Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.[Li]CCCC.[Cl:12][C:13]1[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:21]([Cl:29])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:30]([C:32]3[N:36]([CH3:37])[C:35]([CH3:38])=[N:34][CH:33]=3)=[O:31])[CH:19]=2)[N:14]=1>C1COCC1>[Cl:12][C:13]1[C:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:21]([Cl:29])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:30]([C:32]3[N:36]([CH3:37])[C:35]([CH3:38])=[N:34][CH:33]=3)([C:6]3[N:2]([CH3:1])[N:3]=[N:4][CH:5]=3)[OH:31])[CH:19]=2)[N:14]=1
Reactant: Cn1ccnn1
Reactant: Cc1ncc(C(=O)c2ccc3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)n1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ncc(C(O)(c2ccc3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)c2cnnn2C)n1C
Temperature: -45 °C
Reaction time: 0.5 h

Procedure:
To a flask containing 1-methyl-1H-1,2,3-triazole (125 mg, 1.5 mmol) was added THF (10 mL) and the colorless solution was cooled to −45° C. Then, n-BuLi (2.5 M in hexanes, 0.6 mL, 1.5 mmol) was added affording a suspension. The suspension was stirred between −40° C. and −10° C. for 30 minutes, then a THF solution of (2,4-dichloro-3-phenylquinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanone (500 mg, 1.26 mmol, Intermediate 18: step b, in 5 mL THF) was introduced and the mixture was allowed to warm up to room temperature. After 1 hour, the reaction mixture was heated to 40° C. for 3 hours and then quenched with aqueous NH4Cl solution. The aqueous portion was extracted with EtOAc (3×50 mL) and then with DCM (3×50 mL). The individual organic portions were washed with brine, dried over MgSO4, filtered, combined and concentrated to dryness. Chromatography on silica gel (5% MeOH-DCM increasing to 10% MeOH) provided material which was re-purified by preparative TLC (5% 2 M-NH3-MeOH-EtOAc) to provide the title compound as light tan solid. 1H NMR (500 MHz, CDCl3) δ 8.45-8.36 (m, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.66-7.46 (m, 4H), 7.46-7.30 (m, 2H), 7.01 (s, 1H), 5.94 (s, 1H), 3.91 (s, 3H), 3.34 (s, 3H), 2.17 (s, 3H). MS (ESI): mass calcd. for C24H20Cl2N6O, 478.1, m/z found 479.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:35])[CH2:10][C@@H:11]([N:24]1[CH:28]=[CH:27][C:26](C2C=CN=CC=2)=[CH:25]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C[C@@H](N1[CH:63]=[CH:62][C:61]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)=C1)C(N[C@H](C(=O)NC)C(C)(C)C)=O)C1C=CC=CC=1.COC1C(C2C=CC(CCC)=CC=2)CC(OC)O1.Cl[Si](C)(C)C>ClCCCl>[CH2:1]([O:8][C:9](=[O:35])[CH2:10][C@@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:67]2[CH:68]=[CH:69][C:64]([CH2:61][CH2:62][CH3:63])=[CH:65][CH:66]=2)=[CH:25]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:17])[CH3:18])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccccc2)c1)C(C)(C)C
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccncc2)c1)C(C)(C)C
Agent: CCCc1ccc(C2CC(OC)OC2OC)cc1
Agent: C[Si](C)(C)Cl
Solvent: ClCCCl
Product: CCCc1ccc(-c2ccn([C@H](CC(=O)OCc3ccccc3)C(=O)N[C@H](C(=O)NC)C(C)(C)C)c2)cc1
Yield: 7 %

