Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH:27]=[CH:26][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][N:20]2[CH3:25])=[O:8])=[CH:5][CH:4]=1.Cl.[OH-].[Na+].N[C:32]1C=CC=C[C:33]=1CCCC1CCCCN1C.C(Cl)(=O)C=CC1C=CC=CC=1>O.N1C=CC=CC=1.C1COCC1>[CH3:25][N:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH:19]1[CH2:18][CH2:17][CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:7](=[O:8])[CH:6]=[CH:5][C:4]1[CH:3]=[CH:27][CH:26]=[CH:33][CH:32]=1
Reactant: CN1CCCCC1CCCc1ccccc1N
Reactant: COc1ccc(C(=O)Nc2ccccc2CCCC2CCCCN2C)cc1
Agent: Cl
Agent: O=C(Cl)C=Cc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CN1CCCCC1CCCc1ccccc1NC(=O)C=Cc1ccccc1
Reaction time: 3 h
Yield: 46 %

Procedure:
A solution of 4-methoxy-2'-[3-(1-methyl-2-piperidyl)propyl]benzanilide (3.5 g., 0.0095 mole) and concentrated HCl (50 ml.) is heated at reflux for 16 hr., diluted with H2O (100 ml.), basified with 50% NaOH, and extracted with Et2O. The Et2O extracts are combined, washed (H2O and saturated NaCl), dried over MgSO4, and concentrated to give 2.2 g. of 2-(o-aminophenylpropyl)-1-methylpiperidine. The amine is dissolved in pyridine (50 ml.) and a solution of cinnamoyl chloride (1.8 g., 0.011 mole) in THF (10 ml.) added. The reaction mixture is stirred for 3 hr., then concentrated to dryness. The residue is dissolved in water, basified with 50% NaOH, and extracted with EtOAc. The EtOAc extracts are washed (H2O + saturated NaCl), dried over magnesium sulfate, and concentrated to give 3.4 g. of oil which is chromatographed on silica AR CC-7 (Mallinckrodt). Elution first with CHCl3 to remove impurities, then with EtOAc to remove the product and concentration of the EtOAc eluate gave 2.3 g. of solid which crystallized from EtOAc yields 1.6 g (46%) of 2'-[3-(1-methyl-2-piperidyl)propyl]cinnamanilide, m.p. 130°-132° C. Further crystallization from ethyl acetate-isopropyl ether provides analytically pure product, m.p. 133.5°-134.5° C.
Reaction SMILES: C(OCC)C.BrBr.Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[Br:15][C:16]1[CH:17]=[C:18]2[C:28](=[CH:29][CH:30]=1)[O:27][C:21]1[CH:22]=[N:23][C:24]([Cl:26])=[CH:25][C:20]=1[C:19]2=[O:31]>[Zn].C1COCC1>[Br:15][C:16]1[CH:17]=[C:18]2[C:28](=[CH:29][CH:30]=1)[O:27][C:21]1[CH:22]=[N:23][C:24]([Cl:26])=[CH:25][C:20]=1[C:19]2([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[OH:31]
Reactant: O=c1c2cc(Br)ccc2oc2cnc(Cl)cc12
Reactant: CCOC(=O)CBr
Agent: BrBr
Agent: [Zn]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 104.2 %

