Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19]C)=[O:18])=[CH:13][C:12]=1[CH3:21].[OH-].[Na+]>CCO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][C:12]=1[CH3:21]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2OC)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(OC)c(-c2ccc(C(=O)O)cc2C)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
Methyl 4-bromo-3-methylbenzoate (Intermediate 17, step 1) (4 g; 17.46 mmol; 1 eq.), 2,5-dimethoxyphenylboronic acid (3.50 g; 19.21 mmol; 1.10 eq.), potassium carbonate (12.07 g; 87.31 mmol; 5 eq.), tetrakis(triphenylphosphine)palladium(0) (2.02 g; 1.75 mmol; 0.10 eq.) were taken in Toluene (20 mL) and water (20 mL) under N2 atmosphere. The reaction mixture was degassed with N2 and then refluxed for 24 hours. The reaction mixture was cooled to RT, filtered over a pad of celite and washed with toluene (200 mL). The filtrate was concentrated to afford a brown oil which was taken up in EtOAc (300 mL). The organic layer was washed with a saturated aqueous solution of NaHCO3 solution (100 mL), water (100 mL) and brine (1000 mL), dried over MgSO4 and concentrated affording methyl 2′,5′-dimethoxy-2-methylbiphenyl-4-carboxylate as a brown oil (5.1 g) used without further purification (HPLC (Method A) Rt 4.73 min (Purity: 59.7%)). A solution of methyl 2′,5′-dimethoxy-2-methylbiphenyl-4-carboxylate (4.50 g; 15.72 mmol; 1 eq.) in EtOH (135 mL) at RT was treated with sodium hydroxide (9.43 mL; 5 M; 47.15 mmol; 3 eq.). The reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated to give a beige solid which was taken up in water (100 mL) and the aqueous phase was washed twice with EtOAc. The aqueous phase was acidified with HCl cc to pH 2. Then it was concentrated until precipitation (volume divided by 2). The suspension was filtered affording the title compound as a beige solid (3.43 g, 80%). 1H NMR (DMSO-d6, 300 MHz) δ 12.91 (br s, 1H), 7.85-7.78 (m, 2H), 7.27-7.24 (d, J=7.17 Hz, 1H), 7.08-6.96 (m, 2H), 6.72-6.71 (d, J=3.01 Hz, 1H), 3.76 (s, 3H), 3.68 (s, 3H), 2.14 (s, 3H). LC/MS (Method A): 270.9 (M−H)−. HPLC (Method A) Rt 3.84 min (Purity: 97.8%).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:16])[C@@H:6]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:7])[CH:2]=[CH2:3].C(N(CC)CC)C.[C:24]([O:28][C:29]([NH:31][C:32]([CH3:38])([CH3:37])[CH2:33][C:34]([OH:36])=O)=[O:30])([CH3:27])(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)[C:50]2[CH:51]=C[CH:53]=[CH:54][C:49]=2N=N1>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:4][C:5](=[O:16])[C@H:6]([NH:7][C:34](=[O:36])[CH2:33][C:32]([NH:31][C:29]([O:28][CH2:24][C:27]1[CH:53]=[CH:54][CH:49]=[CH:50][CH:51]=1)=[O:30])([CH3:37])[CH3:38])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@H](N)CCc1ccccc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCOC(=O)[C@@H](CCc1ccccc1)NC(=O)CC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
D-Homophenylalanine allyl ester (350 mg; 1.60 mmol), triethylamine (445 μl; 3.19 mmol) and 3-t-butoxycarbonylamino-3-methylbutanoic acid (412.8 mg; 1.64 mmol) were dissolved in dry methylene chloride (3 ml) and stirred at room temperature to give a homogeneous solution. BOP was added to the solution over 5 minutes and the reaction mixture stirred together at room temperature for 12 h. The reaction mixture was quenched by adding brine (10 ml) directly to the reaction. The crude products were isolated by extraction with methylene chloride (2×25 ml); the combined methylene chloride extracts dried with powdered anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The pale yellow oil thus obtained was subjected to column chromatography on silica gel using an eluant of ethyl acetate and hexanes (1:1 v/v). In this way, 432 mg (59.7%) of the desired product was isolated as a colorless oil. FAB-MS: -calculated for C26H32N2O5 452.2; found 453.4 (M+1).
