Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[H-].[Na+].F[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1>CN(C=O)C.O>[N:1]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)c1ccc(F)cc1
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2cnc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
To a solution of (2.3 g, 19.46 mmol) 1H-benzimidazole in DMF (80 mL) at 0° C. was added sodium hydride (0.78 g, 19.46 mol, 60 wt. %) and the reaction mixture was stirred at 0° C. for 30 minutes, then at room temperature for 1 hour. Methyl 4-fluorobenzoate (3.0 g, 19.46 mmol) was then added and the reaction mixture was heated at 85° C. for 24 h. The reaction mixture was cooled to room temperature, diluted with water (300 mL) and extracted with dichloromethane (4×250 mL). The combined organic layers were washed with water (2×250 mL), saturated aqueous sodium chloride (200 mL), dried (magnesium sulfate) and the solvent removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 2:10) provided 3.7 g (76%) of methyl 4-(1H-benzimidazol-1-yl)benzoate as a white solid. To a solution of methyl 4-(1H-benzimidazol-1-yl)benzoate (3.7 g, 14.7 mmol) dissolved in THF/MeOH (1:1, 90 mL) was added 1.0 M aqueous NaOH (0.587 g, 14.67 mmol) and the reaction mixture was allowed to stir for 12 h at room temperature and the solvent removed in vacuo. The residue was diluted with water (100 mL), cooled to 0° C., and the pH was adjusted to 6.0 with 1.0 N aqueous HCl. The resulting precipitate was filtered and dried to afford 3.4 g (96%) of 4-(1H-benzimidazol-1-yl)benzoic acid as a white solid. MS [239.0 m/e (M+H)].
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[CH:34]=[CH:33][O:32][CH:31]=1)(=[O:29])=[O:28].C([O-])=O.[NH4+]>>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[CH:34]=[CH:33][O:32][CH:31]=1)(=[O:28])=[O:29]
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1ccoc1
Agent: O=C[O-]
Agent: [NH4+]
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccncn2)c1Cl)c1ccoc1

Procedure:
Following a procedure analogous to the procedure described in Example 26 using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide (114 mg, 0.212 mmol) and ammonium formate (134 mg, 2.11 mmol), the title compound was obtained as a white solid (33 mg, 29% yield). MS (ESI): 503 [M+H]+.
Reaction SMILES: [NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.Br[C:39]1[CH:44]=[CH:43][N:42]=[C:41]([O:45][CH3:46])[CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1)=[O:22])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:39]2[CH:44]=[CH:43][N:42]=[C:41]([O:45][CH3:46])[CH:40]=2)=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(N)=O)CCOCC1
Reactant: COc1cc(Br)ccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(-c2ccc(C[C@H](NC(=O)C3(NC(=O)OC(C)(C)C)CCOCC3)C(N)=O)cc2)ccn1
Temperature: 85 °C
Yield: 88.8 %

