Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CO[C:12](=[O:19])[C@H:13]([C@H:15]([CH2:17][CH3:18])[CH3:16])[NH2:14].Cl>C1COCC1.C(OCC)C.O>[NH2:14][C@@H:13]([C@H:15]([CH3:16])[CH2:17][CH3:18])[C:12]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:19]
Reactant: CC[C@H](C)[C@H](N)C(=O)OC
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC[C@@H](C)[C@H](N)C(O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 4.5 %

Procedure:
A 1 M solution of phenylmagnesium bromide (49.0 g, 0.27 mol) in THF was added dropwise to (S)-isoleucine methyl ester hydrochloride (9.8 g, 54.0 mmol) at 0° C. and then stirred for 17 h at room temperature. The reaction mixture was cooled to 0° C., quenched with dropwise addition of saturated NH4Cl and then diluted with AcOEt and water until partition occurred. Organic products were extracted into AcOEt (3×50 ml), dried over MgSO4/K2CO3 and concentrated to obtain a crude product. The crude product was dissolved in diethyl ether (150 ml), treated with concentrated HCl until all of the amine was converted to its HCl salt. The amine-HCl salt was stirred overnight, diluted with water until partition occured. The non-basic organics were extracted into diethyl ether (5×100 ml) and then the aqueous layer was made basic with NaOH pellets. After stirring for 4 h, organic products were extracted into AcOEt (4×75 ml) and dried over MgSO4/K2CO3. Concentration gave a crude product (6.1 g, 42%) as a pale yellow solid. This contaminated with the amino ester derived from the starting material, however was used for the next step without further purification. A small amount of the crude product (1.1 g) was purified over silica gel by means of dry-flash column chromatography, eluting first with CH2Cl2, then with a mixture of AcOEt and petrol, increasing from 40% up to 80%. From this, a pure amino alcohol 13 (654 mg, 60%) was obtained as a white amorphous solid. m.p. 128–129° C. (lit 135–136° C.). [α]D25=−128.17° (c, 4.26 in CHCl3) (lit: −124.1° (c, 1.23 in CHCl3)). δH 0.72 (3H, t, J=7.2 Hz, CH3), 0.94 (3H, d, J=6.9 Hz, CH3), 0.80–1.10 (1H, m, CH2), 1.40–1.60 (1H, m, CH), 1.76–1.94 (1H, m, CH2), 0.60–2.10 (3H, OH and NH2), 3.85 (1H, d, J=1.5 Hz, CH—NH2), 7.10–7.70 (10H, m, Ar—H). δC 12.1 (CH3—CH2), 18.7 (CH3—CH), 22.5 (CH2), 34.8 (CH—Me), 60.9 (CH—NH2), 79.6 (C), 125.5, 125.9, 126.1, 126.5, 127.8, 128.2, 144.9, 147.9 (Ar). νmax (cm−1): 3343, 3279 (N—H and O—H), 3085, 3023 (Ar C—H), 2959, 2926, 2873 (methyl and methylene C—H), 1589, 1491, 1447 (Ar C═C). m/e 270 (MH+, 4%), 252 (20%), 86 (100%).
Reaction SMILES: [C:1]1([C@@H:7]([CH3:13])[CH2:8][NH:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:15]([CH:19]([CH3:21])[CH3:20])[C:16](O)=[O:17]>>[CH:19]([C@@H:15]1[S:11][C:10]([NH:9][CH2:8][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:13])=[N:12][C:16]1=[O:17])([CH3:21])[CH3:20]
Reactant: C[C@@H](CNC(N)=S)c1ccccc1
Reactant: CC(C)C(Br)C(=O)O
Product: CC(C)[C@@H]1SC(NC[C@H](C)c2ccccc2)=NC1=O

