Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[CH:17]=1)=[O:14].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13]([NH:12][C:7]2[C:8]3[C:3](=[C:2]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:11]=[CH:10][CH:9]=3)[CH:4]=[CH:5][CH:6]=2)=[O:14])=[CH:17][C:18]=1[N:24]1[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(NC(=O)Nc2cccc3c(Br)cccc23)cc1N1CCN(C)CC1
Product: COc1ccc(NC(=O)Nc2cccc3c(-c4ccccc4)cccc23)cc1N1CCN(C)CC1

Procedure:
The title compound was prepared from N-[5-bromonaphth-1-yl]-N'-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]urea (E19) and phenylboronic acid using a similar procedure to Example 4 (47%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][S:15]([C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH2:20][CH2:21][NH:22][CH:23]2[CH3:28])(=[O:17])=[O:16]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:22]3[CH2:21][CH2:20][C:19]4[C:24](=[CH:25][CH:26]=[CH:27][C:18]=4[S:15]([CH3:14])(=[O:16])=[O:17])[CH:23]3[CH3:28])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2c1cccc2S(C)(=O)=O
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cccc(S(C)(=O)=O)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Methanesulfonyl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:12][CH:11]3[CH2:13][N:14]([C:16](=[O:19])[CH2:17][CH3:18])[CH2:15][CH:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH:22]1[C:31]2[C:26](=[CH:27][C:28](B(O)O)=[CH:29][CH:30]=2)[CH:25]=[CH:24][N:23]=1.C(O)(O)=O>O1CCOCC1>[CH:22]1[C:31]2[C:26](=[CH:27][C:28]([C:2]3[CH:21]=[CH:20][C:5]([C:6]([N:8]4[CH2:12][CH:11]5[CH2:13][N:14]([C:16](=[O:19])[CH2:17][CH3:18])[CH2:15][CH:10]5[CH2:9]4)=[O:7])=[CH:4][CH:3]=3)=[CH:29][CH:30]=2)[CH:25]=[CH:24][N:23]=1
Reactant: CCC(=O)N1CC2CN(C(=O)c3ccc(Br)cc3)CC2C1
Reactant: OB(O)c1ccc2cnccc2c1
Agent: O=C(O)O
Solvent: C1COCCO1
Product: CCC(=O)N1CC2CN(C(=O)c3ccc(-c4ccc5cnccc5c4)cc3)CC2C1
Temperature: 150 °C
Yield: 49.2 %

Procedure:
1.4 1-[5-(4-Bromo-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propan-1-one (100 mg; 0.285 mmol) and isoquinolin-6-ylboronic acid (55.2 mg; 0.31 mmol) are dissolved in 1,4-dioxane dried (max. 0.005% H2O), SeccoSolv® (5.0 ml; 0.058 mol) and the mixture is purged with nitrogen for 5 minutes. Sodium carbonate anhydrous (90.6 mg , 0.86 mmol) and bis(triscyclohexyl-phosphine)-palladium(II) dichloride, 99% (6.4 mg, 8.7 μM) are added and the reaction mixture is heated to 150° C. for 90 min under microwave. The mixture is extracted with ethyl acetate/water. The organic layer is dried over MgSO4, filtered off and evaporated in vacuo. The product is purified on prep. HPLC to afford 56 mg (49%) 1-[5-(4-isoquinolin-6-yl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propan-1-one (“A1”) as a white solid;
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]([O:13][CH3:14])=[O:12].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[N:23]1[CH:32]=[C:26]2[C:27]([NH2:31])=[N:28][CH:29]=[CH:30][C:25]2=[N:24]1>C(Cl)Cl>[CH3:14][O:13][C:11](=[O:12])[NH:31][C:27]1[C:26]2=[CH:32][N:23]([C:17]3[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:16]=3[Cl:15])[N:24]=[C:25]2[CH:30]=[CH:29][N:28]=1
Reactant: COC(=O)Cl
Reactant: Nc1nccc2nn(-c3c(Cl)cccc3Cl)cc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Nc1nccc2nn(-c3c(Cl)cccc3Cl)cc12
Temperature: 25 °C
Yield: 49.4 %