Procedure:
(S)-tert-Butyl 4-(1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 16, step (i), 250 mg) and 4-bromo-2-methoxypyridine (91 mg) in acetonitrile (8 mL) were treated with aqueous sodium carbonate solution (2M, 0.5 mL) and nitrogen was bubbled through the mixture. 1,1 bis(Di-tert-butylphosphino)ferrocene palladium dichloride (5 mg) was added and the mixture was heated at 85° C. for 18 h. The mixture was evaporated onto silica and purified by chromatography on silica eluting with ethyl acetate to afford the sub-titled compound (214 mg).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[C:27]([O:34][CH3:35])[CH:26]=1>>[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][CH2:2][C@H:3]2[N:8]([C:9]([C:11]3[N:12]=[C:13]([CH3:23])[S:14][C:15]=3[C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)=[O:10])[CH2:7][C@H:6]3[C@@H:4]2[CH2:5]3)=[O:30])=[C:27]([O:34][CH3:35])[CH:26]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: COc1cc(Cl)ccc1C(=O)O
Product: COc1cc(Cl)ccc1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(C)sc1-c1cccc(C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 4-Chloro-2-methoxy-benzoic acid. LC-MS (basic): tR=0.96 min; [M+H]+=496.0.
Reaction SMILES: [F:1][CH2:2][C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[CH:8]=1)([CH3:6])[CH2:4][F:5].[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[N:30]=[CH:29][N:28]=[C:27]2[O:36][C:37]1[CH:38]=[C:39]([CH:41]=[CH:42][CH:43]=1)[NH2:40]>CN(C)C1C=CN=CC=1.C1COCC1>[F:5][CH2:4][C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13]([NH:40][C:39]2[CH:41]=[CH:42][CH:43]=[C:37]([O:36][C:27]3[C:26]4[C:31](=[CH:32][C:33]([O:34][CH3:35])=[C:24]([O:23][CH3:22])[CH:25]=4)[N:30]=[CH:29][N:28]=3)[CH:38]=2)=[O:21])[CH:8]=1)([CH3:6])[CH2:2][F:1]
Reactant: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)no1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(CF)CF)on4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
A mixture of phenyl 5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate from the previous step (0.089 g, 0.3 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (0.089 g, 0.3 mmol), and 4-(dimethylamino)pyridine (0.03 g) in THF (6 mL) was stirred at room temperature overnight. The reaction was quenched with water and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluting with 70-95% EtOAc/hexane) to afford 1-[5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl]-3-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]urea as solid (0.055 g, 31%). 1H NMR (300 MHz, DMSO-d6) δ 9.70 (s, 1H), 9.02 (s, 1H), 8.57 (s, 1H), 7.57 (m, 2H), 7.40 (m, 2H), 7.27 (d, 1H), 6.98 (d, 1H), 6.77 (s, 1H), 4.71 (s, 2H), 4.56 (s, 2H), 4.00 (s, 3H), 3.98 (s, 3H), 1.28 (s, 3H); LC-MS (ESI) m/z 500 (M+H)+.
Reaction SMILES: [CH2:1]([SnH:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].C([N-]C(C)C)(C)C.[Li+].Cl[C:23]1[N:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:25][N:24]=1>C1COCC1>[CH2:29]([C:26]1[CH:25]=[N:24][C:23]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:10][CH2:11][CH2:12][CH3:13])=[N:28][CH:27]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: CCCCCCCCCc1cnc(Cl)nc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCc1cnc([Sn](CCCC)(CCCC)CCCC)nc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Tri-n-butylstannane (ALDRICH, 0.40 ml) was added dropwise, with vigorous stirring, to a solution of lithium diisopropylamide (ALDRICH, 0.75 ml) in dry THF (3 ml) at 0° C. After stirring for 20 minutes a solution of 2-chloro-5-nonylpyrimidine (ALFA, 0.200 g) in THF (3 ml) was added dropwise at −78° C., under argon atmosphere. After 1 hour at −78° C. the cooling bath was removed and the reaction mixture warmed up to 0° C. The mixture was stirring for 3 hours at 0° C., then quenched with saturated NH4Cl (10 ml), diluted, extracted with ethyl acetate (3×10 ml), dried over MgSO4, concentrated under vacuum and purified by column chromatography on silica gel, eluting with hexane to afford 0.5 g of the title compound as a yellow oil. Although the material obtained contained a small amount of 5-nonyl-pyrimidine, it was used for the next step without further purification.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31]>>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30]([NH:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([NH:10][C@H:1]1[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]1)[CH:20]=[CH:19]2)=[O:31]
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: O=C=Nc1ccccc1F
Product: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)Nc1ccccc1F

Procedure:
The title compound, MS: m/e=413.7 (M+H+), was prepared in accordance with the general method 4 of example 16 from (R)—N2-indan-1-yl-quinoline-2,6-diamine and 2-fluorophenyl-isocyanate.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].[C:8]1(C)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClC1C=CC=CC=1>[CH3:11][C:10]1[CH:9]=[CH:8][CH:13]=[CH:12][C:2]=1[C:3]([OH:5])=[O:4]
Reactant: Cc1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: Clc1ccccc1
Product: Cc1ccccc1C(=O)O
Reaction time: 0.25 h

