Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][Br:6])C.Br.[Br:11][C:12]1[C:17]([NH2:18])=[N:16][C:15](Br)=[CH:14][N:13]=1>CC(O)C>[Br:11][C:12]1[N:13]2[CH:14]=[CH:15][N:16]=[C:4]2[C:5]([Br:6])=[N:18][CH:17]=1
Reactant: Nc1nc(Br)cnc1Br
Reactant: CCOC(CBr)OCC
Agent: Br
Solvent: CC(C)O
Product: Brc1ncc(Br)n2ccnc12

Procedure:
Bromoacetaldehyde diethyl acetal (49 mL, 326 mmol) and 48% hydrobromic acid is heated to reflux for 1.5 h, then poured into propan-2-ol (600 mL) and quenched with NaHCO3. After filtering, 2,5-dibromo-3-aminopyrazine (41.34 g, 163 mmol) is added to the solution and heated at reflux overnight. The reaction is cooled and solvents removed in vacuo, followed by addition of aq. NaHCO3 and extraction with EtOAc. The organic phase is dried over MgSO4, filtered, and concentrated in vacuo to afford a brown solid. 1H NMR (250 MHz, CDCl3) δ(ppm) 7.86 (s, 1H), 7.93-7.94 (d, 1H), 7.98-7.99 (d, 1H); m/z (APCI) 278 (M+H)+; m.p 132-135° C.
Reaction SMILES: [Si:1]([O:8][CH:9]([CH:27]([CH3:29])[CH3:28])[C:10](=O)/[C:11](=[CH:22]/[N:23](C)C)/[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:30]N>C(O)C>[Si:1]([O:8][CH:9]([C:10]1[C:11]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])=[CH:22][NH:23][N:30]=1)[CH:27]([CH3:29])[CH3:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)C(O[Si](C)(C)C(C)(C)C)C(=O)/C(=C/N(C)C)C(=O)OCc1ccccc1
Reactant: NN
Solvent: CCO
Product: CC(C)C(O[Si](C)(C)C(C)(C)C)c1n[nH]cc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of benzyl (2Z)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[(dimethylamino)methylene]-5-methyl-3-oxohexanoate (0.13 g, 0.31 mmol) in ethanol (3.1 mL) was added hydrazine (0.28 mL, 3.1 mmol). The mixture was stirred at ambient temperature. After 30 min, the mixture was concentrated to dryness and taken into the next reaction. MS 389.1 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.Cl.[C:12]1([C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:12]1([C:18]2[CH2:23][CH2:22][N:21]([C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=3)[CH2:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C1=C(c2ccccc2)CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2CC=C(c3ccccc3)CC2)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 1-fluoro-4-nitrobenzene (2.71 ml), 1,2,3,6-tetrahydro-4-phenylpyridine hydrochloride (5 g) and potassium carbonate (8.83 g) in dimethylsulfoxide (50 ml) was stirred for 1 hour at 100° C. The reaction mixture was pulverized with water. The precipitate was collected by filtration, and dried under reduced pressure to give 4-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)nitrobenzene.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Br:7][C:8]1[CH:13]=[CH:12][C:11](CC(O)=O)=[CH:10][CH:9]=1.C(Cl)Cl>CN(C)C=O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:1][C:2]([Cl:4])=[O:3])=[CH:10][CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1ccc(Br)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccc(Br)cc1
Reaction time: 0.5 h

Procedure:
Initially, oxalyl chloride is added to an equimolar amount of p-bromophenylacetic acid (C) in an inert solvent, preferably methylene chloride, at about room temperature, with a catalytic amount of dimethylformamide. The mixture is stirred for about 30 minutes, after which the product, p-bromophenylacetyl chloride (D), is isolated by conventional means.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.Br[C:8]1[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=1.C(N(CC)CC)C>CN(C)C=O>[N:1]1([C:8]2[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=2)[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1csc(Br)n1
Reactant: C1CSCCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1csc(N2CCSCC2)n1

