Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([O:13][CH2:14]C)=[O:12].[OH-].[NH4+]>CO>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: [Mg]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1Cc2ccccc2N1
Temperature: 0 °C

Procedure:
Magnesium turnings (3.60 g) are added to a mixture of ethyl indole-2-carboxylate (I, Aldrich Chemical, 13.963 g) in methanol (200 ml). After evolution of gas has started, the mixture is placed in an ice bath and the temperature kept below 45°. After 4.5 hours all of the magnesium is used up and the temperature is 7°. At this time the mixture is added to ice cold hydrochloric acid (3N, 120 ml). The acidic mixture is then made alkaline (pH 10) with ammonium hydroxide (3N). The mixture is then extracted with methylene chloride (3×). The combined organic layers are dried over magnesium sulfate and concentrated to give the title compound.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=O)=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:46][C@H:47]([C:51]([OH:53])=[O:52])[C@@H:48]([CH3:50])[OH:49]>>[C:1]([O:18][CH:19]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([NH:46][C@H:47]([C:51]([OH:53])=[O:52])[C@@H:48]([CH3:50])[OH:49])=[O:30])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCCCCC(=O)O
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCCCCC(=O)N[C@H](C(=O)O)[C@@H](C)O
Yield: 88.4 %

Procedure:
Starting from 5-(3-hexadecanoyloxyoctadecanoyl)aminovaleric acid (1.27 g) and L-threonine (950 mg), N-[5-(3-hexadecanoyloxyoctadecanoyl)aminovaleryl]-L-threonine (1.3 g) was obtained as crystals according to a similar manner to that of Example 6.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:7])[CH2:5][OH:6].[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11](F)[CH:10]=1>CN(C)C=O>[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([O:6][CH2:5][CH:4]([CH3:7])[CH3:3])[CH:10]=1
Reactant: CC(C)CO
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)COc1cc(Br)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a suspension of sodium hydride (60% w/w, 20.5 g) in N,N-dimethylformamide (365 ml) was added 2-methyl-1-propanol (48.7 ml) dropwise below 30° C. over 2 hours under nitrogen atmosphere. To the mixture was added 4-bromo-2-fluorobenzoic acid (50.0 g) slowly below 35° C. To the reaction mixture was added N,N-dimethylformamide (600 ml) and the mixture was stirred at room temperature for 4 days. The reaction mixture was partitioned between water (2000 ml) and hexane (1000 ml). The water layer was separated and acidified with 37% hydrochloric acid. The precipitate was collected by filtration, washed with water and dried at 55° C. to give 4-bromo-2-isobutoxybenzoic acid (62.4 g) as a white solid.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:28]=[C:27]([NH2:29])[N:26]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[CH3:36])[N:25]=2)=[CH:20][CH:19]=1>CN(C=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:28]=[C:27]([NH:29][C:2]3[N:10]=[CH:9][CH:8]=[CH:7][C:3]=3[C:4]([NH2:6])=[O:5])[N:26]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[CH3:36])[N:25]=2)=[CH:22][CH:23]=1
Reactant: NC(=O)c1cccnc1Cl
Reactant: Cc1ccccc1-n1nc(-c2ccc(F)cc2)cc1N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1ccccc1-n1nc(-c2ccc(F)cc2)cc1Nc1ncccc1C(N)=O
Temperature: 150 °C
Yield: 14 %

Procedure:
A mixture of 2-chloronicotinamide (59 mg, 0.37 mmol), potassium carbonate (57 mg, 0.41 mmol), 3-(4-fluorophenyl)-1-(2-methylphenyl)-1H-pyrazol-5-amine (100 mg, 0.37 mmol) (Intermediate G), and copper (II) acetate (1.4 mg, 0.007 mmol) in DMF (1 mL) was heated (150° C.) in a sealed tube for 16 h. The mixture was cooled to rt, filtered through a silica gel plug using ethyl acetate as eluent, concentrated to dryness, and subjected to HPLC purification using a gradient elution from 30% to 90% acetonitrile in water to afford 20 mg (14%) of the desired product.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[N:4][NH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:19][N:20]([CH:22]=O)C>O>[Br:1][C:2]1[C:3]([CH3:12])=[N:4][N:5]([CH2:6][C:2]2[CH:3]=[N:4][N:20]([CH3:19])[CH:22]=2)[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1[nH]nc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CCOC(=O)c1c(Br)c(C)nn1Cc1cnn(C)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 23 %