Procedure:
DIPEA (51 μL, 0.3 mmol) and then methyl chloroformate (19 μL, 0.25 mmol) were added to a solution of 2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine-4-ylamine (60 mg, 0.21 mmol) in DCM (2 mL). The reaction was stirred at room temperature until completion as determined by TLC. The mixture was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (40-50% ethyl acetate in cyclohexane) to afford the title compound as a white solid (35 mg, 49% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.54 (d, J=0.9 Hz, 1H), 7.97 (d, J=7.3 Hz, 1H), 7.86 (d, J=1.4 Hz, 1H), 7.84 (d, J=0.6 Hz, 1H), 7.80-7.78 (m, 1H), 7.72 (dd, J=7.3, 0.9 Hz, 1H), 3.97 (s, 3H). LCMS (Method B): RT=2.71 min, m/z: 337 [M+H+].
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:18][C:17]1[CH:20]=[CH:21][C:14]([OH:13])=[CH:15][CH:16]=1
Reactant: NNC(=S)NC1CC2C=CC1C2
Reactant: O=Cc1ccc(O)cc1
Product: Oc1ccc(C=NNC(=S)NC2CC3C=CC2C3)cc1

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.56 mmol) and 4-hydroxybenzaldehyde (68 mg, 0.56 mmol) similar to Example 3 and isolated as a yellow solid (47 mg, 29%). 1H NMR (CDCl3): 9.00 (s, 1H), 7.68 (s, 1H), 7.52 (d, J=8.7 Hz, 2H), 7.43 (d, J=6.9 Hz, 1H), 6.88 (d, J=8.7 Hz, 2H), 6.23-6.14 (m, 2H), 4.30-4.26 (m, 1H), 3.05 (s, 1H), 2.96 (s, 1H), 1.94-1.86 (m, 1H), 1.66 (d, J=9.0 Hz, 1H), 1.51 (d, J=9.0 Hz, 1H), 1.45-1.38 (m, 1H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:15](=[O:32])[NH:16][C:17]1[CH:18]=[C:19]2[C:30](=[O:31])[NH:29][N:28]=[CH:27][C:21]3=[C:22]([Cl:26])[NH:23][C:24]([CH:25]=1)=[C:20]23)[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(C)(C)C.Cl>O1CCOCC1>[NH2:7][C@H:8]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:15]([NH:16][C:17]1[CH:18]=[C:19]2[C:30](=[O:31])[NH:29][N:28]=[CH:27][C:21]3=[C:22]([Cl:26])[NH:23][C:24]([CH:25]=1)=[C:20]23)=[O:32]
Reactant: CC(C)(C)OC(=O)NC(C(=O)Nc1cc2c3c(c(Cl)[nH]c3c1)C=NNC2=O)C1CCCCC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](C(=O)Nc1cc2c3c(c(Cl)[nH]c3c1)C=NNC2=O)C1CCCCC1

Procedure:
Preparation of the title compound from Intermediate 198(a) (75 mg, 0.159 mmol) and 4.0 M HCl in dioxane (0.8 mL) was carried out analogously to Example 91. Isolation, also in an analogous manner, afforded the title compound (65 mg, 0.159 mmol) as a yellow powder in 99% yield.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([NH2:33])[C:18]([NH:19][C@@H:20]4[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:34](OCCCC)=O>C(#N)C.[Cu](Br)Br>[C:1]1([S:7]([N:10]2[CH:11]=[CH:12][C:13]3[C:14]2=[N:15][CH:16]=[C:17]2[C:18]=3[N:19]([C@@H:20]3[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:21]3)[N:34]=[N:33]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@@H]1CCCN(Cc2ccccc2)C1
Reactant: CCCCON=O
Agent: Br[Cu]Br
Solvent: CC#N
Product: O=S(=O)(c1ccccc1)n1ccc2c1ncc1nnn([C@@H]3CCCN(Cc4ccccc4)C3)c12
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 65.1 %

