Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[OH:32][C@@H:33]([CH3:37])[C:34](O)=[O:35]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)[C@@H:19]([NH:21][C:34](=[O:35])[C@@H:33]([OH:32])[CH3:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@H](O)C(=O)O
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc(C(F)(F)F)cc1
Product: C[C@H](O)C(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc(C(F)(F)F)cc1

Procedure:
Prepared as described in Example 105 using (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(trifluoromethyl)phenyl]propan-2-amine (59a, 21 mg, 50 μmol) and (S)-2-hydroxypropanoic acid (12 mg, 150 μmol). Yield 13 mg (56%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[NH:10][CH2:11][C:12](=[O:28])[NH:13][C:14]1[C:18]([C:19]2[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[N:20]=2)=[N:17][O:16][N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:36]([O:43][C:44](=[O:56])[NH:45][C:46]1[CH:51]=[CH:50][C:49]([C:52](=[O:55])[CH2:53]Br)=[CH:48][CH:47]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:36]([O:43][C:44](=[O:56])[NH:45][C:46]1[CH:47]=[CH:48][C:49]([C:52](=[O:55])[CH2:53][N:20]2[C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=[C:19]2[C:18]2[C:14]([NH:13][C:12](=[O:28])[CH2:11][NH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:29])=[N:15][O:16][N:17]=2)=[CH:50][CH:51]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C(Nc1ccc(C(=O)CBr)cc1)OCc1ccccc1
Reactant: O=C(CNC(=O)OCc1ccccc1)Nc1nonc1-c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CNC(=O)OCc1ccccc1)Nc1nonc1-c1nc2ccccc2n1CC(=O)c1ccc(NC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.3 %

Procedure:
To a stirred solution of 0.4 g of {[4-(1H-benzoimidazol-2-yl)-furazan-3-ylcarbamoyl]-methyl}-carbamic acid benzyl ester (0.97 mmol, 1 eq.) in 6 mL of N,N′-dimethylformamide are added 0.2 g of potassium carbonate (1.4 mmol; 1.45 eq.) at room temperature followed by the addition of 0.41 g of [4-(2-bromo-acetyl)-phenyl]-carbamic acid benzyl ester (CAS 157014-41-0) (1.16 mmol; 1.2 eq.). The reaction mixture is stirred for 2 h at room temperature and is then diluted with 20 mL of ethyl acetate. The solution is washed with water (2×10 mL) and brine (2×10 mL), dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue is then dissolved in hot ethyl acetate (2 mL) and the solution is placed in an ice-bath. After 0.5 h, the resulting suspension is filtered and the solid is washed with cold ethyl acetate (1 mL) to afford 0.2 g of the desired product as a white powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:18])=[CH:12][CH:11]=2)[C:3]=1[N+:19]([O-:21])=[O:20].[C:22]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].[OH-].[Na+]>CC(C)=O>[OH:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:4]2[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:22]([O:30][CH2:31][CH3:32])=[O:29])[C:3]=2[N+:19]([O-:21])=[O:20])=[CH:11][CH:12]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Nc2ccc(CCO)cc2)n1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1nc(C)nc(Nc2ccc(CCO)cc2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 116.3 %

Procedure:
To a stirred solution of 2-{4-[(6-chloro-2-methyl-5-nitro-4-pyrimidinyl)amino]phenyl)}ethanol (step 1, 2.0 g, 6.48 mmol) in acetone (61 ml) was added diethyl malonate (1.53 g, 9.54 mmol) at 0° C., then aqueous NaOH solution (11N, 2 ml, 22 mmol) was added dropwise over 20 min. After addition, the mixture was stirred at room temperature for 1 h. The reaction was quenched with water (120 ml), and the pH value was adjusted to 8.0 by addition of acetic acid. The whole was extracted with ethyl acetate (100 ml×3). The organic layer was washed with brine (50 ml), dried (MgSO4), and concentrated. Removal of excess diethyl malonate by azetropical distillation with toluene afforded 3.26 g (72%) of the title compound as a brown oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:6](=[O:7])[N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.C(=O)(O)[O-].[Na+]>C1COCC1>[OH:7][CH:6]1[N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][C:2]1([CH3:22])[CH3:1]
Reactant: CC(C)(C)OC(=O)C1CC(C)(C)C(=O)N1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1CC(C)(C)C(O)N1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
Et3BHLi (134 mL, 134 mmol, 1M in THF) was added slowly to a mixture of 137c (35 g, 112 mmol) in THF (1 L) at −78° C. and stirred for 2 h. See FIG. 1. Saturated aqueous sodium bicarbonate solution (500 mL) was added, stirred for 30 min, then extracted with DCM (1 L×3). The combined organic extracts were washed with brine (1 L×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give di-tert-butyl 5-hydroxy-4,4-dimethylpyrrolidine-1,2-dicarboxylate 137d as a colorless oil (38 g, crude).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8](=O)[NH:7][C:6]=2[CH:16]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:18]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8]([Cl:18])=[N:7][C:6]=2[CH:16]=1
Reactant: O=C1Nc2cc(Br)ccc2Oc2cscc21
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: ClC1=Nc2cc(Br)ccc2Oc2cscc21

