Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[N:9][C:10]([Cl:23])=[CH:11][C:12]=1[C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[C:19]([F:22])[CH:18]=[CH:17][CH:16]=2)(=O)=O.[Li+].[Cl-].[CH2:28]([Sn](CCCC)(CCCC)C=C)[CH2:29]CC>CN(C=O)C.O>[Cl:23][C:10]1[CH:11]=[C:12]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[C:19]([F:22])[CH:18]=[CH:17][CH:16]=3)[C:7]([CH:28]=[CH2:29])=[CH:8][N:9]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=S(=O)(Oc1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1)C(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Temperature: 65 °C
Reaction time: 10 h
Yield: 458.4 %

Procedure:
To a solution of 6-chloro-4-(4-fluoro-1H-indol-2-yl)pyridin-3-yl trifluoromethanesulfonate (50 mg, 0.12 mmol), LiCl (8 mg, 0.19 mmol) in DMF (0.8 mL) was added tributyl(vinyl)stannane (80 mg, 0.25 mmol) dropwise at 25° C. under nitrogen. The mixture was stirred at 65° C. for 10 hours. The mixture was diluted with H2O, extracted with EtOAc, then the combined organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude product. It was purified by column (PE:EA=5:1) to obtain the product of 2-(2-chloro-5-vinylpyridin-4-yl)-4-fluoro-1H-indole (150 mg, yield: 40%). 1H-NMR (CDCl3, 400 MHz) δ 8.45 (s, 1H), 7.41 (s, 1H), 7.15 (d, J=2.4 Hz, 1H), 6.88 (d, J=6.0 Hz, 1H), 6.79 (t, J=6.0 Hz, 1H), 6.35˜6.41 (m, 1H), 6.07˜6.10 (m, 1H), 5.77 (d, J=17.6 Hz, 1H), 5.49˜5.62 (m, 2H). MS (M+H)+: 273/275.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1O.CCN=C=NCCCN(C)C.CS(O)(=O)=O>O.C(Cl)(Cl)Cl>[F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:5]([C:6]2[O:8][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=2)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)c(C(F)(F)F)c1
Reactant: Nc1ccccc1O
Agent: CCN=C=NCCCN(C)C
Agent: CS(=O)(=O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)cc(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
4-Fluoro-3-nitro-5-trifluoromethyl benzoic acid (1.00 g, 4.0 mmol), 2-aminophenol (0.47 g, 4.4 mmol), CHCl3 (20 mL), and WSC (0.83 g, 4.4 mmol) were added together and stirred at room temperature for 1 hour. Water was added, and this was extracted with chloroform/acetone (3:1). After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. To a dioxane (20 mL) solution of the solid obtained was added methanesulfonic acid (2.28 g, 24 mmol), and this was heated to reflux for 18 hours. After the reaction solution was cooled, water was added, and the precipitated crystals were filtered, and after being washed with water were dried to yield the title compound (0.70 g, 54% yield) as yellowish-brown crystals.
Reaction SMILES: [Si]([O:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[CH:18][CH:17]=[CH:16]2)=[CH2:10])(C(C)(C)C)(C)C.C1C(=O)N([Br:28])C(=O)C1>C1COCC1.O>[Br:28][CH2:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[CH:18][CH:17]=[CH:16]2)=[O:10]
Reactant: C=C(O[Si](C)(C)C(C)(C)C)c1cccc2cccnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: O=C(CBr)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
To a solution of 8-(1-((tert-butyldimethylsilyl)oxy)vinyl)quinoline (300 mg, 1.045 mmol) in THF (5 mL) and water (1 mL) was added NBS (203 mg, 1.149 mmol), and the resulting mixture was stirred at 25° C. for 30 min. The mixture was diluted with water (5 mL) and extracted in to EtOAc (2×5 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo to yield crude 2-bromo-1-(quinolin-8-yl)ethanone (200 mg) (used without further purification in subsequent transformations): 1H NMR (400 MHz, DMSO-d6) δ 8.99-8.98 (1H, m), 8.27-8.23 (1H, m), 8.17-8.15 (1H, m), 7.67-7.63 (1H, m), 5.18 (1H, s), 5.02 (1H, s), 2.78 (2H, s). m/z (ESI, +ve) 249.9 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=O>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH3:6])[CH:12]1[C:8]1[S:7][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1cccs1
Reactant: CNCCNC
Solvent: Cc1ccccc1
Product: CN1CCN(C)C1c1cccs1

