Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.[CH:26]([NH2:29])([CH3:28])[CH3:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH:29][CH:26]([CH3:28])[CH3:27])=[O:17])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: CC(C)N
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Product: CC(C)NC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
50 mg of 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to isopropylamine via Procedure G. The product was purified on reverse phase HPLC to yield N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-isopropylterephthalamide. MS (Q1) 394 (M)+.
Reaction SMILES: CO[C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][CH:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH:21]3[OH:29])[CH:13]=2)[N:6]=1)=[O:4].[NH2:30][C@H:31]1[CH2:36][CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]1>O>[NH2:11][C:10]1[C:5]([C:3]([NH:30][C@H:31]2[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]2)=[O:4])=[N:6][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][C@@H:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][C@@H:21]3[OH:29])[CH:13]=2)=[CH:8][N:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: COC(=O)c1nc(-c2cccc(CNC3c4ccccc4CC3O)c2)cnc1N
Solvent: O
Product: Nc1ncc(-c2cccc(CN[C@@H]3c4ccccc4C[C@@H]3O)c2)nc1C(=O)N[C@H]1CCCNC1
Temperature: 120 °C
Yield: 58.7 %

Procedure:
A mixture of 3-amino-6-{3-[(2-hydroxy-indan-1-ylamino)-methyl]-phenyl}-pyrazine-2-carboxylic acid methyl ester (400.0 mg, 1.02 mmol) and 1,1-dimethylethyl (3S)-3-aminopiperidine-1-carboxylate (970.0 mg, 4.84 mmol) was heated to 120° C. overnight. The reaction mixture was poured into water (100 mL), and extracted with ethyl acetate (2×50 mL) then dried over anhydrous sodium sulfate and filteration, concentration and purified by column chromatography (3% MeOH/Dichloromethane) and subsequently it was treated with 4.0 M HCl in dioxane (20 mL) to give 3-amino-6-[3-({[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}methyl)phenyl]-N-[(3S)-piperidin-3-yl]pyrazine-2-carboxamide, 275.0 mg (58.7% yield). 1H NMR (400 MHz, d4-MeOH): δ 8.72 (s, 2H), 8.18 (s, 1H), 7.80 (d, 1H), 7.60 (m, 2H), 7.38 (m, 3H), 4.80 (s, 1H), 4.50(s, 2H), 4.40 (m, 1H), 3.65 (m, 2H), 3.42 (m, 5H), 3.16 (m, 2H), 2.15 (m, 2H), 1.87 (m, 1H); MS (EI) for C26H30N6O2: 459.31 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][N:7]1[CH2:12][C:11]2[CH:13]=[C:14](Br)[CH:15]=[N:16][C:10]=2[NH:9][C:8]1=[O:18])[CH3:2].BrC1C=N[C:24]2NC(=O)N(CCN(C)C)[CH2:28][C:23]=2[CH:22]=1>>[C:23]([O:19][C:4](=[O:3])/[CH:5]=[CH:6]/[C:14]1[CH:15]=[N:16][C:10]2[NH:9][C:8](=[O:18])[N:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:19])[CH2:12][C:11]=2[CH:13]=1)([CH3:22])([CH3:24])[CH3:28]
Reactant: CN(C)CCN1Cc2cc(Br)cnc2NC1=O
Reactant: CCOC(=O)CCN1Cc2cc(Br)cnc2NC1=O
Product: CCOC(=O)CCN1Cc2cc(/C=C/C(=O)OC(C)(C)C)cnc2NC1=O
Yield: 21 %

