Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=3)(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[C:5]([Cl:29])=[CH:4][N:3]=1.CO.C(O)(=O)C.C([O-])(O)=O.[Na+]>[Fe].CCOC(C)=O.O>[NH2:26][C:22]1[CH:21]=[C:20]([S:17]([NH:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][NH:8][C:6]3[C:5]([Cl:29])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:11]=2)(=[O:18])=[O:19])[CH:25]=[CH:24][CH:23]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2cccc(CNc3nc(Cl)ncc3Cl)c2)c1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cccc(S(=O)(=O)Nc2cccc(CNc3nc(Cl)ncc3Cl)c2)c1
Temperature: 70 °C
Yield: 24.6 %

Procedure:
Into a reaction flask was added N-(3-{[(2,5-dichloropyrimidin-4-yl)amino]methyl}phenyl)-3-nitrobenzenesulfonamide (0.20 g, 0.44 mmol), methanol (20 mL), acetic acid (2.0 mL), and water (1 mL). Then iron (0.25 g, 4.5 mmol) powder was added. The reaction mixture was heated at 70° C. for 2 hours. After cooling, the mixture was filtered and washed with EtOAc. The filtrate was concentrated under vacuum to give a residue, which was treated with NaHCO3 (saturated aqueous solution) and EtOAc. The organic layer was dried and concentrated under vacuum. The resulting crude product was then purified by silica gel column chromatography to provide the desired product (46 mg, 25%). LCMS for C17H16Cl2N5O2S (M+H)+: m/z=424.0, 426.0.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[N:18]=2)[CH:12]=1)[S:6]([CH3:9])(=[O:8])=[O:7].[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=1>>[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([NH:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][C:26]4[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=4)[N:18]=3)[CH:12]=2)[S:6]([CH3:9])(=[O:8])=[O:7])=[O:39])=[CH:36][CH:35]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Product: CS(=O)(=O)N(CCCNC(=O)c1ccc(Cl)cc1)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Compound 2 was coupled with 4-chlorobenzoic acid following procedure K. LC-MS showed the product had the expected M+H+ of 594. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.23 (d, 1H) 8.1 (d, 1H) 7.6 (d, 2H) 7.5 (d, 2H) 7.4 (m, 2H), 7.3 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 6.7 (d, 2H), 4.5 (s, 2H) 3.6 (t, 2H), 3.1 (d, 2H), δ 3.0 (s, 3H), 2.8 (t, 2H), δ 1.8 (m, 2H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][C@H:24]([OH:39])[CH2:25][O:26][C:27]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]2[C:28]=1[CH2:29][CH2:30][C:31](=[O:38])[NH:32]2>>[OH:39][C@H:24]([CH2:25][O:26][C:27]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]2[C:28]=1[CH2:29][CH2:30][C:31](=[O:38])[NH:32]2)[CH2:23][NH:22][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NC[C@H](O)COc1ccc(O)c2c1CCC(=O)N2
Reactant: CCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Product: CCCCS(=O)(=O)Nc1ccc(N2CCC(NC[C@H](O)COc3ccc(O)c4c3CCC(=O)N4)CC2)cc1

