Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(OCC)(=O)C>CN(C=O)C>[CH2:29]([N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCBr
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 70 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 1-bromohexane (0.192 g, 1.16 mmol) in DMF (5.3 mL). Heat at 70° C. overnight, then increase the temperature to 100° C. for additional two hours. Cool the reaction mixture to room temperature and add ethyl acetate (150 mL). Wash with 1.0 N NaOH (1× 50 mL), brine (1× 50 mL), dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 7% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 368.2 (M+H)+, HRMS calcd for C22H30N3O2 368.2338 (M+H)+, found 368.2334, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=11.6 min, 97.8% purity.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]([CH3:24])[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:11]2[C:16]=1[CH:15]=[CH:14][C:13]([Cl:17])=[CH:12]2)=[O:7].[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C)C=O>[N:25]([CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]([CH3:24])[C:10]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:11]2[C:16]=1[CH:15]=[CH:14][C:13]([Cl:17])=[CH:12]2)=[O:7])=[N+:26]=[N-:27]
Reactant: Cn1c(C(=O)NCCCCl)c2ccc(Cl)cc2c1-c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C(=O)NCCCN=[N+]=[N-])c2ccc(Cl)cc2c1-c1ccccc1
Temperature: 0 °C

Procedure:
A suspension of 14.4 g. of 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid (3-chloropropyl)amide in 80 ml. of dimethylformamide is treated with 5.2 g. of sodium azide and the mixture is stirred at 60° C. for 4 hours. The mixture is cooled and poured on to 500 ml. of ice-water. The separated product is removed by filtration under suction, washed with water and dissolved in methylene chloride. The organic solution is washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. The solid residue is triturated with a small amount of ether and filtered, whereby there is obtained 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid (3-azidopropyl)amide having a melting point of 143°-146° C. (decomposition) which can be used in the process without further purification. An analytical sample is obtained by recrystallization from methanol and has a melting point of 148°-150° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[NH:6][CH:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[CH:3]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH3:28][S:29]([C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30]>>[Br:1][C:2]1[N:6]([S:38]([C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([S:29]([CH3:28])(=[O:31])=[O:30])[CH:33]=2)(=[O:40])=[O:39])[CH:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[CH:3]=1
Reactant: CS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: COC(=O)c1c[nH]c(Br)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc(Br)n(S(=O)(=O)c2cccc(S(C)(=O)=O)c2)c1
Yield: 91.9 %

Procedure:
Using methyl 5-bromo-1H-pyrrole-3-carboxylate (2.89 g), sodium hydride (60% in oil, 850 mg), 15-crown-5 (4.69 g) and 3-methylsulfonylbenzenesulfonyl chloride (4.38 g), a procedure as in Reference Example 146 was performed to give the title compound as white crystals (yield 5.50 g, 92%).
Reaction SMILES: [NH2-].[Li+].[CH2:3]([OH:6])[CH:4]=[CH2:5].C[O:8][C:9](=O)[CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15]([OH:22])=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:13]=1.C1(C)C=CC=CC=1>C(O)(=O)C>[CH2:3]([O:6][C:9](=[O:8])[CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]([CH3:19])([CH3:21])[CH3:20])[C:15]([OH:22])=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:13]=1)[CH:4]=[CH2:5]
Reactant: C=CCO
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Li+]
Agent: [NH2-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C=CCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 150 °C

Procedure:
0.2 g of lithium amide and in the course of 5 hours 38 g of allyl alcohol are added at 150° C. under nitrogen to 146 g of 3-(3,5-di-t-butyl-4-hydroxyphenyl)-propionic acid methyl ester. After completion of the addition, stirring is maintained at 150° C. for a further 10 hours. The brownish reaction mixture is cooled to about 100° C., and 150 ml of toluene, 0.5 g of concentrated acetic acid and 10 g of "Celite Hyflow Supercel" (product of Johns Manville Corp., USA) are added. There is thus obtained, after filtration and then removal of the solvent in vacuo, the title compound in crystalline form, m.p. about 40° C.
Reaction SMILES: [Br-].[CH3:2][O:3][CH2:4][CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH:32]([C:34]1[N:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]2=[N:36][C:35]=1[C:43]([O:45][CH2:46][CH3:47])=[O:44])=O.O>C1COCC1>[CH3:2][O:3][CH2:4][CH2:5]/[CH:6]=[CH:32]/[C:34]1[N:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]2=[N:36][C:35]=1[C:43]([O:45][CH2:46][CH3:47])=[O:44]
Reactant: CCOC(=O)c1nc2ccccn2c1C=O
Reactant: COCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1nc2ccccn2c1/C=C/CCOC
Reaction time: 0.5 h
Yield: 12 %