Procedure:
According to the procedure of Preparation 130(d), except substituting 3-(6-bromo-2-oxo-1,4-dihydro-2H-pyrido[2,3-d]pyrimidin-3-yl)propionic acid ethyl ester for the 6-bromo-3-(2-dimethylamino-ethyl)-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one, the title compound (0.39 g, 21%) was prepared as a white solid: MS (ESI) m/e 376 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[C:28]=2[Cl:35])[C:7]=1[N:8](C(OC1C=CC=CC=1)=O)[C:9]([O:11][C:12]1C=CC=CC=1)=[O:10])#[N:2]>CO>[C:1]([C:3]1[CH:4]=[N:5][N:6]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[C:28]=2[Cl:35])[C:7]=1[NH:8][C:9]([O:11][CH3:12])=[O:10])#[N:2]
Reactant: N#Cc1cnn(-c2ccc(Cl)c(Cl)c2Cl)c1N(C(=O)Oc1ccccc1)C(=O)Oc1ccccc1
Solvent: CO
Product: COC(=O)Nc1c(C#N)cnn1-c1ccc(Cl)c(Cl)c1Cl
Yield: 58.5 %

Procedure:
A stirred mixture of 4-cyano-5-di(phenoxycarbonyl)amino-1-(2,3,4-trichlorophenyl)pyrazole (30 g) in methanol (600 ml) was heated at reflux for 80 hours. After cooling the reaction mixture was evaporated and the residue was suspended in dichloromethane (250 ml). The insoluble material was filtered off to give 4-cyano-5-methoxycarbonylamino-1-(2,3,4-trichlorophenyl)pyrazole (11.5 g), m.p. 205°-207° C., in the form of a colourless solid.
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[C:8]([C:9]#[N:10])=[C:7]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6][N:5]=1.O.O.O.C([O-])(=O)C.[Na+].[CH:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)(=O)C.O.C(O)C.C(OCC)(=O)C>[CH2:26]([NH:3][C:4]1[C:8]([C:9]#[N:10])=[C:7]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[S:6][N:5]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: N#Cc1c(N)nsc1Nc1ccccc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1c(NCc2ccccc2)nsc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
Sodium borohydride (4.12 g, 1.09.1 mmol) was added portion wise to a mixture of 3-amino-5-phenylamino-isothiazole-4-carbonitrile (1.57 g, 7.27 mmol), sodium acetate trihydrate (2.97 g, 21.81 mmol) and benzaldehyde (0.74 ml, 7.27 mmol) in acetic acid (2.3 ml), water (9 ml) and ethanol (7 ml) at 0° C. The solution was stirred at ambient temperature for 30 minutes, and then diluted with ethyl acetate (EtOAc) (55 ml). The organic layer was washed with a 10% solution of sodium hydroxide (3×35 ml) and brine (35 ml), dried and evaporated to give an oil, which was purified on silica gel (hexane/EtOAc, 1:1) to afford a solid (1.45 g, 65%).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH3:4].[CH3:24][C:25]1([CH3:43])[CH:34]([N:35]2[C:39]([CH:40]=O)=[CH:38][N:37]=[CH:36]2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=[O:42])[O:26]1>C1COCC1>[CH:40]([C:39]1[N:35]([CH:34]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27](=[O:42])[O:26][C:25]2([CH3:43])[CH3:24])[CH:36]=[N:37][CH:38]=1)=[CH:2][CH2:3][CH3:4]
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1C=O
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC=Cc1cncn1C1c2ccccc2C(=O)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of propyltriphenylphosphonium bromide (0.157 g, 0.41 mmol) in THF (1 mL) at −78° C. is added sodium hexamethyldisilylamide (1M in THF, 0.44 mL, 0.44 mmol) and the mixture is allowed to warm to ambient temperature over 10 min. This solution is cooled to −20° C. and 3-(3,3-dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carbaldehyde (0.10 g, 0.37 mmol) in THF (0.2 mL) is added. The cooling bath is removed and the mixture is stirred at ambient temperature overnight, then filtered. The filtrate is concentrated in vacuo to give the crude 4-(5-but-1-enyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one which is used in the next step without further purification; MS (ESI) m/z 297.1 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([CH3:14])([CH3:13])[CH2:11][NH2:12].[C:15](N1C=CN=C1)([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)=[O:16]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([CH3:14])([CH3:13])[CH2:11][NH:12][C:15]([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)=[O:16]
Reactant: CC(C)(CN)c1cc2ccccc2[nH]1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(CNC(=O)n1ccnc1)c1cc2ccccc2[nH]1
Reaction time: 3 h
Yield: 72.5 %

