Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[O:28]([CH:35]([CH3:39])[C:36](Cl)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([CH2:25][CH3:26])[C:36](=[O:37])[CH:35]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:39])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: CC(Oc1ccccc1)C(=O)Cl
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)C(C)Oc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and 2-phenoxypropionyl chloride.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][N:40]([CH3:56])[CH:41]1[CH2:46][CH2:45][N:44]([C:47]2[CH:52]=[C:51](B(O)O)[CH:50]=[CH:49][N:48]=2)[CH2:43][CH2:42]1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:39][N:40]([CH3:56])[CH:41]1[CH2:42][CH2:43][N:44]([C:47]2[CH:52]=[C:51]([C:2]3[C:10]4[C:9]([NH:11][C@H:12]([C:14]5[N:19]([C:20]6[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=6)[C:18](=[O:26])[C:17]6=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]6[N:15]=5)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=4[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=3)[CH:50]=[CH:49][N:48]=2)[CH2:45][CH2:46]1
Reactant: CN(C)C1CCN(c2cc(B(O)O)ccn2)CC1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
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: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3ccnc(N5CCC(N(C)C)CC5)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 104.3 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) was treated with (2-(4-(dimethylamino)piperidin-1-yl)pyridin-4-yl)boronic acid (43 mg, 0.17 mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol), aqueous solution 2M of sodium carbonate (200 μl, 0.4 mmol) and 5 ml N,N-dimethylformide as a solvent according to the method described in Preparation 186 but stirring at 100° C. overnight. The crude was purified by reverse phase using SP1® Purification System (hexane-ethyl acetate) to obtain 60 mg (75% yield) of the title compound. Purity 75%.
Reaction SMILES: [NH2:1][C@@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@@H:2]([NH:1][C:30]([NH:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=2)=[O:31])[C:3]1=[O:20]
Reactant: CN1C(=O)[C@H](N)N=C(c2ccccc2)c2ccccc21
Reactant: COc1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: COc1cccc(NC(=O)N[C@@H]2N=C(c3ccccc3)c3ccccc3N(C)C2=O)c1
Reaction time: 8 h

Procedure:
Equimolar amounts of 3-(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 3-methoxyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 216°-219° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:12]([NH:13][CH3:14])[CH2:11][N:10]([C:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=4)[CH2:19][CH2:18]3)=[O:16])[CH2:9]2)=[CH:4][CH:3]=1.Cl[C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33]>>[CH:35]([O:34][C:32](=[O:33])[N:13]([C@H:12]1[C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][N:10]([C:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:11]1)[CH3:14])([CH3:37])[CH3:36]
Reactant: CC(C)OC(=O)Cl
Reactant: CN[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(Cl)cc1
Product: CC(C)OC(=O)N(C)[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 136, the title compound [(3S,4R)-4-(4-chloro-phenyl)-1-(5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid isopropyl ester was prepared from 4-[(3R,4S)-3-(4-chloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-5′-carbonitrile using isopropyl chloroformate instead of ethyl chloroformate and was obtained as a colorless foam. MS m/e: 510.4 [M]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:26]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)=[O:27])=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18]C(=O)OC(C)(C)C)=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([NH:4][C:5]1[S:6][C:7]([C:26]([NH:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=2)=[O:27])=[C:8]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(C(=O)NCc2ccc([N+](=O)[O-])cc2)s1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nc(CCc2ccc(N)cc2)c(C(=O)NCc2ccc([N+](=O)[O-])cc2)s1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
tert-Butyl {4-[2-(2-(acetylamino)-5-{[(4-nitrobenzyl)amino]carbonyl}-1,3-thiazol-4-yl)ethyl]phenyl}carbamate (135 mg) and TFA (2 ml) were combined at 0° C. The reaction mixture was stirred at room temperature for an hour, and concentrated in vacuo. The residue was dissolved in MeOH and CHCl3, and made basic (pH=8) by 1N—NaOH. The mixture was concentrated in vacuo. The residual solid was washed with water to give 2-(acetylamino)-4-[2-(4-aminophenyl)ethyl]-N-(4-nitrobenzyl)-1,3-thiazole-5-carboxamide (92.5 mg) as a pale yellow solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[CH2:11]([NH2:14])[C:12]#[CH:13]>>[N:14]1[CH:11]=[CH:12][CH:13]=[C:1]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[CH2:3][C:2]=12
Reactant: C#CCN
Reactant: O=C1Cc2ccccc2C1
Product: c1ccc2c(c1)Cc1ncccc1-2
Yield: 56 %

