Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC[CH2:3][C:4]1[C:5]2[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=2[C:7]2[C:8](=[O:21])[NH:9][C:10]([NH:14]C(=O)C(C)(C)C)=[N:11][C:12]=2[CH:13]=1.[C:26](O)(=[O:28])C>C[O-].[Na+]>[NH2:14][C:10]1[NH:9][C:8](=[O:21])[C:7]2[C:6]3[CH:22]=[CH:23][CH:24]=[CH:25][C:5]=3[C:4]([CH2:3][O:28][CH3:26])=[CH:13][C:12]=2[N:11]=1
Reactant: CC(C)(C)C(=O)Nc1nc2cc(CCBr)c3ccccc3c2c(=O)[nH]1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: COCc1cc2nc(N)[nH]c(=O)c2c2ccccc12
Temperature: 65 °C

Procedure:
A solution of N-(6-(bromoethyl)-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.28 g, 0.72 mmole) in 0.3M sodium methoxide (25 ml) was stirred and heated at 65° C. under a nitrogen atmosphere for 4 hours. After cooling, the mixture was acidified to pH 6 with glacial acetic acid, and then all solvent was removed under reduced pressure. The residue was triturated with water (20 ml), then filtered, washed with water and acetone, and dried to give 3-amino-6-(methoxymethyl)benzo[f]quinazolin-1(2H)-one as an off-white solid. (0.12 g, 58%) 1H NMR(DMSO-d6, 200 MHz) d 3.39(s, 3H, OCH3); 4.85(s, 2H, CH2); 6.54(br s, 2H, NH2); 7.33(s, 1H, Ar): 7.44(dt, J=6.9, 1.4 Hz, 1H, Ar); 7.59(dt, J=6.9, 1.4 Hz, 1H, Ar); 7.96(dd, J=8.2, 1.0 Hz, 1H, Ar); 9.69(d, J=8 Hz, 1H, Ar); 11.11(br s, 1H, NH); 11.91(br s, <1H, pyr-NH+). Anal. Calculated for C14H13N3O2.1/2HOAc.1/10H2O: C, 62.75; H, 5.34; N, 14.64. Found C, 62.74; H, 5.31; N, 14.64.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[C:5]([CH3:10])[O:4][N:3]=1.[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:28][CH2:29][CH2:30][CH3:31])[N:24]([CH2:25][CH2:26][NH2:27])[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1>>[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:28][CH2:29][CH2:30][CH3:31])[N:24]([CH2:25][CH2:26][NH:27][C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:10])=[O:9])[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: Cc1noc(C)c1C(=O)O
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)c1c(C)noc1C
Yield: 33.2 %

Procedure:
Using the general method of Example 97 3,5-dimethylisoxazole-4-carboxylic acid (0.25 g, 1.7 mmole) was reacted with 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.5 g, 1.7 mmol) to provide 0.23 g of N-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,5-dimethyl-4-isoxazolecarboxamide as a white powder, m.p. 188-189° C. Analysis: Calculated for C21H25N7O2: %C, 61.90; %H, 6.18; %N, 24.06. Found: %C, 61.92; %H, 6.15; %N, 24.28. HRMS (EI) calcd for C21H25N7O2 (M+) 407.2069. found 407.2068.
Reaction SMILES: [NH3:1].[C:2]([C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[S:11](Cl)(=[O:13])=[O:12])#[N:3]>O1CCOCC1.O>[NH2:3][C:2]1[C:4]2[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=2[S:11](=[O:13])(=[O:12])[N:1]=1
Reactant: N
Reactant: N#Cc1c(Cl)cccc1S(=O)(=O)Cl
Solvent: O
Solvent: C1COCCO1
Product: NC1=NS(=O)(=O)c2cccc(Cl)c21