Procedure:
To a solution of 2-(indol-2-yl)-2-methylpropylamine (363.2 mg) in tetrahydrofuran (10 ml) was added 1,1'-carbonyldiimidazole (340 mg) in small portions at room temperature. After stirring for 3 hours, the reaction mixture was evaporated in vacuo. The residue was purified by silica gel column chromatography (3% methanol-chloroform) to give N-[2-(indol-2-yl)-2-methylpropyl]-1-imidazolecarboxamide (395 mg) as crystals.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[F:7][C:8]([F:32])([F:31])[C:9]1[N:13]2[N:14]=[C:15]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:32][C:8]([F:7])([F:31])[C:9]1[N:13]2[N:14]=[C:15]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:2][C:3]([O:5][CH3:6])=[O:4])=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1
Reactant: Oc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.8 %

Procedure:
Methyl 2-bromoacetate (0.418 mL, 4.42 mmol) was added to 4-[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenol (obtained as described in Example 513, preparation of starting materials) (1.07 g, 2.94 mmol) and potassium carbonate (0.814 g, 5.89 mmol) in DMF (20 mL). The resulting suspension was stirred at ambient temperature for 16 hours. The reaction mixture was evaporated to dryness then water (50 mL) added and stirring continued for 20 minutes. The resulting precipitate was collected by filtration, washed with water then ether and dried to afford methyl 2-[4-[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]acetate (1.290 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[F:59][C:60]1[CH:61]=[C:62]([CH2:66][NH2:67])[CH:63]=[CH:64][CH:65]=1>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:19][CH2:20][CH:21]([C:24]([NH:67][CH2:66][C:62]3[CH:63]=[CH:64][CH:65]=[C:60]([F:59])[CH:61]=3)=[O:25])[CH2:22][CH2:23]2)=[O:17])=[CH:4][CH:3]=1
Reactant: NCc1cccc(F)c1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cccc(F)c1)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (100 mg, 0.252 mmol), EDCI (72.5 mg, 0.378 mmol), and 1-hydroxybenzotriazole (51.1 mg, 0.378 mmol) were dissolved in DCM (Volume: 3.0 ml). The reaction was stirred at room temperature for 10 minutes before Hunig's Base (0.066 ml, 0.378 mmol) and (3-fluorophenyl)methanamine (0.043 ml, 0.378 mmol) were added. The reaction was allowed to stir overnight at room temperature. The reaction was diluted with water and ethyl acetate. The organic phase was washed with 1N HCl, saturated sodium bicarbonate, and brine. The organic phase was dried over magnesium sulfate, filtered, and concentrated. The crude material was triturated with ethyl acetate to obtain product as a white solid. (Yield: 57 mg, white solid) 1H-NMR (400 MHz, DMSO-d6) 8.38, 7.63, 7.54, 7.35, 7.21, 7.13-7.00, 6.73, 5.49, 4.44, 4.28, 4.13-3.91, 2.94, 1.72, 1.44
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16](Cl)=[N:15][N:14]3[CH:20]=2)=[C:7]([O:21][CH3:22])[CH:6]=1)(=[O:4])=[O:3].[H][H]>[Pd]>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][N:14]3[CH:20]=2)=[C:7]([O:21][CH3:22])[CH:6]=1)(=[O:4])=[O:3]
Reactant: COc1cc(S(N)(=O)=O)ccc1-c1cn2nc(Cl)ccc2n1
Reactant: [H][H]
Agent: [Pd]
Product: COc1cc(S(N)(=O)=O)ccc1-c1cn2ncccc2n1