Procedure:
The title compound was prepared from butane-1-sulfonic acid [4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example 228) and 5-(3-amino-(2S)-2-hydroxy-propoxy)-8-hydroxy-3,4-dihydro-1H-quinolin-2-one (which was obtained in Example 12) according to the procedure of Example 278 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.82 (t, J=7.3 Hz, 3 H), 1.20–1.40 (m, 4 H), 1.50–1.70 (m, 2 H), 1.80–1.95 (m, 2 H), 2.39 (t, J=7.3 Hz, 2 H), 2.50–2.80 (m, 5 H), 2.85 (t, J=7.3 Hz, 2 H), 2.85–3.00 (m, 2 H), 3.45–3.60 (m, 2 H), 3.75–3.85 (m, 3 H), 6.44 (d, J=8.7 Hz, 1 H), 6.60 (d, J=8.7 Hz, 1 H), 6.89 (d, J=9.0 Hz, 2 H), 7.04 (d, J=9.0 Hz, 2 H), 8.74 (s, 1 H); MS (ES) m/z: 546.9 (MH+); HRMS Calcd. for C27H39N4O6S (MH+): 547.2590. Found: 547.2583.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([C:19]4([C:25]5[CH:33]=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][CH:26]=5)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[S:17][CH:18]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.CN(C([O:41][N:42]1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NO[Si](C(C)(C)C)(C)C>CN(C=O)C>[OH:41][NH:42][C:29](=[O:31])[C:28]1[CH:27]=[CH:26][C:25]([C:19]2([C:16]3[S:17][CH:18]=[C:14]([C:11]4[CH:12]=[N:13][C:8]([N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)=[CH:9][CH:10]=4)[N:15]=3)[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)=[CH:33][CH:32]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CN1CCN(c2ccc(-c3csc(C4(c5ccc(C(=O)O)cc5)CCOCC4)n3)cn2)CC1
Agent: CC(C)(C)[Si](C)(C)ON
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(-c3csc(C4(c5ccc(C(=O)NO)cc5)CCOCC4)n3)cn2)CC1
Reaction time: 2 h

Procedure:
4-(4-{4-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-thiazol-2-yl}-tetrahydro-pyran-4-yl)-benzoic acid (200 mg, 0.215 mmol), HATU (90 mg, 1.1 eq), H2N-OTBS (2.0 eq), and TEA (0.1 mL, 3 eq) were mixed in DMF and stirred for 2 hours. The reaction mixture was washed with water and then extracted with EtOAc. The organic phase was evaporated, suspended in 1N HCl, and slowly evaporated at 50° C. for 30 minutes to give title compound. MS found for C25H29N5O3S as (M+H)+ 480.15. 1H NMR (400 MHz, dmso-d6): δ: 11.13 (s, 1H), 8.99 (s, 1H), 8.68 (d, J=2.4 Hz, 1H), 8.00 (dd, J=8.8, 6.4 Hz, 1H), 7.81 (s, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.8 Hz, 1H), 3.73-3.70 (m, 2H), 3.61-3.56 (m, 2H), 3.53-3.50 (m, 4H), 2.65-2.60 (m, 2H), 2.44-2.20 (m, 4H), 2.38-2.32 (m, 2H), 2.22 (s, 3H).
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)=O.CO>C1(C)C=CC=CC=1.CCOCC>[C:17]([O:16][C:14]([NH:13][C@@H:5]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[C@@H:4]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:3]=[O:2])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)[C@H](OCc1ccccc1)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CCOC=O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H](C=O)OCc1ccccc1

Procedure:
A solution of 980 mg. (S)-3-t-butoxycarbonylamino-(R)-2-benzyloxy-4-cyclohexylbutyric acid methyl ester (Ii) in dry toluene (5 ml.) was cooled and stirred at -78° C. while a solution of diisobutylaluminum hydride (DIBAL-H, 6.05 ml.) was added dropwise so that the temperature did not exceed -65° C. 15 minutes after completion of the DIBAL-H addition dry ethyl formate (0.48 ml.) was added dropwise followed by dry methanol (0.6 ml.), stirring being then continued another 15 minutes at -78° C. whereupon a 50% aqueous solution of Rochelle salts was added (10 ml.) followed by ether (50 ml.), and the mixture was brought to room temperature. The emulsion was allowed to separate and the ether layer was washed with brine, dried and concentrated to give 880 mg. (97%) of the title aldehyde which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9](=[O:11])(=[O:10])[N:8]([CH2:12][CH2:13][CH2:14]Br)[C:7](=[O:16])[C:6]=2[CH:17]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[N:24]1[CH2:29][CH2:28][N:27]([CH2:14][CH2:13][CH2:12][N:8]2[C:7](=[O:16])[C:6]3[CH:17]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[S:9]2(=[O:11])=[O:10])[CH2:26][CH2:25]1
Reactant: O=C1c2cc(F)ccc2S(=O)(=O)N1CCCBr
Reactant: c1cnc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2cc(F)ccc2S(=O)(=O)N1CCCN1CCN(c2ncccn2)CC1

