Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH2:13]OS(C)(=O)=O)[CH2:10][CH:11]=[CH2:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH2:13][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[CH2:10][CH:11]=[CH2:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: c1c[nH]cn1
Reactant: C=CC[C@H](COS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Solvent: CC#N
Product: C=CC[C@H](Cn1ccnc1)c1ccc(Cl)c(Cl)c1
Yield: 63.7 %

Procedure:
4(S)-(3,4-Dichlorophenyl)-5-(methanesulphonyloxy)pent-1-ene (8.25 g) (see Preparation 93) and imidazole (5.3 g) were dissolved in anhydrous acetonitrile (80 ml) and the mixture heated under reflux for 6 days. The solvent was removed under reduced pressure to give a residue which was partitioned between diethyl ether and aqueous saturated sodium hydrogen carbonate solution (pH of the aqueous phase was kept >7). The phases were separated and the aqueous phase extracted with diethyl ether. The combined organic extracts were then washed with water, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to give a residue which was chromatographed on silica gel, eluting with a solvent gradient of 98:2 changing to 95:5, by volume, dichloromethane:methanol to give 4(S)-(3,4-dichlorophenyl)-5-(imidazol-1-yl)pent-1-ene (4.78 g) as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH2:6][CH2:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C:3](O)=[O:4].C(Cl)(=O)C([Cl:22])=O>>[CH3:1][C:2]([CH3:18])([CH2:6][CH2:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C:3]([Cl:22])=[O:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(CCC(=O)OCc1ccccc1)C(=O)O
Product: CC(C)(CCC(=O)OCc1ccccc1)C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3.1 g of 2,2-dimethyl-4-benzyloxycarbonylbutyric acid and 3.3 ml of oxalyl chloride was refuxed for 1 h. After being cooled to room temperature, the solution was concentrated in vacuo and dried overnight The obtained oil was not further purified for the next reaction.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=O)[C:10]([CH3:20])([CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C:10]([CH3:20])([CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)C(=O)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Product: CC1(C)Cc2ccccc2N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
To a solution of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-3,3-dimethyl-4-quinolinone (128 mg, 0.47 mmol) in methylanol (2 mL) at 0° C. was added portionwise sodium borohydride (18 mg, 0.47 mmol) and the reaction mixture was stirred at 0° C. for 3 h. The reaction mixture was then quenched with sat'd NH4Cl (2 mL), extracted with ethyl acetate (2×5 mL), dried (Na2SO4) and concentrated. A solution of this crude material in ethyl acetate (3 mL) was hydrogenated under an atmosphere of hydrogen with 10% Pd/C (20 mg) and a trace of conc. H2SO4 at rt for 16 h. Filtration over Celite™ afforded 100 mg (84%) of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-3,3-dimethylquinoline. Data for 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-3,3-dimethylquinoline:
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[CH2:6][N:5]=[N:4][CH2:3]1.C[Si]([N:12]=[C:13]=[S:14])(C)C>C(O)C>[CH3:1][C:2]1([CH3:7])[CH2:6][N:5]([C:13](=[S:14])[NH2:12])[N:4]=[CH:3]1
Reactant: CC1(C)CN=NC1
Reactant: C[Si](C)(C)N=C=S
Solvent: CCO
Product: CC1(C)C=NN(C(N)=S)C1
Yield: 2.5 %

Procedure:
3.0 g (1 mol equiv.) 4,4-Dimethyl-4,5-dihydro-3H-pyrazole (synthesized as described in WO 2008/034863) and 5.6 mL (1.3 mol equiv.) trimethylsilyl isothiocyanate were added to 30 mL ethanol and the reaction mixture was refluxed for 5 hours. Silica gel was added and volatiles were removed under reduced pressure. Purification by flash chromatography on silica gel (Et2O:PA=2:1) afforded 3.91 g (81%) 4,4-dimethyl-4,5-dihydro-pyrazole-1-carbothioic acid amide. 1H NMR (400 MHz, CDCl3) δ 1.27 (s, 6H), 3.94 (s, 2H), 5.82-6.34 (br.s., 1H), 6.50-7.00 (br.s., 1H), 6.80 (s, 1H).
Reaction SMILES: [CH:1]([P:4](=[O:10])([CH:7]([CH3:9])[CH3:8])[CH:5]=[CH2:6])([CH3:3])[CH3:2].[CH3:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:12]([CH3:11])[CH2:6][CH2:5][P:4]([CH:7]([CH3:9])[CH3:8])([CH:1]([CH3:3])[CH3:2])=[O:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=CP(=O)(C(C)C)C(C)C
Reactant: CNCc1ccccc1
Product: CC(C)P(=O)(CCN(C)Cc1ccccc1)C(C)C
Temperature: 200 °C

