Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2(O)[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)=[C:5]([N+:18]([O-:20])=[O:19])[CH:4]=[N:3]1.COCCN(S(F)(F)[F:31])CCOC.C([O-])(O)=O.[Na+].Cl>C(Cl)Cl.C1COCC1.O>[F:31][C:7]1([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][C:5]=2[N+:18]([O-:20])=[O:19])[CH2:16][CH2:15][C:10](=[O:11])[CH2:9][CH2:8]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: Cn1ncc([N+](=O)[O-])c1C1(O)CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1ncc([N+](=O)[O-])c1C1(F)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8-(2-methyl-4-nitro-pyrazol-3-yl)-1,4-dioxaspiro[4.5]decan-8-ol (3.68 g, 13.0 mmol) in dry DCM (80 mL) under nitrogen was added dropwise a solution of deoxo-Fluor® (50% in THF, 14.1 mL, 39.0 mmol). The reaction mixture was stirred at room temperature for 1 hr. After cooling to 0° C., saturated aqueous NaHCO3 (100 mL) was added, dropwise initially, and the mixture was extracted with DCM (2×75 mL). The combined organic layers were dried over MgSO4, and concentrated under reduced pressure. Purification via silica gel column chromatography (30-50% EtOAc/isohexane) gave a pale yellow oil. A portion of this oil (780 mg, 2.74 mmol) was dissolved in THF (20 mL) and treated with 2 M aqueous HCl (3 mL). The reaction mixture was stirred at room temperature for 4 hr, heated at 60° C. for 7 hr and stirred at room temperature for 18 hr. Water (10 mL) was added and the mixture extracted with EtOAc (100 mL). The organic layer was washed with brine (20 mL), separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (25-40% EtOAc/isohexane) gave 4-fluoro-4-(2-methyl-4-nitro-pyrazol-3-yl)cyclohexanone as a white solid (490 mg, 30% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.10 and 8.09 (2s, 1H), 4.17 and 4.15 (2s, 3H), 3.16-2.94 (m, 2H), 2.84-2.72 (m, 2H), 2.51 (dd, J=15.4, 5.6 Hz, 2H), 2.43-2.33 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:11][CH2:12][CH2:13][N:14]([CH3:21])[C:15](=[O:20])[O:16][CH:17]([CH3:19])[CH3:18])=[N:7][C:6]=12.O.O.[CH3:24][O:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].COCCOC>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:24][O:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:11][CH2:12][CH2:13][N:14]([CH3:21])[C:15](=[O:20])[O:16][CH:17]([CH3:19])[CH3:18])=[N:7][C:6]=12
Reactant: COc1cnccc1B(O)O
Reactant: CC(C)OC(=O)N(C)CCNc1ccn2ncc(Br)c2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1cnccc1-c1cnn2ccc(NCCN(C)C(=O)OC(C)C)nc12
Yield: 77 %

Procedure:
To 80 mg (0.22 mmol) of isopropyl (2-((3-bromopyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)(methyl)-carbamate was added (3-methoxypyridin-4-yl)boronic acid dihydrate (56 mg, 0.27 mmol), K3PO4 (143 mg, 0.67 mmol), PdCl2(PPh3)2 (16.8 mg, 0.022 mmol), 3 mL of DME and 1 mL of water. This mixture was microwaved at 140° C. for 0.5 hr. After cooling, it was diluted with EtOAc, and washed with water and brine. The organic layer was dried over MgSO4, concentrated, and purified on the PREP HPLC to afford the desired product in 77% yield (66.4 mg). 1H NMR (400 MHz, Acetone) δ ppm 2.87 (br. s., 3 H) 2.99 (br. s., 3 H) 3.58-3.71 (m, 2 H) 3.73-3.82 (m, 2 H) 4.09 (s, 3 H) 4.82 (td, J=6.25, 2.91 Hz, 1 H) 6.45 (br. s., 1 H) 8.21 (br. s., 1 H) 8.35 (s, 1 H) 8.43 (d, J=6.06 Hz, 1 H) 8.58 (s, 1 H) 8.77 (br. s., 1 H); LRMS (ESI) m/e 385.0 [(M+H)+, calcd for C19H24N6O3 384.0].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]([N:8]([CH2:28][CH2:29][N:30]([CH3:41])[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C:9]1[C:10]([C:23]([O:25]CC)=O)=[N:11][CH:12]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:14]=1)=[O:7])[CH3:2].C1CCN2C(=NCCC2)CC1.OS([O-])(=O)=O.[Na+]>CCO.O>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][C:13]2[CH:14]=[C:9]3[C:10]([C:23]([OH:25])=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:42])[C:6](=[O:7])[N:8]3[CH2:28][CH2:29][N:30]([CH3:41])[C:31]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[O:32])=[N:11][CH:12]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)CC(=O)N(CCN(C)C(=O)OCc1ccccc1)c1cc(Cc2ccc(F)cc2)cnc1C(=O)OCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN(C)C(=O)OCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of ethyl 3-{[3-(ethyloxy)-3-oxopropanoyl][2-(methyl {[(phenylmethyl)oxy]carbonyl}amino)ethyl]amino}-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate (1.32 g, 2.3 mmol) in EtOH (25 mL) under nitrogen was treated with DBU (0.54 mL, 3.55 mmol). After stirring at ambient temperature for 5 min., the reaction mixture was treated with 1N NaHSO4 (3.6 mL). The resulting slurry was diluted with water, filtered, the filtered solid was washed with 1:1 water:EtOH, and Et2O and thoroughly dried under high vacuum to provide the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (q, J=6.96 Hz, 3 H), 2.84 (d, J=15.02 Hz, 3 H), 3.42-3.50 (m, 1 H), 3.54 (t, J=4.94 Hz, 1 H), 4.03 (s, 1 H), 4.14 (s, 1 H), 4.19-4.27 (m, 2 H), 4.32-4.38 (m, 2 H), 4.72 (s, 1 H), 4.93 (s, 1 H), 7.00 (d, J=4.21 Hz, 1 H), 7.10 (t, J=8.79 Hz, 2 H), 7.19-7.30 (m, 4 H), 7.30-7.39 (m, 2 H), 8.04 (s, 1 H), 8.41 (s, 1 H), 8.49 (s, 1 H); ES+ MS: 534 (M+H+).
Reaction SMILES: [CH:1]1([C:7](=O)[CH2:8][C:9]#[N:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:12][OH:13]>CCO>[NH2:10][C:9]1[O:13][N:12]=[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:8]=1
Reactant: N#CCC(=O)C1CCCCC1
Reactant: NO
Solvent: CCO
Product: Nc1cc(C2CCCCC2)no1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 3-cyclohexyl-3-oxopropanenitrile (1 g, 6.6 mmol, Step A) in EtOH (1 mL) at RT was added hydroxylamine (0.81 mL, 50% in H2O). The reaction was stirred 12 h at RT. The solid was filtered off, washed with 1N NaOH, then H2O and dried over P2O5 to give 5-amino-3-cyclohexylisoxazole.
