Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([NH:20][C:21](=[O:23])[CH3:22])[C:14]=3[Cl:24])[C:5]2=[N:4][C:3]=1[CH3:25].[H-].[Na+].Br[CH2:29][C:30]([O:32]CC)=[O:31].O>CN(C)C=O.C(O)C.[OH-].[Na+]>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([CH2:29][C:30]([OH:32])=[O:31])[C:21](=[O:23])[CH3:22])[C:14]=3[Cl:24])[C:5]2=[N:4][C:3]=1[CH3:25]
Reactant: CC(=O)Nc1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: CC(=O)N(CC(=O)O)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Yield: 59.7 %

Procedure:
To a solution of 3-bromo-8-(2,6-dichloro-3-acetylaminobenzyloxy)-2-methylimidazo[1,2-a]pyridine (222 mg) in N,N-dimethylformamide (2 ml) was added sodium hydride (24 mg, 60% oil dispersion) at ambient temperature. The mixture was stirred for half an hour at the same temperature and then ethyl bromoacetate (100 mg) was added thereto in one portion. The mixture was stirred for 2 hours at the same temperature and poured into water. The separated oil was extracted with dichloromethane. The extract was washed with water, dried, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to give an oil, which was dissolved in a mixture of ethanol (10 ml) and 1N sodium hydroxide solution (2 ml). The solution was refluxed for one and half hour. The organic solvent was removed under reduced pressure. The aqueous layer was adjusted to pH 4 with diluted hydrochloric acid to give 3-bromo-8-[2,6-dichloro-3-(N-carboxymethyl-N-acetylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (150 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)Br.C(N(CC)CC)C.[NH2:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1>O1CCCC1>[CH3:1][O:2][C:3](=[O:12])[CH:4]([NH:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: NC1Cc2ccccc2C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C(NC1Cc2ccccc2C1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of racemic α-bromophenylacetic acid methyl ester, 5.0 g (22.0 mmol) in 200 mL of tetrahydrofuran was added 3.4 mL (22.0 mmol) of triethylamine and 8.8 g (66.0 mmol) of 2-aminoindan. The reaction mixture was refluxed for four hours, cooled to ambient temperature and concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and water. The mixture was washed with saturated sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography using chloroform as eluent and was concentrated to dryness to give a quantitative yield of the desired mixture of isomers as a tan, viscous oil. MS (ion spray) 282.2 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:7]([NH2:19])[CH:6]=1)[CH3:2].[H-].[Na+].Br[CH:24](Br)[CH3:25].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[N:11]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:25][CH2:24][NH:19]2)=[O:20])[CH3:2]
Reactant: CC(Br)Br
Reactant: CCOC(=O)c1ccc(NC(=O)OC(C)(C)C)c(N)c1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)NCCN2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Amino-4-tert-butoxycarbonylamino-benzoic acid ethyl ester (3.1 g, 11.1 mmol) was dissolved in dimethylformamide (50 mL) and treated with NaH (−55% dispersion in oil) (0.3 g, 12.2 mmol). The reaction mixture was stirred at room temperature for 1 hour, dibromoethane (8.3 g, 3.8 mL, 44.2 mmol) was then added, and the mixture stirred for further 1 hour at room temperature. K2CO3 (6.11 g, 44.2 mmol) was added and the reaction mixture was stirred at 70° C. for 17 hours. A further aliquot of NaH (˜55% dispersion in oil) (0.3 g, 12.2 mmol) was added and, 3 hours later, a further aliquot of dibromoethane (2.1 g, 11.1 mmol). Stirring was continued at 70° C. for 18 hours. Water was added and the mixture was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated. The residue was purified by flash chromatography, yielding 3,4-dihydro-2H-quinoxaline-1,6-dicarboxylic acid 1-tert-butyl ester 6-ethyl ester as a light yellow solid, 1.0 g (29%), MS (ISP): m/e=307.3 (M+H+.); δH (300 MHz; CDCl3) 7.58 (1H, d), 7.34 (1H, d), 7.25 (1H, s), 4.33 (2H, q), 4.09 (1H, bs), 3.79 (2H, m), 3.43 (2H, m), 1.53 (9H, s), 1.37 (3H, t).
Reaction SMILES: FC1C=C(C2N=C(SC)N=C(N3CCOC[C@@H]3C)C=2)C=NC=1.Cl[C:24]1[CH:29]=[C:28]([C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[S:37][CH3:38])[N:27]=[C:26]([S:39][CH3:40])[N:25]=1.[OH:41][CH2:42][CH2:43][NH:44][C:45]([NH:47][C:48]1[CH:53]=[CH:52][C:51](B2OC(C)(C)C(C)(C)O2)=[CH:50][CH:49]=1)=[O:46]>>[F:36][C:34]1[CH:33]=[CH:32][C:31]([S:37][CH3:38])=[C:30]([C:28]2[N:27]=[C:26]([S:39][CH3:40])[N:25]=[C:24]([C:51]3[CH:52]=[CH:53][C:48]([NH:47][C:45]([NH:44][CH2:43][CH2:42][OH:41])=[O:46])=[CH:49][CH:50]=3)[CH:29]=2)[CH:35]=1
Reactant: CSc1nc(Cl)cc(-c2cc(F)ccc2SC)n1
Reactant: CC1(C)OB(c2ccc(NC(=O)NCCO)cc2)OC1(C)C
Agent: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Product: CSc1nc(-c2ccc(NC(=O)NCCO)cc2)cc(-c2cc(F)ccc2SC)n1