Procedure:
A 3-neck RBF equipped with an addition funnel and reflux condenser was charged with zinc dust (37.9 g, 580 mmol) and diethyl ether (300 ml). Bromine (1.544 ml, 29.0 mmol) was added drop wise to the stirring suspension at RT. After 5 minutes, ethyl 2-bromoacetate (32.3 ml, 290 mmol) was added drop wise via addition funnel over the time period of 1 hour. The reaction mixture was heated to reflux for one hour. 7-Bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-one (30 g, 97 mmol) was added in one portion followed by THF (200 ml). After stirring at 40° C. for 10 minutes, the reaction mixture was cooled to RT and quenched with saturated aqueous ammonium chloride solution (250 mL). The reaction mixture was stirred for 1 hour before diluting with EtOAc and filtering through a pad of celite. The organic layer was separated, washed with brine and dried over MgSO4. The solution was concentrated under reduced pressure to afford ethyl 2-(7-bromo-3-chloro-5-hydroxy-5H-chromeno[2,3-c]pyridin-5-yl)acetate (40.3 g) which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[C:16]([CH:17]=[O:18])=[CH:15][NH:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[C:19](=O)([O-])[O-].[K+].[K+].IC.O>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:13]([CH3:19])[N:14]=[CH:15][C:16]=2[CH:17]=[O:18])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: O=C([O-])[O-]
Reactant: CC(C)Oc1ccc(-c2n[nH]cc2C=O)cc1Cl
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CI
Product: CC(C)Oc1ccc(-c2c(C=O)cnn2C)cc1Cl
Temperature: 70 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
To a mixture of 3-(3-chloro-4-isopropoxyphenyl)-1H-pyrazole-4-carbaldehyde (530 mg, 1.76 mmol, 1.00 equiv) and potassium carbonate (828 mg, 5.99 mmol, 3.40 equiv) in acetonitrile (100 mL) was added iodomethane (852 mg, 6.00 mmol, 3.41 equiv) dropwise. The reaction was stirred at 70° C. for 8 h. The resulting mixture was cooled to room temperature then concentrated under vacuum. The residue was dissolved in 20 mL of H2O and then extracted with 3×30 mL ethyl acetate. The combined organic layers was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column, XSelect CSH Prep C18 OBD Column, 5 μm, 19×150 mm; mobile phase, water with 10 mmol NH4HCO3 and MeCN (38.0% MeCN up to 45.0% in 15 min); Detector, UV 254/220 nm to afford 100 mg (18%) of 5-[3-chloro-4-(propan-2-yloxy)phenyl]-1-methyl-1H-pyrazole-4-carbaldehyde as colorless oil. 1H-NMR (300 MHz, DMSO-d6): δ 9.55 (s, 1H), 8.03 (s, 1H), 7.73 (d, J=2.1 Hz, 1H), 7.51 (dd, J=8.4 Hz, 2.1 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 4.85-4.77 (m, 1H), 3.78 (s, 3H), 1.33 (d, J=7.5 Hz, 6H) ppm. LCMS (method C, ESI): RT=0.92 min, m/z=279.0 [M+H]+ and 120 mg (22%) of the other regioisomer, 3-(3-chloro-4-isopropoxyphenyl)-1-methyl-1H-pyrazole-4-carbaldehyde as a colorless oil. 1H-NMR (300 MHz, DMSO-d6): δ 9.83 (s, 1H), 8.51 (s, 1H), 7.96 (d, J=2.1 Hz, 1H), 7.82 (dd, J=8.4 Hz, 2.1 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 4.77-4.69 (m, 1H), 3.94 (s, 3H), 1.32 (d, J=7.5 Hz, 6H) ppm.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].N1C=CC=CC=1.C(N(CC)CC)C.[C:35](Cl)(=[O:43])[O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C)C=O>[CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:35](=[O:43])[O:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N)c3)ccc21
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
N1-Methyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (2.163 g, 7.66 mmol) synthesized in Production example 5-1 was dissolved in N,N-dimethylformamide (50 ml) under nitrogen atmosphere; pyridine (0.93 ml, 11.5 mmol), triethylamine (2.4 ml, 17.24 mmol) and phenyl chlorocarbonate (1.44 ml, 11.5 mmol) were sequentially added dropwise while cooled with an ice water bath; and the reaction mixture was heated to room temperature while stirred. After 1 hour, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and then the residue was purified by silica gel column chromatography (eluent; ethyl acetate), precipitated from ethyl acetate-hexane (1:10), filtered off, and dried under aeration to yield the title compound (2.731 g, 6.79 mmol, 88.6%) as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH2:26][CH3:27])[C:22]=4[NH2:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:31]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH2:26][CH3:27])[C:22]=4[NH:28][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:31]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1cccc(-c2ccccc2)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(CC)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(CC)c4Nc4cccc(-c5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-ethyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-phenyl-pyridine.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[BH4-].[Na+].O1CCCC1.[O:11]=[C:12]([NH:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[C:28]([N:30]1[C@@H:42]2[C@@H:33]([C@H:34]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[NH:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:41]=32)[CH2:32][CH2:31]1)=[O:29])[CH2:13][CH2:14][CH2:15][CH2:16][C:17](OC)=[O:18]>O.C(O)C>[OH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]([NH:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[C:28]([N:30]1[C@@H:42]2[C@@H:33]([C@H:34]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[NH:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:41]=32)[CH2:32][CH2:31]1)=[O:29])=[O:11]
Reactant: COC(=O)CCCCC(=O)N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCCCCO)N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Yield: 90.9 %