Procedure:
0.03 mol of 5-fluoro-2-(3-bromopropyl)-1,2-benzisothiazol-3(2H)one 1,1-dioxide and 0.03 mol of 1-(2-pyrimidinyl)piperazine are stirred at 50° to 60° C. with 0.03 mol of K2CO3 in 100 ml of absolute DMF for 2 hours. The mixture is then evaporated, water is added to the residue and the base is extracted with methylene chloride. Purification is carried out by chromatography on silica gel; the eluting agent is CH2Cl2 /CH2OH (98:2), recrystallisation is on roluol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](I)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[F:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:20]=[CH:19][C:18]=1[NH2:32].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.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.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]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:32][C:18]2[CH:19]=[CH:20][C:21]([O:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:22][C:17]=2[F:16])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Reactant: Nc1ccc(OCCN2CCOCC2)cc1F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1cccc(Nc2ccc(OCCN3CCOCC3)cc2F)c1C(=O)OC
Yield: 93 %

Procedure:
A mixture of 3-iodophthalic acid dimethyl ester (2.0 g, 6.2 mmol), 2-fluoro-4-(2-morpholin-4-yl-ethoxy)-phenylamine (1.5 g, 6.2 mmol), Pd2(dba)3 (0.26 g, 0.28 mmol), rac-BINAP (0.12 g, 0.19 mmol), and cesium carbonate (2.8 g, 8.6 mmol), in 12 mL toluene was heated to reflux under nitrogen for 18 hours. The reaction mixture was cooled, diluted with CH2Cl2 (15 mL), and filtered through Celite, and the filter was washed with additional CH2Cl2 (25 mL). The filtrate was evaporated in vacuo, and the residue was purified by ISCO silica gel flash chromatography using a methylene chloride-methanol gradient, eluting 2.5 g of the product at 95:5 methylene chloride-methanol, in 93% yield; 1H NMR (DMSO-d6) δ 2.47 (t, J=4.7, 4H), 2.69 (t, J=5.6 Hz, 2H), 3.58 (t, J=4.7, 4H), 3.80 (s, 6H), 4.10 (t, J=5.6 Hz, 2H), 6.76-6.83 (m, 2H), 6.97 (dd, J=12.6 Hz, J=2.7 Hz, 1H), 7.06 (dd, J=7.5 Hz, J=0.9 Hz, 1H), 7.23 (t, J=9.2 Hz, 1H), 7.34 (t, J=8.0 Hz, 1H), 7.69 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20](F)[N:19]=4)[C:11]=3[CH:10]=2)[CH:6]=[N:7][CH:8]=1)[CH3:2].[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[N:19]=4)[C:11]=3[CH:10]=2)[CH:6]=[N:7][CH:8]=1)[CH3:2]
Reactant: C1CNCCN1
Reactant: CCc1cncc(-c2cc3c(cn2)cnn3-c2cccc(F)n2)c1
Product: CCc1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCNCC3)n2)c1
Yield: 18 %

Procedure:
Following the procedures as described in EXAMPLE 8 and starting with 6-(5-ethylpyridin-3-yl)-1-(6-fluoropyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine and piperazine, 104 was obtained as an off-white solid (22.3 mg, 18%) over 2 steps. 1H NMR (400 MHz, DMSO) δ 9.35-9.27 (s, 1H), 9.16-9.08 (d, J=2.0 Hz, 1H), 9.08-9.01 (s, 1H), 8.67-8.59 (s, 1H), 8.57-8.50 (d, J=1.9 Hz, 1H), 8.30-8.21 (s, 1H), 7.85-7.73 (m, 2H), 7.66-7.44 (m, 2H), 7.28-7.23 (d, J=7.7 Hz, 1H), 6.85-6.78 (d, J=8.4 Hz, 1H), 3.65-3.57 (m, 4H), 2.98-2.81 (m, 4H), 2.79-2.70 (q, J=7.6 Hz, 2H), 1.75-1.52 (m, 3H), 1.32-1.24 (t, J=7.6 Hz, 3H).; MS (ESI) m/z: 386.2 [M+H]+
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:2][C:3]2[N:4]=[C:5]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:6][C:7]=2[CH3:8])=[CH:27][CH:28]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(OCc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 88.4 %