Procedure:
Method as described for intermediate 5 using 4-chloro-6-(5-fluoro-2-(methylthio)phenyl)-2-(methylthio)pyrimidine and 1-(2-hydroxyethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 18). Reaction mixture was partitioned between DCM and water, the organic phase passed through a PTFE hydrophobic frit and the solvent removed in vacuo. The residue was purified further by flash chromatography (40-100% EtOAc in petroleum ether (40:60) followed by 0-15% MeOH in petroleum ether (40:60) to afford 1-(4-(6-(5-fluoro-2-(methylthio)phenyl)-2-(methylthio)pyrimidin-4-yl)phenyl)-3-(2-hydroxyethyl)urea as a brown solid, (200 mg, 54%).
Reaction SMILES: [C:1]1([C:7]([C:9]2[N:17](S(C3C=CC=CC=3)(=O)=O)[C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:27].[CH2:28]([O:35][NH2:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.N1C=CC=CC=1.[NH4+].[Cl-]>ClCCCl>[ClH:27].[CH2:28]([O:35][N:36]=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9]1[NH:17][C:12]2=[CH:13][N:14]=[CH:15][CH:16]=[C:11]2[CH:10]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(c1ccccc1)c1cc2ccncc2n1S(=O)(=O)c1ccccc1
Reactant: NOCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClCCCl
Product: c1ccc(CON=C(c2ccccc2)c2cc3ccncc3[nH]2)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 42 %

