Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:19]=[CH:18]2)=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:28]I>>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:19]=[C:18]2[CH3:28])=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(-n2cnc(-c3ccccc3)c2)cc1
Product: Cc1nc(-c2ccccc2)cn1-c1ccc(CCO[Si](C)(C)C(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 5 from 1-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]-4-phenyl-1H-imidazole and methyl iodide. MS (ESI) m/z 393 [M+H]+.
Reaction SMILES: N1C=CN=C1.[OH:6][CH2:7][C@@H:8]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10].[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C=O)C>[CH3:12][N:11]([C:9](=[O:10])[C@H:8]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:7][O:6][Si:26]([CH3:28])([CH3:27])[C:29]([CH3:32])([CH3:31])[CH3:30])[O:13][CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CON(C)C(=O)[C@@H](CO)NC(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CON(C)C(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74 %

Procedure:
Imidazole (1.8 g, 26.5 mmol) was added to a solution of (R)-benzyl 3-hydroxy-1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (3 g, 10.6 mmol) in DMF (dimethyl formamide, 15 mL) followed by TBDMSiCl (tert-butyldimethylsilyl chloride, 2.4 g, 15.95 mmol). The reaction stirred for 12 hrs at room temperature under nitrogen atmosphere and was quenched with aqueous ammonium chloride (100 ml). The aqueous layer was extracted with methylene chloride (200 mL) and ethyl acetate (100 mL) and the organic layers were washed with brine and concentrated. The crude product was purified by column chromatography using 10% EtOAc (ethylacetate)-hexanes to give an oil (3 g, 74% yield). 1H NMR (400 MHz, CDCl3) δ=0 (s, 6H), 0.9 (s, 9H), 3.2 (s, 3H), 3.8 (s, 3H), 3.8-3.9 (m, 2H), 4.8 (broad s, 1H), 5.1 (q, 2H), 5.7 (d, 1H), 7.2-7.4 (m, 5H).
Reaction SMILES: [I:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]C(C)(C)C)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O[CH2:27][CH:28]1[CH2:30][CH2:29]1>CCO.CCO.CCO.CCO.[Ti]>[I:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:27][CH:28]3[CH2:30][CH2:29]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(I)cccc1-2
Reactant: OCC1CC1
Agent: [Ti]
Solvent: CCO
Product: O=C(OCC1CC1)c1ncn2c1[C@@H]1CCN1C(=O)c1c(I)cccc1-2
Reaction time: 0.5 h

Procedure:
3.0 g (5.5 mmol) of tert.butyl (S)-12,12a-dihydro-8-iodo-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate, 20 ml (250 mmol) of hydroxymethyl-cyclopropane and 0.7 g (3 mmol) of tetraethyl orthotitanate are stirred at 120° overnight, the solution is evaporated to dryness, the residue is taken up in chloroform and stirred for 0.5 hour with 30 ml of a saturated potassium fluoride solution. The resulting emulsion is filtered through siliceous earth, the organic phase is separated, washed with water, dried over magnesium sulphate and evaporated. By recrystallization from ethyl acetate there is obtained cyclopropylmethyl (S)-12,12a-dihydro-8-iodo-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate of melting point 190°-191°.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=[CH:2]1.[Br:12][C:13]1[C:14]([Cl:20])=[C:15](F)[CH:16]=[CH:17][CH:18]=1>>[ClH:20].[Br:12][C:13]1[C:14]([Cl:20])=[C:15]([O:11][CH:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]3[S:1][CH:2]=[CH:3][C:4]2=3)[CH:16]=[CH:17][CH:18]=1
Reactant: Fc1cccc(Br)c1Cl
Reactant: OC1CCNCc2sccc21
Product: Cl
Product: Clc1c(Br)cccc1OC1CCNCc2sccc21

Procedure:
The same method as in Example 3 was conducted using 5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepin-4-ol (Reference Example 35) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-bromo-2-chloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4]Cl.[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1>>[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH2:4][C:3]4[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:2]=4[Cl:1])[CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1
Reactant: ClCc1cc(Cl)ccc1Cl
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(Cc3cc(Cl)ccc3Cl)CC2)nn1