Procedure:
Synthesis was performed from N-[(2R)-2-phenylpropyl]thiourea and 2-bromo-3-methylbutyric acid according to Method D3.
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][P:6]([OH:8])[OH:7].[OH-].[Na+].[O-:12][Mn](=O)(=O)=O.[K+].P(O)O.Cl.S(=O)(O)[O-].[Na+]>CC(C)=O.O>[CH3:1][CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][P:6](=[O:12])([OH:8])[OH:7]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)CCCP(O)O
Agent: Cl
Agent: O=S([O-])O
Agent: OPO
Solvent: CC(C)=O
Solvent: O
Product: CC(C)CCCP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-methylpentyl phosphonous acid (0.64 g, 4.2 mmole) in acetone (10 ml) and water (10 ml) was added a solution of sodium hydroxide (0.208 g, 0.005 mole) in water (10 ml) until a pH of about 7 was reached. A solution of KMnO4 (0.399 g, 2.52 mmole) in water (10 ml) was added slowly to the vigorously stirred solution of phosphonous acid at 20°-25° C. After the addition (5 minutes), the reaction mixture was stirred for 5 minutes at ambient temperature and acidified with concentrated HCl acid until a pH of 1 was reached. Saturated sodium bisulfite solution was added to the reaction mixture thereby resulting in formation of a precipitate.
Reaction SMILES: N1([C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[O:7])C=CN=C1.CI.[CH:25]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26]1>C(#N)C.C(Cl)Cl>[CH:25]1([N:29]2[CH2:34][CH2:33][N:32]([C:6]([N:8]3[CH2:13][CH2:12][N:11]([C:14]4[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=4)[CH2:10][CH2:9]3)=[O:7])[CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26]1
Reactant: C1CC(N2CCNCC2)C1
Reactant: CC(=O)c1ccc(N2CCN(C(=O)n3ccnc3)CC2)cc1
Solvent: CC#N
Solvent: ClCCl
Solvent: CI
Product: CC(=O)c1ccc(N2CCN(C(=O)N3CCN(C4CCC4)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1-{4-[4-(imidazole-1-carbonyl)-piperazin-1-yl]-phenyl}-ethanone (8 mmol) in acetonitrile (15 mL) is added MeI (32 mmol). The mixture is stirred at rt for 24 h. Solvent is removed in vacuo to yield a light yellow solid. The solid is dissolved in DCM (40 mL), followed by the addition of 1-cyclobutylpiperazine (8 mmol) and TEA (8 mmol). The mixture is stirred at rt for 24 h, washed with aqueous sodium bicarbonate (20 mL). The organic layer is dried over MgSO4 and solvent removed to give the crude product, which is purified by column chromatography (5% MeOH in DCM) to give the pure title compound. 1H NMR (300 MHz, CDCl3) δ 7.87 (d, 2H), 6.86 (d, 2H), 3.49-3.33 (m, 12H), 2.76-2.71 (m, 1H), 2.53 (s, 3H), 2.32 (t, 4H), 2.05-2.01 (m, 2H), 1.91-1.85 (m, 2H), 1.76-1.69 (m, 2H); LC-MS (M+1) 371.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[N:34][CH:33]=2)[CH:27]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[N:34][CH:33]=2)[CH:27]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnnc2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnnc3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) and 3-oxo-3-(3-pyridazin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K9) according to the general procedure M. Obtained as a light yellow solid (184 mg).
Reaction SMILES: C([O:5][C:6](=[O:42])[CH:7]([NH:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:41])[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)=[O:19])[CH2:8][CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])(C)(C)C.C(O)(C(F)(F)F)=O>ClC(Cl)C>[C:35]1([CH2:34][C:33]([NH:32][C:29]2[CH:30]=[CH:31][C:26]([C:23]3[CH:24]=[CH:25][C:20]([C:18]([NH:17][C@H:7]([C:6]([OH:42])=[O:5])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:19])=[CH:21][CH:22]=3)=[CH:27][CH:28]=2)=[O:41])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)CCC(NC(=O)c1ccc(-c2ccc(NC(=O)Cc3ccccc3)cc2)cc1)C(=O)OC(C)(C)C
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC[C@H](NC(=O)c1ccc(-c2ccc(NC(=O)Cc3ccccc3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
2-[(4′-Phenylacetylamino-biphenyl-4-carbonyl)-amino]-pentanedioic acid di-tert-butyl ester (45 mg) was dissolved in dichloroethane (3 mL) and added to TFA (1 mL). The mixture was stirred at room temperature for 3 hrs. Reaction was complete as determined by TLC. Solvent was removed and the resulting solid was dried under vacuum overnight. N-({4′[(phenylacetyl)amino]-1,1′-biphenyl-4-yl}carbonyl)-L-glutamic acid was obtained in 84.2% yield (30.3 mg). MS (ESI) m/z 461.
Reaction SMILES: [CH3:1][N:2]([CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][O:33]1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[N:20]=[C:19]([CH2:21][CH2:22][CH:23]4[CH2:29][CH2:28][CH2:27][CH2:26][C:25](=O)[NH:24]4)[NH:18][C:15]3=[N:16][CH:17]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:46])=CC=1>>[CH3:1][N:2]([CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][O:33]1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[N:20]=[C:19]([CH2:21][CH2:22][CH:23]4[CH2:29][CH2:28][CH2:27][CH2:26][C:25](=[S:46])[NH:24]4)[NH:18][C:15]3=[N:16][CH:17]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: CN(CC1CCCO1)S(=O)(=O)c1ccc(-c2cnc3[nH]c(CCC4CCCCC(=O)N4)nc3c2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CN(CC1CCCO1)S(=O)(=O)c1ccc(-c2cnc3[nH]c(CCC4CCCCC(=S)N4)nc3c2)cc1
Yield: 95.4 %