Procedure:
23.5 g (267 mmol) of N,N′-dimethylethylenediamine were dissolved in 300 ml of toluene and treated with 29.8 g (266 mmol) of thiophene-2-carbaldehyde. The clear mixture was refluxed for 4 hours using a Dean-Stark trap. After that time 4.9 ml of water had separated in the trap. After cooling, the solution was filtered and evaporated. The oily residue was destilled in vacuo. Yield: 45 g.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[C:12]1[CH:20]=[C:19]2[C:15]([C:16]([CH3:23])([CH3:22])[C:17](=[O:21])[NH:18]2)=[CH:14][C:13]=1[CH3:24].[CH2:27](I)[CH2:28][CH3:29]>>[F:26][C:2]([F:25])([F:1])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[C:12]1[CH:20]=[C:19]2[C:15]([C:16]([CH3:22])([CH3:23])[C:17](=[O:21])[N:18]2[CH2:27][CH2:28][CH3:29])=[CH:14][C:13]=1[CH3:24]
Reactant: Cc1cc2c(cc1-c1cc(C=O)ccc1OC(F)(F)F)NC(=O)C2(C)C
Reactant: CCCI
Product: CCCN1C(=O)C(C)(C)c2cc(C)c(-c3cc(C=O)ccc3OC(F)(F)F)cc21

Procedure:
The intermediate 4-trifluoromethoxy-3-(3,3,5-trimethyl-2-oxo-1-propyl-2,3-dihydro-1H-indol-6-yl)-benzaldehyde was prepared in a similar manner to example 21a using 4-trifluoromethoxy-3-(3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-benzaldehyde (example 21b) and propyl iodide. 1H NMR (300 MHz, CDCl3, ppm): δ: 0.93(t, J=7.3 Hz, 3 H), 1.45(s, 6 H), 1.70(m, 2 H), 2.10(s, 3 H), 3.66 (m, 2 H), 6.63 (s, 1 H), 7.11 (s, 1 H), 7.52–7.55 (m, 1 H), 7.85 (m, 1 H), 7.98 (m, 1H), 10.05 (s, 1 H).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH3:15]O>S(=O)(=O)(O)O.CCOC(C)=O>[NH2:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:8]([O:10][CH3:15])=[O:9])(=[O:4])=[O:3]
Reactant: CO
Reactant: NS(=O)(=O)c1cc(C(=O)O)ccc1Cl
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Yield: 95 %

Procedure:
3-(Aminosulfonyl)-4-chlorobenzoic acid (943 mg, 4.0 mmol) was heated at 70° C. in CH3OH (10 mL) with 3 drops of concentrated sulfuric acid for 34 hours. The reaction mixture was diluted with EtOAc (20 mL), washed with water, brine, and dried (Na2SO4). The solvent was evaporated to afford the product (950 mg, 95%) as a white solid. MS (ES+) m/z 250 [M+H]+.
Reaction SMILES: ClC1C([N+]([O-])=O)=C(Cl)C(Cl)=C(Cl)C=1Cl.ClC1C([N+]([O-])=O)=C(F)C(F)=C(F)C=1Cl.ClC1C([N+]([O-])=O)=C(F)C(F)=C(Cl)C=1Cl.Cl[C:44]1[C:49]([N+:50]([O-:52])=[O:51])=[C:48]([F:53])[C:47]([Cl:54])=[C:46]([Cl:55])[C:45]=1Cl>C(#N)C>[Cl:55][C:46]1[CH:45]=[CH:44][C:49]([N+:50]([O-:52])=[O:51])=[C:48]([F:53])[C:47]=1[Cl:54]
Reactant: O=[N+]([O-])c1c(F)c(Cl)c(Cl)c(Cl)c1Cl
Agent: O=[N+]([O-])c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: O=[N+]([O-])c1c(F)c(F)c(Cl)c(Cl)c1Cl
Agent: O=[N+]([O-])c1c(F)c(F)c(F)c(Cl)c1Cl
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Cl)c(Cl)c1F
Yield: 28 %