Procedure:
As described in Example 1(d) for the preparation of N-(2,2-dimethyl-1(S)-methylcarbamoylpropyl)-3(R)-(3-pyridin-4-yl-1H-pyrrol-1-yl)succinamic acid benzyl ester, 3(R)-amino-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic acid benzyl ester trifluoroacetate salt (prepared as described in Example 1(b); 522 mg, 1.16 mmol) was condensed with crude 2,5-dimethoxy-3-(4-propylphenyl)-tetrahydrofuran (1.29 mmol) in 1,2-dichloroethane with chlorotrimethylsilane at 90° C. over 3 days. The crude dark oil was purified via flash column chromatography with 1% HOAc/10% MeOH/CH2Cl2 as eluant to provide 40 mg(7%) of N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]-3(R)-[3-(4-propylphenyl)-1H-pyrrol-1-yl]succinamic acid benzyl ester as a solid, mp 63-5° C.: 1H NMR (CDCl3): ∂ 7.40 (d, 2H, J=8.1 Hz), 7.34-7.20 (m, 5H), 7.14 (d, 2H, J=8.1 Hz), 7.00 (t, 1H, J=1.9Hz), 6.78 (t, 1H, J=2.5 Hz), 6.56 (t, 1H, J=1.9 Hz), 6.24 (d, 1H, J=8.7 Hz), 5.70 (d, 1H, J=4.7 Hz), 5.16-4.96 (m, 3H), 4.00 (d, 1H, J=9.0 Hz), 3.38 (dd, 1H, J=5.6, 16.8 Hz), 3.10 (dd, 1H, J=8.7, 16.8 Hz), 2.76 (d, 3H, J=5.0 Hz), 2.59 (d, 1H, J=7.2 Hz), 2.56 (d, 1H, J=7.8 Hz), 1.65 (q, 2H, J=7.5 Hz), 0.96 (t, 3H, J=7.5 Hz), 0.86 (s, 9H). IR (KBr): 3314, 2959, 1736, 1648, 1560, 1165, 697 cm−1. HRFABMS: Calculated for C31H39N3O4Cs (M+Cs+): 650.1995. Found: 650.1977. Anal: Calculated for C31H39N3O4.0.3 C6H14: C, 72.33; H, 7.62; N, 7.71. Found: C, 72.36; H, 7.77; N, 7.38.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[CH:6]=[C:7]([CH:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])[S:8][C:4]=2[CH:3]=1.CS(O[CH2:23][C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=O)=O>C1COCC1.CN(C=O)C.CCOCC>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[CH:6]=[C:7]([CH:9]([CH:13]([CH3:14])[CH3:15])[C:10]([O:12][CH2:23][C:24]3[NH:25][CH:26]=[CH:27][C:28]=3[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:11])[S:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)OCc1[nH]ccc1Cc1ccccc1
Reactant: CC(C)C(C(=O)O)c1cc2ccc(Cl)cc2s1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)C(C(=O)OCc1[nH]ccc1Cc1ccccc1)c1cc2ccc(Cl)cc2s1
Reaction time: 48 h

