Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[N:5]([C:14]1[CH:19]=[C:18]([CH:20]=[O:21])[N:17]=[C:16]([NH2:22])[C:15]=1[N+:23]([O-:25])=[O:24])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)[CH3:2].C1(C)C=CC(S([CH2:36][N+:37]#[C-:38])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([O:3][C:4](=[O:26])[N:5]([C:14]1[CH:19]=[C:18]([C:20]2[O:21][CH:38]=[N:37][CH:36]=2)[N:17]=[C:16]([NH2:22])[C:15]=1[N+:23]([O-:25])=[O:24])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(C=O)nc(N)c1[N+](=O)[O-]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(-c2cnco2)nc(N)c1[N+](=O)[O-]
Reaction time: 1 h
Yield: 64.1 %

Procedure:
(2-Amino-6-formyl-3-nitro-pyridin-4-yl)-(6-methyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (190 mgs/0.529 mmols) was dissolved in MeOH (5 mls). Added (4-tolylsulphonyl)methylisocyanide (124 mgs/0.634 mmols) followed by anhydrous potassium carbonate (200 mgs/1.45 mmols). Stirred under N2 for 1 hr then concentrated in vacuo. Partitioned between EtOAc (100 mls) and H2O (50 mls). Organic collected, washed with brine, dried over Na2SO4, filtered and concentrated to a black resin. Purification by column chromatography eluting with 90:10 DCM/MeOH gave the title compound (135 mgs) as a crude brown solid.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([CH3:18])=[C:9]1[S:19](=[O:38])(=[O:37])[NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[CH:23][C:22]=1[C:33]([F:36])([F:35])[F:34])=O)(C)(C)C.[ClH:39].C(OCC)(=O)C>>[ClH:39].[N:30]1[CH:29]=[CH:28][C:27]([C:24]2[CH:25]=[CH:26][C:21]([NH:20][S:19]([C:9]3[NH:8][C:16]4[C:11]([C:10]=3[CH3:18])=[CH:12][C:13]([F:17])=[CH:14][CH:15]=4)(=[O:37])=[O:38])=[C:22]([C:33]([F:36])([F:35])[F:34])[CH:23]=2)=[CH:32][CH:31]=1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(-c3ccncc3)cc2C(F)(F)F)n(C(=O)OC(C)(C)C)c2ccc(F)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3ccncc3)cc2C(F)(F)F)[nH]c2ccc(F)cc12

Procedure:
This compound was prepared in analogy to example 27b starting from 5-fluoro-3-methyl-2-(4-pyridin-4-yl-2-trifluoromethyl-phenylsulfamoyl)-indole-1-carboxylic acid tert-butyl ester (0.052 g), 2.5 N HCl/ethyl acetate (10.0 ml) to obtain the title compound (0.041 g) as a brownish amorphous powder. MS (ISN): 448.4 (M−H)−
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C@H:3]([NH:10]C(=O)[C@](OC)(C1C=CC=CC=1)C(F)(F)F)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.CC(C)(C)[C@@H](NC(=O)[C@](OC)(C1C=CC=CC=1)C(F)(F)F)C1C=CC=CN=1.Br>O>[CH3:1][C:2]([CH3:27])([CH3:26])[CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[NH2:10]
Reactant: CO[C@@](C(=O)N[C@H](c1ccccn1)C(C)(C)C)(c1ccccc1)C(F)(F)F
Agent: Br
Agent: CO[C@@](C(=O)N[C@@H](c1ccccn1)C(C)(C)C)(c1ccccc1)C(F)(F)F
Solvent: O
Product: CC(C)(C)C(N)c1ccccn1

Procedure:
Solutions of (R)—N—((S)-2,2-dimethyl-1-(pyridin-2-yl)propyl)-3,3,3-trifluoro-2-methoxy-2-phenylpropanamide (0.56 g, 1.472 mmol) or (R)—N—((R)-2,2-dimethyl-1-(pyridin-2-yl)propyl)-3,3,3-trifluoro-2-methoxy-2-phenylpropanamide (0.56 g, 1.472 mmol) in 48 wt % aqueous hydrogen bromide (5.02 mL, 44.2 mmol) were heated under microwave irradiation at 160° C. for 2 h. The mixtures were diluted with water (25 mL), extracted with dichloromethane (3×25 mL), and the dichloromethane extracts discarded. The aqueous solutions were basified with 2 M aqueous NaOH (25 mL) then extracted with dichloromethane (3×25 mL). These extracts were dried (MgSO4), filtered, then concentrated to give enantiomeric 2,2-dimethyl-1-(pyridin-2-yl)propan-1-amine derived from first-eluting diastereomer (0.175 g) and enantiomeric 2,2-dimethyl-1-(pyridin-2-yl)propan-1-amine derived from second-eluting diastereomer (0.200 g) as yellow oils.
Reaction SMILES: Br[C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]1([CH2:15][SH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)C(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:15]([S:16][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ncccc1Br
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncccc1SCc1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 59.3 %

