Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[O:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[NH:40][CH:39]=[C:38]3[CH:44]=O)[CH2:28][CH2:27]1>CO.N1CCCCC1>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:44]/[C:38]3[C:37]4[C:41](=[CH:42][CH:43]=[C:35]([O:34][CH2:33][CH2:32][N:29]5[CH2:30][CH2:31][O:26][CH2:27][CH2:28]5)[CH:36]=4)[NH:40][CH:39]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: O=Cc1c[nH]c2ccc(OCCN3CCOCC3)cc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ccc(OCCN5CCOCC5)cc24)C3=O)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.067 g, 0.19 mmol) obtained in Example A16, Step 1 in methanol (5.0 mL) was added with 5-(2-morpholinoethoxy)-1H-indole-3-carboxaldehyde (0.044 g, 0.16 mmol). Then, the mixture was added with 5 drops of piperidine, and the mixture was stirred at 50° C. for 2 hours. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (95:5)) to obtain tert-butyl (Z)-4-[(6-hydroxy-2-{[5-(2-morpholinoethoxy)-1H-indol-3-yl]methylene}-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.076 g, 81%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[F:10].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20]>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=2[F:10])=[CH:14][C:13]=1[C:19]([F:20])([F:21])[F:22]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=Cc1cnc(Cl)c(F)c1
Product: O=Cc1cnc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D1 starting from 6-chloro-5-fluoro-3-pyridinecarbaldehyde and 4-chloro-3-(trifluoromethyl)phenol. LC-MS (ESI): m/z 320 [M+H]+; 3.62 min (ret time).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[O-]CC.[Na+].Cl.Cl.Cl[CH2:13][C:14]1[CH:19]=[C:18]([CH2:20][N:21]([CH3:23])[CH3:22])[CH:17]=[CH:16][N:15]=1.Cl>C(O)C.O>[CH3:22][N:21]([CH2:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([CH2:13][S:5][CH2:4][CH2:3][NH2:2])[CH:19]=1)[CH3:23]
Reactant: NCCS
Reactant: CN(C)Cc1ccnc(CCl)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(C)Cc1ccnc(CSCCN)c1
Reaction time: 1 h
Yield: 73.6 %

Procedure:
Cysteamine hydrochloride (3.75 g) was added to a stirred solution of sodium ethoxide (prepared from 2.83 g sodium) in ethanol (200 ml) and the mixture was cooled to less than 10°. 2-Chloromethyl-4-dimethylaminomethylpyridine dihydrochloride (7.3 g) was added portionwise and the solution was stirred for 1 hour. Water (200 ml) was added, the pH was adjusted to ca. 4 with hydrochloric acid and the volume was reduced to ca. 100 ml. The solution was extracted with chloroform, the aqueous phase was basified to pH 12 and extracted with chloroform to give 2-(4-dimethylaminomethyl-2-pyridylmethylthio)ethylamine (4.7 g) as an oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH:11]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[CH2:12]>CC([O-])=O.CC([O-])=O.[Pd+2].CC#N>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:12]=[CH:11][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C=Cc1ccncc1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(C=Cc2ccncc2)cc1
Temperature: 100 °C
Yield: 35.4 %

Procedure:
To a CH3CN solution of 1-iodo-4-nitrobenzene (498 mg, 2 mmol) and 4-vinylpyridine (262 mg, 2.5 mmol) was added TEA (350 μL, 2.5 mmol) and Pd(OAc)2 (0.45 mg, 0.2 mmol). The mixture was heated to 100° C. for 48 hr in a capped Pyrex tube. It was then cooled to room temperature, quenched with 1N HCl (20 mL) and concentrated under reduced pressure. The mixture was filtered and the solid was taken up in EtOAc (30 mL) and washed with 1N NaOH (30 mL). The organic layer was concentrated, dried over Na2SO4 and concentrated to give 4-[2-(4-nitro-phenyl)-vinyl]-pyridine as yellow solid (160 mg, 37%).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH:11]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)[CH:12]([N:15]([CH3:17])[CH3:16])[CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:26].C(=O)([O-])[O-].[K+].[K+]>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>[CH3:16][N:15]([CH3:17])[CH:12]([CH2:13][CH3:14])[CH:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([C:25]([O:24][CH3:23])=[O:26])=[CH:28][CH:29]=3)[S:3][C:4]=2[CH:10]=1)[N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: CCC(C(c1ccc2nc(Br)sc2c1)n1ccnc1)N(C)C
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCC(C(c1ccc2nc(-c3ccc(C(=O)OC)cc3)sc2c1)n1ccnc1)N(C)C
Temperature: 80 °C