Procedure:
The title compound is synthesized as described for 7-[2-(6-{4-cyano-phen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-thione (compound A2) from 125 mg of N-methyl-4-{2-[2-(7-oxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-N-(tetrahydro-furan-2-ylmethyl)-benzenesulfonamide (compound B10) and 104 mg of Lawesson's reagent. Purification by chromatography on flash silica gel (eluent gradient: dichloromethane/0-10 vol. % ethanol) affords 123 mg of the title compound as a waxy solid. ESI-MS: 528.9 (MH+). TLC: Rf=0.43 (dichloromethane/ethanol 10:1 parts by volume).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)C1C=CC=CC=1>O.[Pd].CO>[C:17]1([CH2:16][C:10]2([CH2:13][CH2:14][OH:15])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OCCC1(Cc2ccccc2)CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: OCCC1(Cc2ccccc2)CCNC1
Reaction time: 24 h

Procedure:
Combine 1-benzyl-3-(phenylmethyl)-3-(2-hydroxyethyl)pyrrolidine (0.72 g, 2.45 mmol) and methanol (20 mL). Add 20% palladium hydroxide-on-carbon (0.231 g). Hydrogenate in a Parr apparatus at an initial pressure of 50 psi. After 24 hours, filter through celite, rinse with methanol. Evaporate the filtrate in vacuo to give the title compound: Rf=0.01 (silica gel, 2% triethylamine/methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])C(=O)C(F)(F)F)[CH:5]=[CH:6][CH:7]=1.O1C(C2C=C(N[C:33]3[N:38]=[C:37]([C:39]4[C:40]([C:48]5[CH:49]=[C:50]([NH:54][C:55](=[O:62])[CH2:56][C:57]6[S:58][CH:59]=[CH:60][CH:61]=6)[CH:51]=[CH:52][CH:53]=5)=[N:41][N:42]5[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=45)[CH:36]=[CH:35][N:34]=3)C=CC=2)=CN=C1>CC(O)C.Cl.C(Cl)Cl>[CH3:20][N:18]([CH3:19])[CH2:17][CH2:16][NH:9][CH2:8][C:4]1[CH:3]=[C:2]([NH:1][C:33]2[N:38]=[C:37]([C:39]3[C:40]([C:48]4[CH:49]=[C:50]([NH:54][C:55](=[O:62])[CH2:56][C:57]5[S:58][CH:59]=[CH:60][CH:61]=5)[CH:51]=[CH:52][CH:53]=4)=[N:41][N:42]4[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=34)[CH:36]=[CH:35][N:34]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)CCN(Cc1cccc(N)c1)C(=O)C(F)(F)F
Reactant: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: CN(C)CCNCc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5cccs5)c4)nn4ccccc34)n2)c1
Temperature: 180 °C
Yield: 66 %

