Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:25])([CH3:24])[O:6][C@H:7]1[CH2:11][C:10](=[O:12])[C:9](=[CH2:13])[C@@H:8]1[CH2:14][Si:15]([CH3:23])([CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:4])[CH3:3].C([BH-](CC)CC)C.[Li+]>C1COCC1>[CH3:4][C:2]([Si:5]([CH3:25])([CH3:24])[O:6][CH:7]1[CH2:11][CH:10]([OH:12])[C:9](=[CH2:13])[CH:8]1[CH2:14][Si:15]([CH3:23])([CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:1])[CH3:3]
Reactant: C=C1C(=O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1C[Si](C)(C)c1ccccc1
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C1C(O)CC(O[Si](C)(C)C(C)(C)C)C1C[Si](C)(C)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a cooled (−78° C.), stirred solution of 36 (4.8 g, 12.81 mmol) in THF (25 mL) in a 100-mL round bottomed flask equipped with an argon inlet was added lithium triethylborohydride (super hydride®, 24.4 mL, 24.4 mmol, 1.0 M THF solution) over a period of 15 minutes. The reaction mixture was stirred at the same temperature for 1 hour and slowly warmed to room temperature to complete the reaction. The reaction mixture was quenched with sodium hydroxide solution (10%, 25 mL) and extracted with ethyl acetate (2×25 mL). The organic layer was separated, washed with brine (50 mL), and dried over magnesium sulfate. Concentration of the organic layer in vacuo gave the crude title compound, 4.58 g in 95% yield in a 8:1 diastereomeric ratio. The title compound was purified by using silica gel flash chromatography ethyl acetate/hexanes (1:4 v/v) to afford the desired diastereomer, 4 g in 83% yield.
Reaction SMILES: Br[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O>>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1
Reactant: O=C1C=C(Br)CCC1
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1C1=CC(=O)CCC1
Yield: 98 %

Procedure:
Synthesized from 3-bromocyclohex-2-enone and 2-methoxyphenylboronic acid according to the general procedure described for the Suzuki coupling. Purification by automated flash chromatography using gradient elution (0 to 80% ethyl acetate/hexanes) yielded the product (166 mg, 98%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.32 (ddd, J=8.3, 7.4, 1.9 Hz, 1H), 7.18 (dd, J=7.7, 1.9 Hz, 1H), 6.96 (dd, J=7.4, 1.1 Hz, 1H), 6.91 (d, J=8.5 Hz, 1H), 6.18 (t, J=1.8 Hz, 1H), 3.83 (s, 3H), 2.73 (td, J=6.1, 1.4 Hz, 2H), 2.48 (t, J=6.3 Hz, 2H), 2.14-2.06 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[N:20][C:19]([Cl:25])=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:26]N1C(=O)CCC1=O>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([Br:26])=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[N:20][C:19]([Cl:25])=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnc(Cl)cc3c2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnc(Cl)cc3c2Br)CC1
Temperature: 85 °C

Procedure:
200 mg of 4-(3-Chloro-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (178) were dissolved in 5 ml of CH3CN and heated to 85° C. Then a mixture of 148 mg of N-bromosuccinimide and 9 mg of AlBN was added as solid and the resulting mixture was heated to reflux for 1 h. The solvent was removed in vacuo and the residue subjected to flash column chromatography. The yield of the isolated product was 41% LCMS: detected mass: 441.03, Rt=2.41 min (Method #1)
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13](I)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:32]B(O)O.C([O-])([O-])=O.[K+].[K+].ClCCl>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([CH3:32])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CB(O)O
Reactant: COC(=O)C1CN(Cc2ccc3c(I)c(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)C1CN(Cc2ccc3c(C)c(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A flask charged with compound methyl 1-((6-((trans)-4-tert-butylcyclohexyloxy)-5-iodonaphthalen-2-yl)methyl)azetidine-3-carboxylate (300 mg, 0.56 mmol), methylboronic acid (66 mg, 1.1 mmol, 2.0 eq), 2 M aq K2CO3 (5 mL, 3.0 equiv) and [1,1-bis(diphenylphosphino) ferroene]dichloropalladium (II) complex with dichloromethane (1:1) (45 mg, 0.05 mmol, 0.1 equiv) was flushed with nitrogen. 1,4-Dioxane (20 mL) was added and the reaction was stirred at 90° C. for 5 h. The solution was cooled to room temperature. The solvent was removed and the residue was purified by column chromatography (PE/EA=1:1) to give compound the title compound as a white solid (80 mg, 33%). ESI-MS (M+H+): 424.3. 1H NMR (400 MHz, CDCl3) δ: 7.88 (d, 1H), 7.64-7.61 (m, 2H), 7.40 (dd, 1H), 7.23 (d, 1H), 4.10-4.08 (m, 1H), 3.79 (s, 2H), 3.74 (s, 3H), 3.59-3.56 (m, 2H), 3.39-3.36 (m, 3H), 2.53 (s, 3H), 2.20-2.17 (m, 2H), 1.86-1.83 (m, 2H), 1.48-1.43 (m, 2H), 1.10-1.26 (m, 3H), 0.86 (s, 9H)
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[C:18]1([C:24](Cl)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:24]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O

