Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([C:5]2[N:10]=[C:9]([NH:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:8]3=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:20]=[CH:21][N:7]3[N:6]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.Cl[C:35]([O:37][CH3:38])=[O:36]>C(Cl)Cl>[C:22]1([C:19]2[CH:20]=[CH:21][N:7]3[C:8]=2[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:10][C:5]([C:2]2([NH:1][C:35](=[O:36])[O:37][CH3:38])[CH2:3][CH2:4]2)=[N:6]3)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC1(c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)CC1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)NC1(c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.2 %

Procedure:
To a stirred solution of 2-(1-aminocyclopropyl)-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (60.0 mg, 0.168 mmol) in DCM (10 mL) was added pyridine (0.0270 mL, 0.337 mmol) followed by methyl chloroformate (0.0140 mL, 0.185 mmol) and the reaction mixture stirred at RT for 2 h then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed water (2×30 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Condition B-93 as described in general methods) to give methyl (1-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopropyl)carbamate (21.0 mg, 30.1%) as white solid. LCMS Condition B-34: retention time 2.29 min, [M+1]=415.0. HPLC Condition B-31: retention time 7.09 min, Purity 99.15%. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99-1.06 (m, 2H), 1.34-1.41 (m, 2H), 3.54 (s, 3H), 4.67 (d, J=4.8 Hz, 2H), 6.68 (d, J=2.7 Hz, 1H), 7.00 (s, 1H), 7.27 (ddd, J=7.5 Hz, J=4.9 Hz, J=1.1 Hz, 1H), 7.35 (d, J=7.9 Hz, 1H), 7.39-7.45 (m, 1H), 7.48-7.57 (m, 4H), 7.70 (d, J=2.7 Hz, 1H), 7.73-7.80 (m, 2H), 8.36-8.41 (m, 1H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:27])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1.I[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH3:9][O:10][C:11](=[O:27])[CH:12]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:15][CH:14]=1)[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: ICC1CCCC1
Reactant: COC(=O)Cc1ccc(OCc2ccccc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)c1ccc(OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 86.6 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23 mL of a 0.31M stock solution, 7.13 mmol) was cooled to −78° C. and then treated with a solution of (4-benzyloxy-phenyl)-acetic acid methyl ester (1.66 g, 6.48 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (16.1 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (1.50 g, 7.13 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 48 h. At this time, the reaction mixture was quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (10 mL). This mixture was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with a saturated aqueous lithium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 98/2 hexanes/ethyl acetate) afforded 2-(4-benzyloxy-phenyl)-3-cyclopentyl-propionic acid methyl ester (1.90 g, 86.6%) as a white wax: mp 55-57° C.; EI-HRMS m/e calcd for C22H26O3 (M+) 338.1881 found 228.1878.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH2:14]([O:16][C:17](=[O:36])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=1)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[CH2:14]([O:16][C:17](=[O:36])[CH2:18][C:19]1[CH:20]=[C:21]([C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[C:4]#[N:5])[C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)[CH3:15]
Reactant: N#Cc1cc(C(F)(F)F)ccc1Br
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)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: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C#N)c1
Temperature: 85 °C
Reaction time: 36 h