Procedure:
Following the procedure of Example 11, making variations only as required to use 2,5-dichlorobenzyl chloride in place of 2-trifluoromethylbenzyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (43% yield). 1H NMR (300 MHz, CDCl3) δ 7.96-8.04, 7.53, 7.16-7.33, 6.96, 3.75-3.84, 3.64, 3.56, 2.62-2.70, 1.53, 1.51, 0.70-0.83, 0.43-0.51, 0.06-0.13. MS (ES+) m/z 434 (M+1).
Reaction SMILES: [C@@H:1]1([N:12]=[N+:13]=[N-:14])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].Cl[C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O[C:39](=[O:41])[CH3:40])(=O)C>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:2]([O:3][C@@H:2]1[C@@H:4]([O:5][C:4](=[O:5])[CH3:6])[C@H:6]([O:7][C:39](=[O:41])[CH3:40])[C@@H:8]([CH2:10][O:11][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][C@H:1]1[N:12]=[N+:13]=[N-:14])(=[O:3])[CH3:1]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Reactant: [N-]=[N+]=N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](N=[N+]=[N-])O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1OC(C)=O
Temperature: 70 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
Composition 4 (3.05 g) was dissolved in dry pyridine (50 ml), chlorotriphenyl-methane (5.01 g) was added and the reaction mixture was stirred at 70° C. for three hours. It was cooled to 0° C., acetic anhydride (6.36 ml) was added dropwise and the mixture was stirred overnight at room temperature. It was poured into ice-water and was diluted with chloroform (300 ml). The organic layer was washed subsequently with water, 2M hydrochloric acid, water, was dried and evaporated to leave 2,3,4-tri-O-acetyl-6-O-trityl-β-D-glucopyranosyl azide (5, 7.67 g, 90%).
Reaction SMILES: CS(C)=O.[C:5]([C:11]([O:13][CH3:14])=[O:12])#[C:6][C:7]([O:9][CH3:10])=[O:8].[NH2:15][C:16]1[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:19]=[C:18]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[C:17]=1[C:32]#[N:33].C(=O)([O-])[O-].[K+].[K+]>O>[NH2:33][C:32]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:11]([O:13][CH3:14])=[O:12])[N:15]=[C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)[C:17]=12
Reactant: COC(=O)C#CC(=O)OC
Reactant: N#Cc1c(-c2cccs2)nn(-c2ccccc2)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1nc2c(c(-c3cccs3)nn2-c2ccccc2)c(N)c1C(=O)OC
Temperature: 25 °C
Reaction time: 60 h
Yield: 85.7 %

Procedure:
A dimethylsulfoxide (20 ml) solution of 10.0 g (70 mmol) of dimethyl acetylenedicarboxylate was dropwise added to a mixture comprised of 2.66 g (10 mmol) of 5-amino-1-phenyl-3-(thiophen-2-yl)pyrazole-4-carbonitrile, 27.6 g (200 mmol) of anhydrous potassium carbonate and 300 ml of dimethylsulfoxide, while cooling with ice, over a period of 30 minutes, and then stirred for further 60 hours at room temperature. During the stirring, the reaction liquid was changed from brown to greenish brown. After the reaction, the liquid reaction mixture was poured into 500 ml of water with ice and stirred for 30 minutes at room temperature. The blackish brown solid thus precipitated was taken out by filtration, dried in air and added to 20 ml of methanol. The white crystals thus formed were taken out by filtration and recrystallized from methanol to obtain 3.50 g of the entitled product as colorless crystals having a melting point of 178° to 180° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([S:21](Cl)(=[O:23])=[O:22])[CH:17]=[CH:18][C:19]=1[CH3:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([S:21]([N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)(=[O:23])=[O:22])[CH:17]=[CH:18][C:19]=1[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1Cl
Reactant: Fc1ccc(C2CCCN2)cc1
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2ccc(F)cc2)cc1Cl

Procedure:
The title compound, off-white solid, m.p. 134° C. and MS: m/e=353 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 3-chloro-4-methyl-benzenesulfonyl chloride.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH:16]=[O:17].[BH4-].[Na+]>C(O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]2[O:17][CH2:16][C:12]3[N:11]([CH:15]=[CH:14][CH:13]=3)[C:3]=2[CH:4]=1)([O-:10])=[O:9]
Reactant: O=Cc1cccn1-c1cc([N+](=O)[O-])ccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc2c(c1)-n1cccc1CO2
Temperature: 60 °C
Reaction time: 5 h
Yield: 68.4 %

Procedure:
1-(2-fluoro-5-nitrophenyl)-1H-pyrrole-2-carbaldehyde (3.95 g, 16.9 mmol) was suspended in ethanol (100 mL) in a 250 mL round bottomed flask and treated with sodium borohydride (767 mg, 20.3 mmol, 1.2 equiv.). The resulting mixture was stirred at 60° C. for 5 hours. The reaction mixture was cooled to ambient temperature, transferred to a separatory funnel and partitioned (CH2Cl2//H2O). The organic phase was washed with H2O (3×50 mL), brine (3×50 mL), dried over Na2SO4 and evaporated in vacuo to give a light yellow residue. The residue was purified by flash chromatography (hexanes→1:9 EtOAc/hexanes) to afford the title compound as a light yellow solid (2.5 g, 68%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:30]=[C:31]=[O:32])[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1>>[CH3:29][O:28][C:26]1[CH:25]=[C:24]([NH:30][C:31](=[O:32])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Reactant: COc1cc(N=C=O)cc(OC)c1
Product: COc1cc(NC(=O)Nc2ccc(-c3c(C(N)=O)[nH]c4cnccc34)cc2)cc(OC)c1

