Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:20][C:19](=[O:21])[NH:18][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1.[NH2:22][C@H:23]([CH3:26])[CH2:24][OH:25]>CN1C(=O)CCC1>[F:17][C:11]1[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][S:8][C:6]1[N:7]=[C:2]([NH:22][C@H:23]([CH3:26])[CH2:24][OH:25])[C:3]2[CH2:20][C:19](=[O:21])[NH:18][C:4]=2[N:5]=1
Reactant: C[C@@H](N)CO
Reactant: O=C1Cc2c(Cl)nc(SCc3cccc(F)c3F)nc2N1
Solvent: CN1CCCC1=O
Product: C[C@H](CO)Nc1nc(SCc2cccc(F)c2F)nc2c1CC(=O)N2
Temperature: 110 °C
Yield: 24.6 %

Procedure:
The product from example 1, step (e) (0.20 g) in NMP (5 ml) was treated with (R)-2-amino-1-propanol (0.56 g) and the reaction mixture was heated at 110° C. for 2 hours. The mixture was evaporated to dryness and the residue purified (HPLC, Symmetry® C18 column, 0.1% aqueous ammonium acetate:acetonitrile isocratic elution 75:25) to afford the title compound (0.055 g).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][C:12]1[CH:42]=[CH:41][C:15]([CH2:16][NH:17][C:18](=[O:40])[CH2:19][N:20]2[CH2:26][CH2:25][CH:24]([CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[C:23]3[CH:35]=[CH:36][CH:37]=[CH:38][C:22]=3[C:21]2=[O:39])=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[CH2:1]([NH:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][NH:17][C:18](=[O:40])[CH2:19][N:20]2[CH2:26][CH2:25][CH:24]([CH2:27][C:28]([OH:30])=[O:29])[C:23]3[CH:35]=[CH:36][CH:37]=[CH:38][C:22]=3[C:21]2=[O:39])=[CH:41][CH:42]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CC1CCN(CC(=O)NCc2ccc(NC(=O)NCc3ccccc3)cc2)C(=O)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC1CCN(CC(=O)NCc2ccc(NC(=O)NCc3ccccc3)cc2)C(=O)c2ccccc21
Temperature: 0 °C
Reaction time: 16 h

Procedure:
40 mg (0.07 mmol) of Example III are dissolved in 3 ml of trifluoroacetic acid and the mixture is stirred at 0° C. for 2 h and at room temp. for 16 h. It is concentrated, and the residue is codistilled repeatedly with CH2Cl2 and dried (31.8 mg). ESI-MS [M+H+]=515.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.Br[CH2:55][CH2:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[CH:57]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[CH2:56][CH3:55])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)OC)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester was reacted with 1-(bromo-propyl)-benzene and NaHCO3 in DMF according to General Procedure P to give (S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-propionic acid methyl ester. This product (12 mg), upon hydrolysis according to General Procedure B, gave the title compound (8 mg). LCMS (m/z): 854.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:13]4[S:18][C:17]([CH:19]=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(Cl)Cl.C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[C:13]4[S:18][C:17]([CH2:19][N:31]5[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]5)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CN1CCNCC1
Reactant: O=Cc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: CN1CCN(Cc2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.2 %

Procedure:
To a mixture of 2-(1H-Indazol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (91 mg, 0.26 mmol), 1-methylpiperazine (34 mg, 0.36 mmol) and acetic acid (15 uL) in 1,2-dichloroethane (2 mL) was added sodium triacetoxyborohydride (60 mg, 0.28 mmol). The reaction mixture was stirred at room temperature overnight and then basified (NaHCO3, saturated), diluted with DCM, and washed with brine. The organic layer was separated, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified using flash chromatography to give the title compound (33 mg).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([CH2:21][O:22][CH:23]([CH3:29])[C:24]([O:26]CC)=[O:25])[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+]>O1CCOCC1.O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([CH2:21][O:22][CH:23]([CH3:29])[C:24]([OH:26])=[O:25])[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(C)OCc1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(OCc1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1)C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
A solution of ethyl 2-[(5-{(1R)-4-cyclohexyl-1 -[2-(hydroxyamino)-2-oxoethyl]butyl}-1,2,4-oxadiazol-3-yl)methoxy]propanoate (Example 51) (184 mg, 0.45 mmol) in 1,4-dioxan (4 ml) and water (2 ml) was cooled to 0° C. and treated with lithium hydroxide monohydrate (2 mg, 0.48 mmol) and stirred at 0° C. for 2 hours. The solvent was partially removed under reduced pressure and diluted with water and washed with diethylether (×2). The aqueous layer was acidified to pH 1 with hydrochloric acid (2M) and washed with ethyl acetate (×2). The combined organic layers were washed with brine, dries over anhydrous sodium sulphate, filtered and the solvent was removed under reduced pressure to afford the title compound as a colourless oil (160 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([CH2:19][C:20]#[CH:21])([CH2:16][C:17]#[CH:18])[C:13](O)=[O:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:23][OH:24]>>[OH:24][NH:23][C:13](=[O:14])[C:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])([CH2:19][C:20]#[CH:21])[CH2:16][C:17]#[CH:18]
Reactant: C#CCC(CC#C)(C(=O)O)S(=O)(=O)c1ccc(OC)cc1
Reactant: NO
Agent: Cl
Product: C#CCC(CC#C)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1
Yield: 85 %