Procedure:
This compound was prepared from thymidine and triphenylmethyl chloride in dry pyridine by the procedure of Horwitz and Urbanski.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[N:6][C:5]=1Cl.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1>CO>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[N:6][C:5]=1[NH:20][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Reactant: COc1ccc(CN)cc1
Solvent: CO
Product: COC(=O)c1cc(Cl)cnc1NCc1ccc(OC)cc1
Yield: 43.6 %

Procedure:
A solution of 2,5-dichloro-nicotinic acid methyl ester (71) (25 g, 121 mmol) in anhydrous methanol was purged with argon and added p-methoxybenzylamine (34.5 mL, 266 mmol) at room temperature. The solution was refluxed overnight under argon. The solution was cooled and the solvent was evaporated under reduced pressure. The residue was taken in dichloromethane, sonicated briefly and undissolved solids were filtered off. The filtrate washed by water, dried over MgSO4 and concentrated. The crude product was purified by flash chromatography eluting with hexane:CH2Cl2 (1:1) to yield 16.2 g (44%) of 5-chloro-2-(4-methoxy-benzylamino)-nicotinic acid methyl ester (72) as a white solids. Mp 94° C. 1H-NMR (DMSO-d6): δ 3.71 (s, 3H), 3.82 (s, 3H), 4.59 (d, J=5.6 Hz, 2H), 6.87 (m, 2H), 7.24 (m, 2H), 8.06 (d, J=2.8 Hz, 1H), 8.27 (m, 1H), 8.32 (d, J=2.8 Hz, 1H); EIMS m/z 307 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:69]=[CH:68][C:52]([CH2:53][NH:54][CH2:55][CH2:56][C:57]2[CH:62]=[C:61]([C:63]([F:66])([F:65])[F:64])[CH:60]=[C:59]([F:67])[CH:58]=2)=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:50]=[CH:51][C:52]([CH2:53][N:54]([CH2:55][CH2:56][C:57]2[CH:62]=[C:61]([C:63]([F:66])([F:64])[F:65])[CH:60]=[C:59]([F:67])[CH:58]=2)[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:68][CH:69]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)c1ccc(CNCCc2cc(F)cc(C(F)(F)F)c2)cc1
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCc2cc(F)cc(C(F)(F)F)c2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75 %

Procedure:
To a solution of 103 mg (0.53 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 169 mg of TBTU (0.53 mmol) in 6 ml DMF, were added 0.45 ml (2.63 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 200 mg (0.57 mmol) of (4-tert-butyl-benzyl)-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 3 h at rt, the reaction mixture was diluted with 80 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; DCM/heptane 9:1) to give 211 mg white solid (70%). MS (EI) 530.2 (M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][C:11]=3[N:12]=2)[CH:7]=1.[CH:29]1[C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]2[C:38]([O:40][C:41](=O)[C:31]=2[CH:30]=1)=[O:39]>>[N:23]1([C:5]2[CH:4]=[CH:3][C:2]([N:1]3[C:38](=[O:39])[C:32]4[C:31](=[CH:30][CH:29]=[C:34]([C:35]([OH:37])=[O:36])[CH:33]=4)[C:41]3=[O:40])=[CH:7][C:6]=2[C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:13][C:11]=3[N:12]=2)[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: Nc1ccc(N2CCOCC2)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Product: O=C(O)c1ccc2c(c1)C(=O)N(c1ccc(N3CCOCC3)c(-c3nc4cc(-c5ccccc5)ccc4o3)c1)C2=O