Procedure:
12.5 ml of 25% ammonia were added at approx. 60° C. to a solution of 11,8 g of 2-cyano-3-chlorobenzenesulphonylchloride in 20 ml of dioxane. After heating on a steam bath for 30 minutes the reaction mixture was cooled and diluted with water. The resulting crystalline product was sucked off, washed with water and dried. The desired product was obtained in a yield of 8.9 g. After recrystallization from ethanol, the product melted at 261°-263° C.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[N:29]1[C:33]([CH3:34])=[N:32][CH:31]=[N:30]1)[C:23](O)=[O:24]>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:12]=[CH:13][C:14]([CH2:17][CH3:18])=[CH:15][N:16]=3)[CH2:7][CH2:6]2)[C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:28]([N:29]3[C:33]([CH3:34])=[N:32][CH:31]=[N:30]3)=[C:20]([F:19])[CH:21]=2)[CH2:2][CH2:3]1
Reactant: CCc1cnc(N2CCC(NC3CC3)CC2)nc1
Reactant: Cc1ncnn1-c1ccc(C(=O)O)cc1F
Product: CCc1cnc(N2CCC(N(C(=O)c3ccc(-n4ncnc4C)c(F)c3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from cyclopropyl-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-amine and 3-fluoro-4-(5-methyl-[1,2,4]triazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 90. LC (method 19): tR=3.69 min; Mass spectrum (ESI+): m/z=450 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]([C:6]([CH3:13])([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH2:5])[CH:2]=[CH2:3].[CH2:14]([N:21]=[C:22]=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1.C(OCC)(=O)C>[CH2:1]([N:4]([C:6]([CH3:12])([CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH:5][C:22](=[O:23])[NH:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:2]=[CH2:3]
Reactant: C=CCN(N)C(C)(C)C(=O)OCC
Reactant: O=C=NCc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCN(NC(=O)NCc1ccccc1)C(C)(C)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
To a solution of ethyl 2-(1-allylhydrazinyl)-2-methylpropanoate (Compound XIV-1) (4.33 g, 23.25 mmol) in THF was added benzyl isocyanate (2.87 ml, 23.25 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (100 ml) and the mixture was washed with water (100 ml) and brine (100 ml). Then the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The crude residue was subjected to silica gel column chromatography (eluent: n-hexane:ethylacetate=1:1 to 1:2) to obtain the title compound (2.55 g, 35%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:28]=[CH:27][C:10]2[C:11]3[N:12]([CH:16]=[C:17]([C:19]4[N:23]([CH:24]([CH3:26])[CH3:25])[N:22]=[CH:21][N:20]=4)[N:18]=3)[CH2:13][CH2:14][O:15][C:9]=2[CH:8]=1)(=O)=O.[CH3:31][C@H:32]1[CH2:36][CH2:35][NH:34][C@@H:33]1[C:37]([NH2:39])=[O:38]>>[CH:24]([N:23]1[C:19]([C:17]2[N:18]=[C:11]3[C:10]4[CH:27]=[N:28][C:7]([N:34]5[CH2:35][CH2:36][C@H:32]([CH3:31])[C@H:33]5[C:37]([NH2:39])=[O:38])=[CH:8][C:9]=4[O:15][CH2:14][CH2:13][N:12]3[CH:16]=2)=[N:20][CH:21]=[N:22]1)([CH3:26])[CH3:25]
Reactant: C[C@H]1CCN[C@@H]1C(N)=O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(OS(=O)(=O)C(F)(F)F)cc1OCC2
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CC[C@H](C)[C@H]3C(N)=O)cc1OCC2

Procedure:
Following the procedures of Example 388, 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl trifluoromethanesulfonate and (2S,3S)-3-methylpyrrolidine-2-carboxamide were reacted to give 406. M/z 432.2, calc., calc. 422.22. 1H NMR (400 MHz, DMSO) δ 9.05 (s, 1H), 7.88 (s, 1H), 7.82 (s, 1H), 7.36 (s, 1H), 6.91 (s, 1H), 6.57 (s, 1H), 6.01-5.88 (m, 2H), 4.49 (d, J=8.8, 4H), 3.88 (s, 1H), 3.55 (t, J=6.7, 2H), 2.32 (dd, J=10.3, 6.4, 1H), 2.18-2.09 (m, 1H), 1.59 (dd, J=12.0, 5.7, 1H), 1.48 (dd, J=6.6, 2.9, 6H), 1.10 (d, J=6.9, 3H)
Reaction SMILES: C([O:4][CH2:5][C:6](Cl)=[O:7])(=O)C.[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:26][C@H:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@@H:28]([NH2:30])[CH3:29])=[C:22]([CH3:25])[CH:23]=3)[CH:18]=[N:17]2)=[CH:12][CH:11]=1.C(N(CC)CC)C>C1COCC1>[F:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:26][C@H:27]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C@@H:28]([NH:30][C:5](=[O:4])[CH2:6][OH:7])[CH3:29])=[C:22]([CH3:25])[CH:23]=3)[CH:18]=[N:17]2)=[CH:14][CH:15]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1O[C@H](c1ccccc1)[C@H](C)N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1O[C@H](c1ccccc1)[C@H](C)NC(=O)CO
Reaction time: 8 h
Yield: 77.4 %

