Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[H-].[Na+].[CH2:11](Br)[C:12]#[CH:13]>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[CH2:13]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:8])[C:12]#[CH:11]
Reactant: OCCCCCCO
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: C#CCOCCCCCCO
Temperature: 0 °C

Procedure:
118 g. of 1,6-hexanediol are introduced into 800 ml. of absolute tetrahydrofuran and, while stirring well, treated portionwise over a period of 4 hours with 30 g. of sodium hydride. 60 ml. of hexamethylphosphoric acid triamide are then added, the mixture is heated to reflux and treated over a period of 12 hours with a solution of 149 g. of propargyl bromide and 200 ml. of tetrahydrofuran. The cooled mixture is poured on to ice-water and extracted three times with ether. The ether solutions are washed with water and sodium chloride solution, dried over sodium sulphate and evaporated. By distillation or chromatography there is obtained pure 6-(2-propynyloxy)-1-hexanol; boiling point (bulb-tube) = 75°C/0.015 mmHg; nD25 = 1.4560.
Reaction SMILES: C1(N[C:5]([C@H:7]2[O:11]C(C(C)C)=[N:9][C@H:8]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:6])CC1.[ClH:22].CC(C)=[O:25]>>[ClH:22].[OH:11][C@@H:7]([C@@H:8]([NH2:9])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([OH:6])=[O:25]
Reactant: CC(C)C1=N[C@@H](Cc2ccccc2)[C@@H](C(=O)NC2CC2)O1
Reactant: CC(C)=O
Agent: Cl
Product: N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Temperature: 50 °C
Reaction time: 23 h
Yield: 36 %

Procedure:
(4S,5S)—N-Cyclopropyl-2-isopropyl-4-benzyl-4,5-dihydro-1,3-oxazole-5-carboxamide (63 mg), acetone (2.5 ml) and concentrated hydrochloric acid (0.25 g) were mixed, and the mixture was stirred at 50° C. for 23 hours. The reaction mixture was concentrated, and isopropanol (5 ml) was added. The mixture was concentrated under reduced pressure. The same operation was further repeated, and then isopropanol (3 ml) was added to precipitate a crystal. The crystal was collected by filtration under reduced pressure, and was dried in vacuum to obtain the title compound as a white crystal (23 mg, yield: 36%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=3[N:16]=[C:15]2[CH:24]2[CH2:26][CH2:25]2)[CH:10]([O:27][CH3:28])[CH2:9]1)=O)(C)(C)C.[ClH:29].O1CCOCC1>>[ClH:29].[CH:24]1([C:15]2[N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]3[O:27][CH3:28])[C:18]3[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=3[N:16]=2)[CH2:25][CH2:26]1
Reactant: COC1CN(C(=O)OC(C)(C)C)CCC1n1c(C2CC2)nc2cc(C)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: COC1CNCCC1n1c(C2CC2)nc2cc(C)ccc21

Procedure:
A solution of 4-(2-cyclopropyl-5-methyl-benzoimidazol-1-yl)-3-methoxy-piperidine-1-carboxylic acid tert-butyl ester (650 mg, 1.69 mmol) in a 4 M HCl/dioxane (3 mL) solution was stirred for 0.5 h. The solvent was removed to provide 2-cyclopropyl-1-(3-methoxy-piperidin-4-yl)-5-methyl-1H-benzoimidazole hydrochloride salt in quantitative yield without further purification.
Reaction SMILES: C([NH:8][C:9]1[C:10]2[CH:11]=[CH:12][C:13]([CH3:19])=[N:14][C:15]=2[CH:16]=[CH:17][N:18]=1)C1C=CC=CC=1.[OH-].[Na+]>S(=O)(=O)(O)O.O>[CH3:19][C:13]1[CH:12]=[CH:11][C:10]2[C:9]([NH2:8])=[N:18][CH:17]=[CH:16][C:15]=2[N:14]=1
Reactant: Cc1ccc2c(NCc3ccccc3)nccc2n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2c(N)nccc2n1
Temperature: 130 °C
Reaction time: 3 h
Yield: 53.5 %

