Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:23][C:24](=[O:39])[C:25]1[CH:30]=[CH:29][C:28]([C:31]([N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:32])=[C:27]([CH3:38])[CH:26]=1)[C:13]1[NH:17][C:16]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]=2[N:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.ClCl>ClCCl.CO>[NH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:23][C:24](=[O:39])[C:25]1[CH:30]=[CH:29][C:28]([C:31]([N:33]2[CH2:34][CH2:35][CH2:36][CH2:37]2)=[O:32])=[C:27]([CH3:38])[CH:26]=1)[C:13]1[NH:17][C:16]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]=2[N:14]=1
Reactant: Cc1cc(C(=O)N[C@@H](CCCNC(=O)OC(C)(C)C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Agent: ClCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C(=O)N[C@@H](CCCN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 54 %

Procedure:
Prepared analogously to Example 17 from (S)—N-[4-(tert-butoxycarbonylamino)-1-(5-chloro-1H-benzimidazol-2-yl)butyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide and trifluoroacetic acid. Yield: 54%; Rf value: 0.21 (silica gel; dichloromethane/methanol=9:1); C24H28ClN5O2 (453.97); mass spectrum: (M+H)+=454/456 (chlorine isotope) and (M−H)-=452/454 (chlorine isotope).
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[CH:12]=[C:11]([F:15])[CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:16]#[N:17])=[CH:4][N:3]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+].[CH3:70][C@H:71]1[C@H:80]([NH2:81])[CH2:79][CH2:78][C:73]2([O:77][CH2:76][CH2:75][O:74]2)[CH2:72]1>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COCCOC>[F:15][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:5]([C:16]#[N:17])=[CH:4][N:3]=[C:2]([NH:81][C@@H:80]4[CH2:79][CH2:78][C:73]5([O:74][CH2:75][CH2:76][O:77]5)[CH2:72][C@H:71]4[CH3:70])[C:14]=3[C:13]=2[CH:12]=1
Reactant: C[C@@H]1CC2(CC[C@H]1N)OCCO2
Reactant: N#Cc1cnc(Cl)c2c1[nH]c1ccc(F)cc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: C[C@@H]1CC2(CC[C@H]1Nc1ncc(C#N)c3[nH]c4ccc(F)cc4c13)OCCO2
Temperature: 85 °C

Procedure:
A flask containing 1-chloro-8-fluoro-5H-pyrido[4,3-b]indole-4-carbonitrile (1.50 g, 6.11 mmol), BINAP (570 mg, 0.916 mmol), Pd2(dba)3 (280 mg, 0.305 mmol), and NaOtBu (1.88 g, 19.5 mmol) was evacuated and refilled with nitrogen (×3). Degassed DME (50 mL) and (7R,8R)-7-methyl-1,4-dioxaspiro[4.5]decan-8-amine (1.26 g, 7.33 mmol) were added to the mixture. The reaction mixture was heated to 85° C. overnight, cooled to room temperature, diluted with EtOAc, and washed with water and brine. The organic layer was dried (sodium sulfate), concentrated, and purified by flash chromatography to afford the title compound. LRMS (APCI) calc'd for (C21H21FN4O2) [M+H]+, 381.2. found 381.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@@H:5]([C@H:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)O)[CH2:4][O:3]1.CC1(C)O[C@@H]([C@@H](C2SC=CC=2)O)CO1.[C-]#[C-].[Na+].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:46][CH2:45]1.N1C(C)=CC=CC=1C.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCCC1.O1CCOCC1.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:14])[O:6][C@@H:5]([C@@H:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[N:44]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[CH:46]=[CH:45]2)[CH2:4][O:3]1
Reactant: CC1(C)OC[C@H]([C@@H](O)c2cccs2)O1
Reactant: c1ccc2c(c1)CCN2
Agent: CC1(C)OC[C@H]([C@H](O)c2cccs2)O1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Product: CC1(C)OC[C@H]([C@@H](c2cccs2)n2ccc3ccccc32)O1
Reaction time: 2 h

