Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:31])[N:14]([N:23]=[C:24]([C:26]3[CH:30]=[CH:29][S:28][CH:27]=3)[CH3:25])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:32]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:31])[N:14]([NH:23][CH:24]([C:26]3[CH:30]=[CH:29][S:28][CH:27]=3)[CH3:25])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: CC(=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21)c1ccsc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21)c1ccsc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 244A (0.070 g, 0.15 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.015 mL, 0.42 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.090 mL, 0.18 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water, and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with dichloromethane to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.26 (m, 3 H) 4.58 (m, 1 H) 5.74 (s, 1 H) 7.07 (m, 1 H) 7.18 (m, 1 H) 7.28 (m, 3 H) 7.37 (s, 1 H) 7.55 (m, 2 H) 7.66 (m, 1 H) 7.96 (d, J=6.62 Hz, 1 H) 8.07 (s, 1 H) 16.30 (s, 1 H). MS (ESI−) m/z 465 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:14][CH:13]([F:15])[CH2:12][N:11]([CH:16]3[CH2:19][O:18][CH2:17]3)[CH2:10][CH2:9]2)=[CH:6][C:5]([C:20]#[N:21])=[CH:4][C:3]=1[NH:22][C:23]1[N:28]=[C:27]([N:29]([CH:39]2[CH2:41][CH2:40]2)CC2C=CC(OC)=CC=2)[C:26]2=[N:42][CH:43]=[C:44]([C:45]#[N:46])[N:25]2[N:24]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:14][CH:13]([F:15])[CH2:12][N:11]([CH:16]3[CH2:19][O:18][CH2:17]3)[CH2:10][CH2:9]2)=[CH:6][C:5]([C:20]#[N:21])=[CH:4][C:3]=1[NH:22][C:23]1[N:28]=[C:27]([NH:29][CH:39]2[CH2:40][CH2:41]2)[C:26]2=[N:42][CH:43]=[C:44]([C:45]#[N:46])[N:25]2[N:24]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN(C5COC5)CC(F)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: ClCCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2CCN(C3COC3)CC(F)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
(+/−)2-((2-chloro-5-cyano-3-(6-fluoro-4-(oxetan-3-yl)-1,4-diazepan-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (89 mg, 0.138 mmol) was taken up in DCE (1 mL) and anisole (0.076 mL, 0.692 mmol) was added, followed by TFA (0.640 mL, 8.30 mmol). The reaction was stirred at room temperature overnight. An additional 1 ml of TFA was added, and the reaction was stirred at room temperature for 4 h. The solvent was removed in vacuo and the material dissolved in MeOH. The material was loaded onto an SCX column (5 g, benzenesulfonic acid sorbent) and the column was flushed with MeOH, then 1:1 DCM/7N NH3/MeOH to obtain the product. The solvent was removed in vacuo and the crude material was purified by preparative HPLC. 2-((2-chloro-5-cyano-3-(6-fluoro-4-(oxetan-3-yl)-1,4-diazepan-1-yl)phenyl)amino)-4-(cyclopropyl amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (12 mg) was obtained as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[CH2:24][C:25]1[N:26]=[C:27](/[CH:30]=[CH:31]/[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[F:39])[O:28][CH:29]=1>>[F:39][C:33]1[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=1/[CH:31]=[CH:30]/[C:27]1[O:28][CH:29]=[C:25]([CH2:24][O:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]3[CH:15]=[CH:14][N:13]=[C:12]3[CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[CH:5]=[CH:6][CH:7]=2)[N:26]=1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)c(F)c1
Reactant: OCC(O)Cc1nccn1CCCc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Product: OCC(O)Cc1nccn1CCCc1cccc(OCc2coc(/C=C/c3ccc(F)cc3F)n2)c1
Yield: 60.4 %

Procedure:
Using 3-{1-[3-(3-hydroxyphenyl)propyl]-1H-imidazol-2-yl}-1,2-propanediol (203 mg), 65% oily sodium hydride (29 mg) and 4-(chloromethyl)-2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazole (197 mg), the same reaction as Example 2 was carried out to yield the titled compound (220 mg).
Reaction SMILES: C([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:11]([CH3:19])[C:10](=[O:20])[O:9]1)C1C=CC=CC=1.[CH3:21]C1C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:21][O:9][C:10](=[O:20])[CH:11]([CH3:19])[CH:12]([NH2:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@@H]1C(=O)ON(Cc2ccccc2)[C@H]1c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)C(C)C(N)c1ccccc1

