Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:1][C:2]1[C:3]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: CCOC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(OC)ccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3)c(-c3ccccc3)c(C)cc2c1
Temperature: 70 °C
Yield: 98 %

Procedure:
Ethyl (2E)-3-(4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}phenyl)-2-propenoate (9) (2.20 g, 5.02 mmol) was dissolved in THF and EtOH (1:1, 50 mL). To this mixture was added 1 N NaOH (50 mL, excess) at room temperature and the stirred reaction heated to 70° C. for 0.5 h. After cooling to RT, the reaction mixture was acidified with 20% aqueous HCl, and then extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure to afford the crude product. The product was purified by flash column chromatography with CHCl3:MeOH (9:1 to 4:1) as an eluent to give 2.02 g (98%) of compound (10) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.70 (d, J=8.0 Hz, 1H), 7.64 (d, J=16.0 Hz, 1H), 7.57 (s, 1H), 7.26 (dd, J1=12.0 Hz, J2=12.0 Hz, 4H), 7.22 (d, J=4.0 Hz, 1H), 7.14 (d, J=1.8 Hz, 2H), 7.12 (s, 1H), 7.06 and 7.04 (dd, J=12.0 Hz, J2=6.8 Hz, 1H), 6.60 (d, J=8.0 Hz, 2H), 6.22 (d, J=16.0 Hz, 1H), 3.92 (s, 3H), 2.24 (s, 3H). LCMS (ESI) m/z 439.07 (M+H)+.
Reaction SMILES: Cl.CC(C)(OC([NH:8][C@H:9]([CH2:13][C:14]1[N:15]=[CH:16][S:17][CH:18]=1)[C:10]([OH:12])=[O:11])=O)C>O1CCOCC1>[NH2:8][C@H:9]([CH2:13][C:14]1[N:15]=[CH:16][S:17][CH:18]=1)[C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cscn1)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H](Cc1cscn1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.8 %

Procedure:
A solution of 4N hydrochloric acid in dioxane (10 ml) was added to a solution of (R)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-3-(4-thiazolyl)propanoic acid (2.0 g, 7.3 mmol) in dioxane (2 ml). The reaction mixture was stirred at room temperature for 3 hours, concentrated in vacuo and the residue was dissolved in water (3 ml). The pH was adjusted to 6.5 with 1N sodium hydroxide and this solution was passed through 20 ml of Dowex® AG50(H+). The column was eluted with water (250 ml) followed by 2% pyridine in water (300 ml). The product containing fractions were concentrated in vacuo to yield 0.94 g of title product.
Reaction SMILES: [S:1]1[C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=[CH:2]1.[C:15]1([CH2:21][C:22](O)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[S:1]1[C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=[C:2]1[C:22](=[O:23])[CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc2c(c1)OCCc1ccsc1-2
Reactant: O=C(O)Cc1ccccc1
Product: O=C(Cc1ccccc1)c1cc2c(s1)-c1ccccc1OCC2

Procedure:
Scheme 7 shows a general method for substitution at the 2-position of 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine intermediates 74 by acylation with a carboxylic acid such as 2-phenylacetic acid to give 1-(4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-2-phenylethanone intermediate 81. Bromination gives 2-bromo-1-(4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-2-phenylethanone intermediate 82. Cyclization with a thioamide compound gives 4-(4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-5-phenylthiazole 83.
Reaction SMILES: [CH3:1][C:2]([O:4][O])=[O:3].[O:6]=[CH:7][C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])O)[OH:11])[OH:9]>CO>[C:2]([O:4][C@H:12]1[C@H:10]([O:11][C:2](=[O:3])[CH3:1])[C@H:8]([O:9][C:7](=[O:6])[CH3:8])[CH2:7][O:6][CH:14]1[OH:15])(=[O:3])[CH3:1]
Reactant: CC(=O)O[O]
Reactant: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CO
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)C(O)OC[C@H]1OC(C)=O
Yield: 56 %

Procedure:
A suspension of peracetyl-D-arabinose (prepared according to the method of Evelyn, Carbohydrate Res., 1982, 100:55-61) (3 g, 9.4 mmol) and alumina (50 mg) in methanol (200 ml) was refluxed for 5 hrs. After filtration of the inorganic substance, the filtrate was concentrated in vacuo to give 2,3,4-tri-O-acetyl-D-arabinopyranose (1.46 g, 56%) as an oil.