Procedure:
A mixture of (R)-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl](2-thienyl)methanol and (S)-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl](2-thienyl)methanol (1.5 g, 7.0 mmol) was dissolved in tetrahydrofuran (28 mL) and sodium acetylide (2.1 g, 7.7 mmol; 18 wt % slurry in xylenes/light mineral oil) and the mixture was stirred for 2 hours. para-Toluenesulfonyl chloride (1.46 g, 7.7 mmol) was added and stirring was continued for 2 hours, then indoline (2.5 g, 21 mmol) was added followed by 2,6-lutidine (0.81 mL, 7.0 mmol). After 72 hours the mixture was quenched with a saturated aqueous solution of ammonium chloride, diluted with ethyl acetate, washed with water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Isco chromatography (Redisep, silica, gradient 1-10% ethyl acetate in hexane) to afford 590 mg that was immediately dissolved in dioxane (10 mL) and treated with dichlorodicyanobenzoquinone (552 mg, 2.4 mmol) and stirred for 30 minutes. The mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate, water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Isco chromatography (Redisep, silica, gradient 1-20% ethyl acetate in hexane) to afford 355 mg of 1-[(S)-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl](2-thienyl)methyl]-1H-indole. HRMS: calcd for C18H19NO2S+H+, 314.12092; found (ESI-FTMS, [M+H]1+), 314.12111.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]2[O:13][C@H:14]3[C:23]4([O:27][CH2:26][CH2:25][O:24]4)[CH2:22][CH2:21][C@@H:20]4[C@@:15]53[CH2:16][CH2:17][N:18]([CH3:29])[C@@H:19]4[CH2:28][C:10]([C:11]=25)=[CH:9][CH:8]=1)(=O)=O.[CH3:32][N:33](C)C=O>C(OCC)(=O)C.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-]#N.[Zn+2].[C-]#N>[CH3:29][N:18]1[CH2:17][CH2:16][C@@:15]23[C:11]4[C:10]5[CH2:28][C@@H:19]1[C@@H:20]2[CH2:21][CH2:22][C:23]1([C@@H:14]3[O:13][C:12]=4[C:7]([C:32]#[N:33])=[CH:8][CH:9]=5)[O:24][CH2:25][CH2:26][O:27]1
Reactant: CN1CC[C@]23c4c5ccc(OS(=O)(=O)C(F)(F)F)c4O[C@H]2C2(CC[C@H]3[C@H]1C5)OCCO2
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CN1CC[C@]23c4c5ccc(C#N)c4O[C@H]2C2(CC[C@H]3[C@H]1C5)OCCO2
Temperature: 40 °C
Yield: 63 %

