Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2](=[C:17]1[C:22](=[O:23])[CH2:21][C:20]([CH3:25])([CH3:24])[CH2:19][C:18]1=[O:26])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]CC1C=CC=CC=1)=[O:8]>CO.[Pd]>[OH:1][C:2](=[C:17]1[C:18](=[O:26])[CH2:19][C:20]([CH3:24])([CH3:25])[CH2:21][C:22]1=[O:23])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CC1(C)CC(=O)C(=C(O)CCCCC(=O)OCc2ccccc2)C(=O)C1
Agent: [Pd]
Solvent: CO
Product: CC1(C)CC(=O)C(=C(O)CCCCC(=O)O)C(=O)C1
Yield: 97.8 %

Procedure:
Benzyl 6-hydroxy-6-(4,4-dimethyl-2,6-dioxocyclohexylidene)-hexanoate (1.50 g, 4.19 mmol) was hydrogenated over Pd/C (10%) (150 mg) in MeOH (20 ml) at room temperature for 10 hours. The catalyst was filtered off, and the filtrate was evaporated, yielding 6-hydroxy-6-(4,4-dimethyl-2,6-dioxocyclohexylidene)-hexanoic acid (1.10 g, 98%);
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:19]I>O1CCCC1.[Cl-].[Na+].O>[Si:10]([O:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][CH3:19])[N:7]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:11])[CH3:12]
Reactant: CI
Reactant: CC(C)(C)[Si](C)(C)OCc1ccnc(N)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CNc1nccc(CO[Si](C)(C)C(C)(C)C)n1
Reaction time: 0.25 h
Yield: 20 %

Procedure:
Under a nitrogen atmosphere, a solution of 2-amino-4-(tert-butyldimethylsilyloxymethyl)pyrimidine (200 mg, 0.84 mmol, Reference Compound No. 5-1) in anhydrous tetrahydrofuran (4.0 mL) was added dropwise to a suspension of sodium hydride (60%, 37 mg, 0.92 mmol) in anhydrous tetrahydrofuran (1.0 mL) under ice-cooling. The mixture was stirred for 15 minutes under ice-cooling, then methyl iodide (57 μL, 0.92 mmol) was added thereto, and the mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into brine (30 mL), then extracted with ethyl acetate (30 mL). The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 43 mg of the title Reference Compound as a colorless oil (Yield: 20%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:19]=[C:18]([CH2:20][CH3:21])[O:17][N:16]=3)[N:4]2[N:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][OH:29]>>[CH2:20]([C:18]1[O:17][N:16]=[C:15]([C:14]2[N:4]3[N:3]=[C:2]([O:29][CH2:28][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=4)[C:11]4[C:6]([C:5]3=[N:12][N:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:19]=1)[CH3:21]
Reactant: CCc1cc(-c2nnc3c4ccccc4c(Cl)nn23)no1
Reactant: OCc1ccccn1
Product: CCc1cc(-c2nnc3c4ccccc4c(OCc4ccccn4)nn23)no1

Procedure:
The title-compound was prepared from 6-chloro-3-(5-ethylisoxazol-3-yl)-1,2,4-triazolo[3,4-a]phthalazine and 2-pyridylcarbinol using the procedure given for Example 1, 1H NMR (360 MHz, CDCl3) δ 1.42 (3H, t, J=7.6 Hz, Me), 2.93 (2H, q, J=7.5 Hz, CH2), 5.78 (2H, s, CH2O), 6.83 (1H, s, Ar—H), 7.29 (1H, m, Ar—H), 7.75-7.85 (3H, m, 3 of Ar—H), 7.99 (1H, m, Ar—H), 8.33 (1H, d, J=7.8 Hz, Ar—H), 8.64-8.72 (2H, m, Ar—H); MS (ES+) m/e 373 [MH]+.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[CH3:11][CH2:12][C:13](=[O:19])[CH2:14][C:15](=[O:18])[CH2:16][CH3:17]>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:14]([C:13](=[O:19])[CH2:12][CH3:11])[C:15](=[O:18])[CH2:16][CH3:17])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCC(=O)CC(=O)CC
Reactant: N#Cc1ccc(C=O)cc1
Product: CCC(=O)C(=Cc1ccc(C#N)cc1)C(=O)CC

