Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](Cl)[N:18]=3)[S:14][C:13]=2[CH:24]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:26][CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1>O1CCOCC1>[C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:26][CH2:27][CH2:28][CH2:29][N:30]4[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]4)[N:18]=3)[S:14][C:13]=2[CH:24]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCN(CCCN)CC1
Reactant: CC(C)(C)OC(=O)NCc1ccc2cc(-c3ccnc(Cl)n3)sc2c1
Solvent: C1COCCO1
Product: CN1CCN(CCCNc2nccc(-c3cc4ccc(CNC(=O)OC(C)(C)C)cc4s3)n2)CC1
Yield: 70.2 %

Procedure:
A mixture of [2-(2-chloropyrimidin-4-yl)-benzo[b]thiophen-6-ylmethyl]-carbamic acid tert-butyl ester (1.47 g, 3.90 mmol) and 1-(3-aminopropyl)-4-methylpiperazine (1.36 g, 8.60 mmol) in dioxane (38 mL) is refluxed for 3 hours. The solvent is removed and the residue is subjected to chromatography on silica gel, eluting with 2.0 M NH3/MeOH in CHCl3 0-10%, to obtain the title compound (1.36 g, 70% yield). ES+(m/z) 497 [M+H].
Reaction SMILES: [CH2:1]1[O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:13]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH3:15]>>[CH2:17]([N:16]([CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:13][CH2:14][CH3:15])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:24][CH2:25][CH3:26]
Reactant: CCCNCCCCCCNCCC
Reactant: CCCCCCCCCC1CO1
Product: CCCCCCCCCC(O)CN(CCC)CCCCCCN(CCC)CC(O)CCCCCCCCC

Procedure:
Condensation of 1-undecene oxide and N,N'-dipropylhexamethylenediamine affords N,N'-(1,6-hexylene)-bis[N-propyl-2-hydroxyundecylamine] (I: R = CH3 (CH2)8, R' = CH3 (CH2)2, X = (CH2)6, Z = H).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][NH:4][CH2:5][C@H:6]([N:13]1[CH:17]=[C:16]([N+:18]([O-])=O)[N:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:23][C:24]1[CH:25]=[C:26]2[C:31](=[C:32]([F:34])[CH:33]=1)[CH2:30][CH:29]([NH:35][C@@H:36]([CH2:40][CH2:41][CH3:42])[C:37](O)=[O:38])[CH2:28][CH2:27]2>>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][NH:4][CH2:5][C@@H:6]([N:13]1[CH:17]=[C:16]([NH:18][C:37](=[O:38])[C@@H:36]([NH:35][CH:29]2[CH2:28][CH2:27][C:26]3[C:31](=[C:32]([F:34])[CH:33]=[C:24]([F:23])[CH:25]=3)[CH2:30]2)[CH2:40][CH2:41][CH3:42])[N:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)CNC[C@@H](c1ccccc1)n1cnc([N+](=O)[O-])c1
Reactant: CCC[C@H](NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Product: CCC[C@H](NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn([C@H](CNCC(C)(C)C)c2ccccc2)cn1

Procedure:
(R)-2,2-dimethyl-N-(2-(4-nitro-1H-imidazol-1-yl)-2-phenylethyl)propan-1-amine was reduced and coupled with (S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the title compound: MS 538 m/z (M+1).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][C:17]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[C:11]([C:9]1[CH:8]=[N:7][N:6]2[C:2]([C:19]3[CH:20]=[CH:21][C:16]([F:15])=[C:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH:18]=3)=[CH:3][N:4]=[C:5]2[N:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cnn2c(Br)cnc2n1
Reactant: OB(O)c1ccc(F)c(-c2ccccn2)c1
Product: CC(C)(C)c1cnn2c(-c3ccc(F)c(-c4ccccn4)c3)cnc2n1
Yield: 29 %