Procedure:
A mixture of phenyl[1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methanone (Reference Example 13) (200 mg, 0.55 mmol), O-benzylhydroxylamine hydrochloride (97 mg, 0.92 mmol) and pyridine (74 μL, 0.92 mmol) in 1,2-dichloroethane (8 mL) was heated at 60° C. After 24 h, saturated NH4Cl (10 mL) was added and the mixture was extracted with EtOAc (2×25 mL). The combined extracts were washed with saturated NaCl (20 mL), dried (Na2SO4) and concentrated under reduced pressure. Purification by column chromatography (silica gel, 1:1 hexanes/EtOAc) gave phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone O-benzyloxime hydrochloride (84 mg, 47%) as a mixture of isomers: mp 153-155° C.; 1H NMR (500 MHz, DMSO-d6) δ 5.35-5.40 (2H, m), 6.66 (0.5H, s), 7.12 (0.5H, s), 7.34-7.56 (10H, m), 8.07 (0.5H, d, J=6.3 Hz), 8.19 (0.5H, d, J=6.3 Hz), 8.29 (0.5H, d, J=6.3 Hz), 8.34 (0.5H, d, J=6.3 Hz), 8.99 (0.5H, s), 9.17 (0.5H, s), 13.04 (0.5H, s), 13.14 (0.5H, s), 15.14 (1H, br s); ESI MS m/z 328 [C21H17N3O+H]+; HPLC (Method A) 98.3% (AUC), tR=19.1 and 19.3 min.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].C([NH:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[CH:30][C:31]3[NH:32][C:33]4[N:49]=[C:37]([NH:38][C:39]5[CH:40]=[CH:41][CH:42]=[C:43]([CH:48]=5)[CH2:44][CH2:45][C:46]=2[CH:47]=3)[N:36]=[CH:35][C:34]=4[Cl:50])[CH2:24][CH2:23]1)=[O:21])(C)(C)C>FC(F)(F)C(O)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:50][C:34]1[CH:35]=[N:36][C:37]2[NH:38][C:39]3[CH:40]=[CH:41][CH:42]=[C:43]([CH:48]=3)[CH2:44][CH2:45][C:46]3[CH:47]=[C:31]([NH:32][C:33]=1[N:49]=2)[CH:30]=[CH:29][C:28]=3[N:25]1[CH2:26][CH2:27][N:22]([C:20]([NH2:19])=[O:21])[CH2:23][CH2:24]1
Reactant: CC(C)(C)NC(=O)N1CCN(c2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)N1CCN(c2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 73.7 %

Procedure:
A solution of N-(tert-butyl)-4-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperazine-1-carboxamide bis(trifluoroacetate) (12 mg, 16 μmol) in trifluoroacetic acid (1 mL) was stirred at 20° C. for 4 h. The reaction mixture was purified by preparative LCMS to give the desired product (8 mg, 72%) as a solid. LCMS for C23H25ClN7O (M+H)+: m/z=450.0. 1H NMR (300 MHz, CD3OD): δ 8.09 (s, 1H), 7.74-7.69 (m, 2H), 7.22-7.11 (m, 2H), 7.04-7.00 (m, 2H), 6.87 (d, J=7.9 Hz, 1H), 3.60 (br s, 4H), 3.14 (s, 4H), 2.89-2.87 (m, 4H).
Reaction SMILES: [CH2:1]([C:8]([N:20]([CH3:22])[CH3:21])([CH2:18][CH3:19])[C:9]([C:11]1[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([CH2:25][NH2:26])[OH:24].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.O>[CH2:1]([C:8]([N:20]([CH3:22])[CH3:21])([CH2:18][CH3:19])[C:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:26][CH2:25][CH2:23][OH:24])=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(Cc1ccccc1)(C(=O)c1ccc(F)cc1)N(C)C
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCC(Cc1ccccc1)(C(=O)c1ccc(NCCO)cc1)N(C)C
Temperature: 140 °C
Reaction time: 16 h

Procedure:
44.9 g (0.15 mol) 2-Benzyl-1-(4-fluorophenyl)-2-dimethylamino-1-butanone and 61.08 g (1.05 mol) ethanolamine are dissolved in 400 ml dimethylacetamide. 41.5 (0.3 mol) Potassium carbonate are added and the suspension is heated to 140° C. while stirring. The reaction mixture is kept at this temperature during 16 hours, cooled to room temperature and diluted with water. The aqueous phase is several times extracted with ethyl acetate, the combined organic extracts washed with water and dried over magnesium sulfate. Evaporation of the solvent gives the crude product as a yellowish-brown oil. The product is purified by chromatography on silica gel (eluent: petroleum ether/ethyl acetate 2:1→1:1). The fractions containing the product are collected to give a slightly yellowish solid product. Recrystallisation from ethyl acetate/hexane gave 2-benzyl-1-[4-(2-hydroxyethylamino)phenyl]-2-dimethylamino-1-butanone as slightly yellowish crystals melting at 109-111° C. Yield: 34.7 g (68%). 1H-NMR data are in agreement with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:15]([O:17][C@H:18]4[C@H:22]5[O:23][CH2:24][C@@H:25]([OH:26])[C@H:21]5[O:20][CH2:19]4)=[N:16][C:11]3=[CH:10][C:9]=2[Cl:35])=[CH:4][CH:3]=1.[NH:36]1[CH2:41][CH2:40][CH:39]([NH:42][C:43](=[O:48])[O:44][CH:45]([CH3:47])[CH3:46])[CH2:38][CH2:37]1>>[Cl:35][C:9]1[CH:10]=[C:11]2[N:16]=[C:15]([O:17][C@@H:18]3[CH2:19][O:20][C@@H:21]4[C@H:25]([OH:26])[CH2:24][O:23][C@H:22]34)[N:14]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:12]2=[N:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([N:36]2[CH2:37][CH2:38][CH:39]([NH:42][C:43](=[O:48])[O:44][CH:45]([CH3:46])[CH3:47])[CH2:40][CH2:41]2)=[CH:3][CH:4]=1
Reactant: CC(C)OC(=O)NC1CCNCC1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(-c3ccc(Br)cc3)nc21
Product: CC(C)OC(=O)NC1CCN(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)CC1