Reaction SMILES: [F:1][CH2:2][CH:3]([O:6][C:7]1[CH:8]=[C:9]([CH:19]=[C:20]([OH:22])[CH:21]=1)[C:10]([NH:12][C:13]1[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=1)=[O:11])[CH2:4][F:5].[N:23]1([C:27]([C:29]2[CH:30]=[C:31]([Cl:36])[C:32](Cl)=[N:33][CH:34]=2)=[O:28])[CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:23]1([C:27]([C:29]2[CH:30]=[C:31]([Cl:36])[C:32]([O:22][C:20]3[CH:19]=[C:9]([CH:8]=[C:7]([O:6][CH:3]([CH2:2][F:1])[CH2:4][F:5])[CH:21]=3)[C:10]([NH:12][C:13]3[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=3)=[O:11])=[N:33][CH:34]=2)=[O:28])[CH2:26][CH2:25][CH2:24]1
Reactant: Cn1ccc(NC(=O)c2cc(O)cc(OC(CF)CF)c2)n1
Reactant: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1ccc(NC(=O)c2cc(Oc3ncc(C(=O)N4CCC4)cc3Cl)cc(OC(CF)CF)c2)n1
Temperature: 120 °C
Reaction time: 4 h
Yield: 73.2 %

Procedure:
A mixture of 3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (200 mg, 0.64 mmol), 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (164 mg, 0.71 mmol) and potassium carbonate (178 mg, 1.28 mmol) in acetonitrile (5 mL) was stirred in a ‘Biotage initiator Microwave’ at 120° C. for 4 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water (100 mL), the organic layer washed with brine (50 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a brown oil which was chromatographed on silica, eluting with a gradient of 50-100% ethyl acetate in isohexane, to give the desired compound (237 mg).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:30]([Cl:31])=[CH:29][C:13]3[NH:14][C:15]([O:17][C:18]4[CH:19]=[CH:20][C:21]([CH3:28])=[C:22]([CH:27]=4)[C:23]([O:25][CH3:26])=[O:24])=[N:16][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO.O>[Cl:31][C:30]1[C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([OH:3])[CH3:2])=[CH:9][CH:8]=2)=[CH:11][C:12]2[N:16]=[C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([CH3:28])=[C:22]([CH:27]=3)[C:23]([O:25][CH3:26])=[O:24])[NH:14][C:13]=2[CH:29]=1
Reactant: COC(=O)c1cc(Oc2nc3cc(-c4ccc(C(C)=O)cc4)c(Cl)cc3[nH]2)ccc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(Oc2nc3cc(-c4ccc(C(C)O)cc4)c(Cl)cc3[nH]2)ccc1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a 0° C. solution of methyl 5-{[5-(4-acetylphenyl)-6-chloro-1H-benzimidazol-2-yl]oxy}-2-methylbenzoate (50 mg, 0.115 mmol) in MeOH (2 mL) was added NaBH4 (6.5 mg, 0.172 mmol). The mixture was warmed to rt and stirred for 15 min. Water (5-6 drops) was added and the mixture was concentrated. The residue was partitioned between Et2O and water. The aqueous phase was extracted with Et2O. The combined ethereal extracts were washed with brine, dried (MgSO4), filtered, and concentrated to afford the desired product, which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl.[W].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:11][Br:12])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Br)cc2ccoc12
Agent: [W]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cc(Br)cc2ccoc12
Yield: 113.1 %

Procedure:
A mixture of 5-bromo-7-methyl-benzofuran (1.01 g), N-bromosuccinimide (1.04 g) and benzoyl peroxide (58 mg) in carbon tetrachloride (10 ml) was heated at reflux for 4 h under a 250 W tungsten lamp. A further portion of benzoyl peroxide (58 mg) was added and heating and irradiation continued for a total of 9 h. The reaction mixture was allowed to cool, diluted with chloroform (30 ml) and washed with 2N sodium hydroxide (40 ml) and then brine (40 ml). The organic phase was dried, filtered and the filtrate evaporated in vacuo to give the title compound as a brown oil (1.57 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[N+:12]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1ccc([N+](=O)[O-])cc1