Procedure:
Prepared by the method of Example 1b), from 2-(5-amino-2-(4-morpholinyl)phenyl)-5-phenylbenzoxazole (175 mg, 0.47 mmol) and 1,2,4-benzenetricarboxylic anhydride (90 mg, 0.47 mmol) the title compound was obtained (136 mg, 53%). 1H NMR (DMSO) δ 8.43(dd, 1H), 8.32(s, 1H), 8.18(d, 1H), 8.09(m, 2H), 7.90(d, 1H), 7.75(m, 3H), 7.65(dd, 1H), 7.50(t, 2H), 7.38(m, 2H), 3.80(m, 4H), 3.05(m, 4H). MS 546 m/z (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[NH:5][N:4]=1)=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:22]([CH3:24])[CH3:23]>C(#N)C>[CH:1]([C:3]1[CH:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[N:5]([CH:22]([CH3:24])[CH3:23])[N:4]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)c1cc(C=O)n[nH]1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)n1nc(C=O)cc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1,1-Dimethylethyl 3-formyl-1H-pyrazole-5-carboxylate (600 mg) and cesium carbonate (996 mg) were dissolved in acetonitrile (60 ml). 2-Iodopropane (0.305 ml) was added and the mixture was stirred at RT for 20 h. A further portion of 2-iodopropane (0.03 ml) was added and the mixture was stirred at RT for 16 h. The solvent was removed in vacuo. The reaction mixture was diluted with water (80 ml) and DCM (80 ml) and separated using a hydrophobic frit. The aqueous layer was extracted with a further quantity of DCM (2×50 ml) using a hydrophobic frit. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (50 g silica), eluting with a gradient of 0-100% ethyl acetate in cyclohexane to give the title compound (377 mg), and a mixture (213 mg) of both isomers. The mixture was purified by flash chromatography on silica gel (20 g silica), eluting with a gradient of 0-50% ethyl acetate in cyclohexane to give another quantity (114 mg) of the title compound (114 mg) as a colourless oil.
Reaction SMILES: [CH3:1][CH:2](/[CH:8]=[CH:9]/[CH:10]=[C:11]([CH3:18])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[CH:3](OC)[O:4]C.C1COCC1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O>[CH3:1][CH:2]([CH:8]=[CH:9][CH:10]=[C:11]([CH3:18])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[CH:3]=[O:4]
Reactant: COC(OC)C(C)/C=C/C=C(C)CCC=C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=CCCC(C)=CC=CC(C)C=O
Reaction time: 24 h
Yield: 101.8 %

Procedure:
To a 250 mL four-neck reaction flask protected from atmospheric moisture by nitrogen gas throughout the course of the reaction a mixture of 12.6 g of (E)-2,6,10-trimethyl-1,1-dimethoxy-3,5,9-undecatriene (0.05 mol) of formula (2A), 100 mL THF and 1.2 g of PTSA was added. After stirred until homogeneous, 22 g of water was added, and additional 24 h of stirring at 20˜25° C. was needed until the reaction completed according to GC. Then a solution of 2 g of NaHCO3 and 20 mL water was added for neutralization. After removal of THF by vacuum distillation, 100 mL of cyclohexane was added and then stratification. The organic layer was washed with 30 mL water, dried over anhydrous magnesium sulfate and subsequently filtered. Removal of the volatile organic solvents by evaporation at reduced pressure afforded 10.5 g of crude 2,6,10-trimethyl-3,5,9-undecatriene-1-aldehyde of formula (12).
Reaction SMILES: [NH:1]=[C:2](SC)[C:3]1[C:4]([CH3:16])=[CH:5][C:6]([CH:13]([CH3:15])[CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[CH3:19][O:20][CH2:21][C:22]([NH:24][NH2:25])=O>C(O)(=O)C>[CH:13]([C:6]1[CH:5]=[C:4]([CH3:16])[C:3]([C:2]2[NH:1][C:22]([CH2:21][O:20][CH3:19])=[N:24][N:25]=2)=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])([CH3:15])[CH3:14]
Reactant: COCC(=O)NN
Reactant: COC(=O)c1cc(C(=N)SC)c(C)cc1C(C)C
Solvent: CC(=O)O
Product: COCc1nnc(-c2cc(C(=O)OC)c(C(C)C)cc2C)[nH]1
Yield: 27.4 %

