Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@H:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=5)[CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:4].[Li+].[OH-].Cl>C1COCC1.CO>[C:38]([O:37][C:35]([N:6]1[C@H:5]([C:3]([OH:4])=[O:2])[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@H:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=5)[CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7]1)=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: COC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)CO3
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)O3
Temperature: 25 °C
Reaction time: 10 h
Yield: 96.7 %

Procedure:
To a solution of (3S,8S)-3-[3-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester 8-methyl ester (0.72 g) in THF:MeOH (3:7, 10 mL) solution, 2 N LiOH solution (4 mL) was added and 0° C., and the resulting reaction mixture was stirred at room temperature for 10 hours. After completion of the reaction, 1N HCl (8 mL) was added to neutralize the base, extracted with ethyl acetate, organic layer was washed with water, brine, dried over sodium sulfate, and the solvent was removed under reduced pressure to afford the product (0.68 g). LCMS (m/z): 587.
Reaction SMILES: [OH:1][CH:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH:3]1[NH:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.[N+:25]([O-])([OH:27])=[O:26].[K+].[Br-]>C(O)(=O)C>[OH:1][CH:2]1[C:7]([CH3:8])([CH3:9])[O:6][C:5]2[CH:10]=[C:11]([N+:25]([O-:27])=[O:26])[S:12][C:4]=2[CH:3]1[NH:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])O
Reactant: CC1(C)Oc2ccsc2C(NC(=O)c2ccc([N+](=O)[O-])cc2)C1O
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC1(C)Oc2cc([N+](=O)[O-])sc2C(NC(=O)c2ccc([N+](=O)[O-])cc2)C1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5,6-Dihydro-6-hydroxy-5,5-dimethyl-7-(4-nitrobenzamido)-7H-thieno[3,2-b]pyran (1.5 g, 4.30 mmol) was treated with 90% nitric acid (2.5 mL, 53.5 mmol) in acetic acid (25 mL) and stirred at 15°-20° C. for 0.5 h. The resultant solution was poured into ice water 100 mL and extracted with 10% isopropanol in dichloromethane. The dichloromethane solution was washed with saturated aqueous sodium bicarbonate and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by medium pressure chromatography using 2% methanol in dichloromethane as the eluant, to give the product, 0.489 g (29%), as a yellow solid: mp 221°-225° C. dec; IR (KBr): 3345, 1647 and 1602 cm-1 ; MS: m/z 394 (MH+); 1H NMR (DMSO-d6): δ 1.26 (s, 3H), 1.45 (s, 3H), 3.90 (dd, J= 8.8 Hz and J=5.9 Hz, 1H, simplifies to d, J=8.8 Hz with D2O), 4.98 (dd, J=7.6 Hz and J=8.8 Hz, 1H, simplifies to d, J=8.8 Hz with D2O), 6.01 (d, J=5.9 Hz, 1H exchanges with D2O), 7.75 (s, 1H), 8.14 (d, J=8.8 Hz, 2H) 8.37 (d, J=8.8 Hz, 2H) and 9.38 (d, J=7.6 Hz, 1H, exchanges with D2O).
Reaction SMILES: [BrH:1].[CH2:2]([N:9]1[CH2:18][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([OH:26])[CH:20]=2)[C:16]2[C:11](=[C:12]([N+:28]([O-])=O)[C:13]([OH:27])=[CH:14][CH:15]=2)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)C.[Ni]>[BrH:1].[NH2:28][C:12]1[C:13]([OH:27])=[CH:14][CH:15]=[C:16]2[C:11]=1[CH2:10][N:9]([CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH2:18][CH:17]2[C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([OH:26])[CH:20]=1
Reactant: O=[N+]([O-])c1c(O)ccc2c1CN(Cc1ccccc1)CC2c1ccc(O)c(O)c1
Agent: [Ni]
Agent: Br
Solvent: CCO
Product: Nc1c(O)ccc2c1CN(Cc1ccccc1)CC2c1ccc(O)c(O)c1
Yield: 91.2 %

Procedure:
1.03 g of 2-benzyl-4-(3,4-dihydroxyphenyl)-7-hydroxy-8-nitro-1,2,3,4-tetrahydroisoquinoline hydrobromide was suspended in 20 ml of ethanol, and after adding thereto 1 ml of Raney nickel, hydrogenation reaction was performed at 40° C. The hydrogenation reaction was over, the reaction mixture was filtered, and concentrated, affording 0.88 g of 8-amino-2-benzyl-4-(3,4-dihydroxyphenyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[CH2:9][CH2:10]O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl.O>[CH3:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[CH2:9][CH2:10][Br:2]
Reactant: Cc1ccc(CCO)cc1C
Reactant: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Cc1ccc(CCBr)cc1C
Temperature: 25 °C

