Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C>C1COCC1>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH:27][S:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)(=[O:12])=[O:11])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.7 %

Procedure:
4-Nitrophenyl sulfonyl chloride (1.1 g, 5.4 mmol) was added in one portion to a stirred solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 4.9 mmol) and diisopropylethylamine in THF (10 ml). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour, after which time the solvent was removed under vacuum to give the title compound (1.92 g, 100% yield) as an orange solid which was used without further purification. Tr=2.00 min m/z (ES+) (M+Na+) 408.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][N:16]([CH2:17][C:18]4[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=4)[C:10]3=[N:9][C:8]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>CC(C)=O>[C:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][N:16]([CH2:17][C:18]4[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=4)[O:24][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:10]3=[N:9][C:8]=2[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc(CN2CCCc3nc(-c4ccccc4)c(-c4ccccc4)nc32)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cccc(CN2CCCc3nc(-c4ccccc4)c(-c4ccccc4)nc32)c1
Temperature: 25 °C

Procedure:
A mixture comprising 3-((2,3-diphenyl-7,8-dihydropyrido[3,2-b]pyrazin-5(6H)-yl)methyl)phenol (140 mg, 0.356 mmol), potassium carbonate (98 mg, 0.712 mmol) and ethyl 2-bromoacetate (119 mg, 0.712 mmol) in acetone (3 ml) was heated at reflux overnight. The suspension was cooled to room temperature and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with EtOAc/iso-hexane to afford the title compound.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:23]=[C:22]4[C:17]([CH2:18][CH2:19][CH:20]([C:24](O)=[O:25])[CH2:21]4)=[CH:16][CH:15]=3)[CH:10]=[CH:9][N:8]=2)=[O:5])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:60][C:61]1[CH:62]=[C:63]([CH:73]=[C:74]([C:76]([F:79])([F:78])[F:77])[CH:75]=1)[CH2:64][NH:65][C:66](=[O:72])[O:67][C:68]([CH3:71])([CH3:70])[CH3:69]>CN(C=O)C.O>[CH:1]1([C:4]([NH:6][C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:23]=[C:22]4[C:17]([CH2:18][CH2:19][CH:20]([C:24]([NH:60][C:61]5[CH:62]=[C:63]([CH:73]=[C:74]([C:76]([F:77])([F:78])[F:79])[CH:75]=5)[CH2:64][NH:65][C:66](=[O:72])[O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:25])[CH2:21]4)=[CH:16][CH:15]=3)[CH:10]=[CH:9][N:8]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(O)C1CCc2ccc(Oc3ccnc(NC(=O)C4CC4)c3)cc2C1
Reactant: CC(C)(C)OC(=O)NCc1cc(N)cc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc(NC(=O)C5CC5)c4)cc3C2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
To a solution of 7-({2-[(cyclopropylcarbonyl)amino]pyridin-4-yl}oxy)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (3.03 g, 8.61 mmol) in DMF (75 mL), was added DIPEA (4.50 mL, 25.8 mmol) and HATU (4.91 g, 12.9 mmol). The reaction mixture was allowed to stir at rt for 30 min, and then tert-butyl [3-amino-5-(trifluoromethyl)benzyl]carbamate (2.50 g, 8.61 mmol) was added. The reaction mixture was allowed to stir for 18 h. Water was added and the precipitate was filtered, washed with water and hexane and dried under vacuum. The residue was purified by column chromatography to give tert-butyl [3-({[7-({2-[(cyclopropylcarbonyl)amino]pyridin-4-yl}oxy)-1,2,3,4-tetrahydronaphthalen-2-yl]carbonyl}-amino)-5-(trifluoromethyl)benzyl]carbamate (3.80 g, 70.6%) as a yellow solid. LCMS: (FA) ES+ 625.6, ES− 623.4.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([CH:10](O)[CH2:11][CH2:12][CH3:13])=[CH:8][N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:5]=2)[CH2:3][CH2:2]1.S(Cl)([Cl:27])=O>ClCCl>[Cl:27][CH:10]([C:9]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][C:6]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=2)=[N:7][CH:8]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCC(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCC(Cl)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1