Reaction SMILES: Cl.O.FC(F)(F)C(O)=O.[CH3:10][C:11]1[CH:16]=[C:15]([C:17]2[N:21](C3CCCCO3)[CH:20]=[N:19][N:18]=2)[CH:14]=[CH:13][C:12]=1[C:28]1[N:33]=[C:32]2[NH:34][C:35]3([CH2:40][CH2:39]3)[C:36](=[O:38])[NH:37][C:31]2=[N:30][CH:29]=1>C(O)C>[CH3:10][C:11]1[CH:16]=[C:15]([C:17]2[NH:21][CH:20]=[N:19][N:18]=2)[CH:14]=[CH:13][C:12]=1[C:28]1[N:33]=[C:32]2[NH:34][C:35]3([CH2:39][CH2:40]3)[C:36](=[O:38])[NH:37][C:31]2=[N:30][CH:29]=1
Reactant: Cc1cc(-c2nncn2C2CCCCO2)ccc1-c1cnc2c(n1)NC1(CC1)C(=O)N2
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2nnc[nH]2)ccc1-c1cnc2c(n1)NC1(CC1)C(=O)N2
Temperature: 80 °C
Yield: 38.5 %

Procedure:
6 N Hydrochloric acid in water (0.171 mL, 1.025 mmol) was added to a stirred mixture of 7′-(2-methyl-4-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)phenyl)-1′H-spiro[cyclopropane-1,2′-pyrazino[2,3-b]pyrazin]-3′(4′H)-one trifluoroacetate (0.109 g, 0.205 mmol) in ethanol (4 mL) at 80° C. The resulting mixture was stirred vigorously and heated at 80° C. under a reflux condenser under nitrogen for 30 min. The resulting mixture was filtered and purified using reverse-phase preparatory HPLC (10-60% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min). Fractions containing the desired product were combined, neutralized with saturated aqueous sodium bicarbonate and most of the solvent removed under reduced pressure. Solids were collected by vacuum filtration, washed thoroughly with water and dried under high vacuum at 45° C. to give the desired product (0.027 g, 0.079 mmol, 39% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.22 (br. s., 1H), 8.63 (br. s., 1H), 7.93 (s, 1H), 7.89 (d, J=7.81 Hz, 1H), 7.62 (s, 1H), 7.58 (s, 1H), 7.47 (br. s., 1H), 2.43 (s, 3H), 1.29-1.38 (m, 2H), 0.95-1.04 (m, 2H); MS (ESI) m/z 334.2 [M+1]+.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[O:6]=[C:7]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])CP(=O)([O-])[O-].[C:24]([O:27][C@H:28]1[CH2:33][CH2:32][C@H:31]2[C@H:34]3[C@H:43]([CH2:44][CH2:45][C@:29]12[CH3:30])[C:42]1[CH:41]=[CH:40][C:39]([O:46][C:47](=[O:54])[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[CH:38][C:37]=1[CH2:36][C@H:35]3CCC=O)(=[O:26])[CH3:25].C(O)(=O)C>CCCCCC.O1CCCC1>[C:24]([O:27][C@H:28]1[CH2:33][CH2:32][C@H:31]2[C@H:34]3[C@H:43]([CH2:44][CH2:45][C@:29]12[CH3:30])[C:42]1[CH:41]=[CH:40][C:39]([O:46][C:47](=[O:54])[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)=[CH:38][C:37]=1[CH2:36][C@H:35]3[CH2:4][CH2:3][CH:2]=[CH:1][C:7](=[O:6])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:26])[CH3:25]
Reactant: [Li]CCCC
Reactant: CCCCCCCCCCCC(=O)CP(=O)([O-])[O-]
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3[C@H](CCC=O)Cc4cc(OC(=O)c5ccccc5)ccc4[C@H]3CC[C@]12C
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CCCCCCCCCCCC(=O)C=CCC[C@@H]1Cc2cc(OC(=O)c3ccccc3)ccc2[C@H]2CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]12
Temperature: -70 °C
Reaction time: 0.67 h

Procedure:
n-Butyl-lithium (0.341 ml. of a 1.6 molar solution in hexane) was added to a stirred solution of 2-oxotridecylphosphonate (0.193 g.) in tetrahydrofuran (10 ml.) which was maintained at -70° C. and the mixture was stirred at that temperature for 40 minutes. A solution of 3-(17β-acetoxy-3-benzoyloxyoestra-1,3,5(10)-trien-7α-yl)propionaldehyde (Example 3; 0.2 g.) in tetrahydrofuran (10 ml.) was added and the mixture was allowed to warm up to laboratory temperature and was stirred at that temperature for 4.5 hours. Acetic acid was added until the mixture was acidic and the mixture was evaporated to dryness. Water (10 ml.) was added and the mixture was extracted three times with ethyl acetate (30 ml. each time). The combined extracts were washed with water, dried and evaporated to dryness and there was thus obtained as residual oil 1-(17β-acetoxy-3-benzoyloxyoestra-1,3,5(10)-trien-7α-yl)hexadec-3-en-5-one.