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(5-(4-bromophenyl)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and isopropyl piperidin-4-ylcarbamate following a procedure analogous to that described for Intermediate 23. LC (method 1): tR=1.04 min; Mass spectrum (ESI+): m/z=688 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](/[C:38](/[CH3:41])=[CH:39]\[CH3:40])[C:6]2[O:10][C:9]([C:11]3[CH:36]=[CH:35][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([C:25]5[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=5)[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:37]=1)#[N:2].ClCCl.CO>C(OCC)(=O)C.[Pd]>[CH:38]([C:5]1[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([C:25]5[N:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=[CH:27][N:26]=5)[CH2:21][CH2:20]4)=[O:16])=[CH:35][CH:36]=3)=[N:8][C:7]=2[CH:37]=[C:3]([C:1]#[N:2])[CH:4]=1)([CH2:39][CH3:40])[CH3:41]
Reactant: C/C=C(/C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(c5nccc(C(F)(F)F)n5)CC4)cc3)oc12
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(c5nccc(C(F)(F)F)n5)CC4)cc3)oc12
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-{5-cyano-7-[(1Z)-1-methylprop-1-en-1-yl]-1,3-benzoxazol-2-yl}-N-({1-[4-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-yl}methyl)benzamide (18 mg) in ethyl acetate (5 ml)/dichloromethane (5 ml)/methanol (5 ml) at 40° C. was added 15 mg of 10% Pd/C and the resulting mixture was degassed and flushed with nitrogen, followed by degassing and flushing with hydrogen using a double balloon. The mixture was stirred under hydrogen at 40° C. overnight, and then filtered, washing with ethyl acetate. The filtrate was concentrated and purified by flash column chromatography on a Biotage Horizon, 25M Si column, eluting with 1 column volume of 10% ethyl acetate in hexanes, followed by a linear gradient of ethyl acetate in hexanes from 10% to 100% over 10 column volumes to afford the title compound. Mass spectrum (ESI) 563.2 (M+1). 1H NMR (500 MHz, CDCl3) δ: 8.47 (d, J=4.8 Hz, 1H), 8.34 (d, J=8.2 Hz, 2H), 7.95 (d, J=8.7 Hz, 2H), 7.49 (s, 1H), 6.73 (d, J=4.8 Hz, 1H), 6.32 (t, J=5.9 Hz, 1H), 4.87 (d, J=13.3 Hz, 2H), 3.44 (t, J=6.7 Hz, 2H), 3.21 (m, 1H), 2.93 (m, 2H), 2.01 (m, 1H), 1.90 (m, 2H), 1.84 (m, 2H), 1.44 (d, J=7.1 Hz, 3H), 1.31 (m, 2H), 0.91 (t, J=8.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][C:8]([O:10]CC2C=CC=CC=2)=[O:9])[NH:5][C:4](=[O:6])[CH2:3]1>C(O)C.[Pd]>[CH3:1][C:2]1([CH2:7][C:8]([OH:10])=[O:9])[NH:5][C:4](=[O:6])[CH2:3]1
Reactant: CC1(CC(=O)OCc2ccccc2)CC(=O)N1
Agent: [Pd]
Solvent: CCO
Product: CC1(CC(=O)O)CC(=O)N1

