Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:19]([CH:25]4[CH2:27][CH2:26]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:3]=1.[O:32]1[CH2:36][CH2:35][NH:34][C:33]1=[O:37]>>[CH:22]1([C:21]2[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:34]5[CH2:35][CH2:36][O:32][C:33]5=[O:37])=[CH:3][C:4]=4[S:28]([CH3:31])(=[O:30])=[O:29])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=[C:19]([CH:25]3[CH2:27][CH2:26]3)[CH:20]=2)[CH2:24][CH2:23]1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: O=C1NCCO1
Product: CS(=O)(=O)c1cc(N2CCOC2=O)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 49.6 %

Procedure:
By reaction and treatment in the same manner as in Example 111 and using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (451 mg) described in Preparation Example 89 and oxazolidin-2-one (78 mg), the title compound (226.6 mg) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Br)=[C:14]([C:20]([CH3:28])([CH3:27])[O:21][SiH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[O:15][C:16]2=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:38]2[C:39]([CH3:48])=[C:40]3[C:45](=[CH:46][CH:47]=2)[O:44][CH2:43][CH2:42][CH2:41]3)O1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:38]3[C:39]([CH3:48])=[C:40]4[C:45](=[CH:46][CH:47]=3)[O:44][CH2:43][CH2:42][CH2:41]4)=[C:14]([C:20]([CH3:28])([CH3:27])[O:21][SiH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[O:15][C:16]2=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1oc(=O)c2cc(OCc3ccccc3)ccc2c1Br
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)ccc2c1CCCO2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(-c2c(C(C)(C)O[SiH2]C(C)(C)C)oc(=O)c3cc(OCc4ccccc4)ccc23)ccc2c1CCCO2
Temperature: 25 °C
Reaction time: 12 h
Yield: 14.6 %

Procedure:
To a solution of 7-Benzyloxy-4-bromo-3-(tert-butyl-dimethyl-silanyloxymethyl)-isochromen-1-one (30 g, 63.1 mmol) and 4,4,5,5-tetramethyl-2-(5-methylchroman-6-yl)-1,3,2-dioxaborolane (51.9 g, 89 mmol) in 1,4-dioxane/H2O (400/100 mL) was added Pd(dppf)Cl2 (4.62 g, 6.31 mmol), Na2CO3 (20 g, 189 mmol), and PPh3 (4.96 g, 18.93 mmol). The resultant mixture was stirred at refluxing under N2. After 12 h, the reaction mixture was cooled to ambient temperature and partitioned between dichloromethane and water. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography column on silica gel to afford title product as a pale solid (5.0 g). LCMS (10-80 AB—2MIN.M): Rt=1.541, purity=93.3%, M+1=542.
Reaction SMILES: [Cl:1][C:2]1[C:14]([OH:15])=[C:13]2[C:5]([N:6]3[CH:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:17][O:16][C:8]4[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]3=4)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]#[N:34]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:17][O:16][C:8]4[CH:9]=[CH:10][CH:11]=[C:12]([C:13]=2[C:14]=1[O:15][CH2:32][C:33]#[N:34])[C:7]3=4
Reactant: Oc1c(Cl)ccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCOc1c(Cl)ccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 85 °C
Yield: 90.2 %

Procedure:
To a mixture of 8-chloro-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol (0.286 g, 0.851 mmol) in DMF (5.0 mL) is added potassium carbonate (0.59 g, 4.25 mmol) and bromoacetonitrile (0.3 mL, 4.25 mmol). The mixture is heated at 85° C for 1 h, then cooled and partitioned between water and Et2O. The organic layer is washed three times with water (50 mL), dried over magnesium sulfate and concentrated. Column chromatography (60 g silica gel) using CH2Cl2/hexane (1/1) as eluent gave 0.2876 g (90%) of 2-[(8-chloro-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]acetonitrile.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.Br[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1>>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([N:1]2[CH2:5][CH2:4][CH:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)[CH:16]=1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: Brc1cccnc1
Product: CC(C)(C)OC(=O)NC1CCN(c2cccnc2)C1
Yield: 67.2 %