Procedure:
A suspension of N-[(3-aminophenyl)methyl]-N-[2-(dimethylamino)ethyl]-2,2,2-trifluoroacetamide (61 mg, 0.21 mmol) and N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(2-thienyl)acetamide (75 mg, 0.17 mmol) (see Example 2, Step B) in i-PrOH (3 mL) was acidified with 3 drops of 12 N HCl and heated in a microwave for 25 min. at 180° C. The reaction mixture was then diluted with DCM, washed with 2 N NaOH, dried over Na2SO4, and adsorbed onto silica gel. The crude product was purified by column chromatography to generate the title compound in 66% yield. 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J=6.8 Hz, 1H), 8.36 (d, J=8.8 Hz, 1H), 8.16 (d, J=5.1 Hz, 1H), 7.80 (d, J=7.2 Hz, 1H), 7.73 (s, 1H), 7.53-7.61 (m, 3H), 7.32-7.45 (m, 4H), 7.01 (s, 2H), 6.90 (t, J=6.6 Hz, 1H), 6.55 (d, J=5.1 Hz, 1H), 3.94 (s, 2H), 3.79 (s, 2H), 2.70 (t, J=5.8 Hz, 2H), 2.42 (t, J=5.9 Hz, 2H), 2.18 (s, 6H). ES-LC/MS m/z=603 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]4[CH:26]=[CH:27][N:28]=[C:24]4[CH:23]=[C:22]([C:29]4[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=4)[N:21]=3)=[CH:16]2)[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>C(Cl)Cl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[CH3:34][N:32]1[CH:33]=[C:29]([C:22]2[N:21]=[C:20]([C:17]3[CH:18]=[CH:19][N:15]([C:4]4([CH2:3][C:1]#[N:2])[CH2:7][NH:6][CH2:5]4)[CH:16]=3)[N:25]3[CH:26]=[CH:27][N:28]=[C:24]3[CH:23]=2)[CH:30]=[N:31]1
Reactant: Cn1cc(-c2cc3nccn3c(-c3ccn(C4(CC#N)CN(C(=O)OC(C)(C)C)C4)c3)n2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2cc3nccn3c(-c3ccn(C4(CC#N)CNC4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 3-(cyanomethyl)-3-(3-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrrol-1-yl)azetidine-1-carboxylate (Preparation O, 79.0 mg, 0.172 mmol) in dry DCM (1.5 mL) was added trifluoroacetic acid (2 mL) and the mixture stirred at ambient temperature for 3 hours. The mixture was concentrated and the residual gel was treated with EtOAc and sonicated until a white suspension. The EtOAc was decanted, the residual solid was washed with EtOAc and dried in vacuum to afford the title compound (trifluoroacetate salt, 100 mg, 99% yield) as an ivory white solid. MS (apci) m/z=359.2.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[O:16][CH3:17])=[O:8])=[C:5]([NH2:18])[NH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:25](OC)(=[O:28])[C:26]#[CH:27]>CCO>[NH2:18][C:5]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[O:16][CH3:17])=[O:8])=[C:2]2[NH:1][C:25](=[O:28])[CH:26]=[CH:27][N:3]2[N:4]=1
Reactant: C#CC(=O)OC
Reactant: COc1ccncc1NC(=O)c1c(N)n[nH]c1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: COc1ccncc1NC(=O)c1c(N)nn2ccc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 27 %

Procedure:
To a mixture of 3,5-diamino-N-(4-methoxy-3-pyridyl)-1H-pyrazole-4-carboxamide 9 (300 mg, 1.209 mmol) and Cs2CO3 (591 mg, 1.814 mmol) in EtOH (5 mL) was added methyl prop-2-ynoate (203.3 mg, 215.1 μL, 2.418 mmol), dropwise, over 15 minutes and the reaction mixture was stirred overnight at room temperature. The mixture was filtered and product purified by preparative HPLC. Solvents were evaporated in vacuum to afford the product as a yellow solid (yield 27%). LC-MS (M+H)+=301.1; 1H NMR (500 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.58 (s, 1H), 8.71 (d, 1H), 8.58 (d, 1H), 7.68 (d, 1H), 6.45 (d, 1H), 6.38-6.28 (m, 2H), 4.25 (s, 3H);
Reaction SMILES: C[C@H](CCCC(C)C)C[CH2:4][CH2:5][C@H:6]([CH2:8][CH2:9][CH2:10][C:11]([CH3:13])=[O:12])C.[O-]Cl.[Na+].CC(O)CCCCCC>C(O)(=O)C>[CH3:13][C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:6][CH2:5][CH3:4]
Reactant: CC(=O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCCCCCC(C)O
Solvent: CC(=O)O
Product: CCCCCCC(C)=O
Yield: 95 %