Procedure:
A stirred solution of 1-benzenesulfonyl-N*4*-((R)-1-benzyl-piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridine-4,5-diamine (300 mg, 0.65 mmol) in acetonitrile (6 ml) was treated with copper (II) bromide (174 mg, 0.78 mmol) and n-butyl nitrite (114 μl, 0.97 mmol) and then heated to 70° C. for 2 hours. After cooling, the reaction was quenched by the addition of 1M aqueous HCl solution (ca. 5 ml) and stirred for 5 minutes. The mixture was basified with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate (3×). The combined extracts were washed with brine, dried with sodium sulfate and concentrated under vacuum to leave a brown residue. Purification by column chromatography on silica gel (gradient: 0 to 60% ethyl acetate in cyclohexane) gave 200 mg (65%) of 6-benzenesulfonyl-1-((R)-1-benzyl-piperidin-3-yl)-1,6-dihydro-1,2,3,5,6-pentaaza-as-indacene as a brown residue. LCMS (Method B, ESI): RT=3.38 min, m+H=473.5; 1H NMR (400 MHz, CDCl3) δ: 9.18 (s, 1H), 8.21 (m, 2H), 7.82 (d, 1H), 7.57 (m, 1H), 7.53-7.46 (m, 2H), 7.30 (s, 5H), 6.75 (d, 1H), 4.88 (m, 1H), 3.61 (dd, 2H), 3.25 (m, 1H), 3.03 (m, 1H), 2.57 (m, 1H), 2.39-2.17 (m, 3H), 2.10-1.87 (m, 2H).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][N:11]=[C:10]3[CH:17]=[CH:18][S:19][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([NH:7][C:8]2[C:13]([NH2:14])=[CH:12][N:11]=[C:10]3[CH:17]=[CH:18][S:19][C:9]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1NC1CCCCC1
Agent: [Pd]
Solvent: CO
Product: Nc1cnc2ccsc2c1NC1CCCCC1
Reaction time: 1 h
Yield: 73.8 %

Procedure:
A mixture of N-cyclohexyl-6-nitrothieno[3,2-b]pyridin-7-amine (0.065 g, 0.23 mmol) and 10% palladium on carbon (0.02 g) in methanol (3 mL) was hydrogenated under balloon pressure of H2 at room temperature for 1 h. The reaction mixture was filtered. The filtrate was concentrated, diluted with dichloromethane, dried over MgSO4, and concentrated. The residue was purified on silica gel (eluting with 0 to 10% MeOH in dichloromethane) to give the desired product (42 mg, 72%). LCMS calculated for C13H18N3S (M+H)+: m/z=248.1. Found: 248.1.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]([NH2:10])[CH2:8][OH:9])=[CH:3][CH:2]=1.C(N(CC)CC)C.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24]>O1CCCC1.CCOCC>[OH:9][CH2:8][C@H:7]([NH:10][C:23]([C:19]1[O:18][CH:22]=[CH:21][CH:20]=1)=[O:24])[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: O=C(Cl)c1ccco1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(N[C@@H](CO)c1ccccc1)c1ccco1
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
A solution of D-(-)-α-phenylglycinol (1.18 g, 8.43 mmole) and triethylamine (3.18 mL, 23 mmole) were dissolved in dry tetrahydrofuran (20 mL), cooled down to 0° C (ice bath) and treated dropwise with furoyl chloride (0.76 mL or 1.0 g, 7.66 mmole). The reaction mixture was stirred at 0° C. for 1.0 hour, diluted with ether (100 mL) and washed with 5% HCl (20 mL). The aqueous phase was re-extracted with ether (100 mL) and the combined ether extracts were washed with brine (20 mL), dried (anhydrous MgSO4), filtered and evaporated to dryness to give the title compound (1.79 g, quantitative crude yield) as a solid, m.p. 130°-131° C.
Reaction SMILES: C(N(CC)CC)C.[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].CN(C1C=CC=CN=1)C.[CH2:25]([C:27]([C:46]1[CH:51]=[CH:50][C:49](/[CH:52]=[CH:53]/[C:54]([C:60]([F:63])([F:62])[F:61])([OH:59])[C:55]([F:58])([F:57])[F:56])=[C:48]([CH3:64])[CH:47]=1)([C:30]1[CH:35]=[CH:34][C:33]([B:36]2[O:40][C:39]([CH3:42])([CH3:41])[C:38]([CH3:44])([CH3:43])[O:37]2)=[C:32]([CH3:45])[CH:31]=1)[CH2:28][CH3:29])[CH3:26]>CN(C)C=O.O>[C:11]([Si:8]([CH3:10])([CH3:9])[O:59][C:54]([C:60]([F:63])([F:62])[F:61])([C:55]([F:56])([F:57])[F:58])/[CH:53]=[CH:52]/[C:49]1[CH:50]=[CH:51][C:46]([C:27]([C:30]2[CH:35]=[CH:34][C:33]([B:36]3[O:40][C:39]([CH3:41])([CH3:42])[C:38]([CH3:44])([CH3:43])[O:37]3)=[C:32]([CH3:45])[CH:31]=2)([CH2:25][CH3:26])[CH2:28][CH3:29])=[CH:47][C:48]=1[CH3:64])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(/C=C/C(O[Si](C)(C)C(C)(C)C)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.7 %