Procedure:
tert-Butyl 3-pyrrolidinylcarbamate (0.099 g, 0.53 mmol; TCI) and 3-bromopyridine (0.050 mL, 0.52 mmol; Aldrich) were processed according to the procedure of Example 1A to provide the title compound (0.092 g, 66%). MS (CI/NH3) m/z 264 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][C:48]1[CH:55]=[CH:54][C:53]([F:56])=[CH:52][C:49]=1[CH2:50][NH2:51]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:51][CH2:50][C:49]4[CH:52]=[C:53]([F:56])[CH:54]=[CH:55][C:48]=4[F:47])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: NCc1cc(F)ccc1F
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCc2cc(F)ccc2F)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 2,5-difluorobenzylamine (Aldrich) to give the title product. LC-MS (ES+) 790 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[C:8]([CH3:13])[CH:7]=1>C(O)C.[B-](F)(F)(F)F.COC1C([P@](CC[P@](C2C=CC=CC=2)C2C(OC)=CC=CC=2)C2C=CC=CC=2)=CC=CC=1.C1CC=CCCC=C1.[Rh]>[CH2:18]([O:17][C:15]([NH:14][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[C:8]([CH3:13])[CH:7]=1)[C:3]([O:2][CH3:1])=[O:25])=[O:16])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)C(=Cc1ccc(Br)c(C)c1)NC(=O)OCc1ccccc1
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: COc1ccccc1[P@](CC[P@](c1ccccc1)c1ccccc1OC)c1ccccc1
Solvent: C1=CCCC=CCC1
Solvent: CCO
Product: COC(=O)[C@H](Cc1ccc(Br)c(C)c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.3 %

Procedure:
A solution of methyl-2-[(benzyloxy)carbonyl]amino-3-(4-bromo-3-methylphenyl)acrylate (10.4 g, 0.0257 mol) in ethanol (200 mL) was degassed with nitrogen. (R,R)-(−)-1,2-bis[(o-methoxyphenyl)(phenyl)phosphino]ethane(1,5-cyclooctadiene) rhodium (I) tetrafluroborate (194 mg, 257 μmol) was added to the reaction solution and nitrogen was bubble through. After five cycles of vacuum/H2, the reaction was heated at a pressure of 50 psi of hydrogen at room temperature. After 24 h, the solvent was removed under reduced pressure. The crude residue was purified by flash column chromatography to yield the desired product (8.7 g, 83%). 1H NMR (400 MHz, CD3OD): δ 7.40 (d, 1H), 7.3 (m, 5H), 7.13 (s, 1H), 6.91 (m, 1H), 5.00 (m, 2H), 4.42 (m, 1H), 3.70 (s, 3H), 3.09 (m, 1H), 2.84 (m, 1H), 2.32 (s, 3H); MF=C19H20BrNO4; LCMS found for C19H20BrNO4Na (M+Na)+: m/z=428, 430.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[N:13]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)=[C:5]([CH3:22])[N:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:3]1=[O:33].[S:34](=O)(=[O:37])([OH:36])[OH:35].O.C(OCC)(=O)C>C(#N)C>[C:18]([C:17]1[CH:16]=[CH:15][C:14]([N:13]2[C:9]([C:6]3[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:33])[N:4]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=4)[C:5]=3[CH3:22])=[C:10]([S:34]([OH:37])(=[O:36])=[O:35])[CH:11]=[N:12]2)=[CH:21][CH:20]=1)#[N:19]
Reactant: O=S(=O)(O)O
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1c(-c2c(S(=O)(=O)O)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a suspension of the compound prepared in Example 1 (2.0 g) in acetonitrile (20 ml) was added concentrated sulfuric acid (1.08 ml) and the resulting mixture was stirred with heating under reflux for three hours. The reaction mixture was cooled to room temperature and thereto were added water (40 ml) and ethyl acetate (40 ml×1, 20 ml×1) such that the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (20 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To the residue was added chloroform (10 ml) and the resulting mixture was stirred at 60° C. for thirty minutes. The mixture was stirred at room temperature overnight and the precipitated crystals were collected by filtration and washed with chloroform to afford 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonic acid (2.06 g).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([CH2:17][N:18]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19]2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][N:6]=1.C(=O)([O-])[O-:30].[K+].[K+].OO>CS(C)=O>[F:1][C:2]1[CH:16]=[C:15]([CH2:17][N:18]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19]2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]([NH2:10])=[O:30])=[CH:7][N:6]=1
Reactant: N#Cc1ccc(Oc2ccc(CN3CCC(c4ccccc4)C3)cc2F)nc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Oc2ccc(CN3CCC(c4ccccc4)C3)cc2F)nc1
Yield: 163.4 %