Procedure:
To a solution of (4R,4aR,7aR,12bS)-3-methyl-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolan]-9-yl trifluoromethanesulfonate (20.77 g, 45.0 mmol) in degassed dimethylformamide (400 mL) was added tetrakis(triphenylphosphine)palladium(0) (5.21 g, 4.50 mmol). After heating to 40° C., zinc cyanide (3.18 g, 27.0 mmol) was added and the reaction mixture heated at 110° C. for 6 hours. The reaction mixture was cooled to room to temperature and diluted with ethyl acetate and filtered through a pad of celite. The filtrate was diluted further with ethyl acetate and washed with water (3×500 mL). The aqueous phase was basified with sodium hydrogen carbonate solution and re-extracted with ethyl acetate and the combined organics dried (MgSO4), filtered and concentrated under reduced pressure. Purification by silica chromatography (100% dichloromethane to 5% NH3/methanol in dichloromethane) gave (4R,4aR,7aR,12bS)-3-methyl-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolane]-9-carbonitrile (10.0 g, 91% pure LCMS, 63% yield over three steps); [M+H]+ 339.1.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].C([O-])([O-])=O.[K+].[K+].[CH2:18](I)[CH2:19][CH3:20]>CC(C)=O.CCOC(C)=O.C(Cl)(Cl)Cl>[OH:11][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:18][CH2:19][CH3:20])=[CH:9][C:4]=1[C:2](=[O:3])[CH3:1]
Reactant: CC(=O)c1cc(O)ccc1O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCCOc1ccc(O)c(C(C)=O)c1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
10 g of 2,5-dihydroxyacetophenone suspended in 100 ml of acetone are placed in a 500 ml round-bottomed flask and 9.14 g of anhydrous K2CO3 are added, followed by addition of 12.4 g of propyl iodide. The reaction medium is refluxed for 30 hours. After cooling to room temperature, the medium is filtered through Celite® and then concentrated. The brown oil obtained is taken up in EtOAc, filtered, washed with water, with 2M HCl solution and then with saturated NaCl solution. The organic phase is evaporated to give a black paste. The paste is taken up in chloroform and filtered. The medium is concentrated to give 11.4 g of a black solid. This solid is taken up in absolute ethanol. The solution is placed in a freezer for 10 minutes; a solid precipitates out, and is collected by filtration. The filtrate is concentrated, taken up in ethanol, cooled in a freezer and then filtered again. This operation is repeated four more times to give 8.35 g of the expected compound in the form of a powder.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([C:34](Cl)=[O:35])=[CH:33][C:28]=2[O:27][CH2:26]1>C(OCC)C.CCCCCC>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH:21][C:34]([C:32]4[CH:31]=[CH:30][C:29]5[O:25][CH2:26][O:27][C:28]=5[CH:33]=4)=[O:35])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc3c(c1)OCO3)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 67 %

Procedure:
By using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 1,3-benzodioxol-5-carbonyl chloride, the title compound was synthesized according to Example 1b. Yield: 67%. Melting point: 165-167° C. (Ethyl ether-hexane).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[C:6]=2[Cl:21].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(P([Pd-3](Cl)(Cl)(P(C2C=CC=CC=2)C2C=CC=CC=2)[C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2].O1CCOCC1>[Cl:21][C:6]1[N:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:8]=[C:9]2[C:5]=1[CH:4]=[CH:3][C:2]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[O:23][CH3:22])=[CH:10]2
Reactant: COc1ccccc1B(O)O
Reactant: FC(F)(F)c1ccc(-n2nc3cc(Br)ccc3c2Cl)cc1
Agent: Cl[Pd-3](Cl)([c-]1cccc1)(P(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccccc1-c1ccc2c(Cl)n(-c3ccc(C(F)(F)F)cc3)nc2c1
Temperature: 160 °C

Procedure:
A mixture of the product of Example 1 Step 3 (100 mg, 0.26 mmol), 2-methoxyphenylboronic acid (50 mg, 0.33 mmol), bis(diphenylphosphino)ferrocenyl palladium(II) dichloride 0) (20 mg), saturated Na2CO3 solution (1 mL) and dioxane (2 mL) was heated at 160° C. for 10 min via microwave irradiation. The title product was then purified by preparative thin layer chromatography on silica eluting with EtAc:hexanes 1:5. MS: (ES (M+1)) 403,405.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.[C:24]1([NH:30][CH2:31][CH2:32][NH2:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[C:24]1([NH:30][CH2:31][CH2:32][NH:33][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: NCCNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1NCCNc1ccccc1

Procedure:
A mixture of 1-fluoro-2-nitrobenzene(15.5g, 110 mmol) and potassium carbonate (15.2 g, 110 mmol) was stirred and a mixture of N-methylpyrrolidone (20 ml) and N-phenylethylenediamine (15.0 g, 110 mmol) was added over 1 h at room temperature. The mixture was stirred for 1 h. Water (200 ml) was added crystals were filtered off and triturated with petroleum ether. Yield 14.7 g, 52%. M.p. 64-66° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6](NC)[CH:5]([C:9]2[CH:10]=[C:11]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:16][N:15](C4CCCCO4)[C:12]3=[CH:13][N:14]=2)[CH2:4][C:3]1=[O:30].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[CH3:1][N:2]1[CH2:6][CH:5]([C:9]2[CH:10]=[C:11]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:16][NH:15][C:12]3=[CH:13][N:14]=2)[CH2:4][C:3]1=[O:30]
Reactant: CNC1C(c2cc3c(-c4ccccc4)nn(C4CCCCO4)c3cn2)CC(=O)N1C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CN1CC(c2cc3c(-c4ccccc4)n[nH]c3cn2)CC1=O
Temperature: 105 °C
Reaction time: 20 h
Yield: 25.6 %