Procedure:
A solution of 392 mg (1.17 mmol) [rac]-1-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butan-1-ol and 0.09 ml (1.22 mmol) thionylchloride in 4 ml dichloromethane were stirred at RT for 1 h. After concentration under reduced pressure 421 mg of pure [rac]-5-(1-chloro-butyl)-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine was isolated.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:10][CH:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:9])=[O:8].[ClH:19].Cl.[CH2:21]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[ClH:19].[ClH:19].[CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:10][CH:11]([N:33]1[CH2:34][CH2:35][N:30]([CH2:21][C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH2:31][CH2:32]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:9])=[O:8]
Reactant: O=C(CN1CCNCC1)c1ccccc1
Reactant: O=S(=O)(CC(Br)c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CN1CCN(C(CS(=O)(=O)c2ccccc2)c2ccccc2)CC1)c1ccccc1
Yield: 99.6 %

Procedure:
A mixture of (2-benzenesulfonylmethyl)-benzyl bromide (0.5 g, 1.54 mmol), N-phenacyl piperazine dihydrochloride (0.32 g, 1.54 mmol) and K2CO3 (0.74 g, 5.38 mmol) in 40 ml of acetone was treated according to general preparation 2 to give 0.4 g of compound (IV-26), yield 50%. M+ 448.
Reaction SMILES: C(O)(=O)/C=[CH:3]/[C:4]([OH:6])=[O:5].[CH:9]1([N:14]2[CH2:19][CH2:18][CH:17]([N:20]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[C:21](=[O:30])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12][CH2:11][CH2:10]1.[OH-:37].[Na+]>>[C:4]([OH:6])(=[O:5])[C:3]([OH:30])=[O:37].[CH:9]1([N:14]2[CH2:19][CH2:18][CH:17]([N:20]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[C:21](=[O:30])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C(O)/C=C/C(=O)O
Reactant: [OH-]
Agent: Cc1cccc(CC(=O)N(c2cccnc2)C2CCN(C3CCCC3)CC2)c1
Agent: [Na+]
Product: O=C(O)C(=O)O

Procedure:
From 3.9 parts of N-(1-cyclopentyl-4-piperidinyl)-3-methyl-N-(3-pyridinyl)benzeneacetamide (E)-2-butenedioate, the free base is liberated in the conventional manner with a diluted sodium hydroxide solution. After extraction with 2,2'-oxybispropane, the latter is washed with water, dried, filtered and evaporated. The residue is converted into the ethanedioate salt in ethanol. The salt is filtered off and crystallized from a mixture of ethanol and 2,2'-oxybispropane, yielding 3 parts of N-(1-cyclopentyl-4-piperidinyl)-3-methyl-N-(3-pyridinyl)benzeneacetamide ethanedioate; mp. 192.6° C.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[CH3:30][C:31]1([CH3:38])[NH:36][CH2:35][CH2:34][NH:33][C:32]1=[O:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:36]4[CH2:35][CH2:34][NH:33][C:32](=[O:37])[C:31]4([CH3:38])[CH3:30])[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: CC1(C)NCCNC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCNC(=O)C3(C)C)n(C)c2n1
Reaction time: 16 h
Yield: 10.5 %