Procedure:
Phosphorus tribromide (0.82 g) was added dropwise to a solution of 3,4-dimethylphenethyl alcohol (1.27 g--see Preparation 17) in carbon tetrachloride (10 ml). The mixture was heated under reflux for 2.5 hours then cooled to room temperature and basified (pit 8) by the dropwise addition of 10% aqueous sodium carbonate (5 ml). The mixture was then diluted with water (20 ml) and extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give the title compound as a colourless oil, yield, 0.5g.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([OH:14])=[C:6]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:5]=1)=[O:3].C(N(C(C)C)CC)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[CH3:40][C:41]([CH3:43])=[O:42]>C(Cl)Cl>[C:15]([C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH2:1][C:41]([OH:42])([CH3:43])[CH3:40])[CH:9]=[C:8]([C:10]([CH3:11])([CH3:13])[CH3:12])[C:7]=1[OH:14])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)=O
Reactant: CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(O)CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of 3,5-di-tert-butyl-4-hydroxyacetophenone (Apim Chemicals, Ltd.) (4 g) in dry methylene chloride (250 mL) is cooled to -78° C. and di-isopropyl ethylamine (7.3 mL) is added followed by trimethylsilyl trifluoromethanesulphonate (Aldrich Chemical Co.) (8.0 mL). The mixture is stirred at -78° C. for 10 minutes and is allowed to warm to ambient temperature over 1 hour. The mixture is cooled again to -78° C. and dry acetone (4.05 mL) is added dropwise. After stirring for 25 minutes, the mixture is washed with 1N aqueous hydrochloric acid and brine. The organic solution is dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure. The crude product is dissolved in methanol-1N aqueous HCl mixture (10:1, v/v, 200 mL) and the homogenous solution is stirred for 1 hour at room temperature. Methanol is removed under reduced pressure; the mixture is washed with methylene chloride. The organic extracts are washed: with aqueous sodium bicarbonate, brine, dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure. The crude product is crystallized from hexane to give 1-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-hydroxy-3-methyl-butan-1-one as orange crystals. Two additional crystallizations give product of analytical purity, mp 113°-14° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:12])([CH3:11])[CH:3]=1.[C:13](Cl)(=[O:15])[CH3:14].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCCl>[C:13]([C:3]1[C:4]([CH3:12])([CH3:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]=1[CH3:1])(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: CC1=CC(C)(C)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)C1=C(C)c2ccccc2C1(C)C
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 20 g 1,3,3-trimethylindene (see e.g. J. Am. Chem. Soc. 76, 5430 (1954) ) 13 g acetyl chloride and 55 ml 1,2-dichloroethane in a nitrogen atmosphere was dosed with stirring 21.5 g aluminum trichloride over a period of one and a half hour and at a temperature of 20-25° C. After an additional stirring period of 30 minutes at 20° C. the mixture was poured on ice and stirred for another hour. The organic layer was washed with subsequently 5%-sodium carbonate solution, saturated sodium chloride solution and concentrated by means of a rotatory evaporator. Vacuum distillation of the residue yielded a 15.3 g of a fraction boiling up to 145° C. at 3 mm Hg. Recrystallization from methanol yielded 10 g 2-acetyl-1,3,3-trimethylindene of 99.8% purity, mp 104.5-105.0° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:21]2[C:29]3[C:24](=[N:25][CH:26]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:28]=3)[N:23](S(C3C=CC(C)=CC=3)(=O)=O)[CH:22]=2)=[N:5][C:6]([NH:9][C:10]([CH3:20])([CH3:19])[C:11]([NH:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[O:12])=[N:7][CH:8]=1)#[N:2].O.O[Li].O>C1COCC1>[C:1]([C:3]1[C:4]([C:21]2[C:29]3[C:24](=[N:25][CH:26]=[C:27]([C:30]([F:31])([F:33])[F:32])[CH:28]=3)[NH:23][CH:22]=2)=[N:5][C:6]([NH:9][C:10]([CH3:20])([CH3:19])[C:11]([NH:13][CH2:14][C:15]([F:18])([F:16])[F:17])=[O:12])=[N:7][CH:8]=1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(NC(C)(C)C(=O)NCC(F)(F)F)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(Nc1ncc(C#N)c(-c2c[nH]c3ncc(C(F)(F)F)cc23)n1)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
2-(5-cyano-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-ylamino)2-methyl-N-(2,2,2-trifluoroethyl)propanamide (29 mg, 0.046 mmol, 1.0Eq.) was dissolved in THF (4 mL) and water (1 mL) and treated with LiOH.H2O (10 mg, 0.23 mmol, 15 eq) and allowed to stir at room temperature overnight. The reaction mixture was concentrated and the residue partitioned between EtOAc and water. The organic phase was washed with saturated aqueous NaHCO3 followed by brine, dried over MgSO4, filtered and the solvent evaporated. The residue was purified by column chromatography (ISCO Companion™, 12 g column, 0-100% EtOAc/Petroleum Ether) to give the title compound as a white solid (13 mg, 60%). MS (ES+) m/e=472. 1H NMR (DMSO) 1.53 (6H, s), 1.58 (6H, s), 3.65-3.69 (2H, m), 3.75-3.79 (2H, m), 8.26-8.34 (2H, m), 8.45 (1H, s), 8.65-8.78) 6H, m), 8.96 (1H, s), 9.29 (1H, s), 13.05 (2H, brs) [1:1 Mixture of rotamers]
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH2:7])=[O:6].CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([NH:30][C:31]([C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)=[O:32])[CH:24]=[CH:23]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[C:5]([C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([NH:30][C:31]([C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)=[O:32])[CH:24]=[CH:23]3)[CH:3]=1)(=[O:6])[NH2:7]
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Reactant: Cc1ccc(C(N)=O)cc1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(C(N)=O)cc1-c1ccc2cc(NC(=O)c3ccsc3)ccc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 7.8 %