Procedure:
2-Bromo-5-(trifluoromethyl)benzonitrile (5.5 g, 22 mmol), [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (7.04 g, 22 mmol), potassium carbonate (7.6 g, 55 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.300 g, 0.25 mmol) were combined in DME (40 mL) and H2O (20 mL). The mixture was purged with N2, and then stirred at 85° C. for 36 hours. After standard work-up, the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:25])[C:13]([CH:23]=O)=[CH:14][N:15]3[CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][C:9]=2[F:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:33]([O:35][C:36](=[O:46])[CH2:37]P(OCC)(OCC)=O)[CH3:34].O>CN(C=O)C>[CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:25])[C:13](/[CH:23]=[CH:37]/[C:36]([O:35][CH2:33][CH3:34])=[O:46])=[CH:14][N:15]3[CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)=[CH:10][C:9]=2[F:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1.0 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde was dissolved in 20 ml of DMF, and 2.0 g of potassium carbonate and 2.8 ml of ethyl(diethoxyphosphoryl)acetate were added, followed by overnight stirring at 60° C. The resulting reaction mixture was cooled to room temperature, water was added, and then the insoluble materials were collected by filtration to obtain 1.2 g of ethyl (2E)-3-[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]acrylate.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7](=[O:29])[C@H:8]([NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH2:17])[CH:11]=1.[N:30]([O-])=O.[Na+].[OH-].[NH4+]>C(O)(=O)C.O>[CH3:5][O:6][C:7](=[O:29])[C@H:8]([NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]2[NH:16][N:30]=[N:17][C:12]=2[CH:11]=1
Reactant: O=N[O-]
Reactant: COC(=O)[C@@H](Cc1ccc(N)c(N)c1)NC(=O)OCc1ccccc1
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)[C@@H](Cc1ccc2[nH]nnc2c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
To a solution of (R)-2-benzyloxycarbonylamino-3-(3,4-diamino-phenyl)-propionic acid methyl ester mono acetate (2.68 g, 6.65 mmol) in acetic acid (30 mL) and water (40 mL), at room temperature was added a solution of sodium nitrite (0.46 g, 6.65 mmol) in water (8 mL), dropwise over several minutes. The resulting mixture was stirred at room temperature for 20 min, then cooled to 0° C., concentrated ammonium hydroxide was added to adjust pH to 11. The mixture was extracted with ethyl acetate twice in the presence of solid sodium chloride, and the organic layers were dried over sodium sulfate. After filtration, solvents were removed in vacuo and the residue was purified by chromatography on silica gel using ethyl acetate/hexanes (6:4) as eluent to afford the title compound as a tan solid (94% yield). 1H-NMR (CD3OD, 500 MHz) δ 7.75 (d, J=8.5 Hz, 1H), 7.58 (s, 1H), 7.31-7.25 (m, 5H), 7.18 (d, J=8.5 Hz, 1H), 5.39 (d, J=8.0 Hz, 1H), 5.10 (d, J=12.0 Hz, 1H), 5.05 (d, J=12.0 Hz, 1H), 4.74 (dd, J=13.5, 6.0 Hz, 1H), 3.73 (s, 3H), 3.34 (dd, J=14.0, 5.5 Hz, 1H), 3.22 (dd, J=13.5, 6.0 Hz, 1H). 13C NMR (CD3OD, 125 MHz) δ 172.1, 156.0, 136.1, 128.6, 128.3, 128.1, 67.2, 55.2, 52.7, 38.5. Mass spec. 355.18 (MH)+.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:39][CH:38]([OH:40])[CH:37]([OH:41])[CH2:36]1>>[F:25][C:18]1[CH:19]=[C:20]([CH3:24])[C:21]([F:23])=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]2[CH2:39][CH:38]([OH:40])[CH:37]([OH:41])[CH2:36]2)=[O:29])[S:14][N:13]=1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)cc1F
Reactant: NCCCCN1CC(O)C(O)C1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN3CC(O)C(O)C3)c2C(N)=O)cc1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]carbamic acid phenyl ester and 1-(4-amino-butyl)-pyrrolidine-3,4-diol by the procedure analogous to Example 8. HPLC ret. time: minutes. 1H NMR (400 MHz, CD3OD) δ7.20 (dd, 1H, J=6.0, 9.2 Hz), 7.04 (dd, 1H, J=6.8, 9.6 Hz), 5.45 (s, 2H), 3.63 (t, 4H, J=5.6 Hz), 3.28 (m), 2.74 (m, 4H), 2.68 (m, 2H), 2.25 (d, 3H, J=2.0 Hz), 1.56 (m, 4H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[OH:12][C:13]1[CH:20]=[CH:19][C:16](C=O)=[CH:15][CH:14]=1.[OH:21]OS([O-])=O.[K+].CCOC(C)=O>CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1.[OH:21][C:16]1[CH:19]=[CH:20][C:13]([OH:12])=[CH:14][CH:15]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=S([O-])OO
Agent: COC(=O)c1ccc(O)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Oc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To prepare methyl 4-hydroxybenzoate, 4-hydroxybenzaldehyde (100 mg) was dissolved in MeOH (10 mL), and OXONE (0.503 g) was added and stirred at room temperature for 18 hours with the reaction having a final volume (11 mL). The reaction was monitored by TLC or GC analysis. EtOAc was added to extract the products and 1N HCl was used to dissolve the salts. The organic extract was washed with 1N HCl (30 mL×3) and brine (30 mL), dried over Na2SO4, and the solvent was removed under reduced pressure to obtain methyl 4-hydroxybenzoate in 4% yield and 4-hydroxyphenol in 77% yield after purification by silica gel column chromatography.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[CH:22]=[C:23](B2OC(CC)(CC)C(CC)(CC)O2)[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:22]=[C:21]([O:20][CH3:19])[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: CCC1(CC)OB(c2cc(OC)cc(OC)c2)OC1(CC)CC
Product: CCCNC(=O)c1nnc2c(-c3cc(OC)cc(OC)c3)cccc2c1N
Yield: 91 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 2-(3,5-dimethoxyphenyl)-4,4,5,5-tetraethyl-(1,3,2)-dioxaborolane (256 mg, 0.97 mmol) were reacted to afford the title compound (110 mg, 93.9% yield) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.57 (br, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.79 (dd, J=7.2 Hz, J′=1.3 Hz, 1H), 7.71 (t, J=7.7 Hz, 1H), 6.79 (d, 3H), 3.83 (s, 6H), 3.47 (q, J=6.7 Hz, 2H), 1.67 (m, J=7.3 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H) MS APCI, m/z=367 (M+H) HPLC 1.98 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH:11]([N:14](CC)C(C)C)(C)[CH3:12].BrCC#N>C1COCC1>[Br:10][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:12][C:11]#[N:14])=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: N#Cc1cc(N)ccc1Br
Reactant: CCN(C(C)C)C(C)C
Agent: N#CCBr
Solvent: C1CCOC1
Product: N#CCNc1ccc(Br)c(C#N)c1
Temperature: 100 °C