Procedure:
2-(6-Chloro-2-benzothienyl)-3-methylbutanoic acid (3.40 mmol) is stirred together with 0.34 g (3.40 mmol) KHCO3 in 10 ml THF/DMF (1:1) for 15 minutes. Then 3.40 mmol of 3-benzylpyrrolylmethyl methanesulfonate in 5 ml THF/DMF (1:1) is added and the mixture stirred for approximately 48 hours. The reaction is diluted with ether, washed with water (3×) and sat. NaCl, dried and solvent is removed to yield 3-benzylpyrrolylmethyl 2-(6-chloro-2-benzothienyl)-3-methylbutanoate.
Reaction SMILES: [I-].C[C:3]1[N:4](CC=C)[C:5]2[C:12]([F:13])=[C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[F:22])[C:10]([C:23]([O:25][CH3:26])=[O:24])=[CH:9][C:6]=2[N+:7]=1[CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCCC1.O>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:12]1[C:5]2[N:4]=[CH:3][N:7]([CH3:8])[C:6]=2[CH:9]=[C:10]([C:23]([O:25][CH3:26])=[O:24])[C:11]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22]
Reactant: C=CCn1c(C)[n+](C)c2cc(C(=O)OC)c(Nc3ccc(I)cc3F)c(F)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCNC1
Solvent: ClCCl
Product: COC(=O)c1cc2c(ncn2C)c(F)c1Nc1ccc(I)cc1F
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 3-allyl-4-fluoro-5-(2-fluoro-4-iodophenylamino)-6-methoxycarbony-1-methyl-3H-benzoimidazol-1-ium iodide, triphenyl phosphine (0.62 g, 2.5 mmoles), palladium tetrakis (0.47 g, 0.48 mmoles) in dichloromethane (15 ml) is cooled at −10° C. Pyrrolidine (0.65 ml) is added dropwise and the reaction mixture is stirred for 2 hours. Water is added and the mixture is extracted with dichloromethane. The organic phases are combined, washed with brine, dried Na2SO4 and concentrated under reduced pressure. The resulting solid is triturated with a mixture of Hexane/Ether (9/1) and isolated by filtration.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O>>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:9]1[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]1)[NH:20][C:19]2=[O:29]
Reactant: COc1ccccc1B(O)O
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Product: COc1ccccc1-c1ccc2nc(-n3cc(C(=O)O)cn3)[nH]c(=O)c2c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 2-methoxyphenylboronic acid in step C. MS (ESI): mass calcd. for C19H14N4O4, 362.1; m/z found, 363.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.00 (br s, 1H), 12.84 (br s, 1H), 8.98 (s, 1H), 8.28 (s, 1H), 8.21 (d, J=1.7 Hz, 1H), 7.97 (dd, J=8.4, 2.1 Hz, 1H), 7.74 (d, J=7.0 Hz, 1H), 7.43-7.39 (m, 2H), 7.19-7.16 (m, 1H), 7.09 (td, J=7.5, 1.0 Hz, 1H), 3.81 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]([CH2:10][CH3:11])([C:7](Cl)=[O:8])[C:4](Cl)=[O:5])[CH3:2].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([NH2:21])[CH:15]=1.C(N(CC)CC)C>ClCCl.O>[CH2:1]([C:3]1([CH2:10][CH3:11])[C:7](=[O:8])[NH:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][C:16]=2[NH:21][C:4]1=[O:5])[CH3:2]
Reactant: CCC(CC)(C(=O)Cl)C(=O)Cl
Reactant: COc1ccc(N)c(N)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1(CC)C(=O)Nc2ccc(OC)cc2NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
Diethylmalonyl dichloride (0.95 ml, 5.5 mmol) was added to a dichloromethane solution (20 ml) of 4-methoxy-o-phenylenediamine (691 mg, 5 mmol) and triethylamine (1.7 ml, 12.5 mmol) at 0° C., and stirred at room temperature overnight. Water was added to the reaction mixture, and extraction with dichloromethane was performed. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1→1:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 452.3 mg (yield: 34%) of 3,3-diethyl-7-methoxy-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione as a yellow oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]1[C:39]([O:40][CH3:41])=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=O)[CH3:30]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([N:24]([CH2:34][C:33]3[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:32]=3[O:31][CH2:29][CH3:30])[CH2:34][C:33]3[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:32]=3[O:31][CH2:29][CH3:30])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1c(C=O)cccc1OC
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: CCOc1c(CN(Cc2cccc(OC)c2OCC)c2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cccc1OC

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2-ethoxy-3-methoxy-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 707.
Reaction SMILES: C1(OC([N:10]2[CH2:16][C:15]3[CH:17]=[C:18]([F:22])[C:19]([F:21])=[CH:20][C:14]=3[NH:13][C:12](=[O:23])[CH2:11]2)=O)C=CC=CC=1>CO.[Pd]>[F:22][C:18]1[C:19]([F:21])=[CH:20][C:14]2[NH:13][C:12](=[O:23])[CH2:11][NH:10][CH2:16][C:15]=2[CH:17]=1
Reactant: O=C1CN(C(=O)Oc2ccccc2)Cc2cc(F)c(F)cc2N1
Agent: [Pd]
Solvent: CO
Product: O=C1CNCc2cc(F)c(F)cc2N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (7,8-difluoro-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid phenyl ester) (2.64 g, 6.15 mmol) in MeOH (30 mL), was added 10% Pd/C (200 mg, 20% w/w) under argon; The reaction was stirred at r.t. for 5 h under hydrogen atmosphere. After completion of the reaction as confirmed by TLC, the reaction mixture was filtered through celite bed and washings were given with EtOAc and MeOH. The solvents were removed in vacuo to afford the crude compound which was purified by column chromatography (silica gel: 1:9 MeOH:CHCl3) to afford pure 7,8-difluoro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one as off white solid (0.98 g, 80%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([N:8]2[CH2:13][CH2:12][O:11][C:10]([CH3:15])([CH3:14])[CH2:9]2)=[N:6][CH:7]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([F:29])=[CH:25][C:26]=2[F:28])[N:21]=[C:20]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[C:19]=1[CH3:36].Cl.O1CCOCC1>CN1C(=O)CCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH:16][C:18]2[C:27]3[C:22](=[CH:23][C:24]([F:29])=[CH:25][C:26]=3[F:28])[N:21]=[C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[C:19]=2[CH3:36])[C:5]([N:8]2[CH2:13][CH2:12][O:11][C:10]([CH3:14])([CH3:15])[CH2:9]2)=[N:6][CH:7]=1
Reactant: CC1(C)CN(c2ncc(Br)cc2N)CCO1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(Br)cnc1N1CCOC(C)(C)C1
Reaction time: 2 h

