Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:20]([NH2:21])=[CH:19][C:18]([C:22]([CH3:25])([CH3:24])[CH3:23])=[N:17]2)=[CH:12][CH:11]=1>O1CCCC1>[NH2:21][C:20]1[N:16]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][OH:8])=[CH:11][CH:12]=2)[N:17]=[C:18]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:19]=1
Reactant: COC(=O)c1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(N)n(-c2ccc(CO)cc2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Lithium aluminium hydride (1M in tetrahydrofuran, 1.83 mL, 1.83 mmol) was added to an ice-cold solution of 4-[5-amino-3-(1,1-dimethylethyl)-1H-pyrazol-yl]-benzoic acid methyl ester [(0.25 g, 0.92 mmol), WO2004060306, p134] in tetrahydrofuran (5 mL), and the mixture was stirred at 0° C. for 1 hour. The reaction was then quenched with water (0.35 mL) and 1M sodium hydroxide solution (0.35 mL) followed by further water (1 mL). The mixture was then extracted with diethyl ether, (10 mL) and the organic solution was dried over sodium sulfate and concentrated in vacuo to afford the title compound as red oil in 98% yield, 220.1 mg.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[H-].[Na+].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C)C=O.C(OCC)C>[Cl:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][N:6]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(OCc2ccccc2)cn1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 12.9 g (0.1 mol) of 5-hydroxy-2-chloropyridine in 50 ml of dimethylformamide is added to a suspension of 4.8 g (0.1 mol) of sodium hydride (a 50% dispersion in mineral oil; washed with toluene) in 100 ml of dimethylformamide. The mixture is stirred until the evolution of hydrogen has ceased and then, after cooling with the aid of an ice-bath, 12.6 g (0.1 mol, 11.5 cc) of benzyl chloride are introduced dropwise. The mixture is heated at 60° C. for one hour, left to stand overnight and then poured into iced water, and extraction is carried out with diethyl ether. The ether phase is washed with water, dried and filtered and the filtrate is evaporated. The product, i.e. 2-chloro-5-benzyloxypyridine, is distilled. Its boiling point (0.1 mm Hg) is 135° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[CH:3]=1.S1(=O)(=O)[N:13]2[CH2:14][CH2:15][CH2:16][C@H:12]2[CH2:11]O1>>[I:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH2:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1
Reactant: O=S1(=O)OC[C@@H]2CCCN21
Reactant: Ic1cccc(I)c1
Product: Ic1cccc(C[C@@H]2CCCN2)c1

Procedure:
(S)-2-(3-Iodo-benzyl)-pyrrolidine was prepared from 1,3-diiodobenzene and (S)-tetrahydro-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide in analogy to the procedure described for Example 4 in U.S. Pat. No. 5,130,432. LC-MS A: tR=0.57 min; [M+H]+=287.99.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]1[CH2:12][CH2:11][CH:10]([C@@H:13]([NH2:17])[C:14](O)=[O:15])[CH2:9][CH2:8]1.O.[OH-].[Na+]>C1COCC1>[NH2:17][C@H:13]([CH:10]1[CH2:11][CH2:12][CH2:7][CH2:8][CH2:9]1)[CH2:14][OH:15]
Reactant: N[C@@H](C(=O)O)C1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H](CO)C1CCCCC1
Temperature: 80 °C
Yield: 43.9 %

Procedure:
To a stirred mixture of LiAlH4 (724 mg, 19.08 mmol) in anhydrous THF (20 mL) at rt was added portionwise 2-cyclohexyl-D-glycine (1 g, 6.36 mmol). The mixture was heated at 80° C. for 4 h. The mixture was cooled to 0° C. and then water (1 mL), 1M aq NaOH (1 mL), and water (3 mL) were added sequentially. The mixture was filtered and the filtrate was partitioned between a mixture of DCM, 1M aq NaOH, and saturated aq sodium potassium tartrate. The organic layer was separated and further washed with 1M aq NaOH. The organic was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to afford (R)-2-amino-2-cyclohexylethanol (400 mg) which was not purified further. LCMS (ESI) m/z 144 (M+H)+.
Reaction SMILES: [N:1]([C:38]([CH2:40][O:41][CH2:42][C:43]([NH:45][CH2:46][C:47]([NH:49][CH2:50][C:51]([NH:53][CH2:54][C:55]([O:57]CC1C=CC=CC=1)=[O:56])=[O:52])=[O:48])=[O:44])=[O:39])([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[H][H]>C(O)C.[Pd]>[N:1]([C:38]([CH2:40][O:41][CH2:42][C:43]([NH:45][CH2:46][C:47]([NH:49][CH2:50][C:51]([NH:53][CH2:54][C:55]([OH:57])=[O:56])=[O:52])=[O:48])=[O:44])=[O:39])([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COCC(=O)NCC(=O)NCC(=O)NCC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COCC(=O)NCC(=O)NCC(=O)NCC(=O)O
Yield: 96.6 %