Procedure:
Diisopropyl(vinyl)phosphine oxide (1.00 g, 6.24 mmol) was combined with N-methylbenzylamine (1.61 mL, 12.48 mmol) in a microwave vial and heated at 200° C. for 4 h total (reaction progress checked after 2 h). The crude mixture was directly purified by flash chromatography (0-10% MeOH/CH2Cl2). Coelution of the product with minor impurities required a second column (0-10% MeOH (w/2 N NH3)/CH2Cl2) to give clean product as a yellow oil. 1H NMR (CDCl3, 600 MHz) δ 7.30-7.20 (m, 5H), 3.50 (s, 2H), 2.76-2.70 (m, 2H), 2.20 (s, 3H), 2.00-1.92 (m, 2H), 1.90-1.84 (m, 2H), 1.17 (dd, J=14.6, 7.2 Hz, 6H), 1.12 (dd, J=15.1, 7.1 Hz, 6H). MS: cal'd 282 (MH+), exp 282 (MH+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:9][CH:10]([O:25][CH2:26][CH3:27])[CH2:11][O:12][C:13]1[C:22]([CH3:23])=[CH:21][C:16]([C:17](OC)=[O:18])=[C:15]([CH3:24])[CH:14]=1)[CH3:8].C(O)C>C1COCC1>[CH2:26]([O:25][CH:10]([O:9][CH2:7][CH3:8])[CH2:11][O:12][C:13]1[C:22]([CH3:23])=[CH:21][C:16]([CH2:17][OH:18])=[C:15]([CH3:24])[CH:14]=1)[CH3:27]
Reactant: CCOC(COc1cc(C)c(C(=O)OC)cc1C)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(COc1cc(C)c(CO)cc1C)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Lithium aluminium hydride solution (1M in THF, 1.17 mL) was added dropwise to a solution of methyl 4-(2,2-diethoxyethoxy)-2,5-dimethylbenzoate (example 18, step c) (0.231 g) in THF (20 mL) at 0° C. The resulting mixture was allowed to warm to RT and stirred for 1 h. Ethanol (0.5 mL) was cautiously added and the reaction concentrated. The residue was partitioned between 1M NaOH (50 mL) and ethyl acetate (100 mL). The aqueous was separated and extracted with ethyl acetate (2×50 mL). The combined organics were washed with brine (50 mL), dried over magnesium sulphate, filtered and evaporated to give the subtitled compound as a clear oil. Yield 0.20 g.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[Br-].[K+].Cl[CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH3:19].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:19][O:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: COCCCCCl
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COCCCCNc1ccccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
Toluene (500 mL) was added to o-nitroaniline (50.0 g, 0.362 mol), tetrabutylammonium bromide (58.3 g, 0.181 mol) and potassium bromide (43.1 g, 0.362 mol). 1-Chloro-4-methoxybutane (66.6 g, 0.543 mol) and 50 w/v % aqueous sodium hydroxide solution (145 mL, 1.81 mol) were added at 20-30° C. The reaction mixture was heated to 85-95° C., and stirred for 6 hr. After allowing to cool to 20-30° C., the reaction mixture was washed successively with water (250 mL), 1N hydrochloric acid (250 mL×2), 5 w/v % sodium bicarbonate water (250 mL) and water (250 mL). The organic layer was concentrated under reduced pressure to the content (250 mL), and toluene (100 mL) was added to give a toluene solution (350 mL) of N-(4-methoxybutyl)-2-nitroaniline (yield 100%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[C:13]4[CH:20]=[C:19]([C:21]([OH:23])=O)[NH:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:10][C:4]=2[S:3]1.[CH3:24][N:25]([CH3:32])[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:24][N:25]([CH3:32])[CH:26]1[CH2:31][CH2:30][N:29]([C:21]([C:19]2[NH:18][C:14]3[N:15]=[CH:16][N:17]=[C:12]([NH:11][C:9]4[CH:8]=[CH:7][C:5]5[NH:6][C:2](=[O:1])[S:3][C:4]=5[CH:10]=4)[C:13]=3[CH:20]=2)=[O:23])[CH2:28][CH2:27]1
Reactant: CN(C)C1CCNCC1
Reactant: O=C(O)c1cc2c(Nc3ccc4[nH]c(=O)sc4c3)ncnc2[nH]1
Product: CN(C)C1CCN(C(=O)c2cc3c(Nc4ccc5[nH]c(=O)sc5c4)ncnc3[nH]2)CC1