Procedure:
2-(4-Methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from (4-methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acid (0.25 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.22 g of the product was isolated. Yield 85%; white solid; mp 156° C.; MS: 321.9 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.00-2.13 (m, 2H), 3.00 -3.30 (m, 4H), 3.90(s, 3H), 7.01 (d, J=9.0 Hz, 2H), 7.82 (d, J=9.0 Hz, 2H), 8.76 (brs, 1H), 10.65 (brs, 1H); IR (KBr, cm-1): 3392 s, 3293 s, 3271 m, 2955 m, 1650 s, 1594 s; Anal. Calc'd for C15H15NO5S: C, 56.07; H, 4.70; N, 4.36. Found: C, 55.65; H, 4.67; N, 4.10.
Reaction SMILES: [OH-].[Na+].C([N+](CCCC)(CCCC)CCCC)CCC.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.[NH:31]1[C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([CH:40]=[O:41])[C:34]=2[CH:33]=[CH:32]1>C1C=CC=CC=1>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:31]2[C:39]3[CH:38]=[CH:37][CH:36]=[C:35]([CH:40]=[O:41])[C:34]=3[CH:33]=[CH:32]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)cccc32)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58.1 %

Procedure:
150 ml of 50% sodium hydroxide, 4.75 g of tetrabutylammonium hydrogenosulfate and 30.24 g of p-toluene sulfonyl chloride were added to a suspension of 20 g of indole 4carboxaldehyde in 600 m1 of benzene and the mixture was stirred or 90 minutes at ambient temperature. After decanting and extracting with benzene, the extracts were washed with water, dried and evaporated to dryness under reduced pressure. The 42.1 g of residue were dissolved in 210 ml of benzene at reflux, and the solution was allowed to cool to ambient temperature over 16 hours, then separated to obtain 23.96 g of the desired product melting at 144 to 146° C. The product was used as is for the following step.
Reaction SMILES: [Cl:1][C:2]1[S:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.C(N(CC)CC)C.[Cl:28][C:29]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>ClCCl>[Cl:28][C:29]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:30]=1[C:31]([NH:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]([N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[S:11][C:2]([Cl:1])=[CH:3][C:4]2=3)=[O:20])=[CH:18][CH:17]=1)=[O:32]
Reactant: Nc1ccc(C(=O)N2CCCCc3sc(Cl)cc32)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2CCCCc3sc(Cl)cc32)cc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To a cooled (ice bath) solution of 0.245 g (0.8 mmol) of 2-chloro-4-(4-aminobenzoyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine and 167 μl (1.2 mmol) of triethylamine in 5 ml of dichloromethane is added 140 μl (1 mmol) of 2,4-dichlorobenzoyl chloride. The solution is stirred under argon at room temperature overnight and diluted with 60 ml of dichloromethane. The mixture is washed with 20 ml each of 2N-citric acid, H2O, 1M NaHCO3, brine and dried (Na2SO4). The solvent is removed and the residue crystallized from ethyl acetate-hexane to give 0.315 g of white crystals, m.p. 187°-189° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]([O:38][CH3:39])([CH3:37])[CH2:25][C:26]1[C:27]([F:36])=[C:28]([OH:35])[CH:29]=[CH:30][C:31]=1[N+:32]([O-:34])=[O:33]>O1CCOCC1.CCOC(C)=O.O>[CH2:15]([O:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([O:35][C:28]3[CH:29]=[CH:30][C:31]([N+:32]([O-:34])=[O:33])=[C:26]([CH2:25][C:24]([O:23][CH3:22])([O:38][CH3:39])[CH3:37])[C:27]=3[F:36])=[CH:3][CH:4]=[N:5]2)=[CH:10][C:9]=1[O:12][CH3:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(C)(Cc1c([N+](=O)[O-])ccc(O)c1F)OC
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])c(CC(C)(OC)OC)c3F)ccnc2cc1OCc1ccccc1