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:13]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([F:20])[CH:5]=1)=[O:3].[OH-].[Na+].ClCCl>CO>[NH2:1][C:2]([C:4]1[C:13]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:20])[CH:5]=1)=[O:3]
Reactant: CCC(CC)Nc1cc(C(=O)OC)c(F)cc1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCC(CC)Nc1cc(C(=O)O)c(F)cc1C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
To a solution of methyl 4-(aminocarbonyl)-2-fluoro-5-(pentan-3-ylamino)benzoate (73.7 mg, 0.26 mmol) in methanol (1 mL) at 0° C. was added 1 N sodium hydroxide (520 uL, 0.52 mmol). The mixture was stirred 30 min at 0° C., and was then warmed to room temperature. Dichloromethane (500 uL) was added to improve solubility, and the homogeneous solution was stirred 3.5 h at room temperature. After acidification with 1 N hydrochloric acid (500 uL), the volatile solvents were removed by rotary evaporation. An insoluble solid material was then isolated from the aqueous residue by filtration. The solid was dried to give 4-(aminocarbonyl)-2-fluoro-5-(pentan-3-ylamino)benzoic acid (61.7 mg, 0.23 mmol, 88% yield). 1H NMR (400 MHz, CD3OD): 7.41 (d, 1H), 7.16 (d, 1H), 3.43-3.28 (m, 1H buried), 1.68-1.46 (m, 4H), 0.95 (t, 6H).
Reaction SMILES: C1(OC(=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12]C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:49][N:50]1[CH2:55][CH2:54][N:53]([CH:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)[CH2:52][CH2:51]1>CN(C)C=O>[F:46][C:43]1[CH:42]=[CH:41][C:40]([NH:39][C:38]([C:35]2([C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([O:25][C:23]4[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:10]([N:59]5[CH2:58][CH2:57][CH:56]([N:53]6[CH2:52][CH2:51][N:50]([CH3:49])[CH2:55][CH2:54]6)[CH2:61][CH2:60]5)=[O:12])[CH:24]=4)=[CH:27][CH:28]=3)=[O:34])[CH2:36][CH2:37]2)=[O:47])=[CH:45][CH:44]=1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1
Reactant: CN1CCN(C2CCNCC2)CC1
Solvent: CN(C)C=O
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccc(F)cc6)CC5)cc4)ccn3)CC2)CC1
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a solution of [4-(4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (50 mg) in N,N-dimethylformamide (1.0 ml) was added 1-methyl-4-(piperidin-4-yl)piperazine (56.7 mg) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solvent was removed under reduced pressure. The solid residue was dried under reduced pressure to provide the titled compound as white powder (37.7 mg, 79%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=2[O:25][CH2:26][C:27]([OH:29])=[O:28])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9].B([C:33]1C=C(C(F)(F)F)C=CC=1O[C@@H](C)C(O)=O)(O)O>>[CH3:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:20]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:18]=[CH:17][C:16]=2[O:25][C@@H:26]([CH3:33])[C:27]([OH:29])=[O:28])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:11][CH2:12][CH2:13][CH2:14]1)=[O:9]
Reactant: Cc1cc(-c2cc(C(F)(F)F)ccc2OCC(=O)O)ccc1C(=O)N1CCCC1
Reactant: C[C@H](Oc1ccc(C(F)(F)F)cc1B(O)O)C(=O)O
Product: Cc1cc(-c2cc(C(F)(F)F)ccc2O[C@@H](C)C(=O)O)ccc1C(=O)N1CCCC1

Procedure:
The title compound was prepared using the product of example 27 step a) and (2S)-2-[2-borono-4-(trifluoromethyl)phenoxy]-propanoic acid [WO2004089885] by the method of example 32 step b).