Procedure:
A mixture of 1-(2-bromobenzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine (663 mg, 1.75 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (409 mg, 2.275 mmol), tetrakis(triphenylphosphine)palladium (505 mg, 0.437 mmol), potassium carbonate (725 mg, 5.25 mmol); DME (25 mL) and water (5 mL) was degassed, filled with N2, and heated to 80° C. for 3 h. The reaction mixture was evaporated, dissolved in 10% methanol in DCM, loaded onto a PTLC plate and eluted with 6% methanol in DCM to yield methyl 4-(6-(2-(dimethylamino)-1-(1H-imidazo 1-yl)butyl)benzo[d]thiazol-2-yl)benzoate. MS ESI: m/z 435.19 [M+1+].
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([N:20]1[C:24]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=O)=[CH:23][N:22]=[CH:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH2:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH:33]1[NH:41][C:42]1[N:43]=[CH:44][C:45]2[CH2:51][NH:50][CH2:49][CH2:48][C:46]=2[N:47]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH2:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH:33]1[NH:41][C:42]1[N:43]=[CH:44][C:45]2[CH2:51][N:50]([C:29](=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][C:24]3[N:20]([C:18]([O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19])[CH:21]=[N:22][CH:23]=3)[CH2:49][CH2:48][C:46]=2[N:47]=1
Reactant: CC(C)(C)OC(=O)n1cncc1CCCCC(=O)O
Reactant: c1ccc2c(c1)CC(Nc1ncc3c(n1)CCNC3)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1cncc1CCCCC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Temperature: 40 °C
Yield: 32.3 %

Procedure:
Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.092 g; 1.5 equiv; 0.48 mmoles) to a solution of 5-(3-tert-butoxycarbonylimidazol-4-yl)pentanoic acid (0.084 g; 1.0 equiv; 0.31 mmoles), N-indan-2-yl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (0.064 g; 0.77 equiv; 0.24 mmoles), 1-hydroxybenzotriazole (0.065 g; 1.5 equiv; 0.48 mmoles), and triethylamine (0.20 mL; 4.5 equiv; 1.44 mmoles) in dichloromethane (15 mL). Heat the mixture to 40° C. for 16 hours. Concentrate the mixture, and then purify the crude product by column chromatography (0 to 10% methanol in dichloromethane) to afford tert-butyl 5-[5-[2-(indan-2-ylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-5-oxo-pentyl]imidazole-1-carboxylate (0.040 g; 25%) as a white solid: MS (m/z): 517 (M+1).
Reaction SMILES: C(OC(N1CCC(N[C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: C1CCNC1
Product: O=C(c1sccc1Nc1ccnc2[nH]ccc12)N1CCCC1

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using pyrrolidine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 313 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 12.40 (1H, br. s.) 10.62 (1H, s) 8.07 (1H, d, J=6.83 Hz) 7.88 (1H, d, J=5.27 Hz) 7.39 (1H, d, J=3.51 Hz) 7.29 (1H, d, J=5.47 Hz) 6.72 (1H, d, J=3.32 Hz) 6.70 (1H, d, J=6.64 Hz) 3.42 (1H, br. s.) 2.47 (4H, dt, J=3.66, 1.78 Hz) 1.75 (4H, br. s.)
Reaction SMILES: I[Si](C)(C)C.[Br:6][C:7]1[CH:31]=[C:30]([C:32]2[C:41]3[C:42]4[CH:48]=[CH:47][CH:46]=[CH:45][C:43]=4[S:44][C:40]=3[C:39]([Br:49])=[C:38]3[C:33]=2[CH:34]=[CH:35][CH:36]=[CH:37]3)[CH:29]=[C:28]([Br:50])[C:8]=1[O:9][C@H:10]([CH2:15][CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27])[C:11]([O:13]C)=[O:12]>C(Cl)Cl>[Br:6][C:7]1[CH:31]=[C:30]([C:32]2[C:41]3[C:42]4[CH:48]=[CH:47][CH:46]=[CH:45][C:43]=4[S:44][C:40]=3[C:39]([Br:49])=[C:38]3[C:33]=2[CH:34]=[CH:35][CH:36]=[CH:37]3)[CH:29]=[C:28]([Br:50])[C:8]=1[O:9][C@H:10]([CH2:15][CH2:16][N:17]1[C:18](=[O:27])[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]1=[O:26])[C:11]([OH:13])=[O:12]
Reactant: COC(=O)[C@@H](CCN1C(=O)c2ccccc2C1=O)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: O=C(O)[C@@H](CCN1C(=O)c2ccccc2C1=O)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.1 %