Procedure:
Triethylamine (0.10 mL, 0.72 mmol), t-butyldimethylsilyl chloride (48.5 mg, 0.322 mmol) and dimethylaminopyridine (1 mg, 0.008 mmol) were added to a solution of (E)-4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-3-buten-2-ol (Example 26-(5); 47.0 mg, 0.082 mmol) in N,N-dimethylformamide (0.10 mL), and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=50/1) to give the title compound (47 mg, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:12][C:13]([CH3:19])([CH3:18])[CH2:14][CH2:15][CH:16]=[O:17].S(=O)(=O)(O)O>CO>[CH3:12][C:13]([CH3:19])([CH3:18])[CH2:14][C:15]([CH:16]=[O:17])=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(C)(C)CCC=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)CC(C=O)=Cc1ccc(Cl)cc1
Reaction time: 3 h

Procedure:
134 g (0.95 mol) of 4-chlorobenzaldehyde are added to a solution of 15.8 g of 50% strength sodium hydroxide solution in 500 ml of methanol, after which 90 g (0.79 mol) of 4,4-dimethylpentanal are added dropwise at 35° C. in the course of 3 hours. Stirring is carried out for three hours, after which the mixture is neutralized with dilute sulfuric acid and evaporated down and the residue is distilled.
Reaction SMILES: C(OC(=O)[NH:10][C:11]([CH3:23])([C:17]1[N:21]=[C:20]([CH3:22])[O:19][N:18]=1)[CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])C1C=CC=CC=1.B(Br)(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:16][S:13]([CH2:12][C:11]([NH2:10])([CH3:23])[C:17]1[N:21]=[C:20]([CH3:22])[O:19][N:18]=1)(=[O:14])=[O:15]
Reactant: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)OCc2ccccc2)no1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(C(C)(N)CS(C)(=O)=O)no1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 39.7 %

Procedure:
To a solution of [2-Methanesulfonyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-carbamic acid benzyl ester (Example 109c, 0.085 g, 241 μmol) in dry CH2Cl2 (1 ml) under argon atmosphere cooled down at 0° C. was slowly added a 1.0M solution of boron tribromide in dichloromethane (265 μl, 265 μmol). The reaction mixture was stirred at 0° C. for 20 minutes and stirred for 1 hour at room temperature The reaction was diluted with dichloromethane and an 2.0M aqueous solution of sodium carbonate was added. The two phases mixture was stirred at room temperature for 30 minutes and was poured into a separatory funnel and the organic phase was collected. The aqueous phase was back-extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a dichloromethane/methanol gradient to yield the title compound (21 mg, 40%) as yellow oil. MS (ESI, m/z): 220.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])=S)=[C:4]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C:3]=1[S:28]([N:31]([CH3:33])[CH3:32])(=[O:30])=[O:29].CS(Cl)(=O)=O.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[N:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])=[C:4]([O:20][Si:21]([C:24]([CH3:25])([CH3:26])[CH3:27])([CH3:22])[CH3:23])[C:3]=1[S:28]([N:31]([CH3:33])[CH3:32])(=[O:30])=[O:29]
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2cccc(Cl)c2Cl)c1O[Si](C)(C)C(C)(C)C
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(N=C=Nc2cccc(Cl)c2Cl)c1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 112.2 %