Procedure:
3-bromo-4-methylbenzamide (22.7 mg, 0.106 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (62.5 mg, 0.165 mmol), Fibercat palladium catalyst (Johnson-Matthey, 35.1 mg), and K2CO3 (2 M in water, 0.24 ml, 0.48 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (1.1 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 80 C for 10 minutes and then for 20 minutes. The reaction was cooled to room temperature, diluted with water (5 ml), extracted with dichloromethane (3×10 ml), diluted with 1,4-dioxane (10 ml), and extracted with EtOAc (3×10 ml). The organic extracts were combined, dried over magnesium sulfate, filtered, concentrated, and purified on HPLC (10%->95% MeCN/water with 0.1% TFA) to afford title compound (3.2 mg, 8%). MS (ESI pos. ion) m/z: 387 (M+H). Calc'd Exact Mass for C23H18N2O2S: 386.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:5]([CH3:21])[C:4](=[O:22])[O:3]1.[OH-:23].[Ba+2].[OH-]>O1CCCC1.O>[CH3:21][CH:5]([CH:6]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]([OH:23])[CH3:1])[C:4]([OH:3])=[O:22]
Reactant: [OH-]
Reactant: CCOC(=O)C1C(C)OC(=O)C(C)C1NCc1ccccc1
Agent: [Ba+2]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C(C)O)C(NCc1ccccc1)C(C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl (2SR,3SR,4RS,5RS)-tetrahydro-2,5-dimethyl-6-oxo-4-benzylamino-2H-pyrane-3-carboxylate (3 mg) and barium hydroxide (7 mg) were dissolved in a mixture of tetrahydrofuran and water (2:1) and stirred vigorously at room temperature for 1 hour. The reaction mixture was treated as in Reference Example 17 to give (2RS,3RS,4SR,5SR)-2-methyl-3-benzylamino-4-ethoxycarbonyl-5-hydroxyhexanoic acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:9][OH:10])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)O1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:26]3[CH:27]=[N:28][NH:29][CH:30]=3)=[CH:3][CH:4]=2)[CH2:9][OH:10])=[CH:12][CH:13]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: OCC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: OCC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1