Procedure:
Prepared from 2-(4-aminosulphonyl-2-methoxyphenyl)-6-chloro-imidazo[1,2-b]pyridazine and hydrogen in the presence of Pd/C analogously to Example 54.
Reaction SMILES: [C:1]([O:24][C:25]1[CH:30]=[CH:29][C:28](C2C=CC(F)=CC=2F)=[CH:27][C:26]=1[C:39]([O:41][CH2:42][CH3:43])=[O:40])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].OC1C=C([C:54]([F:57])([F:56])[F:55])C=CC=1C(O)=O>>[C:1]([O:24][C:25]1[CH:30]=[C:29]([C:54]([F:57])([F:56])[F:55])[CH:28]=[CH:27][C:26]=1[C:39]([O:41][CH2:42][CH3:43])=[O:40])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)Oc1ccc(-c2ccc(F)cc2F)cc1C(=O)OCC
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)Oc1cc(C(F)(F)F)ccc1C(=O)OCC

Procedure:
Ethyl 2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyloxy)-4-(trifluoromethyl)benzoate was prepared in a similar fashion as ethyl 4-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyloxy)-2′,4′-difluorobiphenyl-3-carboxylate, using the appropriate 2-hydroxy-4-(trifluoromethyl)benzoic acid starting material. Mass calculated for C32H39F3O4=544.64. found: [M+Na]+=567.3.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]#[N:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1.[S:14]1C=CC=C1CC(O)=O.Cl>O>[O:1]=[C:2]1[N:6]([CH2:7][C:8](=[S:14])[NH2:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1
Reactant: N#CCn1c(=O)sc2ccccc21
Reactant: O=C(O)Cc1cccs1
Agent: Cl
Solvent: O
Product: NC(=S)Cn1c(=O)sc2ccccc21
Reaction time: 18 h
Yield: 85 %

Procedure:
To a stirred slurry containing 38 grams (0.2 moles) of 2-oxo-3-benzothiazoline acetonitrile, 15.2 grams (0.2 moles) of thiolacetic acid (dried over MgSO4) and 300 ml. of anhydrous ethyl ether, dried hydrogen chloride gas is bubbled through the suspension at -5° to 0° C. for 3 hours. External cooling was removed and the reaction mixture is stirred at 25°-30° C. for 18 hours. The solid is collected by filtration, washed with 500 ml. of anhydrous ethyl ether and air-dried at 25°-30° C. for one hour. The solid (41 grams) was slurried with 700 ml. of water for one hour. After the addition of 300 ml. of water and 25 grams (0.25 moles) of concentrated hydrochloric acid stirring is continued at 25°-30° C. for another hour. The solid is collected by filtration, washed with water until neutral and air-dried at 25°-30° C. The product, 2-oxo-3-benzothiazoline ethanethioamide, mp. 205°-207° C. with decomposition, is obtained in 85% yield. After recrystallization from heptane/tetrahydrofuran (1:1), it melted at 216°-217° C.
Reaction SMILES: C([N:8]1[CH2:27][CH2:26][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:16][C@@H:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH3:18])[C:10]=2[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.C(N(CC)C(C)C)(C)C>ClCCCl>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C@H:17]([NH:16][C:15]2[C:10]3[CH2:9][NH:8][CH2:27][CH2:26][C:11]=3[N:12]=[CH:13][N:14]=2)[CH3:18])=[CH:20][CH:21]=1
Reactant: C[C@@H](Nc1ncnc2c1CN(Cc1ccccc1)CC2)c1ccc(Cl)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1ncnc2c1CNCC2)c1ccc(Cl)cc1
Yield: 118.4 %