Procedure:
To a solution of N-[4-chloro-2-tert-butyldimethylsilyloxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]-N′-(2,3-dichlorophenyl)thiourea (270 mg, 0.45 mmol) in dichloromethane (10 mL) at 0° C., methanesulfonyl chloride (0.07 mL, 0.9 mmol) and triethylamine (0.13 mL, 0.9 mmol) were added. 4-Dimethylaminopyridine was added as a catalyst. The reaction mixture was stirred at 0° C. for 1 hour, then it was partitioned between dichloromethane and water. The combined organic phase was dried and concentrated to give the desired product (270 mg, crude). 1H NMR (CDCl3) δ 0.47 (s, 6H), 1.05 (s, 9H), 2.9 (s, 6H), 7.08 (d, 1H), 7.12 (d, 1H), 7.2 (t, 1H), 7.31 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:13][CH2:14][NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:7][CH:6]=1.C([Li])CCC.[C:37](Cl)(=[O:41])[O:38][CH2:39][CH3:40].[Cl-].[Na+]>O1CCCC1.CCCCCC>[CH2:39]([O:38][C:37]([N:15]([CH2:14][CH2:13][CH:12]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][CH:9]=1)[S:16]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)(=[O:17])=[O:18])=[O:41])[CH3:40]
Reactant: CCOC(=O)Cl
Reactant: COCOc1ccc(CC(CCNS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)N(CCC(Cc1ccc(OCOC)cc1)c1cccnc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
In argon atmosphere, 329 mg of N-[4-(4-methoxymethyloxyphenyl)-3-(3-pyridyl)butyl]-4-chlorobenzene sulfonamide was dissolved in 12 ml of dry tetrahydrofuran, and cooled to 0° C., followed by addition of 0.67 ml of the solution of 1.55M n-butyl lithium in hexane, which was then stirred for 30 minutes. At the same temperature, 116 mg of ethyl chlorocarbonate dissolved in 3 ml of dry tetrahydrofuran was added dropwise and stirred at room temperature for 24 hours. To the reaction mixture was added saturated aqueous sodium chloride, and the organic phase was separated which was then extracted with ethyl acetate. The organic phases combined were washed in saturated aqueous sodium chloride and dried over magnesium sulfate, so the solvent was distilled off under reduced pressure. The obtained residue was subjected to preparative silica gel TLC which was then developed with methanol-methylene chloride (4:96 v/v) to obtain 204 mg of N-ethoxycarbonyl-N-[4-(4-methoxymethyloxyphenyl)-3-(3-pyridyl)butyl]-4-chlorobenzene sulfonamide from a band of 0.36 to 0.53.
Reaction SMILES: [CH2:1]([O:8][N:9]([C:28]([Cl:30])=[O:29])[C@H:10]1[CH2:15][N:14](C(OC(C)(C)C)=O)[C@H:13]([C:23]2[S:27][N:26]=[CH:25][N:24]=2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl.O1CCOCC1>[ClH:30].[S:27]1[C:23]([C@H:13]2[NH:14][CH2:15][C@H:10]([N:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:28]([Cl:30])=[O:29])[CH2:11][CH2:12]2)=[N:24][CH:25]=[N:26]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)C(=O)Cl)CC[C@H]1c1ncns1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Cl)N(OCc1ccccc1)[C@@H]1CC[C@@H](c2ncns2)NC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2S,5R)-tert-butyl 5-(benzyloxy(chlorocarbonyl)amino)-2-(1,2,4-thiadiazol-5-yl)piperidine-1-carboxylate was dissolved in 4 N HCl in dioxane (10 mL). The mixture was stirred at rt for 0.5 h and then concentrated to provide the crude ((3R,6S)-6-(1,2,4-thiadiazol-5-yl)piperidin-3-yl)(benzyloxy)carbamic chloride HCl salt, which was directly used in the next step. ESI-MS (EI+, m/z): 445 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.[CH:17]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=[CH2:18].[OH-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[N:6]([CH2:18][CH2:17][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:5]=2[CH2:4][CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Reactant: C=Cc1ccncc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Product: Cc1ccc2c(c1)c1c(n2CCc2ccncc2)CCN(C)CC1
Temperature: 110 °C
Yield: 68.1 %

