CH2:25]4)=[CH:12][CH:13]=3)[C:8](=[O:30])[C:7](=[O:31])[C:6]=2[C:5]=1[F:32])[CH3:2]
Reactant: CCCC1CCC(COc2ccc3c(c2F)C(O)C(O)c2c-3ccc(OCC)c2F)CC1
Solvent: CS(C)=O
Product: CCCC1CCC(COc2ccc3c(c2F)C(=O)C(=O)c2c-3ccc(OCC)c2F)CC1
Yield: 89.7 %

Procedure:
IBX (9.03 g, 32.25 mmol) was added to 100 mL of DMSO, the resultant mixture was agitated at room temperature for 30 minutes, and then compound (64) (3.6 g, 8.062 mmol) was added thereto, and the resultant mixture was further agitated for 3 hours. The reaction mixture was filtered, 200 mL of water was added to a filtrate, and the resultant mixture was extracted with 100 mL of ethyl acetate three times. Combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, and then dried over magnesium sulfate, and a solvent was distilled off by an evaporator. The residue was recrystallized from toluene, and thus 2-ethoxy-1,8-difluoro-7-((4-propylcyclohexyl)methoxy)phenanthrene-9,10-dione (65) (3.2 g, yield 34.5%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=O)[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=[S:34])[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1NC(=O)C2(CC(c3cccc(F)c3)Oc3ccc(Br)cc32)N1
Solvent: C1COCCO1
Product: O=C1NC(=S)NC12CC(c1cccc(F)c1)Oc1ccc(Br)cc12
Yield: 11.2 %

Procedure:
A suspension of 6-bromo-2-(3-fluorophenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (300 mg, 0.77 mmol) and Lawesson's reagent (312 mg, 0.77 mmol) in dry 1,4-dioxane (10 mL) was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-(3-fluorophenyl)-2′-thioxospiro[chroman-4,4′-imidazolidine]-5′-one (35 mg, 17%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:5]2[C:21]([CH3:26])=[N:22][CH2:23][CH2:24][O:25][C:4]=12.[BH3-]C#N.[Na+]>CCO>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:13])=[C:5]2[CH:21]([CH3:26])[NH:22][CH2:23][CH2:24][O:25][C:4]=12
Reactant: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)c2c1OCCN=C2C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)c2c1OCCNC2C
Temperature: 65 °C
Yield: 36.8 %

Procedure:
To 6-methoxy-1-methyl-8-(phenylsulfonyl)-3,8-dihydro-4H-[1,4]oxazepino[6,7-e]indole (Intermediate 34, 0.010 g, 0.027 mmol) dissolved in EtOH (2 mL), NaCNBH3 (3.5 mg, 0.054 mmol) was added and the reaction mixture was heated at 65° C. for 2 hours. The reaction mixture was quenched by addition of water and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (3.7 mg). MS m/z 373 [M+H]+.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N([O-])=O.[Na+]>S(=O)(=O)(O)O.O>[CH3:14][S:11]([C:8]1[CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]([C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]=2)=[CH:10][CH:9]=1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc(N)c(C(=O)O)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 3.0 mmol 2-amino-5-methanesulfonyl-benzoic acid in a mixture of 1.7 ml sulfuric acid and 1.7 ml water was added dropwise a solution of 3.92 mmol sodium nitrite in 1.7 ml water at such rate that the temperature did not exceed 3° C. The mixture was stirred at 0° C. for 1 hour. A solution of 3.0 mmol KI in 1.7 ml water was added dropwise at 0° C. The brown suspension was allowed to warm to rt and stirred for 30 minutes. Excess iodine was destroyed by addition of a few drops of a sodium hydrogenosulfite solution. The solid was filtered, washed with water and dried (HV, 50° C., 1 hour) to yield the title compound. MS (m/e): 325.0 (M−H, 100%)
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[C:10](=O)[CH2:9][C:8]2([CH3:18])[CH3:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:15][O:14][C:13]1[CH:12]=[C:11]2[C:7](=[CH:6][C:5]=1[O:4][CH3:3])[C:8]([CH3:18])([CH3:17])[CH:9]=[CH:10]2
Reactant: COc1cc2c(cc1OC)C(C)(C)CC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1OC)C(C)(C)C=C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 14 %

Procedure:
Then, 1.1 g (28 mmol) of sodium borohydride were added to a solution of 1.9 g (9.2 mmol) of 5,6-dimethoxy-3,3-dimethylindan-1-one in methanol (30 ml), and the mixture was stirred for 5 minutes at room temperature. After methanol was removed from the reaction mixture by concentration under reduced pressure, water was added to the residue, and the mixture was extracted with diethyl ether. An organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Added to a solution of the resultant residue in toluene (50 ml) was 90 mg (0.47 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was stirred for 20 minutes at 120° C. The reaction mixture was concentrated under reduced pressure, and the resultant crude oil was purified by column chromatography on silica gel to obtain 264 mg (yield: 15%) of 5,6-dimethoxy-1,1-dimethylindene as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([S:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CN(C)C1CCc2[nH]c3ccc(NS(=O)(=O)c4ccccc4)cc3c2C1
Yield: 32.9 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.6 μL (0.051 mMol) benzenesulfonyl chloride, 5.6 mg (34%) of the title compound were recovered as a light beige solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1F)=[O:4].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[CH2:19][NH2:20].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[CH2:19][NH:20][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[C:2]([F:14])([F:13])[F:1]
Reactant: NCc1cc(Cl)cc(Cl)c1
Reactant: O=C(c1ccc(F)cc1F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(c1ccc(F)cc1NCc1cc(Cl)cc(Cl)c1)C(F)(F)F
Yield: 42.6 %

Procedure:
A mixture of 2,2,2,2′,4′-pentafluoroacetophenone (1.05 g, 5.0 mmol), 3,5-dichlorobenzylamine (0.88 g, 5.0 mmol), N,N-diisopropylethylamine (1.7 mL, 10.0 mmol) and acetonitrile (25 mL) was heated at reflux for 18 h, cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate; this solution was washed with water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using 5% ethyl acetate in hexanes as eluent to yield the title compounds as a yellowish solid (0.78 g, 43%). 1H NMR (400 MHz, CDCl3): δ 9.28 (br s, 1 H), 7.88 (m, 1 H), 7.34 (s, 1 H), 7.22 (s, 2 H), 6.44 (m, 1 H), 6.30 (dd, 1 H), 4.43 (d, 2 H).