Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.[NH2:27][CH:28]([CH3:31])[CH2:29][OH:30].Cl>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:27][CH:28]([CH3:31])[CH2:29][OH:30])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1
Reactant: CC(N)CO
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Agent: Cl
Solvent: c1ccncc1
Product: CC(CO)Nc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1Cl
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 73.1 %

Procedure:
1-(5-Amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (200 mg) and 2-amino-1-propanol (200 mg) were added to pyridine (700 mg), and the mixture was stirred at 50° C. for 1.5 hours. Concentrated hydrochloric acid (200 mg) was added to the reaction mixture, and the resultant mixture was concentrated under reduced pressure. Ethanol (3 ml) was added to the residue, and deposits were collected by filtration and washed with ethanol and disopropyl ether in that order to obtain the title compound (167 mg) as a yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([CH3:27])[C:24]=1[O:25]C)[C:5]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:6].Cl.N1C=CC=CC=1>>[CH3:27][C:23]1[CH:22]=[C:4]([CH:3]=[C:2]([CH3:1])[C:24]=1[OH:25])[C:5]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:6]
Reactant: COc1c(C)cc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc1C
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc(C)c1O
Temperature: 0 °C

Procedure:
3-(3,5-Dimethyl-4-methoxybenzoyl)-2-phenylbenzofuran (17.8 g., 0.05 mol.) is combined with 50 g. of freshly distilled pyridine hydrochloride and the mixture is refluxed 1 hour. The hot mixture is poured with stirring onto an ice-dilute hydrochloric acid mixture and the precipitate is collected to give 3-(3,5-dimethyl-4-hydroxybenzoyl)-2-phenylbenzofuran.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]([CH3:13])[C:7](=[O:14])[C:6]=2[CH:15]=1.[Cu][C:17]#[N:18]>N1C=CC=CC=1>[C:17]([C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]([CH3:13])[C:7](=[O:14])[C:6]=2[CH:15]=1)#[N:18]
Reactant: CN1CC(=O)Nc2ccc(Br)cc2C1=O
Reactant: N#C[Cu]
Solvent: c1ccncc1
Product: CN1CC(=O)Nc2ccc(C#N)cc2C1=O

Procedure:
15.0 g of 7-bromo-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione and 7.5 g of copper (I) cyanide (freshly prepared) are mixed well in a mortar and heated from 165° to 195° with 7.2 ml of dry pyridine (freshly distilled over potassium hydroxide) under argon over a period of 3 hours. After cooling to 150°, the solid mass is dissolved in about 250 ml of boiling dimethylformamide. The mixture is left to cool, poured into 800 ml of ice-water and extracted three times with 500 ml of chloroform each time. The organic extracts are washed with 250 ml of 2 N hydrochloric acid and three times with 500 ml of water each time, dried in the presence of active carbon and evaporated. The residue is dissolved in about 1 l of methanol. The solution is concentrated to a volume of 250 ml, treated with active carbon and cooled to 5°. The precipitated material is filtered off under suction and dried, there being obtained 7-cyano-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione as white crystals of melting point 256°-258°.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:15]2[C:20]([CH3:22])([CH3:21])[O:19][C:18]([NH:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:17][S:16]2(=[O:31])=[O:30])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[CH:24]1([NH:23][C:18]2[O:19][C:20]([CH3:22])([CH3:21])[CH:15]([C:11]3[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=3)[S:16](=[O:31])(=[O:30])[N:17]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CC1(C)OC(NC2CCCCC2)=NS(=O)(=O)C1c1cccc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: CC1(C)OC(NC2CCCCC2)=NS(=O)(=O)C1c1cccc(O)c1
Reaction time: 3.5 h
Yield: 24.1 %