Procedure:
A 2.13 g. portion of 7-bromo-thieno[3,4-b][1,5]benzoxazepin-10(9H)-one (Example 9) and 1.5 g. of phosphorus pentachloride in 40 ml. of dry toluene are reacted as described in Example 9, giving 7-bromo-10-chloro-thieno[3,4-b][1,5]benzoxazepine which is further reacted with N-methylpiperazine in 15 ml. of dry toluene giving the base compound as a foam which is then converted to the hemifumarate, m.p. 196°-197° C.
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([OH:9])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:10]1([OH:20])[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1>>[C:10]1([O:20][CH2:6][CH:7]([OH:9])[CH2:8][NH:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: Oc1cccc2c1CCCC2
Reactant: CC(C)(C)N1CC(O)C1
Product: CC(C)(C)NCC(O)COc1cccc2c1CCCC2

Procedure:
1-(tert.-butyl)-3-azetidinol and 5,6,7,8-tetrahydro-α-naphthol were reacted in the same manner as in Example 1 to form 1-(5,6,7,8-tetrahydro-α-naphthoxy)-3-(tert.-butylamino)-2-propanol. A hydrochloric acid gas was blown into the obtained propanol. As a result, 1-(5,6,7,8-tetrahydro-1-naphthoxy)-3-(tert.-butylamino)-2-propanol hydrochloride having a melting point of 148°-150° C. was obtained. The yield was 70%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH:23]=[CH2:24])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[F:47][C:48]1[CH:53]=[C:52](I)[CH:51]=[CH:50][C:49]=1[C:55]([F:58])([F:57])[F:56].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12](/[CH:23]=[CH:24]/[C:52]2[CH:51]=[CH:50][C:49]([C:55]([F:57])([F:58])[F:56])=[C:48]([F:47])[CH:53]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: Fc1cc(I)ccc1C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Fc1cc(/C=C/c2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)ccc1C(F)(F)F
Temperature: 80 °C
Yield: 67 %

Procedure:
A vessel containing 3,4-bis(benzyloxy)-6-ethenylpyridazine (Intermediate 78, 1.09 g, 3.42 mmol), tris-(2-methylphenyl)phosphane (0.208 g, 0.685 mmol), 2-fluoro-4-iodo-1-(trifluoromethyl)benzene (1.191 g, 4.11 mmol) and palladium(II) acetate (0.038 g, 0.171 mmol) was evacuated and acetonitrile (10 ml) and triethylamine (9.07 ml, 65.1 mmol) were added in vacuo and then the mixture was flushed with nitrogen. The reaction was then heated in the microwave at 80° C. for 4 hours and, upon cooling, was diluted with dichloromethane and washed with saturated aqueous ammonium chloride solution. The organics were dried (MgSO4), filtered and solvent removed in vacuo to give a brown oil which was purified by column chromatography (silica, eluting with 30-100% dichloromethane in petrol) to yield 3,4-bis(benzyloxy)-6-[(E)-2-[3-fluoro-4-(trifluoromethyl)phenyl]ethenyl]pyridazine (1.1 g, 2.29 mmol, 67% yield).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[C:21]([OH:25])(=[O:24])[CH:22]=[CH2:23].C(=O)=O>CN(C)C=O>[C:21]([O:25][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:4]=1)(=[O:24])[CH:22]=[CH2:23]
Reactant: C=CC(=O)O
Reactant: BrCc1cccc(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CC(=O)OCc1cccc(-c2ccccc2)c1
Reaction time: 2 h