Procedure:
Iodotrimethylsilane (2.8 mL, 1 N in methylene chloride) was added dropwise to a -10° C., stirred solution of (R)-2-[2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d ]thiophen-11-yl)-phenoxy]-4-(1, 3-dioxo-1, 3-dihydro-isoindol-2-yl)-butyric acid, methyl ester (0.770 g, 0.953 mmol) in methylene chloride (14 mL) under a try N2 atmosphere. The solution was allowed to warm to ambient temperature and was stirred overnight. The reaction mixture was quenched, further diluted with water (100 mL), and partitioned between water and methylene chloride (2×75 mL). Methylene chloride extracts were concentrated and triturated with pet. ether. It was then recrystallized from acetic acid to provide the title compound as a grey solid (0.228 g, 52%): mp 215-217° C.: NMR (CDCl3); δ8.35 (d, J=8 Hz, 1 H), 7.89-7.86 (m, 2 H), 7.82 (dd, J=8, 1 Hz, 1 H), 7.76-7.71 (m, 2 H), 7.67(ddd, J=8, 7, 1 Hz, 1 H), 7.63-7.59 (m, 3 H), 7.58 (ddd, J=8, 7, 1 Hz, 1 H), 7.42 (ddd, J=8, 7, 1 Hz, 1 H), 7.20 (ddd, J=8, 7, 1 Hz, 1 H), 6.81(d, J=8 Hz, 1 H), 5.27 (t, J=7 Hz, 1 H, 1 H), 4.12 (m, 2 H), 2.65 (t, J =7 Hz, 2); MS (EI): [M+], 3 bromine isotope pattern, 791 (75%), 793 (98%), 795 (100%), 797 (38%); Anal. Calc. for C34H2OBr3NO5S: C, 51.41, H, 2.54, N, 1.76. Found: C, 51.65, H, 2.37, N, 1.70.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]([CH3:47])([CH3:46])[CH2:27][CH2:28][N:29]1[C:34]2[C:35]([O:39][CH3:40])=[CH:36][CH:37]=[CH:38][C:33]=2[C:32]([CH2:43][CH3:44])([CH2:41][CH3:42])[O:31][C:30]1=[O:45]>>[CH2:1]([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:24])[CH2:21][NH:25][C:26]([CH3:47])([CH3:46])[CH2:27][CH2:28][N:29]2[C:34]3[C:35]([O:39][CH3:40])=[CH:36][CH:37]=[CH:38][C:33]=3[C:32]([CH2:43][CH3:44])([CH2:41][CH3:42])[O:31][C:30]2=[O:45])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC1(CC)OC(=O)N(CCC(C)(C)N)c2c(OC)cccc21
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Product: CCC1(CC)OC(=O)N(CCC(C)(C)NCC(O)c2ccc(OCc3ccccc3)c3c2OCC(=O)N3)c2c(OC)cccc21

Procedure:
The product is prepared analogously to Example 14a starting from 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 1-(3-amino-3-methyl-butyl)-4,4-diethyl-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one. The crude product is purified by column chromatography (silica gel, dichloromethane/MeOH 95:5).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[CH3:19][N:20]([CH3:23])[CH:21]=O>ClCCl>[CH3:19][N:20]([CH:23]=[N:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])[CH3:21]
Reactant: COC(=O)c1ccccc1N
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccccc1N=CN(C)C

Procedure:
To a stirred solution of 7.56 g of methyl anthranilate in 50 ml of dimethylformamide at 0° C. was added 5.6 ml of phosphorous oxychloride during 15 m. The mixture was heated at 55 for 45 m, cooled to 0, and diluted with dichloromethane. The mixture was basified at 0° C. by slow addition of cold 1N NaOH to pH 9. The dichloromethane layer was separated, washed with water, dried and concentrated to an oil.
Reaction SMILES: CO[C:3](=[O:30])[C:4]1[CH:9]=[C:8]([CH:10]2[CH2:14][CH2:13][O:12][CH2:11]2)[C:7]([C:15]([F:18])([F:17])[F:16])=[CH:6][C:5]=1[NH:19][C:20](OC1C=CC(Cl)=CC=1)=[O:21].[CH3:31][S:32]([NH:35][NH2:36])(=[O:34])=[O:33].CCN(C(C)C)C(C)C>O1CCOCC1>[O:21]=[C:20]1[N:36]([NH:35][S:32]([CH3:31])(=[O:34])=[O:33])[C:3](=[O:30])[C:4]2[C:5](=[CH:6][C:7]([C:15]([F:18])([F:17])[F:16])=[C:8]([CH:10]3[CH2:14][CH2:13][O:12][CH2:11]3)[CH:9]=2)[NH:19]1
Reactant: COC(=O)c1cc(C2CCOC2)c(C(F)(F)F)cc1NC(=O)Oc1ccc(Cl)cc1
Reactant: CS(=O)(=O)NN
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(C3CCOC3)cc2c1=O
Temperature: 80 °C
Reaction time: 18 h
Yield: 70.6 %

