Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:11](=[CH2:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([NH2:25])C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[NH2:25][CH2:17][C@@H:11]([C@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3])[CH3:10])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: C=C(C(=O)OCC)[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: NCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)[C@@H](CN)[C@@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 144 h
Yield: 101.7 %

Procedure:
To a solution of ethyl 2-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]acrylate (25.84 g) in methanol (517 ml) was added benzylamine (11.79 g) at room temperature. After stirring for 6 days, 10% palladium hydroxide on carbon (2.58 g) was added and the mixture was stirred under hydrogen atmosphere for 5 hours. After the termination of reaction, the mixture was concentrated to give crude ethyl (2S,3R)-2-aminomethyl-3-(t-butyldimethylsilyloxy)butanoate (28.02 g). This compound was immediately used as the starting compound for the next transformation without further purification.
Reaction SMILES: [O:1]=O.[Br:3][C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([Br:17])=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1.[OH-].[Na+]>[Br-].[NH4+].[NH4+].[NH4+].[NH4+].[Br-].[Br-].[Br-]>[Br:3][C:4]1[C:5](=[O:1])[C:6]2[C:14](=[CH:15][CH:16]=1)[C:13]1[C:8](=[CH:9][C:10]([Br:17])=[CH:11][CH:12]=1)[CH:7]=2
Reactant: O=O
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Agent: [Br-]
Agent: [NH4+]
Agent: [Na+]
Product: O=C1C(Br)=CC=C2C1=Cc1cc(Br)ccc12
Yield: 83.2 %

Procedure:
Into a three-necked, 300-mL flask equipped with a stirrer, a molecular-oxygen-containing gas (air) inlet tube and a gas outlet tube (fitted with a condenser), 2,7-dibromofluorene (9.30 g, 0.029 mol) was charged, followed by its dissolution with “Cactus Solvent P-150” (product of Nikko Petrochemicals Co., Ltd.; 100 g). Subsequent to addition of tetraammonium bromide (0.24 g) and a 48% aqueous solution of sodium hydroxide (2.66 g), the resulting mixture was vigorously stirred at 60° C. for 2 hours while introducing air at a flow rate of 0.1 L/min. After completion of the stirring, the reaction mixture was allowed to stand, and the resulting “Cactus Solvent P-150” layer was collected. The “Cactus Solvent P-150” layer was then subjected to acid washing, followed by water washing until its pH arose to 7. “Cactus Solvent P-150” was then distilled off to recover crude crystals of 2,7-dibromofluorenone. The content of 2,7-dibromofluorene in the crude crystals at that time was 0%. Those crude crystals were recrystallized from N,N′-dimethylformamide (15 g) to afford 2,7-dibromofluorenone as yellow crystals (7.67 g).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH3:11][C:12]([CH3:19])([CH3:18])[C:13](=O)[CH2:14][C:15]#[N:16]>C(O)C>[Br:2][C:3]1[CH:4]=[C:5]([N:9]2[C:15]([NH2:16])=[CH:14][C:13]([C:12]([CH3:19])([CH3:18])[CH3:11])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1cccc(Br)c1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2cccc(Br)c2)n1
Yield: 54 %

Procedure:
A mixture of 3-bromophenylhydrazine hydrochloride (5.00 g, 22.4 mmol) and 4,4-dimethyl-3-oxo-pentanenitrile (4.29 g, 33.6 mmol) in absolute ethanol (55 mL) was stirred at reflux for 18 h and cooled, then concentrated in vacuo. The residue was suspended in sat. aq. NaHCO3 (50 mL) and extracted with EtOAc (3×50 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo. The residue was purified by FCC, using 0-5% [2M NH3 in MeOH] in DCM, to give the title compound (3.56 g, 54%). LCMS (Method 1): Rt 3.33 min, m/z 294, 296 [MH+].
Reaction SMILES: O=[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1.[NH2:15][OH:16].Cl>>[OH:16][N:15]=[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1
Reactant: NO
Reactant: NC(=O)NC1CCC(=O)c2sccc21
Agent: Cl
Product: NC(=O)NC1CCC(=NO)c2sccc21

