Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:43])[C@@H:24]([NH:25][C:26](=[O:42])[C:27]([C:32]3[N:33]=[C:34]([NH:37]C(=O)CCl)[S:35][CH:36]=3)=[N:28][O:29][CH2:30][CH3:31])[C@H:21]2[S:20][CH2:19][C:18]=1[CH:44]([S:46][C:47]1[NH:51][N:50]=[N:49][N:48]=1)[CH3:45])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC(N)=S>O1CCCC1.C(O)C.[Br-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:43])[C@@H:24]([NH:25][C:26](=[O:42])[C:27]([C:32]3[N:33]=[C:34]([NH2:37])[S:35][CH:36]=3)=[N:28][O:29][CH2:30][CH3:31])[C@H:21]2[S:20][CH2:19][C:18]=1[CH:44]([S:46][C:47]1[NH:51][N:50]=[N:49][N:48]=1)[CH3:45])=[O:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1csc(NC(=O)CCl)n1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: NC(N)=S
Agent: [Br-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 52.9 %

Procedure:
To a solution of 2.2 g of 7β-{α-ethoxyimino-[2-(chloroacetamido)thiazol-4-yl]acetamido}-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid benzhydryl ester in 20 ml of tetrahydrofuran is added a solution of 550 mg of thiourea in 20 ml of ethanol, followed by addition of 50 mg of triethylbenzylammonium bromide. The mixture is stirred for 20 hours at room temperature and concentrated. The residue is dissolved in a mixture of ethyl acetate and tetrahydrofuran and the solution was washed with aq. sodium bicarbonate solution and then water, followed by drying over anhydrous magnesium sulfate. The dried solution is subjected to distillation of the solvent to give powder which is washed with chloroform and ether and dried. The procedure yields 1.047 g of 7β-[α-ethoxyimino-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid benzhydryl ester. Yield 52.9%
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH3:28])[C:5](=[O:27])[CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH3:26].[OH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33].N1C=CN=C1.C1CCC(N=C=NC2CCCCC2)CC1>CC(=O)OCC>[OH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([NH:1][CH2:2][CH2:3][N:4]([CH3:28])[C:5](=[O:27])[CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH3:26])=[O:33]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)N(C)CCN
Reactant: O=C(Cl)c1ccccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)N(C)CCNC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.4 %

Procedure:
To a solution of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-aminoethyl)-N-methyldocosa-4,7,10,13,16,19-hexaenamide (104 mg, 0.27 mmol), 2-hydroxybenzoyl chloride (37 mg, 0.27 mmol) and imidazole (19 mg, 0.27 mmol) in EA (4 mL) at 0° C. was added dropwise a solution of DCC (0.57 g, 0.27 mmol) in EA (4 mL). The mixture was stirred (RT, 16 h), filtered and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel, eluting with EA-PE (1:3) to afford 2-hydroxy-N-(2-((4Z,7Z,10Z,13Z,16Z,19Z)-N-methyldocosa-4,7,10,13,16,19-hexaenamido)ethyl)benzamide (100 mg, 73%) as a colorless oil. Mass calculated for C32H44N2O3=504.70. found: [M+H]+=505.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)=[CH:5][C:4]=1[O:33][C@@H:34]1[CH2:38][CH2:37][O:36][CH2:35]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)=[CH:5][C:4]=1[O:33][C@@H:34]1[CH2:38][CH2:37][O:36][CH2:35]1
Reactant: COc1ccc(-c2ccnn2-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1O[C@@H]1CCOC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2ccnn2-c2ccc(N3CCNCC3)cc2)cc1O[C@@H]1CCOC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
Into a vial was added tert-butyl 4-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]piperazine-1-carboxylate (20.0 mg, 0.0384 mmol) and 1 mL of a 20% (v/v) solution of TFA in CH2Cl2. The reaction was stirred at room temperature for 1 hour and then the solvent was removed under reduced pressure. The residue was dissolved in 10 mL of ethyl acetate and washed once with 10 mL of saturated aqueous NaHCO3. The organic layer was then dried over sodium sulfate and concentrated under reduced pressure to give 13 mg (0.0309 mmol, 80%) of 1-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]piperazine as a yellow oil. LC/MS (EI) tR 2.02 (Method C), m/z 421.2 (M++1). 1H NMR (CDCl3 300 MHz) δ 1.9 (m, 4H); 3.0 (d, 4H); 3.1 (d, 4H); 3.7-3.9 (m, 3H); 3.8 (s, 3H); 4.6 (m, 1H); 6.4 (s, 1H); 6.5 (s, 1H); 6.8 (m, 3H); 7.0 (d, 1H); 7.2 (d, 2H); 7.7 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:26])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1.C(N(CC)C(C)C)(C)C.[CH:36]1([C:39](Cl)=[O:40])[CH2:38][CH2:37]1>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:26][C:39]([CH:36]2[CH2:38][CH2:37]2)=[O:40])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1
Reactant: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: O=C(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NC(=O)C2CC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.2 %