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.C1(C)C=CC(S(O[CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:12][O:11][C:10]1[C:2]([O:1][CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)=[CH:3][C:4]([N+:13]([O-:15])=[O:14])=[C:5]([CH:9]=1)[C:6]([NH2:8])=[O:7]
Reactant: COc1cc(C(N)=O)c([N+](=O)[O-])cc1O
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccncc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(N)=O)c([N+](=O)[O-])cc1OCCOc1ccncc1
Temperature: 80 °C
Yield: 68.2 %

Procedure:
4-Hydroxy-5-methoxy-2-nitrobenzamide (1.86 g, 9.5 mmol) and 2-(4-pyridyloxy)ethyl paratoluene sulphonate (3.3 g, 11.2 mmol) were mixed in the presence of potassium carbonate (1.7 g, 12.3 mmol) and anhydrous DMF (25 ml) and heated at 80° C. for 2 hours. The reaction mixture was allowed to cool overnight, the DMF was removed by evaporation and the residue was quenched into water (250 ml). The solid was collected by filtration and washed with a mixture of acetone/ether (1/1) to give 5-methoxy-2-nitro-4-(2-(4-pyridyloxy)ethoxy)benzamide as a cream solid (2.16 g, 68%).
Reaction SMILES: C[C:2]1(C)[N:6](C)[CH2:5][C@@H:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=2)[O:3]1.[ClH:22].Cl.CC(C)(C)C(OC1C=C(C=CC=1)[C@@H](O)CNC)=O>CCOCC>[ClH:22].[CH3:17][C:16]([CH3:19])([CH3:18])[C:15]([O:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[CH:4]([OH:3])[CH2:5][NH:6][CH3:2])=[O:20]
Reactant: CN1C[C@@H](c2cccc(OC(=O)C(C)(C)C)c2)OC1(C)C
Agent: CNC[C@H](O)c1cccc(OC(=O)C(C)(C)C)c1
Agent: Cl
Solvent: CCOCC
Product: CNCC(O)c1cccc(OC(=O)C(C)(C)C)c1
Yield: 70 %

Procedure:
The filtrate obtained in the previous reaction containing (R)-2,2,3-trimethyl-5-(m-trimethylacetoxyphenyl)-1,3-oxazolidine (1.8 g, 6.2 mmole) in 60 ml of ether was treated with hydrogen chloride gas until the solution was no longer turbid. This mixture was then evaporated to dryness and the residue was dissolved in a small amount of ethanol and then diluted with hexane. The hydrolysis and crystallization took place in the solution to give 1.2 g of the final product, (R)-m-(trimethylacetoxy)-α-[(methylamino)methyl]benzyl alcohol hydrochloride, 70% yield. mp 128°-130° C, αD25° = -36.7° (C2H5OH). ir (KBr): 3370, 2960, 2795, 2420, 1750, 1610, 1590, 1460, 1240 and 110 cm-1. nmr (CD3COCD3. D2O): δ 7.5 - 6.8 (m, 4H), 5.3 (dd, 1H, J = 5 and 10Hz), 3.8 (b, 3H), 3.4 (m, 2H), 2.9 (s, 3 H) and 1.4 (s, 9H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:17][C:11]3[C:12](=[O:16])[NH:13][N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH2:25][C:26]1[N:31]=[C:30]([O:32][CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH:29]=[CH:28][CH:27]=1)(=O)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:17][C:11]3[C:12](=[O:16])[N:13]([CH2:25][C:26]4[N:31]=[C:30]([O:32][CH:33]5[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:38]5)[CH:29]=[CH:28][CH:27]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(COS(C)(=O)=O)n2)CC1
