Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[CH3:4][O:5][C:6](=[O:60])[NH:7][C@H:8]([C:12]([N:14]1[CH2:18][C@@H:17]([O:19][CH3:20])[CH2:16][C@H:15]1[C:21]1[NH:22][CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[C:36]([Cl:38])[C:35]([NH:39][C:40]([C:42]4[CH:43]=[N:44][C:45]([N:48]5[CH2:53][CH2:52][NH:51][CH2:50][C@H:49]5[CH3:54])=[CH:46][CH:47]=4)=[O:41])=[CH:34][C:33]=3[O:55][C:56]([F:59])([F:58])[F:57])=[CH:28][CH:27]=2)[N:25]=1)=[O:13])[CH:9]([CH3:11])[CH3:10].C(N(CC)C(C)C)(C)C.[CH3:70][C:71](C)([CH3:75])[C:72](Cl)=O>CC(N(C)C)=O>[CH3:4][O:5][C:6](=[O:60])[NH:7][C@H:8]([C:12]([N:14]1[CH2:18][C@@H:17]([O:19][CH3:20])[CH2:16][C@H:15]1[C:21]1[NH:22][CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[C:36]([Cl:38])[C:35]([NH:39][C:40]([C:42]4[CH:43]=[N:44][C:45]([N:48]5[CH2:53][CH2:52][N:51]([C:71]([CH3:75])([CH3:72])[CH3:70])[CH2:50][C@H:49]5[CH3:54])=[CH:46][CH:47]=4)=[O:41])=[CH:34][C:33]=3[O:55][C:56]([F:59])([F:58])[F:57])=[CH:28][CH:27]=2)[N:25]=1)=[O:13])[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](OC)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCNC[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](OC)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCN(C(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
To a solution of ((S)-1-{(2S,4S)-2-[4-(5′-chloro-4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-4-methoxy-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester tri-HCl (10 mg, 0.01 mmol; Preparation 28) in DMA (1 mL) was added N,N-diisopropylethylamine (9.44 μL, 0.05 mmol) followed by 2,2-dimethylpropanoyl chloride (1.31 mg, 0.01 mmol). The reaction mixture was stirred at RT overnight, concentrated by rotary evaporation, dissolved in 1:1 acetic acid:water (1.5 mL) and purified by reverse phase HPLC to provide the di-TFA salt of the title compound (7 mg, 51% yield) (m/z): [M+H]+ calcd for C44H52ClF3N8O7 897.36. found 897.8.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:7]=2[CH:6]=1)=O.O.[NH2:16][NH2:17]>C(O)C>[Cl:14][C:12]1[CH:11]=[CH:10][C:8]2[S:9][C:5]([C:3]([NH:16][NH2:17])=[O:2])=[CH:6][C:7]=2[CH:13]=1
Reactant: NN
Reactant: COC(=O)c1cc2cc(Cl)ccc2s1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cc2cc(Cl)ccc2s1
Temperature: 0 °C

Procedure:
8.00 g (35.3 mmols) of 5-chloro-2-benzo[b]thiophenecarboxylic acid methyl ester and 10 ml of hydrazine hydrate in 100 ml of absolute ethanol are boiled under reflux for 45 minutes. The cooled suspension is diluted with 100 ml of ice water and the product is filtered off. It is washed with two 40 ml portions of methanol and dried in vacuo. 5-Chloro-2-benzo[b]thiophene-carboxylic acid hydrazide with a melting point of 254°-255° is obtained.