Procedure:
Trifluoroacetic acid (5 mL) was added to RhCl3.nH2O (10 mg). To this suspension (the Rh complex was insoluble), K2S2O8 (1.40 g) was added, and the mixture was stirred in air for 15 minutes. After toluene (5 mL) was added, the mixture was stirred under CO for 24 hours, and then analyzed by GC-MS, in a usual manner (see above), with chlorobenzene as an internal standard. No toluic acid formed. When the rhodium chloride-catalyzed reaction was run for 61 hours under similar conditions, about 185 mg of p-toluic acid formed (TON=38).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:11]=[C:12]([C:16]4[CH:20]=[C:19]([C:21](O)=[O:22])[O:18][N:17]=4)[CH:13]=[CH:14][CH:15]=3)[S:8][C:4]=2[CH:3]=1.Cl.[CH3:27][O:28][C:29]([C@@H:31]1[CH2:35][CH2:34][CH2:33][NH:32]1)=[O:30]>>[CH3:27][O:28][C:29]([C@@H:31]1[CH2:35][CH2:34][CH2:33][N:32]1[C:21]([C:19]1[O:18][N:17]=[C:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([F:1])[CH:25]=[CH:24][C:5]=4[N:6]=3)[CH:11]=2)[CH:20]=1)=[O:22])=[O:30]
Reactant: O=C(O)c1cc(-c2cccc(Nc3nc4ccc(F)cc4s3)c2)no1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Product: COC(=O)[C@@H]1CCCN1C(=O)c1cc(-c2cccc(Nc3nc4ccc(F)cc4s3)c2)no1
Yield: 41 %

Procedure:
The title compound was prepared according to the procedure as set forth in Example 5, except that 3-[3-(6-fluoro-benzothiazol-2-ylamino)-phenyl]-isoxazole-5-carboxylic acid was used instead of the compound of Example 2 and (S)-pyrrolidine-2-carboxylic acid methyl ester hydrochloride was used in place of (S)-Val-OMe.HCl to yield 41% of the title compound. Mass (ES+): 467 (M++1), 489 (M++Na); IR (KBr): 3295, 3110, 2951, 1742, 1626, 1613, 1568 (br), 1454, 1411; 1H NMR (DMSO-d6) δ: 1.70-2.39 (4×m, 4H), 3.65 (s, 3H), 3.64, 3.92 (2×m, 2H), 4.55, 5.10 (2×m, 1H), 7.17 (m, 1H), 7.52-7.64 (m, 3H), 7.65 (s, 1H), 7.75 (dd, 1H), 7.95 (m, 1H), 8.32 (m, 1H), 10.68 (s, 1H).
Reaction SMILES: [N+](=[CH2:3])=[N-].[Cl:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]>CCOCC>[Cl:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH3:3])=[O:8]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1ccccc1Cl
Solvent: CCOCC
Product: COC(=O)c1ccccc1Cl
Temperature: 0 °C
Yield: 72.4 %

Procedure:
An excess solution of diazomethane in ether was added to an ice-cooled and stirred solution of o-chlorobenzoic acid (7.6 g, 48.6 mmol) in 50 ml of ether. After concentration, the residue was distilled under reduced pressure to give a colorless transparent oil of methyl o-chlorobenzoate (6.0 g, 35.2 mmol, yield 72.4%, b.p. 92°-93° C./7 mmHg), which was assigned the structure by the following data:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=O)=[CH:11][CH:10]=2)[CH:6]=[N:7][CH:8]=1)#[N:2].[CH3:21][CH:22](C)[C@H:23]([NH2:25])[CH3:24]>>[C@H:23]([NH:25][C:16](=[O:18])[C:15]([C:12]1[CH:11]=[CH:10][C:9]([C:5]2[CH:6]=[N:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)=[CH:14][CH:13]=1)([CH3:20])[CH3:19])([CH2:22][CH3:21])[CH3:24]
Reactant: CC(C)[C@@H](C)N
Reactant: CC(C)(C(=O)O)c1ccc(-c2cncc(C#N)c2)cc1
Product: CC[C@@H](C)NC(=O)C(C)(C)c1ccc(-c2cncc(C#N)c2)cc1
Yield: 48 %