Procedure:
To a solution of 3-bromo-2-methylpyridine (1.0 g) in toluene (12 mL) were added phenylmethanethiol (794 mg), N,N-diisopropylethylamine (1.65 g), tris(dibenzylideneacetone)dipalladium(0) (213 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (269 mg), and the mixture was stirred under an argon atmosphere at 80° C. for 4 hr. The reaction mixture was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→3:1) to give the title compound as a yellow solid (yield 742 mg, 59%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)[OH:22])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(Br)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of 4-(4-bromobenzoyl)-piperidine-1-carboxylic acid tert-butyl ester (1.47 g, 4.00 mmol) in absolute EtOH (25 mL) was added NaBH4 (227 mg, 6.00 mmol). The mixture was stirred at room temperature for 2 hours. Standard work-up and purification gave 4-[(4-bromo-phenyl)-hydroxymethyl]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (1.480 g, 100%). 1H NMR (CDCl3) δ 1.07-1.27 (m, 2H), 1.62-1.72 (m, 1H), 1.88 (d, 1H, J=13.2 Hz), 2.35 (d, 1H, J=3.3 Hz), 2.50-2.65 (m, 2H), 4.04-4.13 (m, 2H), 4.33 (dd, 1H, J=7.2, 3.3 Hz), 7.16 (d, 2H, J=8.4 Hz), 7.45 (d, 2H, J=8.4 Hz).
Reaction SMILES: C([Mg]Br)C1C=CC=CC=1.C1([Mg]Br)C=CC=CC=1.C([CH:25]([NH2:43])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[C:34]([C:39]([F:42])([F:41])[F:40])=[N:35][NH:36][C:37]=2[CH3:38])=[CH:29][CH:28]=1)C1C=CC=CC=1.CC1NN=C(C(F)(F)F)C=1C1C=CC(CC(N)C2C=CC=CC=2)=CC=1>>[CH3:38][C:37]1[NH:36][N:35]=[C:34]([C:39]([F:42])([F:41])[F:40])[C:33]=1[C:30]1[CH:31]=[CH:32][C:27]([CH2:26][C:25]#[N:43])=[CH:28][CH:29]=1
Reactant: Cc1[nH]nc(C(F)(F)F)c1-c1ccc(CC(N)Cc2ccccc2)cc1
Agent: Br[Mg]Cc1ccccc1
Agent: Br[Mg]c1ccccc1
Agent: Cc1[nH]nc(C(F)(F)F)c1-c1ccc(CC(N)c2ccccc2)cc1
Product: Cc1[nH]nc(C(F)(F)F)c1-c1ccc(CC#N)cc1

Procedure:
The product of Example 37B can also be reacted with benzyl magnesium bromide or phenyl magnesium bromide under the Grignard reaction conditions described in Example 5 to give (following deprotection by the method of Example 37C) 1-benzyl-2-[4-(5-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-phenyl]-ethylamine and 2-[4-(5-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-phenyl]-1-phenyl-ethylamine respectively.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]([F:20])([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[CH3:21].[OH-].[Na+]>O1CCOCC1.CO>[CH3:21][C:5]1[CH:6]=[C:7]([C:11]([F:20])([C:12]([F:13])([F:14])[F:15])[C:16]([F:19])([F:18])[F:17])[CH:8]=[C:9]([CH3:10])[C:4]=1[C:3]([OH:22])=[O:2]
Reactant: COC(=O)c1c(C)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1C(=O)O
Temperature: 60 °C
Reaction time: 15 h
Yield: 97.6 %