Procedure:
In a high-pressure vessel was placed 1-methyl-5-(methylamino)-4-(3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)pyrrolidin-2-one 259 (70.0 mg, 0.17 mmol) and trifluoroacetic acid (5 mL). The vessel was sealed and the reaction mixture was stirred at 105° C. for 20 h. The reaction mixture was cooled to RT, and triethylsilane (0.50 mL) was added. The vessel was resealed, and the reaction mixture was stirred at 75° C. After 2 h, more triethylsilane (0.5 mL) was added at RT, and the reaction mixture was stirred in a sealed vessel at 95° C. for 17 h. Volatile solvent was evaporated in vacuo. The resultant crude oil was dissolved in DMF (2 mL). Black insoluble material was filtered and rinsed well with methanol (2×2 mL). The combined filtrates were evaporated in vacuo and the crude product was purified by reverse phase HPLC to give 263 as a white solid (12.7 mg, 25.2%). 1H NMR (400 MHz, DMSO) δ 13.37 (broad s, 1H), 9.08 (s, 1H), 8.04 (d, J=7.4 Hz, 2H), 7.98 (s, 1H), 7.54 (t, J=7.6 Hz, 2H), 7.44 (d, J=7.4 Hz, 1H), 3.98-3.85 (m, 1H), 3.75 (t, J=9.0 Hz, 1H), 3.53 (dd, J=9.3, 7.2 Hz, 1H), 2.78 (s, 3H), 2.66 (dd, J=8.8, 2.9 Hz, 2H). LC/MS: m/z 293.1 [M+1]
Reaction SMILES: C(O[C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])[CH2:10]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][C:42](C(O)=O)=[CH:41][CH:40]=2)=[CH:35][CH:34]=1.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>ClCCl.C(OCC)(=O)C>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]2[CH:44]=[CH:43][C:42]([C:6]([NH:8][CH:9]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=4[C:17]([O:19][CH3:20])=[O:18])[CH2:10]3)=[O:7])=[CH:41][CH:40]=2)=[CH:37][CH:38]=1
Reactant: COC(=O)c1ccccc1N1CCCC(NC(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1N1CCCC(NC(=O)c2ccc(-c3ccc(Cl)cc3)cc2)C1
Temperature: 0 °C
Yield: 71.4 %