Procedure:
Subsequent hydrogenation (H2 /Pd-C) yields the same saturated C-18 alcohol: ##STR22## Other methods used to oxidize 2° alcohol 9 to "phytone" include: (a) aqueous NaOCl (bleach) in acetic acid; such conditions give >95% yield of 2-octanone from 2-octanol. See: J. Org. Chem., 45, 2030 (1980).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([OH:8])=O)[CH3:2].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:42][C:43]1[CH:55]=[CH:54][C:53]([F:56])=[CH:52][C:44]=1[O:45][CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([N:49]1[CH2:48][CH2:47][CH:46]([O:45][C:44]2[CH:52]=[C:53]([F:56])[CH:54]=[CH:55][C:43]=2[Cl:42])[CH2:51][CH2:50]1)=[O:8])[CH3:2]
Reactant: CCOC(=O)CC(=O)O
Reactant: Fc1ccc(Cl)c(OC2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)N1CCC(Oc2cc(F)ccc2Cl)CC1
Reaction time: 8 h
Yield: 69.4 %

Procedure:
To a stirred solution of malonic acid monoethyl ester (0.5 g, 0.00377 mole) in DMF (10 mL) was added DIPEA (1.18 g, 0.0094 mole), HOBt (0.608 g, 0.0045 mole) and EDCI.HCl (0.865 g, 0.0045 mole). After 2 minutes 4-(2-chloro-5-fluoro-phenoxy)-piperidine hydrochloride (1 g, 0.003 7 mole) and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The organic layers were dried over sodium sulfate and concentrated under reduced pressure to get afford 0.9 g (70%) of 3-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid ethyl ester. LC-MS purity: 344.78 (M+1)+, 82.56%. To a stirred solution of 3-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid ethyl ester (0.9 g, 0.0026 mole) in a mixture of THF (10 mL), methanol (3 mL) and H2O (2 mL) was added LiOH.H2O (0.218 g, 0.0052 mole) at ambient temperature and the resulting mixture was stirred for 30 minutes. Volatiles were then evaporated and the resulting residue was diluted with water, acidified with 10% aqueous HCl solution. The product was extracted with ethyl acetate, and the organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 0.6 g (73%) of 3-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid. LC-MS purity: 316.72 (M+1)+, 75.8%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])([OH:13])[CH2:9]1)[C:2]1C=CC=C[CH:3]=1.ICCC.N1CCOCC1>CN(C)C=O>[F:21][C:15]1[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=1[C:10]1([OH:13])[CH2:11][CH2:12][N:8]([CH2:1][CH2:2][CH3:3])[CH2:9]1
Reactant: OC1(c2cccc(F)c2F)CCN(Cc2ccccc2)C1
Solvent: C1COCCN1
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCN1CCC(O)(c2cccc(F)c2F)C1

Procedure:
Preparation according to Example 34: (−)-1-benzyl-3-(2,3-difluorophenyl)pyrrolidin-3-ol (0.40 g, 1.38 mmol), dimethyl formamide (3 mL), iodopropane (1.35 mL, 13.8 mmol) and morpholine (2 mL). Purification by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 40:60 to 60:40). Yield: 0.174 g. [α]D=−22.1° (methanol). The amine was converted to the fumaric acid salt and recrystallized from methanol/diethyl ether/diisopropyl ether: M.p. 97-100° C.; MS m/z (relative intensity, 70 eV) 241 (M+, 10), 212, (bp), 182 (34), 84 (53), 57 (14).
Reaction SMILES: [OH:1][CH:2]([CH:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)[C:3]([F:6])([F:5])[F:4].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[OH:1][CH:2]([CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]1)[C:3]([F:5])([F:6])[F:4]
Reactant: OC1CCC(C(O)C(F)(F)F)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C1CCC(C(O)C(F)(F)F)CC1