Procedure:
2,6-Dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-benzoic acid methyl ester (7 g, 0.021 mol) (Example I2) was dissolved in dioxane (70 ml) and methanol (15 ml), then aqueous sodium hydroxide (4N) (52.2 ml, 0.21 mol) was added. The mixture was stirred at 60° C. for 15 hours. The methanol was evaporated and the mixture was cooled to 0° C. before acidifying to pH=1 by addition of concentrated hydrochloric acid. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate and concentrated to give the 2,6-dimethyl-4-(1,2,2,2-tetra-fluoro-1-trifluoromethyl-ethyl)-benzoic acid (6.52 g, 98% yield). 1H-NMR (CDCl3, 400 MHz): 7.31 (s, 2H), 2.49 (s, 6H) ppm.
Reaction SMILES: COC1C=C2C(=CC=1)C=C(B(O)O)C=C2.BrC1C=CN=CC=1[N+]([O-])=O.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH:34]=[C:33]([C:38]1[CH:43]=[CH:42][N:41]=[CH:40][C:39]=1[N+:44]([O-])=O)[CH:32]=[CH:31]2>>[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH:34]=[C:33]([C:38]1[CH:43]=[CH:42][N:41]=[CH:40][C:39]=1[NH2:44])[CH:32]=[CH:31]2
Reactant: COc1ccc2cc(-c3ccncc3[N+](=O)[O-])ccc2c1
Agent: COc1ccc2cc(B(O)O)ccc2c1
Agent: O=[N+]([O-])c1cnccc1Br
Product: COc1ccc2cc(-c3ccncc3N)ccc2c1
Yield: 90.6 %

Procedure:
Synthesized from (6-methoxynaphthalen-2-yl)boronic acid and 4-bromo-3-nitropyridine according to an analogous synthetic method to Preparation Example 79, 4-(6-methoxynaphthalen-2-yl)-3-nitropyridine (2.1 g) was used according to an analogous synthetic method to Example 22 to provide the title compound (1.7 g).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH:20]=[CH:19][C:11]=1[C:12]([O:14]C(C)(C)C)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[C:1]([NH:9][C:10]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH:20]=[CH:19][C:11]=1[C:12]([OH:14])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1-c1ccc(C(=O)O)c(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 mL of trifluoroacetic acid was added no the obtained tert-butyl 2-(benzamido)-4-(2-methylphenyl)benzoate and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and methanol was added to the obtained residue and a solid substance was separated by filtration to obtain 14 mg of 2-(benzamido)-4-(2-methylphenyl)benzoic acid as white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[N:20][CH:21]=2)[CH:13]=[CH:12][N:11]=1.Cl.Cl.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][C:33]=2[C:41]([F:44])([F:43])[F:42])[CH2:27][CH2:26]1>>[CH3:24][N:25]1[CH2:26][CH2:27][N:28]([CH2:31][C:32]2[CH:40]=[CH:39][C:35]([C:36]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([NH:9][C:10]4[CH:15]=[C:14]([C:16]5[CH:17]=[N:18][CH:19]=[N:20][CH:21]=5)[CH:13]=[CH:12][N:11]=4)[CH:4]=3)=[O:37])=[CH:34][C:33]=2[C:41]([F:44])([F:42])[F:43])[CH2:29][CH2:30]1
Reactant: Cc1ccc(N)cc1Nc1cc(-c2cncnc2)ccn1
Reactant: CN1CCN(Cc2ccc(C(=O)Cl)cc2C(F)(F)F)CC1
Agent: Cl
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1Nc1cc(-c2cncnc2)ccn1

Procedure:
This compound was prepared in the same manner as in Example 1, except that 4-methyl-3-[4-(5-pyrimidinyl)pyridin-2-ylamino]aniline (Reference Example 22) and 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylbenzoyl chloride dihydrochloride (Reference Example 2) were used, and that the resulting crude crystals were washed with ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@@H:4]([O:22][CH2:23][CH3:24])[C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:8]=1[F:21])O.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3](=[O:25])[C@@H:4]([O:22][CH2:23][CH3:24])[CH2:5][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:8]=1[F:21]
Reactant: CCO[C@H](C(=O)OC)[C@H](O)c1ccc(OCc2ccccc2)cc1F
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1F)C(=O)OC

Procedure:
In analogy to the procedure described in example 17 c], (2S,3R)-3-(4-benzyloxy-2-fluoro-phenyl)-2-ethoxy-3-hydroxy-propionic acid methyl ester was treated with triethylsilane in trifluoroacetic acid to yield (2S)-3-(4-benzyloxy-2-fluoro-phenyl)-2-ethoxy-propionic acid methyl ester as colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21](O)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:24]([C:27]2[CH:28]=[N:29][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:42])=O>ClCCl.CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([Cl:42])=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:24]([C:27]2[CH:28]=[N:29][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Reaction time: 2 h