Procedure:
Similarly, levorotatory 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea is reacted with NH2OH.HCl to afford optically active 4,5,6,7-tetrahydro-7-(hydroxyimino)benzo[b]thien-4-ylurea.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C:6]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:5]=2[NH:4][C:3]1=[O:36].[C:37](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.C(OCC)(=O)C>[C:31]([O:30][C:29](=[O:35])[NH:28][C:24]1([C:21]2[CH:22]=[CH:23][C:18]([C:9]3[C:10]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:11][C:5]4[N:4]([CH3:37])[C:3](=[O:36])[C@@H:2]([CH3:1])[O:7][C:6]=4[N:8]=3)=[CH:19][CH:20]=2)[CH2:25][CH2:26][CH2:27]1)([CH3:32])([CH3:34])[CH3:33]
Reactant: O=C([O-])[O-]
Reactant: C[C@H]1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2NC1=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H]1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2N(C)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.1 %

Procedure:
A solution of (R)-tert-butyl 1-(4-(3-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (100 mg, 0.206 mmol) in DMF (2 ml) was added potassium carbonate (85 mg) and iodomethane (15p1, 0.247 mmol). The reaction mixture was stirred at room temperature for 16 h then was diluted with ethyl acetate (20 ml). Washed with water, brine, and dried with Na2SO4, filtered and concentrated to give crude product which was purified by column (Biotage, size: 25 g) eluted with ethyl acetate/cyclohexane (0-50%) to afford product (33 mg). 1H NMR (500 MHz, CDCl3): 7.19-7.32 (m, 10H), 4.96 (q, 1H), 3.39 (s, 3H), 2.43-2.48 (m, 4H), 2.04 (m, 1H), 1.80 (m, 1H), 1.70 (d, 3H), 1.24-1.36 (m, 9H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.Cl.[CH2:32]([C:34]1[O:35][CH:36]=[C:37](/[CH:39]=[CH:40]/[C:41]2[C:42]([OH:52])=[N:43][N:44]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH:45]=2)[N:38]=1)[CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:32]([C:34]1[O:35][CH:36]=[C:37](/[CH:39]=[CH:40]/[C:41]2[C:42]([O:52][CH2:2][C:3]3[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]4[N:10]=[C:11]([C:15]5[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=5)[O:12][C:13]=4[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=3)=[N:43][N:44]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH:45]=2)[N:38]=1)[CH3:33]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)cc1
Reactant: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2O)co1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4coc(CC)n4)cc3OC)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 21.1 %

Procedure:
A mixture of ethyl (4-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (1.48 g), 4-[(E)-2-(2-ethyl-1,3-oxazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-ol.hydrochloride (1.07 g), potassium carbonate (1.05 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with acetone-hexane (1:5-1:4-1:3, v/v) to give ethyl {4-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-oxazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (480 mg, yield 20%) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 155-157° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24](O)=[O:25])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27]([NH:34][CH3:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24](=[O:25])[N:34]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:35])=[CH:12][N:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CNCc1ccccc1
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)O)c2c1
Product: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)N(C)Cc3ccccc3)c2c1

Procedure:
As described in example 1E, 100 mg of 1-(tert-butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid was coupled with benzyl-methyl-amine to give 100 mg of [4-(benzyl-methyl-carbamoyl)-6,8-dimethoxy-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester. MS: APCI (M+H) calc'd for C26H31N3O5+H 466.5; found 466.0.
Reaction SMILES: [N:1]([CH:4]1[C@@H:8]2[CH2:9][N:10]([C:12]3[N:17]=[C:16]([C:18]4[O:22][C:21]([C:23]5[CH:28]=[CH:27][C:26]([CH2:29][N:30]([CH3:38])[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:25][CH:24]=5)=[N:20][N:19]=4)[C:15]([N:39]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[N:14][CH:13]=3)[CH2:11][C@@H:7]2[CH2:6][CH2:5]1)=[N+]=[N-]>[Pd]>[NH2:1][CH:4]1[C@@H:8]2[CH2:9][N:10]([C:12]3[N:17]=[C:16]([C:18]4[O:22][C:21]([C:23]5[CH:28]=[CH:27][C:26]([CH2:29][N:30]([CH3:38])[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:25][CH:24]=5)=[N:20][N:19]=4)[C:15]([N:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:47]([O:49][C:50]([CH3:52])([CH3:51])[CH3:53])=[O:48])=[N:14][CH:13]=3)[CH2:11][C@@H:7]2[CH2:6][CH2:5]1
Reactant: CN(Cc1ccc(-c2nnc(-c3nc(N4C[C@@H]5CCC(N=[N+]=[N-])[C@@H]5C4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Agent: [Pd]
Product: CN(Cc1ccc(-c2nnc(-c3nc(N4C[C@@H]5CCC(N)[C@@H]5C4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Reaction time: 4.5 h
Yield: 77.2 %