Procedure:
This compound was prepared in 29% yield as described in the final paragraph of Example 2, step d, but using 7-bromo-3-tert-butylimidazo[1,2-b][1,2,4]triazine instead of 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine, and using 4-fluoro-3-(pyridin-2-yl)phenylboronic acid instead of 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile: 1H NMR (400 MHz, CDCl3) δ 1.50 (9H, s), 7.29-7.33 (2H, m), 7.80 (1H, m), 7.86 (1H, m), 8.07 (1H, m), 8.25 (1H, s), 8.59 (1H, s), 8.66 (1H, dd, J 2.3, 7.4 Hz), 8.77 (1H, m); MS (ES+) m/z 348 M+H]+. Anal. Found: C, 66.95; H, 5.15; N, 19.00%. Required for C20H18FN5.0.75H2O: C, 66.56; H, 5.45; N, 19.41%.
Reaction SMILES: [CH:1]1([CH:7]([O:27][CH3:28])[C:8]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:9]=2[CH2:10][O:11][Si](C(C)(C)C)(C)C)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[CH:1]1([CH:7]([O:27][CH3:28])[C:8]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:9]=2[CH2:10][OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(c1ccc(C(F)(F)F)cc1CO[Si](C)(C)C(C)(C)C)C1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COC(c1ccc(C(F)(F)F)cc1CO)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
To a solution of (2-(cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)benzyloxy)(tert-butyl)dimethylsilane (1.13 g, 2.4 mmol) in THF (5 mL) at room temperature was added TBAF in THF (1.0 M, 4.8 mL, 4.8 mmol). The mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. Combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography over 25+M Biotage silica column (eluted with 0-30% ethyl acetate in heptane) to afford the title compound (633.9 mg, 88%). 1H NMR (400 MHz, CDCl3) δ ppm 0.91-1.27 (m, 6H) 1.63-1.70 (m, 3H) 1.72-1.81 (m, 1H) 2.07 (d, J=12.86 Hz, 1H) 2.33-2.42 (m, 1H) 3.18 (s, 3H) 4.10 (d, J=7.88 Hz, 1H) 4.78 (dd, J=5.81, 3.32 Hz, 2H) 7.43 (d, J=7.88 Hz, 1H) 7.55 (d, J=8.30 Hz, 1H) 7.69 (s, 1H).
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH2:7][CH2:8][OH:9])(=[O:5])[OH:4])[CH3:2].[CH2:10]1[O:12][CH2:11]1.[OH-].[K+]>O>[CH2:1]([P:3]([CH2:6][CH2:7][CH2:8][OH:9])(=[O:4])[O:5][CH2:10][CH2:11][OH:12])[CH3:2]
Reactant: C1CO1
Reactant: CCP(=O)(O)CCCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCP(=O)(CCCO)OCCO
Yield: 95 %

Procedure:
A 500 ml five-neck flask equipped with gas inlet tube, thermometer, high-performance stirrer and reflux condenser with gas incineration is charged with 152 g (1 mol) of ethyl(3-hydroxypropyl)phosphinic acid (produced similarly to Example 13). Ethylene oxide is passed in at room temperature. A reaction temperature of 70° C. is set with cooling, followed by further reaction at 80° C. for 1 hour. The ethylene oxide takeup is 64.8 g. The acid number of the product is less than 1 mg KOH/g. 186 g (95% of theory) of 2-hydroxyethyl ethyl(3-hydroxy-propyl)phosphinate are obtained as colorless, water-clear liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([Cl:29])=[C:11]([CH:22]=[CH:23][C:24]=1[S:25]([CH3:28])(=[O:27])=[O:26])[C:12]([O:14]CC1C=CC=CC=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Na]>C(O)C>[CH2:1]([O:8][C:9]1[C:10]([Cl:29])=[C:11]([CH:22]=[CH:23][C:24]=1[S:25]([CH3:28])(=[O:27])=[O:26])[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)OCc2ccccc2)c(Cl)c1OCc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
2.5 g of benzyl 3-benzyloxy-2-chloro-4-methanesulfonylbenzoate was put into 50 ml of ethanol, and 25 ml of an aqueous solution containing 1 g of sodium hydrochloride was added thereto. The mixture was stirred at room temperature for 30 minutes. Then, ethanol was distilled off, and water was added to the residue. The mixture was washed with chloroform. The aqueous layer was acidified with concentrated hydrochloric acid and then extracted with chloroform. The extract was dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain a crude product of the above identified compound. The crude product was washed with ethanol-isopropyl ether to obtain 1.0 g of the desired product.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.N1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C[O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1>C(OCC)C>[CH:17]1[C:21]2[C:21](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:20]=[CH:19][C:18]=1[C:29]1[CH:30]=[CH:31][C:26]([CH2:25][C:24]([OH:23])=[O:33])=[CH:27][CH:28]=1
Reactant: c1ccncc1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Product: O=C(O)Cc1ccc(-c2ccc3ccccc3c2)cc1
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
Trifluoromethane sulfonic anhydride (32.2 mmol) was added dropwise over 5 minutes to a −40° C. pyridine (70 mL) solution of (4-hydroxy-phenyl)-acetic acid methyl ester (5.35 g, 32.2 mmol). The reaction was stirred at −40° C. for 10 minutes and then at 0° C. for 2 hours. The reaction was diluted with diethyl ether and washed with water and 2N hydrochloric acid. The organic portion was dried over magnesium sulfate and concentrated in vacuo. The crude residue was chromatographed on a Biotage Flash 40M column eluting with ethyl acetate/hexanes (1:4) to provide the title compound as a clear, colorless oil, which crystallized upon standing 9.27 g, 97%). 1H NMR (400 MHz, CDCl3) δ 7.37-7.34 (m, 2H), 7.24-7.21 (m, 2H), 3.70 (3H), 3.64 (2H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1>C(Cl)(Cl)Cl.CO>[F:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][NH:6]2)=[C:2]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:10]=1
Reactant: NCc1ccncc1
Reactant: Fc1nc(Cl)c2nc[nH]c2n1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Fc1nc(NCc2ccncc2)c2nc[nH]c2n1
Temperature: 20 °C
Reaction time: 3 h
Yield: 54.1 %