Procedure:
Into a 200 mL four-neck flask equipped with a stirrer, a thermometer, and a cooling tube, 20.0 g of 3-(bromomethyl)biphenyl, 39.3 g of anhydrous dimethylformamide, 13.4 g of anhydrous potassium carbonate, and 6.2 mg of methoquinone were charged, and acrylic acid was added thereto at room temperature. After the completion of foaming of carbon dioxide, the mixture was heated to a reaction temperature of 90° C. and a reaction was caused to proceed for two hours. The temperature was decreased to room temperature, and then dilution with 120 mL of water, extraction with 100 g of toluene, and washing with water were performed. The resultant crude reaction product was purified with a silica gel column to obtain 16.1 g of meta-phenylbenzyl acrylate. The obtained meta-phenylbenzyl acrylate was a colorless, transparent liquid at ordinary temperature and had a refractive index of 1.5888 and a viscosity of 24 mPa·s at 25° C. The measurement result of 1H-NMR is shown below.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4](Cl)[N:3]=1.C(N(CC)C(C)C)(C)C.[CH:21]1([NH2:25])[CH2:24][CH2:23][CH2:22]1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:25][CH:21]2[CH2:24][CH2:23][CH2:22]2)[N:3]=1
Reactant: NC1CCC1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Clc1nc(NC2CCC2)c2nc[nH]c2n1
Temperature: 75 °C
Yield: 86.8 %

Procedure:
A 12 L, 4-neck, round-bottomed flask fitted with a mechanical stirrer, digital thermometer, heating and cooling capabilities, condenser, addition funnel, and nitrogen inlet and outlet, was flushed with nitrogen and charged with 492.9 g (2.61 moles) of 2,6-dichloro-9H-purine, 497.7 mL (2.87 moles) of N,N-diisopropylethylamine, and 3.65 L of anhydrous 1-butanol. The mixture was stirred and heated to 75° C. and 244.9 mL (2.87 moles) of cyclobutylamine in 1.25 L of anhydrous 1-butanol, was added during about 1 hour at a temperature of 75° C.-77° C. The reaction temperature and stirring was maintained for 4.5 hours. The mixture was cooled to 5° C. over a period of 1 hour. The product was filtered and the filter cake was washed three times with a total of 0.9 L of 1-butanol. The filter cake was collected and dried at 75° C./20 mm Hg for 24 hours to give 506.6 g of light yellow crystalline solid. Theoretical yield was 583.3 g. Actual yield was 86.9%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([S:13](Cl)(=[O:15])=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][S:13]([C:7]1[C:6](=[O:17])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]([CH3:12])[CH:8]=1)(=[O:15])=[O:14])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: Cn1cc(S(=O)(=O)Cl)c(=O)c2ccc(Cl)cc21
Product: Cn1cc(S(=O)(=O)NCc2ccccc2)c(=O)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
7-Chloro-1-methyl-4-oxo-1,4-dihydroquinoline-3-sulphonyl chloride (9.2 g) was added portionwise to a stirred solution of benzylamine (10.5 ml) in absolute alcohol (300 ml). The mixture was stirred at ambient temperature for 24 hours, then evaporated to dryness. The residue was crystallised from industrial methylated spirit to give the novel compound N-benzyl-7-chloro-1-methyl-4-oxo-1,4-dihydroquinoline-3-sulphonamide, m.p. 208°-210°.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33](O)=[O:34])(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][CH2:40][C@@H:41]([OH:43])[CH3:42]>>[OH:43][C@@H:41]([CH3:42])[CH2:40][NH:39][C:33](=[O:34])[C:32]1[CH:36]=[CH:37][CH:38]=[C:30]([S:27]([CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:29])=[O:28])[CH:31]=1
Reactant: C[C@H](O)CN
Reactant: O=C(O)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Product: C[C@H](O)CNC(=O)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 57.9 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and (S)-1-amino-2-propanol (23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 34 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 588 [M+H]+.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:5][CH:4]([CH2:6][O:7][C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][C:13]4([CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]4)[C:14]3=[O:17])=[CH:10][CH:9]=2)[CH2:3]1.[CH3:25]C(C)([O-])C.[K+].CI.CCOC(C)=O>C1COCC1.CCCCCCC>[F:1][C:2]1([F:24])[CH2:5][CH:4]([CH2:6][O:7][C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][C:13]4([CH2:22][CH2:21][CH:20]([O:23][CH3:25])[CH2:19][CH2:18]4)[C:14]3=[O:17])=[CH:10][CH:9]=2)[CH2:3]1
Reactant: CC(C)(C)[O-]
Reactant: O=C1c2cc(OCC3CC(F)(F)C3)ccc2CC12CCC(O)CC2
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC1CCC2(CC1)Cc1ccc(OCC3CC(F)(F)C3)cc1C2=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 59.7 %