Reactant: O=c1[nH]ncc2cc(-c3ccc(Cl)cc3)sc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(Cn3ncc4cc(-c5ccc(Cl)cc5)sc4c3=O)n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-(4-chlorophenyl)thieno[2,3-d]pyridazin-7(6H)-one (0.32 g, 1.22 mmol) in DMF (10 mL) was added 60% sodium hydride in oil (0.06 g, 1.34 mmol, 55%). Stirred for 10 minutes under N2 atmosphere before addition of tert-butyl 4-[(6-{[(methylsulfonyl)oxy]methyl}pyridin-2-yl)oxy]piperidine-1-carboxylate (crude product from step d) dissolved in DMF (10 mL). The resulting mixture was stirred for 18 hours at room temperature followed by prep-HPLC purification to give the product. Yield: 0.22 g (32% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.60-7.64 (m, 2H), 7.40-7.51 (m, 4H), 6.75 (d, 1H, J=7.28 Hz), 6.54 (d, 1H, J=8.24 Hz), 5.47 (s, 2H), 4.90-4.99 (m, 1H), 3.58-3.70 (m, 2H), 2.94-3.04 (m, 2H), 1.73-1.82 (m, 2H), 1.47-1.60 (m, 2H), 1.39 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 162.9, 157.3, 155.1, 153.7, 152.5, 140.3, 139.5, 136.4, 136.1, 133.1, 131.2, 129.8, 128.3, 118.9, 114.2, 110.3, 79.7, 70.6, 55.7, 41.3, 30.8, 28.7.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1)#[N:19]>C1COCC1>[C:18]([C:20]1[CH:21]=[C:22]([NH:26][C:27]([NH:17][CH2:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][CH:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH2:12]2)=[O:28])[CH:23]=[CH:24][CH:25]=1)#[N:19]
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: NCCCN1CCC(Cc2ccccc2)CC1
Solvent: C1CCOC1
Product: N#Cc1cccc(NC(=O)NCCCN2CCC(Cc3ccccc3)CC2)c1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
4-benzyl-1-(3-amino-n-prop-1-yl)piperidine (300 mg, 1.29 mmol, 1 eq) was dissoved in THF at 25° C. under N2 then 3-cyanophenyl isocyanate (186 mg, 1.29 mmol, 1 eq) was added. TLC after 30 minutes shows the reaction complete. The solvent was removed in vacuo then the residue was purified over silica gel in 100% EtOAc to 8:2 chloroform/MeOH to yield 437 mg of an amber oil as product. NMR (300 MHz, DMSO-d6) δ 9.90-9.50 (m, 1H); 9.32 (s, 1H); 7.93 (s, 1H); 7.59 (d, 1H, J=7 Hz); 7.43 (t, 1H, J=7 Hz); 7.40-7.24 (m, 3H); 7.24-7.10 (m, 3H); 6.68 (t, 1H, J=7 Hz); 3.50-3.25 (m, 2H); 3.25-3.07 (m, 2H); 3.07-2.90 (m, 2H); 2.90-2.60 (m, 2H); 2.60-2.40 (m, 2H); 2.00-1.60 (m, 5H); 1.60-1.30 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[OH:44])O1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[OH:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccccc4O)nccc3c2)cc1

Procedure:
To a microwave vial charged with 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate JJJ) (100 mg, 0.224 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (49 mg, 0.224 mmol), potassium carbonate (155 mg, 1.121 mmol) and Pd(Ph3P)4 (26 mg, 0.022 mmol) was added Dioxane (1120 μl) and Water (374 μl) and irradiated at 100° C. for 30 min affording conversion to desired product as the primary species. The organic layer was decanted, the aqueous rinsed with EtOAc and the combined organics dried under reduced pressure. The crude material will be used as is for subsequent reactions. m/z (ESI) 504.0 (M+H)+
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([N:15]([CH2:19][CH3:20])[C:16](Cl)=[O:17])[CH3:14]>C(Cl)(Cl)Cl>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:16](=[O:17])[N:15]([CH2:19][CH3:20])[CH2:13][CH3:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)C(=O)Cl
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)N1CCN(c2ccccc2)CC1
Temperature: 40 °C
Reaction time: 5 h
Yield: 29.5 %

Procedure:
In 70 ml of chloroform was dissolved 12.0 g (0.074 mole) of 1-phenylpiperazine at room temperature, and a solution of 10.9 g (0.08 mole) of diethylcarbamoyl chloride in 30 ml of chloroform was dropped to the above solution over a period of 30 minutes. Then, the mixture was stirred at 40° C. for 5 hours and then cooled. The precipitated white crystal was removed, and the filtrate was concentrated under reduced pressure and 50 ml of a 25% aqueous solution of sodium hydroxide was added. The mixture was extracted 2 times with 50 ml of benzene and dried with anhydrous sodium sulfate. The solvent was removed by distillation to obtain crude 1-phenyl-4-diethylcarbamoylpiperazine as the residue. By distillation under reduced pressure, 5.7 g of a purified product having a boiling point of 180.5° C. at 2.3 mm Hg was obtained. The yield was 29.5%. The elementary analysis values are as follows.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]([C:10](=O)[NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[NH:19][CH:20]1[CH2:23][CH:22]([C:24]#[N:25])[CH2:21]1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C>[C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]([C:10]1[N:19]([CH:20]2[CH2:23][CH:22]([C:24]#[N:25])[CH2:21]2)[C:13]2[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=2[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1NC1CC(C#N)C1
Solvent: CC(=O)O
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1C1CC(C#N)C1
Reaction time: 8 h
Yield: 70.6 %

Procedure:
A solution of {(S)-1-[2-(3-cyanocyclobutylamino)-4-fluorophenylcarbamoyl]-ethyl}carbamic acid tert-butyl ester (0.31 g, 0.83 mmol) in acetic acid (5 mL) was stirred at 70° C. for 16 hours and then at 80° C. for 8 hours. The mixture was concentrated in vacuo and the residue dissolved in DCM then washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography (Si—PPC; eluting with ethyl acetate in cyclohexane 0-100%) to give the title compound as colourless gum (0.21 g, 73%). LCMS (Method J): RT 2.87 min [M+H]+ 358.0
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:12]2=[C:13]3[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:14]3=[N:15][CH:16]=[C:11]2[NH:10][C:9]1=[O:28].[H-].[Na+].Br[CH2:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=1.O>CN(C)C=O.CCOC(C)=O>[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:12]2=[C:13]3[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:14]3=[N:15][CH:16]=[C:11]2[N:10]([CH2:32][C:33]2[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=2)[C:9]1=[O:28]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: C[C@@H]1CCCC[C@@H]1n1c(=O)[nH]c2cnc3c(ccn3COCC[Si](C)(C)C)c21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CCCC[C@@H]1n1c(=O)n(Cc2ccc(C#N)cc2)c2cnc3c(ccn3COCC[Si](C)(C)C)c21
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
To a solution of 1-[(1S,2R)-2-methylcyclohexyl]-6-{[2-(trimethylsilyl)ethoxy]methyl}-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (100 mg) in N,N-dimethylformamide (1 mL) was added 60% sodium hydride (13 mg) at 4° C. The mixture was stirred at the same temperature for 0.5 hour. To the mixture was added 4-(bromomethyl)benzonitrile (73 mg) and the solution was stirred at ambient temperature for 1 hour. To the solution was added water and EtOAc. The mixture was extracted with EtOAc and washed with brine. The extract was dried over MgSO4, filtrated and evaporated. The residue was purified by column chromatography on silica gel with EtOAc and n-hexane (1:3 to 1:1) to give 4-({1-[(1S,2R)-2-methylcyclohexyl]-2-oxo-6-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-3(2H)-yl}methyl)benzonitrile (117 mg) as a white amorphous.