Procedure:
2,2-Bis-(4-chloro-phenyl)-ethanol was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LC/MS: (PS-A2) Rt 2.72 [M+H]+ 299.00.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][N:26]1[C:30](=[O:31])[C:29]([CH3:33])([CH3:32])[NH:28][C:27]1=[O:34]>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:28]4[C:29]([CH3:33])([CH3:32])[C:30](=[O:31])[N:26]([CH3:25])[C:27]4=[O:34])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: CN1C(=O)NC(C)(C)C1=O
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4(C)C)nc3)CC2)c(C)c1
Yield: 63.7 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (156 mg) described in Preparation Example 145 and 3,5,5-trimethylimidazolidine-2,4-dione (63 mg) m described in Preparation Example 218 and by the reaction and treatment in the same manner as in Example 536, the title compound (115 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C@H:11]2[CH2:15][CH2:14][C@@H:13]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[CH2:12]2)[CH3:9])=[CH:4][C:3]=1[O:24][CH3:25].C[Si]([N:30]=[N+:31]=[N-:32])(C)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C@H:11]2[CH2:15][CH2:14][C@@H:13]([C:16]3[CH:17]=[CH:18][C:19]([C:20]4[NH:32][N:31]=[N:30][N:21]=4)=[CH:22][CH:23]=3)[CH2:12]2)[CH3:9])=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: COc1cc([C@@H](C)N[C@H]2CC[C@@H](c3ccc(C#N)cc3)C2)ccc1F
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: COc1cc([C@@H](C)N[C@H]2CC[C@@H](c3ccc(-c4nnn[nH]4)cc3)C2)ccc1F
Temperature: 118 °C
Reaction time: 8 h

Procedure:
4-[(1R,3S)-3-[[(1R)-1-(4-fluoro-3-methoxy-phenyl)ethyl]amino]cyclopentyl]benzonitrile (5.1 g, 14.4 mmol) in toluene (160 ml) was treated with trimethylsilylazide (9.5 ml, 72 mmol, dropwise addition) followed by SnBu2O (717 mg, 2.88 mmol). The reaction mixture was stirred at 118° C. overnight. The precipitate was filtered off, and the filtrate was evaporated and purified by flash chromatography (gradient of 0-10%, MeOH in DCM containing 2% NEt3). The product thus obtained was precipitated from EtOH, redissolved in DCM and extracted with aqueous HCl (pH 1). The aqueous phase was neutralized to pH 5-6 with NaOH aq. (1M), and the resulting precipitate was filtered off and dried to afford the title compound. 1H NMR (300 MHz, DMSO) δ 7.89 (d, J=8.2 Hz, 2H), 7.39 (dd, J=8.3, 1.8 Hz, 1H), 7.33-7.23 (m, 3H), 7.14-7.03 (m, 1H), 4.38 (q, J=6.5 Hz, 1H), 3.86 (s, 3H), 3.45-3.32 (m, 1H), 3.09-2.95 (m, 1H), 2.38-2.25 (m, 1H), 2.10-1.64 (m, 5H), 1.56 (d, J=6.7 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:22])[C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1.C(O)(C(F)(F)F)=O>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:19][C:18]([F:20])([F:21])[CH:17]([C:14]1[CH:15]=[CH:16][C:11]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:12][CH:13]=1)[OH:22]
Reactant: OC(c1ccc(Br)cc1)C(F)(F)F
Reactant: Fc1cccc([Mg]Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: OC(c1ccc(-c2cccc(F)c2)cc1)C(F)(F)F
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
To Pd(PPh3)4 (2.1 g, 1.823 mmol) was added 3-fluorophenylmagnesium bromide (55 mls, 1.0 M in THF, 55 mmol) at 0° C. over 15 minutes. The ice bath was removed and the mixture was stirred for 30 minutes. 1-(4-Bromophenyl)-2,2,2-trifluoroethanol (4.65 g, 18.23 mmol) in THF (50 mls) was added over 10 minutes. The mixture was heated to reflux for 3 hours and was shown complete by LC (Sunfire column, TFA). The mixture was cooled, quenched with H2O, rotary evaporated to remove most of the THF, and extracted 3 times with CH2Cl2. The organics were combined washed with brine, dried over MgSO4, and concentrated. Chromatography (SiO2, CH2Cl2) gave 4.64 g of 2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethanol. Yield 94%.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1.Br[CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([CH2:17][CH2:16][N:1]2[C:5]3=[CH:6][N:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:9]=[C:4]3[CH:3]=[CH:2]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: BrCCC1CCCCC1
Reactant: CCOC(=O)c1cc2cc[nH]c2cn1
Product: CCOC(=O)c1cc2ccn(CCC3CCCCC3)c2cn1