Procedure:
Briefly, isoxazolidinone 40 (>99% ee) was converted to the amino acid 47 following the same procedure as set forth above. The mixture of amino acid 47 (0.07 g, 0.36 mmol) and pTSA (0.15 g, 0.79 mmol) was dissolved in dry methanol (5 mL) and refluxed for 12 hours. Methanol was removed under vacuum, and the residue was basified with 10% aqueous NaHCO3 solution. The precipitated aminoester was extracted with CH2Cl2 (3×5 mL). Organic extracts were combined and dried on anhydrous Na2SO4. Solvent was removed under vacuum to afford pure methyl ester 48 as an oily liquid. [α]D20=−31.7 (c 1.04, chloroform). Literature (Davies et al., J. Chem. Soc. Chem. Commun., 1153ff (1993), which is hereby incorporated by reference): [α]D20=−29.2 (c 1.00, chloroform) for absolute configuration (2R,3S). Therefore, absolute configuration of methyl ester and hence of isoxazolidinone was deemed to be (2R,3S).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=O)=O)=CC=1.[CH3:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[C:25]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[NH:26]2.[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[CH3:19][CH2:18][O:17][C:15]([CH2:14][O:13][CH2:12][CH2:11][N:26]1[C:27]2[C:23](=[C:22]([CH3:21])[CH:30]=[CH:29][CH:28]=2)[CH:24]=[C:25]1[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:16]
Reactant: CCOC(=O)COCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)c1cc2c(C)cccc2[nH]1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COCCn1c(C(=O)OCC)cc2c(C)cccc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 45.4 %

Procedure:
A solution of ethyl [2-(toluene-4-sulfonyl-oxy)ethoxy]acetate (3.90 g, 12.9 mmol) in N,N-dimethylformamide (10 ml) was added dropwise to a mixture of ethyl 4-methyl-1H-indole-2-carboxylate (2.50 g, 12.3 mmol), 60% sodium hydride (0.50 g, 12.5 mmol) and N,N-dimethylformamide (45 ml) at room temperature, and the resulting mixture was stirred at room temperature for 7 hours. The reaction mixture was poured into a 10% aqueous sodium chloride solution and extracted with ethyl acetate, and the extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate: n-hexane=2:98) to obtain 1.86 g of ethyl 1-[(2-ethoxycarbonylmethoxy)ethyl]-4-methyl-1H-indole-2-carboxylate as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14]([CH2:15][C:5]2=[C:4]([NH2:17])[C:3]=1[C:18]#[N:19])=[CH:13][CH:12]=[C:11]([OH:16])[CH:10]=3.Br[CH2:21][CH2:22][NH2:23].BrCCOCC>>[NH2:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14]([CH2:15][C:5]2=[C:4]([NH2:17])[C:3]=1[C:18]#[N:19])=[CH:13][CH:12]=[C:11]([O:16][CH2:21][CH2:22][NH2:23])[CH:10]=3
Reactant: NCCBr
Reactant: N#Cc1c(N)nc2c(c1N)Cc1ccc(O)cc1O2
Agent: CCOCCBr
Product: N#Cc1c(N)nc2c(c1N)Cc1ccc(OCCN)cc1O2