Procedure:
The reaction described in Preparation 26 was repeated, but using 1.53 g of thiomorpholine, 2.36 g of ethyl 2-bromothiazole-4-carboxylate, 2.02 g of triethylamine and 40 ml of dimethylformamide, giving the title compound as a pale yellow powder.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C([N-]C(C)C)(C)C.[Li+].[CH:17](=[O:23])[CH:18]=[CH:19][CH:20]=[CH:21][CH3:22]>C1COCC1>[OH:4][CH:3]([CH2:5][C:17](=[O:23])[CH:18]=[CH:19][CH:20]=[CH:21][CH3:22])[CH2:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: CC=CC=CC=O
Reactant: COC(=O)CC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC=CC=CC(=O)CC(O)CC(=O)OC
Temperature: -78 °C
Reaction time: 16 h
Yield: 24.4 %

Procedure:
To a cold (-30° C.) solution of methyl acetoacetate (41.5 g, 357 mmol) in THF (500 mL) was added lithium diisopropylamide (476 mL, 1.5M solution in cyclohexane, 714 mmol). The resultant solution was stirred for 15 minutes at -30° C. After cooling to -78° C., 2,4-hexadienal (34.3 g, 357 mmol) was added and the solution stirred for 10 minutes at -78° C. and for 16 hours at ambient temperature. The solution was concentrated under reduced pressure and the residual syrup was partitioned between 1N HCl and ethyl acetate. The organic layer was washed with brine (2x), dried (Na2SO4), and concentrated. The residue was purified by chromatography on silica gel (diethyl ether:hexane/2:1) to afford 18.5 g (24.4%) of the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([NH:36][CH2:37][CH2:38][CH3:39])[CH2:34][CH3:35]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:36]([CH2:37][CH2:38][CH3:39])[CH2:33][CH2:34][CH3:35])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Reactant: CCCNCCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (13.28 g, 0.04 mole) and 1,1'-carbonyldiimidazole (7.14 g, 0.044 mole) in 300 ml of tetrahydrofuran was stirred at room temperature for 6 hrs. Then, under nitrogen atmosphere, dipropylamine (12.12 g, 0.12 mole) was added and the reaction mixture was heated at reflux for 3 hrs. The reaction mixture was filtered and the filtrate was evaporated to dryness. The solid was dried under high vacuum overnight and was recrystallized from isopropyl alcohol-water. The crystalline solid was collected by filtration, washed with water, and dried under high vacuum over the weekend to give 9.0 g (54%), mp 153°-55° C.
Reaction SMILES: Br[CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[CH3:18][S-:19].[Na+]>CN(C)C=O>[CH3:15][C:13]1[CH:14]=[C:5]2[CH2:4][CH:3]([CH2:2][S:19][CH3:18])[O:17][C:6]2=[C:7]2[C:12]=1[NH:11][C:10](=[O:16])[CH:9]=[CH:8]2
Reactant: C[S-]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CBr)C2
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCC1Cc2cc(C)c3[nH]c(=O)ccc3c2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
A solution of 2-bromomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (2.942 g) in dimethylformamide (120 ml) was combined with aqueous 15% sodium thiomethoxide (9.4 ml), and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. Water was added to the residue, and extracted with chloroform. The chloroform extract was washed with diluted hydrochloric acid, diluted caustic soda and water in this order, and dried. The resultant material was crystallized from tetrahydrofuran to obtain 2.355 g of the title compound as colorless prisms (mp. 203°-206° C.) (yield: 90.1%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[NH:22][CH:21]=[C:20]([C:23]([OH:25])=O)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.Cl.[CH3:27][O:28][CH2:29][CH2:30][NH:31][C:32]([C@H:34]1[CH2:39][CH2:38][C@H:37]([NH2:40])[CH2:36][CH2:35]1)=[O:33]>>[CH3:27][O:28][CH2:29][CH2:30][NH:31][C:32]([C@H:34]1[CH2:35][CH2:36][C@H:37]([NH:40][C:23]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:7]4[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:15]=3[NH:22][CH:21]=2)=[O:25])[CH2:38][CH2:39]1)=[O:33]
Reactant: COCCNC(=O)[C@H]1CC[C@H](N)CC1
Reactant: COc1ccc(-c2ncnc3c(C(=O)O)c[nH]c23)c(OCC2CC2)c1
Agent: Cl
Product: COCCNC(=O)[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A73) and trans-4-amino-cyclohexanecarboxylic acid (2-methoxy-ethyl)-amide hydrochloride (A196) the title compound is obtained as colorless solid.
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(N(CC)CC)C.[NH2:21][CH2:22][CH:23]([OH:26])[CH2:24][OH:25]>C(Cl)Cl>[OH:26][CH:23]([CH2:24][OH:25])[CH2:22][NH:21][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: NCC(O)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)NCC(O)CO)cc1
Reaction time: 2 h