Procedure:
The produre described in Example 19 was repeated by using 2.6 g 4-cyanobenzaldehyde and 5.0 g 3,5-heptanedione. Yield 2.8 g, mp 59°-60° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([CH3:59])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24](=[O:58])[NH:25][C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:28][C:27]=3[C:38]3[CH:43]=[C:42]([C:44](=[O:57])[NH:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[C:49]([C:53]([F:56])([F:55])[F:54])[CH:48]=4)[CH:41]=[CH:40][N:39]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7].[CH3:60]OCCNC>>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:60])[C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]([CH3:59])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24](=[O:58])[NH:25][C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]4)=[CH:28][C:27]=3[C:38]3[CH:43]=[C:42]([C:44](=[O:57])[NH:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[C:49]([C:53]([F:54])([F:55])[F:56])[CH:48]=4)[CH:41]=[CH:40][N:39]=3)[CH:19]=2)[CH2:12][CH2:13]1)=[O:7]
Reactant: CNCCOC
Reactant: COCCNC(=O)N1CCN(CCN(C)Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1
Product: COCCN(C)C(=O)N1CCN(CCN(C)Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1

Procedure:
This compound was prepared according to the procedure described for the synthesis of N-(2-methoxyethyl)-4-(2-(methyl(3-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)benzyl)amino)ethyl)piperazine-1-carboxamide Example 208 substituting 2-methoxy-N-methylethanamine in place of 2-methoxyethanamine. LC-MS (ES, m/z): 829 [M+H]+ H-NMR (300 MHz, DMSO, ppm): 12.31 (s, 1H), 9.56 (t, J=3.6 Hz, 1H), 8.93 (d, J=6 Hz, 1H), 8.31 (d, J=6 Hz, 2H), 8.04 (s, 1H), 7.94 (d, J=9 Hz, 1H), 7.84-7.86 (m, 1H), 7.56-7.71 (m, 7H), 7.30 (d, J=9 Hz, 1H), 4.63 (d, J=3 Hz, 2H), 4.26 (s, 2H), 3.45 (t, J=6.6 Hz, 2H), 3.23-3.32 (m, 16H), 3.17 (s, 1H), 3.00 (s, 4H), 2.80 (s, 3H), 2.63 (s, 3H), 1.60-1.74 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12](O)=[O:13])[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[CH2:23][CH2:22]3)[CH:16]=1)[CH2:6][C:5]2([CH3:35])[CH3:34].[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>CN(C)C1C=CN=CC=1.ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:13])[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[CH2:25][CH2:26]3)[CH:16]=1)[CH2:6][C:5]2([CH3:35])[CH3:34]
Reactant: CS(N)(=O)=O
Reactant: Cc1ccccc1N1CCN(c2cccc(C3CC(C)(C)c4cc(F)cc(C(=O)O)c4N3)c2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccccc1N1CCN(c2cccc(C3CC(C)(C)c4cc(F)cc(C(=O)NS(C)(=O)=O)c4N3)c2)CC1
Yield: 29.8 %