Procedure:
2,4-diamino-8-(2-aminoethoxy)-5H-chromeno[2,3-b]pyridine-3-carbonitrile was prepared from 2,4-diamino-8-hydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile in the same manner as described in Example 10 using 2-bromoethylamine in lieu of 2-bromoethyl-ethylether. The product was isolated as a tan solid (167 mg, 51% yield). 1H NMR (400 MHz, DMSO) δ 8.180 (bs, 2H), 7.100 (d, 1H), 6.762 (d, 1H), 6.646 (bs, 1H), 4.154 (t, 2H), 3.573 (s, 2H), 3.155 (t, 2H); m/z 398 (M+H). TNFα release assay IC50: 6.9 μM; Rat LPS Assay 88% inhibition at 20 mpk (IP).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH2:25][CH2:26][CH3:27])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:24])=[N:15][N:16]2[C:21]([OH:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=12)=[O:12])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:37][CH2:38][CH:39]([C:44]([F:47])([F:46])[F:45])[C:40]([F:43])([F:42])[F:41]>CN(C=O)C>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH2:25][CH2:26][CH3:27])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:24])=[N:15][N:16]2[C:21]([O:22][CH2:37][CH2:38][CH:39]([C:40]([F:41])([F:42])[F:43])[C:44]([F:45])([F:47])[F:46])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=12)=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(F)C(CCBr)C(F)(F)F
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(O)cc(C)cc12)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCCC(C(F)(F)F)C(F)(F)F)cc(C)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
A solution of 40 mg (0.10 mmol) of rac-[1-{[7-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carbonyl)amino]}-1-methylbutyl)carbamic acid tert-butyl ester (Example 141A) in 1 ml of DMF was admixed with 65 mg (0.2 mmol) of caesium carbonate and 78 mg (0.3 mmol) of 4-bromo-1,1,1-trifluoro-2-(trifluoromethyl)butane (CAS: 203303-02-0). The reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated off under reduced pressure. The residue was partitioned between dichloromethane and water, the phases were separated and the organic phase was concentrated under reduced pressure, which gave 55 mg (51% yield, 54% pure) of the target compound, which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:18])=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[C:19]([NH2:23])(=[O:22])[CH2:20][CH3:21].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[CH3:18][C:10]1[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:23][C:19](=[O:22])[CH2:20][CH3:21])[CH:7]=2)=[CH:14][CH:13]=[C:12]([N+:15]([O-:17])=[O:16])[N:11]=1
Reactant: CCC(N)=O
Reactant: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(Cl)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])nc2C)ccn1
Temperature: 90 °C
Yield: 73.8 %

Procedure:
A mixture of Example A3 (0.50 g, 1.882 mmol), propionamide (0.550 g, 7.53 mmol), Cs2CO3 (0.920 g, 2.82 mmol), and X-phos (0.045 g, 0.094 mmol) in dioxane (10 mL) was sparged with Ar, treated with Pd2(dba)3 (0.086 g, 0.094 mmol), sparged again with Ar and heated at 90° C. for 20 h. The mixture was cooled to RT, treated with EtOAc and the solids removed via filtration. The filtrate was washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/DCM) to afford N-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)propionamide (420 mg, 74%). MS (ESI) m/z: 303.1 (M+H+).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]23[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH:19]2[O:18][C:17]2[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:16]3=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1(O)C=CC=CC=1>>[F:29][C:25]1[C:17]2[O:18][CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:15]3([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[C:16]=2[CH:28]=[CH:27][CH:26]=1
Reactant: Fc1cccc2c1OC1CCCCCC21c1ccc(OCc2ccccc2)cc1
Solvent: Oc1ccccc1
Product: Oc1ccc(C23CCCCCC2Oc2c(F)cccc23)cc1