Procedure:
A flask charged with tert-butyl N-[[4-[5-[6-[(3aR,6aS)-6-azido-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-3-[bis(tert-butoxycarbonyl)amino]pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (400 mg, 0.55 mmol) and Pd/C (108 mg, 1.0 mmol) was flushed under N2 followed by evacuating under vacuum. EtOH (3 mL) was added under inert atmosphere followed by evacuating under vacuum. The reaction mixture was stirred for 4.5 h under an atmosphere of H2. The reaction mixture was filtered and the solvent was evaporated under reduced pressure to obtain tert-butyl N-[[4-[5-[6-[(3aR,6aS)-6-amino-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-3-[bis(tert-butoxycarbonyl)amino]pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (300 mg, 78%). LC/MS m/z 707.5 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[C:16](=[O:17])[N:15]([CH2:18][C:19]3[CH:24]=[CH:23]C(C(F)(F)F)=CC=3)[N:14]=[CH:13]2)[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].C1(CN2C(=O)N(C3SC(C(OCC)=O)=C(C)N=3)C=N2)CC1>>[CH:19]1([CH2:18][N:15]2[C:16](=[O:17])[N:12]([C:4]3[S:5][C:6]([C:7]([OH:9])=[O:8])=[C:2]([CH3:1])[N:3]=3)[CH:13]=[N:14]2)[CH2:24][CH2:23]1
Reactant: CCOC(=O)c1sc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)nc1C
Agent: CCOC(=O)c1sc(-n2cnn(CC3CC3)c2=O)nc1C
Product: Cc1nc(-n2cnn(CC3CC3)c2=O)sc1C(=O)O
Yield: 92 %

Procedure:
Following the procedure as described in Example 20, making variation as required to replace ethyl 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate with ethyl 2-(1-(cyclopropylmethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a white solid in 92% yield: 1H NMR (300 MHz, DMSO-d6) δ 13.39 (br s, 1H), 8.72 (s, 1H), 3.63 (d, J=7.1 Hz, 2H), 2.57 (s, 3H), 1.19-1.04 (m, 1H), 0.53-0.42 (m, 2H), 0.36-0.27 (m, 2H); MS (ES−) m/z 279.0 (M−1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH2:33][CH2:34]OS(C3C=CC(C)=CC=3)(=O)=O)[CH:29]=2)[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH2:33][CH2:34][N:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:10][C:11]3=[O:15])[CH:29]=2)[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)C3)cc1
Product: CC(C)(C)OC(=O)N1CCc2cc(CCn3ccc(OCc4ccccc4)cc3=O)ccc2C1

Procedure:
6-[2-(4-Benzyloxy-2-oxo-2H-pyridin-1-yl)-ethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester is prepared as example 24.1 from 604 mg (3.00 mmol) 4-benzyloxy-1H-pyridin-2-one and 1.30 g (3.01 mmol) 6-[2-(toluene-4-sulfonyloxy)-ethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 10c).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li]CCCC.[CH2:15]([N:17]([CH2:32][CH3:33])[CH2:18][CH2:19][N:20]1[C:30]2[C:25](=[C:26]([Br:31])[CH:27]=[CH:28][CH:29]=2)[C:23](=[O:24])[C:21]1=[O:22])[CH3:16].[NH4+].[Cl-]>C1COCC1>[CH2:32]([N:17]([CH2:15][CH3:16])[CH2:18][CH2:19][N:20]1[C:30]2[C:25](=[C:26]([Br:31])[CH:27]=[CH:28][CH:29]=2)[C:23]([OH:24])([C:5]2[O:1][C:2]3[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=3[CH:4]=2)[C:21]1=[O:22])[CH3:33]
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c(Br)cccc21
Reactant: c1ccc2occc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN(CC)CCN1C(=O)C(O)(c2cc3ccccc3o2)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.2 %