Procedure:
A mixture of 6-fluoro-4,4-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (100 mg, 0.21 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (60 mg, 0.31 mmol), 4-dimethylaminopyridine (38 mg, 0.31 mmol), methane sulfonamide (60 mg, 0.63 mmol) in dichloromethane (10 mL) was refluxed for 12 h. Removal of the solvent to afford the oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-{6-fluoro-4,4-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carbonyl}-methanesulfonamide (34.5 mg, 30%) as a light yellow solid: MS (ESI) M+1=551.4.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=2)[N:11]=[C:10]([NH:24][CH:25]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[N:9]=1>C1C=CC=CC=1>[Cl:23][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[C:10]([NH:24][CH:25]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:9]=[C:8]([O:4][CH:1]([CH3:3])[CH3:2])[N:13]=2)[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Reactant: CC(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(OC(C)C)n2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of isopropanol (2 mL) and sodium hydroxide (95 mg, 2.27 mmol) in benzene (10 mL) was heated to reflux for 2 hours with stirring under nitrogen atmosphere and then cooled to 25° C. followed by the addition of compound 133 (0.3 g, 0.78 mmol) at same temperature. The mixture was heated to reflux for 6 hours, concentrated under vacuum and diluted with water (10 mL). The precipitated solid was filtered off and purified by column chromatography (1-2% MeOH—CHCl3) to afford the title compound E21 as an off-white solid (0.30 g, 94%). mp 136-138° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 7.0); solvent B=CH3CN], Gradient elution program: T/% B=0/60, 10/60, 25/80, 40/80, 45/60, 50/60; 268 nm, Rt 30.06 min, 98.78% purity; MS (CI): m/z 406 (M+H, 100).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][CH:9]([C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1)[N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)(C)(C)C.N1C=CC=CC=1>C(#N)C>[OH:6][CH2:7][CH2:8][CH:9]([C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1)[N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: CC(C)(C)[Si](C)(C)OCCC(c1ccc(C#N)cc1)n1ccnc1
Solvent: CC#N
Solvent: c1ccncc1
Product: N#Cc1ccc(C(CCO)n2ccnc2)cc1
Reaction time: 1 h

Procedure:
The 4-[3-(tert-butyl-dimethyl-silanyloxy)-1-imidazol-1-yl-propyl]-benzonitrile (2.0 gm, mmol) was suspended in acetonitrile (20 mL) in a teflon flask and HF/pyridine (4 mL) was added and the reaction was stirred for 1 hour. The reaction was quenched with cold aqueous sodium hydroxide and the resulting solution was concentrated in vacuo. The residue was dissolved in methylene chloride and chromatographed on silica gel eluting with 1:1 ethyl acetate:hexanes. The desired fractions were concentrated in vacuo to give the desired product as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19]Br)[NH:12][C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[N:10]1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]1[CH2:32][OH:33]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][N:26]2[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]2[CH2:32][OH:33])[NH:12][C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[N:10]1
Reactant: OC[C@H]1COCCN1
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Product: COC(=O)C1=C(CN2CCOC[C@@H]2CO)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 53.3 %

Procedure:
Methyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.98 g, 2 mmol) was reacted with (S)-morpholin-3-ylmethanol (0.24 g, 2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a pale yellow solid (0.56 g, 53%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:13]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][CH2:28]O)[CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:13]([N:20]1[CH2:21][CH2:22][CH:23]([CH2:26][CH2:27][CH2:28][O:1][C:2]2[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=2)[CH2:24][CH2:25]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)Cc1cccc(OCCCC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
To a solution of methyl 3-hydroxyphenylacetate (0.409 g, 2.4 mmol), 3-(N-Boc-piperidin-4-yl)-propan-1-ol (0.50 g, 20.5 mmol) and triphenylphosphine (0.645, 24.6 mmol) in THF, was added diisopropyl azodicarboxylate at 0° C. slowly, then the ice bath was removed and the reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was dissolved in methylene chloride (2 mL) and loaded on a silica gel column. The product was eluted with 20% ethyl acetate in hexane, to afford methyl 3-(3-(N-Boc-piperidin-4-yl)-propoxy)-phenylacetate (0.5 g, 62%). 1H NMR (500 MHz, CDCl3) 1.1 (m, 2H), 1.4 (m, 2H), 1.46 (s, 9H), 1.66 (d, 2H), 1.78 (m, 2H), 2.67 (t, 2H), 3.58 (s, 2H), 3.68 (s, 3H), 4.05 (m, 2H), 6.75 (m, 3H), 7.18 (dd, 1H).
Reaction SMILES: [NH:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[C:4](=[O:11])[NH:3][C:2]1=[O:12].[H-].[Na+].[CH3:15]I>CN(C)C=O>[CH3:15][N:3]1[C:4](=[O:11])[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[NH:1][C:2]1=[O:12]
Reactant: O=C1NC(=O)C2(CCCCC2)N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)NC2(CCCCC2)C1=O
Temperature: 50 °C