Procedure:
N-Benzyl-2-methyl-1,6-naphthyridin-5-amine (1.42 g, 5.7 mmol) was dissolved in sulfuric acid (6 mL) and water (3 mL). The solution was heated to 130° C. and stirred for 3 hours. The reaction mixture was poured into ice water and neutralized with sodium hydroxide adjusting pH to 8-10. The solution was then concentrated under reduced pressure. The solid was triturated in ethanol (30 mL×2) and filtered. The filtrate was concentrated to dryness and purified by reverse phase column chromatography, and a brown solid (485 mg) was obtained. MS (ESI): m/z 160 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.[NH:7]1[CH2:12][CH2:11][CH2:10][C@@H:9]([NH:13][C:14]2[C:19](=[O:20])[NH:18][CH:17]=[C:16]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH:15]=2)[CH2:8]1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]([N:7]1[CH2:12][CH2:11][CH2:10][C@@H:9]([NH:13][C:14]2[C:19](=[O:20])[NH:18][CH:17]=[C:16]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH:15]=2)[CH2:8]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: O=c1[nH]cc(-c2ccncc2)cc1N[C@@H]1CCCNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCC[C@@H](Nc2cc(-c3ccncc3)c[nH]c2=O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22.2 %

Procedure:
Chloroacetyl chloride (0.021 mL, 0.26 mmol) was added to a solution of (R)-5-(piperidin-3-ylamino)-[3,4′-bipyridin]-6(1H)-one hydrochloride (100 mg, 0.26 mmol) and triethylamine (0.17 mL, 1.2 mmol) in dichloromethane (5.0 mL) at 0° C. The solution was stirred at 0° C. for 30 min and was concentrated. The residue was diluted with water and extracted with 5% methanol in ethyl acetate. The organic layer was dried over sodium sulphate, filtered, and concentrated. The residue was purified on silica gel eluting with 10% methanol in dichloromethane to provide 20 mg of the title compound: 1H NMR (300 MHz, DMSO-d6) 11.80-11.95 (m, 1H), 8.45-8.60 (m, 2H), 7.60-7.70 (m, 2H), 7.20-7.35 (m, 1H), 6.70-6.95 (m, 1H), 5.50-5.80 (m, 1H), 4.20-4.50 m, 1H), 3.45-3.95 (m, 1H), 2.95-3.40 (m, 2H), 2.65-2.90 (m, 1H), 1.35-2.15 (m, 2H); MS (ES) m/z 347 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[Br:31][CH2:32][CH2:33]Br>CN(C)C=O>[Br:31][CH2:32][CH2:33][N:19]1[C:18]([O:22][CH3:23])=[N:17][C:16]2[C:20]1=[N:21][C:13]([O:12][CH2:8][CH2:9][CH2:10][CH3:11])=[N:14][C:15]=2[NH2:24]
Reactant: BrCCBr
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(OC)n(CCBr)c2n1

Procedure:
The compound obtained in Example 2-1 step (v) (2 g), potassium carbonate (3.7 g) and 1,2-dibromoethane (0.6 ml) were added to dimethylformamide (20 ml), and the same manner to Example 2-13 step (i) was conducted to give the titled compound as a cream colored solid. Yield: 1.2 g (62%).
Reaction SMILES: [CH:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:12]([N:20]=[C:21]=[O:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCOCC>[C:12]([NH:20][C:21]([NH:11][CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: NC1CCCc2ccccc21
Solvent: CCOCC
Product: O=C(NC(=O)c1ccccc1)NC1CCCc2ccccc21
Yield: 78.6 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-1-naphthylamine (10.01 g) and ether (100 ml) is stirred under a nitrogen atmosphere and a solution of benzoyl isocyanate (9.99 g) in ether (90 ml) is added dropwise. After the addition is completed, the mixture is stirred for 0.5 hour and cooled in ice. The product is collected and washed with cold ether (50 ml) to afford 15.7 g of the title compound, m.p. 166° to 169° C. Recrystallization from acetone affords 13.61 g, m.p. 171° to 173° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11]O)[C:4]=2[O:3]1.[ClH:14]>O>[Cl:14][CH2:11][C:10]1[C:4]2[O:3][C:2]([CH3:13])([CH3:1])[CH2:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Cl
Reactant: CC1(C)Cc2cccc(CO)c2O1
Solvent: O
Product: CC1(C)Cc2cccc(CCl)c2O1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 2,3-dihydro-2,2-dimethylbenzofuran-7-ylmethanol (6.3 grams, 0.035 mole) and concentrated hydrochloric acid (38%) was stirred at ambient temperature for 0.75 hour. The reaction mixture was diluted with water (50 ml) and extracted with diethyl ether. The extract was washed successively with a 10% aqueous solution of sodium hydroxide and a saturated aqueous sodium chloride solution. The dried (sodium sulfate) extract was concentrated under reduced pressure, yielding 7-chloromethyl-2,3-dihydro-2,2-dimethylbenzofuran. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11](=[N+]=[N-])[C:12](=[O:19])[CH2:13][CH:14]1[NH:17][C:16](=[O:18])[CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C([O-])(=O)C.[Rh+2].C([O-])(=O)C.C1C=CC=CC=1>[N:17]12[C:16](=[O:18])[CH2:15][CH:14]1[CH2:13][C:12](=[O:19])[CH:11]2[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: [N-]=[N+]=C(C(=O)CC1CC(=O)N1)C(=O)OCc1ccccc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: O=C1CC2CC(=O)N2C1C(=O)OCc1ccccc1
Temperature: 80 °C
Yield: 77.5 %