Procedure:
4-Methyl 4-benzyloxycarbonylmethyl azetidin-2-one (2) (2.3 g) was dissolved in ethanol (50 ml) and hydrogenated over 10% Pd/C (250 mg) for one hour. The solution was filtered and a further quantity of catalyst (250 mg) added. The hydrogenation was continued for a further hour and the solution filtered through kieselguhr and evaporated. 4-Methyl-4-carboxymethylazetidin-2-one (3) was obtained as a colourless gum which solidified on standing (1.4 g; 98%), νmax (CHCl3 or KBr disc) 3300, 1730, 1695 cm-1. δ ppm (DMSO) 1.38 (3H, s, CH3), 2.57 (2H, s, CH2CO2H), 2.57 and 2.81 (2H, two doublets [AB system] J 14 Hz C3-methylene), 7.90 (1H, s, NH [exchangeable]), 7.0 to 8.5 (1H, br. signal, CO2H [exchangeable]).
Reaction SMILES: [C:1]([C:3]1[C:12]2[CH:11]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5][CH:4]=1)#[N:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:8]2)#[N:2]
Reactant: COC(=O)c1ccc2c(c1)C(C#N)=CCC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2cccc(C#N)c2c1

Procedure:
The remaining naphthoate (11) was treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in dioxane to aromatize the adjacent ring to give the methyl 8-cyano-2-naphthoate (13). Then, the nitrile was reduced via hydrogentation and the methyl ester saponified to the carboxylic acid. This acid was then N-BOC-protected to give N-(BOC)-8-aminomethyl-2-naphthoic acid (14) as an intermediate for incorporation into the cyclic peptide.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].Br[C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][N:17]=1>>[CH3:22][C:20]1[CH:19]=[CH:18][N:17]=[C:16]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])[CH:21]=1
Reactant: Cc1ccnc(Br)c1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: Cc1ccnc(C#Cc2c(-c3ccccc3)noc2C)c1
Yield: 52 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-bromo-4-methylpyridine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 72 mg, 52%) which was obtained as a light brown solid. MS: m/e=275.2 [M+H]+.
Reaction SMILES: Cl.[NH:2](C(OCC1C=CC=CC=1)=O)[C@H:3]([C:11]([NH:13][C@H:14]([C:23]([NH2:25])=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO.[C].[Pd]>[NH2:2][C@H:3]([C:11]([NH:13][C@H:14]([C:23]([NH2:25])=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)=[O:12])[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)Cc1ccccc1

Procedure:
The hydrochloride named above can be prepared in the following manner: 4.62 g of Z-Phe-Tyr-NH2 are hydrogenated in 50 ml of methanol in the presence of 4 ml of hydrochloric acid in methanol (2.53 N) and 0.5 g of palladium-carbon (10%). After filtering the catalyst and evaporating the filtrate the HCl.H-Phe-Tyr-NH2 is obtained as a white foam. Rf-value on silicagel (with chloroform-methanol) is 0.42.
Reaction SMILES: [CH:1]([C:4]1[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:6]2[C:11]([C:12]=1[C:13]([OH:15])=O)=[CH:10][CH:9]=[C:8]([O:16][CH3:17])[CH:7]=2)([CH3:3])[CH3:2].C(Cl)(C(Cl)=O)=O.[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:35][NH2:36].CCN(CC)CC>C(Cl)Cl.CCOC(C)=O.CN(C=O)C>[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:35][NH:36][C:13]([C:12]1[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[CH:9][CH:10]=2)[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:4]=1[CH:1]([CH3:2])[CH3:3])=[O:15]
Reactant: COc1ccc2c(C(=O)O)c(C(C)C)n(Cc3ccccn3)c2c1
Reactant: NCc1ccc(F)c(F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccn3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-isopropyl-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 139, 415 mg, 1.28 mmol) in CH2Cl2 (20 ml) at 0° C. was added (COCl)2 (2 M in CH2Cl2, 1.6 ml, 3.20 mmol) and a catalytic amount of DMF. The mixture was stirred at room temperature for 1 h, and was concentrated in vacuo. The residue was dissolved in CH2Cl2 (20 ml), cooled to 0° C., and 3,4-difluorobenzylamine (0.23 ml, 1.92 mmol) was added, followed by Et3N (0.53 ml, 3.84 mmol). The reaction was stirred at room temperature for 4 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[C:15](OC(=O)C)(=[O:17])[CH3:16]>OS(O)(=O)=O.C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:15](=[O:17])[CH3:16])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: CC(=O)OC(C)=O
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CC(=O)n1c2ccccc2c2cc(Br)ccc21
Temperature: 25 °C
Yield: 52.1 %