Procedure:
A 250 mL flask fitted with a condenser was charged with (R)-6-benzyl-N-(1-(4-chlorophenyl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (4.43 g, 11.7 mmol), 1,2-dichloroethane (50 mL), α-chloroethyl chloroformate (1.5 mL, 14 mmol) and finally N,N-diisopropylethylamine (2.4 mL, 14 mmol), and the resultant red-brown solution was placed in an oil bath at 60° C. Additional α-chloroethyl chloroformate (2.0 mL, 18.4 mmol, 1.6 eq) was added after 2.5 h. After 4 h the mixture was concentrated to a brown oil and the residue was dissolved in methanol (50 mL), and heated at reflux for 1 h. After cooling, the mixture was concentrated in vacuo, and the residue was partitioned between 4/1 ethyl acetate/CH2Cl2 (100 mL) and 0.5M aq. NaH2PO4 (100 mL). The organic layer was extracted with 1M citric acid (2×25 mL), and the combined aqueous layers were basified to pH>12 with 50% aqueous KOH (50 mL), and extracted with CH2Cl2 (250 mL, 50 mL). The combined CH2Cl2 extracts were dried (Na2SO4) and concentrated to give an orange solid foam (4.0 g), which was purified by basic alumina column (0-5% MeOH/CH2Cl2) to give a light yellow foam (1.48 g).
Reaction SMILES: CN(C)C=O.P(Br)(Br)([Br:8])=O.[CH3:11][O:12][C:13]1[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=[C:27]([CH3:35])[C:14]=1[C:15]([C:17]1[C:22]([O:23][CH3:24])=[CH:21][N+:20]([O-])=[CH:19][C:18]=1[Cl:26])=[O:16]>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13]1[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=[C:27]([CH3:35])[C:14]=1[C:15]([C:17]1[C:22]([O:23][CH3:24])=[CH:21][N:20]=[C:19]([Br:8])[C:18]=1[Cl:26])=[O:16]
Reactant: O=P(Br)(Br)Br
Reactant: COc1cc(C)c(C(=O)c2c(Cl)c[n+]([O-])cc2OC)c(OC)c1OC
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc(C)c(C(=O)c2c(OC)cnc(Br)c2Cl)c(OC)c1OC
Yield: 743 %

Procedure:
5 ml of dimethylformamide was added to 2.5 ml of toluene, the mixture was cooled with ice, and 0.7 g (0.2 mmol) of phosphorus oxybromide was dropwise added thereto. After the mixture was stirred under cooling with ice for 10 minutes, 0.42 g (0.1 mmol) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-chloro-5-methoxypyridine-N-oxide obtained in Synthesis Example 14 (a) was added thereto. After the mixture was stirred under cooling with ice for 30 minutes, the temperature was recovered to room temperature, followed by stirring for 2 hours. 10 ml of water was added to the mixture to terminate the reaction, and ethyl acetate was added thereto for extraction. The organic layer was dried over anhydrous sodium sulfate, subjected to filtration and purified by silica gel column chromatography to obtain 0.32 g (yield 65%) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-2bromo-3-chloro-5-methoxypyridine (compound No. 245; m.p. 97-99° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][N:6]([CH3:11])[C:7]=1[C:8]([NH2:10])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.[OH-].[K+]>C1COCC1.C(O)(C)C>[CH3:1][O:2][C:3]1[N:4]=[CH:5][N:6]([CH3:11])[C:7]=1[CH2:8][NH2:10]
Reactant: COc1ncn(C)c1C(N)=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COc1ncn(C)c1CN
Temperature: 60 °C
Reaction time: 7 h
Yield: 37.3 %

Procedure:
In a 250 ml, three-necked flask fitted with a magnetic stirrer, a reflux condenser and under inert atmosphere, 4-methoxy-1-methyl-1H-imidazole-5-carboxamide x93 (1.45 g, 9.5 mmol) is dissolved at room temperature in anhydrous THF (80 ml). Lithium aluminium hydride (685 mg, 18 mmol) is added by portions while the temperature is rising to 30° C. The mixture is stirred for 7 h at 60° C. and cooled down to room temperature. Then isopropanol is added and the mixture is stirred for a further 16 hours at room temperature. First HCl 37% (W/W) is added to the rectional mixture to reach pH 1, then 5 N KOH to adjust pH to 10. The solvents are removed under vacuum. The residue is dissolved in a mixture of CH2Cl2/MeOH (80/20), filtered through a celite pad and concentrated to dryness. Purification by preparative chromatography on silicagel (conditions: CH2Cl2/MeOH/NH4OH: 90/10/1 (v/v/v)) affords 500 mg of 1-(4-methoxy-1-methyl-1H-imidazol-5-yl)methanamine x94.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[O:12]1[C:17]2=[CH:18][CH:19]=[CH:20][C:16]2=[CH:15][CH:14]=[C:13]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1/[CH:27]=[CH:28]/[S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[O:12]1[C:17]2=[CH:18][CH:19]=[CH:20][C:16]2=[CH:15][CH:14]=[C:13]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1/[CH:27]=[CH:28]/[S:29]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10])(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)/C=C/c1ccccc1-c1ccc2cccc-2o1
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)/C=C/c1ccccc1-c1ccc2cccc-2o1
Reaction time: 2 h
Yield: 46 %