Procedure:
A mixture of calcium chloride (88 mg, 0.8 mmol), sodium borohydride (60 mg, 1.6 mmol), tetrahydrofuran (2.5 ml) and ethanol (2.5 ml) was stirred under a nitrogen atmosphere under ice-cooling for 30 min. To the mixture was added methyl 6-oxo-6-[((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl]carbonyl}cyclohexyl)amino]hexanoate (106 mg, 0.20 mmol) under ice-cooling, and the mixture was stirred at room temperature for 16 hrs. Water was added, and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to column chromatography using basic silica gel and eluted with ethyl acetate to give the title compound (89 mg, 92%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][C:27]=2[F:33])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])([OH:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:34]I>[Ag-]=O.C(OCC)C>[F:1][C:2]1[C:3]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][C:27]=2[F:33])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])([O:15][CH3:34])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCC1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Agent: O=[Ag-]
Solvent: CCOCC
Product: COC1(CNC(=O)OC(C)(C)C)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C

Procedure:
1,1-Dimethylethyl {[1-({3,4-difluoro-2[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidine-3-yl]methyl}carbamate (8.0 mg, 0.014 mmol) and silver (I) oxide (12 mg, 0.05 mmol) were taken into methyl iodide (0.5 mL) and the mixture was brought to reflux for 4 hours. The suspension was then cooled to room temperature and diluted with an excess of ethyl ether then filtered. The filtrate was concentrated and purified by silica gel flash chromatography using hexanes:ethyl acetate (1:1) as eluent to give 1,1-dimethylethyl {[1-({3,4-difluoro-2[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(methyloxy)azetidine-3-yl]methyl}carbamate (2 mg). The material was taken into TFA (0.5 mL) and allowed to stand for 5 minutes then concentrated in vacuo. The residue was azetroped twice from methanol (2 mL) and the residue dried in vacuo to afford 6-{[3-(aminomethyl)-3-(methyloxy)azetidin-1-yl]carbonyl}-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline trifluoroacetate salt (2.3 mg, 27% yield) as an amorphous solid. MS (EI) for C18H17F3IN3O: 492 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]2[C:27](=[O:28])[O:26][C:25]([CH3:30])([CH3:29])[O:24][C:23]=2[CH:31]=1.O.CO>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:17]=[CH:16][C:13](/[CH:14]=[N:18]/[C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[O:28])[O:26][C:25]([CH3:29])([CH3:30])[O:24][C:23]=4[CH:31]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(C#Cc2ccc(Cl)cc2)cc1
Reactant: CC1(C)OC(=O)c2ccc(N)cc2O1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: CC1(C)OC(=O)c2ccc(/N=C/c3ccc(C#Cc4ccc(Cl)cc4)cc3)cc2O1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
A solution of 4-[(4-chlorophenyl)ethynyl]benzaldehyde (1.31 g, 5.43 mmol) and 7-amino-2,2-dimethyl-4H-1,3-benzodioxin-4-one (1.00 g, 5.18 mmol) in toluene (20 ml) was heated at reflux for 18 h with azeotropic removal of water. Then the reaction mixture was cooled to rt and MeOH (20 ml) was added. The precipitate was filtered off, washed with MeOH and dried under reduced pressure to give 1.95 g of the titled compound as a yellow powder (91%). 1H NMR (CDCl3, 300 MHz) δ 8.42 (s, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.91 (d, J=8.2 Hz, 2H, 7.65 (d, J=8.2 Hz, 2H), 7.50 (d, J=8.7 Hz, 2H), 7.37 (d, J=8.7 Hz, 2H), 6.91 (dd, J=8.3, 1.9 Hz, 1H), 6.74 (d, J=1.9 Hz, 1H), 1.77 (s, 6H).
Reaction SMILES: BrC1C=CC([C@H]2C3C(=CC=C(OCCCN4CCCCC4)C=3)[C@@H]3CCC(=O)[N:10]3[CH2:9]2)=CC=1.[C:32]1([C@H:38]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([O:48][CH2:49][CH2:50][CH2:51][N:52]4[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]4)[CH:46]=3)[C@@H:41]3[CH2:58][CH2:59][C:60](=O)[N:40]3[CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[N:52]1([CH2:51][CH2:50][CH2:49][O:48][C:45]2[CH:46]=[C:47]3[C:42](=[CH:43][CH:44]=2)[C@@H:41]2[CH2:58][CH2:59][CH2:60][N:40]2[CH2:39][C@H:38]3[C:32]2[CH:33]=[CH:34][C:35]([C:9]#[N:10])=[CH:36][CH:37]=2)[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57]1
Reactant: O=C1CC[C@H]2c3ccc(OCCCN4CCCCC4)cc3[C@H](c3ccccc3)CN12
Reactant: O=C1CC[C@H]2c3ccc(OCCCN4CCCCC4)cc3[C@H](c3ccc(Br)cc3)CN12
Product: N#Cc1ccc([C@@H]2CN3CCC[C@H]3c3ccc(OCCCN4CCCCC4)cc32)cc1