Procedure:
Acetoxyacetyl chloride (0.071 mL, 0.66 mmol) was added to a solution of (1R,2S)-1-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yloxy)-1-phenylpropan-2-amine (62 mg, 0.17 mmol) and triethylamine (0.18 mL, 1.3 mmol) in THF (2.5 mL) at r.t. The mixture was stirred overnight and concentrated. The residue was dissolved in methanol (2 mL) and 28% ammonia (2 mL) and stirred at r.t. overnight. The title compound (57 mg, 80%) was obtained after purification by semi-preparative HPLC.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5](OC)(=[O:9])[CH:6]([CH3:8])[CH3:7]>>[C:5]([NH:3][CH2:2][CH2:1][NH2:4])(=[O:9])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(C)C
Reactant: NCCN
Product: CC(C)C(=O)NCCN
Temperature: 80 °C
Reaction time: 15 h
Yield: 76 %

Procedure:
A mixture of ethylenediamine (308 g) and methyl isobutyrate (87.15 g) was stirred at 80° C. for 15 hours. After removal of excess ethylenediamine under reduced pressure, the residue was dissolved in ethyl acetate (100 ml). Insoluble material was filtered off and the filtrate was concentrated and distilled to give N-isobutyrylethylenediamine (84.45 g).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:25]=[CH:24][C:12]3[N:13]([C@H:17]4[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]4)[CH2:14][CH2:15][O:16][C:11]=3[CH:10]=2)O1.[CH2:27]([N:31]1[CH:36]=[CH:35][C:34](OS(C(F)(F)F)(=O)=O)=[C:33]([Cl:45])[C:32]1=[O:46])[CH2:28][CH2:29][CH3:30].C([O-])(O)=O.[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:27]([N:31]1[CH:36]=[CH:35][C:34]([C:9]2[CH:25]=[CH:24][C:12]3[N:13]([CH:17]4[CH2:18][CH2:19][C:20](=[O:23])[CH2:21][CH2:22]4)[CH2:14][CH2:15][O:16][C:11]=3[CH:10]=2)=[C:33]([Cl:45])[C:32]1=[O:46])[CH2:28][CH2:29][CH3:30]
Reactant: CC1(C)OB(c2ccc3c(c2)OCCN3[C@H]2CC[C@H](O)CC2)OC1(C)C
Reactant: CCCCn1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCCCn1ccc(-c2ccc3c(c2)OCCN3C2CCC(=O)CC2)c(Cl)c1=O
Temperature: 25 °C
Yield: 15.6 %

Procedure:
A mixture of intermediate D15 (0.15 g, 0.418 mmol), intermediate D4 (0.139 g, 0.418 mmol), tetrakis(triphenylphosphine)palladium(0) (0.0241 g, 0.0209 mmol) and an aqueous saturated NaHCO3 solution (1 ml) in dioxane (4 ml), was heated at 150° C. for 10 min. under microwave irradiation. After cooling to r.t., the r.m. was filtered through diatomaceous earth, treated with EtOAc and the organic layer was washed with water and then with brine. The organic fraction was dried (Na2SO4), filtered and the solvent was evaporated in vacuo. The crude residue was purified by column chromatography (silica gel; 0-10% EtOAc/DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield D23 (0.027 g, 15.59%).
Reaction SMILES: [CH2:1]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:13][CH:14]([C:20]([CH3:22])=O)[C:15](OCC)=[O:16]>C1C=CC=CC=1>[OH:16][C:15]1[C:8]2[C:9](=[CH:11][CH:12]=[C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH:7]=2)[N:10]=[C:20]([CH3:22])[C:14]=1[CH3:13]
Reactant: CCCCCc1ccc(N)cc1
Reactant: CCOC(=O)C(C)C(C)=O
Solvent: c1ccccc1
Product: CCCCCc1ccc2nc(C)c(C)c(O)c2c1
Yield: 42 %