Procedure:
A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (20.18 g), 4-benzyloxyphenol (17.70 g), anhydrous potassium carbonate (12.22 g) and N,N-dimethylformamide (200 mL) was stirred at 90° C. for 15 hrs. The reaction mixture was poured into water, and the precipitated solid was collected by filtration, and dried with air to give crystals (29.03 g, 88%) of 4-[(4-benzyloxyphenoxy)methyl]-5-methyl-2-phenyloxazole. Recrystallization from ethyl acetate-hexane gave colorless leaflet crystals. melting point: 126-127° C. A mixture of the obtained 4-[(4-benzyloxyphenoxy)methyl]-5-methyl-2-phenyloxazole (22.6 g), 5% palladium carbon (10.0 g) and tetrahydrofuran (300 mL) was subjected to catalytic hydrogenation at room temperature and 1 atm. After filtering off the catalyst, the solvent was evaporated under reduced pressure to give crystals (16.3 g, 95%) of 4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenol. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 168-169° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=2.[S:17]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18]1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]([CH2:22][C:19]2[CH:20]=[CH:21][S:17][CH:18]=2)[C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=2
Reactant: CCOC(=O)c1ccc2[nH]c(C)c(C)c2c1
Reactant: OCc1ccsc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccsc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A 500 mg portion of ethyl 2,3-dimethyl-1H-indole-5-carboxylate was dissolved in 24 ml of toluene, and 0.39 ml of 3-thienylmethanol and 1.00 g of cynomethylene tri-N-butylphospholan were added at room temperature, followed by overnight stirring at 110° C. A 0.39 ml portion of 3-thienylmethanol and 1.00 g of cyanomethylene tri-N-butylphospholan were added to the reaction liquid, followed by stirring at 110° C. for 8 hours. After evaporation of the solvent under a reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:20 to 1:10) to obtain 378 mg of ethyl 2,3-dimethyl-1-(3-thienylmethyl)-1H-indole-5-carboxylate as a yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[O:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[CH2:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([N:32]5[CH2:31][CH2:30][N:29]([CH2:28][C@H:24]6[CH2:25][CH2:26][CH2:27][O:23]6)[CH2:34][CH2:33]5)=[O:20])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1
Reactant: C1CO[C@H](CN2CCNCC2)C1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCN(C[C@H]2CCCO2)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (S)-1-((tetrahydrofuran-2-yl)methyl)piperazine (1.2 equiv) to give 199 (M+1 466.0)
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[C:18]([N:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:8])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1CCCCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C1CCCCCN1C(=O)c1ccccc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Under a stream of nitrogen, 200 g of ε-caprolactam are introduced into a 1 l four-necked flask fitted with stirrer and thermometer and melted. 226 g of N,N-diisopropyl-N-ethylamine (Hunig base) and 250 g of benzoyl chloride are then added dropwise simultaneously over the course of 2 hours, with stirring. The temperature is maintained initially at 90° C.and then increased further to 110° C. When the reaction is complete, the melt, at 80° C., is introduced into 350 ml of water at room temperature and stirred. After one hour, the precipitated benzoylcaprolactam is filtered off and dried. The N-benzoylcaprolactam is obtained in a yield of 95% and a purity of >99% by GC. The Hunig base is worked up as in Example 1. The precipitated N,N-diisopropyl-N-ethylamine (water content: 0.13%) can again be reused without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:12].IC.[C:15](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[C:3]([O:12][CH3:15])=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([F:10])([F:11])[F:9]
Reactant: Oc1cccc(C(F)(F)F)c1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cccc(C(F)(F)F)c1F
Temperature: 0 °C
Reaction time: 17 h
Yield: 90.7 %