Procedure:
Mix 5-amino-2-bromobenzonitrile (0.76 mmol) in anhydrous THF (3 ml), N,N-diisopropylethylamine (0.92 mmol), and bromoacetonitrile (1.0 mmol) at room temperature under inert atmosphere. Heat the mixture to 100° C. for 16 h in a sealed tube. Cool in ice bath, filter the precipitate and evaporate the filtrate to dryness to afford a crude residue. Purify by flash chromatography (Silica gel-CHCl3/Ethanol/NH4OH 9:1:0.1) to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:9]=2)=[CH:4][CH:3]=1.Br[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>ClCCl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:15][CH2:14]3)[N:10]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: BrCCc1ccccn1
Reactant: Clc1ccc(-c2cc(C3CCNCC3)n(-c3ccccc3)n2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Clc1ccc(-c2cc(C3CCN(CCc4ccccn4)CC3)n(-c3ccccc3)n2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of INTERMEDIATE 5 (30 mg, 0.089 mmol) in dichloromethane (0.4 mL) was added 2-(2-bromoethyl)pyridine (28.4, 0.107 mmol). The mixture was stirred at 60° C. overnight, and then cooled to room temperature. The mixture was diluted with EtOAc, and washed with water. The organic layer was separated, dried and concentrated. The resulting residue was purified by preparative TLC (using 2 M NH3 in MeOH/MeOH/DCM/0.05 mL/5 mL/9.5 mL) to give the title compound. LC-MS m/z 443.17 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24](Br)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].CC1(C)C(C)(C)OB([C:34]2[CH2:35][CH2:36][CH2:37][N:38]([C:40](=[O:42])[CH3:41])[CH:39]=2)O1.C([O-])(=O)C.[K+].O1CCOCC1>O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:36]3[CH2:35][CH2:34][CH2:39][N:38]([C:40](=[O:42])[CH3:41])[CH:37]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: CC(=O)N1C=C(B2OC(C)(C)C(C)(C)O2)CCC1
Reactant: O=C(c1ccc(Oc2ncccc2Br)cc1)c1nc2ccccc2[nH]1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1C=C(c2cccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CCC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 0.2 %

Procedure:
To a degassed solution of (1H-benzo[d]imidazol-2-yl)(4-(3-bromopyridin-2-yloxy)phenyl)methanone (706 mg, 1.791 mmol), 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridin-1(2H)-yl)ethanone (0.5 g, 1.991 mmol), potassium acetate (1.5 g, 15.28 mmol), and dioxane (10 mL) was added A-Phos (140 mg, 0.198 mmol). The solution was stirred at 80° C. After 16 hours, the reaction was allowed to cool to room temperature, diluted with H2O (10 mL), and the aqueous layer extracted with DCM (5 mL). The combined organic layers were concentrated in vacuo and purified by Prep TLC (1:1 hexanes/EtOAc) to give 1-(5-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)-3,4-dihydropyridin-1(2H)-yl)ethanone (1.6 mg, 3.65 μmol) as a light yellow film. MS (ESI, pos. ion) m/z: 439.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][CH:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[C:4]([C:19]([OH:21])=O)=[C:3]1[CH3:22].[NH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][N:28]=[C:27]2[Cl:33]>>[Cl:33][C:27]1[C:26]2[C:30](=[CH:31][CH:32]=[C:24]([NH:23][C:19]([C:4]3[CH:5]([C:9]4[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][CH:10]=4)[CH2:6][C:7](=[O:8])[N:2]([CH3:1])[C:3]=3[CH3:22])=[O:21])[CH:25]=2)[NH:29][N:28]=1
Reactant: CC1=C(C(=O)O)C(c2ccc(C(F)(F)F)cc2)CC(=O)N1C
Reactant: Nc1ccc2[nH]nc(Cl)c2c1
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Cl)c3c2)C(c2ccc(C(F)(F)F)cc2)CC(=O)N1C