Procedure:
(C18H37)2NCOCH2OCH2CO-Gly-Gly-Gly-OCH2Ph (1.0 g, 1.1 mmol) was dissolved in absolute ethanol (100 mL), 10% Pd/C (0.2 g) was added, and this mixture was shaken under 70 psi hydrogen pressure for 3 h in a Parr apparatus. The reaction mixture was heated to reflux and filtered through a celite layer and the solvent was evaporated under reduced pressure to leave (C18H37)2NCOCH2OCH2CO-Gly-Gly-Gly-OH as a white solid (0.86 g, 96%), mp 163–164° C. 1H-NMR (300 MHz, δ, CD3OD): 0.90 (6H, t, J=6.9 Hz), 1.29 (64H, m), 1.57 (4H, bs), 3.21 (2H, t, J=7.8 Hz), 3.35 (2H, t, J=7.8 Hz), 3.93 (2H, s), 3.94 (2H, s), 3.97 (2H, s), 4.12 (2H, s), 4.40 (2H, s). IR (KBr, cm−1): 1740 (CO), 1650 (CO).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:32]3[CH2:37][CH2:36][C@@H:35]([N:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)[CH2:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[S:19][C:20]([CH2:30][CH3:31])=[C:21](C5C=CC(C)=CC=5)[N:22]=4)=[CH:13][CH:12]=3)[C:3]=12.[C:45]1([CH3:54])[CH:50]=[CH:49][CH:48]=[C:47](B(O)O)[CH:46]=1>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:32]3[CH2:33][CH2:34][C@@H:35]([N:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)[CH2:36][CH2:37]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[S:19][C:20]([CH2:30][CH3:31])=[C:21]([C:47]5[CH:48]=[CH:49][CH:50]=[C:45]([CH3:54])[CH:46]=5)[N:22]=4)=[CH:13][CH:12]=3)[C:3]=12
Reactant: CCc1sc(Nc2ccc(-c3nn([C@H]4CC[C@@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2)nc1-c1ccc(C)cc1
Reactant: Cc1cccc(B(O)O)c1
Product: CCc1sc(Nc2ccc(-c3nn([C@H]4CC[C@@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2)nc1-c1cccc(C)c1

Procedure:
The procedure described for cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-ethyl-4-(4-methylphenyl)-1,3-thiazol-2-amine was used to convert m-tolylboronic acid (0.175 g, 1.29 mmol) to the title compound. Purification of the product by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 10.0-12.0 min) afforded cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-ethyl-4-(3-methylphenyl)-1,3-thiazol-2-amine as an off-white solid (0.051 g, 0.084 mmol); RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 10.13 min; MS (MH)+ 608.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:15][C:14](=[O:16])[C:13]2=[CH:17][N:18]=[CH:19][N:12]2[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[I:25]I>C1COCC1>[CH2:1]([O:8][CH2:9][C:10]1[NH:15][C:14](=[O:16])[C:13]2=[CH:17][N:18]=[C:19]([I:25])[N:12]2[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(COCc2ccccc2)nn2cncc12
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=c1[nH]c(COCc2ccccc2)nn2c(I)ncc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
To a solution of compound 4 (4.9 g, 19.1 mmol) in THF (120 mL) was added n-BuLi (23 mL) dropwise at −78° C. and the resulting reaction mixture was stirred below −70° C. for one hour, followed by dropwise addition of iodine (19.4 g, 76.3 mmol) in THF (60 mL) at the same temperature. The reaction was allowed to warm to room temperature slowly. The reaction was quenched with saturated aqueous Na2SO3 solution (60 mL), and it was then extracted with EtOAc (60 mL×3). The organic phases were combined and dried over Na2SO4. The solid was filtered and the filtrate was concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel column (eluted with PE/EtOAc=10:1 to 2:1) to afford compound 5 (4.1 g, 56% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.16 (s, 1H), 7.84 (s, 1H), 7.42˜7.29 (m, 5H), 4.62 (s, 2H), 4.40 (s, 2H). LC-MS: m/z 383.2 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][C:10]3([CH2:16][CH2:15][CH:14]([C:17](O)=[O:18])[CH2:13][CH2:12]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.O.ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[Cl:62][C:63]1[C:64]([N:69]2[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]2)=[N:65][CH:66]=[CH:67][CH:68]=1>C1COCC1>[Cl:62][C:63]1[C:64]([N:69]2[CH2:70][CH2:71][N:72]([C:17]([CH:14]3[CH2:13][CH2:12][C:10]4([O:9][N:8]=[C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[CH2:11]4)[CH2:16][CH2:15]3)=[O:18])[CH2:73][CH2:74]2)=[N:65][CH:66]=[CH:67][CH:68]=1
Reactant: Clc1cccnc1N1CCNCC1
Reactant: O=C(O)C1CCC2(CC1)CC(c1ccccc1)=NO2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(C1CCC2(CC1)CC(c1ccccc1)=NO2)N1CCN(c2ncccc2Cl)CC1
Reaction time: 8 h