Procedure:
A solution of methyl 5-(imino(methylthio)methyl)-2-isopropyl-4-methylbenzoate (compound 196.5, 800 mg, 3.01 mmol, 1.00 equiv) and 2-methoxyacetohydrazide (compound 190.6, 1.90 g, 18.3 mmol, 5.00 equiv) in acetic acid (30 mL) was stirred for 2 h at 80° C. in an oil bath, then concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:50-1:2) as eluent to yield 250 mg (27%) of methyl 2-isopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoate as a clear oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)[C@H](C)O)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f7) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [H-].[Na+:2].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=O.Cl[CH2:13][C:14](=[O:20])[CH2:15][C:16]([O:18][CH3:19])=[O:17]>C1COCC1>[CH2:10]([O:9][C:3]([C:4]1[CH2:13][C:14]([O-:20])=[C:15]([C:16]([O:18][CH3:19])=[O:17])[C:5]=1[CH3:7])=[O:8])[CH3:11].[Na+:2]
Reactant: COC(=O)CC(=O)CCl
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)C(C(=O)OC)=C([O-])C1
Temperature: 18 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
In a 12 L round bottom flask, NaH (60% dispersion in mineral oil, 159 g, 3985 mmol) was added in portions to stirred anhydrous THF (4004 mL) to give a gray suspension. The mixture was cooled to about 5° C. in an ice/salt bath before ethyl acetoacetate (506 mL, 3985 mmol, Alfa Aesar) in anhydrous THF (200 mL) was added dropwise via an addition funnel over about 1 h during which time the temperature gradually increased to about 18° C. After the addition was complete, the reaction was stirred at ambient temperature for about 1 h and then a solution of methyl 4-chloroacetoacetate (230 mL, 1993 mmol, Oakwood) in anhydrous THF (200 mL) was added dropwise via an addition funnel over about 1 h. The resulting mixture was stirred at ambient temperature for about 2 h and then heated at about 50° C. for about 16 h. The reaction mixture was concd in vacuo. The orange solid was cooled to about 5° C. and an ice/water mixture (2 L) was added. The suspension was mixed by rotating on the rotovap without vacuum for about 30 min. The solid was collected by filtration and washed with ice-cold water (750 mL). Once most of the solvent (about 90%) had been removed, the wet solid was triturated with MeCN (750 mL), stirred for about 30 min and then the solid was collected by filtration while washing with Et2O (2×500 mL). The solid was dried in air for about 16 h and then in vacuo at about 55° C. to give sodium 4-(ethoxycarbonyl)-2-(methoxycarbonyl)-3-methylcyclopenta-1,3-dienolate (485 g, 98%): 1H NMR (DMSO-d6) δ 3.95 (q, J=7.1 Hz, 2H), 3.48 (s, 3H), 2.69 (q, J=2.0 Hz, 2H), 2.47 (t, J=2.1 Hz, 3H), 1.15 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:16][CH:15]=2)[C:6]2=[N:7][CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[CH3:28][N:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[CH2:1]([C:3]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][CH:22]3[CH2:23][CH2:24][N:25]([CH:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)[CH2:26][CH2:27]3)=[CH:16][CH:15]=2)[C:6]2=[N:7][CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CN1CCC(=O)CC1
Reactant: CCc1nc2c(C)ccnc2n1Cc1ccc(NCC2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: CCc1nc2c(C)ccnc2n1Cc1ccc(NCC2CCN(C3CCN(C)CC3)CC2)cc1
Reaction time: 0.33 h
Yield: 53.6 %

Procedure:
A solution of Compound 165 (0.250 g, 0.69 mmol) in 1,2-dichloroethane (3.5 mL) was added with 1-methyl-4-piperidone (0.128 mL, 1.04 mmol) followed by stirring for 20 minutes. The mixture was added with sodium triacetoxyborohydride (0.439 g, 2.07 mmol) followed by stirring at room temperature for 4 hours. The reaction mixture was added with a 2 mol/L aqueous sodium hydroxide solution, and extracted with dichloromethane three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:2 mol/L ammonia-methanol solution=19:1). The obtained crystals were recrystallized from ethanol-diisopropyl ether to obtain Compound 166 (0.172 g, 0.37 mmol, 54%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[C:4]([O:11][CH3:12])[CH:3]=1.[OH-:13].[Na+]>CO>[Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]([NH2:7])=[O:13])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: [OH-]
Reactant: COc1cc(Br)cc(C)c1C#N
Agent: [Na+]
Solvent: CO
Product: COc1cc(Br)cc(C)c1C(N)=O
Temperature: 25 °C
Yield: 90 %