Procedure:
A solution of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (250 mg, 0.64 mmol), 3,3-dimethylpiperazin-2-one (100 mg, 0.78 mmol) and molecular sieves (4 Å, powdered, 1 g) in DCE (15 mL) was stirred at ambient temperature for 4 h. Sodium triacetoxyborohydride (204 mg, 0.96 mmol) was added and the mixture stirred for 16 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH, 100:0 to 98:2 to 95:5) to afford 649 as a yellow solid (34 mg, 11%). LCMS (method I): RT=3.12 min, M+H+=504. 1H NMR (CDCl3, 400 MHz) δ 8.02 (m, 1 H), 7.79 (m, 1 H), 7.30 (m, 2 H), 5.75 (bs, 1 H), 4.34 (m, 4 H), 3.94 (s, 2 H), 3.92 (s, 3 H), 3.87 (m, 4 H), 3.38 (q, J=7.4 Hz, 2), 3.23 (m, 2 H), 2.80 (m, 2 H), 1.54 (s, 6 H) and, 1.47 (t, J=7.4 Hz, 3 H)
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[C:7]([O:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][NH2:18])=[O:13])([CH3:10])([CH3:9])[CH3:8].C(N(C(C)C)CC)(C)C>ClCCl>[C:7]([O:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][NH:18][C:2](=[O:3])[O:4][CH2:5][Cl:6])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=C(Cl)OCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCCNC(=O)OCCl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of chloromethyl chloroformate (2.84 g) in dichloromethane (10 ml) was added dropwise with stirring to an ice-cold solution of 3-(N-tert-butoxycarbonylamino)-propylamine (3.49 g) and diisopropylethylamine (3.10 g) in dichloromethane (30 ml). After stirring for a further 3 hours at room temperature, the mixture was extracted with ice-cold 0.5 M hydrochloric acid followed by water and aqueous sodium bicarbonate. Drying over magnesium sulfate and evaporation in vacuo gave the title compound as colourless crystals.
Reaction SMILES: [OH:1][CH:2]1[CH:6]([OH:7])[CH:5]([N:8]2[C:12]3[N:13]=[C:14]([S:27][CH3:28])[N:15]=[C:16]([NH:17][CH:18]4[CH2:20][CH:19]4[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:11]=3[N:10]=[N:9]2)[CH2:4][CH:3]1[C:29]([NH:31][C:32]1[CH:37]=[CH:36]C=CC=1)=[O:30].[CH2:38]([O:40]CCCN)[CH3:39]>>[CH2:38]([O:40][CH2:36][CH2:37][CH2:32][NH:31][C:29]([CH:3]1[CH2:4][CH:5]([N:8]2[C:12]3[N:13]=[C:14]([S:27][CH3:28])[N:15]=[C:16]([NH:17][CH:18]4[CH2:20][CH:19]4[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:11]=3[N:10]=[N:9]2)[CH:6]([OH:7])[CH:2]1[OH:1])=[O:30])[CH3:39]
Reactant: CCOCCCN
Reactant: CSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)Nc4ccccc4)C(O)C3O)c2n1
Product: CCOCCCNC(=O)C1CC(n2nnc3c(NC4CC4c4ccccc4)nc(SC)nc32)C(O)C1O