Procedure:
4-Chloro-7-benzyloxy-6-methoxy-quinoline (WO2008112407, 1.5 g) was mixed with 3-(2,2-dimethoxypropyl)-2-fluoro-4-nitrophenol (WO0047212) (1.5 eq) in dioxane (30 ml). The reaction was refluxed for three days and diluted with EtOAc, water and extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column to give 7-(benzyloxy)-4-(3-(2,2-dimethoxypropyl)-2-fluoro-4-nitrophenoxy)-6-methoxyquinoline (650 mg). This product was mixed with 2NHCl (3 ml) and acetone (30 ml) and refluxed for 6 hours. The reaction was diluted with EtOAc and neutralized with saturated NaHCO3, further extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column to give 1-(3-(7-(benzyloxy)-6-methoxyquinolin-4-yloxy)-2-fluoro-6-nitrophenyl)propan-2-one (500 mg) which was mixed with iron (500 mg) and NH4Cl (50 mg) in EtOH/H2O (20 ml, 4/1). The reaction was refluxed for 4 hours, filter through Celite and evaporated. The residue was extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column to give 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-benzyloxyquinoline (250 mg).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH3:14])([CH3:13])[C:5]1=[O:15])(=O)C.Cl.C(OC)(C)(C)C>O>[CH3:13][C:6]1([CH3:14])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:5]1=[O:15]
Reactant: CC(=O)N1C(=O)C(C)(C)c2ccccc21
Agent: Cl
Solvent: COC(C)(C)C
Solvent: O
Product: CC1(C)C(=O)Nc2ccccc21

Procedure:
3.50 g (17.2 mmol) 1-acetyl-3,3-dimethyl-1,3-dihydro-indol-2-one were refluxed in 50 mL of a 6N hydrochloric acid solution for 1h. After cooling the reaction mixture was divided between tert-butylmethylether and water. The organic phase was washed with water, dried and evaporated down. The residue was crystallised from PE. The solid was suction filtered and dried at 80° C. in the CAD.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][C@@H:23]2[C@@H:28]3[CH2:29][C@@H:25]([CH:26]=[CH:27]3)[C@@H:24]2[C:30]([NH2:32])=[O:31])=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH2:33]1[O:36][C@@H:34]1[CH3:35].C(=O)([O-])[O-]>CO>[Cl:1][C:2]1[C:3]([NH:22][C@@H:23]2[C@@H:28]3[CH2:29][C@@H:25]([CH:26]=[CH:27]3)[C@@H:24]2[C:30]([NH2:32])=[O:31])=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][N:19]([CH2:33][C@H:34]([OH:36])[CH3:35])[CH2:18][CH2:17]4)[CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C[C@@H]1CO1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4cnn(C5CCNCC5)c4)nc23)[C@H]2C=C[C@@H]1C2
Agent: O=C([O-])[O-]
Solvent: CO
Product: C[C@@H](O)CN1CCC(n2cc(-c3nc4c(N[C@H]5[C@@H](C(N)=O)[C@@H]6C=C[C@H]5C6)c(Cl)cnc4[nH]3)cn2)CC1
Reaction time: 8 h