Procedure:
6′-((3,3-difluorocyclobutyl)methoxy)-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′ (3′H)-one (Intermediate 13, 2.98 g, 8.85 mmol) was dissolved in THF (35 mL) under an atmosphere of nitrogen, and the solution was cooled to 0° C. Potassium tert-butoxide (2.98 g, 26.6 mmol) was added portionwise and the mixture was stirred at 0° C. for 15 min. Methyl iodide (1.11 mL, 17.7 mmol) was added. The cooling bath was removed, and the mixture was stirred at r.t. overnight. Water (200 mL) was added and the resulting solution was partitioned between additional water (200 mL) and EtOAc (400 mL). The organic phases was dried (MgSO4) and concentrated, and the product was isolated using column chromatography (0-50% EtOAc in heptane) providing 1.85 g (59% yield) of the title compound. MS (ES+) m/z 351 [M+H]+.
Reaction SMILES: C1COCC1.CO.[F:8][C:9]([F:40])([F:39])[O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]([O:27][CH2:28][C:29]3[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=3)[C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][CH:12]=1>O>[F:8][C:9]([F:39])([F:40])[O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[C:19]([O:27][CH2:28][C:29]3[CH:38]=[CH:37][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=3)[C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(COc2cc(-c3ccc(OC(F)(F)F)cc3)cc3ccccc23)cc1
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(COc2cc(-c3ccc(OC(F)(F)F)cc3)cc3ccccc23)cc1

Procedure:
To a THF/MeOH solution (ca. 1/1, 2 mL) of the intermediate from Step C (40 mg, 0.09 mmol) was added LiOH monohydrate (20 mg, 0.49 mmol) in 1 mL water. The solution was stirred at room temperature until no ester remained by HPLC analysis. The solution was concentrated and partitioned between ethyl acetate and aqueous 1N HCl. The organic phase was washed with brine, dried over MgSO4 and filtered. The solution was then concentrated to give the title compound which was used without further purification. LCMS1 4.27 min. (M+H)=439
Reaction SMILES: [N:1]([C:4]1[N:12]=[C:11]([F:13])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[C@@H:14]1[O:34][C@H:33]([CH2:35][O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:15]1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N+]=[N-].[BH4-].[Na+]>CC(O)C.O>[CH2:17]([O:16][C@H:15]1[C@H:24]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:33]([CH2:35][O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:34][C@H:14]1[N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:11]([F:13])=[N:12][C:4]=2[NH2:1])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: [N-]=[N+]=Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 0 %

Procedure:
6-Azido-2-fluoro-9-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)purine (0.28 g, 0.48 Mmol) was dissolved in warm 2-propanol (3 mL) and then cooled to about 25° C. To the resulting solution was added sodium borohydride (18 mg, 0.48 Mmol) and the mixture was stirred at room temperature for 10 minutes and then at reflux for 15 minutes. The reaction was complete as determined by TLC so it was cooled to room temperature and diluted with water (10 mL). The resulting precipitate was recovered by filtration to obtain 0.19 g of the title compound; mp 159°-161° C. (from toluene/ethanol). This material was identical by IR and TLC with an authentic sample of the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][C@H:13]3[CH2:16][C@H:15]([N:17]4[C:21]5=[N:22][CH:23]=[CH:24][CH:25]=[C:20]5[N:19]=[C:18]4[O:26][CH3:27])[CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1>[Pd].CO>[CH3:27][O:26][C:18]1[N:17]([C@H:15]2[CH2:16][C@H:13]([NH:12][C:8]3[CH2:7][NH:6][C:5]4[C:10](=[CH:11][CH:2]=[CH:3][CH:4]=4)[N:9]=3)[CH2:14]2)[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[N:19]=1
Reactant: COc1nc2cccnc2n1[C@H]1C[C@H](Nc2cnc3ccc(Cl)cc3n2)C1
Agent: [Pd]
Solvent: CO
Product: COc1nc2cccnc2n1[C@H]1C[C@H](NC2=Nc3ccccc3NC2)C1
Reaction time: 72 h