Product: O=C(O)Cc1ccccc1Nc1ccc([N+](=O)[O-])cc1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 4-nitroaniline to yield 2-[(4-nitrophenyl)amino]phenylacetic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:13]([CH2:20][O:21][CH2:22][CH3:23])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.BrC1C=CC2C3N(CCCOC(C)C)C(COCC)=NC=3C=[N:32]C=2C=1.[CH2:49]([N:51]1[CH2:55][CH2:54][NH:53][C:52]1=[O:56])[CH3:50].N1CCCC1=O>>[NH2:32][C:8]1[C:7]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([OH:18])([CH3:19])[CH3:17])[C:6]=2[C:5]2[CH:4]=[CH:3][C:2]([N:53]3[CH2:54][CH2:55][N:51]([CH2:49][CH3:50])[C:52]3=[O:56])=[CH:11][C:10]=2[N:9]=1
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCOC(C)C
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1CC(C)(C)O
Reactant: CCN1CCNC1=O
Agent: O=C1CCCN1
Product: CCOCc1nc2c(N)nc3cc(N4CCN(CC)C4=O)ccc3c2n1CC(C)(C)O

Procedure:
The general methods described in Parts A and B of Example 2 were followed using 1-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol in lieu of 7-bromo-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinoline and 1-ethylimidazolidin-2-one in lieu of 2-pyrrolidinone. The product, 1-[4-amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]-3-ethylimidazolidin-2-one was isolated as a peach colored crystalline solid, m.p. 210-212° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=O)=[C:5]([C:11]([OH:13])=[O:12])[C:4]=1[O:14][CH3:15].[NH2:16][C@@H:17]([C:22]([OH:24])=[O:23])[C:18]([SH:21])([CH3:20])[CH3:19]>O>[CH3:15][O:14][C:4]1[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH:9]2[NH:16][C@@H:17]([C:22]([OH:24])=[O:23])[C:18]([CH3:20])([CH3:19])[S:21]2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: COc1ccc(C=O)c(C(=O)O)c1OC
Solvent: O
Product: COc1ccc(C2N[C@@H](C(=O)O)C(C)(C)S2)c(C(=O)O)c1OC
Temperature: 60 °C
Reaction time: 8 h

Procedure:
2.1 g (10 mmoles) of opianic acid are dissolved in 30 ml of hot water and the solution is cooled to about 60° C. After adding 1.5 g (10 mmoles) of D-penicillamine, an oily product separates from the opalescent solution which becomes crystalline after standing overnight. The title acid is obtained in a yield of 2.75 g (80.5%) and can be recrystallized from methanol by adding water, m.p.: 90°-91° C., [α]D20 =+326° (c=0.772, methanol).
Reaction SMILES: [NH2:1][C:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[CH2:22]([O:29][C:30](Cl)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:30]([NH:1][C:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1)([O:29][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:31]
Reactant: NC1(C(=O)O)CCCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: ClCCl
Product: O=C(NC1(C(=O)O)CCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 911.5 %

Procedure:
To a stirred suspension of 12.9 g (0.010 mole) of 1-amino-1-cyclopentane carboxylic acid in 500 ml of methylene chloride is added 25 ml (0.10 mole) of N,O-bis(trimethylsilyl)acetamide. The mixture is stoppered and stirred at room temperature for 3 days, whereupon complete solution is obtained. 17 g (0.10 mole) of benzylchloroformate is added and the mixture stirred for an additional 1 hour. It is then washed with 300 ml each 2N HCl, water and saturated brine and dried over sodium sulfate. Filtration, evaporation and trituration with hexane gives 24 g of 1-carbobenzoxyamino-1-cyclopentane carboxylic acid, mp. 93°-5° C. 5.3 g (0.020 mole) of 1-carbobenzoxyamino-1-cyclopentane carboxylic acid is dissolved in 100 ml dimethylformamide and 3.1 g (0.020 mole) of 1-hydroxybenzotriazole hydrate and 2.5 g (0.020 mole) of 1,3-diisopropylcarbodiimide are added. The mixture is stirred at room temperature for three hours and 1.8 g (0.020 mole) of 4-amino-1-butanol is added. Stirring at room temperature is continued for 24 hours. The solvent is removed in vacuo and replaced with 500 ml of methylene chloride. The mixture is washed with 2N HCl, saturated sodium bicarbonate solution and water and dried over sodium sulfate. Filtration and evaporation gives 6.7 g of 1-carbobenzoxyamino-1-cyclopentane carboxylic acid, 4-hydroxybutylamide, m.p 117°-8° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]2[C:25](=[O:30])[NH:26][CH2:27][C:28]#[N:29])=[CH:13][C:12]=1[F:31])(C)(C)C.[CH3:33][S:34]([OH:37])(=[O:36])=[O:35].CCOCC>O1CCCC1>[S:34]([OH:37])(=[O:36])(=[O:35])[CH3:33].[C:28]([CH2:27][NH:26][C:25]([CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH:19]1[CH2:18][S:17][C:14]1[CH:15]=[CH:16][C:11]([S:10][CH2:9][CH2:8][NH2:7])=[C:12]([F:31])[CH:13]=1)=[O:30])#[N:29]
