Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[O:100])[CH2:3][NH:4][C:5](=[O:99])[C@@H:6]([NH:13][C:14](=[O:98])[C@@H:15]([N:17]([CH3:97])[C:18]([C@H:20]([CH2:86][C:87](=[O:96])[S:88][CH2:89][C:90]1[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=1)[NH:21][C:22](=[O:85])[C@H:23]([CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1)[NH:24][C:25](=[O:77])[C@H:26]([CH:74]([CH3:76])[CH3:75])[NH:27][C:28](=[O:73])[C@H:29]([CH3:72])[NH:30][C:31](=[O:71])[C@H:32]([CH2:67][CH:68]([CH3:70])[CH3:69])[N:33]([CH3:66])[C:34](=[O:65])[CH2:35][NH:36][C:37](=[O:64])[C@H:38]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[N:39]([CH3:56])[C:40](=[O:55])[C@H:41]([CH3:54])[NH:42][C:43](=[O:53])[CH2:44][NH:45]C(=O)OC(C)(C)C)=[O:19])[CH3:16])[CH2:7][O:8]C(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:45][CH2:44][C:43](=[O:53])[NH:42][C@@H:41]([CH3:54])[C:40](=[O:55])[N:39]([CH3:56])[C@@H:38]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:37](=[O:64])[NH:36][CH2:35][C:34](=[O:65])[N:33]([CH3:66])[C@@H:32]([CH2:67][CH:68]([CH3:70])[CH3:69])[C:31](=[O:71])[NH:30][C@@H:29]([CH3:72])[C:28](=[O:73])[NH:27][C@@H:26]([CH:74]([CH3:75])[CH3:76])[C:25](=[O:77])[NH:24][C@@H:23]([CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1)[C:22](=[O:85])[NH:21][C@H:20]([C:18](=[O:19])[N:17]([C@@H:15]([CH3:16])[C:14]([NH:13][C@@H:6]([CH2:7][OH:8])[C:5]([NH:4][CH2:3][C:2]([NH2:1])=[O:100])=[O:99])=[O:98])[CH3:97])[CH2:86][C:87](=[O:96])[S:88][CH2:89][C:90]1[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=1
Reactant: CC(C)C[C@@H](C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(=O)SCc1ccccc1)C(=O)N(C)[C@@H](C)C(=O)N[C@@H](COC(C)(C)C)C(=O)NCC(N)=O)C(C)C)N(C)C(=O)CNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](C)NC(=O)CNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@@H](C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(=O)SCc1ccccc1)C(=O)N(C)[C@@H](C)C(=O)N[C@@H](CO)C(=O)NCC(N)=O)C(C)C)N(C)C(=O)CNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](C)NC(=O)CN
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.9 %

Procedure:
S-Benzyl (9S,12S,18S,21S,24S,27S,30S)-30-(((S)-1-(((S)-1-((2-amino-2-oxoethyl)amino)-3-(tert-butoxy)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamoyl)-12,27-dibenzyl-18-isobutyl-24-isopropyl-2,2,9,11,17,21-hexamethyl-4,7,10,13,16,19,22,25,28-nonaoxo-3-oxa-5,8,11,14,17,20,23,26,29-nonaazadotriacontane-32-thioate (Compound P-146) (11.8 mg, 0.0083 mmol) was dissolved in dichloromethane (150 μL), TFA (75.0 μL, 0.973 mmol) was added and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (0.1% aqueous FA solution: 0.1% FA-acetonitrile solution) to afford the title compound (7.3 mg, 69.5%).
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][O:12][C:11]2=[O:15])=[N:6][CH:5]=1.Cl.[CH3:18][C:19]1[C:20]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:21][C:22]([CH3:26])=[C:23]([CH3:25])[CH:24]=1>>[CH3:18][C:19]1[C:20]([N:27]2[CH2:28][CH2:29][N:30]([C:3]([C:4]3[CH:9]=[CH:8][C:7]([N:10]4[CH2:14][CH2:13][O:12][C:11]4=[O:15])=[N:6][CH:5]=3)=[O:16])[CH2:31][CH2:32]2)=[N:21][C:22]([CH3:26])=[C:23]([CH3:25])[CH:24]=1
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Reactant: COC(=O)c1ccc(N2CCOC2=O)nc1
Agent: Cl
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCOC4=O)nc3)CC2)nc1C
Yield: 21.4 %