Procedure:
The subtitle compound was prepared according to the method of example 39, step a) using the product of example 20, step b) and 3-ethyoxypropylamine.
Reaction SMILES: O.[PH2]([O-])=O.[Na+].[C:6]([C:8]1[CH:26]=[CH:25][C:11]([O:12][CH2:13][C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:16])[CH3:15])=[CH:10][CH:9]=1)#N.N1C=CC=CC=1.C(O)(=[O:35])C>O.[Ni]>[CH:6]([C:8]1[CH:26]=[CH:25][C:11]([O:12][CH2:13][C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:16])[CH3:15])=[CH:10][CH:9]=1)=[O:35]
Reactant: CC(=O)O
Reactant: CC(C)(COc1ccc(C#N)cc1)NC(=O)OC(C)(C)C
Agent: [Ni]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(COc1ccc(C=O)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
The title compound was synthesized by referring to J. Chem. Soc., 1962, 3961. To a solution of sodium hypophosphite monohydrate (1.5 g) in water (3 ml) were sequentially added tert-butyl [2-(4-cyanophenoxy)-1,1-dimethylethyl]carbamate (500 mg), pyridine (10 ml) and acetic acid (5 ml). While stirring at room temperature, Raney nickel (50% suspension in water) (2 ml) was added dropwise to the reaction mixture and the solution was stirred for 15 minutes at room temperature and for 1 hour at 40° C. After filtration through celite pad and several wash with tetrahydrofuran and methanol, the solvent was evaporated in vacuo, and the residue was neutralized by adding a saturated aqueous solution of sodium bicarbonate. After extraction with ethyl acetate, the solution was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (443 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]1[CH:30]=[CH:29][C:13]2[N:14]([CH3:28])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:27])[NH2:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].O.C(=O)([O-])[O-].[K+].[K+].N1([C:50]([O:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[O:51])C=CN=C1>C(#N)C>[CH3:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][O:52][C:50](/[N:27]=[C:25](\[NH2:26])/[C:22]1[CH:21]=[CH:20][C:19]([NH:18][CH2:17][C:15]2[N:14]([CH3:28])[C:13]3[CH:29]=[CH:30][C:10]([C:8]([N:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:9])=[CH:11][C:12]=3[N:16]=2)=[CH:24][CH:23]=1)=[O:51]
Reactant: CCCCCCOC(=O)n1ccnc1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCCCOC(=O)/N=C(\N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Temperature: 15 °C
Reaction time: 0.25 h

Procedure:
1-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula-5 (100 g) was added to acetonitrile (1200 ml) and water (800 ml) at 25-35° C. and then cooled to 12-18° C. Potassium carbonate (138 g) was added to the reaction mixture and stirred for 15 minutes at 12-18° C. A solution of hexyl 1H-imidazole-1-carboxylate compound of formula-4 (66 g) in acetonitrile (150 ml) was slowly added to the reaction mixture over a period of 25 minutes at 12-18° C. and stirred for 14 hours at 15-20° C. After completion of the reaction, water was added to the reaction mixture and stirred for 30 minutes. Filtered the solid, washed with acetonitrile followed by aqueous acetonitrile and then dried to get title compound. Dichloromethane was added to the obtained compound and stirred for 15 minutes. Water was added to the reaction mixture and stirred for 20 minutes at 25-35° C. Both the organic and aqueous layers were separated, and the dichloromethane layer was washed with water followed by sodium chloride and then distilled off completely under reduced pressure. Acetone (600 ml) was added to the obtained residue and stirred for 45 minutes at 25-35° C. to obtain a clear solution. Water (500 ml) was added to the obtained solution and stirred for 45 minutes at 25-35° C. to get the solid. Filtered the solid, washed with water and finally with methyl tertiary butyl ether and then dried to get the pure title compound. Further the obtained solid recrystallized from ethylacetate and ethanol.
Reaction SMILES: [CH3:1][C:2](=[CH2:34])[CH:3]([N:17]1[CH:20]([Cl:21])[CH:19]([NH:22]C(=O)COC2C=CC=CC=2)[C:18]1=[O:33])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5].P(Cl)(Cl)(Cl)(Cl)Cl.N1C2C(=CC=CC=2)C=CC=1.[Cl-].[Na+]>C(O)CC.C(Cl)(Cl)Cl>[CH3:34][C:2](=[CH2:1])[CH:3]([N:17]1[CH:20]([Cl:21])[CH:19]([NH2:22])[C:18]1=[O:33])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5]
Reactant: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCCO
Solvent: c1ccc2ncccc2c1
Product: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(N)C1Cl
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5 mmoles of p-nitrobenzyl 3-methyl-2-(2-oxo-4-chloro-3-phenoxyacetamido-1-azetidinyl)-3--butenoate in 20 ml. of chloroform cooled to -10° C. were added 30 mmoles of phosphorus pentachloride and an excess of quinoline (30 mmoles plus). The reaction mixture was stirred for 30 min. and was then cooled to -30° C. To the cold mixture were added 2 ml. of n-propyl alcohol with stirring and the reaction mixture was allowed to stand in an ice bath for about 3 min. Thereafter 5 ml. of a saturated aqueous solution of sodium chloride were added followed by the addition of 100 ml. of petroleum ether. The product precipitated as a gum from which the liquid phase was decanted. The gum solidified on treatment with 5 ml. of saturated aqueous sodium chloride. The product was filtered and dried. There were obtained 400 mg. of the deacylated product as the hydrochloride salt represented by the following formula. ##STR56## wherein pNB=p-nitrobenzyl.
Reaction SMILES: Br[C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.CCN(CC)CC.[C:18]([PH2:22])([CH3:21])([CH3:20])[CH3:19]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([PH:22][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)([CH3:21])([CH3:20])[CH3:19]
Reactant: BrC1=Cc2ccccc2C1
Reactant: CC(C)(C)P
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)PC1=Cc2ccccc2C1
Temperature: 25 °C