Reaction SMILES: BrC1C2N(N=C(Cl)N=2)C=CC=1.ClC1N=C2C(B(O)O)=CC=CN2N=1.[Cl:25][C:26]1[N:42]=[C:29]2[C:30]([C:34]3[CH:39]=[N:38][C:37]([O:40][CH3:41])=[CH:36][N:35]=3)=[CH:31][CH:32]=[CH:33][N:28]2[N:27]=1.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([C:56]2[CH:61]=[CH:60][C:59]([NH2:62])=[CH:58][CH:57]=2)[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[Cl:25][C:26]1[N:42]=[C:29]2[C:30]([C:34]3[CH:39]=[N:38][C:37]([O:40][CH3:41])=[CH:36][N:35]=3)=[CH:31][CH:32]=[CH:33][N:28]2[N:27]=1.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([C:56]2[CH:61]=[CH:60][C:59]([NH:62][C:26]3[N:42]=[C:29]4[C:30]([C:34]5[CH:39]=[N:38][C:37]([O:40][CH3:41])=[CH:36][N:35]=5)=[CH:31][CH:32]=[CH:33][N:28]4[N:27]=3)=[CH:58][CH:57]=2)[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Agent: COc1cnc(-c2cccn3nc(Cl)nc23)cn1
Agent: Clc1nc2c(Br)cccn2n1
Agent: OB(O)c1cccn2nc(Cl)nc12
Product: COc1cnc(-c2cccn3nc(Nc4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)nc23)cn1

Procedure:
A solution of 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (0.29 g, 1.25 mmol) in anhydrous tetrahydrofuran (6.0 mL) was cooled to −78° C. under nitrogen as n-butyllithium (2N in tetrahydrofuran, 1.87 mmol) was added dropwise. The mixture was stirred at −78° C. for 30 minutes then trimethylboronate (0.213 mL, 1.87 mmol) was added, and the reaction was slowly warmed and stirred at room temperature for 2 hours. Hydrochloric acid solution (2N, 2 mL) was added and the reaction was stirred for 1 hour then extracted with dichloromethane, combined, and concentrated. The crude was triturated with ether to give 2-chloro-[1,2,4]triazolo[1,5-a]pyridine-8-boronic acid (0.174 g, 69%). MP=227-229° C. MS=198 (MH)+. 284b) 2-Chloro-8-(5-methoxy-pyrazin-2-yl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 2-chloro-[1,2,4]triazolo[1,5-a]pyridine-8-boronic acid in a manner analogous to Example 2c (0.115 g, 51%). %). MP=210° C. (dec.). MS=262 (MH)+. 284c) 4-{4-[8-(5-Methoxy-pyrazin-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(5-methoxy-pyrazin-2-yl)-[1,2,4]triazolo[1,5-a]pyridine and 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester with 2,2′-bis-dicyclohexylphosphanyl-biphenyl as the ligand in a manner analogous to Example 2d (0.039 g, 19%). MP=193-195° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.75 (s, 1H), 9.69 (s, 1H), 8.87 (d, 1H), 8.49 (m, 1H), 8.35 (m, 1H), 7.65 (m, 2H), 7.20 (m, 3H), 4.08 (m, 2H), 4.02 (s, 3H), 2.80 (m, 2H), 2.62 (m, 1H), 1.72 (m, 2H), 1.51 (m, 2H), 1.40 (s, 9H). MS=502 (MH)+.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][CH2:8][CH2:9][C:10]1([O:13][CH3:14])[CH2:12][CH2:11]1)=[O:6].[H-].[Na+]>C1COCC1>[CH3:14][O:13][C:10]1([CH2:9][CH2:8][N:7]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])[CH2:12][CH2:11]1
Reactant: COC1(CCNC(=O)NCCCl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(CCN2CCNC2=O)CC1
Temperature: 25 °C
Yield: 54.7 %

Procedure:
A −20° C. solution of 1-(2-chloroethyl)-3-(2-(1-methoxycyclopropyl)ethyl)urea (0.429 g, 1.944 mmol) in THF (10 mL), under argon, was treated with NaH (60% in mineral oil, 0.194 g, 4.86 mmol), and the mixture allowed to warm to RT as the cooling bath expired. The mixture was cooled to 0° C., quenched with satd. NH4Cl, warmed to RT, treated with brine, extracted with EtOAc (2×) and the combined organics were dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 1-(2-(1-methoxycyclopropyl)ethyl)imidazolidin-2-one (196 mg, 55%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 6.22 (s, 1 H), 3.32-3.27 (m, 2 H), 3.19-3.17 (m, 2 H), 3.14 (s, 3 H), 3.12-3.11 (m, 2 H), 1.67-1.65 (m, 2 H), 0.63-0.62 (m, 2 H), 0.39-0.38 (m, 2 H); MS (ESI) m/z: 185.1 (M+H+).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[C:10]([C:12]([O:14]CC)=[O:13])[N:11]=[C:5]2[CH:4]=1.[BrH:17]>>[BrH:17].[OH:2][C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[C:10]([C:12]([OH:14])=[O:13])[N:11]=[C:5]2[CH:4]=1