Procedure:
150 mg (458 μmol) 4-[(2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (prepared according to example 30) were transformed in analogy to example 4 using N,N-dimethylpiperidin-4-amine to give after working up and purification 10 mg (5%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]3[C:16]([O:18]CC3C=CC=CC=3)=[O:17])=[N:7][C:6]=2[CH:26]=1>C(O)C.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]3[C:16]([OH:18])=[O:17])=[N:7][C:6]=2[CH:26]=1
Reactant: Cc1ccc2oc(N3CCCC[C@H]3C(=O)OCc3ccccc3)nc2c1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc2oc(N3CCCC[C@H]3C(=O)O)nc2c1
Reaction time: 3 h
Yield: 99.2 %

Procedure:
Benzyl (2S)-1-(5-methyl-1,3-benzoxazol-2-yl)-2-piperidinecarboxylate (0.19 g) [see Preparation 17] was dissolved in ethanol (5 ml) and 10% palladium on carbon (0.05 g) was added. The reaction mixture was hydrogenated at 15 psi for 3 hours at room temperature, after which time 10% palladium on carbon (25 mg) was added and the mixture was hydrogenated for a further 1 hr, the catalyst was then filtered off through a plug of arabocel and washed with ethanol. The solvent was removed under reduced pressure to afford (2S)-1-(5-methyl-1,3-benzoxazol-2-yl)-2-piperidinecarboxylic acid (0.14 g) as a solid.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[H-].[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[O:21])[CH3:20])[N:14]=1.C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.Cl>C1COCC1.C(O)C>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[O:21])[CH2:20][C:3]([C:2]([F:1])([F:8])[F:9])=[O:5])[N:14]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1cccc(Cl)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(CC(=O)C(F)(F)F)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a mixture of ethyl trifluoroacetate (17.2 g) and sodium hydride (60% in oil, 5.7 g) in THF (200 ml) is added a solution of 1A (11.2 g) in THF (50 ml) with ethanol (2 drops) and a solution of dibenzo-18-crown-6 (415 mg) in THF (70 ml). The reaction mixture is stirred for 60 h at ambient temperature. After heating for 1 h at reflux temperature, the mixture is acidified with 2M hydrochloric acid and extracted with ethyl acetate. The organic phase is dried and evaporated. One obtains the crude title compound as an oily product (21.5 g).
Reaction SMILES: C(OC1C(OC)=CC([B:12]([OH:14])[OH:13])=CC=1OC)C.C(OC1C(OC)=CC(I)=CC=1OC)C.I[C:32]1[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH2:41][C:42]([F:45])([F:44])[F:43])=[C:34]([O:46][CH3:47])[CH:33]=1>>[CH3:47][O:46][C:34]1[CH:33]=[C:32]([B:12]([OH:14])[OH:13])[CH:37]=[C:36]([O:38][CH3:39])[C:35]=1[O:40][CH2:41][C:42]([F:45])([F:44])[F:43]
Reactant: COc1cc(I)cc(OC)c1OCC(F)(F)F
Reactant: CCOc1c(OC)cc(B(O)O)cc1OC
Agent: CCOc1c(OC)cc(I)cc1OC
Product: COc1cc(B(O)O)cc(OC)c1OCC(F)(F)F