Procedure:
The title compound is prepared from 2-indanone and propargylamine following a procedure analogous to that described in Step 1 of Intermediates 1 and 2. Yield: 56% of theory; Mass spectrum (ESI+): m/z=168 [M+H]+.
Reaction SMILES: C[N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.[NH2:18][C:19]1[C:23](C#N)=[C:22]([C:26]#[N:27])[NH:21][N:20]=1>C(O)(=O)C>[C:19]([C:23]1[C:22]([C:26]#[N:27])=[N:21][N:20]2[C:5]([C:7]3[CH:8]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=[N:2][C:17]=12)#[N:18]
Reactant: N#Cc1[nH]nc(N)c1C#N
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: N#Cc1nn2c(-c3cccc(C(F)(F)F)c3)ccnc2c1C#N

Procedure:
A mixture of 4.86 g. of 3-dimethylamino-3'-(trifluoromethyl)acrylophenone, 50 ml. of glacial acetic acid and 2.66 g. of 3-aminopyrazole-4,5-dicarbonitrile is refluxed for 10 hours and the solvent removed under reduced pressure. The residue is treated with trifluoroacetic anhydride to give the product of the example. cl EXAMPLE 44
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([NH2:16])[N:3]=1.[N:17]([O-])=[O:18].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([N:17]=[O:18])=[C:4]([NH2:16])[N:3]=1
Reactant: O=N[O-]
Reactant: Nc1cc(OCc2ccccc2)nc(N)n1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(N)c(N=O)c(OCc2ccccc2)n1
Temperature: 80 °C

Procedure:
2,6-Diamino-4-benzyloxypyrimidine (0.5 g, 2.3 mmol) was dissolved in warm acetic acid (30%, 10 ml) and the reaction mixture was heated to 80° C. A solution of sodium nitrite (0.22 g, 3.19 mmol) in water (5 ml) was added dropwise over 1 h, when an excess of oxidant was evident by starch-iodide paper. The reaction mixture was allowed to cool to room temperature, and the violet crystals which deposited were collected and washed with water (0.53 g, 98%), m.p. decomposed 209° C.; (Found: C, 55.32; H, 5.28; N, 26.47% C11H11N5O2 0.1 H2O C, 55.98; H, 4.75; N, 29.69%); νmax/cm−1 3408 (NH), 2952 (CH2), 1610 (C6H5), 1518 (NO); δH (200 MHz, d6-DMSO) 5.69 (2H, s, OCH2), 7.44-7.68 (5H, m, C6H5), 8.0 (2H, d, NH2), 8.17 (1H, s, NH) , 10.19 (1H, s, NH); m/z (+EI) 245 (M+, 25%), 91 (100), 65 (9).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[NH:4]1[CH:8]=[CH:7][C:6]([C:9](O)=[O:10])=[CH:5]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:1]([O:3][C:9]([C:6]1[CH:7]=[CH:8][NH:4][CH:5]=1)=[O:10])[CH3:2]
Reactant: CCO
Reactant: O=C(O)c1cc[nH]c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc[nH]c1
Temperature: 60 °C
Yield: 79.8 %

Procedure:
Ethanol (3.2 mL, 54 mmol) and 4-dimethylamino pyridine (DMAP) (54 mg, 0.45 mmol) were added to a mixture of pyrrole-3-carboxylic acid (500 mg, 4.5 mmol) and dicyclohexylcarbodiimide (1.11 g, 5.4 mmol) (Aldrich, Milwaukee, Wis.) in tetrahydrofuran (THF) (15 mL). After heating at 60° C. for 10 hours, the reaction was cooled. The precipitate was filtered off, washed with ethyl acetate, the combined filtrate was concentrated and purified on a silica gel column to give 500 mg (81%) of 1H-pyrrole-3-carboxylic acid ethyl ester as a colorless oil.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[N+:11]([CH2:14][CH3:15])([O-:13])=[O:12].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH3:9][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:1]=[C:14]([N+:11]([O-:13])=[O:12])[CH3:15])[CH:3]=1
Reactant: CC[N+](=O)[O-]
Reactant: COc1cccc(C=O)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1cccc(C=C(C)[N+](=O)[O-])c1