Procedure:
2-Aminobenzenesulfonamide (38 mg, 0.22 mmol) was dissolved in pyridine (2 ml), (E)-2-(4-benzofuran-2-ylphenyl)ethenesulfonyl chloride (70 mg, 0.22 mmol) was added and the mixture stirred for 2 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (46 mg, 46%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])([O:3]C(C)(C)C)=O.[CH2:17]([NH:24][CH2:25]C(OCC)=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[CH2:17]([N:24]1[CH2:25][C:1](=[O:3])[NH:8][C@@H:9]([CH2:10][CH2:11][S:12][CH3:13])[C:14]1=[O:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)CNCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CSCC[C@@H]1NC(=O)CN(Cc2ccccc2)C1=O
Temperature: 20 °C
Reaction time: 2 h

Procedure:
The title compound was prepared according to the procedure described in Example 2, Step A, except using Boc-L-methionine (10.0 g, 40.0 mmol), ethyl N-benzylglycinate (7.75 g, 40.0 mmol), HOBT (5.41 g, 40.0 mmol) and EDC.HCl (7.68 g, 40.00 mmol) in dimethylformamide. Upon completion of the reaction, the dimethylformamide was removed in vacuo and the crude product partitioned between ethyl acetate and water. The organic phase was washed with water and saturated sodium chloride solution, then dried over sodium sulfate. The solvent was removed in vacuo and the residue taken up in methylene chloride (200 mL). Trifluoroacetic acid (100 mL) was added and the reaction stirred at 20° C. for 2 h. The volatiles were removed in vacuo and the residue partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate. The title compound was obtained as a white solid (9.08 g). NMR (CHCl3, 300 MHz) δ 7.4-7.2 (6H, m); 4.60 (2H, AB q, J=13 Hz); 4.24 (1H, m); 3.85 (2H, AB q, J=18 Hz); 2.63 (2H, t, J=7Hz); 2.3-2.1 (2H, m); 2.1 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][O:8][C:9]([C:11]2[N:16]3[C:17](=[O:29])[C@@H:18]([NH:19][C:20](=[O:28])[CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:15]3[S:14][CH2:13][C:12]=2[CH2:30]Cl)=[O:10])=[CH:5][CH:4]=1.[SH:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[C:22]1([CH2:21][C:20]([NH:19][C@@H:18]2[C:17](=[O:29])[N:16]3[C:11]([C:9]([O:8][CH2:7][C:6]4[CH:32]=[CH:33][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)=[O:10])=[C:12]([CH2:30][S:34][C:35]4[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=4)[CH2:13][S:14][C@H:15]23)=[O:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Sc1ccncc1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)C2=C(CSc3ccncc3)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Temperature: 0 °C
Yield: 93.5 %

Procedure:
To a stirred and ice cold solution of 7β-phenylacetamido-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (1) (4.87 g; 10 mMol.) and 4-mercaptopyridine (1.45 g; 1.3 Eq.) in N,N-dimethylformamide (15 ml) is added sodium hydrogen carbonate (1.09 g; 1.3 Eq.), and the mixture is stirred at room temperature for 1 hour. The reaction mixture is diluted with ice water and separating solidis collected by filtration, dissolved in ethyl acetate, washed with water, dried, and concentrated under reduced pressure. The residue is washed with ether to give p-methoxybenzyl 7β-phenylacetamido-3-(4-pyridyl)thiomethyl-3-cephem-4-carboxylate (2) (5.25 g).