Procedure:
To a suspension of (3-methoxypropyl) (triphenyl)phosphonium bromide (3.56 g) in THF (50 ml) was added potassium tert-butoxide (0.38 g) at −78° C., and the mixture was stirred at the same temperature for 30 min. Ethyl 3-formylimidazo[1,2-a]pyridine-2-carboxylate (1.7 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (256 mg).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])[CH:2]=1.S(=O)(=O)(O)O.Cl[C:22]1C(CSCCNC2NC(=S)C(CC3C=NC=CC=3)=CN=2)=NC=C[CH:27]=1.C(O)C.O>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[CH:12][C:13]([O:15][CH2:22][CH3:27])=[O:14])[CH:2]=1
Reactant: S=c1[nH]c(NCCSCc2ncccc2Cl)ncc1Cc1cccnc1
Reactant: O=C(O)C=Cc1cnc2ccccc2c1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)C=Cc1cnc2ccccc2c1

Procedure:
A solution of 3-quinolineacrylic acid (63.71 g) and concentrated sulphuric acid (25 ml) in ethanol (350 ml) was refluxed for 18 hours. The product was obtained according to the procedure of Example 8 (i), giving ethyl 3-quinolineacrylate, m.p. 86.5°-88° (Ex ethanol-water).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C([Li])CCC.CCCCCC.[CH:22]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][C:25]=1[O:30][CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:23].[Cl-].[NH4+]>O1CCCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([CH:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][C:25]=3[O:30][CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[OH:23])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCOc1cnccc1C=O
Reactant: Brc1ccc(C2CC2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCOc1cnccc1C(O)c1ccc(C2CC2)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 4-cyclopropylbromobenzene (synthesized as described in WO0268439; 2.5 g, 0.0127 mol) in tetrahydrofuran (20 ml), a 1.58 mol/L n-butyllithium/n-hexane solution (8.4 ml, 0.0133 mol) was added dropwise at −70° C. over 8 minutes. After stirring at −70° C. for 1 hour, a tetrahydrofuran solution of 4-formyl-3-[2-(trimethylsilyl)ethoxymethoxy]pyridine (4.2 g, 0.0165 mol) was added over 5 minutes and stirred at −70° C. for 2.5 hours. After addition of saturated aqueous ammonium chloride, the reaction mixture was warmed to room temperature and extracted twice with ethyl acetate. The organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50) to give (4-cyclopropylphenyl)-[3-[2-(trimethylsilyl)ethoxymethoxy]pyridin-4-yl]-methanol (2.5 g, 53%) as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:5][C:3]=1[NH2:4].[C:16]1(=O)[O:21][C:19](=[O:20])[C:18]2[CH2:22][CH2:23][CH2:24][CH2:25][C:17]1=2.O>C(O)(=O)C>[F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:5][C:3]=1[N:4]1[C:19](=[O:20])[C:18]2[CH2:22][CH2:23][CH2:24][CH2:25][C:17]=2[C:16]1=[O:21]
Reactant: Nc1cc(OC2CCCC2)c(Cl)cc1F
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: O
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Yield: 65 %

Procedure:
A solution of 2-fluoro-4-chloro-5-cyclopentyloxyaniline (0.50 g, 2.18 mmol) and 3,4,5,6-tetrahydrophthalic anhydride (0.398 g, 2.61 mmol) in acetic acid (3.0 ml) was stirred for 3 hours under refluxing. Water (20 ml) was added to the resulting reaction mixture, and the mixture was extracted with ethyl acetate (20 ml×3 times). The organic layer was dried, and the solvent was distilled off under reduced pressure. The resulting pale yellow oily substance was purified by silica gel column chromatography (development solvent: hexane/ethyl acetate=8/1) to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide as a colorless transparent oily substance (0.513 g, 1.41 mmol, 65% yield). Ethanol (1.0 ml) was added thereto for recrystallization to obtain the product as a white solid.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[O:10][CH2:11][O:12][C:8]=2[C:7]([C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[C:9]2[O:10][CH2:11][O:12][C:8]=2[C:7]([C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c2c1OCO2
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C(=O)O)c2c1OCO2
Yield: 98.7 %