Procedure:
2-(4-Chloro-phenoxycarbonylamino)-5-(tetrahydro-furan-3-yl)-4-trifluoromethyl-benzoic acid methyl ester (80 mg, 0.18 mmol) was dissolved in dioxane (1 mL) and, after addition of CH3SO2NHNH2 (21.8 mg, 1.1 equiv) and i-Pr2NEt (61.7 μL, 2 equiv), the mixture was stirred for 18 h (TLC control) at 80° C. The crude product was purified by flash chromatography with DCM to DCM/MeOH 85:15 as eluent. The obtained product was dried, dissolved in a small quantity of DCM and precipitated with hexanes. The white solid was filtered off and dried to provide the title compound (50 mg, 70% yield) (394 [M+H]+, rt 4.58 min.).
Reaction SMILES: COP([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])(OC)=O.[O:15]=[C:16]1[C:25](=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[NH:17]1>C1(C)C=CC=CC=1.C1COCC1>[C:11]([O:10][C:8]([CH:7]=[C:25]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[NH:17][C:16]1=[O:15])=[O:9])([CH3:12])([CH3:13])[CH3:14]
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Reactant: CCOC(=O)C1CCCCCCC(=O)C(=O)N1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCCCCCC(=CC(=O)OC(C)(C)C)C(=O)N1
Reaction time: 0.42 h

Procedure:
Potassium hexamethyldisilylamide (40.5 mL of a 0.58M solution in toluene, 23.5 mmol) is added to THF (60 mL), and then cooled to 0° C. t-Butyl dimethylphosphonoacetate (4.6 mL, 23.5 mmol) is added dropwise, and the reaction is warned to room temperature and stirred for 25 minutes. Ethyl 2,3-di-oxo-1-azacyclodecane-10-carboxylate (2.83 g, 11.74 mmol) is added in THF (15 mL), and the reaction is stirred at room temperature for 2.5 hours. The reaction is quenched with saturated ammonium chloride, and then extracted several times with ethyl acetate. The combined organic layers are dried (MgSO4), and the solvent is evaporated. The product is purified by silica gel chromatography (30% ethyl acetate/hexane) to give ethyl 3-t-butoxycarbonylmethylidene-2-oxo-1-azacyclodecane-10-carboxylate.
Reaction SMILES: Cl.[N:2]1([C:8]2[N:9]=[CH:10][CH:11]=[C:12]3[CH:16]=[CH:15][S:14][C:13]=23)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.O=[CH:27][CH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH:35][C:36](=[O:38])[CH3:37])[CH2:31][CH2:30]1>C1COCC1>[S:14]1[C:13]2=[C:8]([N:2]3[CH2:3][CH2:4][N:5]([CH2:27][CH2:28][C@H:29]4[CH2:34][CH2:33][C@H:32]([NH:35][C:36](=[O:38])[CH3:37])[CH2:31][CH2:30]4)[CH2:6][CH2:7]3)[N:9]=[CH:10][CH:11]=[C:12]2[CH:16]=[CH:15]1
Reactant: c1cc2ccsc2c(N2CCNCC2)n1
Reactant: CC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4ccsc34)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution under Ar of commercially available 7-piperazine-1-yl-thieno[2,3-c]pyridine hydrochloride [CAS-No. 850734-85-9] (150 mg, 0.59 mmol) in THF (14 ml) were added subsequently iPr2NEt (0.1 ml, 0.59 mmol), trans-N-[4-(2-oxo-ethyl)-cyclohexyl]-acetamide [CAS-No. 946599-01-5, WO 2007/093540] (118 mg, 0.64 mmol) and Na(AcO)3BH (373 mg, 1.76 mmol). After stirring 18 h at room temperature the reaction mixture was partitioned between sat. aq. NaHCO3 sol. and EtOAc. The aqueous layer was extracted one more time with EtOAc. The combined organic layers were washed with H2O and brine and dried over MgSO4. After evaporation of the solvent, the crude product was purified by flash chromatography on silica gel (heptane to EtOAc) to yield the title compound as an off-white solid (82 mg, 36%), MS (ISP) m/z=387.2 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:11])[CH:3]=1.CCN(C(C)C)C(C)C.[CH2:21]([NH:28][CH2:29][CH2:30][OH:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH2:21]([N:28]([CH2:29][CH2:30][OH:31])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[F:11])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OCCNCc1ccccc1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(Br)cc1F)N(CCO)Cc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-2-fluorobenzoyl chloride (1 g, 4.21 mmol) in THF (14.04 mL) was added DIEA (1.103 mL, 6.32 mmol) and 2-(benzylamino)ethanol (0.764 g, 5.05 mmol) at room temperature. The reaction mixture was stirred for overnight. The reaction mixture was extracted with EtOAc. The organic layer was washed with water and brine. After dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, the crude N-benzyl-4-bromo-2-fluoro-N-(2-hydroxyethyl)benzamide was used for the next step (83%). LCMS (m/z): 352/354 (MH+), 0.83 min.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=7)=[C:24]([C:34](=[O:37])[NH:35][CH3:36])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH:11]([CH2:45][NH:46][CH2:47][C:48]([O:50]CC)=[O:49])[N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.O[Li].O>O1CCOCC1.O>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=7)=[C:24]([C:34](=[O:37])[NH:35][CH3:36])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH:11]([CH2:45][NH:46][CH2:47][C:48]([OH:50])=[O:49])[N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)CNCC1Oc2ccc(-c3cc4c(C(=O)NC)c(-c5ccc(F)cc5)oc4cc3N(C)S(C)(=O)=O)nc2-c2cc3c(F)cccc3n21
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CNCC(=O)O)O4)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution of ethyl 2-(((11-fluoro-2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-6-yl)methyl)amino)acetate (35 mg, 0.048 mmol) in 1,4-dioxane/H2O (3.0 mL/0.5 mL) was added LiOH.H2O (20 mg, 0.45 mmol). The mixture was stirred at room temperature overnight. Then it was concentrated in vacuo, neutralized with HCl (aq. 5%), extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated to provide Compound 116 (30 mg, yield: 91%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.58 (d, J=4.8 Hz, 1H), 8.00˜8.07 (m, 2H), 7.85 (s, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.43 (t, J=8.8 Hz, 2H), 7.20˜7.29 (m, 1H), 7.09 (s, 1H), 6.89˜6.97 (m, 1H), 6.85 (br. s, 1H), 3.19 (s, 3H), 3.07 (m, 2H), 2.88 (s, 3H), 2.83 (s, 3H). MS (M+H)+: 702.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:14][C:13]=1[Cl:26])=[O:11].Cl>C1COCC1.O>[Cl:26][C:13]1[CH:14]=[C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH:16]=[CH:17][C:12]=1[C:10](=[O:11])[CH2:9][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: O=C(CBr)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cn1cncn1)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Reaction time: 2.5 h
Yield: 80.3 %