Procedure:
Applying the synthetic procedure of 4-ethoxy-3,5-dimethoxyphenylboronic acid from 4-ethoxy-1-iodo-3,5-dimethoxybenzene in Reference Example 3, the title compound was prepared as a colorless amorphous powder (369.0 mg, yield: 48%) from 1-iodo-3,5-dimethoxy-4-(2,2,2-trifluoroethoxy)-benzene (1.00 g, 2.76 mmol).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][C:14]1[CH:15]=[C:16]([CH:39]=[CH:40][CH:41]=1)[CH2:17][N:18]([CH2:29][C:30]1[NH:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[N:31]=1)[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1.CCN(CC)CC>O=S(Cl)Cl.CN(C1C=CN=CC=1)C>[NH:31]1[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=[C:30]1[CH2:29][N:18]([CH2:17][C:16]1[CH:15]=[C:14]([CH:41]=[CH:40][CH:39]=1)[CH2:13][NH:12][C:4](=[O:6])[C:3]1[C:7]([CH3:11])=[CH:8][CH:9]=[N:10][C:2]=1[CH3:1])[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1
Reactant: NCc1cccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)c1
Reactant: Cc1ccnc(C)c1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: Cc1ccnc(C)c1C(=O)NCc1cccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)c1
Temperature: 25 °C
Yield: 43.3 %

Procedure:
A solution of 2,4-dimethyl-nicotinic acid (56 mg, 0.37 mmol) in SOCl2 (˜3 mL, excess) was heated to 80° C. for 4 hours. The condenser was removed and the mixture was flushed with N2 at 80° C. for ˜5 minutes and then dried in vacuo for 10 minutes. The resulting syrup was dissolved in CH2Cl2 (2.0 mL) and added to a stirring mixture of (3-aminomethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (147 mg, 0.37 mmol), Et3N (0.26 mL, 1.85 mmol) and a catalytic amount of DMAP. The reaction mixture was stirred ovemight at room temperature. Purification of the crude yellow foam by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 100:1:1) followed by radial chromatography on silica gel (1 mm plate, EtOAc/MeOH/NH4OH, 200:1:1) afforded the desired amide (85 mg, 43%) as a light yellow foam.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][NH:11]2)=[CH:5][C:4]=1[F:20].CCN(C(C)C)C(C)C.[C:30](Cl)(=[O:33])[O:31][CH3:32].Cl>ClCCl>[Cl:2][C:3]1[C:4]([F:20])=[CH:5][C:6]([CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][N:11]2[C:30]([O:31][CH3:32])=[O:33])=[CH:7][C:8]=1[F:9]
Reactant: COC(=O)C1CCNC(c2cc(F)c(Cl)c(F)c2)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2cc(F)c(Cl)c(F)c2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
Methyl 2-(4-chloro-3,5-difluorophenyl)piperidine-4-carboxylate hydrochloride (1.82 g, 5.58 mmol) was dissolved in dichloromethane (50 mL). DIPEA (2.430 mL, 13.95 mmol) and methyl carbonochloridate (0.527 mL, 6.70 mmol) were added and the mixture was stirred at room temperature for 3 h. 0.1 M HCl was added and the aqueous layer was extracted with DCM. The combined organic layers were filtered through a phase separator and evaporated to yield dimethyl 2-(4-chloro-3,5-difluorophenyl)piperidine-1,4-dicarboxylate (1.83 g, 94%). MS m/z 348 (M+H)+
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH3:11])[N+:9]=1[O-])([CH3:4])([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:15]>C(Cl)Cl>[C:1]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:11][Cl:15])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1oc(C(C)(C)C)[n+]([O-])c1C
Solvent: ClCCl
Product: Cc1oc(C(C)(C)C)nc1CCl
Yield: 75.5 %

Procedure:
30 g of the above prepared 2-tert-butyl-4,5-dimethyl-oxazole 3-oxide (˜115 mmol) was dissolved in 390 ml of CH2Cl2 and treated dropwise with 12.74 ml of POCl3 (139 mmol). The reaction mixture was refluxed over night and then quenched by carefully pouring onto crashed ice/3N NaOH. Separation of the layers, additional extraction of the aqueous phase with CH2Cl2, drying of the combined organic phase over sodium sulfate, evaporation of the solvents, and, finally, flash chromatography (SiO2, hexane/AcOEt=85/15) yielded 16.29 g of the title compound as white crystals of mp. 41–44°.
Reaction SMILES: C1(S([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:29]#[N:30])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][OH:28])[CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:31]=[CH:32][CH:33]=[N:34][C:11]2=3)(=O)=O)C=CC=CC=1.C(N(CC)CC)C>CO>[OH:28][CH2:27][CH2:26][N:23]1[CH2:22][CH2:21][CH:20]([O:19][C:18]2[C:13]3[C:12]4[CH:31]=[CH:32][CH:33]=[N:34][C:11]=4[NH:10][C:14]=3[CH:15]=[N:16][C:17]=2[C:29]#[N:30])[CH2:25][CH2:24]1
Reactant: N#Cc1ncc2c(c1OC1CCN(CCO)CC1)c1cccnc1n2S(=O)(=O)c1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: N#Cc1ncc2[nH]c3ncccc3c2c1OC1CCN(CCO)CC1
Yield: 45.6 %