Procedure:
To a solution of 3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine (200 mg, 0.57 mmol) in THF (2 mL) was added N,N-diisopropyl ethyl amine (0.15 mL, 0.86 mmol), 4-dimethylaminopyridine (8 mg, 0.06 mmol) and cyclopropanecarbonyl chloride (68 μL, 0.75 mmol). The resulting suspension was stirred for 18 h at ambient temperature before it was extracted with a mixture of aqueous sodium carbonate (saturated, 20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=40:40:20 to 10:70:20) afforded the title compound (226 mg, 95%) as a light yellow solid. MS: m/e=417.3 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[C:8]([O:15]CC2C=CC=CC=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>[C].[Pd].CO>[C:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[C:8]([OH:15])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1nc(NC(C)=O)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1nc(NC(C)=O)ccc1O
Yield: 79 %

Procedure:
1.57 g (4.7 mmol) of the obtained methyl 6-acetylamino-3-benzyloxypicolinate and 0.2 g of 10% palladium carbon were added to 100 ml of methanol, and the mixture was hydrogenated under atmospheric pressure. After completion of the reaction, the reaction mixture was filtered and concentrated to obtain crystals, which were washed with diisopropyl ether to obtain methyl 6-acetylamino-3-hydroxypicolinate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][NH:27][CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:31]1([CH2:36][CH2:37][C:38](O)=[O:39])[CH2:35][CH2:34][CH2:33][CH2:32]1.CCN(CC)CC>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][N:27]([C:38](=[O:39])[CH2:37][CH2:36][N:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCN1CCCC1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CNCC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CN(C(=O)CCN1CCCC1)CC2
Temperature: 25 °C