Procedure:
A mixture of 2-fluoro-3-(trifluoromethyl)-phenol (4.87 g, 27.04 mmol) and iodomethane (4.60 g, 32.4 mmol) in acetone (50 mL) is cooled to 0° C. and then 325 mesh potassium carbonate (4.48 g, 32.4 mmol) is added. The reaction is warmed to rt and stirred for 17 hours under N2. The reaction filtered to remove the solids, and the filtrate is acidified with 1 N HCl. The mixture is diluted with water and extracted with Et2O. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford 4.76 g (91%) of 2-fluoro-3-methoxybenzotrifluoride that is utilized without purification. Rf=0.35 (4/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:32][C:33]1[CH:34]=[C:35]([C:40]2[CH:41]=[C:42]([C:59]([NH2:61])=[O:60])[C:43]3[NH:44][C:45]4[CH:46]=[C:47]([N:53]5[CH2:58][CH2:57][O:56][CH2:55][CH2:54]5)[CH:48]=[CH:49][C:50]=4[C:51]=3[N:52]=2)[CH:36]=[CH:37][C:38]=1[OH:39].[O:62]1[CH2:67][CH2:66][N:65]([CH2:68][CH2:69]O)[CH2:64][CH2:63]1>C1COCC1>[Cl:32][C:33]1[CH:34]=[C:35]([C:40]2[CH:41]=[C:42]([C:59]([NH2:61])=[O:60])[C:43]3[NH:44][C:45]4[CH:46]=[C:47]([N:53]5[CH2:54][CH2:55][O:56][CH2:57][CH2:58]5)[CH:48]=[CH:49][C:50]=4[C:51]=3[N:52]=2)[CH:36]=[CH:37][C:38]=1[O:39][CH2:69][CH2:68][N:65]1[CH2:66][CH2:67][O:62][CH2:63][CH2:64]1
Reactant: NC(=O)c1cc(-c2ccc(O)c(Cl)c2)nc2c1[nH]c1cc(N3CCOCC3)ccc12
Reactant: OCCN1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: NC(=O)c1cc(-c2ccc(OCCN3CCOCC3)c(Cl)c2)nc2c1[nH]c1cc(N3CCOCC3)ccc12
Reaction time: 8 h
Yield: 0 %

Procedure:
Diethyl azodicarboxylate (0.012 mL, 0.074 mmol) was added to a solution of triphenylphosphine (19 mg, 0.074 mmol), 2-(3-chloro-4-hydroxyphenyl)-7-morpholino-5H-pyrido[3,2-b]indole-4-carboxamide (16 mg, 0.037 mmol) and 2-morpholinoethanol (9.0 μL, 0.074 mmol) in dry THF (0.5 mL) at RT under nitrogen. After stirring overnight, the solvent was removed and preparative HPLC (PHENOMENEX® Luna C18 30×100 10u Column, Solvent A=10 mM NH4OAc in 95% water:5% acetonitrile; B=10 mM NH4OAc in 5% water:95% acetonitrile, gradient of 10 to 100% B over 25 min at 30 mL/min) followed by SCX capture and release with 2 N NH3 in MeOH afforded 2-(3-chloro-4-(2-morpholinoethoxy)phenyl)-7-morpholino-5H-pyrido[3,2-b]indole-4-carboxamide (4.9 mg, 8.2 nmol, 22% yield) as a solid. MS (ESI) m/z 536.38 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.26 (1H, s), 8.54 (1H, s), 8.34 (1H, d, J=2.01 Hz), 8.27 (1H, s), 8.21 (1H, dd, J=8.69, 2.14 Hz), 8.07 (1H, d, J=8.56 Hz), 7.84 (1H, s), 7.32 (1H, d, J=8.81 Hz), 7.20 (1H, d, J=2.01 Hz), 7.00 (1H, dd, J=8.81, 2.01 Hz), 4.26 (2H, t, J=5.79 Hz), 3.74-3.85 (4H, m), 3.53-3.66 (4H, m), 3.18-3.28 (4H, m), 2.78 (2H, t, J=5.67 Hz), 2.52-2.59 (4H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]=[N:17][C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].[BH4-].[Na+].O.C1(C)C=CC=CC=1>C(O)(=O)C>[CH3:9][C:4]1[CH:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][NH:17][C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[C:2]([CH3:1])=[C:6]([CH3:7])[C:5]=1[CH3:8]
Reactant: CC1=C(C)C(c2ccccc2C=Nc2c(C)cc(C)cc2C)C(C)=C1C
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CC1=C(C)C(c2ccccc2CNc2c(C)cc(C)cc2C)C(C)=C1C
Yield: 79.3 %