Procedure:
5-Bromo-2-(2,2-dimethylmorpholino)pyridin-3-amine (0.087 g, 0.31 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.071 g, 0.25 mmol), and hydrochloric acid, 4.0M in 1,4-dioxane (0.07 mL, 0.28 mmol) were stirred in NMP (0.5 mL) then microwaved at 150° C. After 2 h, the reaction was diluted with EtOAc and washed once with satd aq. sodium bicarbonate and once with brine. After drying over anhydrous sodium sulfate, filtration, and concentration, the brown residue was purified with silica gel chromatography (0-40% EtOAc in hexanes) to yield mostly N-(5-bromo-2-(2,2-dimethylmorpholino)pyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. Mass Spectrum (ESI) m/e=540.1 (M+1).
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[CH2:14][O:13][C:12]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([C:34]([NH:36][CH2:37][C:38]4[CH:43]=[CH:42][C:41]([F:44])=[C:40]([F:45])[CH:39]=4)=[O:35])=[C:20]([CH:31]([CH3:33])[CH3:32])[N:21]3[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:17][CH:16]=2)=[N:11]1)C1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl>[F:45][C:40]1[CH:39]=[C:38]([CH:43]=[CH:42][C:41]=1[F:44])[CH2:37][NH:36][C:34]([C:19]1[C:18]2[C:22](=[CH:23][C:15]([C:12]3[O:13][CH2:14][C@H:10]([CH2:9][OH:8])[N:11]=3)=[CH:16][CH:17]=2)[N:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[C:20]=1[CH:31]([CH3:33])[CH3:32])=[O:35]
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C3=N[C@@H](COCc4ccccc4)CO3)cc2n1Cc1ccccn1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C3=N[C@@H](CO)CO3)cc2n1Cc1ccccn1

Procedure:
Following General Procedure H, (S)-6-(4-(benzyloxymethyl)-4,5-dihydrooxazol-2-yl)-N-(3,4-difluorobenzyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide was prepared (10 mg, 0.015 mmol), was then reacted with BBr3 (1M in CH2Cl2, 0.05 ml, 0.05 mmol) in CH2Cl2 (2 ml) at −78° C. for 1 h, quenched with water, diluted with EtOAc, washed organic with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (5:95 MeOH—CH2Cl2) to yield the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8].I[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.CCCCCC>CN(C)P(N(C)C)(N(C)C)=O.[Cu]I>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:5]([O:4][CH3:3])[CH:6]=2)=[CH:14][CH:15]=1
Reactant: COc1cccc(N)c1
Reactant: Cc1ccc(I)cc1
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cccc(Nc2ccc(C)cc2)c1
Temperature: 55 °C

Procedure:
To a suspension of 0.11 g (4.6 mmol, hexane washed 3 x, 50-60% in oil) sodium hydride in 1.0 mL of hexamethylphosphoramide was cannulated a solution of 0.11 g (0.89 mmol) of 3-methoxyaniline in 2.0 mL hexamethylphosphoramide. The resulting mixture was heated at 55° C. for 20 min. To this was added 0.18 g (0.93 mmol) of copper(I) iodide and the mixture was heated at 55° C. for 1.5 hours. 4-iodotoluene was added and the reaction heated at 85° C. for 3 hours. The reaction mixture was allowed to cool to room temperature, hexane was added and the reaction was then loaded onto a silica gel column. The mixture was purified by flash chromatography (100% hexane, 5% ethyl acetate in hexanes) to give the title compound as an orange oil. PNMR (300 MHz, CDCl3) d 2.30 (3 H, s), 3.76 (3 H, s), 5.65 (1 H, s), 6.43 (1 H, m), 6.57 (1 H, d, J=1.6 Hz), 6.58 (1 H, m), 7.01 (2 H, d, J=8.5 Hz), 7.09 (2 H, d, J=8.5 Hz), 7.15 (1 H, d, J=8.6 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[C:11]([OH:13])=[O:12].[C:14]([O-])(O)=O.[Na+]>CO.S(=O)(=O)(O)O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=C([O-])O
Reactant: O=C(O)c1c(Br)ccc2c1OCO2
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(Br)ccc2c1OCO2
Yield: 55 %