Reactant: CCOC(=O)c1cn2ccc(OC)cc2n1
Agent: Br
Product: O=C(O)c1cn2ccc(O)cc2n1
Yield: 93 %

Procedure:
A mixture of ethyl 7-methoxyimidazo[1,2-a]pyridine-2-carboxylate (0.22 g, 1.0 mmol) and 48% hydrobromic acid (20 mL) was heated at reflux for 3 days. After the completion of reaction, the reaction mixture was concentrated and the residue obtained was washed with diethyl ether and dried under reduced pressure to afford 7-hydroxyimidazo[1,2-a]pyridine-2-carboxylic acid hydrobromide salt as a brown solid (0.24 g, 93%). 1H-NMR (CD3OD, 300 MHz): δ 8.57 (m, 1H), 8.44 (s, 1H), 7.07 (m, 1H), 6.95 (m, 1H) ppm; MS (ESI): 178.1 (M+1).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[N:16]=3)[C:12]([Cl:30])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.Br[CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47]>C(Cl)Cl>[Si:46]([O:45][CH2:44][CH2:43][NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[N:16]=3)[C:12]([Cl:30])=[CH:11][N:10]=2)[CH2:4][CH2:3]1)([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47]
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCN[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Temperature: 75 °C

Procedure:
To a scintillation vial containing N2′-(trans-4-aminocyclohexyl)-5′-chloro-N6-(3-fluorobenzyl)-2,4′-bipyridine-2′,6-diamine (17 mg, 0.040 mmol) and K2CO3 (22.06 mg, 0.160 mmol) was added DMF (0.3 ml) and (2-bromoethoxy)(tert-butyl)dimethylsilane (9.55 mg, 0.040 mmol). The reaction mixture was capped and heated to 75° C. for 7 hr. The reaction mixture was diluted with DCM and washed with H2O, sat NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. The crude solid was purified by reverse phase preparative HPLC. Collected fractions were combined, neutralized with Saturated NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, concentrated and used directly in next step. LCMS (m/z): 584.3 (MH+), retention time=0.87 min.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[N:14][C:15]([N:19](C(OC(C)(C)C)=O)[NH:20][C:21](OC(C)(C)C)=O)=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:35]([F:38])([F:37])[F:36])(=O)=O)C=CC=CC=1.[C:39](O)(=O)C>>[CH3:39][C:21]1[N:14]2[C:13]3[CH:12]=[C:11]([C:35]([F:38])([F:37])[F:36])[NH:10][C:18]=3[CH:17]=[CH:16][C:15]2=[N:19][N:20]=1
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(C(F)(F)F)n2S(=O)(=O)c2ccccc2)n1
Reactant: CC(=O)O
Product: Cc1nnc2ccc3[nH]c(C(F)(F)F)cc3n12

Procedure:
A solution of di-tert-butyl 1-[1-(phenylsulfonyl)-2-(trifluoro methyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]hydrazine-1,2-dicarboxylate (0.66 g, 1.2 mmol, from Step 3) in acetic acid (20 mL) was heated at 180° C. for 5 minutes in the microwave. The acetic acid was removed in vacuo. The residue was dissolved in EtOAc and washed with an additional NaHCO3 solution. The organic layer was dried over sodium sulfate, filtered and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-10% MeOH in DCM. Yield: (0.14 g, 49%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[O:21][CH2:20][C:19]=2[CH2:26][OH:27])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.CCOCC>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH2:23][C:22]([CH3:24])([CH3:25])[O:21][CH2:20][C:19]=2[CH:26]=[O:27])=[CH:14][CH:13]=1
Reactant: CC1(C)CC(c2ccc(Cl)cc2)=C(CO)CO1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(C)CC(c2ccc(Cl)cc2)=C(C=O)CO1
Reaction time: 0.5 h

Procedure:
To a solution of oxalyl chloride (1.1 g) in dichloromethane (30 mL) at −78° C. was added dimethylsulfoxide (6.12 mL). The mixture was stirred at the temperature for 30 minutes, and then a solution of EXAMPLE 15D (1.2 g) in dichloromethane (10 mL) was added. The mixture was stirred at −78° C. for 2 hours before the addition of triethylamine (10 mL). The mixture was stirred overnight and the temperature was allowed to rise to room temperature. The mixture was diluted with ether (300 mL) and washed with water, brine and dried over Na2SO4. Concentration of the solvent and column purification (5% ethyl acetate in hexane) gave the product.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([OH:39])[C@@H:11]([NH:15][C:16](=[O:38])[CH:17]([CH2:27][C:28]1([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:30][CH2:29]1)[CH2:18][C:19]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:20])[CH2:12][CH2:13][CH3:14].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C@@H:11]([NH:15][C:16](=[O:38])[CH:17]([CH2:27][C:28]1([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:30][CH2:29]1)[CH2:18][C:19]([N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)=[O:20])[CH2:12][CH2:13][CH3:14])=[O:39]
Reactant: CCC[C@H](NC(=O)C(CC(=O)N1CCOCC1)CC1(Cc2ccccc2)CC1)C(O)c1nc2ccccc2o1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCC[C@H](NC(=O)C(CC(=O)N1CCOCC1)CC1(Cc2ccccc2)CC1)C(=O)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
To a solution of N-[(S)-1-(Benzoxazol-2-yl-hydroxy-methyl)-butyl]-2-(1-benzyl-cyclopropylmethyl)-4-morpholin-4-yl-4-oxo-butyramide (55 mg, 0.103 mmol) in dry dichloromethane under N2 was added a solution of Dess-Martin Periodinane solution in dichloromethane (15% wt in DCM, 0.206 mmol) and stirred at room temperature for 1 hr. The mixture was quenched with a solution Na2SO3 (65.4 mg) in saturated NaHCO3 (20 mL). The aqueous layer was extracted with dichloromethane (2×25 mL). Organic extracts dried (MgSO4) and concentrated under reduced pressure. Residue purified by silica gel column chromatography eluting with a mixture of ethyl acetate and heptane (1:1 then 2:1) to give N-[(S)-1-(Benzoxazole-2-carbonyl)-butyl]-2-(1-benzyl-cyclopropylmethyl)-4-morpholin-4-yl-4-oxo-butyramide as white solid (43 mg).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1>C1COCC1>[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[CH:3]=2)[OH:17])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: COc1ccccc1Br
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1cccc(C(O)c2ccc(Br)cc2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a suspension of magnesium (2.4 g, 100 mmmol), in THF (20 mL) at room temperature was added dropwise a solution of bromoanisole (9.1 mL, 71.4 mmol) in THF (30 mL). The reaction mixture was stirred at room temperature for 2 h and at 60° C. for 2 h. The mixture was cooled to room temperature and a solution of 4-bromobenzaldehyde (13.2 g, 71.4 mmol) was added over 5 min. The reaction mixture was stirred at room temperature for 3 h and was quenched by addition of aqueous saturated ammonium chloride (NH4Cl) (30 mL). The aqueous layer was washed with ether (3×40 mL), dried over Na2SO4 and concentrated. Purification by flash chromatography with hexanes/EtOAc (10:1) afforded 16.95 g of (4-bromo-phenyl)-(3-methoxy-phenyl)-methanol. 1HNMR (400 MHz, CDCl3) δ 7.46-7.41 (comp, 2H), 7.27-7.18 (comp, 3H), 6.91-6.87 (comp, 2H), 6.81-6.78 (m, 1H), 5.73 (s, 1H), 3.76 (s, 3H); MS (M+1) 294.2.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:16])[CH:12]=[C:13]([CH3:15])[CH3:14])[CH:7]=[CH:8][CH:9]=1.[CH3:17]I>CS(C)=O>[CH3:17][N:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Br:3])[CH:5]=1)[C:11](=[O:16])[CH:12]=[C:13]([CH3:14])[CH3:15]
Reactant: CI
Reactant: CC(C)=CC(=O)Nc1cccc(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)=CC(=O)N(C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