Procedure:
To a 15-mL round-bottomed flask was added 7-chloro-N-(−3-(2-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)cyclobutyl)quinoxalin-2-amine (example 19, 118 mg, 0.310 mmol) and palladium on activated carbon (10 wt. %, 33.0 μl, 0.310 mmol) in methanol. The reaction mixture was stirred under a hydrogen balloon for 3 days. The solution was filtered and concentrated in vacuo to give the crude material as a yellow oil. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g, 0-20% (2M ammonia in methanol) in dichloromethane gradient) to provide N-(trans-3-(2-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)cyclobutyl)-3,4-dihydroquinoxalin-2-amine (80 mg, 0.230 mmol, 74.1% yield) as light-yellow glass. M+1: 349.1. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.68 (br. s, 1 H) 2.52 (d, J=2.05 Hz, 2 H) 3.33-3.52 (m, 2 H) 3.81 (s, 2 H) 4.25 (s, 3 H) 4.68-4.81 (m, 1 H) 5.40 (quin, J=8.59 Hz, 1 H) 6.58 (dd, J=7.53, 1.39 Hz, 1 H) 6.76 (td, J=7.50, 1.60 Hz, 1 H) 6.84 (td, J=7.50, 1.60 Hz, 1 H) 7.05 (d, J=7.16 Hz, 1 H) 7.10 (dd, J=7.82, 5.04 Hz, 1 H) 7.75 (dd, J=7.82, 1.39 Hz, 1 H) 8.16 (dd, J=4.97, 1.46 Hz, 1 H).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:16]=[CH:15][C:6]([CH2:7][NH:8][S:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])=[CH:5][C:4]=1[NH:17][C:18]1[N:22]([CH3:23])[C:21]2[CH:24]=[C:25]([N:29]3[CH2:34][CH2:33][CH:32]([C:35]([F:38])([F:37])[F:36])[CH2:31][CH2:30]3)[C:26]([Cl:28])=[CH:27][C:20]=2[N:19]=1.ClC1C=C(C=CC=1)C(OO)=[O:46].C(Cl)(Cl)Cl.P(Br)(Br)Br>[Cl-].[Na+].O.O.C(Cl)Cl>[F:40][C:2]([F:1])([F:39])[C:3]1[CH:16]=[CH:15][C:6]([CH2:7][NH:8][S:9]([C:11]([CH3:12])([CH3:14])[CH3:13])(=[O:46])=[O:10])=[CH:5][C:4]=1[NH:17][C:18]1[N:22]([CH3:23])[C:21]2[CH:24]=[C:25]([N:29]3[CH2:30][CH2:31][CH:32]([C:35]([F:37])([F:36])[F:38])[CH2:33][CH2:34]3)[C:26]([Cl:28])=[CH:27][C:20]=2[N:19]=1
Reactant: Cn1c(Nc2cc(CNS(=O)C(C)(C)C)ccc2C(F)(F)F)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: BrP(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cn1c(Nc2cc(CNS(=O)(=O)C(C)(C)C)ccc2C(F)(F)F)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of N-(4-trifluoromethyl-3-(5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino)benzyl)-2-methylpropane-2-sulfinamide (140 mg, 0.23 mmol), m-chloroperoxybenzoic acid (198 mg, 1.15 mmol) and CHCl3 (7 mL) was stirred at rt for 15 min. The mixture was poured into brine and extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was mixed with PBr3 (144 mg, 0.50 mmol) and DCM (5 ml) and the mixture was stirred at rt overnight. The mixture was poured into H2O and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. Purification by column chromatography gave the title compound.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:27]1([C:34]2[N:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]=2)[CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:30]2[CH2:31][CH2:32][CH2:33][N:27]([C:34]3[N:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)[CH2:28][CH2:29]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: c1ccc2nc(N3CCCNCC3)ncc2c1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCCN(c3ncc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-[1.4]diazepan-1-yl-quinazoline