Procedure:
To 9.61 g (0.049 mol) of 2-bromo-1H-indene and 1.13 g (0.98 mmol) of Pd(PPh3)4 in 25 ml of toluene, 7.5 ml (5.45 g, 0.054 mol) of Et3N and 4.88 g (0.054 mol) of tBuPH2 were added. This mixture was refluxed for 14 hours, cooled to room temperature, and filtered through glass frit (G3) to separate out compound 15. The filtrate was evaporated to dryness. The crude product was distilled in vacuum (108–110° C./3 mm). Yield 3.07 g (31%) of crystalline solid of 14.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:19]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:9][CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCCBr
Reactant: O=Cc1ccc(O)cc1
Product: CCCCCCCCCCCCCOc1ccc(C=O)cc1
Yield: 178 %

Procedure:
General procedure K was used to convert 4-hydroxybenzaldehyde (8.2 mmols) and 1-bromononane (12.3 mmols) to 7.3 mmols (87%) of the title product was recovered. 1H NMR (300 MHz, CDCl3) δ 9.88 (s, 1H), 7.83 (d, J=8.8 Hz, 2H), 6.99 (d, J=8.7 Hz, 2H), 4.04 (t, J=6.5 Hz, 2H), 1.76-1.88 (m, 2H), 1.52-1.08 (m, 20H), 0.88 (t, J=6.7 Hz, 3H).
Reaction SMILES: [CH2:1]([Si:3]([CH2:7][CH3:8])([CH2:5][CH3:6])Cl)[CH3:2].[CH2:9]([O:16][C:17](=[O:32])[NH:18][CH2:19][C@@H:20]([OH:31])[CH2:21][N:22]1[CH2:29][CH2:28][C:25]2([CH2:27][CH2:26]2)[C@H:24]([OH:30])[CH2:23]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1[CH:37]=[CH:36]N=C1>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH2:9]([O:16][C:17](=[O:32])[NH:18][CH2:19][C@@H:20]([O:31][Si:3]([CH2:36][CH3:37])([CH2:5][CH3:6])[CH2:1][CH3:2])[CH2:21][N:22]1[CH2:29][CH2:28][C:25]2([CH2:27][CH2:26]2)[C@H:24]([O:30][Si:3]([CH2:7][CH3:8])([CH2:5][CH3:6])[CH2:1][CH3:2])[CH2:23]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1c[nH]cn1
Reactant: O=C(NC[C@@H](O)CN1CCC2(CC2)[C@H](O)C1)OCc1ccccc1
Reactant: CC[Si](Cl)(CC)CC
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)O[C@H](CNC(=O)OCc1ccccc1)CN1CCC2(CC2)[C@H](O[Si](CC)(CC)CC)C1
Yield: 90.4 %