Procedure:
A mixture of 71.9 g (0.528 mole) of m-anisaldehyde, 118.9 g (1.584 mole) of nitroethane, 40.7 g (0.528 mole) of ammonium acetate, and 350 ml of glacial acetic acid was heated to reflux for one hour. The mixture was then allowed to cool and partitioned between ether and water. The ether layer was separated and washed sequentially with water 3N sodium hydroxide, water and brine. The organic phase was dried over anhydrous magnesium sulfate and evaporated in vacuo to give the crude product. After a preliminary distillation at 125° C./0.0001 mm, the product was finally crystallized from absolute ethanol to yield the pure product, a yellow solid, mp 40°-42° C.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[N:14]=[N+:15]([O-:26])[C:16]3[CH:25]=[C:24]4[C:20]([CH2:21][CH2:22][CH2:23]4)=[CH:19][C:17]=3[N:18]=2)[CH2:5][CH2:4]1.CO.CC[O:31]C(C)=O>>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[N:14]=[N+:15]([O-:26])[C:16]3[CH:25]=[C:24]4[C:20]([CH2:21][CH2:22][CH2:23]4)=[CH:19][C:17]=3[N+:18]=2[O-:31])[CH2:5][CH2:4]1
Reactant: CCOC(C)=O
Reactant: COC1CCN(CCCNc2nc3cc4c(cc3[n+]([O-])n2)CCC4)CC1
Solvent: CO
Product: COC1CCN(CCCNc2n[n+]([O-])c3cc4c(cc3[n+]2[O-])CCC4)CC1

Procedure:
H2O2 (70%, 0.92 mL, ca. 18.3 mmol) was added dropwise to a stirred solution of TFM (2.6 mL, 18.3 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 58 (655 mg, 1.8 mmol) and TFA (0.71 mL, 9.2 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 20° C. for 8 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with DCM (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 58 (360 mg, 55%) and (ii) 1,4-dioxide 59 (213 mg, 31%) as a red solid: mp (MeOH/EtOAc) 128-130° C.; 1H NMR δ 8.42 (br s, 1H, NH), 8.11 (s, 1H, H-9), 8.10 (s, 1H, H-5), 3.62-3.68 (m, 2H, CH2N), 3.28-3.36 (m, 4H, OCH3, CHO), 3.08 (dt, J=7.5, 1.1 Hz, 2H, H-6), 3.03 (dt, J=7.5, 1.1 Hz, 2H, H-8), 2.69-2.76 (m, 2H, CH2N), 2.55 (br t, J=6.2 Hz, 2H, CH2N), 2.26-2.34 (m, 2H, CH2N), 2.17 (p, J=7.5 Hz, 2H, H-7), 1.94-2.03 (m, 2H, CH2), 1.88 (p, J=6.2 Hz, 2H, CH2), 1.72-1.81 (m, 2H, CH2); 13C NMR δ 155.4, 149.5, 145.5, 138.1, 129.5, 115.7, 111.7, 75.8, 57.2, 55.4, 50.8 (2), 41.6, 33.3, 32.3, 30.3 (2), 25.5, 25.1. Anal. calcd for C19H27N5O3.H2O: C, 58.3; H, 7.5; N, 17.9. Found: C, 58.4; H, 6.8; N, 17.6%.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C([N:12]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[CH2:13]1)C1C=CC=CC=1>C1C=CC=CC=1>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][CH:14]1[CH2:15][CH2:16][N:12]([C:1]([Cl:4])=[O:2])[CH2:13]1
Reactant: COc1ccccc1OC1CCN(Cc2ccccc2)C1
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccccc1OC1CCN(C(=O)Cl)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
To a stirred solution of 60 ml of 2 molar phosgene (0.11 mole) in benzene under nitrogen gas was added dropwise a solution of 29.3 g (0.1 mole) of 1-benzyl-3-(2-methoxyphenoxy)pyrrolidine in 100 ml of benzene. The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated in vacuo to give an oil. The oil was triturated with warm 30/60 petroleum ether and the petroleum ether was decanted to remove benzyl chloride. On the third trituration the oil solidified to give 19.65 g of crude product. The combined petroleum ether decantate, on cooling, yielded an additional 4.8 g, m.p. 80°-81° C. The combined yield was 23.45 g (91.7%). Recrystallization of a 1.25 g sample from 25 ml of 30/60 petroleum ether gave fine white crystals, m.p. 80.5°-82° C. The yield of purified product based on this aliquot was 22.6 g (88%).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35](B(O)O)[CH:36]=2)[CH:31]=[CH:30][N:29]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:35]3[CH:36]=[C:37]4[C:32]([CH:31]=[CH:30][N:29]=[CH:28]4)=[CH:33][CH:34]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1ccc2ccncc2c1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccc3ccncc3c2)c1