Procedure:
87 mg of solid yellow 3-{4-[3-(3,5-dimethoxyphenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 3,5-dimethoxyphenyl isocyanate.
Reaction SMILES: [N+:1]([CH2:4][CH:5]([C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)[CH2:6][C:7]([O:9]CC)=[O:8])([O-:3])=[O:2].[OH-].[Na+].Cl>CO>[N+:1]([CH2:4][CH:5]([C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)[CH2:6][C:7]([OH:9])=[O:8])([O-:3])=[O:2]
Reactant: CCOC(=O)CC(C[N+](=O)[O-])c1ccsc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CC(C[N+](=O)[O-])c1ccsc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a solution of ethyl 4-nitro-3-(thiophen-3-yl)butanoate (4.3 g, 18.2 mmol) in MeOH (40 mL) at 0° C. was added 3 N aqueous NaOH (10 mL). The resulting mixture was stirred at room temperature overnight. 2 N HCl was then added to adjust pH to 3˜4 followed by extraction with DCM. The organic extract was washed with brine and dried over anhydrous Na2SO4. After filtration, the solution was concentrated to give the title compound (3.4 g, 87%).
Reaction SMILES: COC1C=CC(C2CCC3C(=CC=C(OC)C=3)C2)=C(N2CC3C(=CC=C(O)C=3)C2)C=1.Cl.ClCCN1CCCCC1.C[O:42][C:43]1[CH:44]=[CH:45][C:46]([CH:67]2[CH2:76][CH2:75][C:74]3[C:69](=[CH:70][CH:71]=[C:72]([O:77]C)[CH:73]=3)[CH2:68]2)=[C:47]([N:49]2[CH2:57][C:56]3[C:51](=[CH:52][CH:53]=[C:54]([O:58][CH2:59][CH2:60][N:61]4[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]4)[CH:55]=3)[CH2:50]2)[CH:48]=1>>[OH:42][C:43]1[CH:44]=[CH:45][C:46]([CH:67]2[CH2:76][CH2:75][C:74]3[CH:73]=[C:72]([OH:77])[CH:71]=[CH:70][C:69]=3[CH2:68]2)=[C:47]([N:49]2[CH2:57][C:56]3[C:51](=[CH:52][CH:53]=[C:54]([O:58][CH2:59][CH2:60][N:61]4[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]4)[CH:55]=3)[CH2:50]2)[CH:48]=1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1N1Cc3ccc(OCCN4CCCCC4)cc3C1)C2
Agent: COc1ccc2c(c1)CCC(c1ccc(OC)cc1N1Cc3ccc(O)cc3C1)C2
Agent: Cl
Agent: ClCCN1CCCCC1
Product: Oc1ccc2c(c1)CCC(c1ccc(O)cc1N1Cc3ccc(OCCN4CCCCC4)cc3C1)C2
Yield: 59.7 %

Procedure:
Synthesized from 2-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]-2,3-dihydro-1H-isoindol-5-ol and 1-(2-chloroethyl)piperidine hydrochloride according to an analogous synthetic method to Preparation Example 40, 2-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]-5-(2-piperidin-1-ylethoxy)-2,3-dihydro-1H-isoindole (218 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (123 mg).
Reaction SMILES: [CH2:1]([C:3]1([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:14][CH:13]=[CH:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:5]=[CH:4]1)[CH3:2].[ClH:25].[NH2:26][OH:27]>O>[ClH:25].[CH2:1]([C:3]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:14][CH:13]=[CH:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH:6]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH2:5])[CH:4]=[N:26][OH:27])[CH3:2].[C:15]1([CH:6]([NH2:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:3]([CH2:1][CH3:2])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:4][NH2:26])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NO
Reactant: CCCCC1(CC)C=NC(c2ccccc2)CC=CCCC=CC1
Agent: Cl
Solvent: O
Product: CCCCC(C=NO)(CC)CC=CCCC=CCC(N)c1ccccc1
Product: CCCCC(CC)(CN)CCCCCCCCC(N)c1ccccc1