Procedure:
Cis-6-(4-Bromo-phenyl)-8-(3-piperidin-1-yl-propoxy)-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one. Prepared as described in Example 42, Step 13, on a 1.23 mmol scale to yield 308.1 mg of a mixture of the desired product and cis-6-phenyl-8-(3-piperidin-1-yl-propoxy)-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][C:16]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26](O)=[CH:25][C:24]=4C)=[O:21])=[CH:15][C:14]=3[CH:31]=2)=[CH:6][CH:5]=1)[CH3:2].S(Cl)(Cl)=O.O.[CH:37](Cl)(Cl)[Cl:38]>N1C=CC=CC=1.C1COCC1.C(OCC)(=O)C>[Cl:38][CH2:37][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:20]([C:16]2[CH2:17][CH2:18][O:19][C:13]3[CH:12]=[CH:11][C:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][CH:8]=4)=[CH:31][C:14]=3[CH:15]=2)=[O:21])=[CH:24][CH:25]=1
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(O)cc2C)CCO3)cc1
Reactant: ClC(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCO3)cc1
Reaction time: 20 h

Procedure:
To a suspension of 7-(4-ethoxyphenyl)-N-(4-hydroxy-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (2.55 g) and pyridine (2 drops) in chloroform (50 ml) was added thionyl chloride (0.8 ml) at room temperature, and the mixture was stirred for 20 hours. To the reaction mixture was added water and then THF, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure to give solid, which was dissolved in THF and ethyl acetate. The mixture was concentrated under reduced pressure to give crystals, which were collected by filtration and washed with dusopropylether to give N-(4-chloromethylphenyl)-7-(4-ethoxyphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (2.42 g) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:16]=[C:15]([CH2:17][N:18]([CH3:30])[S:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=2)(=[O:21])=[O:20])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[C:36]([O:38][CH3:39])[CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[F:31][C:32]1[CH:33]=[C:34]([C:2]2[CH:16]=[C:15]([CH2:17][N:18]([CH3:30])[S:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=3)(=[O:21])=[O:20])[CH:14]=[CH:13][C:3]=2[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH:35]=[C:36]([O:38][CH3:39])[CH:37]=1
Reactant: CN(Cc1ccc(OCC(=O)OC(C)(C)C)c(Br)c1)S(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: COc1cc(F)cc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(F)cc(-c2cc(CN(C)S(=O)(=O)c3ccc(F)c(Cl)c3)ccc2OCC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Yield: 45.6 %

Procedure:
To a mixture of tert-butyl 2-(2-bromo-4-((3-chloro-4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)acetate (10) (140 g, 0.27 mol, 1 eq), 3-fluoro-5-methoxyphenylboronic acid (45.7 g, 0.27 mol, 1 eq, Combi-Blocks Inc., San Diego, Calif., USA) and potassium carbonate (111 g, 0.81 mol, 3 eq) in dioxane/water (3:1, 800 mL) was added tetrakis(triphenylphoshine)palladium (3.08 g, 2.7 mmol, 0.01 eq). The mixture was heated at 60° C. for 3 h under N2. Solvent was evaporated, and the solid was dissolved in DCM and filtered. The DCM was evaporated and the crude product was recrystallized from ethanol to yield tert-butyl 2-(3-fluoro-5-methoxyphenyl)-4-((3-chloro-4-fluoro-N-methylphenylsulfonamido)methyl)phenoxyacetate (11) (70 g, 41%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[N+]([O-])([O-])=O.[NH4+].[Ce].[Ce].[I:19]I>C(#N)C>[I:19][C:8]1[CH:9]=[C:5]([C:3](=[O:4])[C:2]([F:1])([F:10])[F:11])[NH:6][CH:7]=1
Reactant: II
Reactant: O=C(c1ccc[nH]1)C(F)(F)F
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Product: O=C(c1cc(I)c[nH]1)C(F)(F)F
Yield: 112.1 %