Procedure:
Prepared in a similar manner to Example 3 from 2-(4-(5-cyanopyridin-3-yl)phenyl)-2-methylpropanoic acid (example 21a) and (R)-3-Methyl-2-butylamine. Yield 48%. 1H NMR (400 MHz, DMSO): δ 0.71-0.73 (d, 3H), 0.74-0.76(d, 3H), 0.91-0.93 (d, 3H), 1.46 (s, 3H), 1.47 (s, 3H), 1.59 (m, 1H), 3.58 (m, 1H), 6.98-7.01 (d, 1H), 7.42-7.44 (d, 2H), 7.77-7.79 (d, 2H), 8.64 (s, 1H), 8.98 (s, 1H), 9.17 (s, 1H). MS (M+H, 336).
Reaction SMILES: Cl[C:2]1[C:3](=[CH:21][N:22]([CH3:24])[CH3:23])[O:4][C:5]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)=[CH:8][C:6]=2[N:7]=1.[C:25]([O:29][C:30](=[O:45])[NH:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH:38]([NH:41][C:42]([NH2:44])=[O:43])[CH2:37][CH2:36]1)([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[C:25]([O:29][C:30](=[O:45])[NH:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:36][CH2:37][CH:38]([NH:41][C:42]([NH:44][C:2]2[C:3](=[CH:21][N:22]([CH3:24])[CH3:23])[O:4][C:5]3[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=4)=[CH:8][C:6]=3[N:7]=2)=[O:43])[CH2:39][CH2:40]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCCCN1CCC(NC(N)=O)CC1
Reactant: CN(C)C=C1Oc2ccc(CCc3cccc(F)c3)cc2N=C1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CN(C)C=C1Oc2ccc(CCc3cccc(F)c3)cc2N=C1NC(=O)NC1CCN(CCCNC(=O)OC(C)(C)C)CC1
Temperature: 23 °C
Yield: 35.5 %

Procedure:
To a solution of {3-chloro-6-[2-(3-fluoro-phenyl)-ethyl]-benzo[1,4]oxazin-2-ylidenemethyl}-dimethyl-amine (500 mg, 1.45 mmol, 1 equiv) and [3-(4-ureido-piperidin-1-yl)-propyl]-carbamic acid tert-butyl ester (435 mg, 1.45 mmol, 1 equiv) in dioxane (15 mL) was added palladium(II) acetate (3.2 mg, 0.0145 mmol, 0.01 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos, 17 mg, 0.029 mmol, 0.02 equiv) and cesium carbonate (709 mg, 2.18 mmol, 1.5 equiv). The reaction mixture was sparged with argon then the reaction vessel sealed (screw cap) and placed in 100° C. oil bath. After 14 h at 100° C. the reaction was cooled to 23° C., and then partitioned between ethyl acetate and water (100 mL each). The organic layer was separated and washed with saturated brine solution (100 mL) then dried (MgSO4), filtered and concentrated. The product was purified using an Isco CombiFlash automated chromatography system. The residue was loaded onto an 80 g silica gel column as a solution in dichloromethane (5 mL) then eluted with 2 M ammonia in methanol in dichloromethane (0-8% 2 M ammonia in methanol linear gradient over 18 column volumes at a flow rate of 60 mL/min) to give 313 mg (0.515 mmol, 36%) of the title compound as a yellow/brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1Br.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:10][O:11][C:12]1[C:13]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Clc1cccc(Cl)c1Br
Reactant: COc1ccccc1B(O)O
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1-c1c(Cl)cccc1Cl
Yield: 77.2 %