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[CH:18]1[C:31]2[C:30]3([CH2:33][N:34]4[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][CH2:35]4)[CH2:32][CH:23]([C:24]4[C:29]3=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:22]=2[CH:21]=[CH:20][CH:19]=1.[Li]C1C=CC2C(=CC=CC=2)N=1>O1CCCC1.C(NC(C)C)(C)C>[CH:28]1[C:29]2[C:30]3([CH2:33][N:34]4[CH2:39][CH2:38][C:37]([C:17]5[C:8]([O:7][CH3:6])=[N:9][C:10]6[C:15]([CH:16]=5)=[CH:14][CH:13]=[CH:12][CH:11]=6)([OH:40])[CH2:36][CH2:35]4)[CH2:32][CH:23]([C:22]4[C:31]3=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:24]=2[CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccc2ccccc2n1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Agent: [Li]C(C)(C)C
Agent: [Li]c1ccc2ccccc2n1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1nc2ccccc2cc1C1(O)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Temperature: -72 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
To a cooled solution (-72° C.) or t-butyllithium (1.7M in pentane, limiting reagent, 1.90 mL, 3.19 mmol) in tetrahydrofuran (24 mL) under nitrogen was added several drops of diisopropylamine (catalytic amount). This was followed by 2-methoxyquinoline (0.69 mL, 4.39 mmol, 1.38 eq). The reaction was stirred at -72° C. for 1 h, warmed to 0° C. and stirred at this temperature for 3 h. After recooling to -72 ° C., a solution of 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) (1.00 g, 3.30 mmol, 1.03 eq) in tetrahydrofuran (3.0 mL) was added dropwise to the lithioquinoline solution. The reaction was stirred at room temperature for 18 h and quenched with water (10 mL). The aqueous phase was extracted with ethyl acetate (200 mL). The organic extract was washed with water (2×200 mL), dried with anhydrous sodium sulfate and reduced to an oil. The reaction mixture was purified by flash chromatography over silica gel (100 mL; eluent: 25% ethyl acetate in hexane) to obtain 1.00 g (66%) of the title compound as a white solid. TLC analysis (Rf 0.19, 25% ethyl acetate in hexane). 1H NMR (CDCl3, 250 MHz) 7.89 (s, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.88 (d, J=7.7 Hz, 1H), 7.59 (dd, J=6.8, 7.3 Hz, 1H), 7.38 (dd, J=7.4, 7.5 Hz, 1H), 7.23 (m, 4H), 6.93 (m, 4H), 4.27 (s, 1H), 4.16 (s, 3H), 3.80 (s, 1H), 3.49 (s, 2H), 2.87 (m, 4H), 2.63 (s, 2H), 2.09 (m, 4H) MS (CI, CH4) m/z 463 (M+1,100), 491 (M+29,19), 445 (23). The free base was dissolved in methylene chloride, treated with ethereal HCl, and the hydrochloride salt was precipitated with ether dilution. The solid was filtered, rinsed with fresh diethyl ether and dried in vacuo (50° C., 10 pascal, 18 h) to yield a white solid, mp 213°-217° C. (dec).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1([CH3:24])[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1.I[Si](C)(C)C>C(#N)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([N:14]2[CH2:15][CH2:16][C:11]([NH2:10])([CH3:24])[CH2:12][CH2:13]2)=[N:18][CH:19]=1
Reactant: CC1(NC(=O)OCc2ccccc2)CCN(c2ccc(Cl)cn2)CC1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CC1(N)CCN(c2ccc(Cl)cn2)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (5′-chloro-4-methyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-yl)-carbamic acid benzyl ester (0.060 g, 0.17 mmol) in acetonitrile (1.0 mL) at room temperature was added iodotrimethysilane (0.04 mL, 0.25 mmol). The reaction mixture was stirred at 50° C. for 30 minutes, concentrated under reduced pressure, and purified by flash chromatography with 3% methanol in dichloromethane to provide titled compound. MS (CI) m/z 226 (M+1)+.