Procedure:
The title compound was prepared from the product of Example 41, Step 2 and 5-amino-3-chloroindazole using the method described in Example 56, Step 3. MS (ES+) m/e 463 [M+H]+
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:14][C:15]([CH3:18])([CH3:17])[O:16][C:11]=2[CH:10]=[C:9]([NH2:26])[CH:8]=1>N1C=CC=CC=1>[F:6][C:7]1[C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:14][C:15]([CH3:18])([CH3:17])[O:16][C:11]=2[CH:10]=[C:9]([NH:26][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=1
Reactant: CC1(C)N=C(c2ccc(F)cc2)c2c(F)cc(N)cc2O1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC1(C)N=C(c2ccc(F)cc2)c2c(F)cc(NS(C)(=O)=O)cc2O1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Methanesulfonylchloride (93 μL) was added dropwise to a solution of 5-fluoro-4-(4-fluorophenyl)-2.2-dimethyl-2H-1,3-benzoxazin-7-amine (a compound of Reference Example 2, 87 mg) in pyridine (2 mL), and said mixture was stirred at 40° C. overnight. The reaction mixture was concentrated in vacuo, and the residue was dissolved in chloroform. The solution was washed successively with water, 10% hydrochloric acid and brine, filtered through a column of porous diatomite [Chem Elut (trade name), Varian Inc.], and the filtrate was concentrated in vacuo. The resulted residue was purified by column chromatography on silica gel (Solvent: n-hexane/ethyl acetate=85/15 to 30/70) to give the titled compound (21 mg) as a colorless powder.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:5]=2[O:4]1.[CH3:15][O:16][CH2:17]OC.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH3:15][O:16][CH2:17][O:1][CH2:2][CH:3]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:5]=2[O:4]1
Reactant: COCOC
Reactant: COc1cccc2c1OC(CO)C2=O
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: ClCCl
Product: COCOCC1Oc2c(OC)cccc2C1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 58 %

Procedure:
2,3-dihydro-2-hydroxymethyl-3-oxo-7-methoxybenzofuran (1.79 g) and dimethoxymethane (10 ml) were dissolved in dichloromethane (25 ml) and phosphorus pentoxide (3.47 g) was added to the obtained solution, followed by stirring the resulting solution at room temperature for 3.5 hours. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layers were combined and washed with water and with saturated brine, followed by drying over magnesium sulfate. Magnesium sulfate was removed by filtration and the solvent was evaporated off. The residue was purified by column chromatography (solvent: n-hexane/ethyl acetate=1/1) to obtain the desired compound (912 mg, yield: 58%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.N[NH:13][C@@H:14]([CH2:19][OH:20])[CH2:15][CH:16]([CH3:18])[CH3:17]>>[OH:20][CH2:19][C@H:14]([NH:13][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([CH3:1])[CH:3]=1)[CH2:15][CH:16]([CH3:18])[CH3:17]
Reactant: Cc1ccc(C(=O)O)cc1C
Reactant: CC(C)C[C@H](CO)NN
Product: Cc1ccc(C(=O)N[C@@H](CO)CC(C)C)cc1C
Yield: 75 %

Procedure:
(R)—N-(1-hydroxy-4-methylpentan-2-yl)-3,4-dimethylbenzamide was prepared in a similar manner as described in example 4 using 3,4-dimethylbenzoic acid and with (R)-aminoleucinol. Yield: 75%. MS (M+H, 250.3).
Reaction SMILES: [CH:1](/[CH:6]1[CH2:11][CH2:10][CH:9]([CH:12]=[O:13])[CH2:8][CH2:7]1)=[CH:2]\[CH2:3][CH2:4][CH3:5].[Cr](O)(O)(=O)=[O:15].C(O)(C)C>CC(C)=O>[CH:1](/[CH:6]1[CH2:7][CH2:8][CH:9]([C:12]([OH:15])=[O:13])[CH2:10][CH2:11]1)=[CH:2]\[CH2:3][CH2:4][CH3:5]
Reactant: O=[Cr](=O)(O)O
Reactant: CCC/C=C/C1CCC(C=O)CC1
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CCC/C=C/C1CCC(C(=O)O)CC1
Reaction time: 1 h
Yield: 49.5 %