Procedure:
Methyl 2-[3-(tert-butoxycarbonylamino)piperidin-1-yl]benzoate (2.34 g, 7.00 mmol) was dissolved in anhydrous dichloromethane (50 mL). While this solution was ice-chilled and stirred, trifluoroacetic acid (5.2 mL, 6.82 mmol) was added and the mixture was stirred for 3 hours. Subsequently, the reaction mixture was concentrated and a 10% hydrochloric acid/methanol mixture (50 mL) was added to the residue. The mixture was stirred at room temperature for 1 hour and was concentrated. The same process was repeated 3 times and the resulting solid were washed with ethyl acetate. This gave 1.33 g of a colorless powder. This product (113 mg) was dissolved in N,N-dimethylformamide (4 mL). While the solution was chilled to 0° C. and stirred, 4′-chlorobiphenyl-4-carboxylic acid (103 mg, 0.443 mmol), 1-hydroxybenzotriazole monohydrate (63.8 mg, 0.417 mmol), N-methylmorpholine (160 μL, 1.46 mmol) and 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride (78.0 mg, 0.407 mmol) were added. The mixture was stirred at 0° C. for 20 min and at room temperature for the following 6 hours. Subsequently, the reaction mixture was diluted with ethyl acetate. The organic layer washed sequentially with 5% aqueous citric acid, a saturated aqueous sodium bicarbonate solution, water and brine. The washed product was dried over anhydrous sodium sulfate and the solvent was concentrated. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=3:1) gave 142 mg of the desired compound as colorless crystals.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:30]([Cl:31])=[CH:29][C:13]3[NH:14][C:15]([O:17][C:18]4[CH:19]=[CH:20][C:21]([CH3:28])=[C:22]([CH:27]=4)[C:23]([O:25][CH3:26])=[O:24])=[N:16][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO.O>[Cl:31][C:30]1[C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([OH:3])[CH3:2])=[CH:9][CH:8]=2)=[CH:11][C:12]2[N:16]=[C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([CH3:28])=[C:22]([CH:27]=3)[C:23]([O:25][CH3:26])=[O:24])[NH:14][C:13]=2[CH:29]=1
Reactant: COC(=O)c1cc(Oc2nc3cc(-c4ccc(C(C)=O)cc4)c(Cl)cc3[nH]2)ccc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(Oc2nc3cc(-c4ccc(C(C)O)cc4)c(Cl)cc3[nH]2)ccc1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a 0° C. solution of methyl 5-{[5-(4-acetylphenyl)-6-chloro-1H-benzimidazol-2-yl]oxy}-2-methylbenzoate (50 mg, 0.115 mmol) in MeOH (2 mL) was added NaBH4 (6.5 mg, 0.172 mmol). The mixture was warmed to rt and stirred for 15 min. Water (5-6 drops) was added and the mixture was concentrated. The residue was partitioned between Et2O and water. The aqueous phase was extracted with Et2O. The combined ethereal extracts were washed with brine, dried (MgSO4), filtered, and concentrated to afford the desired product, which was used in the next step without further purification.
Reaction SMILES: CC([O-])(C)C.[Na+].Br[C:8]1[CH:9]=[C:10]([CH3:33])[C:11]([NH:14][C:15]2[N:16]=[CH:17][C:18]3[C:23]4[CH:24]=[CH:25][N:26]=[CH:27][C:22]=4[N:21]([CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[C:19]=3[N:20]=2)=[N:12][CH:13]=1.[N:34]1([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[NH4+].[Cl-]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:28]1([N:21]2[C:19]3[N:20]=[C:15]([NH:14][C:11]4[N:12]=[CH:13][C:8]([N:37]5[CH2:36][CH2:35][N:34]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38]5)=[CH:9][C:10]=4[CH3:33])[N:16]=[CH:17][C:18]=3[C:23]3[CH:24]=[CH:25][N:26]=[CH:27][C:22]2=3)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cc1cc(Br)cnc1Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)cnc1Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Temperature: 140 °C
Yield: 53.4 %

Procedure:
Sodium 2-methylpropan-2-olate (0.100 g, 1.06 mmol) was combined with compound 77 (0.150 g, 0.354 mmol) and tert-butyl 1-piperazinecarboxylate (0.099 g, 0.532 mmol) in 1,4-dioxane (3 ml). Nitrogen was bubbled through the solution for 1 min before adding XANTPHOS (0.031 g, 0.053 mmol) and Pd2(dba)3 (0.024 g, 0.026 mmol). The reaction mixture was heated to 140° C. using microwave irradiation for 1 hour. The reaction mixture was poured into sat. NH4Cl, and extracted with 10% isopropanol/DCM. The organic layer was dried over MgSO4 and concentrated in vacuum. The crude product was purified by flash column chromatography, eluting with a gradient of DCM-7% methanol/DCM to provide compound 78 as a brown oil (100 mg). LCMS-ESI (POS), M/Z, M+1: Found 529.3.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH2:25])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH-].[Na+]>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:16][C:15]2[CH:19]=[CH:20][CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Sc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1ccc(Sc2c(NCc3ccccc3)cc(C(=O)O)cc2S(N)(=O)=O)cc1