Procedure:
A mixture of 4-(3-benzyloxycarbonyl-3-diazo-2-oxopropyl)-azetidin-2-one (718 mg. 2.5 mMol), rhodium (II) acetate (5 mg) and anhydrous benzene (50 ml) is deoxygenated by bubbling nitrogen through it for 45 minutes. The mixture is then stirred and heated in an oil bath maintained at 80° C. for 70 minutes. After cooling to room temperature, the mixture is filtered and the filtrate is evaporated under vacuum to an oil. Crystallization from ethyl acetate (5 ml)-diethylether (20 ml) provides benzyl 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (502 mg, 77% yield) as small, white prisms: mp 100°-102°; IR (CH2Cl2) 1770; 1741 cm-1 ; UV (dioxane) 220 nm; NMR (CDCl3, 300 MHz) α 2.43 (dd,1,J=8 and 19, H4a), 2.94 (dd,1,J=6.5 and 19, H4b), 2.99 (dd,1,J=2 and 16, H6B), 3.63 (dd,1,J=5 and 16, H6α), 4.18 (m,1,H5), 4.76 (S,1,H2), 5.23 (S,2,CH2 φ), and 7.40 (S,5,ArH); MS m/e 259 (M+), 231 (M+-28), 217 (M+-42), 203, 187, 186, 168 (M+-91), 124, and 91.
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[NH:21][N:20]=[C:19]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:18]=2)=[CH:9]1)(OC(C)(C)C)=O.N1C2C(=CC=CC=2)C(C2NN=C(NC3C=CC=CC=3)C=2)=C1>>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[NH:21][N:20]=[C:19]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([S:29]([NH2:32])(=[O:30])=[O:31])=[CH:27][CH:28]=3)[CH:18]=2)=[CH:9]1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc(Nc3ccc(S(N)(=O)=O)cc3)n[nH]2)c2ccccc21
Agent: c1ccc(Nc2cc(-c3c[nH]c4ccccc34)[nH]n2)cc1
Product: NS(=O)(=O)c1ccc(Nc2cc(-c3c[nH]c4ccccc34)[nH]n2)cc1
Yield: 88 %

Procedure:
Prepared in 88% yield from 4-[5-(N-BOC-indol-3-yl)-1H-pyrazol-3-ylamino]-benzenesulfonamide analogous to the procedure for the preparation of [5-(1H-indol-3-yl)-1H-pyrazol-3-yl]-phenyl-amine [Example 1(J)]. 1H NMR (300 MHz, DMSO-d6) δ12.27 (s, 1H), 11.44(s, 1H), 9.01 (s, 1H), 7.80 (d, 1H, J=7.2 Hz), 7.76 (d, 1H, J=2.1 Hz), 7.64, (d, 2H, J=9.0 Hz), 7.44-7.49 (m, 3H), 7.12-7.18 (m, 2H), 7.03 (s, 2H), 6.20 (s, 1H). Anal. (C17H15N5O2S) C, H, N, S. Calculated C=57.78, H=4.28, N=19.82, S=9.07; found C=57.67, H=4.25, N=19.58, S=9.09.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].C(Cl)CCl.C1C=CC2N(O)N=[N:23]C=2C=1.N>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:4]=1[C:5]([NH2:23])=[O:6]
Reactant: COc1cc(C)ccc1C(=O)O
Reactant: On1nnc2ccccc21
Agent: N
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1cc(C)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a mixture of 2-methoxy-4-methylbenzoic acid (20 g, 120.4 mmol), EDC (23.1 g, 120.4 mmol) and HOBt (16.3 g, 120.4 mmol) in dichloromethane (1 L) was added NH3 (7N in MeOH, 52 mL, 3 eq) dropwise. The reaction mixture was stirred at room temperature overnight then washed successively with HCl (1N), saturated aq.NaHCO3, water and brine, dried over MgSO4, filtered and evaporated. The residue was recrystallized from ethyl acetate/hexane to give 16.5 gr of 2-methoxy-4-methylbenzamide (83% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH:18]([O:20]C(=O)C)[C:17](=[O:24])[NH:16][C:15]1=[O:25])[C:8]2=[O:13])([O-:3])=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH:18]([OH:20])[C:17](=[O:24])[NH:16][C:15]1=[O:25])[C:8]2=[O:13])([O-:3])=[O:2]
Reactant: CC(=O)OC1CC(N2Cc3c(cccc3[N+](=O)[O-])C2=O)C(=O)NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: O=C1NC(=O)C(N2Cc3c(cccc3[N+](=O)[O-])C2=O)CC1O