Procedure:
A solution of 3-bromo-9H-carbazole (10.00 g, 40.6 mmol), acetic anhydride (8.30 g, 81 mmol) together with 2 drops of H2SO4 in chloroform (150 mL) was refluxed overnight. After cooling to room temperature, the solution was washed with water. Upon evaporation of the solvent, the crude product was purified by crystallization from hexane/DCM and hexane/EtOAc to yield 1-(3-bromo-9H-carbazol-9-yl)ethanone (6.1 g, 51% yield) as a light yellow solid.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:69])[C:49]4[CH:50]=[CH:51][C:52]5[C:53](=[N:63][N:64]([CH:66]([CH3:68])[CH3:67])[CH:65]=5)[C:54]=4[O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:78]>CO.O>[ClH:78].[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:48](=[O:69])[C:49]4[CH:50]=[CH:51][C:52]5[C:53](=[N:63][N:64]([CH:66]([CH3:67])[CH3:68])[CH:65]=5)[C:54]=4[O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)n1cc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c2n1
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)n1cc2ccc3c(=O)c(-c4ccc(C5(N)CCC5)cc4)c(-c4ccccc4)oc3c2n1
Yield: 71 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(2-isopropyl-6-oxo-8-phenyl-2,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (3 mL), water (7 mL) and 1 M HCl (0.2 mL) and chromatographed on a 5 g C18 cartridge {gradient 30 to 70% MeOH in water+1 M HCl (60 μL in each 10 mL of eluent)} to give the title compound (30.2 mg, 71%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.70 (s, 1H), 8.54 (br s, 3H), 7.74 (d, J=8.8 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.50-7.38 (m, 7H), 7.32 (d, J=8.3 Hz, 2H), 4.96 (septet, J=6.7 Hz, 1H), 2.61-2.49 (m, 4H), 2.23-2.12 (m, 1H), 1.86-1.75 (m, 1H), 1.60 (d, J=6.7 Hz, 6H). LCMS (Method E): RT=3.58 min, [M+H]+=450.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][C:4]=1[CH3:16].COC1C=CC(C=O)=CC=1C.[Br:28]Br>C(Cl)(Cl)Cl>[Br:28][C:8]1[CH:7]=[C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:4]([CH3:16])[C:3]=1[O:2][CH3:1]
Reactant: BrBr
Reactant: CCOC(=O)CCc1ccc(OC)c(C)c1
Agent: COc1ccc(C=O)cc1C
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCc1cc(C)c(OC)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85 %

Procedure:
To a solution of ethyl 3-(4-methoxy-3-methylphenyl)propionate (derived from 10.0 g (66.6 mmol) of 4-methoxy-3-methylbenzaldehyde) in chloroform (200 ml) was added dropwise bromine (10.6 g, 66.6 mmol). The mixture was stirred for 12 hours at room temperature. The reaction mixture was washed with water, an aqueous solution of sodium thiosulfate, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (hexane→hexane/ethyl acetate, 9:1) to give 17.0 g (yield 85%; 3 steps) of the above-titled compound as an oily product.