Procedure:
To a reaction vessel, 0.74 g (2.50 m mol) of pentachloronitrobenzene, 1.77 g (13.00 m mol) of DFI, and 25 ml of acetonitrile were charged and reacted at 84° C. for 2 hours in a nitrogen atmosphere. After finishing the reaction, formation of dichlorotrifluoronitrobenzene (master ion, 245, master ion +2 247, master ion +4 249, base peak 245) was confirmed by GC-MS measurement on the reaction mixture, and the yield was 28.0% by GC analysis. Formation of trichloro-difluoronitrobenzene (master ion 261, master ion +2 263, master ion +4 265, base peak 205) was also confirmed and the yield was 11.3%. Formation of tetrachlorofluoronitrobenzene (master ion 277, master ion +2 279, master ion +4 281, master ion +6 283, base peak 221) was further confirmed and the yield was 9.0%.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:43][C:44]([F:47])([F:46])[F:45])(=O)=O.O>CS(C)=O>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH2:43][C:44]([F:47])([F:46])[F:45])[CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: O=C(NC(COCC1CCNCC1)c1ccccc1Cl)c1ccc2c(Cl)c[nH]c2c1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(NC(COCC1CCN(CC(F)(F)F)CC1)c1ccccc1Cl)c1ccc2c(Cl)c[nH]c2c1
Yield: 29.6 %

Procedure:
To a solution of 3-chloro-N-[1-(2-chlorophenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (700 mg, 1.6 mmol) in 5 mL of DMSO was added potassium carbonate (1.0 g, 7.9 mmol) and 2,2,2-trifluoroethyl trifluoromethane-sulfonate (364 mg, 1.6 mmol). The reaction was allowed to stir at room temperature overnight after which time water was added and the resulting precipitate was isolated by filtration. Purification of the filtrate (SiO2: 30% EtOAc in hexane) provided 250 mg (30%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:4].[Br:24]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([Br:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)=[O:4]
Reactant: COC(=O)c1ncc2c(Oc3ccc(F)cc3)cccc2c1O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1nc(Br)c2c(Oc3ccc(F)cc3)cccc2c1O
Temperature: 25 °C
Yield: 55.5 %

Procedure:
A mixture of 8-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester (1.21 g, 3.87 mmol), N-bromosuccinimide (723 mg, 4.06 mmol) and benzoyl peroxide (47 mg, 0.19 mmol) in carbon tetrachloride (20 mL) was refluxed for 4 h before it was cooled to room temperature and partitioned between dichloromethane and water. The organic layer was washed with saturated aqueous sodium bicarbonate, brine, and was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of dichloromethane and hexane to give the title compound as a pale yellow solid (843 mg): MS: (+) m/z 392.00, 393.93 (M+1, 79Br/81Br).
Reaction SMILES: C([O:5][C:6](=[O:48])[C@@H:7]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39](=[O:47])[NH:40][C:41]1[NH:42][CH2:43][CH2:44][CH2:45][N:46]=1)(=[O:32])=[O:31])[CH2:8][NH:9][C:10](=[O:28])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]2[NH:22][CH2:23][CH2:24][CH2:25][N:26]=2)=[CH:13][CH:12]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:42]1[CH2:43][CH2:44][CH2:45][N:46]=[C:41]1[NH:40][C:39]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[S:30]([NH:29][C@@H:7]([CH2:8][NH:9][C:10](=[O:28])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]2[NH:26][CH2:25][CH2:24][CH2:23][N:22]=2)=[CH:13][CH:12]=1)[C:6]([OH:48])=[O:5])(=[O:32])=[O:31])=[O:47]
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1ccccc1C(=O)NC1=NCCCN1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccccc2C(=O)NC2=NCCCN2)C(=O)O)cc1)NC1=NCCCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
54 mg (0.08 mmol) of (2S)-2-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid tert-butyl ester was dissolved in 2 ml of dichloromethane and 2 ml of trifluoroacetic acid was added. The solution was stirred at room temperature for 3 hours. The solvent was removed in vacuo and toluene was added to the residue and then removed in vacuo. The residue was dissolved in acetonitrile/water (1/1) and lyophilized. Yield 34 mg. MS (ES+): m/e=627 (M+H+).
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=[C:13]3[C:29]2[CH:34]=[C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[N:32]=[C:31](S(C)(=O)=O)[N:30]=2)=[N:8][N:9]=1)([CH3:3])[CH3:2].[CH:49]([NH2:52])([CH3:51])[CH3:50]>CN1C(=O)CCC1.O>[CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=[C:13]3[C:29]2[CH:34]=[C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[N:32]=[C:31]([NH:52][CH:49]([CH3:51])[CH3:50])[N:30]=2)=[N:8][N:9]=1)([CH3:2])[CH3:3]
Reactant: COc1ccc(COc2cc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ccc(-c5nnc(NC(C)C)o5)cc34)nc(S(C)(=O)=O)n2)cc1
Reactant: CC(C)N
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(COc2cc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ccc(-c5nnc(NC(C)C)o5)cc34)nc(NC(C)C)n2)cc1
Temperature: 120 °C
Yield: 86.1 %