Procedure:
The title compound 447 was synthesized from compound 33 (51 mg) using procedure F described for the synthesis of phenol 807. Yield: 31 mg (77%). 1H-NMR (400 MHz, CDCl3): δ ppm 7.14-7.07 (m, 2H), 6.93 (ddd, J=10.68, 8.09, 1.20 Hz, 1H), 6.78 (dt, J=8.02, 7.80, 4.33 Hz, 1H), 6.74-6.68 (m, 3H), 5.00 (dd, J=7.26, 1.60 Hz, 1H), 4.95 (s, 1H), 2.40-2.28 (m, 1H), 2.22 (td, J=14.78, 7.49, 7.49 Hz, 1H), 2.14-2.04 (m, 1H), 1.86 (tdd, J=14.64, 12.73, 1.56, 1.56 Hz, 1H), 1.78-1.49 (m, 4H), 1.16-0.96 (m, 1H), 1.43-1.29 (m, 1H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH:7]([NH:16][C:17](=[O:33])[CH:18]([NH:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.[H-].[Na+].C(OCC)(=O)C>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:34])[CH:7]([NH:16][C:17](=[O:33])[CH:18]([NH:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:13][CH:14]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(O)cc1)C(=O)OC(C)(C)C
Reactant: BrCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(OCC2CCCCC2)cc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
A solution of the product from Example 24 (0.20 g, 0.42 mmol) and bromomethylcyclohexane (0.6 μL, 0.45 mmol) in DMF (2 mL) was added sodium hydride (60% in dispersion oil, 0.016 g, 0.42 mmol). The reaction mixture was stirred at 0° C. for 30 minutes and warmed to room temperature. The reaction mixture was poured into a separatory funnel containing ethyl acetate (50 mL) and water (50 mL). The organic phase was collected, washed with brine, and dried. The residue was purified by chromatography (silica gel, ethyl acetate/hexane) to give the title compound (0.13 g).
Reaction SMILES: [CH2:1]([OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].I[CH:16]([CH3:20])[C:17]([O-:19])=[O:18].[Na+]>>[CH3:20][CH:16]([O:14][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:17]([OH:19])=[O:18]
Reactant: CC(I)C(=O)[O-]
Reactant: CCCCCCCCCCCCCO
Agent: [Na+]
Product: CCCCCCCCCCCCCOC(C)C(=O)O

Procedure:
Similarly, 2-methyl-3-oxahexadecanoic acid is prepared from tridecanol and sodium 2-iodopropionate using the procedure of Example 1.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(N([SiH3:18])C(C)C)(C)C>>[SiH3:18][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH:2]1[CH3:1]
Reactant: CC(C)N([SiH3])C(C)C
Reactant: CC1Cc2ccccc2N1
Product: CC1Cc2ccccc2N1[SiH3]
Reaction time: 24 h

Procedure:
In a 500 ml Schlenk flask, 62.5 g (0.5 mol) 2-methylindoline and 131 g (1.0 mol) di-isopropylaminosilane were stirred at ambient temperature under a nitrogen atmosphere for 24 hours. The relatively lower boiling point by-product di-isopropylamine was removed with vacuum at a pressure of 20 mmHg and room temperature (25° C.). The reaction mixture was stirred for another 24 hours. The end-product N-silyl-2-methylindoline was obtained by vacuum distillation. The compound was characterized by mass spectroscopy (MS). The end-product was characterized by mass spectroscopy (MS) which is provided in FIG. 4 and shows, among other things, peaks at 163, 162, 148, 132, 117, 105, 91, and 77. The molecular weight of the N-silyl-2-methylindoline was 163.29.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:39])([F:38])[F:37])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:40]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([NH2:40])=[O:26])=[C:21]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:37])([F:39])[F:38])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)cc1OCc1ccccc1C(F)(F)F
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCc1cc2ncn(-c3cc(OCc4ccccc4C(F)(F)F)c(C(N)=O)s3)c2cn1
Temperature: 120 °C
Reaction time: 3.5 h

Procedure:
A mixture of 1.05 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3H-imidazo[4,5-c]pyridin-3-yl]-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate (compound B2a) and 100 ml of a saturated solution of ammonia in methanol was stirred in an autoclave at 120° C. for 3.5 h. The reaction mixture was allowed to cool down to room temperature, concentrated to dryness, dissolved in dichloromethane and filtered through a plug of silica gel (eluents: dichloromethane/ethyl acetate) to yield the title product.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[C:15]1([C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:11]2[CH2:10][CH2:9][N:8]([CH2:7][CH2:6][CH2:5][NH:4][CH2:1][CH3:2])[CH2:13][CH2:12]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)NCCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CCNCCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Yield: 64.9 %