Procedure:
A solution of 9-benzenesulfonyl-5-[1-(2-hydroxyethyl)-piperidin-4-yloxy]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (125 mg, 0.26 mmol) and triethylamine (1 mL) in methanol (10 mL) was heated to 60° C. for 3 hours. The mixture was concentrated in-vacuo and the resultant residue purified by flash chromatography (silica, 10 g column, ISCO, 0-8% methanol in dichloromethane). The resultant material was triturated with acetonitrile and methanol to afford the title compound as an off-white solid (40 mg, 45%). LCMS (Method C): RT=4.83 min, M+H+=338.2. 1H NMR (400 MHz, DMSO-d6): 8.79 (s, 1H), 8.70 (dd, J=4.8, 1.6 Hz, 1H), 8.59 (dd, J=7.9, 1.7 Hz, 1H), 7.47 (dd, J=7.9, 4.8 Hz, 1H), 4.71-4.69 (m, 1H), 4.38 (s, 1H), 3.49 (s, 2H), 2.93-2.81 (m, 2H), 2.40 (t, J=6.3 Hz, 2H), 2.15 (t, J=11.1 Hz, 2H), 2.06 (d, J=12.0 Hz, 2H), 1.93-1.92 (m, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11](O)=[O:12].C(OC(=O)C)(=O)C>O>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][CH:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCc1ccccc1
Reactant: O=CO
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=CNCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
3-Phenylproylamine (10 ml, 70.0 mmol) was added at 0° C. dropwise to formic acid (80 ml). Acetic acid anhydride (30 ml) was added dropwise to the reaction mixture. After the addition the reaction mixture was warmed to room temperature. It was stirred for 2.5 h. It was cooled to 0° C. Water (30 ml) was added dropwise. The reaction mixture was warmed to room temperature. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (300 ml). The organic phase was washed with saturated sodium chloride solution (2×150 ml) and with saturated sodium hydrogen carbonate solution (200 ml). It was dried over magnesium sulfate. The solvent was removed in vacuo to furnish 5.82 g of N-(3-phenylpropyl)formamide, which was used without further purification.
Reaction SMILES: [ClH:1].CC(C)(C)C(O[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[C:16]([O:20][CH3:21])=[CH:17][CH:18]=[CH:19][C:11]=2[S:10][CH2:9]1)=O>O1CCOCC1>[ClH:1].[NH2:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[C:16]([O:20][CH3:21])=[CH:17][CH:18]=[CH:19][C:11]=2[S:10][CH2:9]1
Reactant: COc1cccc2c1NC(=O)[C@@H](NOC(=O)C(C)(C)C)CS2
Agent: Cl
Solvent: C1COCCO1
Product: COc1cccc2c1NC(=O)[C@@H](N)CS2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
10.4 mL of a solution of hydrogen chloride in dioxane (4 M) are placed in a 100 mL round-bottomed flask containing 450 mg of 55 (1.387 mmol). The mixture is stirred for 3 hours at room temperature under argon. A white precipitate forms, which is filtered off by suction and washed with 3 mL of dioxane and then 5 mL of isopropyl ether. 259 mg of amine 56 (cream-coloured solid) are thus obtained in the form of the hydrochloride.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[CH:15][N:16]=2)[CH:13]=1)[C:5](=O)[CH3:6].[C:18]([CH2:20][C:21]([NH2:23])=[O:22])#[N:19].C[O-].[Na+]>CN(C)C=O>[CH3:6][C:5]1[NH:23][C:21](=[O:22])[C:20]([C:18]#[N:19])=[CH:3][C:4]=1[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[CH:15][N:16]=2)[CH:13]=1
Reactant: N#CCC(N)=O
Reactant: CC(=O)C(=CN(C)C)c1ccc2nccn2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1[nH]c(=O)c(C#N)cc1-c1ccc2nccn2c1
Yield: 50.7 %