Procedure:
3-Phenyl-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carboxylic acid (750 mg, 2.9 mmol) was slowly added to a solution of N-ethyldiisopropylamine (1.02 g, 7.1 mmol), 1-hydroxybenzotriazole hydrate (320 mg, 2.4 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (758 mg, 2.4 mmol) and 1-(3-chloropyridin-2-yl)piperazine (467 mg, 2.4 mmol) in abs. THF (17 ml). The reaction mixture was stirred overnight and the solvent removed under vacuum. The residue was taken up in EtOAc (100 ml). The precipitate formed was removed by suction-filtration. The organic phase was washed successively with sat. aq. NaCl solution, sat. aq. NaHCO3 solution, sat. aq. ammonium sulphate solution and sat. aq. NaCl solution, dried over magnesium sulphate and the solvent removed under vacuum. The precipitate and the residue were purified by column chromatography (silica gel, hexane/EtOAc 1:1). The desired product [4-(3-chloropyridin-2-yl)piperazin-1-yl]-(3-phenyl-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)methanone was obtained as a cis isomer (294 mg, 24% of the theoretical amount) and trans isomer (192 mg, 15% of the theoretical amount).
Reaction SMILES: Cl[C:2]1[N:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].[OH-].[NH4+:16]>O1CCCC1>[NH2:16][C:2]1[N:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5]
Reactant: CON(C)C(=O)c1ccc(Cl)nc1Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(Cl)nc1N
Yield: 8 %

Procedure:
2,6-Dichloro-N-methoxy-N-methyl-nicotinamide (202.4 mg, 0.8610 mmol, Example 1) and concentrated ammonium hydroxide (1.8 mL, 29.4%, Fisher) in tetrahydrofuran (2.5 mL) were heated to 155° C. in the microwave for 2 hr. The reaction mixture was concentrated and the residue was purified on silica gel with hexanes/ethyl acetate to give 2-Amino-6-chloro-N-methoxy-N-methyl-nicotinamide (14.3 mg, 8% yield). HRMS, observed: 215.0463, Calcd for M+: 215.0462.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][CH:21]([O:24][CH3:25])[O:22][CH3:23]>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH2:20][CH:21]([O:24][CH3:25])[O:22][CH3:23])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11]
Reactant: COC(CBr)OC
Reactant: CC(=O)c1ccc(O)c(Cl)c1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(COc1ccc(C(C)=O)c(N)c1Cl)OC
Temperature: 65 °C
Yield: 56.6 %