Procedure:
A solution of 4-nitrobenzenesulfonyl chloride (Fluka, 1.00 g; 4.51 mmol) in DCM (20 mL) was treated with triethylamine (1.25 ml; 9.02 mmol) and 3-amino-1,2-propanediol (Aldrich, 518 μl; 6.77 mmol). After 2 hours, the organic solvents were evaporated in vacuo, the residue was taken up in EtOAc and extracted with a saturated NH4Cl solution. The combined organic layers were dried over MgSO4 and evaporated to dryness to give the title compound as a yellow solid.
Reaction SMILES: C(N(CC)CC)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH:29]([C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47])[C@H:30]([C:38]([NH:40][C@H:41]([C:43]([OH:45])=O)[CH3:42])=[O:39])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[CH:56]1[C:64]2[C:63]3[CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][C:62]=3[O:61][C:60]=2[CH:59]=[CH:58][C:57]=1[NH2:70]>>[CH2:49]([O:48][C:46]([NH:29][C@H:30]([C:38]([NH:40][C@H:41]([C:43]([NH:70][C:57]1[CH:58]=[CH:59][C:60]2[O:61][C:62]3[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65][C:63]=3[C:64]=2[CH:56]=1)=[O:45])[CH3:42])=[O:39])[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:47])[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 25.6 %

Procedure:
Following the procedure of Example 30, triethylamine (0.43 mL, 3.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.31 g, 1.6 mmol), N-hydroxybenzotriazole (0.22 g, 1.6 mmol), N-Cbz-Phe-Ala-OH (0.51 g, 1.4 mmol), and 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (0.25 g, 1.2 mmol) provided N-[(benzyloxy)carbonyl]-L-phenylalanyl-N1-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-yl-L-alaninamide (0.17 g). MS (ESI) m/z 554 ([M+H]+).
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]1[N:5]=[C:6]([CH:22]([CH3:24])[CH3:23])[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:8]=1[C:9]([O:11]CC)=[O:10].CO.OP(O)(O)=O>C1COCC1>[CH3:3][C:4]1[N:5]=[C:6]([CH:22]([CH3:24])[CH3:23])[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:19])([CH3:21])[CH3:20])[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)c1c(C)nc(C(C)C)n1COCC[Si](C)(C)C
Agent: O=P(O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(C(C)C)n(COCC[Si](C)(C)C)c1C(=O)O
Temperature: 40 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
Lithium hydroxide (2 mL, 2 mmol, 1 M in H2O) was added to a solution of ethyl 4-methyl-2-(1-methylethyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylate (133 mg, 0.41 mmol) in THF:MeOH (6 mL/2 mL). The reaction mixture was heated at 40° C. and stirred overnight. The mixture was then acidified by H3PO4 (1N), extracted with 10% MeOH in CHCl3 and the organic layer was dried over sodium sulfate. The solvent was evaporated and dried in vacuo to give the title compound (122 mg, >99%) as a yellow gel which was directly used in the next step without purification. LCMS: m/z 299 (M+1).
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>C(O)(=O)C>[C:1]([C:5]1[C:13]2[O:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([N+:16]([O-:18])=[O:17])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])O
Reactant: CC(C)(C)c1cccc2c1OCC2(C)C
Solvent: CC(=O)O
Product: CC(C)(C)c1cc([N+](=O)[O-])cc2c1OCC2(C)C
Temperature: 22 °C
Reaction time: 4 h
Yield: 18.5 %