Procedure:
Treatment of 2,6-dichlorobromobenzene (25.0 g, 0.110 mol) with 2-methoxybenzeneboronic acid (25.22 g, 0.166 mol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (2.33 g, 2.96 mmol), and potassium carbonate (34.15 g, 0.247 mmol) generally according to the procedure described for Intermediate 37 provided 21.5 g (77%) of 2′,6′-dichloro-1,1′-biphenyl-2-yl methyl ether. Treatment of 2′,6′-dichloro-1,1′-biphenyl-2-yl methyl ether (19.0 g, 75.06 mmol) with boron tribromide (18.78 g, 1.0 M in dichloromethane) generally according to the procedure described for Intermediate 163 provided 17.89 g (99%) of 2′,6′-dichloro-111′-biphenyl-2-ol as a light yellow solid. mp 100-103° C.; Anal. calcd. for C12H8Cl2O: C, 60.28H, 3.37. Found: C, 60.29; H, 3.13.
Reaction SMILES: C1(B([O:14][B:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)C2C=CC=CC=2)C=CC=CC=1.O[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[O:36][C:37]2[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=2[N:39]=1>O1CCCC1>[C:22]1([B:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:14][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[O:36][C:37]3[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=3[N:39]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(B(OB(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Reactant: Oc1ccccc1-c1nc2ccccc2o1
Solvent: C1CCOC1
Product: c1ccc(B(Oc2ccccc2-c2nc3ccccc3o2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of diphenylborinic anhydride (5.0 g; 0.014 mole) in tetrahydrofuran (20 ml) was added to a solution of 2-(2′-hydroxyphenyl)benzoxazole (3.1 g; 0.014 mole) in tetrahydrofuran (10 ml). The reaction mixture was refluxed under nitrogen for 2 h and allowed to cool to room temperature, then kept in the refrigerator for 18 h. The product was filtered off under suction, washed with methanol and dried under vacuum at 80° C. for 6 h. Yield 4.4 g (84%). The product was further purified by sublimation (85%). M.p 195° C. (DSC, onset); Tg 59° C. Elemental analysis:
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[C:5]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][N:11]2[C:21](=[O:22])[CH2:20][NH:19][C:18](=O)[CH:17]=[C:12]23)[N:6]=1.O=P(Cl)(Cl)Cl.[CH:29]1([C:32]2[N:33]=[CH:34][NH:35][CH:36]=2)[CH2:31][CH2:30]1.N1C=CC=CC=1>ClCCCl.O>[CH:29]1([C:32]2[N:33]=[CH:34][N:35]([C:18]3[CH:17]=[C:12]4[C:13]5[C:8]([CH2:9][CH2:10][N:11]4[C:21](=[O:22])[CH2:20][N:19]=3)=[C:7]([C:5]3[N:6]=[C:2]([CH3:1])[O:3][CH:4]=3)[CH:16]=[CH:15][CH:14]=5)[CH:36]=2)[CH2:31][CH2:30]1
Reactant: c1nc(C2CC2)c[nH]1
Reactant: Cc1nc(-c2cccc3c2CCN2C(=O)CNC(=O)C=C32)co1
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(-c2cccc3c2CCN2C(=O)CN=C(n4cnc(C5CC5)c4)C=C32)co1
Temperature: 100 °C
Reaction time: 0.02 h
Yield: 23.4 %