Procedure:
Under inert gas, 548 mg of [5-(3-benzyloxyphenyl)-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-yl]cyclohexylamine were initially charged in 20 ml of methanol and, with addition of 263 mg of 10% Pd/C, stirred under a hydrogen atmosphere for 3.5 hours. The completeness of the conversion was checked by LCMS, and the reaction was once again admixed with 263 mg of 10% Pd/C and stirred under a hydrogen atmosphere for 2 days. After filtration to remove the solid residues, the filtrate was freed of the solvent under reduced pressure and dried under high vacuum. A portion (105 mg) of the residue thus obtained (468 mg) was purified in a purification laboratory by means of preparative HPLC, and the product-containing fractions were freed of the organic solvent under reduced pressure. The aqueous residue was lyophilized. This gave the product (66 mg) with a molecular weight of 352.4 g/mol (C17H24N2O4S); MS (ESI): m/e=353 (M+H+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:29][CH2:30][CH2:31][O:32][C:33]4[N:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=4)=[N:12][N:13]([CH3:28])[C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][N:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1.C[OH:41]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:29][CH2:30][CH2:31][O:32][C:33]4[N:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=4)=[N:12][N:13]([CH3:28])[C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH2:26][OH:41])=[CH:21][N:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CO
Reactant: CC(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCOc3ncc(Cl)cn3)nn2C)nc1
Product: CC(CO)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCOc3ncc(Cl)cn3)nn2C)nc1
Reaction time: 48 h

Procedure:
Streptomyces rimosus subsp. rimosus ATCC10970 maintained on a quarter strength ATCC172 agar slope was inoculated as a loopful of spores into a 300 ml Erlenmeyer flask containing 50 ml of AS-7H inoculum medium. This was allowed to incubate for 2 days at 28° C., 200 rpm on an Infors Multitron™ Shaker with 1″ throw. 2 mls of this inoculum medium was then transferred to each of twenty 300 ml Erlenmeyer flask containing 50 ml of AP-5H production medium and incubated under the same conditions for a further 24 hours. At this point 5 mg of N-(4-(1,3-benzodioxol-5-yl)-3-{-2-[(5-chloro-2-pyrimidinyl)oxy]ethoxy}-1-methyl-1H-pyrazol-5-yl)-5-isopropyl-2-pyridinesulfonamide (Preparation 12) dissolved in 0.5 ml of methanol was added to each of the flasks and the fermentation allowed to continue under the same conditions for a further 96 hours. Each flask was then extracted with 200 mls of ethyl acetate and the combined ethyl acetate solubles concentrated to dryness to give a gum solid.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][CH:7]1[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5].C(O[CH:19](N(C)C)[N:20]([CH3:22])[CH3:21])(C)(C)C>>[CH2:2]([O:3][C:4](=[O:5])[CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10]/[C:11](=[CH:19]\[N:20]([CH3:22])[CH3:21])/[C:12]1=[O:13])[CH3:1]
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CCOC(=O)CC1CCC/C(=C\N(C)C)C1=O

Procedure:
Ethyl 2-cyclohexanoneacetate (100 mg, 0.54 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (116 mg) as a brown oil which was used directly in the next step. MS ISP (m/e): 194.2 (100) [(M-EtOH+H)+], 240.2 (90) [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([O:20][CH2:21][CH2:22][C:23](O)=[O:24])[C:17]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[C:16]([NH:35][S:36]([C:39]3[CH:44]=[CH:43][C:42]([C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:41][CH:40]=3)(=[O:38])=[O:37])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:49]([C:52]1[CH:58]=[CH:57][CH:56]=[CH:55][C:53]=1[NH2:54])([CH3:51])[CH3:50]>>[CH:49]([C:52]1[CH:58]=[CH:57][CH:56]=[CH:55][C:53]=1[NH:54][C:23](=[O:24])[CH2:22][CH2:21][O:20][C:18]1[C:17]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])=[C:16]([NH:35][S:36]([C:39]2[CH:40]=[CH:41][C:42]([C:45]([CH3:48])([CH3:46])[CH3:47])=[CH:43][CH:44]=2)(=[O:37])=[O:38])[N:15]=[C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13][CH2:12]2)[N:19]=1)([CH3:51])[CH3:50]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1OCCC(=O)O
Reactant: CC(C)c1ccccc1N
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1OCCC(=O)Nc1ccccc1C(C)C