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[N:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:13]=[C:12]([C:18]2[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.C(N(CC)CC)C.Cl[CH2:36][CH2:37][S:38](Cl)(=[O:40])=[O:39].Cl.[F:43][CH:44]1[CH2:47][NH:46][CH2:45]1>C(Cl)Cl>[F:43][CH:44]1[CH2:47][N:46]([CH2:36][CH2:37][S:38]([N:2]2[CH2:3][CH:4]([C:6]3[CH:27]=[CH:26][C:9]4[C:10]5[N:14]([CH:13]=[C:12]([C:18]6[N:19]([CH:23]([CH3:24])[CH3:25])[N:20]=[CH:21][N:22]=6)[N:11]=5)[CH2:15][CH2:16][O:17][C:8]=4[CH:7]=3)[CH2:5]2)(=[O:40])=[O:39])[CH2:45]1
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CNC3)cc1OCC2
Reactant: FC1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CN(S(=O)(=O)CCN4CC(F)C4)C3)cc1OCC2
Reaction time: 18 h
Yield: 32.6 %

Procedure:
8-Azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride from Example 65 (200 mg, 0.517 mmol) was stirred in DCM (2 mL) with triethylamine (145 L, 1.04 mmol) for 1 h before the addition of 2-chloroethanesulfonyl chloride (84 mg, 0.52 mmol). After stirring for 1 h further triethylamine (73 L, 0.52 mmol) was added and the mixture stirred for 18 h before diluting with DCM and washing with water followed by brine. The resultant solution was concentrated in vacuo to give a brown oil which was used in the subsequent step without purification. A portion of the brown oil (81 mg, 0.18 mmol) was stirred in 3 mL IMS at RT with 3-fluoro-azetidine hydrochloride (22 mg, 0.22 mmol) and triethylamine (56 L, 0.4 mmol) for 18 h before being concentrated in vacuo. The resultant residue was dissolved in DCM and the solution washed with water then brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant light brown oil was subjected to flash chromatography (SiO2, gradient 0 to 2% MeOH in DCM) to give 204 as a white solid (37 mg, 40%). 1H NMR δ (ppm)(CDCl3): 8.49 (1 H, d, J=8.30 Hz), 7.84 (1 H, d, J=0.64 Hz), 7.62 (1 H, s), 7.12 (1 H, dd, J=8.34, 1.88 Hz), 7.00 (1 H, d, J=1.83 Hz), 5.99-5.91 (1 H, m), 5.19-5.13 (0.5 H, m), 5.05-4.99 (0.5 H, m), 4.49-4.46 (2 H, m), 4.45-4.41 (2 H, m), 4.26 (2 H, t, J=8.24 Hz), 4.06 (2 H, t, J=7.28 Hz), 3.80-3.63 (3 H, m), 3.27-3.22 (1 H, m), 3.21-3.16 (1 H, m), 3.06-3.00 (2 H, m), 2.97-2.90 (2 H, m), 1.60-1.54 (6 H, m). LCMS: RT=2.94 min, M+H+=516
Reaction SMILES: [C:1]([N:4]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[C:5](=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:8]([O:27][CH3:28])[CH:7]=1)(=[O:3])[CH3:2].[CH3:37][I:38]>>[I-:38].[C:1]([N:4]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N+:32]=1[CH3:37])[C:5](=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:8]([O:27][CH3:28])[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2ccccn2)C(C)=O)cc1OC
Reactant: CI
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2cccc[n+]2C)C(C)=O)cc1OC
Product: [I-]
Yield: 99.3 %

Procedure:
The title compound is prepared by the procedure of Example 28 using 0.322 g of product from Example 49 and 4.6 g of methyl iodide. The residue is recrystallized from methyl alcohol to give 0.411 g of the desired product as yellow crystals.