Procedure:
To benzo[b]furan (76.4 mg, 2.1 eq) in anhydrous THF (2 mL) at −40° C. (bath temperature) was added n-BuLi (0.423 mL, 1.53 M in hexanes, 2.1 eq). The resulting light yellow coloured solution was stirred for 30 minutes, after which 1-(2-diethylaminoethyl)-4-bromoisatin (100.0 mg, 3.08×10−4 mol) in anhydrous THF (2 mL) was added. Stirring was continued at −40° C. for 9 hours. Saturated aqueous NH4Cl (1.5 mL) was added and the mixture was allowed to warm to room temperature. The mixture was extracted with EtOAc and the combined extracts were dried (anhydrous Na2SO4). After filtration, the solvent was removed in vacuo. Purification was carried out by column chromatography (silica gel, eluting 1%-2% MeOH in CHCl3) to give the title compound as a yellow oil (29.0 mg, 21%).
Reaction SMILES: [CH2:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8]C2CCCCO2)=[C:6]([O:17][CH3:18])[CH:5]=1)[CH:2]=[CH2:3].C([Li])(CC)C.C([O:27][B:28](OC(C)C)[O:29]C(C)C)(C)C>C1COCC1>[CH2:1]([C:4]1[CH:5]=[C:6]([O:17][CH3:18])[C:7]([OH:8])=[C:15]([B:28]([OH:29])[OH:27])[CH:16]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1ccc(OC2CCCCO2)c(OC)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: C=CCc1cc(OC)c(O)c(B(O)O)c1
Reaction time: 0.17 h
Yield: 41 %

Procedure:
2-(4-Allyl-2-methoxyphenoxy)tetrahydropyran (2.0 g, 8.05 mmol) was dissolved in dry THF (70 ml) and the solution cooled to −78° C. sec-Butyl lithium (1.3M in hexanes, 7.4 ml, 9.62 mmol) was added dropwise with stirring over 10 minutes, the reaction was stirred at −78° C. for 2 hours. Triisopropoxy borane (3.4 ml, 14.6 mmol) was added and stirring continued for 4hours at −78° C. The reaction was quenched with water, acidified to pH 1 with 2N hydrochloric acid and extracted with ether (2×200 ml). The combined extracts were dried with magnesium sulphate and concentrated under vacuum. The oily solid produced was triturated with cyclohexane and the solid filtered off to give the title compound (41%); MS 207 (M-H)−; HPLC retention time (system 1) 2.73 minutes.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:37][CH2:38][O:39][C:40]1[CH:46]=[C:45]([CH:47]2[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][CH3:55])[CH2:49][CH2:48]2)[CH:44]=[CH:43][C:41]=1[NH2:42].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[CH:44][C:45]([CH:47]4[CH2:48][CH2:49][N:50]([CH2:53][CH2:54][CH3:55])[CH2:51][CH2:52]4)=[CH:46][C:40]=3[O:39][CH2:38][CH3:37])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: CCCN1CCC(c2ccc(N)c(OCC)c2)CC1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: CCCN1CCC(c2ccc(Nc3nccc(-c4c(-c5ccc(OCC)c(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)c(OCC)c2)CC1
Temperature: 130 °C
Yield: 62.2 %

Procedure:
5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (100 mg, 0.2 mmol), 2-(2-ethyloxy)-4-(1-propyl-4-piperidinyl)aniline (Example 154, step E) (47 mg, 0.18 mmol), and p-toluenesulfonic acid (90 mg, 0.47 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 130° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 3 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (82 mg, 0.112 mmol, 63%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.73 (s, 1H), 9.32 (d, J=6.78 Hz, 1H), 8.40 (s, 1H), 8.26 (d, J=5.13 Hz, 1H), 8.05 (d, J=2.01 Hz, 1H), 7.72 (dd, J=8.70, 2.11 Hz, 1H), 7.64-7.71 (m, 2H), 7.40-7.45 (m, 1H), 7.32-7.40 (m, 1H), 7.24 (d, J=8.61 Hz, 1H), 7.17 (t, J=8.06 Hz, 2H), 6.91-6.97 (m, 2H), 6.76 (dd, J=8.24, 1.47 Hz, 1H), 6.61 (d, J=5.13 Hz, 1H), 4.24 (q, J=6.71 Hz, 2H), 4.08 (q, J=6.96 Hz, 2H), 2.93 (d, J=10.80 Hz, 2H), 2.38-2.45 (m, J=4.03 Hz, 1H), 2.16-2.27 (m, 2H), 1.91 (d, J=9.71 Hz, 2H), 1.67-1.75 (m, 2H), 1.64 (dd, J=12.00, 2.84 Hz, 2H), 1.38-1.46 (m, 5H), 1.26 (t, J=6.87 Hz, 3H), 0.84 (t, J=7.33 Hz, 3H). MS (ESI): 732 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C1COCC1>[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([N:13]2[CH2:14][CH2:15][CH2:16][CH:11]([C:10]#[C:9][C:6]3[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=3)[CH2:12]2)=[O:32])=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Fc1ccc(C#CC2CCCNC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)N1CCCC(C#Cc2ccc(F)cc2)C1
Temperature: 0 °C
Reaction time: 24 h
Yield: 45 %