Procedure:
Using a method similar to Example 371, (±)-6-[2-fluoro-4-(3-phenyl-pyrrolidin-1-ylmethyl)-phenoxy]-nicotinonitrile (compound of example 375, step 2) (0.225 g, 0.603 mmol), potassium carbonate (0.0425 g, 0.308 mmol), and 30% hydrogen peroxide solution (aq) (0.203 mL, 1.79 mmol) in dimethylsulfoxide (6.0 mL) provide 0.197 g (83%) of the title compound as a white solid: high resolution mass spectrum (electrospray): m/z calc for C23H23FN3O2 392.1774, found 392.1760; 1H NMR (methanol-d4): 8.62 (d, 1H, J=2.4 Hz), 8.32 (d, 1H, J=2.9, 8.8 Hz), 7.41-7.25 (m, 7H), 7.25-7.19 (m, 1H), 7.15 (d, 1H, J=8.3 Hz), 3.83 (d, 1H, J=13.2 Hz), 3.80 (d, 1H, J=13.2 Hz), 3.51-3.41 (m, 1H), 3.18 (d, 1H, J=9.3 Hz), 3.02-2.94 (m, 1H), 2.86 (td, 1H, J=5.9, 8.8 Hz), 2.63 (t, 1H, J=8.8 Hz), 2.46-2.35 (m, 1H), 2.05-1.94 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[NH:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]([NH2:20])=[O:19])=[CH:17][C:12]=2[N:11]=[CH:10]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:8][C:4]1[N:3]=[C:2]([N:11]2[C:12]3[CH:17]=[C:16]([C:18]([NH2:20])=[O:19])[CH:15]=[CH:14][C:13]=3[N:9]=[CH:10]2)[CH:7]=[N:6][CH:5]=1
Reactant: NC(=O)c1ccc2[nH]cnc2c1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2ncn(-c3cncc(Cl)n3)c2c1
Temperature: 90 °C

Procedure:
A mixture of 2,6-dichloropyrazine (2.0 g, 13.4 mmol), 1H-benzimidazole-5-carboxamide (2.0 g, 12.3 mmol) and cesium carbonate (5.6 g, 17.2 mmol) in DMF (10 mL) was heated at 90° C. for 3 h. The solution was cooled to RT and diluted with ethyl acetate (20 mL) and filtered. The solid material was washed with chloroform-methanol (20 mL, 4:1) and the combined filtrates concentrated in vacuo. The residue thus obtained (3.02 g) was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([NH:15]C(=O)C(Cl)(Cl)Cl)[C:12]2[C:7](=[C:8]([CH2:32][CH2:33][CH3:34])[C:9]3[O:25][C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:23][C:22](=[O:31])[C:10]=3[CH:11]=2)[N:6]=1)=[O:4].N>S(=O)(=O)(O)O>[NH2:15][C:13]1[C:12]2[C:7](=[C:8]([CH2:32][CH2:33][CH3:34])[C:9]3[O:25][C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:23][C:22](=[O:31])[C:10]=3[CH:11]=2)[N:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:14]=1
Reactant: CCCc1c2nc(C(=O)OC)cc(NC(=O)C(Cl)(Cl)Cl)c2cc2c(=O)cc(C(=O)OCC)oc12
Agent: N
Agent: O=S(=O)(O)O
Product: CCCc1c2nc(C(=O)OC)cc(N)c2cc2c(=O)cc(C(=O)OCC)oc12
Reaction time: 0.5 h