Procedure:
At room temperature, 56.2 g (284 mmol) of 4-(1-hydroxy-2,2,2-trifluoroethyl)cyclohexanol and 91.7 g of pyridinium chlorochromate were stirred in 1 l of dichloromethane for 8 hours. The solvent was removed under reduced pressure and the residue was purified by filtration through silica gel (heptane/ethyl acetate 1:1), to give the title product as a colourless oil.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.C([O-])([O-])=O.[K+].[K+].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)#[N:13]>CC#N>[O:5]1[CH2:4][CH:3]1[CH2:1][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]#[N:13])=[CH:15][CH:16]=1
Reactant: ClCC1CO1
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(OCC2CO2)cc1
Yield: 75 %

Procedure:
Epichlorohydrin (800 mL) and K2CO3 (414 g) were added to a stirred solution of p-cyanophenol (238 g) in 2.0 L MeCN and the reaction mixture was refluxed under inert atmosphere for 2 h. The hot solution was filtered and the filtrate concentrated giving a clear oil which was crystallized from di-iso-propyl ether giving the product in 75% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:18][C:16]=3[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])([O-])=O>O1CCOCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:18][C:16]=3[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12]
Reactant: CCOc1ccc(-c2nc3cc(-c4ccccc4)ccc3o2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1COCCO1
Product: CCOc1ccc(-c2nc3cc(-c4ccccc4)ccc3o2)cc1N
Yield: 51.5 %

Procedure:
Prepared by the method of Example 15e), from palladium (10 mol %) on carbon (10 mg, 0.1 mmol) and 2-(3-nitro-4-ethoxyphenyl)-5-phenylbenzoxazole (100 mg, 0.3 mmol) in dioxane (1 ml) which gave the crude subtitle compound (51 mg, 56%) as a white solid which was sufficiently pure (by TLC and 1H NMR spectroscopy) to be used in the next step, RF(2:1 Petrol-EtOAc) 0.50; 1H NMR (CDCl3) δ 7.92(1H, d, J=1.0, Ar), 7.68–7.60(4H, m, Ar), 7.57–7.51(2H, m, Ar), 7.47(2H, brt, J=7.0 Hz, Ar), 7.36(1H, tt, J=1.0, 6.5 Hz, Ar), 6.89(1H, d, J=8.5 Hz, Ar), 4.16(2H, q, J=7.0 Hz, CH2), 3.98(2H, brs, NH2), 1.49(1H, t, J=2.5 Hz, CH3).
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]N)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].C(O)(=[O:17])C.N([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH2:1]([O:5][CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:17])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCc1ccc(CN)cc1
Reactant: CC(=O)O
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCCOCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 78 %

Procedure:
To a mixture of 4-butoxymethyl-benzylamine (250 mg, 1.3 mmol) described in Manufacturing Example 33-1-2, acetic acid (2 mL) and water (2 mL) was added sodium nitrite (1.1 g, 16 mmol) at 0° C., which was stirred for 40 minutes at room temperature. The reaction mixture was partitioned into ethyl acetate and water. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. Methanol (2 mL) and potassium carbonate (360 mg, 2.6 mmol) were added to the residue, and the reaction mixture was stirred for 1.5 hours at room temperature. The reaction mixture was concentrated under a reduced pressure. The residue was purified by neutral silica gel column chromatography (ethyl acetate:heptane=1:1) to obtain the title compound (200 mg, 78%).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][C:6](=[O:8])[O:5][C:3]1=O.[NH2:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18]C)=[O:16])=[CH:13][CH:12]=1.CC1(C)CC(=O)OC(=O)C1>>[CH3:9][C:2]1([CH3:1])[CH2:7][C:6](=[O:8])[N:10]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:20][CH:21]=2)[C:3]1=[O:5]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CC1(C)CC(=O)OC(=O)C1
Product: COC(=O)c1ccc(N2C(=O)CC(C)(C)C2=O)cc1

Procedure:
The desired product was prepared by substituting methyl 4-aminobenzoate and 2,2-dimethylsuccinic anhydride for ethyl 4-aminobenzoate and 3,3-dimethylglutaric anhydride, respectively, in Example 119A. MS (DCI) m/e 262 (M+H)+.