Procedure:
Reaction of 3-ethyl-3-n-butyl-12-phenyl-1-aza-1,5,9-cyclododecatriene with hydroxylamine hydrochloride, in the presence of hydrochloric acid and water, to 2-ethyl-2-n-butyl-11-phenyl-11-amino-undeca-4,8-dienal-oxime, and hydrogenation of this to yield 1-phenyl-10-ethyl-10-n-butyl-1,11-diaminoundecane; b.p. 155°-158° C./5 Pa; nD20 =1.5045.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[CH2:3][CH:4]1[CH2:7][CH:6]([C:8](O)=[O:9])[CH2:5]1.Cl.[CH3:14][NH:15][O:16][CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O.C(N(CC)CC)C.CN(C=O)C>[CH3:17][O:16][N:15]([CH3:14])[C:8]([CH:6]1[CH2:7][CH:4]([CH2:3][C:2]([CH3:12])([CH3:11])[CH3:1])[CH2:5]1)=[O:9]
Reactant: CC(C)(C)CC1CC(C(=O)O)C1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CC(CC(C)(C)C)C1
Yield: 101 %

Procedure:
3-(2,2-Dimethylpropyl)cyclobutanecarboxylic acid (75.2 g) and DMF (600 mL) were mixed. After an addition of N,O-dimethylhydroxylamine hydrochloride (51.7 g), triethylamine (92.4 mL), HOBt.H2O (81.2 g) and WSC.HCl (101.6 g) to the mixture, the mixture was stirred at RT overnight. Water was poured into the reaction and the mixture was extracted with ethyl acetate/hexane=1/1. The organic layer was washed with 1 N hydrochloric acid, water, aqueous 10 w/v % sodium carbonate and water, then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo to give the title compound (95.2 g) as a crude product.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]([NH:10][C@H:11]([C:16]([NH:18][C@@H:19]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)[CH3:20])=[O:17])[CH2:12][CH2:13][CH2:14][NH2:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:34].[N:35]1([C:40](N)=[NH:41])C=CC=N1.C(N(CC)CC)C.CCN(C(C)C)C(C)C>CN(C)C=O>[ClH:34].[C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]([NH:10][C@H:11]([C:16]([NH:18][C@@H:19]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)[CH3:20])=[O:17])[CH2:12][CH2:13][CH2:14][NH:15][C:40](=[NH:35])[NH2:41])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](NC(=O)[C@H](CCCN)NC(=O)C(c1ccccc1)c1ccccc1)c1ccc(Br)cc1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)C(c1ccccc1)c1ccccc1)c1ccc(Br)cc1
Yield: 74.3 %

Procedure:
Prepared according to the method described in Example 2(f) above from (R)-N2 -(diphenylacetyl)-(S)-N-[1-(4-bromophenyl)ethyl]ornithine amide (free base; 0.20 g; 0.39 mmol; from step (d) above), 1H-pyrazole-1-carboxamidine mono hydrochloride (0.06 g; 0.39 mmol), triethylamine (0.08 g; 0.78 mmol; instead of DiPEA) and dimethyl formamide (1 mL), 5 hours reaction time. The solution was concentrated under vacuum and the crude product chromatographed on silica gel eluting with MeOH:CHCl3 :ammonium hydroxide (3:6:1). Conversion of the eluted compound to the hydrochloride salt gave the title compound as a white solid (0.17 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]O)=[C:11]([F:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.P(Br)(Br)[Br:25]>C(OCC)C.O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][Br:25])=[C:11]([F:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc(OCc2ccccc2)cc1F
Reactant: BrP(Br)Br
Solvent: O
Solvent: CCOCC
Solvent: c1ccncc1
Product: Fc1cc(OCc2ccccc2)ccc1CBr

Procedure:
A stirred, cooled (ice bath) solution of 4-benzyloxy-2-fluoro-benzyl alcohol (Compound 9, 15 g, 64.6 mmol) in anhydrous diethyl ether (100 mL) was treated with pyridine (5.75 mL, 71.1 mmol) followed by phosphorus tribromide (6.13 mL, 64.6 mmol). After 90 min. the reaction mixture was diluted with water and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as an oil that solidified on standing (18 g, 89.5%).
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[N:15][CH:16]=2)[CH2:8][CH2:7][NH:6]1)([O-:3])=[O:2].C[O:19][C:20](=O)[C:21]#[CH:22]>CO>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][N:9]2[C:5]3=[C:4]([N+:1]([O-:3])=[O:2])[CH:22]=[CH:21][C:20](=[O:19])[N:6]3[CH2:7][CH2:8]2)=[CH:16][N:15]=1
Reactant: C#CC(=O)OC
Reactant: O=[N+]([O-])C=C1NCCN1Cc1ccc(Cl)nc1
Solvent: CO
Product: O=c1ccc([N+](=O)[O-])c2n1CCN2Cc1ccc(Cl)nc1
Yield: 52.3 %