Procedure:
The product of step (a) (1.0 g) was dissolved in concentrated sulphuric acid (1 ml) and stirred vigorously for 0.5 hours. The deep red solution was then poured into iced aqueous ammonia solution (100 ml), and the precipitate filtered to give the title compound, 0.5 g, as an orange powder, mp 265°-270° C. (decomposes).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:26][CH2:27][CH2:28][CH3:29])=[C:21]([CH:25]=1)[C:22](O)=[O:23].O.O[N:32]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>CN(C)C=O.[OH-].[NH4+].O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:26][CH2:27][CH2:28][CH3:29])=[C:21]([CH:25]=1)[C:22]([NH2:32])=[O:23]
Reactant: On1nnc2ccccc21
Reactant: CCCOc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCCOc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
To a solution of 5-({[(Z)-(6-bromo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)-2-propoxybenzoic acid (30 mg, 65 μmol) in N,N-dimethylformamide (1 mL) is added 1-hydroxybenzotriazole hydrate (22 mg, 0.16 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31 mg, 0.16 mmol), and 1-methylmorpholine (25 μL, 0.23 mmol). After shaking at room temperature for 1 hour, to the reaction mixture is added 30% aqueous ammonium hydroxide (5 drops). After 10 minutes of agitation, water is added to the mixture, precipitating a solid, which is collected by filtration, washed with water and methanol, and then dried under house vacuum to give 5-({[(Z)-(6-bromo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)-2-propoxybenzamide (17 mg, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.CC(C1C=CC=C(Cl)C=1)=O.[NH2:27][C:28]1[C:32]([C:33]#[N:34])=[CH:31][NH:30][N:29]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:29]3[N:30]=[CH:31][C:32]([C:33]#[N:34])=[C:28]3[N:27]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1c[nH]nc1N
Reactant: O=C(CC(=O)C(F)(F)F)c1cccc(Cl)c1
Agent: CC(=O)c1cccc(Cl)c1
Product: N#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(Cl)c3)nc12
Yield: 46.5 %

Procedure:
Reaction of 1-(3-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (251 mg, 1.0 mmol), prepared from commercially available 3-chloro-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (150 mg, 46%). MS (ISP) 323.1 [(M+H)+]; mp 204° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH2:23][C:24](=[O:35])[N:25]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:26][CH3:27])=[CH:11][N:10]=1)(C)(C)C.[ClH:37]>CCOC(C)=O>[ClH:37].[NH2:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH2:23][C:24]([N:25]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:26][CH3:27])=[O:35])=[CH:11][N:10]=1
Reactant: CCN(Cc1ccccc1)C(=O)Cc1cnc(CNC(=O)OC(C)(C)C)c2cc(OC)c(OC)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCN(Cc1ccccc1)C(=O)Cc1cnc(CN)c2cc(OC)c(OC)cc12
Yield: 95 %

Procedure:
As described in Example 1, 84 mg of {4-[(benzyl-ethyl-carbamoyl)-methyl]-6,7-dimethoxy-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester was treated with HCl in EtOAc to give 64 mg (95%) of 2-(1-aminomethyl-6,7-dimethoxy-isoquinolin-4-yl)-N-benzyl-N-ethyl-acetamide hydrochloride. MS: APCI (M+H) calc'd for C23H27N3O3+H 394.5; found 394.2.
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[C@@H:7]([NH:15][CH2:16][C@@H:17]([OH:29])[C@@H:18]([NH2:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:6]1)[CH:2]=[CH2:3].[C:30](O)(=[O:36])[CH2:31][CH2:32][CH2:33][CH:34]=[CH2:35]>CC(=O)OCC>[CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[C@H:7]([NH:15][CH2:16][C@@H:17]([OH:29])[C@@H:18]([NH:28][C:30](=[O:36])[CH2:31][CH2:32][CH2:33][CH:34]=[CH2:35])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c2cc(Br)ccc21
Reactant: C=CCCCC(=O)O
Solvent: CCOC(C)=O
Product: C=CCCCC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CN[C@@H]1C[C@@H](OCC=C)c2ccc(Br)cc21
Yield: 62 %