Procedure:
The procedure described in Example 2 was repeated by use of 3-[2-(4-t-butoxycarbonylpiperazinyl)-6-(4-t-butyl-phenylsulfonylamino)-5-(2-methoxyphenoxy)-4-pyrimidinyloxy]-propionic acid and 2-isopropylaniline, to thereby obtain the title compound as a pale yellow oil.
Reaction SMILES: C(O)CCC.[CH2:6]([N:8]([CH2:18][CH3:19])[C:9]1[CH:10]=[C:11]([OH:17])[C:12](=[CH:15][CH:16]=1)[CH:13]=O)[CH3:7].[N+:20]([CH2:23][C:24](OCC)=[O:25])([O-:22])=[O:21].N1CCCCC1>C(O)(=O)C>[N+:20]([C:23]1[C:24](=[O:25])[O:17][C:11]2[C:12]([CH:13]=1)=[CH:15][CH:16]=[C:9]([N:8]([CH2:18][CH3:19])[CH2:6][CH3:7])[CH:10]=2)([O-:22])=[O:21]
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Solvent: CCCCO
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCN(CC)c1ccc2cc([N+](=O)[O-])c(=O)oc2c1
Temperature: 25 °C

Procedure:
A mixture containing n-butanol (20 mL), 4-diethylamino salicylaldehyde (1.4 g, 7.2 mmol), ethyl nitroacetate (0.8 mL, 7.2 mmol), molecular sieves 4 Å (100 mg), piperidine (0.1 mL) and acetic acid (0.2 mL) was refluxed for a period of 24 h. Upon cooling to room temperature, a bright yellow solid formed, which was collected and dissolved in DMF (15 mL) at 80° C. It was filtered again to remove the molecular sieves. The filtrate, upon addition to 100 ml of ice-cold water, yielded 3-nitro-7-diethylamino coumarin as a bright yellow solid: 1.40 g, 73%. A small amount of this compound was recrystallized from DMF to give an analytical sample; mp 193-195° C. 1H-NMR (CDCl3, 300 MHz) δ 1.27 (t, J=7.14 Hz, 6H), 3.48 (q, J=7.86 Hz, 4H), 6.50 (s, 1H), 6.70 (d, J=6.71 Hz, 1H), 7.42 (d, J=7.42 Hz, 2H), 8.72 (s, 1H). HRMS m/e calculated for MH+ C13H14N2O4 263.1041; found 263.1032.
Reaction SMILES: [ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:29]1([CH:35]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:36][CH2:37]Br)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:37][CH2:36][CH:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Reactant: BrCCC(c1ccccc1)c1ccccc1
Agent: Cl
Product: O=C1N(CCC(c2ccccc2)c2ccccc2)CN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2

Procedure:
The title compound, white solid, m.p. 219° C. and MS: m/e=564.5 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and 3,3-diphenyl-1-propylbromide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[O:12]1[CH2:17][CH2:16][CH:15](/[CH:18]=[CH:19]/[C:20](O)=[O:21])[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:20](=[O:21])/[CH:19]=[CH:18]/[CH:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: O=C(O)/C=C/C1CCOCC1
Product: O=C(/C=C/C1CCOCC1)Nc1ccc(Br)cc1[N+](=O)[O-]