Procedure:
5-Bromo-1,3-benzodioxole-4-carboxylic acid (0.34 g, 1.39 mmol) was dissolved in methanol (25 mL). A few drops of concentrated sulfuric acid were added and the solution was heated to reflux for 60 h at which time TLC analysis indicated the reaction complete. The reaction was cooled and poured into a solution of 5% NaHCO3 (25 mL) and extracted with ethyl acetate. The organic layers were dried with magnesium sulfate and concentrated by rotary evaporation to afford 0.20 g of product (0.77 mmol, 55% yield) as an off-white solid. 1H NMR (CDCl3) δ 7.11 (d, J=8.3 Hz, 1H), 6.78 (d, J=8.3 Hz, 1H), 6.09 (s, 2H), 3.95 (s, 3H).
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]([CH2:10]Br)[C:6]([NH2:9])=[N:7][CH:8]=1.[CH2:12]([O:14][C:15](=[O:27])[CH2:16][NH:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH3:13].C(N(CC)CC)C>CN(C=O)C.O>[CH2:12]([O:14][C:15](=[O:27])[CH2:16][N:17]([CH2:10][C:5]1[C:6]([NH2:9])=[N:7][CH:8]=[C:3]([Br:2])[CH:4]=1)[CH2:18][CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)[CH3:13]
Reactant: Nc1ncc(Br)cc1CBr
Reactant: CCOC(=O)CNCCCN1CCOCC1
Agent: Br
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(CCCN1CCOCC1)Cc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution of 5-bromo-3-bromomethyl-pyridin-2-ylamine hydrobromide (11.2 g, 32.3 mmol) and (3-morpholin-4-yl-propylamino)acetic acid ethyl ester (7.44 g, 32.3 mmol) in DMF (200 mL) was treated with triethylamine (9.5 mL, 68 mmol). After stirring at room temperature overnight, the mixture was diluted with H2O (400 mL) and then extracted with EtOAc (5×250 mL). The combined organic layers were washed with H2O (2×200 mL) and brine (200 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo to give the title compound (11.8 g, 87%) as a yellow oil: MS (ESI) m/e 415 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(CC)CC)C.Cl.[N:17]1([CH2:23][CH2:24][C:25]2[N:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]3=[C:27]([C:34](Cl)=[O:35])[N:26]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:34]([C:27]2[N:26]=[C:25]([CH2:24][CH2:23][N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[N:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=23)=[O:35])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(F)c1
Reactant: O=C(Cl)c1nc(CCN2CCOCC2)n2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc(F)c1)c1nc(CCN2CCOCC2)n2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.1 %