Procedure:
The title compound was prepared by alkylation of ethyl 1H-pyrrolo[2,3-c]pyridine-5-carboxylate with (2-bromoethyl)cyclohexane in a manner similar to step 6 of example 1. 1H NMR (CDCl3) δ ppm 8.86 (s, 1H), 8.50 (s, 1H), 7.33 (d, 1H, J=3.0 Hz), 6.66 (d, 1H, J=3.0 Hz), 4.52 (q, 2H, J=6.9 Hz), 4.29 (t, 2H, J=7.5 Hz), 1.66-1.83 (m, 7H), 1.48 (t, 3H, J=7.2 Hz), 1.18-1.32 (m, 4H), 0.93-1.05 (m, 2H). LCMS (APCI, M+H+): 301.1
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH:25]([C:29]([OH:31])=[O:30])[CH2:24]1>>[NH:2]1[CH:3]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([N:23]5[CH2:28][CH2:27][CH2:26][CH:25]([C:29]([OH:31])=[O:30])[CH2:24]5)=[O:20])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:5]=[N:1]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: O=C(O)C1CCCNC1
Product: O=C(O)C1CCCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)C1

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and piperidine-3-carboxylic acid to give 263. MS: (ESI+)=396.1
Reaction SMILES: C([O:3][P:4]([CH2:9][N:10]1[C:19]2[C:14](=[CH:15][C:16]([N+:26]([O-:28])=[O:27])=[C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:18]=2)[NH:13][C:12](=[O:29])[C:11]1=[O:30])(=[O:8])[O:5]CC)C.C[Si](C)(C)Br.O>C(#N)C>[N+:26]([C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][C:17]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[N:10]([CH2:9][P:4]([OH:5])(=[O:3])[OH:8])[C:11](=[O:30])[C:12](=[O:29])[NH:13]2)([O-:28])=[O:27]
Reactant: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(N3CCOCC3)cc21)OCC
Agent: C[Si](C)(C)Br
Solvent: O
Solvent: CC#N
Product: O=c1[nH]c2cc([N+](=O)[O-])c(N3CCOCC3)cc2n(CP(=O)(O)O)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.5 %

Procedure:
259 mg of (6-nitro-7-morpholino-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl)methanephosphonic acid diethyl ester is mixed in 10 ml of absolute acetonitrile with 628 mg of trimethylbromosilane and stirred for 1 hour at room temperature. A little water is added, and it is evaporated to dryness. The residue is chromatographed on silanized silica gel with methanol as eluant. 60 mg of (6-nitro-7-morpholino-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl)methanephosphonic acid is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[O:30]1[CH2:34][CH2:33][C@H:32]([OH:35])[CH2:31]1.CC(C)([O-])C.[Na+]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:35][C@H:32]2[CH2:33][CH2:34][O:30][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:26])[CH3:27])[C:6]=2[N:7]=1
Reactant: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(Cl)c34)cc2o1
Reactant: O[C@H]1CCOC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(O[C@H]5CCOC5)c34)cc2o1
Temperature: 75 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
To a solution of 6-(2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), (S)-tetrahydrofuran-3-ol (1.1 equiv) in 1,4-dioxane (0.2 M) was added sodium tert-butoxide (1.1 equiv). The reaction was stirred at 75° C. for 5 h. The reaction mixture was quenched with saturated aqueous sodium chloride and then washed with ethyl acetate. The organic phase was combined and washed with saturated aqueous sodium chloride. The organic layer was dried (magnesium sulfate), filtered, and concentrated. The crude was purified by silica gel column chromatography (0-90%) ethyl acetate in hexane) to give the title compound (90% yield) as yellow solid; 1H NMR (400 MHz, DMSO-d6) δ ppm −0.07 (s, 9H) 0.84-0.90 (m, 2H) 1.99-2.10 (m, 1H) 2.26 (dtd, J=13.96, 8.25, 8.25, 6.25 Hz, 1 H) 2.63 (s, 3 H) 3.53-3.62 (m, 2 H) 3.73-3.81 (m, 2 H) 3.84 (d, J=10.54 Hz, 1 H) 3.93 (dd, J=10.54, 4.30 Hz, 1 H) 5.57 (s, 2 H) 5.72-5.80 (m, 1 H) 7.59-7.64 (m, 1 H) 7.66 (d, J=8.59 Hz, 1 H) 7.89 (s, 1 H) 7.91 (d, J=0.78 Hz, 1 H); MS (ESI) m/z 501.1 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:16][CH3:17].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:16][CH3:17]
Reactant: CCI
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In DMF (120 ml) was dissolved 2-bromophenol (12 g). To the mixture was added potassium carbonate (12.5 g) and then was added iodoethane (6.7 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=12/1) to give 1-bromo-2-ethoxybenzene (12.2 g).