Procedure:
1,2,4-Triazole (249 g) was added carefully (small portions) to a mixture of sodium hydride (85 g) in THF (6000 mL). After 30 minutes a solution of 2-bromo-1-[2-chloro-4-(4-chlorophenoxy)phenyl]ethanone (1322 g) in THF (500 mL) was slowly added and the mixture was stirred for 150 min. The pH was adjusted to 7 with dil. hydrochloric acid whereupon water was added (3000 mL). The precipitate was filtered off and washed with MTBE. The organic phase was then concentrated and the resulting solid was filtered off to yield the desired material (1008 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([O:25][CH:26]2[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[CH2:41][CH:42]([F:44])[F:43])(=O)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[N:17]([CH2:41][CH:42]([F:44])[F:43])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([O:25][CH:26]2[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3c2)CC1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)n3CC(F)F)CC1

Procedure:
The title compound was prepared in analogy to example 40a), from 4-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indole-2-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester and 2,2-difluoroethyl trifluoromethanesulfonate. Off-white solid. MS (m/z): 535.5 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:24])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[NH:18][CH:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]([CH2:36][CH3:37])[CH2:34][CH3:35]>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:24])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:32][CH:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[CH:17]=[CH:16]4)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)[nH]ccc2c1
Reactant: CCC(CC)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CC)Cn1ccc2cc(-c3cc(C(=O)NC4CC4)ccc3C)ccc2c1=O
Temperature: 80 °C
Reaction time: 17 h

Procedure:
To a solution of the product of Example 11 (100 mg) in DMF (3 mL) was added potassium carbonate (217 mg) followed by 3-(bromomethyl)pentane (0.44 mL) and the mixture stirred at 80° C. for 17 hrs. The reaction mixture was filtered and purified by HPLC to give the title compound (55.0 mg) as a solid.