Procedure:
To a solution of 3-fluoroaniline (0.052 mL, 0.54 mmol) and triethylamine (0.16 mL, 1.14 mmol) in CH2Cl2 (10 mL) was added 3-(2-morpholin-4-yl-ethyl)-imidazo[1,5-a]pyridine-1-carbonyl chloride hydrochloride (150 mg, 0.45 mmol). The mixture was stirred at ambient temperature for 1 h then washed with sat. aq. NaHCO3 (20 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (30 mg, 18%). 1H NMR (DMSO-d6) δ 10.02 (1H), 8.45 (1H), 8.15 (1H), 7.88 (1H), 7.70 (1H), 7.43 (1H), 7.20 (1H), 6.95 (1H), 6.85 (1H), 3.58 (4H), 3.25 (2H), 2.80 (2H), 2.44 (4H); m/z (M+H)=369.22.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.CC(C)([O-])C.[K+].[O:16]1[CH2:21][CH2:20][CH2:19][O:18][CH:17]1[C:22]1[CH:23]=[CH:24][C:25]([C:28]2[S:36][C:35]3[C:30](=[N:31][CH:32]=[CH:33][C:34]=3Cl)[CH:29]=2)=[N:26][CH:27]=1.O>CS(C)=O>[O:16]1[CH2:21][CH2:20][CH2:19][O:18][CH:17]1[C:22]1[CH:23]=[CH:24][C:25]([C:28]2[S:36][C:35]3[C:30](=[N:31][CH:32]=[CH:33][C:34]=3[O:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=3[F:9])[CH:29]=2)=[N:26][CH:27]=1
Reactant: Clc1ccnc2cc(-c3ccc(C4OCCCO4)cn3)sc12
Reactant: Nc1ccc(O)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
To a solution of aminophenol 4 (8.40 g, 66.1 mmol) in DMSO (75 ml) in a 250 mL round-bottom flask was added potassium tert-butoxide (8.77 g, 78 mmol). After 30 min, chloride 29 (20 g, 60.1 mmol) was added and the mixture was heated at 100° C. for 1.5 h. After cooling to r.t., the mixture was poured into water (300 mL) at 40° C. and the formed suspension was stirred for 30 min. The solid was collected by filtration, washed with water (2×30 mL) and dried under vacuum for 2 h. It was then triturated with Et2O (60 mL) for 2 h and collected by filtration to give a brown solid of 31 (23.8 g, 56.2 mmol, 94% yield). MS (m/z): 424.1 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[Cl:23]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:20]3[CH:19]=[CH:18][C:17]([Cl:16])=[C:22]([Cl:23])[CH:21]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccc(Cl)c(Cl)c1

Procedure:
The title compound, MS: m/e=363.7 (M+H+), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3,4-dichlorobenzene boronic acid.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:10]1[N:15]=[CH:14][N:13]=[C:12](O)[C:11]=1[F:17])[CH3:9].[ClH:18]>ClCCl.P(Cl)(Cl)(Cl)=O>[Cl:18][C:12]1[C:11]([F:17])=[C:10]([CH2:8][CH3:9])[N:15]=[CH:14][N:13]=1
Reactant: Cl
Reactant: CCc1ncnc(O)c1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1ncnc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
78.24 ml of triethylamine was added to a solution prepared by dissolving 80 g of 6-ethyl-5-fluoro-4-hydroxypyrimidine in 240 ml of dichloromethane, and 57.4 ml of phosphorus oxychloride was slowly added thereto over 30 min. The resulting solution was refluxed for 5 hours to complete the reaction, and cooled to room temperature. Then, 352 ml of 3N HCl was added thereto while maintaining the temperature at below 20° C. The resulting aqueous mixture was extracted with 100 ml of dichloromethane. The organic layer was washed with 100 ml of water, was dried over magnesium sulfate, and concentrated under a reduced pressure to obtain the title compound as an oil (85.9 g, yield: 95%).
Reaction SMILES: C[O:2][C:3](=[O:39])[C@:4]([CH3:38])([CH2:19][CH:20]1[CH2:26][N:25]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23]2[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=2[N:21]1[CH3:37])[NH:5][C:6]([O:8][CH:9]1[CH:16]2[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:18][CH:10]1[CH2:11]3)[CH2:15]2)=[O:7].[OH-].[Li+]>O1CCOCC1.O>[CH:10]12[CH2:18][CH:14]3[CH2:13][CH:12]([CH2:17][CH:16]([CH2:15]3)[CH:9]1[O:8][C:6]([NH:5][C@:4]([CH3:38])([C:3]([OH:39])=[O:2])[CH2:19][CH:20]1[CH2:26][N:25]=[C:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:23]3[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=3[N:21]1[CH3:37])=[O:7])[CH2:11]2
Reactant: COC(=O)[C@](C)(CC1CN=C(c2ccccc2)c2ccccc2N1C)NC(=O)OC1C2CC3CC(C2)CC1C3
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CN1c2ccccc2C(c2ccccc2)=NCC1C[C@](C)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O

Procedure:
To a stirred solution of N-[(2-adamantyloxy)carbonyl]-β-(2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-yl )-α-methyl-alanine methyl ester (diastereomeric mixture, 5.3 g, 10 mmol) in a mixture of 150 mL dioxane and 75 mL water was added lithium hydroxide (0.72 g, 30 mmol).