Procedure:
Following the procedure as described in Example 3, STEP B, the title compound was prepared from 4-bromo-2-nitro-phenylamine (2.06 g, 9.47 mmol) and (E)-3-(tetrahydro-pyran-4-yl)-acrylic acid (prepared as described in PCT Publication WO 2005/101989 (A2,A3), 1.14 g, 7.29 mmol) and was obtained as a yellow solid.
Reaction SMILES: C(N1CC[CH2:6][CH:5](CCN2C(OC)=NC3C2=NC(O[C@@H](C)CCC)=NC=3N)[CH2:4]1)C.[CH2:29]([O:33][C:34]1[N:42]=[C:41]2[C:37]([N:38]=[C:39]([O:55][CH3:56])[N:40]2[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)=[C:36]([NH2:57])[N:35]=1)[CH2:30][CH2:31][CH3:32].ICC>>[CH2:29]([O:33][C:34]1[N:42]=[C:41]2[C:37]([N:38]=[C:39]([O:55][CH3:56])[N:40]2[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH:49]2[CH2:50][CH2:51][N:52]([CH:5]([CH3:6])[CH3:4])[CH2:53][CH2:54]2)=[C:36]([NH2:57])[N:35]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCCC3CCNCC3)c2n1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(CC)C3)c2n1
Solvent: CCI
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCCC3CCN(C(C)C)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 46 from 2-(butyloxy)-8-(methyloxy)-9-[6-(4-piperidinyl)hexyl]-9H-purin-6-amine and 2-iodoethane.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH:10]1([NH2:13])[CH2:12][CH2:11]1>C(#N)C>[CH:10]1([NH:13][C:2]2[N:3]=[C:4]([NH:13][CH:10]3[CH2:12][CH2:11]3)[CH:5]=[C:6]([Cl:8])[N:7]=2)[CH2:12][CH2:11]1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: NC1CC1
Solvent: CC#N
Product: Clc1cc(NC2CC2)nc(NC2CC2)n1
Reaction time: 0.5 h

Procedure:
A solution of 151.5 g (1 mol) of 2,4,6-trichloropyrimidine in 300 ml of acetonitrile is taken and 285 g (5 mols) of cyclopropylamine are added dropwise at 20°-30°, whilst cooling. The solution is warmed to 40° for 5 hours and to 70° for about 12 hours. The suspension is concentrated to dryness on a rotary evaporator and the residue is thoroughly stirred with 1,500 ml of methylene chloride and 1,000 ml of water for 30 minutes. The undissolved constituent is filtered off on a cloth filter. It consists of practically pure 4,6-di-cyclopropylamino-2-chloropyrimidine. The phases of the filtrate are separated and the organic phase is again extracted with water, dried and concentrated to give an oil. This is distilled under a high vacuum (boiling point 149°-51°/0.1 mm) and is then recrystallised from methanol, with addition of water. The colourless product has a melting point of 58°-60°.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:12]=[C:13]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16]2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].CO.[Li+].[OH-].Cl>C1COCC1>[N:15]1([C:13]2[CH:14]=[C:9]([CH:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:34])=[O:2])[CH:10]=[C:11]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:26][CH:25]=3)[CH:12]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: COC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(N2CCc3ccccc32)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(N2CCc3ccccc32)c1
Yield: 8 %

Procedure:
A solution of 2-[5-(2,3-dihydro-indol-1-yl)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid methyl ester, MeOH (1 mL), THF (1 mL) and 10% aq. LiOH solution (0.5 mL) was stirred at 40° C. overnight. The solution was then acidified with aq. 2M HCl and extracted with DCM (3×1 mL). The organic layers were filtered through PTFE filter and concentrated to yield an oil. The residue was purified using reverse phase preparative HPLC (H2O: MeCN) to give the title product in 8% yield as a yellow oil.
Reaction SMILES: P(=O)(O)(O)O.[N+]([O-])(O)=O.[C:10]([C:14]1[N:15]=[C:16](N)[S:17][CH:18]=1)([CH3:13])([CH3:12])[CH3:11].N([O-])=O.[Na+].[Na+].[Br-:25].[OH-].[K+]>O>[Br:25][C:16]1[S:17][CH:18]=[C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:15]=1
Reactant: CC(C)(C)c1csc(N)n1
Reactant: [Br-]
Agent: O=N[O-]
Agent: O=P(O)(O)O
Agent: [K+]
Solvent: O
Solvent: O=[N+]([O-])O
Product: CC(C)(C)c1csc(Br)n1
Temperature: 0 °C
Yield: 69 %