Procedure:
By reaction and treatment in the same manner as in Example 63 and using 6-(2-oxooxazolidin-3-yl)nicotinic acid methyl ester (250 mg) described in Preparation Example 138 and 1-(3,5,6-trimethylpyridin-2-yl)piperazine hydrochloride (328 mg) described in Preparation Example 52 after neutralization and conversion to a free form, the title compound (95 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][CH:15]=[C:14]([F:22])[C:13]=3[CH:23]=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][CH:15]=[C:14]([F:22])[C:13]=3[CH2:23][OH:24])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3c(ncc(F)c3C=O)N21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3c(ncc(F)c3CO)N21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
To a solution of 0.800 g (4R,9aR)-7-fluoro-8-formyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (intermediate i, examples 54–61) in 15 mL tetrahydrofurane was added 0.052 g lithium borohydride and the mixture was stirred at room temperature for 0.5 h. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed twice with water dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel with methylenechloride:ethyl acetate (3:2) to yield 0.56 g (4R,9aR)-7-fluoro-8-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester as colorless foam.
Reaction SMILES: Br[CH2:2][C:3]#[C:4][C:5]([CH2:15][CH3:16])([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)[CH2:6][CH3:7].[P:17]([O:24]CC)([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>>[CH2:6]([C:5]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)([CH2:15][CH3:16])[C:4]#[C:3][CH2:2][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[CH3:7]
Reactant: CCOP(OCC)OCC
Reactant: CCC(C#CCBr)(CC)OC1CCCCO1
Product: CCOP(=O)(CC#CC(CC)(CC)OC1CCCCO1)OCC
Temperature: 130 °C