Procedure:
To a solution of 4-benzyloxy-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (100 mg, 0.26 mmol) in DMF (3 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU) (148 mg, 0.389 mmol), 3-(pyrrolidin-1-yl)propanoic acid hydrochloride (56 mg, 0.31 mmol), and Et3N (73 μL, 0.52 mmol). The reaction mixture was stirred at room temperature under Ar until the reaction was complete. The reaction was quenched with water and extracted with CH2Cl2. The organic layer was washed with H2O and 5% LiCl, dried with Na2SO4, filtered and concentrated. Purification by flash column chromatography (silica gel, 5% CH3OH in CH2Cl2) gave 4-(benzyloxy)-1-(5-methyl-2-(3-(pyrrolidin-1-yl)propanoyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridine-2(1H)-one as a yellow foam. The free base was converted to the HCl salt to give the title compound (75 mg, 86%) as a yellow solid: mp 110-115° C.; 1H NMR (500 MHz, CD3OD) δ 7.79-7.76 (m, 1H), 7.61-7.55 (m, 1H), 7.49-7.36 (m, 6H), 7.05-7.02 (m, 1H), 6.55-6.52 (m, 1H), 6.33-6.32 (m, 1H), 5.26 (s, 2H), 4.06 (t, J=5.5 Hz, 1H), 3.94 (t, J=5.5 Hz, 1H), 3.70-3.69 (m, 5H), 3.54-3.50 (m, 2H), 3.18-2.89 (m, 8H), 2.18-2.04 (m, 4H); ESI MS m/z 511 [M+H]+; HPLC (Method B) 97.7% (AUC), tR=13.6 min.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:14][CH2:13]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH:15]1[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][CH2:9][NH2:8])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)NCCCN1CCC(c2ccccn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCN1CCC(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
3-[4-(2-Pyridyl)-piperidine-1-yl]propylamine (Scheme 6). To 1-Benzyl-4-(2-pyridyl)-piperidine (3.26 g, 12.9 mmol) in dry methanol (25 ml), 10% palladium hydroxide (1.9 g) was added and the solution was hydrogenated at 200 psi for 24 hours. The solution was filtered over celite, concentrated to give 2.1 g (99%) of 4-(2-pyridyl)-piperidine which was used as such for the subsequent step. A mixture of 3-bromopropylamine hydrobromide (20 g, 91.3 mmol), potassium carbonate (37.85 g, 273.9 mmol) and di-tert-butyldicarbonate (21.90 g, 100 mmol) in methanol was stirred at room temperature for 24 hours. The reaction mixture was concentrated and partitioned between 250 ml EtOAc and 50 ml water, dried over sodium sulfate, filtered and concentrated. Purification of the crude product by column cromatography (Hexane: EtOAc, 4.5:0.5) gave 17.5 g (80%) of the product as a pale yellow oil. To a stirred solution of the 4-(2-pyridyl)-piperidine (1.86 g, 11.4 mmol) in dioxane (20 ml), N-(tert-butoxycarbonyl)-3-bromopropylamine (2.82 g, 11.4 mmol) and potassium carbonate (3.16 g, 22.9 mmol) were added and the solution refluxed for 24 hours. The reaction mixture was cooled to room temperature, concentrated and partitioned between 40 ml chloroform and 5 ml water. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate: methanol, 4:1) to yield 1.86 g (49%) of the required product as a colorless oil; 1H-NMR (CDCl3): δ 1.45 (s, 9 H), 1.54-1.69 (m, 8 H), 2.21-2.68 (m, 2 H), 2.74-2.80 (m, 1 H), 3.02-3.22 (m, 4 H), 5.41 (s, 1H), 7.13-7.17 (m, 1 H), 7.33 (d, J=7.93 Hz, 1 H), 7.63 (t, J=7.6 Hz, 1 H), 8.54 (d, J=4.6 Hz, 1 H). To N-(tert-butoxycarbonyl)-3-[4-(2-pyridyl)-piperidin-1-yl]propylamine (0.15 g, 0.45 mmol) in 5 ml of dichloromethane, 1 ml of trifluoroacetic acid was added and the solution stirred at room temperature for 1 hour. The solution was concentrated, neutralized with 10% KOH solution and extracted into 25 ml of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 0.098 g (100%) of 3-[4-(2-pyridyl)-piperidin-1-yl]propylamine which was used as such for the subsequent step (step h).
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:12][CH2:11][C:10]([CH2:18][CH3:19])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]2)=[N:4][CH:3]=1.[CH2:20]([NH:22][C:23]([NH:25][C:26]1[S:27][C:28]2[C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)=[CH:33][C:32](B(O)O)=[CH:31][C:29]=2[N:30]=1)=[O:24])[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:18]([C:10]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:12][N:7]([C:5]2[S:6][C:2]([C:32]3[CH:33]=[C:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=4)[C:28]4[S:27][C:26]([NH:25][C:23](=[O:24])[NH:22][CH2:20][CH3:21])=[N:30][C:29]=4[CH:31]=3)=[CH:3][N:4]=2)[CH2:8][CH2:9]1)[CH3:19]
Reactant: CCOC(=O)C1(CC)CCN(c2ncc(Br)s2)CC1
Reactant: CCNC(=O)Nc1nc2cc(B(O)O)cc(-c3ccccn3)c2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)OCC)CC4)s3)cc(-c3ccccn3)c2s1
Temperature: 120 °C
Yield: 35.4 %