Procedure:
Step EE (1): (2R,3S)-1-((1S,3R)-3-(Allyloxy)-6-bromo-2,3-dihydro-1H-inden-1-ylamino)-3-amino-4-(3,5-difluorophenyl)butan-2-ol from Step EA (1) was coupled with hex-5-enoic acid by following a procedure analogous to Step EA (2) to afford 1.9 g (62% yield) of N-((2S,3R)-4-((1R,3R)-3-(allyloxy)-6-bromo-2,3-dihydro-1H-inden-1-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)hex-5-enamide. MS (M+2H)+ 564.95. 1H NMR (500 MHz, CDCl3) δ ppm 1.58-1.69 (m, 3H) 1.87-2.00 (m, 4H) 2.03-2.16 (m, 2H) 2.64-2.73 (m, 2H) 2.76-2.85 (m, 2H) 3.04 (dd, J=14.34, 4.58 Hz, 1H) 3.48-3.53 (m, 1H) 4.04-4.21 (m, 4H) 4.76 (t, J=5.80 Hz, 1H) 4.93 (s, 1H) 4.96 (dd, J=3.51, 1.37 Hz, 1H) 5.20 (dd, J=10.38, 1.22 Hz, 1H) 5.28-5.34 (m, 1H) 5.60-5.76 (m, 2H) 5.90-5.99 (m, 1H) 6.63-6.68 (m, 1H) 6.73-6.78 (m, 2H) 7.28 (d, J=8.24 Hz, 1H) 7.41 (dd, J=7.93, 1.83 Hz, 1H) 7.51 (s, 1H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[OH:14])[CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7].OS(O)(=O)=O.[CH3:20][C:21](=[CH2:23])[CH3:22].C([O-])(O)=O.[Na+]>O1CCOCC1.O>[I:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[OH:14])[CH2:5][C@@H:6]([C:8]([O:10][C:21]([CH3:23])([CH3:22])[CH3:20])=[O:9])[NH2:7]
Reactant: C=C(C)C
Reactant: N[C@@H](Cc1ccc(O)c(I)c1)C(=O)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)c(I)c1
Temperature: 25 °C
Yield: 58 %