Procedure:
1.63 Grams of 4-n-pentylaniline and 1.44 g of ethyl 2-methylacetoacetate were refluxed in benzene in the presence of a Lewis acid catalyst for 3 hours. The reaction mixture was washed with a saturated sodium hydrogencarbonate solution and a saturated brine and dried over-anhydrous sodium sulfate. After the solvent was evaporated, the resultant intermediate was refluxed in diphenyl ether for 30 minutes and allowed to cool to produce precipitates, which were collected by filtration under reduced pressure to obtain 1.01 g of 4-hydroxy-2,3-dimethyl-6-n-pentyl-quinoline (yield 42%). Its NMR spectral data are shown in the following Table 2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[N:8]/[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:3][CH:2]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]([N+:40]#[C-:41])S(C2C=CC(C)=CC=2)(=O)=O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].COC(C)(C)C>CN(C=O)C>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:40]=[CH:41][N:8]([CH:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]3)[C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][N:3]=2)=[CH:25][CH:24]=1
Reactant: [C-]#[N+]C(c1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(/N=C/c2ccncn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccc(F)cc3)c2-c2ccncn2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of tert-butyl 4-{[(1E)-pyrimidin-4-ylmethylene]amino}piperidine-1-carboxylate (C13) (57.66 g, 198.6 mmol), 1-fluoro-4-{isocyano[(4-methylphenyl)sulfonyl]methyl}benzene (C2) (38.30 g, 132.4 mmol) and potassium carbonate (36.59 g, 264.8 mmol) in DMF (575 mL) was stirred for 18 hours. The reaction was filtered, and the solids were washed with ethyl acetate and discarded. The combined filtrates were diluted with ethyl acetate (1 L) and washed with water (2×1 L), and the combined aqueous layers were extracted with ethyl acetate (500 mL). Concentration of the combined organic layers in vacuo provided a solid, which was heated at reflux with tert-butyl methyl ether (400 mL), then cooled to room temperature and granulated for 1 hour. The solid was collected by filtration and washed with additional tert-butyl methyl ether; this filtrate was concentrated under reduced pressure and treated in the same way, using 75 mL of tert-butyl methyl ether, to obtain a second crop. The combined solids provided the product as a white solid. Yield: 41.70 g, 98.47 mmol, 74%. 1H NMR (400 MHz, CDCl3) δ 1.49 (s, 9H), 1.81-1.92 (m, 2H), 2.16 (br d, J=12 Hz, 2H), 2.77-2.85 (m, 2H), 4.30 (br s, 2H), 4.90 (tt, J=12.0, 3.8 Hz, 1H), 7.04 (dd, J=8.7, 8.7 Hz, 2H), 7.17 (dd, J=5.3, 1.4 Hz, 1H), 7.41 (dd, J=8.9, 5.4 Hz, 2H), 7.79 (s, 1H), 8.57 (d, J=5.4 Hz, 1H), 9.29 (d, J=1.5 Hz, 1H).
Reaction SMILES: [N:1]([C:4]1([C:9](Cl)=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]1)=[N+:2]=[N-:3].[CH2:12]([O:19][CH2:20][CH2:21][NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[N:1]([C:4]1([C:9]([NH:22][CH2:21][CH2:20][O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]1)=[N+:2]=[N-:3]
Reactant: NCCOCc1ccccc1
Reactant: [N-]=[N+]=NC1(C(=O)Cl)CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: [N-]=[N+]=NC1(C(=O)NCCOCc2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Azidocyclopentan-1-carbonylchloride (16.8 g) was added to a mixture of 2-benzyloxyethylamine (14.7 g), K2CO3 (16.6 g) and acetone at 0° C. After stirring at room temperature for 2 h the mixture was filtered, concentrated in vacuo and after addition water (100 ml) extracted with diethyl ether (2×100 ml).The combined organic phases were washed with brine and dried (Na2SO4). Evaporation of the solvents gave the crude 12a as an oil: 22.3 g.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[C:27]([O:29][CH3:30])=[O:28]>ClCCl.N1C=CC=CC=1>[C:11]1([C:12]([NH:21][C:22]2[CH:26]=[CH:25][S:24][C:23]=2[C:27]([O:29][CH3:30])=[O:28])=[O:13])[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=1[S:9][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:1]([NH:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[C:27]([O:29][CH3:30])=[O:28])=[O:19]
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: COC(=O)c1sccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1sccc1NC(=O)c1ccccc1SSc1ccccc1C(=O)Nc1ccsc1C(=O)OC
Temperature: 23 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
A solution of 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane was added to a solution of methyl 3-amino-2-thiophenecarboxylate (1.82 g, 11.6 mmol) in 14 mL of pyridine at 23° C. The reaction mixture was stirred for 18 hours at 23° C. under nitrogen atmosphere. The precipitate formed was collected by filtration, then triturated with 5% aqueous HCl and washed with water to yield the crude product. The crude material was recrystallized first from ethanol, then from acetonitrile-DMF to yield 2.0 g of the title compound, mp 250-252° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([NH2:13])=[N:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:14][NH2:15]>O>[NH2:13][C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:15][CH3:14])[CH:7]=2)=[N:9][N:10]=1
Reactant: CN
Reactant: Nc1nnc(-c2ccnc(Cl)c2)s1
Solvent: O
Product: CNc1cc(-c2nnc(N)s2)ccn1
Temperature: 130 °C
Yield: 47 %