Procedure:
A solution of (R)-1-(4-fluorophenyl)-6-(6-morpholin-4-yl-pyridine-3-sulfonyl]-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylic acid (0.29 g) in dry dichloromethane (9 mL) was treated with oxalyl chloride (0.21 g) for 30 minutes. One drop of N,N-dimethylformamide was added and the reaction mixture stirred for a further 2 hours. The reaction mixture was concentrated under reduced pressure and the product used without further purification.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[CH3:13][O:14][C:15]([NH:17][NH:18][CH:19]([CH3:21])[CH3:20])=[O:16].CCN(C(C)C)C(C)C.[Br:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[NH:42][C:41]([CH:43]3[CH2:47][CH2:46][CH2:45][NH:44]3)=[N:40][CH:39]=2)=[CH:34][CH:33]=1>C(Cl)Cl>[CH3:13][O:14][C:15]([NH:17][N:18]([C:5]([N:44]1[CH2:45][CH2:46][CH2:47][CH:43]1[C:41]1[NH:42][C:38]([C:35]2[CH:36]=[CH:37][C:32]([Br:31])=[CH:33][CH:34]=2)=[CH:39][N:40]=1)=[O:11])[CH:19]([CH3:21])[CH3:20])=[O:16]
Reactant: Brc1ccc(-c2cnc(C3CCCN3)[nH]2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)NNC(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NN(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Temperature: 0 °C
Yield: 33.4 %

Procedure:
Triphosgene (1.05 g) was dissolved in DCM (17 mL) and stirred at 0° C. N′-Isopropyl-hydrazine-carboxylic acid methyl ester (1.00 g) and DIPEA (1.5 mL) were dissolved in DCM (25 mL), and mixture was added to triphosgene solution and stirred for 10 minutes. 5-(4-Bromo-phenyl)-2-pyrrolidin-2-yl-1H-imidazole (2.65 g) was added. Reaction was stirred at room temperature for 1 hour and extracted twice with water (10 mL), once with brine (10 mL), and evaporated under vacuum. The resulting oil was subjected to silica gel chromatography using a 40 g ISCO column and effluent of 0-100% ethyl acetate:hexanes. The fractions containing product were combined and the solvent was removed under vacuum, giving N′-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-N′-isopropyl-hydrazine-carboxylic acid methyl ester (533 mg, 16%).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[I-:27].[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O>[OH:1][C:3]1([CH2:2][I:27])[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:11][C:10]=2[F:26])[CH2:7][CH2:8]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CI)CC3)c(F)c2)C(=O)O1

Procedure:
A mixture of (S)-N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (10.0 mmol) and sodium iodide (11.0 mmol) in presence of catalytic p-toluene sulfonic acid in dimethyl formamide at a temperature 50-60° C. for 12 hours to provide crude (S)-N-{3-[4-(4-hydroxy-4-iodomethylpiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide which was purified by silica gel column chromatography and used further.
Reaction SMILES: [C:1]([CH:3]([C:11]1([CH3:15])[CH2:14][O:13][CH2:12]1)[NH:4][S:5]([C:7]([CH3:10])([CH3:9])[CH3:8])=[O:6])#[N:2].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:23][OH:24]>C(O)C>[C:7]([S:5]([NH:4][CH:3]([C:11]1([CH3:15])[CH2:12][O:13][CH2:14]1)[C:1]([NH2:2])=[N:23][OH:24])=[O:6])([CH3:10])([CH3:8])[CH3:9]
Reactant: NO
Reactant: CC1(C(C#N)NS(=O)C(C)(C)C)COC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC1(C(NS(=O)C(C)(C)C)C(N)=NO)COC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 114.8 %

Procedure:
To a solution of N-[cyano-(3-methyloxetan-3-yl)methyl]-2-methyl-propane-2-sulfinamide (example 251a, 680 mg, 2.95 mmol) in Ethanol (15 ml) was added potassium carbonate (408 mg, 2.95 mmol) and hydroxylamine hydrochloride (226 mg, 3.25 mmol). The reaction mixture was stirred at room temperature for 30 minutes followed by stirring at 50° C. overnight. The reaction was diluted with ethanol and sonicated a few minutes followed by removal of insolubles by filtration. The filtrate was concentrated in vacuo to dryness to yield a crude yellow gum of the title compound (892 mg) which was used without any purification. MS (ESI, m/z): 264.3 (M+H+).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:15])=[N+]=[N-]>C1COCC1.CO.[Pd]>[Cl:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[N:7]=[C:6]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[O:23][CH3:24])[C:5]([CH2:4][NH2:1])=[CH:14]2
Reactant: COc1ccc(F)cc1-c1nc2c(Cl)cccc2cc1CN=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1nc2c(Cl)cccc2cc1CN
Reaction time: 2 h