Procedure:
To a solution of 7-tert-butyl-2,3-dihydro-3,3-dimethylbenzofuran (10.0 g 49.0 mmol) in glacial acetic acid (80 mL) is added dropwise 70% HNO3 (4.0 mL, 5.7 g, 63.7 mmol). The reaction mixture darkens to a deep green color over the course of the addition. The reaction is monitored by TLC (2% EtOAc/hexanes), and is allowed to stir at 22° C. for 4 h. Then the reaction mixture is partitioned between Et2O (100 mL) and H2O (2×100 mL). The ethereal layer was washed with saturated aqueous Na2CO3 (50 mL), dried (MgSO4), filtered and evaporated to a red solid (9.12 g). Crystallization from hexane provides the title compound as orange prisms (2.26 g, 18.5%). A second crop yields slightly less pure material (4.93 g, 40.3%) which was used without further purification, mp=93°-94° C.
Reaction SMILES: C(O[C:6](=[O:17])[NH:7][C:8]1[C:13]([CH:14]=[O:15])=[C:12]([Cl:16])[CH:11]=[CH:10][N:9]=1)(C)(C)C.[NH2:18][CH2:19][CH2:20]O.CC(O)=O>C1(C)C=CC=CC=1>[Cl:16][C:12]1[C:13]2[CH:14]3[O:15][CH2:20][CH2:19][N:18]3[C:6](=[O:17])[NH:7][C:8]=2[N:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1nccc(Cl)c1C=O
Reactant: NCCO
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=C1Nc2nccc(Cl)c2C2OCCN12
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.4 %

Procedure:
tert-Butyl(4-chloro-3-formylpyridin-2-yl)carbamate (2.0 g, 7.79 mmol), 2-aminoethanol (0.57 g, 9.35 mmol), and AcOH (0.47 g; 7.79 mmol) were suspended in toluene (20 mL), and stirred overnight at room temperature. The reaction mixture was concentrated, and suspended in hexanes/ether (5/1, v/v). The resulting precipitate was filtered, suspended in NMP (3 mL) in 20 ml seal tube, and heated for 30 min. at 150° C. The crude product was purified directly via HPLC to provide 42 (270 mg, 10% yield) as a solid. LC-MS (M+H=226, obsd.=226).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]2[C@H:12]([CH:13]=O)[O:11][C:10]([CH3:16])([CH3:15])[N:9]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br-].[CH2:25]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:26][CH3:27].[NH2-].[Na+]>O1CCCC1>[CH:13](/[C@H:12]1[O:11][C:10]([CH3:16])([CH3:15])[N:9]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[C@H:8]1[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[CH:25]/[CH2:26][CH3:27]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H](C=O)OC1(C)C
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC/C=C\[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1.4 g (4.3 mmol) of tert-butyl (4S,5R)-4-(cyclohexylmethyl)-5-formyl-2,2-dimethyl-3-oxazolidinecarboxylate (WO 87/05302) and 1.79 g (4.3 mmol) of instantylide, consisting of propyltriphenylphosphonium bromide and sodium amide, in 50 ml of tetrahydrofuran is stirred at room temperature under nitrogen for 30 minutes. Subsequently, the reaction mixture is partitioned between water and ethyl acetate. The organic phase is separated, dried over sodium sulphate and evaporated under reduced pressure. For purification, the residue is chromatographed on 80 g of silica gel using a 1:1 mixture of methylene chloride and petroleum ether as the eluent. There are obtained 900 mg of tert-butyl (4S,5R)-5-[(Z)-1-butenyl]-4-(cyclohexylmethyl)-2,2-dimethyl-3-oxazolidinecarboxylate as a resin; MS: 352 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]2[CH:7]=[C:8]([C:11]([NH2:13])=O)[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.S(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:14])[C:6]2[CH:7]=[C:8]([C:11]#[N:13])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: CC1(C)COc2ccc(C(N)=O)cc21
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CC1(C)COc2ccc(C#N)cc21