Procedure:
1-(2-Amino-3-chloro-4-hydroxy-phenyl)-ethanone (15.5 g, 83.8 mmol), Cs2CO3 (54.6 g, 167 mmol) and 2-bromo-1,1-dimethoxy-ethane (14.78 mL, 126 mmol) was dissolved in DMF (125 mL) under an atmosphere of nitrogen. The reaction was heated to 65° C. for 6 hours. The reaction was determined to be complete by LC/MS. The reaction was taken up in EtOAc (500 mL) and washed with 5% LiCl(aq) (3×250 mL). Organics were dried over Na2SO4, filtered and solvent removed under reduced pressure. 1-[2-Amino-3-chloro-4-(2,2-dimethoxy-ethoxy)-phenyl]-ethanone (12.99 g, 57%) was isolated by silica gel chromatography as a white solid.
Reaction SMILES: [NH:1]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:2]([C:26](O)=O)[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[Br:51][C:52]1[CH:53]=[C:54]([NH2:59])[C:55]([NH2:58])=[CH:56][CH:57]=1.C(O)(=O)C>O1CCCC1>[Br:51][C:52]1[CH:57]=[CH:56][C:55]2[NH:58][C:26]([C@@H:2]([NH:1][C:29](=[O:30])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:59][C:54]=2[CH:53]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: Nc1ccc(Br)cc1N
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)c1nc2cc(Br)ccc2[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a solution of Boc-Asn(Trt)-OH (1.05 g, 2.21 mmol) in anhydrous tetrahydrofuran (4 mL) cooled in an ice water bath was added 4-methylmorpholine (0.365 mL, 3.32 mmol) and isobutyl chloroformate (0.316 mL, 2.43 mmol). The reaction mixture was stirred for 1 hour at 0° C. and then 4-bromo-1,2-benzenediamine (414 mg, 2.21 mmol) was added. The reaction mixture was allowed to warm to room temperature over 2 hours and then stirred an additional 2 hours. The reaction mixture was concentrated in vacuo and dried. To the resulting residue was added acetic acid (12 mL, 210 mmol) and the mixture stirred at 65° C. for 2 hours. The reaction was concentrated in vacuo and the residue taken up in ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution, and brine. The organic layer was dried over anhydrous magnesium sulphate, filtered, and concentrated in vacuo to give crude product that was purified by silica gel column chromatography eluting with a 0-100% ethyl acetate/methylene chloride gradient. This provided the title compound (1.38 g, 61%) as a light tan solid.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([NH:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C(Cl)Cl>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([NH:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(NC(=O)CCC)ccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2cc(NC(=O)CCC)ccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5-butanoylamino-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][CH:5]1[C:11](=[O:12])[N:10]([CH3:13])[C:9]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:8]=2[C:7](Cl)=[N:6]1.CC1(C)C(C)(C)OB([C:32]2[CH:41]=[CH:40][C:35]3[NH:36][C:37](=[O:39])[NH:38][C:34]=3[CH:33]=2)O1.[Cl-].[Li+].O.[OH-].[Cs+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.O1CCOCC1>[Br:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][CH:5]1[C:11](=[O:12])[N:10]([CH3:13])[C:9]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:8]=2[C:7]([C:32]2[CH:41]=[CH:40][C:35]3[NH:36][C:37](=[O:39])[NH:38][C:34]=3[CH:33]=2)=[N:6]1
Reactant: CC1(C)OB(c2ccc3[nH]c(=O)[nH]c3c2)OC1(C)C
Reactant: CN1C(=O)C(Cc2ccccc2Br)N=C(Cl)c2cc(Cl)ccc21
Agent: [Pd]
Agent: [Cl-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CN1C(=O)C(Cc2ccccc2Br)N=C(c2ccc3[nH]c(=O)[nH]c3c2)c2cc(Cl)ccc21
Temperature: 100 °C
Yield: 18.9 %

Procedure:
(E)-3-(2-Bromobenzyl)-5,7-dichloro-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one (150 mg, 0.364 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one (95 mg, 0.364 mmol) and lithium chloride (46 mg, 1.09 mmol) were added to 1,4-dioxane (3 mL). Nitrogen was bubbled into the solution as reagents were added. Tetrakis(triphenylphosphine) palladium(0) (42 mg, 0.036 mmol) was added followed by cesium hydroxide monohydrate (183 mg, 1.09 mmol) and water (1 mL). After bubbling nitrogen through for 5 minutes, the reaction mixture was heated to 100° C. under a nitrogen atmosphere. After heating for 1 hour, the mixture was cooled to ambient temperature, diluted with ethyl acetate (25 mL), washed with water (2×20 mL), then brine (20 mL), dried with sodium sulfate, decanted then concentrated in the presence of silica. The dried silica-bound residue was dry loaded onto a silica gel column and eluted with a gradient of 60-100% ethyl acetate in hexanes then a gradient of 0-25% methanol in ethyl acetate to yield (Z)-3-(2-bromobenzyl)-7-chloro-1-methyl-5-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1H-benzo[e][1,4]diazepin-2(3H)-one (35 mg, 19%). 1H NMR (300 MHz, DMSO-d6) δ 3.32 (s, 3H) 3.49 (m, 2H), 3.82 (t, 1H), 6.89-7.17 (m, 3H), 7.28-7.71 (m, 7H), 10.70 (s, 1H), 10.87 (s, 1H); ESI m/z measured 509.0359 [M+H]+, calculated 509.0380.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:40](I)[CH:41]=[CH2:42].[OH-].[Na+].C1(NC2CCCCC2)CCCCC1>C1COCC1.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]([CH2:42][CH:41]=[CH2:40])[C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C=CCI
Agent: C1CCC(NC2CCCCC2)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=CCN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 196.5 %