Procedure:
4-Bromo-2-methoxy-6-methyl benzonitrile (7.3 g, 32.4 mmol) was stirred in MeOH (100 mL) and 5N NaOH (100 mL) at 100° C. for 12 hours. The reaction was cooled to room temperature and the methanol was removed under reduced pressure. The reaction mixture was extracted with CH2Cl2 and the solvent was removed under reduced pressure to yield the product (7.13 g, 90%). 1H NMR (300 MHz, CDCl3): δ 7.03 (d, 1H), 6.94 (d, 1H), 5.83 (br s, 2H), 3.85 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:13]([NH2:14])=[CH:12][C:11]([C:15]2[C:16]([CH3:21])=[N:17][O:18][C:19]=2[CH3:20])=[CH:10][C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].[CH2:22]([O:24][C:25](OCC)(OCC)OCC)[CH3:23]>CC(O)=O>[CH3:21][C:16]1[C:15]([C:11]2[CH:10]=[C:3]([C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5])[C:2]3[N:1]=[C:25]([O:24][CH2:22][CH3:23])[NH:14][C:13]=3[CH:12]=2)=[C:19]([CH3:20])[O:18][N:17]=1
Reactant: CCOC(OCC)(OCC)OCC
Reactant: CON(C)C(=O)c1cc(-c2c(C)noc2C)cc(N)c1N
Solvent: CC(=O)O
Product: CCOc1nc2c(C(=O)N(C)OC)cc(-c3c(C)noc3C)cc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)-N-methoxy-N-methylbenzamide (25 g, 0.086 mol) was dissolved in a 1:1 mixture (32 mL total) of tetraethylorthocarbonate and AcOH and allowed to stir under air at room temperature for 1.5 hr. The reaction mixture was concentrated in vacuo at room temperature and the crude residue was dissolved in EtOAc. The solution was washed three times with bicarb, once with water, and organic layer was concentrated in vacuo to give 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-N-methoxy-N-methyl-1H-benzo[d]imidazole-4-carboxamide as a dark oil. Crude material was used without further purification.
Reaction SMILES: [C:1]1(C)[CH:6]=CC(S(OCC#C)(=O)=O)=C[CH:2]=1.[CH3:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:17]=1[NH2:18]>O>[CH3:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:17]=1[NH:18][CH2:6][C:1]#[CH:2]
Reactant: Cc1cccc(C)c1N
Reactant: C#CCOS(=O)(=O)c1ccc(C)cc1
Solvent: O
Product: C#CCNc1c(C)cccc1C

Procedure:
Propargyl p-toluenesulphonate (6.0 g, 0.05 mole) was heated with 2,6-dimethylaniline (6.0 g, 0.05 mole) on steam bath for 2 hours, poured into water (100 ml), extracted into methylenedichloride (50 ml), dried (MgSO4), filtered, solvent evaporated and the product distilled to give 2,6-dimethylphenyl propargylamine, identical with that in Route II. Subsequent preparative steps were as outlined in Route II.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3([OH:38])[CH2:24][CH2:23][N:22]([C:25]4[CH:26]=[CH:27][C:28]5[N:29]([C:31]([C:34]([F:37])([F:36])[F:35])=[N:32][N:33]=5)[N:30]=4)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].OC1C=CC(C2(O)CCN(C3C=CC4N(C(C(F)(F)F)=NN=4)N=3)CC2)=CC=1.CS(N1CCN(CCCOC2C=CC(C3CCN(C4CCC5N(C(C(F)(F)F)=NN=5)N=4)CC3)=CC=2)CC1)(=O)=O>>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3([OH:38])[CH2:24][CH2:23][N:22]([C:25]4[CH2:26][CH2:27][C:28]5[N:29]([C:31]([C:34]([F:36])([F:37])[F:35])=[N:32][N:33]=5)[N:30]=4)[CH2:21][CH2:20]3)=[CH:17][CH:18]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(CCOc2ccc(C3(O)CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Agent: CS(=O)(=O)N1CCN(CCCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Agent: Oc1ccc(C2(O)CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Product: CC(=O)N1CCN(CCOc2ccc(C3(O)CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1

Procedure:
The 4-[4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl]-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol used as starting material was obtained in 55% yield by an analogous method to Example 36, preparation of starting materials, starting from 4-(4-hydroxyphenyl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol and 2-(4-acetylpiperazine-1-yl)ethanol (obtained as described in PCT Int. Appl. WO2003064413, Example 28, preparation of starting materials).