Procedure:
A mixed solution of 2-nitromethylene-3-(2-chloro-5-pyridylmethyl) imidazolidine (12.7 g), propiolic acid methyl ester (4.2 g) and methanol (100 ml) was refluxed under heating for about 20 hours. Subsequently methanol was distilled off under reduced pressure, and the residue was refined by a silica-gel column chromatography to give the desired 1,2,3,5-tetrahydro-1-(2-chloro-5-pyridylmethyl)-8-nitroimidazo[1,2-a] pyridin -5-one (8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[Si:23]([O:30][C@H:31]([C:47]1[CH:52]=[CH:51][C:50]([OH:53])=[C:49]([CH2:54][OH:55])[CH:48]=1)[CH2:32][NH:33][C:34]([CH3:46])([CH3:45])[CH2:35][C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=1)[C:39](O)=[O:40])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[Si:23]([O:30][C@H:31]([C:47]1[CH:52]=[CH:51][C:50]([OH:53])=[C:49]([CH2:54][OH:55])[CH:48]=1)[CH2:32][NH:33][C:34]([CH3:46])([CH3:45])[CH2:35][C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=1)[C:39]([NH:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:40])([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:25])[CH3:24]
Reactant: NCCc1ccc(Cl)cc1
Reactant: CC(C)(Cc1cccc(C(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(Cc1cccc(C(=O)NCCc2ccc(Cl)cc2)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Reaction time: 48 h

Procedure:
2-(4-Chlorophenyl)ethylamine (164 mg, 1.06 mmol) was added to a mixture of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (203 mg, 1.06 mmol), 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]-2-methylpropyl}benzoic acid (Preparation 37) (500 mg, 1.06 mmol), 1-hydroxybenzotriazole hydrate (160 mg, 1.06 mmol) and triethylamine (440 □l, 3.20 mmol) in dichloromethane (30 ml). The resulting solution was stirred for 48 hours under nitrogen. The solvent was removed in vacuo and the residue taken up in ethyl acetate (30 ml), washed with water (20 ml), sodium hydrogen carbonate (0.5 M, 2×20 ml), brine (2×20 ml), dried (sodium sulfate) and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 by volume) to furnish the title compound, the resulting material was taken up in methanol and evaporated, then taken up in diethylether and evaporated to yield a white foam (480 mg). 1H NMR (400 MHz, CD3OD) δ=7.64-7.60 (2H, m), 7.36-7.19 (7H, m), 7.05 (1H, dd), 6.72 (1H, d), 4.71-4.67 (1H, m), 4.60 (2H, dd), 3.57 (2H, t), 2.93-2.61 (6H, m), 1.09 (3H, s), 1.06 (3H, s), 0.78 (9H, s), −0.04 (3H, s), −0.22 (3H, s). LRMS (electrospray) m/z 611 [M+H]+, 633 [M+Na]+
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:26]=[CH:25][C:24]([Cl:27])=[N:23][C:8]=3[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])=[N:10][CH:11]([O:12]C(=O)C)[C:5]2=[N:4][NH:3]1.C(O)CC.[OH-].[K+].C(O)(=O)C>O>[O:1]=[C:2]1[N:6]2[C:7]3[CH:26]=[CH:25][C:24]([Cl:27])=[N:23][C:8]=3[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])=[N:10][CH:11]([OH:12])[C:5]2=[N:4][NH:3]1
Reactant: CC(=O)OC1N=C(c2ccccc2Cl)c2nc(Cl)ccc2-n2c1n[nH]c2=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCCO
Solvent: O
Product: O=c1[nH]nc2n1-c1ccc(Cl)nc1C(c1ccccc1Cl)=NC2O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
9 grams of 1-keto-4-acetoxy-6-(o-chlorophenyl)-8-chloro-1,2-dihydro-4H-s-triazolo-(4,3-a)-pyrido-(2,3-f)-(1,4)-diazepine were stirred with 60 ml. of n-propanol and a mixture of 10 grams of powdered potassium hydroxide and 100 ml. of n-propanol added. The mixture was stirred for 15 minutes at room temperature. Then it was acidified with glacial acetic acid and 600 ml. of water added. The reaction product crystallized out. It was filtered off with suction and then washed with water. The product can be recrystallized from dimethylformamide-ether whereupon it is subsequently boiled with ethanol for 30 minutes for the complete removal of the dimethyl formamide. Yield 5 grams; M.P. 260°-262° C.