Procedure:
(1S,2S,3R,4R)-3-[6-Chloro-2-(1-piperidin-4-yl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine-7-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (Compound LVII above) (100 mg, 0.2 mmol) was combined with (R)-(−)-propylene oxide (25.6 mg, 0.442 mmol) and MP-Carbonate (140 mg, 0.442 mmol) in methanol (10 mL) and stirred in a sealed tube overnight. The product was filtered and the filtrate concentrated to afford a solid which was purified via reverse phase chromatography (Gilson) to afford following extractive neutralization of fractions and concentration the title compound as a white solid. 1H NMR (d-chloroform): 14.01 (br s, 1H), 7.92 (s, 1H), 7.83 (s, 1H), 7.69 (s, 1H), 7.13 (br s, 1H), 6.83 (s, 1H), 6.37 (1, 2H), 6.15 (d, J=9 Hz, 1H), 5.25 (t, J=9 Hz, 1H), 4.26 (m, 1H), 3.89 (m, 1H), 3.22 (d, J=10 Hz, 1H), 3.11 (s, 1H), 2.99 (d, J=10 Hz, 1H), 2.86 (s, 1H), 2.81 (m, 2H), 2.66-2.13 (m, 7H), 2.03 (m, 2H), 1.61 (d, J=10 Hz, 1H), 1.22 (d, J=7 Hz, 3H). MS: 510.9 (M+H). HPLC retention time: 1.59 minutes (G Method).
Reaction SMILES: CN1CCOCC1.Cl.[NH2:9][C@H:10]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15])[CH:11]([CH3:13])[CH3:12].C[Si](C)(C)Cl.[C:29](Cl)(=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1>C1COCC1>[CH3:37][O:36][C:33]1[CH:34]=[CH:35][C:30]([C:29]([NH:9][C@H:10]([C:14]([N:16]2[CH2:23][CH2:22][CH2:21][C@H:17]2[C:18]([OH:20])=[O:19])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:38])=[CH:31][CH:32]=1
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N[C@H](C(=O)N2CCC[C@H]2C(=O)O)C(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-methylmorpholine (46 ml) was added to a mixture of L-valyl-L-proline hydrochloride (34 g) in THF (850 ml), followed by trimethylchlorosilane (41 ml) maintaining the temperature below 30° C. The mixture was stirred for 2 hours and then cooled to 0° C. Further N-methylmorpholine (16.5 ml) was added, followed by a solution of 4-anisoyl chloride (18 ml) in THF (25 ml), maintaining the temperature below 5° C. After 15 minutes, the mixture was filtered and the filtrate concentrated in vacuo to a yellow oil. The oil was dissolved in ethyl acetate (100 ml) and basified to pH 7-8 with saturated potassium bicarbonate solution (100 ml). The aqueous layer was separated and washed with ethyl acetate (50 ml). The aqueous layer was then acidified to pH 2-3 with 2M hydrochloric acid solution and extracted with ethyl acetate (150 ml). The organic extract was concentrated under vacuum and toluene (150 ml) was added. The solution was again concentrated under vacuum until about 50 ml of toluene was collected. The solution was then added dropwise to hexane (400 ml) with stirring to give a white solid, which was filtered, washed with hexane and dried under vacuum to give N-(4-methoxybenzoyl)-L-valyl-L-proline (40 g), having a similar NMR to that given in Procedure 1, step (iii) above.
Reaction SMILES: C(OC([NH:8][N:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(C)(C)C.Cl.C(=O)(O)[O-].[Na+]>>[C:18]([N:9]([C:10](=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[NH2:8])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)NN(C(=O)c1ccccc1)C(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(C)N(N)C(=O)c1ccccc1
Yield: 86.7 %

Procedure:
The N-t-butoxycarbonyl-N'-t-butyl-N'-benzoylhydrazine (52 g, 0.18 mol) was stirred at room temperature in a methanolic hydrochloric acid solution for 4 days. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate. The white precipitate was filtered, washed with water and dried in vacuo to give 30 g of N'-t-butyl-N'-benzoylhydrazine: m.p. 124°-125° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([PH:8](=[O:12])OCC)[O:5][CH2:6][CH3:7])[CH3:2].[CH2:13]([Li])[CH2:14][CH2:15][CH3:16].Cl>CCCCCC>[CH2:13]([PH:8](=[O:12])[CH:4]([O:3][CH2:1][CH3:2])[O:5][CH2:6][CH3:7])[CH2:14][CH2:15][CH3:16]
Reactant: [Li]CCCC
Reactant: CCOC(OCC)[PH](=O)OCC
Agent: Cl
Solvent: CCCCCC
Product: CCCC[PH](=O)C(OCC)OCC