Procedure:
8.05 g of 7-nitro-benzo[1,3]dioxole-4-carboxylic acid is reacted with hydrogen in 650 ml of ethanol with 800 mg of palladium/carbon catalyst under normal pressure at room temperature. It is filtered through diatomaceous earth and concentrated by evaporation in a vacuum. 6.82 g of 7-amino-benzo[1,3]dioxole-4-carboxylic acid is obtained as a brown solid, flash point 196-197° C.
Reaction SMILES: [CH3:1][C:2]1[C:20]([CH3:21])=[C:19]([CH3:22])[C:18]([CH3:23])=[C:17]([CH3:24])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12](OCC)=[O:13])[CH2:7][CH2:6]1.[NH2:25][NH2:26]>C(O)C>[CH3:1][C:2]1[C:20]([CH3:21])=[C:19]([CH3:22])[C:18]([CH3:23])=[C:17]([CH3:24])[C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:25][NH2:26])=[O:13])[CH2:9][CH2:10]1
Reactant: NN
Reactant: CCOC(=O)CN1CCN(Cc2c(C)c(C)c(C)c(C)c2C)CC1
Solvent: CCO
Product: Cc1c(C)c(C)c(CN2CCN(CC(=O)NN)CC2)c(C)c1C

Procedure:
Synthesized according to General Procedure C: 6{14} (2.40 g, 7.23 mmol, 1 equiv.), anhydrous hydrazine (0.68 mL, 21.7 mmol, 3 equiv.), ethanol (14.5 mL). Recrystallization from EtOH afforded 1{14} (1.88 g, 82%) as a light yellow crystalline solid. 1H-NMR (500 MHz, CDCl3): δ 8.19 (br s, 1H), 3.85 (d, 2H, J=5.0 Hz), 3.55 (s, 2H), 3.05 (s, 2H), 2.47 (br s, 8H), 2.30 (s, 6H), 2.25 (s, 3H), 2.23 (s, 6H). 13C-NMR (125 MHz, CDCl3): δ 170.7, 133.9, 133.9, 132.4, 131.6, 60.6, 56.4, 54.0, 52.5, 17.0, 16.8, 16.6.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Br[CH2:22][CH:23]([CH3:25])[CH3:24]>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:13](=[O:16])[N:14]([CH2:22][CH:23]([CH3:25])[CH3:24])[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CC(C)CBr
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)n[nH]c1=O
Product: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(CC(C)C)c1=O
Yield: 69.9 %

Procedure:
Using 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 1-bromo-2-methylpropane as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 69.9%.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][S:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1>>[Br:28][C:25]1[CH:24]=[CH:23][C:22]([S:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:32][CH2:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:29])=[CH:27][CH:26]=1
Reactant: NCCc1ccc(O)cc1
Reactant: O=C(CSc1ccc(Br)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Product: O=C(NCCc1ccc(O)cc1)c1ccc2n1Cc1ccccc1N(C(=O)CSc1ccc(Br)cc1)C2

Procedure:
The title compound was synthesized in the manner of Example 81 from 2,2,2-trichloro-1-[10-{[(4-bromophenyl)thio]acetyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl]-ethanone of Example 80 and 4-(2-aminoethyl)-phenol, m.p. 168-169° C. MS [(+)ESI, m/z]: 574 [M+H]+
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][C:13]1[C:18](=[O:19])[CH2:17][CH:16]([C:20]([CH3:22])=[CH2:21])[CH2:15][CH:14]=1>ClC1C=CC=CC=1.O1CCOCC1>[CH:17]1[C:16]([CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=[C:13]([CH3:12])[C:18]=1[OH:19]
Reactant: C=C(C)C1CC=C(C)C(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc(C(C)C)cc1O
Temperature: 180 °C
Yield: 85 %