Procedure:
The product of stage (c) was boiled under reflux in benzene (5 ml) with thionyl chloride for 6 hours. Washing with water, drying over magnesium sulphate and running down gave, after recrystallisation from petroleum ether (bp 60°-80° C.), 0.6 g of title product, mp 70°-72° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][CH:8]1[CH:12]([CH:13]2[O:22][CH:16]3[O:17][C:18]([CH3:21])([CH3:20])[O:19][CH:15]3[CH:14]2[OH:23])[NH:11][C:10](=O)[CH2:9]1>O1CCCC1>[OH:23][CH:14]1[CH:15]2[CH:16]([O:17][C:18]([CH3:21])([CH3:20])[O:19]2)[O:22][CH:13]1[CH:12]1[CH:8]([OH:7])[CH2:9][CH2:10][NH:11]1
Reactant: CC1(C)OC2OC(C3NC(=O)CC3O)C(O)C2O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)OC2OC(C3NCCC3O)C(O)C2O1
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 77 %

Procedure:
To a well-stirred, nitrogen-blanketed suspension of lithium aluminum hydride (2.3 g, 60.0 mmol) in anhydrous tetrahydrofuran (150 mL), lactam IV (3.0 g, 11.5 mmol) was added in portions during 3-5 min at 25° C. Caution: and H2 evolution. This mixture was refluxed for 20 h then cooled to 0°-5° C. and the reaction quenched by the careful, sequential addition of water (2.5 mL), 1N NaOH (2.5 mL) and water 7.5 mL). This mixture was stirred at about 5° C. for 20 min then filtered through a pad of Celite. The collected aluminate salts were washed with tetrahydrofuran (200 mL) and the combined filtrate and wash was concentrated to dryness at reduced pressure, leaving 1.7 g of [3aR-[3aα,5α(2R*,3S*),6α,6aα]]-2-(Tetrahydro-6-hydroxy-2,2-dimethylfuro[2,3-d]-1,3-dioxol-5-yl)-3-pyrrolidinol (V) as a white powder. The collected aluminate salts were refluxed with 100 mL of tetrahydrofuran-water (9:1) for 45 min. The salts were filtered, washed with tetrahydrofuran (50 mL) and the combined filtrate evaporated to dryness, leaving 0.5 g more of V for a total yield of 77%. An analytical sample was obtained as fine, colorless needles by recrystallization from methanol mp 223°-225° C. (dec); [α]D25 =-5.0 (c 0.32, H2O); 1H NMR (CDCl3) δ 5.92 (d, 1, J=3.8 Hz, H-1), 4.55 (d, 1, J=3.8 Hz, H-2), 4.40 (ddd, J=5.3, 3.6, 1.6 Hz, H-6), 4.25 (d, 1, J=2.6 Hz, H-3), 4.13 (dd, 1, J=7.8, 2.6 Hz, H-4), 3.50 (m, 3, OH, NH), 3.18 (ddd, 1, J-11.2, 7.8, 7.6 Hz, H-8'), 3.12 (dd, 1, J=7.8, 3.6 Hz, H-5), 2.86 (ddd, 1, J=11.2, 9.5, 5.1 Hz, H-8), 2.05 (dddd, J=13.8, 9.5, 7.6, 5.3 Hz, H-7'), 1.86 (dddd, J=13.8, 7.8, 5.1, 1.6 Hz, H-7), 1.50 (s, 3, CH3), 1.32 (s, 3, CH3); 13C NMR δ 26.1, 26.6, 35.4, 43.2, 61.6, 70.6, 75.6, 77.9, 85.3, 103.8, 110.1; mass spectrum, m/z(rel intensity) 246 (MH+,100), 188 (MH+ -C3H6O, 52).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:38]=[CH:37][C:14]2[N:15]([CH2:19][C:20]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([O:35][CH3:36])[CH:29]=4)[CH2:24][CH2:23]3)=[O:21])[C:16](=[O:18])[O:17][C:13]=2[CH:12]=1)(C)(C)C>Cl.O1CCOCC1>[NH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:38]=[CH:37][C:14]2[N:15]([CH2:19][C:20]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([O:35][CH3:36])[CH:29]=4)[CH2:24][CH2:23]3)=[O:21])[C:16](=[O:18])[O:17][C:13]=2[CH:12]=1
Reactant: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(OCCNC(=O)OC(C)(C)C)ccc43)CC2)ccc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(OCCN)ccc43)CC2)ccc1Cl