Procedure:
To a stirred solution of 6-chloro-2-fluoro-9H-purine (0.9 g, 5.22 mmol) in BunOH (60 mL) under Ar, cooled to −20° C., was added Pri2NEt (2.5 mL, 14.35 mmol) followed by 4-(aminomethyl)pyridine (0.58 mL, 5.69 mmol). The reaction mixture was stirred at-20° C. for 3 h, and then allowed to return to RT over 2 h and stirred at RT for a further 48 h, when TLC (9:1 CHCl3/MeOH) indicated that the reaction had gone to completion. The solvent was evaporated in vacuo and the residue was purified by gradient column chromatography on silica gel, eluted with CHCl3/MeOH (100:0→90:10), to afford the title compound as a white solid (0.69 g, 54%). Mp>340° C. 1H-NMR (d6-DMSO, 250 ME): δ 4.67 (d, 2H, J=6.35 Hz, —HNCH2-Pyr), 7.34, 8.50 (2×m, 4H, Pyr), 8.14 (s, 1H, —N═CH—NH—), 8.84 (bs, 1H, —HNCH2-Pyr), 13.13 (bs, 1H, —N═CH—NH—). FAB-MS m/z (relative intensity): 245 ([M+H]+, 27), 176 (15), 154 (100), 136 (77). Accurate Mass (M+H): Actual: 245.0951, Measured: 245.0942. Microanalysis (Expected:Measured) C11H9N6F.0.6H2O: C, 51.80:52.08; H, 4.03:3.84; N, 32.95:31.29.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9](Br)[C:10]([O:13][CH3:14])=[N:11][CH:12]=1.[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B1OC(C([O-])=O)C=CO1)#[N:17].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:9]1[C:10]([O:13][CH3:14])=[N:11][CH:12]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:8]=1)#[N:17]
Reactant: COc1ncc(-c2ccccn2)cc1Br
Reactant: N#Cc1ccccc1B1OC=CC(C(=O)[O-])O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ncc(-c2ccccn2)cc1-c1ccccc1C#N
Temperature: 140 °C
Reaction time: 5 h

Procedure:
Tetrakistriphenylphosphine palladium (0.15 g) was added to a mixed solution of 0.50 g of 5-(2-pyridyl)-3-bromo-2-methoxypyridine, 0.42 g of 2-(2-cyanophenyl)-1,3,2-dioxaborinate, 0.82 g of cesium carbonate and 20 ml of dimethylformamide and the mixture was stirred at 140° C. in a nitrogen atmosphere for 5 hours. After cooling to room temperature, ethyl acetate was added thereto, the mixture was washed with water and a saturated saline solution and dried over magnesium sulfate. The solvent was concentrated in vacuo and the residue was purified by a silica gel column chromatography (ethyl acetate:hexane=1:3) to give 0.36 of the title compound as pale yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=O)[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:20][CH2:19][S:18][CH2:17]1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(=[CH:40][C:41]([O:43][CH3:44])=[O:42])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[CH:40][C:41]([O:43][CH3:44])=[O:42])[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:20][CH2:19][S:18][CH2:17]1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)N1CCSC1
Solvent: ClCCl
Product: COC(=O)C=C1C[C@@H](C(=O)N2CCSC2)N(C(=O)OC(C)(C)C)C1
Temperature: 40 °C
Yield: 50 %