Procedure:
Ethyl 1-(5-bromothiazol-2-yl)-4-ethyl-piperidine-4-carboxylate (66 mg, 0.19 mmol), 2-(ethylcarbamoylamino)-7-(2-pyridyl)-1,3-benzothiazol-5-yl-boronic acid (50 mg, 0.15 mmol) and cesium carbonate (42 mg, 0.22 mmol) were suspended in DMF (1 mL) in a 5 mL microwave vessel and the mixture degassed with Ar for 5 min. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with DCM (10 mg, 0.01 mmol) was added to the mixture, then the vessel was sealed and heated at 120° C. for 60 min in a microwave. The mixture was cooled to rt then evaporated to dryness and the crude residue purified over a 12 g silica-gel column using a MeOH: DCM elution gradient (0-5%) to obtain the product as a viscous oil (30 mg, 36% yield). MS: 565.17 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:41])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[CH:30]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:41])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([N:35]5[CH2:36][CH2:37][CH2:38][CH2:39]5)[CH:30]=4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(N4CCCC4)c3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(N4CCCC4)c3)c1)=N2

Procedure:
The title compound was prepared from (5-methyl-2-{3-oxo-3-[3-(2-pyrrolidin-1-yl-pyridin-4-yl)-phenyl]-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M291) (311 mg, 0.53 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (154 mg, 63%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13]C#N)=[O:11])[CH:2]=1.C(N(CC)CC)C>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:2]=1
Reactant: N#CCOC(=O)CCCc1cccnc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)CCCc1cccnc1
Yield: 91.3 %

Procedure:
A mixture of cyanomethyl 4-(pyridin-3-yl)butanoate (0.57 g, 2.81 mmol) and triethylamine (57 mg, 0.56 mmol) in dry methanol (10 ml) was heated under reflux overnight, and evaporated to give a residue. The resultant residue was subjected to purification using column chromatography on silica gel to afford a target product, methyl 4-(pyridin-3-yl)butanoate (0.46 g, 92%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([CH2:20][N:21]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)=[O:29])[CH2:22][CH2:23][NH:24][C:25]([NH2:27])=O)[CH2:3]1.[CH3:41][S:42](Cl)(=[O:44])=[O:43].O.C(OCC)(=O)C>N1C=CC=CC=1>[C:25]([NH:24][CH2:23][CH2:22][N:21]([CH2:20][C@@H:4]1[CH2:3][C@@H:2]([O:1][S:42]([CH3:41])(=[O:44])=[O:43])[CH2:6][N:5]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:8])[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:29])#[N:27]
Reactant: NC(=O)NCCN(C[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)O[C@@H]1C[C@@H](CN(CCNC#N)C(=O)OCc2ccc([N+](=O)[O-])cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (2S, 4R)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-2-[N-(4-nitrobenzyloxycarbonyl)-N-(2-ureidoethyl)amino]methylpyrrolidine (1.75 g) in pyridine (17.5 ml) was added methanesulfonyl chloride (0.60 ml) at 0°~10° C. The mixture was stirred at the same temperature for 1 hour and at ambient temperature for 15 hours. The mixture was poured into a mixture of water (100 ml) and ethyl acetate (100 ml). The organic layer was washed in turn with 1N hydrochloric acid (100 ml×3), saturated sodium hydrogen carbonate (100 ml) and brine (100 ml), dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (30 g) and eluted with a mixture of methanol and chloroform (1:99 v/v) to give (2S, 4R)-2-[N-{2-(cyanoamino)ethyl}-N-(4-nitrobenzyloxycarbonyl)aminomethyl]-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.53 g).
Reaction SMILES: I[C:2]1[C:3]([NH2:10])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CC1(C)C(C)(C)OB([C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)O1.[F-].[Cs+].[Cl-].[NH4+]>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[NH2:23][C:22]1[CH:24]=[CH:25][C:19]([C:2]2[C:3]([NH2:10])=[N:4][CH:5]=[CH:6][C:7]=2[O:8][CH3:9])=[CH:20][CH:21]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: COc1ccnc(N)c1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: COc1ccnc(N)c1-c1ccc(N)cc1
Temperature: 80 °C
Yield: 81.3 %