Procedure:
A mixture of Compound 403 (2.0 g) and triethyl phosphite (4.2 ml) was heated to 130° C. for 1.5 h. Excess triethyl phosphite was removed in vacuo (oil pump) for 2 h to give the title compound (2.2 g). 1H NMR: 0.96 (m, 6H), 1.35 (t, 6H), 1.45-1.95 (m, 10H), 2.81 (d, J=21.7 Hz, 2H), 3.50 (m, 1H), 3.93 (m, 1H), 4.18 (m, 4H), 5.05 (m, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[C:11]([C:15]([F:18])([F:17])[F:16])[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:19][N:20](C)C=O.C([Cu])#N>C(OCC)(=O)C>[OH:14][CH2:13][C:12]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:19]#[N:20])=[CH:3][CH:4]=2)=[N:9][S:10][C:11]=1[C:15]([F:18])([F:17])[F:16]
Reactant: CN(C)C=O
Reactant: OCc1c(-c2ccc(I)cc2)nsc1C(F)(F)F
Agent: N#C[Cu]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-c2nsc(C(F)(F)F)c2CO)cc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
Into a 50-mL round-bottom flask was placed [3-(4-iodophenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methanol (148 mg, 0.38 mmol, 1.00 equiv), N,N-dimethylformamide (5 mL), CuCN (52 mg). The resulting solution was stirred overnight at 130° C. in an oil bath. The resulting solution was diluted with 15 mL of ethyl acetate. The resulting mixture was washed with 5×10 mL of saturated aqueous sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (17:83), to afford 68 mg (62%) of 4-[4-(hydroxymethyl)-5-(trifluoromethyl)-1,2-thiazol-3-yl]benzonitrile as a white solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7](N2CCOCC2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1NC2N(CC3C=CC=CC=3[Cl:48])N=NC=2C(=O)N=1)(C)(C)C.C(N(CC)C1C=CC=CC=1)C.O=P(Cl)(Cl)Cl>>[C:1]([C:5]1[N:6]=[C:7]([Cl:48])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(=O)c2nnn(Cc3ccccc3Cl)c2[nH]1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
5-tert-Butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine A mixture of 5-tert-butyl-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(4H)-one (12.3 mg, 38.7 μmol) and N,N-diethylaniline (12.3 μL, 77.4 μmol) in POCl3 (250 μL, 2.73 mmol) was refluxed for 3 h under N2 atmosphere. The reaction mixture was concentrated in vacuo, diluted with EtOAc, washed with cold H2O and brine, dried over Na2SO4 and concentrated in vacuo to afford crude 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine. The residue was used for the next reaction without further purification.
Reaction SMILES: O.[NH2:2][NH2:3].CO[C:6](=[O:38])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]2[C:16]3[C:23]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH:9]=1>C1COCC1.CO>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]2[C:16]3[C:15]([NH:14][C:10]4[CH:9]=[C:8]([CH2:7][C:6]([NH:2][NH2:3])=[O:38])[CH:13]=[CH:12][CH:11]=4)=[N:20][CH:19]=[N:18][C:17]=3[O:21][C:22]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:25][CH:26]=1
Reactant: NN
Reactant: COC(=O)Cc1cccc(Nc2ncnc3oc(-c4ccccc4)c(-c4ccc(OC)cc4)c23)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Nc4cccc(CC(=O)NN)c4)c23)cc1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
Add 215 mg (4.3 mmol) of hydrazine hydrate at RT to 100 mg (0.215 mmol) of 3-{[5-(4-methoxy-phenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenylacetic acid methyl ester (Example 28), dissolved in 1.5 ml of THF and 2 ml of methanol. Stir the mixture at 65° C. for 1 h and at RT overnight and then concentrate under reduced pressure. After stirring with diisopropyl ether, filter off the solid with suction and dry under reduced pressure. 89.3 mg (89.3% of theory) of the target product are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][CH2:14][CH2:15][NH:16][C:17]2[C:29]3[N:28]4[C:23]([C:24]([C:30]5[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=5[CH3:38])=[CH:25][CH:26]=[CH:27]4)=[CH:22][C:21]=3[N:20]=[C:19]([CH3:39])[CH:18]=2)=O)=[CH:6][C:5]=1[O:40][CH3:41])[CH3:2].[AlH3].N(CC)(C)C>C1COCC1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:13][CH2:14][CH2:15][NH:16][C:17]2[C:29]3[N:28]4[C:23]([C:24]([C:30]5[C:31]([CH3:38])=[CH:32][C:33]([CH3:37])=[CH:34][C:35]=5[CH3:36])=[CH:25][CH:26]=[CH:27]4)=[CH:22][C:21]=3[N:20]=[C:19]([CH3:39])[CH:18]=2)=[CH:6][C:5]=1[O:40][CH3:41])[CH3:2]
Reactant: CCOc1ccc(CC(=O)NCCNc2cc(C)nc3cc4c(-c5c(C)cc(C)cc5C)cccn4c23)cc1OC
Agent: CCN(C)C
Agent: [AlH3]
Solvent: C1CCOC1
Product: CCOc1ccc(CCNCCNc2cc(C)nc3cc4c(-c5c(C)cc(C)cc5C)cccn4c23)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Treat a solution of 2-(4-ethoxy-3-methoxy-phenyl)-N-{2-[2-methyl-9-(2,4,6-trimethyl-phenyl)-pyridino[2,3-b]indolizin-4-ylamino]-ethyl}-acetamide (0.08 g, 0.145 mmol) in THF (5 mL) with AlH3.NMe2Et (3 mL, 1.45 mmol) and heat to reflux for 14 h. Cool the resulting mixture to ambient temperature, quench with Na2CO3.10H2O (0.3 g) and stir at ambient temperature for 15 min. Filter the solution through Celite and wash with several portions of CH2Cl2. Concentrate the filtrate in vacuo to dryness and purify by preparative TLC (10% MeOH in CH2Cl2 with 0.5% ammonium hydroxide) to the title compound as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O.[CH2:22](Br)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(OCC)(=O)C>[CH2:22]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCCCCCCCOc1ccc(C(=O)OC)cc1
Yield: 86.2 %