Procedure:
To a solution of Example 1A (5.77 g, 0.0192 mol) in anhydrous dichloromethane (30 mL) was added methyl (triphenylphosphoranylidene)-acetate (8.22 g, 0.0246 mol) and the resulting solution heated to 40° C. for two days. The mixture was cooled, concentrated and purified by column chromatography (ethyl acetate/hexane, 4/6) to provide the titled compound (3.42 g). MS (ESI APCI) m/e 355 (M−H)+; 1H NMR (400 MHz, DMSO-d6): δ ppm 5.87 (m, 1H), 4.41-4.78 (m, 4H), 4.31 (d, 1H), 3.74-3.78 (m, 2H), 3.17 (t, 2H), 3.04 (t, 1H), 2.74-2.80 (d, 1H), 1.40 (s, 9H).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([NH2:26])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7].N1C=CC=CC=1.[C:34](Cl)(=[O:36])[CH3:35]>O1CCCC1>[CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([NH:26][C:34](=[O:36])[CH3:35])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: CN(C)CCNC(=O)c1cccc2nc3ccc4c(N)cccc4c3nc12
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc2c1ccc1nc3cccc(C(=O)NCCN(C)C)c3nc12
Reaction time: 1 h

Procedure:
To a solution of 4-amino-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide (20 mg) in tetrahydrofuran (5 mL) was added pyridine (0.1 mL) and acetyl chloride (20 μL). After stirring for 1 hour the reaction mixture was extracted into ethyl acetate, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent removed in vacuo The residue was triturated with ether to yield the title compound as a yellow solid (10 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15](O)=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CSC.B>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([CH2:15][OH:16])[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H](C(=O)O)C1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@H](CO)C1
Temperature: 40 °C
Yield: 96 %

Procedure:
Racemic trans 3-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (1 g, 4.11 mmol) was dissolved in THF (30 mL) and borane dimethylsulfide 2M in THF (3 mL, 6 mmol) was added slowly. The resulting colorless solution was stirred at 40° C. After 4 hours the reaction mixture was cooled to 0° C., quenched by addition of saturated aqueous NaHCO3, and extracted twice with EtOAc. The combined organic layers were dried (Na2SO4), filtered and evaporated to give 0.905 g of crude racemic trans 3-hydroxymethyl-cyclohexyl-carbamic acid tert-butyl ester as a colorless oil (>95% yield).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:13]([F:12])[CH:14]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: Nc1cccc(F)c1
Product: Fc1cccc(Nc2nc(Cl)nc3nc[nH]c23)c1

Procedure:
This compound was prepared in a similar manner as described in example 2, by reaction of 2,6-dichloropurine with 3-fluoroaniline. The reaction mixture was then evaporated on a rotary vacuum evaporator and the residue was partitioned between ethyl acetate and 0.5 M HCl. The organic layer was washed with water, dried with MgSO4, and evaporated to give a yellow solid (3.72 g). The crude product was purified by flash chromatography. Yield: 2.20 g yellow crystalline powder. TLC (chloroform-methanol; 85:15): homogenous. HPLC purity: 98+%
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH:6]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7]1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:11][CH:8]1[CH2:9][CH2:10][N:6]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:7]1)(=[O:4])=[O:3]
Reactant: OC1CCNC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCN(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methansulfonyl chloride (1.93 ml) added to an ice cooled solution of 3-pyrrolidinol (871.0 mg) and triethylamine (3.47 ml) in dichloromethane (30.0 ml). After 10 mins the coolant was removed and the mixture was stirred at room temperature for 2 h. The mixture was washed with 10% KHSO4 and 10% aq. K2CO3. The organic layer was passed through a hydrophobic frit and the solvent was evaporated.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[C:11]([N:23]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[N:10]([CH3:43])[N:9]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:39]([C:36]1[CH:35]=[CH:34][C:33]([S:30]([N:23]([C:11]2[N:10]([CH3:43])[N:9]=[C:8]([O:7][CH2:6][CH2:5][OH:4])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])(=[O:31])=[O:32])=[CH:38][CH:37]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: COCCOCN(c1c(-c2ccc(C(F)(F)F)cc2)c(OCCOC(C)=O)nn1C)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COCCOCN(c1c(-c2ccc(C(F)(F)F)cc2)c(OCCO)nn1C)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 2-({5-{{[4-(tert-butyl)phenyl]sulfonyl}[(2-methoxyethoxy)methyl]amino}-1-methyl-4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}oxy)ethyl acetate (Preparation 13) (200 mg) in methanol (20 ml) was added a solution of potassium carbonate (90 mg) in water (5 ml), at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was stripped down and the residue partitioned between ethyl acetate (15 ml) and water (15 ml). The aqueous layer was extracted with ethyl acetate (2×15 ml). The combined organics were back-washed with brine (15 ml). The solution was dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield the desired product as an off white solid (170 mg).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:17][C@H:18]3[C:23]([O:25][C:26](C)(C)C)=[O:24])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO.[Cl:40]CCl.Cl>C(OCC)C>[ClH:40].[F:36][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:17][C@H:18]3[C:23]([O:25][CH3:26])=[O:24])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COC(=O)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
A mixture of (1R*,2R*,5S*,6R*)-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 25; 44 mg, 0.08 mmol), methanol (0.1 ml), dichloromethane (0.6 ml) and 1M HCl in diethyl ether (1 ml) was kept at room temperature for 3 weeks. The mixture was concentrated to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:10])([CH2:6][C:7]([OH:9])=[O:8])[C:3](O)=[O:4].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(OC(C)=O)(C)C>[CH2:24]([NH:31][C:3](=[O:4])[C:2]([F:10])([F:1])[CH2:6][C:7]([OH:9])=[O:8])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)CC(F)(F)C(=O)O
Reactant: NCc1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(=O)OC(C)C
Product: O=C(O)CC(F)(F)C(=O)NCc1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 56.8 %