Procedure:
A mixture of p-toluenesulfonic acid (1.4 g) and carvone (11.3 g) in chlorobenzene/1,4-dioxane (4:1 by volume; 75 mL) was heated at 180° C. for 35 min, then rapidly cooled using the cold-finger, and extracted with 10% NaOH solution (3×100 mL). The combined aqueous extract was washed with CH2Cl2 (2×100 mL), neutralized by dropwise addition of conc H2SO4, and extracted with CH2Cl2 (3×100 mL). The organic extract was washed with sat NaHCO3 (100 mL), dried with MgSO4, and concentrated in vacuo to give carvacrol (9.6 g; 85%).
Reaction SMILES: COC1C=CC(C[O:8][C:9]([C:11]2[CH:57]=[CH:56][C:14]([C:15]([S:17][CH:18]3[N:21]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=4)=[O:23])[C:20](=[O:35])[CH:19]3[CH:36]=[P:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:16])=[CH:13][CH:12]=2)=[O:10])=CC=1>FC(F)(F)C(O)=O.C(OCC)(=O)C>[C:9]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([S:17][CH:18]2[N:21]([C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=3)=[O:23])[C:20](=[O:35])[CH:19]2[CH:36]=[P:37]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:16])=[CH:56][CH:57]=1)([OH:10])=[O:8]
Reactant: COc1ccc(COC(=O)c2ccc(C(=O)SC3C(C=P(c4ccccc4)(c4ccccc4)c4ccccc4)C(=O)N3C(=O)OCc3ccc([N+](=O)[O-])cc3)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(C(=O)SC2C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-(4-p-methoxybenzyloxycarbonylbenzoylthio)-1-p-nitrobenzyloxycarbonyltriphenylphosphoranylidenemethyl-2-azetidinone (1.65 g) and anizole (0.54 g) in trifluoroacetic acid (4.1 ml) was stirred for 0.5 hour at 0° C. Evaporation of trifluoroacetic acid gave an oily residue which was dissolved in ethyl acetate. The ethyl acetate solution was extracted with aqueous potassium carbonate. The aqueous layer was washed with ether, acidified with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over anhydrous sodium sulfate and evaporated to give 4-(4-carboxybenzoylthio)-1-p-nitrobenzyloxycarbonyltriphenylphosphoranylidenemethyl-2-azetidinone.
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:32](=[O:33])[N:6]2[C:7]([C:16]([O:18][CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[C:8](OS(C)(=O)=O)[CH2:9][S:10][C@H:5]12)=[O:2].[Na].[SH:35][C:36]1[S:40][N:39]=[N:38][CH:37]=1.C(OCC)(=O)C>CN(C=O)C>[CH:1]([NH:3][C@@H:4]1[C:32](=[O:33])[N:6]2[C:7]([C:16]([O:18][CH:19]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])=[C:8]([S:35][C:36]3[S:40][N:39]=[N:38][CH:37]=3)[CH2:9][S:10][C@H:5]12)=[O:2]
Reactant: Sc1cnns1
Reactant: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=CN[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Sc3cnns3)CS[C@H]12
Temperature: -20 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a solution of diphenylmethyl 7β-formamido-3-methanesulfonyloxy-3-cephem-4-carboxylate (1 g) in DMF (10 ml) was added sodium salt of 5-mercapto-1,2,3-thiadiazole (445 mg) at −30° C. After being stirred at −20° C. for 1 hour, the mixture was poured into a mixture of ice water and ethyl acetate. The organic layer was separated washed with water and brine, dried over magnesium sulfate, and evaporated to give diphenylmethyl 7β-formamido-3-[(1,2,3-thiadiazol-5-yl)thio]-3-cephem-4-carboxylate (961 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]([N:15]([CH:20]3[CH2:22][CH2:21]3)[C:16]([NH:18][CH3:19])=[S:17])[CH3:14])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.I[CH2:24][CH3:25]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]([N:15]([CH:20]3[CH2:21][CH2:22]3)[C:16](=[N:18][CH3:19])[S:17][CH2:24][CH3:25])[CH3:14])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=S)N(C1CC1)C(C)c1nc(-c2cccc(Cl)c2)no1
Reactant: CCI
Solvent: CO
Product: CCSC(=NC)N(C1CC1)C(C)c1nc(-c2cccc(Cl)c2)no1
Yield: 96.1 %