Reaction SMILES: [N:1]([C:4]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O)=[N+]=[N-].O=S(Cl)[Cl:25]>>[Cl:25][C:6]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:1]=[C:4]2[C:5]=1[CH:15]=[CH:16][CH:17]=[C:18]2[C:19]([F:22])([F:21])[F:20]
Reactant: O=S(Cl)Cl
Reactant: [N-]=[N+]=Nc1c(C(=O)Nc2ccccc2)cccc1C(F)(F)F
Product: FC(F)(F)c1cccc2c(Cl)n(-c3ccccc3)nc12

Procedure:
2-Azido-N-phenyl-3-trifluoromethyl-benzamide (310 mg, 1 mmol, compound of formula (X)) was heated in 2 ml of SOCl2 in a sealed vial at 100° C. for 4 hours. After evaporation of SOCl2 in vacuo the residue was purified by column chromatography on silica (n-heptane/ethyl acetate, 50:50, as eluent). Yield: 212 mg (72%).
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[Cl:29])=O)(=O)OC.O.[NH2:31][NH2:32]>>[Cl:29][C:23]1[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]=1[C:20]1[CH:19]=[C:4]2[C:3]([C@:2]3([CH3:1])[C:8]([CH3:10])([CH3:9])[C@H:5]2[CH2:6][CH2:7]3)=[N:32][N:31]=1
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Reactant: COP(=O)(CC(=O)c1ccc(F)cc1Cl)OC
Reactant: NN
Solvent: O
Product: CC1(C)[C@H]2CC[C@]1(C)c1nnc(-c3ccc(F)cc3Cl)cc12

Procedure:
yellow solid. MS (EI): 316.0 (M+). Prepared from (1S,4R)-1,7,7-trimethyl-bicyclo [2.2.1]heptane-2,3-dione, [2-(2-Chloro-4-fluoro-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](/[N:11]=[C:12](/[NH:32][C:33](=[O:42])[CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)\[NH:13][CH2:14][CH2:15][CH2:16][C@H:17]2[C:20](=[O:21])[NH:19][C@@H:18]2[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:43]1([N:49]=[C:50]=[O:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]1([CH2:7][CH2:8][C:9](/[N:11]=[C:12](/[NH:32][C:33](=[O:42])[CH2:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)\[NH:13][CH2:14][CH2:15][CH2:16][C@H:17]2[C:20](=[O:21])[N:19]([C:50](=[O:51])[NH:49][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@@H:18]2[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=C(CCc1ccccc1)/N=C(\NCCC[C@H]1C(=O)N[C@@H]1C(=O)OCc1ccccc1)NC(=O)CCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCc1ccccc1)/N=C(\NCCC[C@H]1C(=O)N(C(=O)Nc2ccccc2)[C@@H]1C(=O)OCc1ccccc1)NC(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 149 (50 mg, 1.0 eq.) in DCM (2 mL) was added phenylisocyanate (29 μL, 3.0 eq.), triethylamine (12 μL, 1 eq.) and DMAP (1 mg). The reaction was stirred for 18 hours at room temperature and then diluted with dichloromethane and washed with 1N HCl and water. The organic layer was then concentrated in vacuo and purified via silica gel chromatography eluting with 15% EtOAc in hexanes to give 150 (10 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[C:28]1([NH:34][C:35]([C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=2)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[O:24]1[CH2:25][CH2:26][N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:14]([NH:13][C:6]3[CH:7]=[CH:8][C:9]4[NH:10][C:41]([C:40]5[CH:39]=[CH:38][C:37]([C:35](=[O:36])[NH:34][C:28]6[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=6)=[CH:44][CH:43]=5)=[N:1][C:4]=4[CH:5]=3)=[O:27])=[CH:16][CH:17]=2)[CH2:22][CH2:23]1
Reactant: O=Cc1ccc(C(=O)Nc2ccccc2)cc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCOCC2)cc1
Product: O=C(Nc1ccccc1)c1ccc(-c2nc3cc(NC(=O)c4ccc(N5CCOCC5)cc4)ccc3[nH]2)cc1

Procedure:
Compound 217 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-morpholinylbenzamide and 4-phenylaminocarbonylbenzaldehyde. [M+H]+ calcd for C31H27N5O3: 518.22; found: 518.03.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7]C(O)=O.C([N:16]([CH2:19]C)CC)C.[Cl:21]C(OCC)=O.[N-]=[N+]=[N-].[Na+]>C1COCC1.O>[Cl:21][C:19]1[C:11]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:13][CH:12]=2)[CH:6]=[CH:7][N:16]=1
Reactant: COc1cccc(C=CC(=O)O)c1
Reactant: CCOC(=O)Cl
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(Cl)nccc2c1
Temperature: 210 °C
Reaction time: 1 h

Procedure:
1-Chloro-6-methoxy-isoquinoline was prepared according to the following procedure. To a solution of 3-methoxy cinnamic acid (25 g, 140.3 mmol) and triethylamine (39.1 mL, 280.6 mmol) in THF (200 mL) was added ethyl chloroformate (20 ml, 210 mmol) dropwise at 0° C. After stirring at this temperature for 1 hour, aqueous NaN3 (14.7 g, 226 mmol in 80 mL H2O) was added dropwise and the reaction mixture was stirred for 16 hours at ambient temperature. Water (220 mL) was added to the mixture and the volatiles were removed in vacuo. The resulting slurry was extracted with toluene (3×110 mL) and the combined organic layers were dried over MgSO4, filtered and concentrated. The dried solution was added dropwise to a heated solution of diphenylmethane (120 mL) and tributylamine (68 mL) at 190° C. The toluene was distilled off during the addition. After complete addition, the reaction temperature was raised to 210° C. for 2 hours. Upon cooling via an ice bath, the precipitated product was collected by filtration, washed with hexanes, and dried to yield the desired product as an off-white solid (14.04 g, 57%): LCMS found 176.1 [M+H]+. 6-Methoxy-2H-isoquinolin-1-one (14.04 g, 80.15 mmol) in POCl3 (30.5 ml) was heated to gentle reflux for 1 hour and the mixture was then concentrated in vacuo. The residue was poured into ice water and brought to pH 10 by the addition of 10 M NaOH. The resulting mixture was extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (0-20% EtOAc/hexane) to afford 13.31 g (86%) of the desired 1-chloro-6-methoxy-isoquinoline intermediate as a white solid. LCMS found 194.19 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:19]=[C:20]=S.[NH2:22][C:23]1[C:24]([NH:34][CH3:35])=[CH:25][C:26]([O:32][CH3:33])=[C:27]([CH:31]=1)[C:28]([OH:30])=[O:29].FC(F)(F)C(=N[Si](C)(C)C)O[Si](C)(C)C.CC(C)N=C=NC(C)C>CN(C=O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[NH:19][C:20]1[N:34]([CH3:35])[C:24]2[CH:25]=[C:26]([O:32][CH3:33])[C:27]([C:28]([OH:30])=[O:29])=[CH:31][C:23]=2[N:22]=1
Reactant: CNc1cc(OC)c(C(=O)O)cc1N
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Agent: CC(C)N=C=NC(C)C
Agent: C[Si](C)(C)N=C(O[Si](C)(C)C)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1cc2c(cc1C(=O)O)nc(Nc1cc(CNC(=O)C3(C(F)(F)F)CC3)ccc1Cl)n2C
Temperature: 25 °C

Procedure:
A mixture of N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide (1.71 g; 5.10 mmol) and 5-amino-2-methoxy-4-(methylamino)benzoic acid (1.00 g; 1.00 mmol) in DMF (20 mL) was stirred over night at rt. The mixture was thereafter heated to 60° C. and BSTFA (1.44 g; 5.61 mmol) was added and stirred for 1 h before the addition of DIC (0.772 g; 6.12 mmol). The resulting mixture was stirred at 80° C. for 3 h. Acetic acid (2 mL) was added and the mixture was concentrated and the residue poured in aqueous NaOH (2 M) and pH adjusted to −3-4. The mixture was extracted with EtOAc and the organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was recrystallized from EtOAc/petroleum ether to give the sub-title compound. Yield: 0.570 g (22%).