Procedure:
To a solution of 2,2-difluorosuccinic acid (2.15 g, 14.0 mmol) in iPrOAc (23 mL) was added trifluoroacetic anhydride (2.34 mL, 16.7 mmol) in one portion at ambient temperature. The reaction solution was stirred at 50° C. for 2 hr. The reaction solution was allowed to cool to 5° C. in an ice bath. Benzyl amine (2.29 mL, 20.9 mmol) was added dropwise while the reaction temperature was maintained below 20° C. The solution was stirred at ambient temperature for 2 hr. The reaction was quenched with water (10 mL) followed by saturated Na2CO3 to pH 8-9. The separated organic phase was discarded. The aqueous phase was acidified with 6 N HCl to pH 1 and extracted with EtOAc (2×100 mL). The combined organic phase was washed with 2 N HCl, brine (100 mL), dried over MgSO4 filtered and concentrated. The intermediate was carried forward without further purification (2.89 g, 56.8% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.28-7.42 (m, 5 H) 7.14-7.21 (m, 1 H) 6.77 (br. s., 1 H) 4.54 (d, J=5.87 Hz, 2 H) 3.39 (t, J=14.18 Hz, 2 H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([Br:12])=[C:6]([CH2:8][C:9](=O)[CH3:10])[CH:7]=1.[NH2:14][C:15]1[C:20]([CH:21]=O)=[CH:19][N:18]=[C:17]([S:23][CH3:24])[N:16]=1.[O-]CC.[Na+]>CCO>[Br:12][C:5]1[C:6]([C:8]2[C:9]([CH3:10])=[N:14][C:15]3[N:16]=[C:17]([S:23][CH3:24])[N:18]=[CH:19][C:20]=3[CH:21]=2)=[CH:7][C:2]([NH2:1])=[C:3]([F:13])[CH:4]=1
Reactant: CC(=O)Cc1cc(N)c(F)cc1Br
Reactant: CSc1ncc(C=O)c(N)n1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CSc1ncc2cc(-c3cc(N)c(F)cc3Br)c(C)nc2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 16.2 %

Procedure:
Treat a solution of 1-(5-amino-2-bromo-4-fluorophenyl)propan-2-one (5 g, 27.62 mmol) and 4-amino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (4.67 g, 27.62 mmol) in EtOH (30 mL) with sodium ethoxide (3.76 g, 55.25 mmol) and stir at RT for 12 h. Concentrate the mixture to dryness, treat with water, extract with EtOAc (3×), wash the combined organics with brine, dry with Na2SO4, concentrate and purify by silica gel chromatography (EtOAc/Pet Ether, 1:4) to afford the title compound (1.7 g, 16% yield). MS (m/z): 379.1/381.1 (M+1).
Reaction SMILES: N[C:2]1C(C)=CC(C#N)=C[C:3]=1CC.Cl[C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([CH3:29])[C:23]=1[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:17]([NH:19][OH:20])=[NH:18]>>[CH2:2]([C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([CH3:29])[C:23]=1[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:17]([NH:19][OH:20])=[NH:18])[CH3:3]
Reactant: Cc1cc(C(=N)NO)cc(Cl)c1NS(C)(=O)=O
Reactant: CCc1cc(C#N)cc(C)c1N
Product: CCc1cc(C(=N)NO)cc(C)c1NS(C)(=O)=O

Procedure:
The title compound is then prepared from the above 4-amino-3-ethyl-5-methyl-benzonitrile in analogy to 3-chloro-N-hydroxy-4-methanesulfonylamino-5-methyl-benzamidine; LC-MS**: tR=0.26 min, [M+1]+=272.32.