Reactant: CC(C)(C)OC(=O)NCCSc1ccc(SCC2CCCCC2C(=O)NCC#N)cc1F
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#CCNC(=O)C1CCCCC1CSc1ccc(SCCN)c(F)c1

Procedure:
(2-{4-[2-(Cyanomethylcarbamoyl)-cyclohexylmethylsulfanyl]-2-fluorophenylsulfanyl}-ethyl)-carbamic acid tert-butyl ester was dissolved in tetrahydrofuran (3 mL) and methanesulfonic acid (0.428 g, 6.6 mmol) was added. The reaction mixture was stirred at room temperature overnight, whereupon ether (100 mL) was added. The supernatant was discarded. The residue was triturated three times with ether (50 mL) then 10% tetrahydrofuran/ether, resulting in a white solid, N-cyanomethyl 2-[4-(2-aminoethylsulfanyl)-3-fluoro-phenylsulfanylmethyl]-cyclohexanecarboxamide mesylate, which was isolated by filtration in near quantitative mass recovery, with a small amount of t-butyl amide present as an inseparable impurity, resulting from addition of tert-butanol across the nitrile group under the acidic Boc-cleavage conditions. MS [ESI, (M+H)+] m/z=412 amu.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([N:14]2[CH2:18][CH:17]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:16]3([C:31]4[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=4)[NH:25][C:24]3=[O:33])[CH:15]2[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=2[F:41])=[O:13])=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-].CO>O1CCCC1.O>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([N:14]2[CH2:18][CH:17]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:16]3([C:31]4[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=4)[NH:25][C:24]3=[O:33])[CH:15]2[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=2[F:41])=[O:13])=[CH:7][CH:6]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(OC(=O)N2CC(CC(C)(C)C)C3(C(=O)Nc4cc(Cl)ccc43)C2c2cccc(Cl)c2F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)CC1CN(C(=O)Oc2ccc(C(=O)O)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 13, rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid 4-methoxycarbonyl-phenyl ester (10 mg, 0.02 mmol) was heated with aqueous LiOH (4 mg, 0.2 mmol) in tetrahydrofuran (3 mL), water (3 mL), and methanol (1 mL) at room temperature for 18 h to give rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid 4-carboxy-phenyl ester as a white solid (Yield, 8 mg, 82%).
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[CH2:9][CH2:8][C:7](=[C:10]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][CH2:16][C:15]3[CH:14]=[CH:13][S:12][C:11]2=3)[CH2:6][CH2:5]1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[BrH:1].[Br:1][C:13]1[S:12][C:11]2[C:10](=[C:7]3[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5][CH2:6]3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][CH2:16][C:15]=2[CH:14]=1
Reactant: CN1CCC(=C2c3ccccc3CCc3ccsc32)CC1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Br
Product: CN1CCC(=C2c3ccccc3CCc3cc(Br)sc32)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 163.7 %

Procedure:
Bromine (0.52 mL, 10.2 mmol) was added dropwise to a chloroform (30 mL) solution of 4-(1-methylpiperidin-4-ylidene)-9,10-dihydro-4H-3-thiabenzo[f]azulene (3.0 g, 10.2 mmol) at 0° C. The mixture was stirred at room temperature for 2 days, and a saturated aqueous sodium bicarbonate solution was then added thereto to allow separation of an organic layer. The organic layer was washed with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvents were distilled off under a reduced pressure, and the residue was then purified by column chromatography (chloroform-methanol=9:1), to give 3.8 g (100%) of the captioned compound in the form of white crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[CH3:9][N:10]1[C:18]2[CH2:17][CH2:16][CH2:15][C:14](=[O:19])[C:13]=2[CH:12]=[CH:11]1.CC(C)([O-])C.[K+].Cl>CC(O)(C)C>[CH3:9][N:10]1[C:18]2[CH:17]=[CH:16][C:15]([CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[C:14]([OH:19])[C:13]=2[CH:12]=[CH:11]1
Reactant: O=Cc1cccnc1
Reactant: Cn1ccc2c1CCCC2=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cn1ccc2c(O)c(Cc3cccnc3)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
500 cm3 of 2-methyl-2-propanol, 75 g of pyridine-3-carboxaldehyde and 100 g of 1-methyl-1,5,6,7-tetrahydroindol-4-one were introduced into a 1-liter reactor equipped with a mechanical stirrer and surmounted by a condenser and a thermometer. After 10 minutes of stirring, 157 g of potassium tert-butoxide were added in small portions over 15 minutes. Following addition, the temperature was held at 75° C. for 1 hour. The reaction mixture was allowed to return to room temperature and then was neutralized (pH=6) with 20% hydrochloric acid. It was poured into 2 kg of ice-water. The precipitate obtained was filtered off with suction and washed with diisopropyl ether and with petroleum ether. It was dried over potash under vacuum at 30° C. This gave 120 g of 1-methyl-5-pyridin-3-ylmethyl-1H-indol-4-ol with a yield of 74%.
Reaction SMILES: C([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17]Cl)(OC(C)(C)C)=O.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][NH:26][C:27](=[O:46])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH:35][CH:36]2[C:45]3[N:44]=[CH:43][CH:42]=[CH:41][C:40]=3[CH2:39][CH2:38][CH2:37]2)=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.C(OCC)(=O)C>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[CH2:17][N:35]([CH2:34][C:31]1[CH:32]=[CH:33][C:28]([C:27]([NH:26][CH2:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)=[O:46])=[CH:29][CH:30]=1)[CH:36]1[C:45]2[N:44]=[CH:43][CH:42]=[CH:41][C:40]=2[CH2:39][CH2:38][CH2:37]1
Reactant: O=C(NCc1ccccn1)c1ccc(CNC2CCCc3cccnc32)cc1
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(NCc1ccccn1)c1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Yield: 28.4 %

Procedure:
N-BOC-chloromethyl benzimidazole (215 mg, 0.84 mmol), N-Pyridin-2-ylmethyl-4-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzamide (AMD9363) (300 mg, 0.84 mmol), and K2CO3 (346 mg, 2.50 mmol) were heated to reflux in CH3CN (4 mL) for 24 hours under N2. The reaction mixture was diluted with 200 mL ethyl acetate, and washed with sat. NaHCO3, then brine, and dried over Na2SO4. Evaporation of the solvent and purification of the residue by flash chromatography on silica gel, followed by radial chromatography on silica gel (1 mm plate, 3:3:94 CH3OH—NH3 H2O—CH2Cl2,), afforded the free base of the title compound (120 mg, 28%) as pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH2:14][N:15]=[N+]=[N-])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C.O>[Pd].CCO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=2)[CH2:14][NH2:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@@H](CN=[N+]=[N-])Oc2ccc(C(F)(F)F)cc2)C1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H]([C@@H](CN)Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
(S)-3-[(S)-2-Azido-1-(4-trifluoromethylphenoxy)ethyl]pyrrolidine-1-carboxylic acid t-butyl ester (2.10 g, 5.24 mmol) was combined with 10% Pd/C, Degussa type, wet 50% (0.05:0.45:0.5, Palladium:carbon black:H2O, 1.1 g, 520 μmol) and EtOH (240 mL). The mixture was stirred under an atmosphere of hydrogen (1 atm) at room temperature for 1 hour. The catalyst was then removed by filtration through Celite (MeOH wash) and the filtrate was concentrated to yield the title compound (1.8 g).