Procedure:
To 5-(2-chloropyridin-4-yl)-1,3,4-thiadiazol-2-amine 8.1.C (1.03 g, 4843 μmol) in a pressure tube was added 16 mL of methylamine 40% in water. The reaction was heated at 130° C. for 3 hours. The pressure tube was cooled down and precipitates were generated. The precipitates were filtered and rinsed with water and dried to afford 476 mg of product 8.1.D (47%).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:37][CH:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CS(C)=O>C(#N)C>[CH3:34][C:23]1[CH:22]=[C:21]([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:45][CH:38]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH3:37])=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Reactant: CC(N)c1ccccc1
Solvent: CC#N
Solvent: CS(C)=O
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NC(C)c4ccccc4)n3Cc3ccccc32)cc1C

Procedure:
A solution of 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 (2 mmol), α-methylbenzylamine (4.2 mmol) in dimethylsulfoxide (7 mmol) and acetonitrile (15 mL) was stirred at 80° C. for 18 hours. The solvents were evaporated and the residue was dissolved in dichloromethane, washed with water, dried over anhydrous sodium sulfate and evaporated. The compound was purified by HPLC (normal phase, Luna® CN bonded packing (Phenomenex, Torrance, Calif.)) and crystallized from ethyl acetate/hexane. (0.93 g), m.p. 118-124°C. MS [(+)ESI, m/z]: 538 [M+H]+Anal. Calcd for C36H33N2O2: C, 80.12; H, 6.16; N, 7.79. Found: C, 79.97; H, 6.27; N, 7.78.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([CH3:26])=[C:7]([CH3:25])[C:8]2[O:12][C:11]([CH3:22])([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:10][C:9]=2[C:23]=1[CH3:24])(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([NH:4][C:5]1[C:6]([CH3:26])=[C:7]([CH3:25])[C:8]2[O:12][C:11]([CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)([CH3:22])[CH2:10][C:9]=2[C:23]=1[CH3:24])[CH3:2]
Reactant: CC(=O)Nc1c(C)c(C)c2c(c1C)CC(C)(CCc1ccc(F)cc1)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCNc1c(C)c(C)c2c(c1C)CC(C)(CCc1ccc(F)cc1)O2
Temperature: 0 °C
Yield: 70.6 %