Procedure:
To a solution of N-[2-(2,3,4,5-tetramethylcyclopentadienyl)phenylmethylene]-N-(2,4, 6-trimethylphenyl)amine (10.0 mmol) in acetic acid (7.0 mL) was added sodium borohydride (13.0 mmol). The mixture was reacted at room temperature for 1 hr. Water and toluene were then added the reaction mixture. The organic layer was dried and concentrated. The obtained oily substance was purified by silica gel column chromatography to give N-[2-(2,3,4,5-tetramethylcyclopentadienyl)phenylmethyl]-N-(2,4,6-trimethylphenyl)amine (2.74 g, yield 69.5%) as a yellow oily substance.
Reaction SMILES: [ClH:1].[C:2]1([C@H:8]2CCC[C@H:9]2[NH2:13])[CH:7]=[CH:6][CH:5]=CC=1.Cl.[C:15]1([C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[NH2:27])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[ClH:1].[C:15]1([C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[N:27]=[C:9]2[CH2:8][CH2:2][CH2:7][CH2:6][CH2:5][NH:13]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N[C@@H]1CCC[C@@H]1c1ccccc1
Reactant: N[C@@H]1CCCC[C@H]1c1ccccc1
Agent: Cl
Product: c1ccc([C@@H]2CCCC[C@H]2N=C2CCCCCN2)cc1

Procedure:
Following the procedure of Example 1, only substituting for cis-2-phenylcyclopentylamine hydrochloride an appropriate amount of trans-2-phenylcyclohexylamine hydrochloride, M.P. 251°-257° C., and employing a reaction time of 38 days, the desired product was obtained, M.P. 236°-239° C.
Reaction SMILES: [C:1]([CH:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23]/[C:24](/[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)=[N:25]\[O:26][CH3:27])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[CH2:4][C:5]([OH:7])=[O:6])#[N:2].[OH-].[Na+:36]>>[C:1]([CH:3]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23]/[C:24](/[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)=[N:25]\[O:26][CH3:27])=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)[CH2:4][C:5]([O-:7])=[O:6])#[N:2].[Na+:36]
Reactant: CO/N=C(\COc1ccc(COc2ccc(C(C#N)CC(=O)O)cc2)cc1)c1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Product: CO/N=C(\COc1ccc(COc2ccc(C(C#N)CC(=O)[O-])cc2)cc1)c1cccc(F)c1
Yield: 71.59 %

Procedure:
Compound 55 was synthesized from 3-cyano-3-{4-[(4-{[(2Z)-2-(3-fluorophenyl)-2-(methoxyimino)ethyl]oxy}benzyl)oxy]phenyl}propanoic acid (0.55 g, 1.2 mmol) and sodium hydroxide (0.092 g, 2.3 mmol) by following the procedure described in scheme 12 (0.4 g, yield: 71.59%); Purity: 96.74%.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.BrC1C=CC2N=CC3NC(=O)N(C4C(C)=NN(C[C:44]([N:46]5[CH2:51][CH2:50][N:49]([CH3:52])[CH2:48][CH2:47]5)=[O:45])C=4)C=3C=2C=1>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH2:20][C:44]([N:46]5[CH2:51][CH2:50][N:49]([CH3:52])[CH2:48][CH2:47]5)=[O:45])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: Cc1nn(CC(=O)N2CCN(C)CC2)cc1-n1c(=O)[nH]c2cnc3ccc(Br)cc3c21
Product: Cc1nn(CC(=O)N2CCN(C)CC2)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Intermediate A using 8-bromo-1-{3-methyl-1-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-1H-pyrazol-4-yl}-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage 133.1.1) to give the title compound as an off-white solid. (HPLC: tR 2.06 min (Method A); M+H=498, 500 MS-ES)