Procedure:
A solution of 3-(4-nitro-1-oxoisoindolin-2-yl)-2,6-dioxo-5-acetoxypiperidine (0.96 g, 3.5 mmol) and p-toluenesulfonic acid (0.33 g, 1.8 mmol) in methanol (10 mL) is heated at reflux for 5 hours. The solvent is removed in vacuo to give 4-nitro-2-(5-hydroxy-2,6-dioxopiperid-3-yl)isoindoline-1-one which is further purified by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C1C=CC2N(O)N=NC=2C=1.[F:25][C:26]1[CH:27]=[C:28](/[C:42](/[NH:45]O)=[N:43]/[H])[CH:29]=[C:30]2[C:34]=1[NH:33][C:32]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:31]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1.C(Cl)CCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:14][N:43]=[C:42]([C:28]3[CH:29]=[C:30]4[C:34](=[C:26]([F:25])[CH:27]=3)[NH:33][C:32]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:31]4)[N:45]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: [H]/N=C(\NO)c1cc(F)c2[nH]c(CCC(=O)OCC)cc2c1
Reactant: CC(C)Oc1ncc(C(=O)O)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: On1nnc2ccccc21
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CCOC(=O)CCc1cc2cc(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)cc(F)c2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
To a solution of 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylic acid (368 mg) in tetrahydrofuran (30 mL) stirred at room temperature was added EDC (654 mg) and HOBT (522 mg). The reaction mixture was stirred at room temperature for 0.5 h. Then ethyl 3-{7-fluoro-5-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-2-yl}propanoate (D163) (500 mg) was added. The reaction mixture was stirred at room temperature for an hour, and then TBAF (1.78 g) was added. The reaction mixture was sealed and heated in Biotage Initiator using initial high to 120° C. for 0.5 h. After cooling the reaction, the solvent was removed. The residue was diluted with EtOAc (30 mL), and the organic phase was washed with water (25 mL×4), dried over sodium sulphate and evaporated in vacuo. The crude product was purified by column chromatography to give ethyl 3-[5-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-7-fluoro-1H-indol-2-yl]propanoate (D166) (600 mg) as a yellow solid. MS (ES): C23H22ClFN4O4 requires 472; found 473.2 (M+H+).
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][C:12]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([C:15](=[O:26])[NH:16][C@@H:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH3:18])[CH2:11][CH2:10]1)C1C=CC=CC=1.[H][H]>[Pd]>[C:30]([O:29][C:28](=[O:34])[NH:27][C:12]1([C:15](=[O:26])[NH:16][C@@H:17]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH3:18])[CH2:13][CH2:14][CH:9]([NH2:8])[CH2:10][CH2:11]1)([CH3:31])([CH3:32])[CH3:33]
Reactant: C[C@@H](NC(=O)C1(NC(=O)OC(C)(C)C)CCC(NCc2ccccc2)CC1)c1ccc(F)cc1
Reactant: [H][H]
Agent: [Pd]
Product: C[C@@H](NC(=O)C1(NC(=O)OC(C)(C)C)CCC(N)CC1)c1ccc(F)cc1

Procedure:
(R)-tert-butyl 4-(benzylamino)-1-(1-(4-fluorophenyl)ethylcarbamoyl)cyclohexylcarbamate (Intermediate 94, the “cis” isomer, 87 mg) was hydrogenated at 1 atm hydrogen gas using 10% Pd/C (26 mg, Degussa type E101 NE/W 50% wet) for 16 hours. The reaction was filtered over celite to yield {4-Amino-1-[(R)-1-(4-fluoro-phenyl)-ethylcarbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester (70 mg). MS MH+ 380.4
Reaction SMILES: [C:1]1([C:11](=[O:14])[CH2:12][CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br-:15].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>COCCOC>[Br:15][CH:12]([CH3:13])[C:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:14]
Reactant: [Br-]
Reactant: CCC(=O)c1cccc2ccccc12
Agent: C[N+](C)(C)c1ccccc1
Solvent: COCCOC
Product: CC(Br)C(=O)c1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 118.2 %