Procedure:
3-Iodo-4-methoxypyridin-2-amine (350 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (322 mg), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane adduct (81 mg) and cesium fluoride (580 mg) were suspended in methanol (5.0 ml), and the suspension was heated under reflux at 80° C. for 19 hours. After leaving to cool, a saturated aqueous ammonium chloride solution was added, and the organic layer was extracted with ethyl acetate and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate:dichloromethane:methanol=5:5:1 (v/v)] to give 245 mg of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]([OH:16])=O.[Cl:17][C:18]1[CH:19]=[C:20]([NH2:30])[CH:21]=[CH:22][C:23]=1[CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27]>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:30][C:14](=[O:16])/[CH:13]=[CH:12]/[C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])[CH:21]=[CH:22][C:23]=1[CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27]
Reactant: CCN(CC)Cc1ccc(N)cc1Cl
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1Cl
Product: CCN(CC)Cc1ccc(NC(=O)/C=C/c2ccc(C(F)(F)F)cc2Cl)cc1Cl

Procedure:
Prepared analogously to Example 143 starting from (E)-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylic acid (Z37b) and 3-chloro-4-diethylaminomethyl-phenylamine (Z35b). The crude product was purified by column chromatography (Alox, neutral, act. II-III, petroleum ether/EtOAc 3:1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.ClC1N=CN=C(C(NC2C=CC(O)=CC=2)=O)C=1.[NH2:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][N:33]=[CH:32]2.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:28][C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[NH:34][N:33]=[CH:32]3)=[O:9])[CH:3]=1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Agent: O=C(Nc1ccc(O)cc1)c1cc(Cl)ncn1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc2[nH]ncc2c1)c1cc(Cl)ncn1

Procedure:
To a cooled (0° C.) solution of 6-chloropyrimidine-4-carbonyl chloride in DCM (60 mL), obtained as described above for Intermediate 7, step 1 (798 mg; 4.51 mmol) was added dropwise, during a period of 30 minutes, a solution of 5-aminoindazole (Aldrich, 500 mg; 3.76 mmol) and DIEA (1.29 ml; 7.51 mmol) in dry DMF (5 mL). At the end of addition the reaction mixture was concentrated in vacuo, diluted with water and extracted with EtOAc. A white precipitate separated from the organic phase. It was filtered and dried in vacuo to afford the title compound as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:14][CH2:15][C:16]#[CH:17])[C:9]=1[O:10][CH2:11][C:12]#[CH:13])C=O.[CH:18]([O:23][CH3:24])([O:21][CH3:22])OC.[Cl-].[NH4+]>CO>[CH3:24][O:23][CH:18]([O:21][CH3:22])[C:4]1[CH:7]=[C:8]([O:14][CH2:15][C:16]#[CH:17])[C:9]([O:10][CH2:11][C:12]#[CH:13])=[C:2]([Cl:1])[CH:3]=1
Reactant: C#CCOc1cc(C=O)cc(Cl)c1OCC#C
Reactant: COC(OC)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: C#CCOc1cc(C(OC)OC)cc(Cl)c1OCC#C
Temperature: 0 °C
Yield: 79.3 %

Procedure:
A solution of 3-chloro-4,5-dipropargyloxybenzaldehyde (1.0 g), trimethyl orthoformate (4.0 g) and ammonium chloride (0.05 g) in methanol (20 ml) was stirred under reflux for 3 hours, and the resultant solution was poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to alumina chromatography using toluene as an eluent to give 3-chloro-4,5-dipropargyloxybenzaldehyde dimetylacetal (0.94 g). nD21.0 1.5344.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[CH3:10]C(C)=O.C(=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: Oc1cc(F)ccc1F
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COc1cc(F)ccc1F

Procedure:
35.0 g of the product of Step A, 350 ml of acetone, 44.6 g of potassium carbonate and 40.7 g of dimethyl sulfate (neutralized on potassium bicarbonte) and was allowed to return to ambient temperature. Water was added and extraction was carried out with ether. The extracts were washed, dried and concentrated to dryness under reduced pressure to obtain 39.8 g of the desired product.