Procedure:
A solution of 1.6 g of 4-(1E-pentenyl)cyclohexanecarboxaldehyde in 120 ml of acetone was cooled to -10° C., treated dropwise with 8N chromic acid (about 10 ml) until the colour of the reaction mixture remained brown-orange and the mixture was stirred for a further 1 hour. Excess chromic acid was reduced by adding isopropanol. The green solution was subsequently partitioned three times in water/methylene chloride. The organic extracts were washed twice with water and the wash-water was back-extracted with methylene chloride. The organic phases were dried over magnesium sulphate and evaporated. The pale brown crystalline residue (2.01 g) was dissolved partially in 20 ml of petroleum ether. Undissolved residue was filtered off and the filtrate was evaporated. Recrystallization of the residue obtained from 60 ml of petroleum ether at -78° C. gave 866 mg (49.5%) of 4-(1E-pentenyl)cyclohexanecarboxylic acid as white crystals.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([C:14]#[N:15])[CH:8]=2)[N:6]=1.[OH2:16]>>[CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([C:14](=[O:16])[NH2:15])[CH:8]=2)[N:6]=1
Reactant: O
Reactant: Cc1nc(-c2ccc(N)c(C#N)c2)c[nH]1
Product: Cc1nc(-c2ccc(N)c(C(N)=O)c2)c[nH]1

Procedure:
A mixture of 2-methyl-4-(3-cyano-4-amino-phenyl)-1H-imidazole (6.2 g), the ion exchanger Amerlite® IRA 400 (OH) (12 g) and water (150 ml) was refluxed for 5 hours. After cooling and filtration, the resulting solution was evaporated to dryness to give 4.1 g of the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]2[O:14][CH2:13][O:12][C:9]([C:10]=1[F:11])=[CH:8][C:4]=2[C:5](O)=[O:6].C(Cl)(=O)C([Cl:18])=O>C(OCC)C.CN(C)C=O>[F:1][C:2]1[C:3]2[O:14][CH2:13][O:12][C:9]([C:10]=1[F:11])=[CH:8][C:4]=2[C:5]([Cl:18])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc2c(F)c(F)c1OCO2
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc2c(F)c(F)c1OCO2
Temperature: 0 °C
Reaction time: 60 h
Yield: 101.4 %

Procedure:
A solution of 15.0 grams (0.0742 mole) of 3,4-difluoromethylenedioxybenzoic acid in 200 mL of diethyl ether was stirred and cooled to 0° C. To this was added one drop of dimethylformamide followed by the dropwise addition of 11.3 grams (0.0890 mole) of oxalyl chloride. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it stirred for 60 hours. After this time the reaction mixture was concentrated under reduced pressure to yield 16.6 grams of 3,4-difluoromethylenedioxybenzoyl chloride.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:13][C:14]1[CH:29]=[CH:28][C:17]([C:18]([N:20]2[CH2:24][CH2:23][CH2:22][CH:21]2C(O)=O)=O)=[CH:16][CH:15]=1.C(OC(C)C)(C)C>C(OC(=O)C)(=O)C>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]2[N:20]3[C:21]([CH2:22][CH2:23][CH2:24]3)=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:28][CH:29]=1
Reactant: O=C(O)C1CCCN1C(=O)c1ccc(F)cc1
Reactant: COC(=O)C#Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)OC(C)C
Product: COC(=O)c1c(-c2ccccc2)c(-c2ccc(F)cc2)n2c1CCC2
Temperature: 28 °C
Reaction time: 4 h

Procedure:
Methyl phenylpropiolate (methyl dehydrocinnamate (0.96 g, 6 mmol)) is dissolved in acetic anhydride (14 ml) and brought to the boiling temperature of acetic anhydride in a hot oil bath (140° C.). The total amount of 1-(4-fluorobenzoyl)pyrrolidine-2-carboxylic acid (1.42 g, 6 mmol) is added, and the thoroughly mixed solution is refluxed (1 28° C.) for 20 h with stirring. After standing for 4 hours and cooling to RT, a pure crystalline solid deposits (TLC: Al2O3, diisopropyl ether, Rf 0.7). The crystals are filtered off with suction, washed with water (20 ml) and finally with isopropyl ether (10 ml). The dried crystals weigh 650 mg (32.5% of theory)