28.7 g of powdered potassium hydroxide were suspended in 300 ml of dimethyl sulfoxide and a solution of 32.6 g of N-(3-bromophenyl)-3,3-dimethyl-acrylamide in 200 ml of dimethylsulfoxide (DMSO) was added dropwise thereto. The mixture was stirred at room temperature for 30 minutes and subsequently a solution of 27.5 g of methyl iodide in 150 ml of DMSO was added dropwise thereto. After 2.5 hours the mixture was poured on to 1 1 of ice/water and extracted with ethyl acetate. The organic phase was washed repeatedly with water, dried and evaporated. The oily residue was distilled in a high vacuum. There were obtained 29.3 g of N-methyl-N-(3-bromophenyl)-3,3-dimethyl-acrylamide as a slightly yellow oil, boiling point 112°-114° C./67 Pa.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([N:15]([CH2:34][C:35]2[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:36]=2)[C:16]2[N:17]=[N:18][N:19]([CH2:21][CH2:22][N:23]3[C:31](=[O:32])[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]3=[O:33])[N:20]=2)[C:10]2[CH:49]=[C:50]([CH3:57])[C:51]([C:53]([F:56])([F:55])[F:54])=[CH:52][C:9]1=2)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.O>[F:48][C:45]([F:46])([F:47])[C:37]1[CH:36]=[C:35]([CH:40]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:38]=1)[CH2:34][N:15]([C@H:11]1[CH2:12][CH2:13][CH2:14][NH:8][C:9]2[CH:52]=[C:51]([C:53]([F:54])([F:55])[F:56])[C:50]([CH3:57])=[CH:49][C:10]1=2)[C:16]1[N:17]=[N:18][N:19]([CH2:21][CH2:22][N:23]2[C:24](=[O:33])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]2=[O:32])[N:20]=1
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCN2C(=O)c3ccccc3C2=O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCN2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-5-((3,5-Bis-trifluoromethyl-benzyl)-{2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-2H-tetrazol-5-yl}-amino)-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (0.12 mmol) in dichloromethane (4 mL), add trifluoroacetic acid (1 mL). After stirring at room temperature for 1 h, quench the reaction with concentrated sodium carbonate (10 mL), and dilute with water (10 mL) and dichloromethane (20 mL). Separate the organic phase and wash the aqueous with dichloromethane (2×10 mL). Dry the combined organics over sodium sulfate, filter, and remove solvent under vacuum, to provide the title compound as a colorless foam. MS (ES+): 712 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH:18]=3)[O:14][N:13]=2)=[CH:7][C:6]=1[CH2:29][CH3:30].CCN(C(C)C)C(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl.CC(=O)OCC>[CH2:27]([N:24]([CH2:25][CH3:26])[C:19]1[CH:18]=[C:17]([C:15]2[O:14][N:13]=[C:12]([C:8]3[CH:9]=[C:10]([CH3:11])[C:5]([O:4][CH2:3][CH2:2][NH:1][S:41]([CH3:40])(=[O:43])=[O:42])=[C:6]([CH2:29][CH3:30])[CH:7]=3)[N:16]=2)[CH:22]=[C:21]([CH3:23])[N:20]=1)[CH3:28]
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OCCN
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
To a solution of crude (4-{3-[4-(2-amino-ethoxy)-3-ethyl-5-methyl-phenyl]-[1,2,4]oxadiazol-5-yl}-6-methyl-pyridin-2-yl)-diethyl-amine (70 mg, 0.17 mmol) and DIPEA (44 mg, 0.342 mmol) in DCM (2 mL), methane sulfonyl chloride (23 mg, 0.205 mmol) is added. The mixture is stirred at rt for 30 min before it is diluted with EA and washed with sat. aq. NaHCO3-solution. The washing is extracted back three times with EA. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates using heptane:EA 1:1 to give the title compound (34 mg) as a pale yellow oil; LC-MS*: tR=1.12 min; [M+1]+=488.05; 1H NMR (CDCl3): δ 1.25 (t, J=6.8 Hz, 6H), 1.33 (t, J=7.5 Hz, 3H), 2.40 (s, 3H), 2.50 (s, 3H), 2.76 (q, J=7.5 Hz, 2H), 3.09 (s, 3H), 3.57-3.67 (m, 6H), 3.99 (t, J=4.8 Hz, 2H), 4.91 (t, J=5.5 Hz, 1H), 7.01 (s, 1H), 7.10 (s, 1H), 7.88 (s, 1H), 7.89 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([NH:16][C:17](=[O:19])[CH3:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>[Pt]=O.C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:11][CH2:12][C@H:13]([NH:16][C:17](=[O:19])[CH3:18])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: CC(=O)N[C@H]1CC[C@H](c2ccc([N+](=O)[O-])cc2)CC1