Procedure:
A mixture of (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1, 60 mg, 0.134 mmol), isoquinolin-7-ylboronic acid (35 mg, 0.202 mmol), 2 M Na2CO3 (0.134 mL) and DME (4 mL) was flushed with argon. PdCl2(dppf)(CH2Cl2) (11 mg, 0.013 mmol) was added and the mixture was subjected to MW irradiation at 140° C. for 30 min. The RM was filtered through a PL-Thiol MP SPE cartridge (StratoSpheres™, 6 mL), the cartridge was washed with MeOH and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative LC-MS to afford the title compound as a beige powder. LC-MS (Condition 6) tR=1.33 min, m/z=495.1 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][CH3:18])=[N:15][CH:16]=3)=[CH:8][C:7]=2[CH:19]=1.C(Cl)Cl.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>O>[CH3:18][NH:17][C:14]1[N:15]=[CH:16][C:11]([C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:19][C:7]=3[CH:8]=2)=[CH:12][CH:13]=1
Reactant: CNc1ccc(-c2cc3cc(OC)ccc3o2)cn1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CNc1ccc(-c2cc3cc(O)ccc3o2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.4 %

Procedure:
[5-(5-Methoxy-benzofuran-2-yl)-pyridin-2-yl]-methylamine (0.24 mmol) was mixed with CH2Cl2 (3 mL) at 0° C. under argon atmosphere. BBr3 (1M in CH2Cl2) (1.0 mL, 1.0 mmol) was added dropwise and the mixture was stirred for 2 h at rt. The mixture was hydrolysed with H2O followed by NaHCO3 (sat. aq.) solution. The resulting mixture was extracted with EtOAc and the organic extracts were dried over Na2SO4. After filtration and evaporation of the solvent, the crude material was purified by preparative HPLC to afford the title compound as a white solid (21 mg). 1H NMR δ ppm 9.10 (s, 1 H) 8.50 (d, 1 H) 7.81 (dd, 1 H) 7.32 (d, 1 H) 6.96 (s, 1 H) 6.81-6.94 (m, 2 H) 6.66 (dd, 1 H) 6.54 (d, 1 H) 2.82 (d, 3 H); MS m/z 241 (M+H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[CH:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=1)=C>>[CH3:10][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19]/[CH:3]=[CH:2]\[CH2:1][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:15][CH:14]=1
Reactant: C=CCc1ccccc1
Reactant: C=COc1ccc(OC)cc1
Product: COc1ccc(O/C=C\Cc2ccccc2)cc1
Reaction time: 16 h
Yield: 55.8 %

Procedure:
Following the general procedure, allyl benzene (50.0 mg, 0.423 mmol, 7) was treated with p-methoxyphenyl vinyl ether (127 mg, 8.46 mmol) and 1.2 mol % of in situ-generated complex la (51.0 μL, 0.10 M, 5.08 μmol; final substrate concentration=8.3 M) and allowed to stir for 16 h. The unpurified product is >98% Z (as determined by 400 MHz 1H NMR analysis). Excess p-methoxyphenyl vinyl ether was removed by vacuum distillation (1.0 torr, 80° C.). The resulting oil was purified by neutral alumina chromatography (100% hexanes to 100:1 hexanes:Et2O) to afford 10a (56.8 mg, 0.236 mmol, 56.0% yield, >98% Z isomer) as a colorless oil. IR (neat): 3027 (w), 3000 (w), 2950 (w), 2908 (w), 2834 (w), 1664 (m), 1502 (s), 1464 (m), 1453 (m), 1441 (m), 1384 (m), 1212 (s), 1179 (m), 1088 (m), 1064 (m), 1034 (m), 989 (m); NMR (400 MHz, CDCl3): δ 7.33-7.25 (4H, m), 7.24-7.18 (1H, m), 7.01-6.95 (2H, m), 6.89-6.84 (2H, m), 6.42 (1H, dt, J=6.0, 1.6 Hz), 4.96 (1H, td, J=7.6, 6.0 Hz), 3.80 (3H, s), 3.58 (2H, dd, J=7.6, 1.2 Hz); 13C NMR (100 MHz, CDCl3): δ 155.4, 151.7, 141.9, 141.2, 128.6, 128.5, 126.0, 117.6, 114.8, 110.6, 55.9, 30.4; HRMS (ESI+) [M+NH4]+ calcd for C16H20NO2. 258.1494, found: 258.1491.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=1.[Br:22][C:23]1[C:24]([Si:35]([CH3:38])([CH3:37])[CH3:36])=[C:25]([F:34])[C:26]([F:33])=[C:27]([CH:32]=1)C(OC)=O>C1COCC1.Cl>[Br:22][C:23]1[C:24]([Si:35]([CH3:38])([CH3:37])[CH3:36])=[C:25]([F:34])[C:26]([F:33])=[C:27]([C:19](=[O:21])[CH2:18][C:15]2[CH:14]=[CH:13][C:12]([Cl:11])=[CH:17][CH:16]=2)[CH:32]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: COC(=O)c1cc(Br)c([Si](C)(C)C)c(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)c1c(Br)cc(C(=O)Cc2ccc(Cl)cc2)c(F)c1F
Reaction time: 0.08 h