Procedure:
A mixture of 5.0 g of 3-iodo-L-tyrosine (Aldrich) and 2.5 mL of conc. H2SO4 in 85 mL of 1,4-dioxane was added to 30 mL of liquid isobutylene (condensed at −78° C.) in a 300 mL pressure bottle. The vessel was stoppered and the contents stirred at RT. After 3 days the bottle was cooled in an ice water bath, opened and the solution poured into a mixture of 10 g of NaHCO3 in 150 mL of water. The resulting mixture was subjected to rotary evaporation to remove isobutylene and dioxane. A white solid resulted which was collected by filtration and dried in vacuo. Analysis by tlc (SiO2, 95:5 CH2Cl2:MeOH) indicated major and minor components at Rf=0.52 and 0.60 respectively. The crude product was purified by flash chromatography on silica gel (95:5 CH2Cl2:MeOH) to afford 3.4 g (58%) of tert-butyl 3-iodo-L-tyrosinate as a white crystalline solid, m.p. 158-159° C.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(OC=3C3C=CC=CC=3)=C3C(=CC=4)NN=C3)=CC=2)CCC1.C(OC(=O)[NH:38][C:39]1([C:43]2[CH:48]=[CH:47][C:46]([C:49]3[C:54](=[O:55])[C:53]4[CH:56]=[CH:57][C:58]5[N:59]=[CH:60][N:61]([CH3:63])[C:62]=5[C:52]=4[O:51][C:50]=3[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:45][CH:44]=2)[CH2:42][CH2:41][CH2:40]1)(C)(C)C>>[NH2:38][C:39]1([C:43]2[CH:44]=[CH:45][C:46]([C:49]3[C:54](=[O:55])[C:53]4[CH:56]=[CH:57][C:58]5[N:59]=[CH:60][N:61]([CH3:63])[C:62]=5[C:52]=4[O:51][C:50]=3[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:47][CH:48]=2)[CH2:40][CH2:41][CH2:42]1
Reactant: Cn1cnc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c21
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5[nH]ncc54)c3=O)cc2)CCC1
Product: Cn1cnc2ccc3c(=O)c(-c4ccc(C5(N)CCC5)cc4)c(-c4ccccc4)oc3c21
Yield: 85 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-2-phenyl-7H-pyrano[2,3-e]indazol-4-one, {1-[4-(1-methyl-6-oxo-8-phenyl-1,6-dihydro-chromeno[7,8-d]imidazol-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a white solid (43 mg, 85%). 1H NMR (400 MHz, DMSO-d6): δ 8.44 (s, 1H), 7.88 (d, J=9.2 Hz, 1H), 7.73 (d, J=9.2 Hz, 1H), 7.54-7.50 (m, 2H), 7.44-7.34 (m, 5H), 7.18-7.13 (m, 2H), 4.21 (s, 3H), 2.42-2.34 (m, 2H), 2.12-2.04 (m, 2H), 2.04-1.94 (m, 1H), 1.70-1.59 (m, 1H). LCMS (Method E): RT=2.86 min, [M+H]+=422.
Reaction SMILES: [N:1]1[C:6]2[O:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[O:10][C:5]=2[CH:4]=[C:3](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:2]=1>C(O)(=O)C.[C].[Pd]>[N:1]1[C:6]2[O:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[O:10][C:5]=2[CH:4]=[C:3]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:2]=1
Reactant: CCOC(=O)/C=C/c1cc2c(nn1)Oc1ccccc1O2
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)CCc1cc2c(nn1)Oc1ccccc1O2
Temperature: 25 °C
Reaction time: 168 h
Yield: 93.2 %

Procedure:
To a solution (20 ml) of ethyl (2E)-3-([1,4]benzodioxino[2,3-c]pyridazin-3-yl)acrylate (649 mg) in acetic acid was added 10% palladium-carbon (100 mg), and the mixture was stirred at room temperature for 7 days under a hydrogen atmosphere. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to give ethyl 3-([1,4]benzodioxino[2,3-c]pyridazin-3-yl)propanoate (609 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6]Cl.[Br:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[CH:12]=[CH:13][C:14]=1[OH:15].C(N(C(C)C)CC)(C)C.[OH-].[Na+]>ClCCl>[Br:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: Oc1ccc(-c2cccc(F)c2)cc1Br
Reactant: COCCOCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCOc1ccc(-c2cccc(F)c2)cc1Br
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.6 %

Procedure:
2-Methoxyethoxymethylchloride (0.67 mL, 5.83 mmol) was added dropwise to a solution of 3-bromo-3′-fluoro-[1,1′-biphenyl]-4-ol (˜5.55 mmol) and diisopropylethylamine (1.93 mL, 11.1 mmol) in dry dichloromethane (20 mL) at room temperature under nitrogen. The reaction mixture was stirred at room temperature under nitrogen for 3 days, 1.0 M aqueous sodium hydroxide (20 mL) added and the biphasic mixture stirred vigorously for 20 minutes. The reaction mixture was partitioned between ethyl acetate (100 mL) and 1.0 M aqueous sodium hydroxide solution (100 mL), the organic phase separated, washed with water (75 mL) and saturated brine (75 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give an orange oil. The crude product was purified by chromatography on silica eluting with a solvent gradient of 0 to 10% ethyl acetate (containing 2% methanol) in hexanes to give 3-bromo-3′-fluoro-4-((2-methoxyethoxy)methoxy)-1,1′-biphenyl (1.57 g, 80% yield) as a colorless oil.