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16](=[O:25])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8][C@H:7]([NH:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:6]1=[O:35].CO.O.O[Li].O>C1COCC1>[O:35]=[C:6]1[N:5]([CH2:4][C:3]([OH:36])=[O:2])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16](=[O:25])[CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8][CH:7]1[NH:26][C:27](=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)c2ccccc2)CN(C(=O)CCc2ccccc2)c2ccccc21
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CN1C(=O)C(NC(=O)c2ccccc2)CN(C(=O)CCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 64 h
Yield: 19 %

Procedure:
(3S)-2-Oxo-3-benzoylamino-5-(3-phenylpropionyl)-2,3,4,5-tetrahydro-1H-1,5-benzo diazepine-1-acetic acid methyl ester (602a; 1.25 g, 2.57 mmol) was dissolved in 11 ml of THF, MeOH and H2O (5:5:1) and treated with LiOH.H2O (42 mg, 0.62 mmol) stirred at RT for 64 h. The reaction was concentrated in vacuo, diluted with H2O and acidified with aq. 1N HCl to give 230 mg of 603a as a white solid.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([Mg]Br)#[CH:10].[Cl-].[NH4+]>C1COCC1.C(OCC)C>[C:2]1([CH:1]([OH:8])[C:9]#[CH:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Mg]Br
Reactant: O=Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#CC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2.65 g of benzaldehyde (Formula 26) in 50 mL of THF at room temperature was added 100 mL of 0.5M ethynylmagnesium bromide in THF. The mixture was stirred at room temperature for 2 hours. Then, the mixture was diluted with diethylether and a saturated solution of ammonium chloride. The mixture was extracted with ethyl acetate. Combined ethyl acetate was washed with brine, dried over sodium sulfate and concentrated. Column chromatography (20% ethyl acetate/hexane) gave 3.17 g of 1-phenyl-prop-2-yn-1-ol (Formula 27) as a light yellow oil. 1H NMR (300 MHz, CDCl3) δ 2.68 (m, 1H), 5.46-5.49 (m, 1H), 7.34-7.43 (m, 3H), 7.55-7.57 (m, 2H).
Reaction SMILES: N1C=CC(C2[CH:11]=[N:10][NH:9]C=2C2C=CC(CCC3C=CC4C(=CC=CC=4)N=3)=CC=2)=CC=1.[CH3:30]NN.[Cl:33][C:34]1[CH:39]=[C:38]([CH2:40][C:41]([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH2:50][C:51]3[CH:60]=[CH:59][C:58]4[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=4)[N:52]=3)=[CH:45][CH:44]=2)=O)[CH:37]=[CH:36][N:35]=1>>[Cl:33][C:34]1[CH:39]=[C:38]([C:40]2[C:41]([C:43]3[CH:48]=[CH:47][C:46]([O:49][CH2:50][C:51]4[CH:60]=[CH:59][C:58]5[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=5)[N:52]=4)=[CH:45][CH:44]=3)=[N:9][N:10]([CH3:11])[CH:30]=2)[CH:37]=[CH:36][N:35]=1
Reactant: O=C(Cc1ccnc(Cl)c1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: c1ccc2nc(CCc3ccc(-c4[nH]ncc4-c4ccncc4)cc3)ccc2c1
Reactant: CNN
Product: Cn1cc(-c2ccnc(Cl)c2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-{2-[4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenyl]-ethyl}-quinoline but substituting methyl hydrazine and 2-(2-Chloro-pyridin-4-yl)-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.19 (m, 2H), 8.07 (d, J=8.3 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.74 (t, J=8.3 Hz, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.58 (s, 1H), 7.55 (t, J=8.3 Hz, 1H), 7.36 (d, J=8.7 Hz, 2H), 7.20 (s, 1H), 7.03 (m, 3H), 5.40 (s, 2H) 3.95 (s, 3H); MS: (M+H m/z=427.0).