Procedure:
A solution of 1.14 g of 1-(3-acetamidopropyl)-4-(diphenylmethylene)piperidine (prepared as described in Preparation 33') in 7 ml of tetrahydrofuran was added dropwise to a suspension of 140 mg of lithium aluminum hydride in 10 ml of tetrahydrofuran at room temperature under a nitrogen atmosphere, and the mixture was heated under reflux for 4 hours. At the end of this time, the mixture was cooled to room temperature, and sodium sulfate decahydrate was added to the mixture to decompose excess lithium aluminum hydride. The insoluble material was removed by filtration. Ethyl acetate was added to the filtrate, and the mixture was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. Evaporation of solvent under reduced pressure gave 710 mg (yield 65%) of the title compound as an oil.
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[O:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1.Cl>CN(C)C1C=CN=CC=1.ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)C(=O)C(C(=O)Nc1cc(Cl)cc(Cl)c1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
To an ice-cooled solution of (1S)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.18 g, 1.0 mmole), triethylamine (0.10 g, 1.0 mmole) and 4-(dimethylamino)pyridine (0.12 g, 1.0 mmole) in dry dichloromethane (25 mL) was added a solution of 3,5dichlorophenyl isocyanate (0.19 g, 1.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 7 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield a yellow oil, which was crystallized from 95% ethanol to yield the title compound as a beige solid (0.20 g, 55% yield), mp=112–114° C.; MS (−) ESI m/z=366 (M−H)−; [α]D25=−25.4° (c=1, EtOH).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][C:18]=3[O:33][CH3:34])=[O:16])[CH2:6][C:5]=12.FC(F)(F)S(O[C:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH:42]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:23][C:21]1[C:20]([C:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH:42]=2)=[CH:19][C:18]([O:33][CH3:34])=[C:17]([CH:22]=1)[C:15]([N:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH2:10][N:4]2[CH:3]=[CH:2][CH:1]=[C:5]2[CH2:6]1)=[O:16]
Reactant: O=S(=O)(OC1=CCCCC1)C(F)(F)F
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)c(Cl)cc1C(=O)N1Cc2cccn2Cc2ccccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C2=CCCCC2)c(Cl)cc1C(=O)N1Cc2cccn2Cc2ccccc21
Temperature: 60 °C
Yield: 70.5 %

Procedure:
(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[5-chloro-2-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone of Step E (0.220 g, 0.459 mmol), cyclohex-1-en-1-yl trifluoromethanesulfonate (0.116 g, 0.505 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.0110 g, 0.0138 mmol) were combined in N,N-dimethyl formamide (2.3 mL). Aqueous sodium carbonate (2 M, 1.15 mL, 2.30 mmol) was added and the reaction heated to 60° C. for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with water and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. Flash column chromatography on silica gel using a solvent gradient from 30 to 40% ethyl acetate in hexane afforded the title compound (0.140 g) as an oil. The oil was dissolved in diethyl ether/petroleum ether and concentrated to afford an amorphous white solid.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9]C)=[CH:7][C:5]([NH2:6])=[C:4]([O:11][CH3:12])[CH:3]=1.C[O:14][C:15]1[CH:23]=[CH:22][C:18](C(Cl)=O)=[CH:17][CH:16]=1>>[Cl:1][C:2]1[C:8]([OH:9])=[CH:7][C:5]2[N:6]=[C:12]([C:18]3[CH:22]=[CH:23][C:15]([OH:14])=[CH:16][CH:17]=3)[O:11][C:4]=2[CH:3]=1
Reactant: COc1cc(Cl)c(OC)cc1N
Reactant: COc1ccc(C(=O)Cl)cc1
Product: Oc1ccc(-c2nc3cc(O)c(Cl)cc3o2)cc1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 16, from 4-chloro-2,5-dimethoxyaniline, and 4-methoxybenzoyl chloride and was obtained as an off-white solid, m.p. 260–262° C.; MS m/e 260 (M−H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1CC#N.S(=O)(=O)(O)O.[C:19]([OH:22])(=[O:21])[CH3:20]>>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH2:20][C:19]([OH:22])=[O:21]
Reactant: COc1ccc(CC#N)c(Cl)c1Cl
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Product: COc1ccc(CC(=O)O)c(Cl)c1Cl
Temperature: 110 °C
Reaction time: 8 h

Procedure:
(2,3-Dichloro-4-methoxyphenyl)acetonitrile (770 mg) was dissolved in a 50% aqueous acetic acid solution (8.00 mL), and then concentrated sulfuric acid (4.00 mL) was added thereto, followed by stirring at 110° C. overnight. The reaction mixture was cooled to room temperature, then ice water was added to the mixture, and the resulting solid was collected by filtration and washed with water to obtain (2,3-dichloro-4-methoxyphenyl)acetic acid (737 mg).