Agent: O=[Pt]
Solvent: CCO
Product: CC(=O)N[C@H]1CC[C@H](c2ccc(N)cc2)CC1

Procedure:
A mixture of 2.62 g. of trans N-[4-(p-nitrophenyl)cyclohexyl]acetamide (obtained as in Example 81) and 10 g. of Adams' platinum oxide catalyst in 150 ml. of ethanol is shaken under hydrogen (for about 10 minutes) until the theoretically required amount of the gas is absorbed. The catalyst is removed on a filter and the filtrate evaporated to dryness. The residual solid is recrystallized from aqueous methanol to give 2.03 g. (87% yield) of trans N-[4-(p-aminophenyl)cyclohexyl]acetamide having a melting point of 195° to 196.5° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH2:4][C:5]([CH2:9][CH3:10])([CH2:7][OH:8])[N:6]=1.[C:11](O)(=[O:15])[CH2:12][CH2:13][CH3:14]>>[CH3:1][C:2]1[O:3][CH2:4][C:5]([CH2:9][CH3:10])([CH2:7][O:8][C:11](=[O:15])[CH2:12][CH2:13][CH3:14])[N:6]=1
Reactant: CCCC(=O)O
Reactant: CCC1(CO)COC(C)=N1
Product: CCCC(=O)OCC1(CC)COC(C)=N1

Procedure:
The 2-methyl-4-ethyl-4-hydroxymethyl-2-oxazoline is reacted with butyric acid in a 1:1 molar ratio following the method of Purcell to produce 2-methyl-4-ethyl-4-butyryloxymethyl-2-oxazoline.
Reaction SMILES: [C:1]([CH:4]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=O)[NH2:2].Cl.N[C@H](C(N)=O)CCC1C=CC=CC=1.C(N1C(=O)CCC1=O)(OCC1C=CC=CC=1)=O.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:1]([CH:4]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)#[N:2]
Reactant: NC(=O)C(CCc1ccccc1)NC(=O)OCc1ccccc1
Agent: Cl
Agent: NC(=O)[C@@H](N)CCc1ccccc1
Agent: O=C1CCC(=O)N1C(=O)OCc1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: N#CC(CCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 75 °C
Reaction time: 24 h

Procedure:
2.78 g of benzyl (1-carbamoyl-3-phenylpropyl)carbamate, prepared from L-homophenylalanine amide hydrochloride and N-Cbz-succinimide, were dissolved in 30 ml of dry pyridine and treated with 6 ml of acetic anhydride. The reaction mixture was stirred at 75° C. for 24 h. The cooled solution was concentrated in vacuo, treated with 100 ml of ethyl acetate, and then extracted three times by shaking with 50 ml each of 5% strength citric acid solution and saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated in vacuo, and chromatographed on silica gel using n-heptane/ethyl acetate (1/1). Benzyl (1-cyano-3-phenylpropyl)carbamate was obtained, which was employed in the next stage without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH2:9][C:2]=12.[O-:10]S([O-])(=O)=O.[Mg+2].[O-][Mn](=O)(=O)=O.[K+].[BH4-].[Na+]>CC(C)=O.O.CC(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH:7]([OH:10])[CH2:8][CH2:9][C:2]=12
Reactant: c1cnc2c(c1)CCC2
Reactant: O=S(=O)([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CC(C)O
Product: OC1CCc2ncccc21
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6,7-dihydro-5H-cyclopenta[b]pyridine (5.0 g, 42 mmol) and MgSO4 (10 g, 84 mmol) in acetone (250 mL) was added a solution of KMnO4 (13 g, 84 mmol) in water (500 mL) at 60 degrees. The mixture was allowed to stir for 30 minutes at 60° C. IPA was slowly added to quench excess KMnO4. The reaction was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and pumped on a high vacuum pump to ensure complete removal of water. The residue was dissolved in ethanol (200 mL), and cooled with an ice bath. To this solution was slowly added NaBH4 (3.2 g, 84 mmol). When TLC showed complete reduction, water was added to quench excess NaBH4. Ethanol was removed on a rotavapor. The crude material was dissolved in EtOAc, washed with aq. NaHCO3, dried over sodium sulfate, and purified by MPLC (MeOH-DCM: 0-7%). The title compound was collected. LC-MS (IE, m/z): 136 [M+1]+.