Procedure:
To a solution of 1-naphthalen-1-yl-propan-l-one (37.8 g) in 1,2-dimethoxyethane (350 mL) at 0° C. was added phenyl trimethylammonium tribromide (83 g). The mixture was stirred at 0° C. for 10 minutes and then at room temperature for 24 hours. The mixture was washed with water (500 mL) and the aqueous phase was extracted with ethyl acetate (2×500 mL). The combined organics were washed with water (2×200 mL), brine (500 mL), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to afford an orange gum. The gum was triturated with diethyl ether and filtered to afford 2-bromo-1-naphthalen-1-yl-propan-1-one (39.8 g, 74%) as an orange solid, 1H NMR (CDCl3): 1.95 (3H, d, J=6.6 Hz), 5.35 (1H, q, J=6.6 Hz), 7.45-7.60 (3H, m), 7.85-7.90 (2H, m), 8.0 (1H, d, J=8.1 Hz), 8.4 (1H, d, J=7.9 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][N+:6]#[C-:7])[CH3:2].CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>C(O)C>[CH2:1]([O:3][C:4](=[O:8])/[C:5](/[N+:6]#[C-:7])=[CH:11]/[N:12]([CH3:14])[CH3:13])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: [C-]#[N+]CC(=O)OCC
Solvent: CCO
Product: [C-]#[N+]/C(=C\N(C)C)C(=O)OCC
Reaction time: 24 h
Yield: 71.1 %

Procedure:
A solution of ethyl-2-isocyanoacetate (10.3 g, 91 mmol) in ethanol (100 ml) was cooled down to 0° C. 1,1-dimethoxy-N,N-dimethyl methanamine (26.6 ml, 200 mmol) was added and the reaction mixture was then allowed to reach RT and stirred for 24 h. The mixture was concentrated and the crude material was purified by flash chromatography (heptane/EtOAc, 100:0 to 40:60) to afford 11 g (64.7 mmol, 71.1% yield) of the title compound. LCMS: (M+H)=169; tR=0.74 min (LC-MS 2); 1H-NMR (CDCl3, 400 MHz) δ (ppm) 7.15 (s, 1H), 4.18 (q, 2H), 3.20 (bs, 6H), 1.26 (t, 3H).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.C1C=CC2N(O)N=NC=2C=1.[NH2:23][C:24]([C:26]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([OH:40])([CH3:39])[CH3:38])=[CH:33][C:32]=2[F:41])[S:28][C:27]=1[NH:42][C:43]1[N:48]=[C:47]([CH2:49][N:50]([CH2:61][C:62]([OH:64])=O)[C:51]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[O:52])[CH:46]=[CH:45][CH:44]=1)=[O:25].[CH3:65][NH:66][CH2:67][CH2:68][OH:69].[N-]=C=O.C(O)C(N)(CO)CO>C(Cl)Cl.CN(C=O)C>[CH2:54]([O:53][C:51](=[O:52])[N:50]([CH2:49][C:47]1[CH:46]=[CH:45][CH:44]=[C:43]([NH:42][C:27]2[S:28][C:29]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([OH:40])([CH3:38])[CH3:39])=[CH:33][C:32]=3[F:41])=[CH:30][C:26]=2[C:24]([NH2:23])=[O:25])[N:48]=1)[CH2:61][C:62]([N:66]([CH2:67][CH2:68][OH:69])[CH3:65])=[O:64])[C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(CN(CC(=O)O)C(=O)OCc4ccccc4)n3)s2)c(F)c1
Reactant: CNCCO
Agent: NC(CO)(CO)CO
Agent: O=C(n1ccnc1)n1ccnc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(CCO)C(=O)CN(Cc1cccc(Nc2sc(-c3ccc(C(C)(C)O)cc3F)cc2C(N)=O)n1)C(=O)OCc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of PS-CDI (152 mg, 0.19 mmol), HOBt (14 mg, 0.091 mmol), {{[6-({3-(Aminocarbonyl)-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-thienyl}amino)pyridin-2-yl]methyl}[(benzyloxy)carbonyl]amino}acetic acid (45 mg, 0.076 mmol) and 2-(methylamino)ethanol (7.0 mg, 0.091 mmol) in 2:1 mixture of DCM (1.6 mL) and DMF (0.8 mL) was heated to 100° C. under the microwave irradiation for 5 min. Upon cooling, MP-isocyanate (241 mg, 0.30 mmol), PS-trisamine (89 mg, 0.30 mmol) and 1 mL DCM were added to a reaction mixture and heated to 100° C. under the microwave irradiation for 10 min. The reaction mixture was filtered, washed with DCM, and concentrated in vacuo to afford the title compound.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[N:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)=[O:5])C.O[Li].O>>[C:18]([C:15]1[N:14]=[CH:13][C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[CH:17][CH:16]=1)#[N:19]
Reactant: CCOC(=O)C1CCN(c2ccc(C#N)nc2)CC1
Agent: [Li]O
Solvent: O
Product: N#Cc1ccc(N2CCC(C(=O)O)CC2)cn1