Procedure:
To a mixture of 3-(4-Fluoro-phenylethynyl)-piperidine hydrochloride (0.14 g, 0.58 mmol) in THF (2.3 ml, 0.5M) was added DIEA (0.5 ml, 2.92 mmol). The reaction mixture was cooled to 0° C. and 4-Fluoro-benzoyl chloride (0.139 g-0.87 mmol) was slowly added. The reaction was to go up to R.T and stirred for 24 h. The solution was concentrated and DCM was added following by HCl 1N. The aqueous phase was separated and organic phase was extracted twice with HCl 1N and twice with water, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (DCM/MeOH:98/2) to afford 0.86 mg (45%) of (4-Fluoro-phenyl)-[3-(4-fluoro-phenylethynyl)-piperidin-1-yl]-methanone as a brown oil. Rf=0.39 (DCM/MeOH:98/2); LCMS (Tr): 4.14 min (Method C); MS (ES+) gave m/z: 326.2; 1H-NMR (CDCl3), δ (ppm): 8.10 (d, 2H), 7.60 (d, 2H), 7.15 (d, 2H), 6.94 (d, 2H), 3.47-3.30 (m, 4H), 2.54 (m, H), 1.63-1.50 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=O.[BH4-].[Na+].C(Br)(Br)(Br)[Br:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CCO>[Br:1][C:2]1[CH:3]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:5]([O:10][CH3:11])=[C:6]([CH2:7][Br:19])[CH:9]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1c(C=O)cc(Br)cc1C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: COc1c(CBr)cc(Br)cc1C(C)(C)C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 5-bromo-3-tert-butyl-2-methoxybenzaldehyde (0.30 g, 1.1 mmol; CASRN 417715-87-8) in EtOH (5 mL) at 0° C. was added NaBH4 (0.042 g, 1.1 mmol). The mixture was stirred for 1 h, and partitioned between 1N HCl and Et2O. The ether layer was evaporated, and the crude benzyl alcohol was dissolved in DCM and treated sequentially with CBr4 (0.55 g, 1.7 mmol) and PPh3 (0.45 g, 1.7 mmol). After stirring 2 h at RT, the reaction mixture was concentrated, and the crude product was purified by SiO2 chromatography eluting with EtOAc/hexane to afford 0.34 g (90%) 5-bromo-1-bromomethyl-3-tert-butyl-2-methoxybenzene (114).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][C:8]=2[O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=2Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1COCC1>[CH:1]1([O:6][C:7]2[C:8]3[O:15][C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=4[C:9]=3[C:10]([CH:11]=[O:12])=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(OC2CCCC2)c(Oc2ccc([N+](=O)[O-])cc2Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=Cc1ccc(OC2CCCC2)c2oc3ccc([N+](=O)[O-])cc3c12
Temperature: 135 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
In a 20 L 4 necked RB Flask, fitted with a mechanical stirrer, reflux condenser, add 4-cyclopentyloxy-3(4′-nitro-2′-bromophenoxy)benzaldehyde (1.3 kg, 3.20 M), dimethyl formamide (7.8 L), sodium carbonate (0.51 kg, 4.8M) at temperature in the range of 25-35° C. under stirring. Heat the reaction mixture to temperature of 130-140° C. and add palladium acetate. Trimer (75 g, 0.11M) and maintain at temperature of 130-140° C. for 1 h under stirring. After 1 hr maintenance, the second lot of palladium acetate trimer (75 g, 0.11M) was added at temperature of 130-140° C. under stirring and maintained for 1 hr. After 2 hr maintenance the third lot of palladium acetate trimer (75 g, 0.11M) was added at temperature of 130-140° C. under stirring and maintained for 1 hr. The progress of the reaction mixture was monitored by HPLC. The reaction mixture was cooled to 70° C. and 4.7 L of THF was added to the reaction mixture and stirred for 30 min. The inorganic insolubles were filtered and washed with THF (1 L×2). Collect the THF MLS and add to DM water (15 L) under stirring. The precipitated product was filtered, washed with water (5 L) and dried in the vacuum oven at temp. below 60° C. The dried product was subjected to reflux in a mixture of THF (1.3 L) and Ethyl acetate (2.6 L) for 2 h and brought to room temperature. The precipitated product was filtered, dried in oven at temp. below 60° C. under vaccum till MC reaches <1%. The dried product appears as pale yello solid, weighs about 650-700 g , yield 60-65%, purity 97-98% by HPLC, m.p. 230-232° C. The IR (KBr) spectrum shows 3120 (CH str), 2960 (CH str), 1682 (CHO str), 1340 (NO2 str)