Procedure:
In 230 ml of N,N-dimethylformamide was dissolved 23.5 g of 4-dimethylamino-3-(imidazo[1,2-a]pyridin-6-yl)-3-buten-2-one. The solution was stirred at 80° to 90° C. for 12 hours, together with 9.48 g of α-cyanoacetamide and 12.2 g of sodium methoxide. After cooling, the solvnt was removed by distillation under reduced pressure and 500 ml of water was added to the residue to dissolve it. The solution was washed with 600 ml of chloroform. Next, about 5 ml of acetic acid was added to the aqueous layer to adjust pH to 6.5. Crystals precipitated upon cooling were taken by filtration. After the crystals were washed with water, acetonitrile and then ether, they were dissolved in 200 ml of a 2.5% aqueous sodium hydroxide solution. The solution was treated with activated charcoal. The filtrate was again adjusted to pH of 6.5 with about 7 ml of acetic acid. Crystals precipitated upon cooling were taken by filtration. After the crystals were washed with water, acetonitrile and then ether, they were recrystallized from 100 ml of N,N-dimethylformamide to obtain 13 g of 1,2-dihydro-6-methyl-2-oxo-5-(imidazo[1,2-a]pyridin-6-yl)-3-pyridinecarbonitrile.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.Cl[CH2:12][C:13]([OH:15])=[O:14].Cl>C1(C)C=CC=CC=1.O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1
Reactant: Sc1ccc(Br)cc1
Reactant: O=C(O)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)CSc1ccc(Br)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To water (600 mL) solution of 88.9 g of sodium hydroxide was added 200 g of 4-bromothiophenol and dropwise added water (300 mL) solution of 105 g of chloroacetic acid, which was then stirred at 60 to 70° C. for 1 hour. After cooling the reaction mixture to 40° C., thereto were added 140 mL of hydrochloric acid and 600 mL of toluene, which was then heated to 80° C. The organic layer was separated and slowly cooled to 5° C. After stirring at the same temperature for 1 hour, the crystals precipitate was collected by filtration to provide 243 g of (4-bromophenylthio)acetic acid as white solid form.
Reaction SMILES: [CH:1]1([CH:4]([O:6][C:7]([N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][C:11]([OH:13])=O)=[O:8])[CH3:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(OCC)=O.Cl.[CH3:34][CH:35]1[CH:40]=[C:39]([C:41]([O:43][CH2:44][C:45]([Cl:48])([Cl:47])[Cl:46])=[O:42])[N:38]2[C:49](=[O:52])[CH:50]([NH2:51])[C@H:37]2[S:36]1>CN(C)CC1C=CC=CC=1.ClCCl>[CH3:34][CH:35]1[CH:40]=[C:39]([C:41]([O:43][CH2:44][C:45]([Cl:48])([Cl:46])[Cl:47])=[O:42])[N:38]2[C:49](=[O:52])[CH:50]([NH:51][C:11](=[O:13])[CH2:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]([O:6][CH:4]([CH:1]3[CH2:2][CH2:3]3)[CH3:5])=[O:8])[C@H:37]2[S:36]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2S1
Reactant: CC(OC(=O)N(CC(=O)O)c1ccccc1)C1CC1
Agent: CCOC(=O)Cl
Agent: CN(C)Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)CN(C(=O)OC(C)C3CC3)c3ccccc3)[C@H]2S1
Reaction time: 1 h
Yield: 88.2 %

Procedure:
A solution of N-(1-cyclopropylethoxycarbonyl)phenylglycine (1.63 g), triethylamine (0.60 g) and dimethylbenzylamine (2 drops) in dried dichloromethane (10 ml) was dropwise added at -10° C. to a solution of ethyl chloroformate (0.67 g) in dried dichloromethane (15 ml), and the mixture was stirred for 1 hour. The mixture was cooled at -10° to 15° C. and to the mixture was dropwise added over 10 minutes a solution of 2,2,2-trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (2.2 g) and triethylamine (0.55 g) in dried dichloromethane (20 ml), after which the mixture was stirred for 2.5 hours at the same temperature. After the reaction, the reaction mixture was in turn washed with water, 2% hydrochloric acid, a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and then dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was pulverized by adding isopropyl ether, after which the powder was collected by filtration and dried to give 2,2,2-trichloroethyl 2-methyl-7-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]amino-3-cephem-4-carboxylate (3.0 g), mp 165° to 167.5° C.