Procedure:
Into a flask were introduced methyl 4-hydroxybenzoate (251.0 g, 1.65 mol), potassium carbonate (276.37 g, 1.99 mol) and 1200 g of acetone. This was refluxed for 45 min followed by the drop-wise addition of 1-octylbromide (386.17 g, 1.99 mol) over a 1 hour period. The reaction mixture was refluxed for two days. Filtration of the cooled reaction mixture and evaporation of the filtrate gave an oil. This was taken up in ethyl acetate and extracted with 5% NaOH (2×100 ml) followed by water (2×100 ml). The organic layer was dried (MgSO4), concentrated, and transferred to a pre-weighed 1L three-necked flask. The contents of the flask were subjected to high vacuum distillation to remove the excess 1-octylbromide. The pot residue gave 376 g (86% yield) of methyl 4-octoxybenzoate.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10]O)=[CH:8][C:7]=1[O:14][CH3:15])(=[O:5])=[O:4].S(Cl)([Cl:19])=O>C(Cl)Cl>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10][Cl:19])=[CH:8][C:7]=1[O:14][CH3:15])(=[O:5])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CO)ccc1S(=O)(=O)N(C)C
Solvent: ClCCl
Product: COc1cc(CCl)ccc1S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.6 %

Procedure:
To a solution of OBS02014 (2.76 g, 10.55 mmol) in anhydrous DCM (50 mL) was added thionyl chloride (1.15 mL, 15.82 mmol). The mixture was stirred at room temperature for 2 h and the volatiles removed in vacuo. The residue was redissolved and co-evaporated three times with DCM (3×20 mL) to give OBS02016 as a brown oil (2.91 g, 99%). TLC [SiO2, EtOAc-n-hexane (1:1)] Rf=0.84; 1H-NMR (270 MHz, CDCl3)=2.96 (6H, s), 3.90 (3H, s), 4.55 (2H, s), 6.95 (1H, dd, J=1.8, 8.0), 7.01 (1H, d, J=1.8), 7.32 (1H, d, J=8.0).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]1([CH2:41][C:42]([O:44][CH3:45])=[O:43])[OH:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:46]O>C(OC)(OC)OC>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]1([CH2:41][C:42]([O:44][CH3:45])=[O:43])[O:40][CH3:46])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: COC(=O)C[C@]1(O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: COC(OC)OC
Product: COC(=O)C[C@]1(OC)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 60 °C

Procedure:
Methyl 2-((2S,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-2-hydroxytetrahydro-2H-pyran-2-yl)acetate (6) (1.4 g, 2.28 mmol) was dissolved in a solution of MeOH (6 mL) and trimethyl orthoformate (4 mL). PL-SO3H resin (Polymer Laboratories, 0.25 g, 3.75 mmol/g loading) was added and the reaction mixture was heated to 60° C. for 4.75 h. The mixture was filtered through cotton, rinsing with MeOH and CH2Cl2, then concentrated to a syrup (1.4 g, 99%). LC/MS tR=3.27 min, calcd for C38H42O8: 626.29, found 649.6 (M+Na)+.
Reaction SMILES: [C:1]([NH:8][C:9]1[C:18]([N+:19]([O-:21])=O)=[CH:17][C:16]([S:22]([NH:25][C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:27])(=[O:24])=[O:23])=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH2:14]2)([C:3]([O:5]CC)=O)=[O:2]>C(O)C.[Pt]>[C:26]([NH:25][S:22]([C:16]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9]2[NH:8][C:1](=[O:2])[C:3](=[O:5])[N:19]([OH:21])[C:18]=2[CH:17]=1)(=[O:24])=[O:23])([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:27]
Reactant: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])cc(S(=O)(=O)NC(=O)C(=O)OCC)c2c1CCCC2
Agent: [Pt]
Solvent: CCO
Product: CCOC(=O)C(=O)NS(=O)(=O)c1cc2c([nH]c(=O)c(=O)n2O)c2c1CCCC2