Procedure:
1,3-diazaspiro[4,5]decane-2,4-dione (4.0 g 0.078 mole) J. Prakt. Chem. 141 5-43 (1934) was added to a suspension of sodium hydride (1.14 g 50% oil dispersion) in dimethylformamide and heated at 50° C. for 1 hour, cooled, methyl iodide added (1.63 ml. 1.1 eq) and the mixture heated at 50° C. The dimethylformamide was removed under reduced pressure and the residue partitioned between ethyl acetate and brine. The organic extract was washed with water, dried (MgSO4), evaporated to dryness and the crystalline residue crystallised from ethyl acetate-light petroleum (40°-60° C.) to give the title compound as white prisms m.p. 214°-215° C. Yield 2.6 g=39%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH:24]=O)[CH:20]=[CH:21][CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(O)(=O)C.C([O-])(=O)C.[Na+].Cl.[NH:38]1[CH2:41][CH:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH2:24][N:38]4[CH2:41][CH:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]4)[CH:20]=[CH:21][CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCc1c(CC=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Reactant: COC(=O)C1CNC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1c(CCN2CC(C(=O)OC)C2)cccc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
To a solution of [3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]acetaldehyde (D78) (160 mg), acetic acid (0.036 mL) and sodium acetate (51.0 mg) in ethanol (20.00 mL) stirred under nitrogen at room temperature was added methyl 3-azetidinecarboxylate hydrochloride (182 mg) in one charge. The reaction mixture was stirred at room temperature for 30 min, then the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (DCM) (20 mL), sodium triacetoxyborohydride (165 mg) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated brine (30 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo to give the crude product methyl 1-{2-[3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]ethyl}-3-azetidinecarboxylate (D90) (200 mg) as a brown oil. The crude product was used for next step without further purification. MS (ES): C27H31ClN2O3S requires 498. found 499.2 (M+H+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12].[F:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][O:23][CH3:24])[CH:17]=[C:16]([F:25])[C:15]=1B1OC(C)(C)C(C)(C)O1>>[F:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][O:23][CH3:24])[CH:17]=[C:16]([F:25])[C:15]=1[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12]
Reactant: COC(=O)c1ccc(F)c(Br)n1
Reactant: COCCOc1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Product: COCCOc1cc(F)c(-c2nc(C(=O)OC)ccc2F)c(F)c1
Yield: 95 %