Procedure:
A glass microwave reaction vessel was charged with N-isopropyl-5-(3-(6-((4-methoxybenzyl)oxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (120 mg, 0.174 mmol) and isopropylamine (0.075 mL, 0.871 mmol) in NMP (1.0 mL). The reaction mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 1 h. The mixture was diluted with water and filtered. The remaining solid was dried to give the crude product (100 mg), which was used in the next step without further purification. MS (ESI, pos. ion) m/z: 668.0 (M+1).
Reaction SMILES: I[C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[Cu](C#N)[C:18]#[N:19]>CN1C(=O)CCC1.CCOC(C)=O>[C:18]([C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8])#[N:19]
Reactant: N#C[Cu]C#N
Reactant: COC(=O)c1snc(-c2ccccc2)c1I
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COC(=O)c1snc(-c2ccccc2)c1C#N
Temperature: 100 °C
Yield: 84.8 %

Procedure:
To a solution of methyl 4-iodo-3-phenylisothiazole-5-carboxylate (Preparation 103D, 600 mg, 1.738 mmol) in NMP (2 mL) was added copper cyanide (311 mg, 3.48 mmol). The resulting mixture was heated at 100° C. in a microwave reactor for 45 min. The reaction mixture was diluted with EtOAc (40 mL), filtered, washed with water (2×20 mL), brine (10 mL) and concentrated. Flash chromatography gave methyl 4-cyano-3-phenylisothiazole-5-carboxylate (360 mg, 1.474 mmol, 85% yield) as a white solid. The compound had an LC/MS M+1=245.1.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@@H:11]2[CH2:13][C@H:12]2[CH2:14][NH2:15])=[N:3]1.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24]>O1CCCC1.C(=O)([O-])O.[Na+]>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@@H:11]2[CH2:13][C@H:12]2[CH2:14][NH:15][C:23](=[O:25])[CH3:24])=[N:3]1
Reactant: Cn1cc2c([C@@H]3C[C@H]3CN)cccc2n1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NC[C@@H]1C[C@H]1c1cccc2nn(C)cc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 52.3 %

Procedure:
To a solution of trans-1-[2-(2-methyl-2H-indazol-4-yl)cyclopropyl]methanamine (100 mg, 0.497 mmol) and triethylamine (104 μL, 0.746 mmol) in tetrahydrofuran (5 mL) was added acetic anhydride (70.5 μL, 0.746 mmol) under ice-cooling, and the mixture was stirred at room temperature for 5 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→10/90) and recrystallization (ethyl acetate/hexane) to give the title compound (63.2 mg, yield 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[CH:14]=[C:15]2[C:19]3=[C:20]([CH2:22][S:23][CH2:24][CH2:25][N:18]3[C@H:17]3[CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][C@@H:16]23)[CH:21]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]2[C:19]3=[C:20]([CH2:22][S:23][CH2:24][CH2:25][N:18]3[C@H:17]3[CH2:26][CH2:27][NH:28][CH2:29][C@@H:16]23)[CH:21]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCSC3
Product: Clc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c(Cl)c1