Procedure:
To 100 ml. of THF were added 10.6 grams (15 mmoles) of Nα -t-butyloxycarbonyl-L-phenylalanine. The mixture was added dropwise over a one hour period to a mechanically stirred suspension of 0.12 moles of potassium hydride in 250 ml. of dried THF containing 0.5 grams of 18-crown-6-ether at 0° C. and under a nitrogen atmosphere. The mixture was stirred for an additional 10 minutes at 0° C., and a solution of 4 ml. (44 mmoles) of allyl iodide in 20 ml. of THF was added dropwise over a 30 minute period. The resulting mixture was maintained for four hours after which a mixture of 4.6 ml. of glacial acetic acid in 20 ml. of THF was added dropwise. The mixture was stirred for 10 minutes and then was poured onto 400 ml. of ice. The aqueous phase was adjusted to pH 8.0 by addition of 1 N sodium hydroxide. The aqueous phase then was extracted with ether and acidified to pH 2.0 with cold 1 N HCl. The aqueous mixture then was extracted with ethyl acetate. The ethyl acetate was extracted with water, dried over magnesium sulfate, and evaporated in vacuo to a syrup. The syrup was dissolved in 200 ml. of ether, and 8 ml. (0.04 moles) of dicyclohexylamine (DCHA) were added. The resulting precipitate was filtered, and the filtrate was extracted successively with 1.5 N citric acid and water. The ether layer was dried over magnesium sulfate and evaporated in vacuo to obtain 9 grams (74%) of the title compound as a syrup.
Reaction SMILES: [CH2:1]([N:3]1[CH2:15][CH2:14][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].[CH2:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([N:3]1[CH2:15][CH2:14][C:6]2[N:7]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: CCN1CCc2[nH]c3ccccc3c2C1
Reactant: C=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCc2c(c3ccccc3n2CCc2ccccc2)C1
Yield: 9.9 %

Procedure:
The title compound was prepared according to General Method 2. 2-Ethyl-2,3,4,5-tetrahydro-5-phenethyl-1H-pyrido[4,3-b]indole was prepared from 2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (See Example 5) (100 mg, 0.5 mmol), styrene (1 mL, 8.64 mmol) and NaH (200 mg, 5 mmol) in DMF (4 ml) at 150° C. for 16 h to obtain 15 mg of 2-ethyl-2,3,4,5-tetrahydro-5-phenethyl-1H-pyrido[4,3-b]indole after purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2Br)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B2OCCCO2)[CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O.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.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:26]2[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Cc2ccccc2Br)CC1
Reactant: c1cncc(B2OCCCO2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Cc2ccccc2-c2cccnc2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
After dissolving 575 mg of 1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-2-(2-bromophenyl)ethanone in 10 ml of N,N-dimethylformamide, there were added 489 mg of 2-(3-pyridyl)-1,3,2-dioxaborinane, 173 mg of tetrakis(triphenylphosphine)palladium(0) and 1.47 g of anhydrous cesium carbonate, and the mixture was stirred at 100° C. for 2 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (379 mg, 66% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([OH:14])[CH:11]([CH3:13])[CH3:12].Br[C:16]1[C:17]([NH2:23])=[N:18][CH:19]=[C:20]([Br:22])[N:21]=1>>[Br:22][C:20]1[N:21]=[C:16]([O:14][CH:10]([C:3]2[C:4]([F:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[Cl:1])[CH:11]([CH3:12])[CH3:13])[C:17]([NH2:23])=[N:18][CH:19]=1
Reactant: CC(C)C(O)c1c(F)ccc(F)c1Cl
Reactant: Nc1ncc(Br)nc1Br
Product: CC(C)C(Oc1nc(Br)cnc1N)c1c(F)ccc(F)c1Cl

Procedure:
5-bromo-3-[1-(2-chloro-3,6-difluoro-phenyl)-2-methyl-propoxy]-pyrazin-2-ylamine was prepared following procedure 2 from 1-(2-chloro-3,6-difluoro-phenyl)-2-methyl-propan-1-ol and 3,5-dibromo-pyrazin-2-ylamine.