Procedure:
Triethylchlorosilane (351 mg, 2.33 mmol) was added to a solution of [(R)-2-hydroxy-3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-carbamic acid benzyl ester (260 mg, 0.78 mmol), imidazole (264 mg, 3.89 mmol), and 4-(dimethylamino)pyridine (1.9 mg, 16 μmol) in N,N-dimethylformamide at RT, then after 90 min the reaction mixture was partitioned between EtOAc and sat. aq. NaHCO3 solution. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; heptane/EtOAc 7:3) afforded the title compound (397 mg, 91%). Light yellow liquid, MS: 563.4 (M+H)+.
Reaction SMILES: CC[C@@H]([C@H]1NC(=O)[C@@H](NC([C@H](N(C([C@H]2N(C(C(O)C)=O)CCC2)=O)C)CC(C)C)=O)[C@@H](C)OC(=O)[C@H](CC2C=CC(OC)=CC=2)N(C)C(=O)[C@H]2N(CCC2)C(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)C(=O)[C@H:11]([CH:76]([CH3:78])[CH3:77])[O:10]C(=O)C[C@@H]1O)C.[NH:80]1[CH2:87][CH2:86][CH2:85][C@H:81]1[C:82]([OH:84])=[O:83].C(OC(=O)C(C)C)(=O)C(C)C.C(N1CCC[C@H]1C(O)=O)(=O)CC>>[C:11]([N:80]1[CH2:87][CH2:86][CH2:85][C@H:81]1[C:82]([OH:84])=[O:83])(=[O:10])[CH:76]([CH3:78])[CH3:77]
Reactant: CC[C@H](C)[C@H]1NC(=O)[C@@H](NC(=O)[C@@H](CC(C)C)N(C)C(=O)[C@@H]2CCCN2C(=O)C(C)O)[C@@H](C)OC(=O)[C@H](Cc2ccc(OC)cc2)N(C)C(=O)[C@@H]2CCCN2C(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)C(=O)[C@H](C(C)C)OC(=O)C[C@@H]1O
Reactant: O=C(O)[C@@H]1CCCN1
Agent: CC(C)C(=O)OC(=O)C(C)C
Agent: CCC(=O)N1CCC[C@H]1C(=O)O
Product: CC(C)C(=O)N1CCC[C@H]1C(=O)O
Yield: 96 %

Procedure:
[Isobutyryl9 ]Didemnin B (33) and [Isobutyryl9, D-Pro8 ] Didemnin B (34). L-Pro (1.15 g, 0.01 mol) was treated with isobutyric anhydride in a procedure like the N-propionylproline synthesis to give N-isobutyrylproline (1.8 g, 96%): fine crystals, mp 80-82° C.; [α]D25 -8.7° (c 1.56, CHCl3). 1H NMR Anal. (C9H15NO3) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:26])[O:21]C(C)(C)C)[CH:15]=[CH:16][C:17]=1[CH3:18])[N:5]=2.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1.C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1.CO>[CH:27]1([C:30]([NH:1][C:2]2[S:3][C:4]3[C:9]([N:10]=2)=[CH:8][CH:7]=[C:6]([O:11][C:12]2[CH:13]=[C:14]([NH:19][C:20](=[O:26])[O:21][CH2:6][CH2:7][CH2:8][CH3:9])[CH:15]=[CH:16][C:17]=2[CH3:18])[N:5]=3)=[O:31])[CH2:29][CH2:28]1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1Oc1ccc2nc(N)sc2n1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: CCCCOC(=O)Nc1ccc(C)c(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 186.7 %

Procedure:
To a solution of tert-butyl {3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-methylphenyl}carbamate (800 mg, 2.14 mmol) in pyridine (10 mL) was added cyclopropanecarbonyl chloride (390 μL, 4.29 mmol), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with methanol (20 mL), anhydrous sodium carbonate (1.0 g, 9.43 mmol) was added, and the mixture was stirred at room temperature for 6 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (100 mL)/tetrahydrofuran (10 mL), washed with 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was triturated with ethyl acetate and diisopropyl ether to give the title compound (880 mg, 93%) as a pale-yellow powder.