Procedure:
In analogy to the procedure described for the synthesis of 5′-Fluoro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid the title compound was prepared from 6′-Cyano-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-carboxylic acid ethyl ester through saponification with LiOH.H2O. The title compound was isolated as yellow solid. MS m/e: 230 [M−H].
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])([CH3:3])[CH3:2].[BH4-].[Na+].C(Cl)Cl>CO>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][OH:9])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)Oc1cccc(CO)c1

Procedure:
To a 1 molar solution of 3-isopropoxy benzaldehyde (102 g, 0.621 moles) in methanol (620 mL) cooled to 0° was added (slowly) sodium borohydride powder (25.8 g, 0.683 moles)-dissolved in a minimum of methylene chloride and passed through a plug of silica gel washing with more methylene chloride until the silica gel was free of the product. The eluent was stripped to an oil and pumped on high vacuum overnight.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][C@H:21]([OH:28])[C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C:18]2=[O:29])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1(C2C=CN=CC=2)CCCC1.[CH3:41][C:42]([CH3:48])([CH2:46][CH3:47])[C:43](Cl)=[O:44]>N1C=CC=CC=1.CCOCC>[CH3:41][C:42]([CH3:48])([CH2:46][CH3:47])[C:43]([O:28][C@@H:21]1[C@@:19]2([CH3:20])[C@@H:15]([CH2:16][CH2:17][C:18]2=[O:29])[C@H:14]2[C@@H:23]([C@:24]3([CH3:27])[C@H:11]([CH2:12][CH2:13]2)[CH2:10][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH2:26][CH2:25]3)[CH2:22]1)=[O:44]
Reactant: CCC(C)(C)C(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2C[C@H](O)[C@]2(C)C(=O)CC[C@@H]32)C1
Agent: c1cc(N2CCCC2)ccn1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCC(C)(C)C(=O)O[C@H]1C[C@H]2[C@@H](CC[C@@H]3C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@]32C)[C@@H]2CCC(=O)[C@@]12C
Temperature: 85 °C
Reaction time: 3 h

Procedure:
3α-tert-butyldimethylsilyloxy-12α-hydroxy-5β-androstan-17-one (5.9 g), 4-pyrrolidinopyridine (0.30 g) and 2,2-dimethylbutyryl chloride (6 ml) are dissolved in pyridine (30 ml) and the solution warmed to 85° C., stirred at that temperature for about 3 hours, cooled, diluted with ether and washed with water, then 0.5M hydrochloric acid. The organic solution is dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by flash chromatography in a gradient of 20% to 30% ether in hexane to give the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8](O)[CH2:9][CH2:10][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)O)=[CH:4][CH:3]=1.[F:21][C:22]([F:31])([F:30])[C:23]1[N:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:9][CH2:10][C@@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=3)[N:29]2[C:26]2[CH:25]=[CH:24][C:23]([C:22]([F:31])([F:21])[F:30])=[N:28][CH:27]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: O[C@H](CC[C@@H](O)c1ccc(Br)cc1)c1ccc(Br)cc1
Product: FC(F)(F)c1ccc(N2[C@H](c3ccc(Br)cc3)CC[C@H]2c2ccc(Br)cc2)cn1
Yield: 10 %

Procedure:
The product from Example 69A (1.0 g, 2.5 mmol) was subjected to the procedure described in Example 182A, substituting 6-(trifluoromethyl)pyridin-3-amine for Example 144C, to give the title compound (0.13 g, 10%).