Procedure:
Using 2,4-dichlorophenyl boronic acid and following the procedures described in EXAMPLE 9, tert-butyl (7bR,11aS)-6-bromo-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate was converted into the title compound of EXAMPLE 13. 1H NMR (CDCl3, 300 MHz): δ 7.19 (m, 3H), 6.93 (s, 1H), 6.83 (s, 1H), 3.78 (m, 2H), 3.59 (m, 1H), 3.41 (m, 1H), 3.19 (m, 2H), 3.0 (m, 2H), 2.82 (m, 4H), 2.58 (m, 1H), 1.80 (m, 2H) LRMS (ES+): 391 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:8]=2[CH:26]=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][Mg+].[Br-].[NH4+].[Cl-]>C1COCC1.C(OCC)C>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)(=[O:17])=[O:18])[C:8]=2[CH:26]([OH:27])[CH3:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(C=O)c(-c3ccccc3)c3ccccc32)cc1
Reactant: C[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(C(C)O)c(-c3ccccc3)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-phenyl-1-(toluene-4-sulfonyl)-1H-indole-2-carbaldehyde (2.11 g, 5.62 mmol) in THF (30 mL) cooled to −78° C. and under a nitrogen atmosphere, was added 3.0M MeMgBr in diethyl ether (2.6 mL). The mixture was stirred at 0° C. for 30 min and then additional 3.0M MeMgBr in diethyl ether (0.3 mL) was added. After 15 min stirring, the reaction mixture was poured into a saturated solution of NH4Cl and extracted with EtOAc (×2). The combined organic layers were washed with water, then dried (Na2SO4) and concentrated in vacuo. The crude material was combined with a second portion of crude reaction mixture obtained following the same method (starting from 140 mg, 3.73 mmol of 3-phenyl-1-(toluene-4-sulfonyl)-1H-indole-2-carbaldehyde) and the combined batches were purified by column chromatography (Si—PCC, gradient 20-100% DCM in pentane) affording the title compound as a gum which then solidified on standing (2.02 g, 86%). 1H NMR (CDCl3, 400 MHz): δ 8.07 (1H, d, J=8.35), 7.80-7.75 (2H, m), 7.51-7.38 (5H, m), 7.33-7.26 (2H, m), 7.20-7.14 (3H, m), 5.25-5.15 (1H, m), 4.06 (1H, d, J=11.01 Hz), 2.31 (3H, s), 1.70 (3H, d, J=6.88 Hz).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=O)[C:2]1=O.[NH2:12][NH:13][C:14]([NH2:16])=[S:15].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>O>[NH:16]1[C:2]2[NH:1][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]=2[N:12]=[N:13][C:14]1=[S:15]
Reactant: NNC(N)=S
Reactant: O=C1Nc2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: S=c1nnc2c([nH]1)[nH]c1ccccc12
Temperature: 25 °C

Procedure:
To a solution of indole-2,3-dione 14b (74 mmol, 1 equiv.) in water (600 mL) is added thiosemicarbazide 14a (81.4 mmol, 1.1 equiv.) and potassium carbonate (11 mmol, 1.5 equiv.) as disclosed in Gladych, J. M. Z.; Hornby, R.; Hunt, J. H.; Jack, D.; Boyle, J. J.; Ferlauto, R. J.; Haff, R. F.; Kornendy, C. G; Standfield, F. J.; Stewart, R. C. J. Med. Chem. 1972, 15, 277-281 and references cited therein. The solution is stirred and refluxed for 7 hours. The red-orange solution is allowed to cool to room temperature overnight. The solution is acidified with acetic acid, and a yellow precipitate forms. The precipitate is filtered and washed with water, and dried under vacuum for 15 hours to yield 1,9-Dihydro-1,3,4,9-tetraaza-fluorene-2-thione 14c as a yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12]C)[C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:14](Cl)(=O)[C:15](Cl)=O.CN(C=O)C.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5]([Cl:11])=[C:6]([C:7]([C:15]2[CH:14]=[CH:6][CH:10]=[CH:2][CH:3]=2)=[O:9])[CH:10]=1
Reactant: COc1cc(Br)cc(C(=O)O)c1Cl
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1cc(Br)cc(O)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 208.2 %

Procedure:
To a suspension of compound 56 (6.0 g, 22.6 mmol) in CH2Cl2 (100 mL) were added oxalyl chloride (2.4 mL, 27.1 mmol) and catalytic amounts of DMF at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was evaporated in vacuo and dried under high vacuum. The crude acid chloride was dissolved with benzene (100 mL) and cooled to 0° C. To the reaction mixture was added AlCl3 (6.9 g, 52.0 mmol) portionwise at 0° C. The mixture was stirred at 90° C. for 15 hours. The mixture was cooled to rt and evaporated in vacuo. The residue was cooled to 0° C. and aq. 1N HCl solution was added. The mixture was extracted with EtOAc (150 mL×1). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the compound 166 (7.33 g, quantitative yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[H-].[Na+].Br[C:13]1[O:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=1.O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][C:13]1[O:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(Br)o1
Reactant: Oc1cc(F)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2cc(F)ccc2F)o1
Reaction time: 1 h
Yield: 22.9 %

Procedure:
To a solution of 2,5-difluorophenol (3360 mg, 25.83 mmol) in N,N-dimethylformamide (60 mL) was sodium hydride (1032 mg, 25.83 mmol, 60% in oil), which was then stirred for 1 hour. 5-Bromo-2-furaldehyde (3826 mg, 21.52 mmol) was added to the reaction solution, and the solution was stirred at 60° C. for 12 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then, concentrated in vacuo. The resulting residue was purified by silica gel chromatography (hexane-ethyl acetate), and the title compound (1104 mg, 4.92 mmol, 22.9%) was obtained.