Procedure:
Following the procedure of Example 8, but using 1.96 g of ethyl diethoxymethylphosphinate and 12.5 ml of a 1.6 molar solution of n-butyl lithium in n-hexane and adding 20 ml of 0.1M hydrochloric acid prior to extraction, n-butyl(diethoxymethyl) phosphine oxide is obtained as a colourless oil.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@H:10]1[C:40]1[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=[C:42]([Br:48])[CH:41]=1)C1C=CC=CC=1.Cl.[H][H]>C1COCC1.CO.[Pd]>[Br:48][C:42]1[CH:41]=[C:40]([C@@H:10]2[O:11][C@H:12]([CH2:31][OH:32])[C@@H:13]([OH:23])[C@H:14]([OH:15])[C@H:9]2[OH:8])[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=1
Reactant: [H][H]
Reactant: COc1cc(Br)cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(Br)cc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1
Yield: 58.9 %

Procedure:
5% palladium/carbon (1.0 g) was added to a solution of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-(3-bromo-5-methoxyphenyl)-D-glucitol (10.0 g) in THF-methanol (ratio: 1:1, 100 ml). Two drops of a 1 M aqueous solution of hydrochloric acid was further added to the mixture, followed by stirring for 30 minutes in a hydrogen atmosphere. After filtrating the reaction mixture, the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain (1S)-1,5-anhydro-1-(3-bromo-5-methoxyphenyl)-D-glucitol (2.9 g).
Reaction SMILES: [OH:1][CH2:2][CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5].[C:17](Cl)(=[O:21])[CH:18]([CH3:20])[CH3:19]>>[C:17]([O:1][CH2:2][CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5])(=[O:21])[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Product: CC(C)=CCCC(C)=CCCC(C)=CCOC(=O)C(C)C
Yield: 7.7 %

Procedure:
A mixture of farnesol (356 mg, 1.6 mmol) and isobutyryl chloride (407 mg, 3.8 mmol) was refluxed for 2 hours. Extraction with hexane, and purification yielded 35.9 mg (yield: 7.8%) of oil having the following physical properties.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9](N(OC)C)=[O:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([Mg]Br)=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH4+].[Cl-]>C1COCC1>[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:9]([C:3]2[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][N:4]=2)=[O:10])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Br[Mg]c1ccc(OCc2ccccc2)cc1
Reactant: CON(C)C(=O)c1ncc(F)cc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(c1ccc(OCc2ccccc2)cc1)c1ncc(F)cc1F
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 3,5-difluoro-N-methoxy-N-methylpyridine-2-carboxamide (2.5 g) in THF (50 mL) was added [4-(benzyloxy)phenyl](bromo)magnesium (1 M solution in THF, 12.3 mL) at −78° C. The mixture was stirred at −78° C. for 3 h, treated with saturated NH4Cl aqueous solution and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane). The product was crystallized from AcOEt/hexane to give the title compound (2.3 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:18][CH2:19][CH2:20][CH2:21]Br>CN(C=O)C>[Br:18][CH2:19][CH2:20][CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(OCCCBr)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of N-(4-hydroxyphenyl)acetamide (10 g) and potassium carbonate (11 g) in DMF (200 ml) was stirred for 20 min at room temperature. 1,3-Dibromopropane (35 ml) was then added and stirring was continued for 4 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was treated with water and extracted with dichloromethane. The organic phase was washed first with dilute sodium hydroxide, then with water, dried and concentrated to give a solid which was triturated with hexane to give the title compound (14 g), MP: 120°.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:8]=1[C:9]([NH2:11])=[O:10])(=O)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>C(O)C>[Cl:16][C:13]1[CH:12]=[C:8]2[C:7](=[CH:15][CH:14]=1)[N:6]=[C:1]([CH2:2][CH2:3][CH3:4])[N:11]=[C:9]2[OH:10]
Reactant: CCCC(=O)Nc1ccc(Cl)cc1C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1nc(O)c2cc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
2-Butyrylamino-5-chloro-benzamide (1.08 g, 4.49 mmol, 1 eq.), 1.000 N NaOH (13.46 mL, 13.5 mmol, 3 eq.) and ethanol (10 mL) were mixed and stirred at rt for 15 minutes. The mixture was acidified to pH=2 with 1.000 N HCl. The mixture was extracted with ethyl acetate. Solids that did not dissolve were filtered and rinsed with diethyl ether to dry. Obtained 810 mg of a white solid product. LCMS detects (M+H)+=223.