Procedure:
[2-(3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-2,3-dihydro-benzooxazol-6-yloxy)-ethyl]-carbamic acid tert-butyl ester (58) (50 mg) was dissolved in HCl-dioxane (2 ml) and the resultant solution was stirred for 1 hour and concentrated to dryness. The crude residue was purified by HPLC to provide 6-(2-amino-ethoxy)-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one: LCMS observed for (M+H)+: 461.5.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:22]=[CH:21][C:20](I)=[CH:19][N:18]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[NH:24]1[CH2:28][CH2:27][NH:26][C:25]1=[O:29]>>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[N:18]=[CH:19][C:20]([N:24]5[CH2:28][CH2:27][NH:26][C:25]5=[O:29])=[CH:21][CH:22]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Ic1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Reactant: O=C1NCCN1
Product: O=C1NCCN1c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1

Procedure:
The title compound was prepared from 3-cyclobutyl-7-[(5-iodo-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E207) and 2-imidazolidinone using the method of Example 261; MS (ES+) m/e 379 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)[C:10](=[O:19])[CH:9]=2)[CH:7]=1.[NH:22]1[C:26]2[CH:27]=[C:28]([NH2:31])[CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1>>[NH:22]1[C:26]2[CH:27]=[C:28]([NH:31][C:15](=[O:17])[CH:14]([N:11]3[CH:12]=[CH:13][C:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:20]#[N:21])=[CH:9][C:10]3=[O:19])[CH3:18])[CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Product: CC(C(=O)Nc1ccc2nc[nH]c2c1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
65 mg (purity 83%, 0.18 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) (Example 2.2B) and 26 mg (0.20 mmol) of 1H-benzimidazole-6-amine were reacted according to General Method 1. Yield: 11 mg (15% of theory)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.CC[O:22][C:23]([CH2:25][CH:26]1[C:31](=O)[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:24]>>[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:27]3[CH:26]([CH2:25][C:23]([OH:24])=[O:22])[CH2:31][CH2:30][CH2:29][C:28]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([S:16][CH3:17])[CH:14]=3)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: CSc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Agent: Cl
Product: CSc1ccc2c(c1)c1c(n2Cc2ccc(Cl)cc2)C(CC(=O)O)CCC1

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-methylthiophenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClC[C:45]1[N:49](C)[N:48]=[C:47]([CH3:51])[CH:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[N:49]([CH3:45])[N:48]=[C:47]([CH3:51])[CH:46]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(CCl)n(C)n1
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: Cc1cc(Cn2nc3nc(C(C)(C)C)nc(N4CCC(F)(F)C4)c3n2)n(C)n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1,3-dimethyl-1H-pyrazole and isolated as light yellow gum. MS (m/e): 391.3 (MH+).