Procedure:
Method 1 was followed using methyl 6-bromo-5-fluoropicolinate (1.0 equiv.) and 2-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.75 equiv.) at 80° C. for 1 hour to give methyl 6-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)-5-fluoropicolinate in 95% yield. LC/MS=341.9 (M+H), Rt=0.89 min.
Reaction SMILES: C([Li])CCC.[CH:6](=[C:10]1[C:18]2[CH:17]=[CH:16][O:15][C:14]=2[CH2:13][CH2:12][CH2:11]1)[CH2:7][CH2:8][CH3:9].[C:19](=[O:21])=[O:20].C(Cl)(Cl)(Cl)Cl>CCOCC>[CH:6](=[C:10]1[C:18]2[CH:17]=[C:16]([C:19]([OH:21])=[O:20])[O:15][C:14]=2[CH2:13][CH2:12][CH2:11]1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCC=C1CCCc2occc21
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCCC=C1CCCc2oc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 1.66 N n-butyl lithium (nBuLi) (328 ml in n-hexane solution) and Et2O (100 ml) was added a mixture of 4-n-butylidene-4,5,6,7-tetrahydrobenzo[b]furan (9.60 g) and Et2O (50 ml) dropwise over 5 minutes while maintaining −30˜−20° C. by dry ice—carbon tetrachloride (CCl4) cooling. The reaction mixture was stirred at r.t. for 1 hour, and was bubbled by carbon dioxide (CO2) gas for 1 hour. The whole mixture was stirred at r.t. overnight and poured into a mixture of water and Et2O. The separated aqueous layer was adjusted to pH 1.4 with 10% HCl, and extracted by AcOEt. The orgaic layer was washed with brine, dried over MgSO4, and evaporated to give 4-n-butylidene-4,5,6,7-tetrahydrobenzo[b]furan-2-carboxylic acid (3.91 g) as a reddish oil, which was used in the next reaction without further purification.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].[Mg].C(O[Si:17]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])OCC)C>CCOCC>[F:8][C:7]1[C:2]([Si:17]([C:2]2[C:3]([F:12])=[C:4]([F:11])[C:5]([F:10])=[C:6]([F:9])[C:7]=2[F:8])([O:21][CH2:22][CH3:23])[O:24][CH2:25][CH3:26])=[C:3]([F:12])[C:4]([F:11])=[C:5]([F:10])[C:6]=1[F:9]
Reactant: CCO[Si](OCC)(OCC)OCC
Reactant: Fc1c(F)c(F)c(Br)c(F)c1F
Agent: [Mg]
Solvent: CCOCC
Product: CCO[Si](OCC)(c1c(F)c(F)c(F)c(F)c1F)c1c(F)c(F)c(F)c(F)c1F
Temperature: 35 °C
Reaction time: 16 h

Procedure:
265.2 mL (1.95 mol, 525.353 g) bromopentafluorobenzene, 52.11 g (2.144 mol) magnesium powder and 216 mL (0.975 mol, 203.025 g) tetraethoxysilane are mixed together at room temperature and diethylether is added dropwise to the vigorously stirred solution until an exothermic reaction is observed (˜240 mL). The solution is stirred for 30 minutes after which additional 90 mL of Et2O is carefully added. After stirring at 35° C. for 16 h the mixture is cooled to room temperature and diethylether evaporated. An excess of n-heptane (˜600 mL) is added to precipitate the magnesium salts. Solution is filtrated and evaporated to dryness. The residue is fractionally distilled under reduced pressure to yield di(pentafluorophenyl)diethoxysilane.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[C:5]([C:11]#[N:12])=[CH:4][C:3]=1[N+:13]([O-])=O.[H][H]>CN(C=O)C.[Pt]>[NH2:13][C:3]1[CH:4]=[C:5]([C:11]#[N:12])[C:6]2[N:10]=[CH:9][NH:8][C:7]=2[C:2]=1[CH3:1]
Reactant: [H][H]
Reactant: Cc1c([N+](=O)[O-])cc(C#N)c2nc[nH]c12
Agent: [Pt]
Solvent: CN(C)C=O
Product: Cc1c(N)cc(C#N)c2nc[nH]c12