Procedure:
An acetonitrile solution (20 ml) of 2-(trifluoroacetyl)-1H-pyrrole (0.5 g), dicerium ammonium nitrate (0.84 g) and iodine (0.47 g) was refluxed for 2 hours. After cooling, the reaction solution was washed with saturated aqueous solution of sodium thiosulfate and saturated aqueous solution of sodium chloride. After drying the organic layer with magnesium sulfate, the solvent was distilled off under the reduced pressure to obtain 4-iodo-2-(trifluoroacetyl)-1H-pyrrole (0.6 g).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:23][CH2:22][C:21]([C:32]([O:34]C)=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:23][CH2:22][C:21]([C:32]([OH:34])=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccccn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.8 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-(2-pyridylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (378 mg) in a mixture of tetrahydrofuran (24 ml) and methanol (24 ml) was added 1N sodium hydroxide solution (8 ml), and the mixture was stirred at room temperature for 2 days. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to neutral, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-(2-pyridylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (260 mg) as yellow crystals.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=CC=1Cl.[Cl-].[Al+3].[Cl-].[Cl-].[Br:19][C:20]1[CH:30]=[C:24]2[C:25]([O:27][C:28](=[O:29])[C:23]2=[CH:22][CH:21]=1)=[O:26]>O.C(OCC)(=O)C>[C:25]([C:24]1[CH:30]=[C:20]([Br:19])[CH:21]=[CH:22][C:23]=1[C:28]([OH:29])=[O:27])(=[O:26])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccccc1
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc(Br)cc1C(=O)c1ccccc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
A mixture of benzene (2.94 ml), o-dichlorobenzene (20 ml) and aluminum chloride (5.87 g) was cooled to 5° C. and 5-bromophthalic anhydride (5.0 g) was added by small portions while maintaining the temperature of the mixture below 10° C. The mixture was stirred at around 25° C. for 1 h and then at 80° C. for 1 h. The reaction mixture was cooled to around 5° C. and ethyl acetate (40 ml) was added dropwise. Water (20 ml) was added dropwise below 40° C. The organic layer was separated and 4N hydrochloric acid (20 ml) was added. The mixture was stirred until the precipitated solid was dissolved. The organic layer was separated and washed with water (20 ml). The solvent was evaporated and toluene (30 ml) and ethyl acetate (3 ml) were added to the residue, which was followed by heating to 80° C. The obtained solution was cooled to 25° C. over 30 min and the precipitated crystals were collected by filtration. The crystals were dissolved in a mixture of toluene (30 ml) and ethyl acetate (1.5 ml) by heating and the obtained solution was cooled to 25° C. and then to 5° C. The precipitated crystals were collected by filtration and washed with toluene, to give the title compound (2.81 g, yield 41.8%).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Br:8])[N:3]=1.[N:9]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C>CCO>[Br:8][C:4]1[N:3]=[C:2]([N:12]2[CH2:13][CH2:14][CH2:15][N:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11]2)[CH:7]=[N:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: Brc1cncc(Br)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCN(c2cncc(Br)n2)CC1
Temperature: 100 °C
Yield: 70 %

Procedure:
A mixture of 2,6-dibromopyrazine (0.47 g, 2 mmol), tert-butyl 1,4-diazepane-1-carboxylate (0.4 g, 2 mmol), and DIPEA (0.78 g, 6 mmol) in EtOH (10 mL) was heated at 100° C. for 15 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (5% to 50%) as eluting solvents to afford tert-butyl 4-(6-bromopyrazin-2-yl)-1,4-diazepane-1-carboxylate as colorless oil (0.5 g, 70%). MS (ESI) m/z: 357 [M+H]+.