Procedure:
Example 108. A mixture of 9-(2-methyloxazol-4-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (140 mg, 0.45 mmol) in DCE (10 mL) was treated with POCl3 (84 μL, 0.91 mmol) and heated to 100° C. for 1 h. The mixture was then allowed to cool to RT, poured onto cold H2O and extracted with DCM. The org. phases were dried over Na2SO4, filtered and concentrated in vacuo. The brown residue obtained was taken up in DCE (5 mL) and 4-cyclopropyl-1H-imidazole (59 mg, 0.54 mmol) and pyridine (110 μL, 1.36 mmol) were then added. The mixture was heated to 100° C. for 1 h, and then allowed to cool to RT, poured onto H2O and extracted with DCM. The org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. Purification by SFC (column: 2-Ethylpyridine 5 μm, 250×30 mm, 60A, Princeton; eluent: 10% MeOH/CO2 for 1 min, then from 10% MeOH/CO2 to 15% MeOH/CO2 in 6 min; then from 15% MeOH/CO2 to 50% MeOH/CO2 in 1 min; flow 100 mL/min; UV detection at 220 nm) afforded the title compound (42 mg) as beige powder. UPLC-MS: MS 400.2 (M+H+); UPLC rt 0.86 min. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 0.61-0.82 (m, 2 H); 0.82-0.91 (m, 2 H); 1.78-1.96 (m, 1 H); 2.56 (s, 3 H); 3.16 (t, J=6.02 Hz, 2 H); 3.89 (t, J=6.15 Hz, 2 H); 4.37 (br. s., 2 H); 6.62 (s, 1 H); 7.19 (d, J=1.25 Hz, 1 H); 7.38-7.48 (m, 1 H); 7.63-7.70 (m, 2 H); 7.78 (dd, J=7.65, 1.13 Hz, 1 H); 7.89 (d, J=1.26 Hz, 1 H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5]CC)=O.[H-].[Na+].[CH3:14][N:15]1C(=O)O[C:18](=[O:19])[C:17]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:16]12.C(OC(C)C)(C)C>CN(C=O)C>[OH:19][C:18]1[C:17]2[C:16](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:15]([CH3:14])[C:3](=[O:5])[C:2]=1[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(O)c2ccccc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
To a solution of diethyl malonate (68.0 g, 0.425 mol) in DMF (400 mL) was added sodium hydride (66% in oil, 10.8 g, 0.30 mol) under ice-cooling, and the mixture was stirred at the same temperature for 5 min and at room temperature for 15 min. N-Methylisatoic anhydride (50.8 g, 0.287 mol) was added to the obtained mixture by small portions, and the mixture was stirred at 120° C. for 3 hr. Diisopropyl ether (500 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration and washed with diisopropyl ether. The obtained solid was suspended in a mixture of methanol (250 mL) and water (500 mL), 5N hydrochloric acid (60 mL) was added dropwise, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with water, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound (41.4 g, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([C:15](O)=[O:16])=[N:13][CH:14]=1)=[O:8].[Cl:22]C1C=C(C=CC=1Cl)CNC(C1SC(C(O)=O)=CC=1)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([C:15]([Cl:22])=[O:16])=[N:13][CH:14]=1)=[O:8]
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)c1ccc(C(=O)O)nc1
Reactant: O=C(O)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)s1
Product: O=C(NCc1ccc(Cl)c(Cl)c1)c1ccc(C(=O)Cl)nc1

Procedure:
Compound (13(b)) was treated in an analogous manner to compound (12(b)) in Example 12 to give 5(3,4-dichlorobenzylcarbamoyl)pyridine-2-carbonylchloride (13(c)) which was used crude in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH2:4][CH2:5][CH:6]=1.C([O:9][CH:10]=[C:11]([C:17](OCC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])C>C(O)C>[O:9]=[C:10]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:17][N:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[N:1]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: NC1=CCCN1
Solvent: CCO
Product: CCOC(=O)c1cn2c(nc1=O)CCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
42 g of 2-amino-pyrroline are dissolved in 400 ml of ethanol and at 0° to 7° C., a solution of 108 g of diethyl ethoxymethylene-malonate in 200 ml ethanol is added dropwise. After the addition is completed, the mixture is stirred for 1 hour at 0° C. and allowed to stand for 12 hours at -5° C. The precipitated crystals are filtered. After evaporation of the alcohol the residue is boiled with 200 ml of benzene. After cooling the insoluble crystals are filtered off. The filtered crystals are combined and recrystallized from ethanol. 50.3 g (48.4%) ethyl 2-oxo-2,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-3-carboxylate are obtained, melting at 193° C.