Procedure:
85% strength phosphoric acid (50 ml) and 65% strength nitric acid (20 ml) were combined at 0° C. 3.12 g (20.0 mmol) of 4-tert-butylthiazol-2-ylamine were added to this solution and a solution of 1.38 g (20 mmol) of NaNO2 in water (10 ml) was subsequently added dropwise at 0° C. in the course of 30 min. The reaction solution was stirred at 0° C. 1 h and then added dropwise to a suspension of 20.0 g of NaBr and 5.8 g of CuBr in water (20 ml) cooled to 0° C. The mixture was stirred until evolution of gas could no longer be observed. Subsequently, the mixture was adjusted to a pH>10 using 50% strength aq. KOH solution and the product was separated off by steam distillation. The distillate was extracted with EE. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. 3.03 g (13.8 mmol, 69%) of 2-bromo-4-tert-butylthiazole were obtained as a residue.
Reaction SMILES: Br[CH:2]1[CH:8]([Br:9])[CH2:7][CH:6]2[C@@H:3]1[CH2:4][C:5]2=[O:10].[C:11]([Si:15]([CH3:29])([CH3:28])[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH3:27])([CH3:14])([CH3:13])[CH3:12]>CC(C)=O>[Br:9][CH:8]1[CH2:7][C@H:6]2[C@H:3]([N:26]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][O:16][Si:15]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:29])[CH3:28])[CH3:27])[C@@H:2]1[CH2:4][C:5]2=[O:10]
Reactant: CNCCCCCCCCCO[Si](C)(C)C(C)(C)C
Reactant: O=C1C[C@H]2C1CC(Br)C2Br
Solvent: CC(C)=O
Product: CN(CCCCCCCCCO[Si](C)(C)C(C)(C)C)[C@H]1[C@@H]2CC(Br)[C@H]1CC2=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (1S)-2,3-dibromo-bicyclo[3.2.0]heptan-6-one (2.15 g, 8.02 mmol) in acetone (20 mL) was added [9-(tert-butyl-dimethyl-silanyloxy)-nonyl]-methyl-amine (5.77 g, 12.3 mmol) and the reaction mixture was stirred at RT for 3 days. After evaporation of the solvent the residue was taken up in diethyl ether/ethyl acetate and washed with a satd NaHCO3 (aq)/brine mixture. The aqueous layer was extracted with diethyl ether. The combined organic layers were dried (Na2SO4), filtered, and concentrated to dryness to afford a dark brown oil, which was purified by column chromatography over silica gel using a gradient of 5-15% diethyl ether/pentane as eluent. After evaporation of the volatiles the title compound was obtained as a light yellow/brown oil.
Reaction SMILES: [CH:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2/[C:17](=[N:19]/[OH:20])/[NH2:18])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:21]([O:28][C:29]([NH:31][C@@H:32]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:33](O)=[O:34])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[NH2:18]/[C:17](=[N:19]\[O:20][C:33](=[O:34])[C@@H:32]([NH:31][C:29](=[O:30])[O:28][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)/[C@@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][N:11]1[S:8]([CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)(=[O:9])=[O:10]
Reactant: O=C(N[C@H](C(=O)O)c1ccccc1)OCc1ccccc1
Reactant: N/C(=N\O)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1
Product: N/C(=N\OC(=O)[C@@H](NC(=O)OCc1ccccc1)c1ccccc1)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1