Procedure:
A mixture of 7-Methyl-6-nitro-1H-benzimidazole-4-carbonitrile (24) (1.010 g, 5.0 mmol) and Pt/C (5% Pt/C sulfided, 0.502 g, 50 wt %, C5002 Engelhard Industries) in DMF (75 mL) is hydrogenated at about 40 psi hydrogen pressure at about 50° C. over about 24 hours. The catalyst is removed from the reaction mixture by filtration through a Celite pad and the filtrate is concentrated in vacuo. The residue obtained is triturated in acetonitrile, and filtered to provide 6-Amino-7-methyl-1H-benzimidazole-4-carbonitrile (10), as a tan solid (0.768 g, 90% Yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1[O:12][CH3:13].C[O:15]C(OC)N(C)C>CN(C=O)C.O.CN(C=O)C>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([CH:11]=[O:15])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: COc1cc(C)c([N+](=O)[O-])cc1Br
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)c([N+](=O)[O-])cc1Br
Temperature: 140 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
To a stirred solution of compound 12 (2.3 g, 9.4 mmol) in dry DMF (15 mL) was added N,N-dimethylformamide dimethyl acetal (DMF·DMA) (6.0 g, 24.5 mmol). After the reaction mixture was heated at 140° C. for 16 h, the dark red solution was cooled to 0° C. and added rapidly to a stirred solution of NaIO4 (10.5 g, 49 mmol) in H2O/DMF (4:1, 25 mL) at 0° C. After 8 h of stirring, the brown solution was filtered, and the reaction flask was rinsed with toluene/EtOAc (1:1, 30 mL) and again filtered. The filtrate was washed with saturated aqueous NaCl solution (45 mL) and extracted with EtOAc (2×45 mL). The organic phase was dried (Na2SO4) and concentrated, and the residue was purified by flash chromatography (hexane/EtOAc 3:1) to afford aldehyde 13 (1.3 g, 54%): Rf0.22 (hexane/EtOAc 3:1); 1H NMR (CDCl3) δ 4.09 (s, 3H), 7.38 (s, 1H), 8.43 (s, 1H), 10.50 (s, 1H); 13C NMR (CDCl3) δ 57.4, 110.5, 116.8, 130.3, 132.6, 142.3, 160.5, 187.7; ESI-HRMS [M-H]−C8H579BrNO4 calcd for m/z 257.9402, found 257.9407.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([N:23]([CH3:25])[CH3:24])[CH2:14][CH2:13][C:12]([NH:21][CH3:22])([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C=O.[C:28](B)#N.[Na].C(O)(=O)C>C(#N)C>[CH3:22][N:21]([CH3:28])[C:12]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11][CH2:10][C:9]([N:23]([CH3:25])[CH3:24])([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:14][CH2:13]1
Reactant: CNC1(c2ccccc2)CCC(c2ccc(OC)cc2)(N(C)C)CC1
Reactant: BC#N
Agent: C=O
Agent: [Na]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1ccc(C2(N(C)C)CCC(c3ccccc3)(N(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of the title compound from Example 69 (111 mg, 0.33 mmol) and formalin (0.45 mL, 37% aqueous solution) in acetonitrile (3 mL) was mixed with sodium cyanoboron hydride (83 mg, 1.32 mmol) and stirred for 45 min at RT. Conc. acetic acid was then added until a neutral reaction occurred and the mixture stirred for 45 min at RT. For work up the solvent was removed in a vacuum, the residue taken up with 2N NaCl (5 mL) and then extracted with ether (3×10 mL). The organic solution was dried over Na2SO4 and concentrated to low volume in a vacuum. The remaining residue was purified by means of flash chromatography with ethyl acetate/methanol (1:2→MeOH).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>O>[S:22]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][O:13][S:22](=[O:24])(=[O:23])[CH3:21])(=[O:24])(=[O:23])[CH3:21]
Reactant: OCCOCCOCCOCCO
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOCCOCCOCCOS(C)(=O)=O
Temperature: 5 °C
Yield: 89.5 %

Procedure:
A 5,000 mL, 3-necked flask equipped with a mechanical stirrer, thermometer and 500 mL addition funnel was charged with tetraethylene glycol (388 g, 2.0 mol) dichloromethane (1,500 mL) and triethylamine (445 g, 4.40 mol). The mixture was stirred and cooled to ca. 5° C., and methanesulfonyl chloride (470 g, 4.1 mol) was added dropwise over 3 hours. The reaction mixture was stirred an additional 3 hours while warming to 25° C., then water (1,000 mL) was added and the phases were separated. The organic layer was washed with ice-cold 6 N HCl (2×1,000 mL) and then washed with 5% Na2CO3, saturated aqueous NaCl, dried, filtered and evaporated in vacuo to yield 627 g (90%) of tetraethylene glycol dimesylate, i.e.,