Procedure:
A suspension of 5-ethoxalylamino-8-ethoxalylaminosulfonyl-1,2,3,4-tetrahydro-6-nitronaphthalene (0.61 g, 1.3 mmol) in 100 ml of ethanol was hydrogenated at room temperature and atmospheric pressure in the presence of 60 mg of 5% platinum on carbon. After the theoretical absorption, the mixture was filtered and the filtrate was evaporated to dryness. The crude product (0.51g) was triturated with 50 ml of water, filtered off and then washed with water and a small amount of cold ethanol affording 0.28 g (53%) of the title compound. M.p. 267° C. decomp. (DSC); IR (KBr): 1725 cm-1 ; 1H-NMR (DMSO-d6) 1.23 (t,J=7Hz, 3H, CH3), 1.57-1.93 (m, 4H, 2CH2), 2.63-3.20 (m, 4H, 2CH2), 4.20 (q,J=7Hz, 2H, CH2), 7.98 (s, 1H, ArH), 11.5 (broad s, 1H, NH, only one exchangeable proton could be seen).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C:6]2=[O:9].[CH3:11][Si]([N-][Si](C)(C)C)(C)C.[Li+].C=O>O1CCCC1>[CH3:1][C:2]1([CH3:10])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][C:5](=[CH2:11])[C:6]2=[O:9]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC1(C)[C@H]2CCC(=O)[C@@H]1C2
Agent: C=O
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C1C[C@H]2C[C@@H](C1=O)C2(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
(1R,5S)-6,6-Dimethylbicyclo[3.1.1]heptan-2-one (0.938 mL, 920 mg) was added to tetrahydrofuran (50 mL) and the mixture was cooled to −78° C. using an isopropanol/dry ice bath. Lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 7.99 mL) was added, and the solution was stirred at −78° C. for 15 minutes. The solution was allowed to warm to 0° C. in a water/ice bath and the mixture was stirred for 45 minutes. Paraformaldehyde (2000 mg) was added. The solution was stirred at 0° C. for 15 minutes, allowed to warm to room temperature and stir for an additional four hours. The reaction was quenched with saturated aqueous ammonium chloride, extracted with diethyl ether, washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by flash column chromatography on silica gel using 5% ethyl acetate in hexanes.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:17][CH2:18][CH2:19]Br>C1(C)C=CC=CC=1>[C:11]1([N:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]3[CH2:18][CH2:19][N:1]=[C:2]23)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BrH:17]
Reactant: Nc1nc2ccccc2n1-c1ccccc1
Reactant: BrCCBr
Solvent: Cc1ccccc1
Product: Br
Product: c1ccc(N2C3=NCCN3c3ccccc32)cc1
Yield: 54.1 %

Procedure:
A solution of 2-amino-3-phenylbenzimidazole (4.18 g., 0.02 mole) and 1,2-dibromoethane (7.52 g., 0.04 mole) in toluene (40 ml.) was heated under reflux for 24 hours. After removal of the solvent the residual oil was crystallised from ethanol/ether. The product (0.950 g.) was recrystallised from ethanol/ether to give the title compound as its hydrobromide (0.875 g., m.p. 225°-228° C).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:26])[C@H:10]2[NH:14][C:15](=[S:25])[NH:16][C:17]([O:19][CH2:20][C:21](Cl)([Cl:23])[Cl:22])=[O:18])[C:7]=1[C:27]([O:29][CH:30]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])(=[O:3])[CH3:2].C(O)(=O)C.P([O-])(O)(O)=O.[K+]>[Zn].O1CCCC1>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:26])[C@H:10]2[NH:14][C:15]([NH2:16])=[S:25])[C:7]=1[C:27]([O:29][CH:30]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])(=[O:3])[CH3:2].[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:26])[C@H:10]2[NH:14][C:15]([NH:16][C:17]([O:19][CH2:20][CH:21]([Cl:22])[Cl:23])=[O:18])=[S:25])[C:7]=1[C:27]([O:29][CH:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:28])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=S)NC(=O)OCC(Cl)(Cl)Cl)[C@H]2SC1
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=S)NC(=O)OCC(Cl)Cl)[C@H]2SC1
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(N)=S)[C@H]2SC1
Reaction time: 1 h