Procedure:
To a stirred solution of 3-(azidomethyl)-8-chloro-2-(5-fluoro-2-methoxyphenyl)-quinoline (210.7 mg, 615 μmol) in THF 5 mL and MeOH 12 mL was added palladium, 10 wt. % on activated carbon (0.329 mmol) and placed under a medium balloon containing H2. The reaction was complete after 2 h, it was filtered (Celite™) and solvents removed.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[N:10]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[CH:12][C:4]=2[CH:3]=1.C([O:24][CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1)(=O)C.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>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.CCOC(C)=O>[F:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[N:10]1[C:5]2[N:6]([CH3:9])[C:7](=[O:8])[C:2]([C:35]3[CH:34]=[C:29]([CH:28]=[CH:27][C:26]=3[CH2:25][OH:24])[C:30]([OH:32])=[O:31])=[CH:3][C:4]=2[CH:12]=[N:11]1
Reactant: Cn1c(=O)c(Br)cc2cnn(-c3c(F)cccc3F)c21
Reactant: COC(=O)c1ccc(COC(C)=O)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1c(=O)c(-c2cc(C(=O)O)ccc2CO)cc2cnn(-c3c(F)cccc3F)c21
Temperature: 130 °C
Yield: 41.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (38 mg, 33 μmol), 5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (373 mg, 1096 μmol), methyl 4-(acetoxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (403 mg, 1206 μmol) were treated with 1,4-dioxane (5.4 mL) and 1 M aqueous Na2CO3 (2.74 mL, 2741 μmol) under argon and heated in a microwave at 130° C. for 30 min. The reaction mixture was treated with EtOAc (20 mL) and extracted with 1N NaOH (2×15 mL). The pH was adjusted to ca. pH 6 with 5N HCl and extracted with DCM (3×20 mL), dried over MgSO4, filtered and concentrated affording the title compound (186 mg) as a yellow tar. The crude residue was used in the next step without further purification. MS (ESI, pos.ion) m/z: 412.1 (M+1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][CH2:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[C@H:18]2[C@H:22]([OH:23])[C@H:21]([OH:24])[C@@H:20]([CH2:25][O:26][CH3:27])[O:19]2)=[C:11]([NH:28][CH2:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:10]=1.C(N(CC)CC)C>ClCCl>[OH:23][C@@H:22]1[C@H:21]([OH:24])[C@@H:20]([CH2:25][O:26][CH3:27])[O:19][C@H:18]1[N:15]1[CH:14]=[N:13][C:12]2[C:16]1=[N:17][C:9]([CH2:8][CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[N:10][C:11]=2[NH:28][CH2:29][CH:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCN)nc32)[C@H](O)[C@@H]1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCNS(C)(=O)=O)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
Methanesulfonyl chloride (27 mg, 0.22 mmol) was added to a stirred solution of (2R,3R,4S,5R)-2-{2-(2-aminoethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (120 mg, 0.23 mmol) (Example 11) and triethylamine (0.1 ml, 0.72 mmol) in dichloromethane (10 ml). The reaction mixture was stirred at room temperature for 2 hr when the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (98:2) increasing in polarity to (95:5). This gave the title compound (87 mg) as a powder. MS: 583 (MH+).
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[N:3]1[CH2:12][CH2:13][CH2:14][C@H:15]([N:18](C)[C:19](=O)OCC1C=CC=CC=1)[CH2:16][OH:17].[H][H]>CO.[Pd]>[OH:17][CH2:16][C@@H:15]([NH:18][CH3:19])[CH2:14][CH2:13][CH2:12][N:3]1[CH2:2][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1
Reactant: [H][H]
Reactant: CN(C(=O)OCc1ccccc1)[C@H](CO)CCCN1C(=O)c2ccccc2C1=O
Agent: [Pd]
Solvent: CO
Product: CN[C@H](CO)CCCN1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.9 %

Procedure:
To a solution of (S)-benzyl 5-(1,3-dioxoisoindolin-2-yl)-1-hydroxypentan-2-yl(methyl)carbamate (5.01 g, 12.65 mmol) in MeOH (100 mL) was added Pd/C (1.0 g). The mixture was transferred to an autoclave reactor, charged with hydrogen (50 psi), and stirred at RT overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure to give (S)-2-(5-hydroxy-4-(methylamino)pentyl)isoindolin (3.2 g, 97%) which was used without purification. LRMS (M+H+) m/z 263.1.