Procedure:
The starting material is prepared as follows: The solution of 4-(4-acetamidophenylmercapto)-3-amino-5-sulfamoylbenzoic acid if 50 ml of water containing 0.4 g of sodium hydroxide is adjusted to pH = 7.4 by the addition of 4N aqueous sodium hydroxide, whereupon 1.3 g of benzylchlorideare added while stirring under nitrogen. As soon as the pH remains constantthe mixture is filtered and the filtrate acidified with glacial acetic acidto a pH of 4-5. The precipitate formed is recrystallized from 50% aqueous ethanol, to yield the 4-(4-acetamidophenylmercapto)-3-benzylamino-5-sulfamoylbenzoic acid melting at 255°-258°.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:13][CH2:12][NH:11][CH2:10][C:9]=3[O:14][C:4]=2[CH:3]=1.[CH:15](=O)C>>[I:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:13][CH2:12][NH:11][CH:10]([CH3:15])[C:9]=3[O:14][C:4]=2[CH:3]=1
Reactant: CC=O
Reactant: Ic1ccc2c3c(oc2c1)CNCC3
Product: CC1NCCc2c1oc1cc(I)ccc21

Procedure:
Synthesized as described for 7-iodo-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine using acetaldehyde. 1H-NMR (400 MHz, CDCl3): δ 1.60 (d, 3H), 2.92 (m, 2H), 3.37 (m, 1H), 3.59 (m, 1H), 4.77 (m, 1H), 7.46 (d, 1H), 7.64 (dd, 1H), 8.07 (d, 1H), 9.58 (bs, 1H), 10.02 (bs, 1H).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[CH2:14][CH2:13][CH2:12][CH:11]([CH2:16][C:17]([N:19]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=O)[C:10]=3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[N:19]1([CH2:17][CH2:16][CH:11]2[CH2:12][CH2:13][CH2:14][C:15]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[CH:9][C:10]2=3)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: O=C(CC1CCCc2c1cnn2-c1ccccc1)N1CCCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(-n2ncc3c2CCCC3CCN2CCCCCC2)cc1
Temperature: 0 °C
Yield: 61.1 %

Procedure:
A solution of 1-(2-(4,5,6,7-tetrahydro-1-phenyl-1H-indazol-4-yl)acetyl)azepane (60 mg, 0.18 mmol) in anhydrous THF (2 mL) is slowly added to a suspension of LiAlH4 (20 mg, 0.53 mmol) in anhydrous THF (10 mL) cooled to 0° C. The mixture is refluxed for 3 hours following the reaction by means of TLC. The mixture is cooled, and water and a NaOH solution are added, the precipitate is filtered and washed with AcOEt. The organic phase is separated and washed with water and dried, giving 4-(2-(azepan-1-yl)ethyl)-4,5,6,7-tetrahydro-1-phenyl-1H-indazole (36 mg, 0.11 mmol, 63%, oil).
Reaction SMILES: [NH2:1][C:2]1[NH:7][CH2:6][C:5]2=[C:8]([CH3:15])[N:9]=[C:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:4]2[N:3]=1.[CH:16]1[C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=[C:18]([Cl:25])[CH:17]=1>>[CH3:15][C:8]1[N:9]=[C:10]([CH2:11][CH:12]([CH3:13])[CH3:14])[N:4]2[C:5]=1[CH2:6][NH:7][C:2]([NH:1][C:22](=[O:23])[C:21]1[CH:20]=[CH:19][C:18]([Cl:25])=[CH:17][CH:16]=1)=[N:3]2
Reactant: Cc1nc(CC(C)C)n2c1CNC(N)=N2
Reactant: O=C(O)c1ccc(Cl)cc1
Product: Cc1nc(CC(C)C)n2c1CNC(NC(=O)c1ccc(Cl)cc1)=N2

Procedure:
N-(3,4-Dihydro-5-methyl-7-isobutylimidazo[ 5,1-f]-as-triazin-2-yl)-p-chlorobenzamide, m.p. 236°-239° was prepared from 2-amino-3,4-dihydro-5-methyl-7-isobutylimidazo[5,1-f]-as-triazine (Example 1d) and P-chlorobenzoic acid. It was converted into its hydrochloride salt m.p. 240°-247°.