Procedure:
To a solution of NaHMDS (1.0 M in THF, 7.7 mL, 7.7 mmol) in anhydrous THF (25 mL) at −78° C. was added a solution of 4-chlorophenylacetic acid (0.528 g, 3.09 mmol) in anhydrous THF (25 mL) over 10 minutes. The solution was stirred for 5 minutes, then a solution of the product of Step C (4.16 g, 7.8 mmol) in THF (25 mL) was added drop wise over 10 minutes. The mixture was stirred at −78° C. for two hours. The mixture was diluted with 2N HCl (aq, 50 mL), then the product was extracted into EtOAc. The organics were dried over Na2SO4, filtered, then concentrated. The resulting residue was purified by silica gel chromatography eluting with 0-50% toluene/hexanes to afford the title compound. 1H NMR (600 MHz, CDCl3): δ 7.74 (dd, J=5.3, 1.8 Hz, 1H); 7.31 (d, J=8.2 Hz, 2H); 7.16 (d, J=8.5 Hz, 2H); 4.22 (s, 2H); 0.48 (s, 9H).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:13].B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:13]
Reactant: COc1cccc2c1CCCC2=O
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=C1CCCc2c(O)cccc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1 mol of 5-methoxy-1-tetralone are dissolved in 5 l of methylene chloride and the solution is cooled to -78° C. 500 ml of boron tribromide in 2.3 1 of methylene chloride are added dropwise to this solution. The mixture is stirred at -78° C. for 30 minutes and then at 0° C. for 2.5 hours and cooled again to -78° and 3 l of methanol are slowly added dropwise. The mixture is evaporated, the residue is taken up in methylene chloride and the mixture is extracted 3 times with 10% strength sodium hydroxide solution. The combined sodium hydroxide solutions are acidified with concentrated hydrochloric acid and extracted 3 times by shaking with methylene chloride. After drying over sodium sulphate, the extract is evaporated. The residue is pure product and does not need to be recrystallized. The melting point is 210°-215° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:25])[CH:3]=1.[I-:26].[Na+]>[Cu]I>[F:8][C:6]1[CH:7]=[C:2]([I:26])[CH:3]=[C:4]([F:25])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Reactant: [I-]
Agent: [Cu]I
Agent: [Na+]
Product: Cc1cnc(N2CCN(C(=O)c3c(F)cc(I)cc3F)CC2)c(C)c1
Yield: 81.3 %

Procedure:
Using (4-bromo-2,6-difluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (820 mg) described in Preparation Example 111, sodium iodide (599 mg) and copper(I) iodide (189 mg) and by the reaction and treatment in the same manner as in Preparation Example 154, the title compound (743 mg) was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[C:13]1(=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[NH:14]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]#[C:5][CH2:4][CH2:3][CH2:2][N:14]1[C:15](=[O:22])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]1=[O:23]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCCCC#Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCC#Cc1ccccn1
Temperature: 150 °C
Yield: 20.7 %

Procedure:
2-(5-bromopent-1-ynyl)pyridine (118 mg, 0.525 mmol), isoindoline-1,3-dione (74 mg, 0.5 mmol) and potassium carbonate (140 mg, 1 mmol) were dissolved in acetone (1 mL). The resulting mixture was heated with microwave at 150° C. for 15 min. The reaction was quenched with water, then acetone was evaporated under reduced pressure. The aqueous layer was extracted with DCM, and the organic layer was washed one time with saturated brine, dried over MgSO4, filtrated and concentrated. Purification by flash chromatography pack 15 g silice 40-60, Cyclohexane/AcOEt: 50/50 to afford 30 mg of 2-(5-(pyridin-2-yl)pent-4-ynyl)isoindoline-1,3-dione (Yield: 20%) as a beige powder (Mp=127-129° C.).