Procedure:
To tetrahydrofuran (20 ml) were added 5-acetylamino-2,4,6,7-tetramethyl-2-[2-(4-fluorophenyl) ethyl]-2,3-dihydrobenzofuran (1.2 g, 3.4 mmol) and lithium aluminum hydride. The mixture was heated under reflux for hours. The reaction mixture was poured into ice water and the product was extracted with ethyl acetate. The extract was washed with water and dried and then the solvent was distilled off. The residue was purified by column chromatography on silica gel (isopropyl ether-ethyl acetate, 2:1) to obtain the desired compound (0.82 g, yield: 71.2%) as oil.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH2:9][CH:10]([CH2:12][S:13]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[O:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:22].C([OH:25])C>>[ClH:22].[C:7]([O:8][CH2:9][CH:10]([NH2:11])[CH2:12][S:13]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:14])(=[O:25])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(CC1COC(c2ccccc2)=N1)c1ccc(O)cc1
Reactant: CCO
Agent: Cl
Product: NC(COC(=O)c1ccccc1)CS(=O)c1ccc(O)cc1

Procedure:
1.3 g (4.3 mM) of the oxazoline from Example 2 was dissolved in 30 mL ethanol and treated with 8 mL lN HCl for 3 hours. The solvents were removed under reduced pressure and the resulting foam was dried under high vacuum for 18 hours at 50° C. to give the title compound.
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15])=[N+]=[N-].[H][H]>C(O)C.O.[C].[Pd]>[NH2:1][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15]
Reactant: [H][H]
Reactant: [N-]=[N+]=NCCn1c(=O)[nH]c2ccccc21
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: NCCn1c(=O)[nH]c2ccccc21
Yield: 89.1 %

Procedure:
In 150 ml of ethanol was dissolved 1.3 g (6.4 mmol) of Compound i followed by addition of a suspension of 65 mg (5 w/w%) of 10% palladium-carbon in 2 ml of water. The mixture was stirred at room temperature for 4.5 hours, with hydrogen gas being bubbled into the mixture. The reaction mixture was then filtered and the filtrate was concentrated to give 1.01 g (89.1%) of 1-(2-aminoethyl)-2,3-dihydro-2-oxo-1H-benzimidazole (Compound j) as white crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:21]=1[NH2:22]>>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: COc1ccc(C)cc1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Product: COc1ccc(C)cc1Nc1cc(C(F)(F)F)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(2-pyridinyl)-6-trifluoromethylpyrimidine (60 mg, 0.23 mmol) and 2-methoxy-5-methylaniline (46 mg, 0.34 mmol) similar to Example 180. After completion of the reaction the solvent was removed under reduced pressure. The product was purified (5 mg) by preparative TLC plate using 1:1 hexane/ethyl acetate as mobile phase. 1H NMR (DMSO-d6): 9.68 (s, 1H), 8.75 (d, J=3.6, 1H), 8.26 (d, J=7.2 Hz, 1H), 8.00 (t, J=7.2 Hz, 1H), 7.55 (dd, J=4.0, 7.2 Hz, 1H), 7.04 (m, 2H), 3.82 (s, 3H), 2.02 (s, 3H).
Reaction SMILES: N[C@H:2]1[C:21](=[O:22])[N:4]2[C:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][C@H:3]12.N([O-])=O.[Na+].[Cl-:27].[Na+]>C(O)C.O.Cl>[Cl:27][C@H:2]1[C:21](=[O:22])[N:4]2[C:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][C@H:3]12
Reactant: [Cl-]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](N)[C@H]2SC1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](Cl)[C@H]2SC1
Temperature: 0 °C
Yield: 73 %

Procedure:
To an ice-cooled solution of t-butyl 7α-amino-3-acetoxymethyl-3-cephem-4-carboxylate (4.0 g, 0.0122 mol) in 75 ml of ethanol, 16.7 ml of water and 16.7 ml of concentrated hydrochloric acid was added portionwise over 15-20 minutes sodium nitrite (1.18 g, 0.017 mol). The reaction mixture was stirred at 0°-5° C. for 2.5 hours, saturated with sodium chloride, extracted with methylene chloride, washed with water, brine, dried Na2SO4 and concentrated to give 3.1 g (73%) of t-butyl 7α-chloro-3-acetoxymethyl-3-cephem-4carboxylate.