Procedure:
The title compound was prepared by a similar method to Preparation 5 from (Z)-(2S)-1-[cyclohexylmethylsulfonyl]-N′2-hydroxy-2-piperidinecarboximidamide [see Preparation 28] and (2S)-2-{[(benzyloxy)carbonyl]amino}-2-phenylethanoic acid to afford benzyl N-[(1S)-2-{[((Z)-amino{(2S)-1-[(cyclohexylmethyl)sulfonyl]piperidyl}methylidene)amino]oxy}-2-oxo-1-phenylethyl]carbamate as an oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:12]=[CH:11][CH:10]=2)O1.Br[C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]([N:31]2[CH2:36][CH2:35][C@:34]([CH2:43][C:44]([OH:47])([CH3:46])[CH3:45])([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[O:33][C:32]2=[O:48])[CH3:30])=[CH:25][CH:24]=1>>[OH:47][C:44]([CH3:45])([CH3:46])[CH2:43][C@@:34]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:33][C:32](=[O:48])[N:31]([C@H:29]([C:26]2[CH:25]=[CH:24][C:23]([C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([N:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)[N:14]=3)=[CH:28][CH:27]=2)[CH3:30])[CH2:36][CH2:35]1
Reactant: CC1(C)OB(c2cccc(N3CCOCC3)n2)OC1(C)C
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cccc(N3CCOCC3)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 4-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]morpholine (purchased from CombiPhos Catalysts Inc., Princeton, N.J., USA) and (S)-3-[(S)-1-(4-bromophenyl)ethyl]-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-1,3-oxazinan-2-one following a procedure analogous to that described in Example 35. LC (method 5): tR=1.68 min; Mass spectrum (ESI+): m/z=516 [M+H]+; 1H NMR (CD3OD) δ 0.95 (s, 3H), 1.24 (s, 3H), 1.58 (d, 3H), 2.17 (s, 2H), 2.25 (m, 1H), 2.47 (m, 2H), 3.08 (m, 1H), 3.66 (m, 4H), 3.83 (m, 4H), 5.58 (q, 1H), 7.12 (4H), 7.25-7.40 (5H), 7.63 (d, 2H), 7.88 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11]([C:13]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:14]=2[O:15][CH2:16][C@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2C(OC(C)(C)C)=O)=[O:12])/[N:7]([CH2:37][C@H:38]2[CH2:42][CH2:41][CH2:40][O:39]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:12])[C:13]2[CH:32]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:30]=[CH:29][C:14]=2[O:15][CH2:16][C@H:17]2[CH2:21][CH2:20][CH2:19][NH:18]2)/[N:7]([CH2:37][C@H:38]2[CH2:42][CH2:41][CH2:40][O:39]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(C(F)(F)F)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCCO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2OC[C@H]2CCCN2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of Example 25A (440 mg, 0.72 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.5 mL) and stirred at room temperature for 2 hours. The reaction was concentrated, taken up in dichloromethane and washed with saturated sodium bicarbonate solution. The aqueous layer was washed with dichloromethane. The combined organic layers were dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 gm particle size) using a gradient of 10-100% acetonitrile (A) and 10 mM ammonium acetate in water (B), at a flow rate of 2.0 mL/min (0-0.1 min 10% A, 0.1-2.6 min 10-100% A, 2.6-2.9 min 100% A, 2.9-3.0 min 100-10% A. 0.5 min post-nm delay) to obtain the title compound (350 mg , 95%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.33 (s, 9 H) 1.39-1.53 (m, 1 H) 1.57-1.69 (m, 1 H) 1.76-1.95 (m, 5 H) 2.40-2.46 (m, 1 H) 2.63-2.74 (m, 2 H) 2.80-2.89 (m, 2 H) 3.58-3.69 (m, 1 H) 3.75-3.82 (m, 1 H) 3.95-4.09 (m, 2 H) 4.18-4.31 (m, 3 H) 7.24-7.29 (m, 2 H) 7.74 (dd, J=8.92, 2.58 Hz, 1 H) 7.99 (d, J=2.38 Hz, 1 H); MS (DCI/NH3) m/z 512 (M+H)+.