Procedure:
The title compound was prepared by following general procedure 4. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46 mmol), tetra n-butyl ammonium chloride (6 mg, 0.023 mmol), 4-vinylpyridine (58 mg, 0.55 mmol) were taken into 50% NaOH (3 mL). The reaction mixture was heated overnight at 110° C. The reaction mixture was extracted with ethyl acetate and organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain 100 mg of 3,9-dimethyl-6-(2-(pyridin-4-yl)ethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole as the TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:17]1[CH:18]=[CH:19][N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[NH:23][CH2:22][C:21]=12.C(N(CC)C(C)C)(C)C>S(Cl)(Cl)=O.ClCCl>[CH:17]1[CH:18]=[CH:19][N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]([C:14]([C:11]3[CH:10]=[CH:9][C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=4)=[CH:13][CH:12]=3)=[O:16])[CH2:22][C:21]=12
Reactant: Cc1cccc(-c2ccc(C(=O)O)cc2)c1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)c1
Reaction time: 2 h
Yield: 82.9 %

Procedure:
A suspension of 3′-methyl-[1,1′-biphenyl]-4-carboxylic acid of Step B (0.50 g, 2.36 mmol) in thionyl chloride (3 mL) was heated at reflux for 30 minutes. After cooling, the thionyl chloride was removed in vacuo. The residue was dissolved in toluene and concentrated in vacuo to give the crude acid chloride as a yellow oil. The acid chloride was then dissolved in dichloromethane (5 mL) and slowly added to a solution of the 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.65 g, 3.53 mmol) and N,N-diisopropylethyl amine (0.90 mL, 5.17 mmol) in dichloromethane (15 mL). After stirring for 2 hours, the reaction was quenched with water. The organic layer was washed with 1 N hydrochloric acid, 1 N sodium hydroxide and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a white foam. Purification of the residue by flash chromatography using a solvent gradient from 15% to 25% of ethyl acetate in hexane gave a white foam which was crystallized by sonication from ethyl acetate/hexane to provide the title compound (0.74 g, 82.8%) as a white solid, m.p. 128–130° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[N+:10]([O-])([OH:12])=[O:11].O>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:9])=[CH:4][C:5]([OH:8])=[C:6]([N+:10]([O-:12])=[O:11])[CH:7]=1
Reactant: Oc1ccc(Br)c(F)c1
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cc(Br)c(F)cc1O
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
To a 0° C. mixture of 4-bromo-3-fluorophenol (70.0 g, 366 mmol) in DCM (500 mL) was added HNO3 (23.0 g, 366 mmol) carefully and the reaction mixture was stirred 30 min. The reaction mixture was poured into water (1 L) and extracted with DCM (3×500 mL). The combined organic portion was washed with brine (300 mL) and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was crystallized from EtOH to give 4-bromo-5-fluoro-2-nitrophenol (42.0 g, 49%). 1H NMR (DMSO-d6, 400 MHz): δ 11.72 (brs, 1H), δ 8.30 (d, J=7.2 Hz, 1H), 7.09 (d, J=10.0 Hz, 1H).