Procedure:
A mixture of 1.16 g of (6R-trans)-3-[(acetyloxy)methyl]-8-oxo-7-[[thioxo[[(2,2,2-trichloroethoxy)carbonyl]amino]methyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, 660 mg of zinc dust, 0.25 ml of glacial acetic acid, 2 ml of 1M aqueous potassium dihydrogen phosphate and 10 ml of tetrahydrofuran was stirred for 1 hour and then filtered. The filtrate was subjected to flash chromatography, eluting with ethyl acetate:petroleum ether in a 1:1 to 1:2 gradient, giving 340 mg of (6R-trans)-3-[(acetyloxy)methyl]-7-[(aminothioxomethyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester and 30 mg of (6R-trans)-3-[(acetyloxy)methyl]-7-[[[[(2,2-dichloroethoxy)carbonyl]amino]thioxomethyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1.[OH:16][CH:17]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]1.Cl>C(O)C>[OH:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:2]2[N:7]=[C:6]([C:8]([NH:10][C:11]3[NH:15][N:14]=[N:13][N:12]=3)=[O:9])[CH:5]=[N:4][CH:3]=2)[CH2:18]1
Reactant: O=C(Nc1nnn[nH]1)c1cncc(Cl)n1
Reactant: OC1CCCNC1
Agent: Cl
Solvent: CCO
Product: O=C(Nc1nnn[nH]1)c1cncc(N2CCCC(O)C2)n1

Procedure:
To a suspension of 1.13 g of 6-chloro-N-(1H-5-tetrazolyl)pyrazine-2-carboxamide in 20 ml of ethanol, 1.52 g of 3-hydroxypiperidine was added, and the mixture was refluxed for 6 hours. The reaction mixture was adjusted with ethanolic hydrogen chloride to pH 3. The precipitate was collected by filtration, and recrystalized from a mixture of dimethylsulfoxide and methanol affording 0.93 g of the desired compound as yellow crystals, m.p. 257°-259° C. (decomp.).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.[Br:26][CH2:27][C:28]([NH:30][C:31]1[CH:35]=[CH:34][O:33][N:32]=1)=[O:29]>C(#N)C.C(OCC)C>[Br-:26].[F:25][C:21]1[CH:20]=[C:19]([C:12]2([C:10]([O:9][C@@H:3]3[CH:4]4[CH2:5][CH2:6][N+:1]([CH2:27][C:28](=[O:29])[NH:30][C:31]5[CH:35]=[CH:34][O:33][N:32]=5)([CH2:8][CH2:7]4)[CH2:2]3)=[O:11])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2cccc(F)c2)CCCCCC1
Reactant: O=C(CBr)Nc1ccon1
Solvent: CC#N
Solvent: CCOCC
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C1(c3cccc(F)c3)CCCCCC1)C2)Nc1ccon1
Product: [Br-]
Reaction time: 8 h
Yield: 60.2 %

Procedure:
1-(3-Fluoro-phenyl)-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 12d) (50 mg) and 2-bromo-N-isoxazol-3-yl-acetamide (Example 13a) (30 mg) were dissolved in acetonitrile (4 mL) and stirred overnight. The solution was diluted with diethyl ether (12 mL) and stirred overnight. The resulting crystals were filtered off, washed with ether (3×10 mL) and dried to afford the titled compound as a solid (48 mg).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][NH:13][CH2:14]2)[CH2:10]1)=[O:8].Cl[C:24]1[N:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[N:25]=1>>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:10][CH:11]2[CH:15]([CH2:14][N:13]([C:24]3[N:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[N:25]=3)[CH2:12]2)[CH2:16]1)=[O:8]
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNCC2C1
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4ccccc4-c4ccccc4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 17 and 2-chloro-4,6-dimethyl-pyrimidine. MS (ESI) mass calcd. for C25H26N4O, 398.5; m/z found, 399.2 [M+H]+.