Procedure:
1-{1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethyl}-1-cyclopropyl-3-methyl-thiourea (287 mg, 0.85 mmol) was mixed with iodoethane (484 mg, 3.4 mmol) in MeOH (5 mL) at 60° C. overnight. The reaction mixture was concentrated and basified with saturated sodium carbonate, then extracted with DCM. The organic layer was dried, concentrated to give the title compound (298 mg, 96 %). 1H-NMR: 8.11 (s, 1H), 8.01 (d, 1H), 7.51 (d, 1H), 7.46 (t, 1H), 5.51 (m, 1H), 3.27 (s, 3H), 2.85-3.00 (m, 2H), 2.60 (m, 1H), 1.79 (d, 3H), 1.30 (t, 3H), 0.83 (m)
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([OH:13])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:48][C:49]1[CH:50]=[C:51]([NH:56][C:57](=[O:69])[C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([C:67]#[N:68])([CH3:66])[CH3:65])[CH:59]=2)[CH:52]=[CH:53][C:54]=1[CH3:55]>CN(C=O)C>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([NH:48][C:49]1[CH:50]=[C:51]([NH:56][C:57](=[O:69])[C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([C:67]#[N:68])([CH3:65])[CH3:66])[CH:59]=2)[CH:52]=[CH:53][C:54]=1[CH3:55])=[O:13]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Reactant: Nc1c(C(=O)O)sc2nccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1sc2nccnc2c1N
Temperature: 80 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
A solution of 7-aminothieno[2,3-b]pyrazine-6-carboxylic acid (8) (1.6 g, 8.20 mmol), HATU (3.43 g, 9.02 mmol) and DIPEA (4.06 mL, 24.59 mmol) in DMF (20 mL) was stirred at rt for 20 min. N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide hydrochloride 6 (2.70 g, 8.20 mmol) was added and stirred overnight at 80° C. Quenched in cold citric acid solution and the resulting precipitate was collected and dried to give crude compound 9 (3.55 g). Triturating with acetonitrile, stirred in water at 90° C. for 30 min, filtrated and dried to yield the title compound 7-amino-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 9 (2.12 g, 55.0%). 1H-NMR (400 MHz, DMSO-d6) 1.77 (s, 6H), 2.23 (s, 3H), 7.06 (br s, 2H), 7.27 (d, J=8.6 Hz, 1H), 7.60 (t, J=7.8 Hz, 2H), 7.75 (m, 1H), 7.82 (br s, 1H), 7.95 (d, J=7.8 Hz, 1H), 8.05 (m, 1H), 8.78 (q, J=2.7 and 2.3 Hz, 2H), 9.47 (br s, 1H), 10.32 (br s, 1H). (m/z)=471 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8]C)=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]([CH3:34])([CH3:33])[CH2:11][C:12]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]2[C:24](=[O:25])[O:23][N:22]=[C:21]([CH3:26])[C:20]=2[CH:27]=1)=[O:14].B(Br)(Br)Br.O>ClCCl>[Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]([CH3:34])([CH3:33])[CH2:11][C:12]([OH:32])([C:28]([F:29])([F:30])[F:31])[C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]2[C:24](=[O:25])[O:23][N:22]=[C:21]([CH3:26])[C:20]=2[CH:27]=1)=[O:14]
Reactant: COc1cccc(C(C)(C)CC(O)(C(=O)Nc2ccc3c(=O)onc(C)c3c2)C(F)(F)F)c1Br
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1noc(=O)c2ccc(NC(=O)C(O)(CC(C)(C)c3cccc(O)c3Br)C(F)(F)F)cc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
78 mg of (+)-6-[4-(2-bromo-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one is mixed in 1.4 ml of dichloromethane at 0° C. with 0.71 ml of a 1 molar solution of boron tribromide in dichloromethane. After 2 hours of stirring at 0° C., the mixture is added to water, extracted with ethyl acetate, the organic phase is dried (Na2SO4) and concentrated by evaporation. After the residue is triturated with hexane, the title compound is obtained in crystalline form, flash point 226-231° C., [α]D=+91.1° (c=0.5 in chloroform)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:17]([O:19][C:20](=[O:30])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:18]>>[CH2:17]([O:19][C:20](=[O:30])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:14]([C:12]2[O:13][C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)=[CH:10][CH:11]=2)=[O:16])[CH:24]=1)[CH3:18]
Reactant: O=C(O)c1ccc(-c2cc(Cl)cc(Cl)c2)o1
Reactant: CCOC(=O)CCc1cccc(N)c1
Product: CCOC(=O)CCc1cccc(NC(=O)c2ccc(-c3cc(Cl)cc(Cl)c3)o2)c1

Procedure:
Carboxylic acid (67) (67 mg, 0.26 mmol) was coupled to aniline (124) (50 mg, 0.26 mmol) using Method C. The residue was purified by column chromatography eluting with 10% EtOAc in heptane to give the title compound.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][N:30]([CH2:34][CH2:35][NH2:36])[CH2:29]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[N:20]1([CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][N:30]([CH2:34][CH2:35][NH:36][C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:29]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: NCCN1CCCC(CN2CCCCCC2)C1
Solvent: CC#N
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCCC(CN3CCCCCC3)C2)c2ccccc21
Yield: 69 %

Procedure:
Prepared analogously to Example 46 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2[3-[(hexahydro-1H-azepin-1-yl)methyl]-piperidin-1-yl]ethanamine in a yield of 69% of theory. Colourless crystals, m.p. 135°-137° C. (acetonitrile).