Procedure:
To ethyl 4-bromo-3-methyl-1H-pyrazole-5-carboxylate (2.56 g, 10.98 mmol) in DMF (30 mL) were added Cs2CO3 (8.94 g, 27.4 mmol) and 4-(chloromethyl)-1-methyl-1H-pyrazole, HCl (2.2 g, 13.17 mmol). The reaction mixture was stirred at room temperature for 20 hours and then diluted with water. The product was extracted into EtOAc. The organic phase was dried over Na2SO4 and concentrated. The crude residue was purified by CombiFlash® chromatography (120 g, column) eluting with a gradient of 10-100% EtOAc in heptane over a period of 180 minutes. The product-containing fractions were combined and concentrated to give the title compound (0.82 g, 23%) and a regioisomer, ethyl 4-bromo-5-methyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole-3-carboxylate (1.32 g, 36.8%).
Reaction SMILES: [CH3:1][OH:2].N1C=CC=CC=1.[CH3:9][C:10]1([C:18](Cl)=[O:19])[CH:15]([CH3:16])[CH2:14][C:13]([CH3:17])=[CH:12][CH2:11]1.Cl>O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:18]([C:10]1([CH3:9])[CH:15]([CH3:16])[CH2:14][C:13]([CH3:17])=[CH:12][CH2:11]1)=[O:19]
Reactant: CO
Reactant: CC1=CCC(C)(C(=O)Cl)C(C)C1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)C1(C)CC=C(C)CC1C
Temperature: 25 °C

Procedure:
0.2 moles (8 ml) methanol, 0.15 moles (12 ml) pyridine and 50 ml toluene were put in a 100-ml beaker with a magnetic stirrer, and the crude product as per (b) was (1,4,6-trimethylcyclohex-3-en-1-carboxylic acid chloride) added dosewise with vigorous stirring. The reaction mixture was stirred for another hour at room temperature and then 25 ml water and 5 ml concentrated hydrochloric acid were added to it. Then the phases were separated, the organic phase dried with sodium sulfate and distilled via the Vigreux column after removal of the solvent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N:13][C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:6]=2Cl.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][NH2:26])[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N:13][C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:6]=2[NH:26][CH2:25][CH2:24][N:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]1
Reactant: Clc1ccc2c(Cl)c3ccccc3nc2c1
Reactant: CN1CCN(CCN)CC1
Product: CN1CCN(CCNc2c3ccccc3nc3cc(Cl)ccc23)CC1

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 3,9-dichloroacridine (J. Med. Chem. 1985, 28. 940-944) and 2-(4-methylpiperazin-1-yl)ethanamine, the title compound was obtained; MS (Found M+1=355).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:14]=[N:13][N:12]([CH2:15][C@@H:16]2[C@H:19]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18](=[O:31])[N:17]2CC2C=CC(OC)=CC=2OC)[N:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].OP([O-])([O-])=O.[K+].[K+]>CC#N.O>[Si:1]([O:8][CH2:9][C:10]1[CH:14]=[N:13][N:12]([CH2:15][C@@H:16]2[C@H:19]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:18](=[O:31])[NH:17]2)[N:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2Cn2ncc(CO[Si](C)(C)C(C)(C)C)n2)c(OC)c1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCc1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)n1
Temperature: 90 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution of benzyl ((2R,3S)-2-((4-(((tert-butyldimethylsilyl)oxy)methyl)-2H-1,2,3-triazol-2-yl)methyl)-1-(2,4-dimethoxybenzyl)-4-oxoazetidin-3-yl)carbamate (1.25 g, 2.1 mmol) in CH3CN (20 mL) was added K2S2O8 (0.73 g, 2.7 mmol) followed by a solution of K2HPO4 (0.84 g, 4.8 mmol) in water (10 mL). After stirring at 90° C. for 1 h, more K2S2O8 (0.23 g, 0.84 mmol) was added. After heating at 90° C. for additional 2 h, the reaction mixture was concentrated in vacuo. The residue was extracted with EtOAc (2×30 mL). Combined organic layers were washed with water, brine, dried with Na2SO4, filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 1-3%) to afford the title compound (0.44 g, 47%) as a pale yellow solid. LCMS: m/z=446.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10]C)=O)[CH:3]=1.Cl.[CH:13]([C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[CH3:23])([CH3:15])[CH3:14].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>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([CH:13]([CH3:14])[CH3:15])=[C:17]([CH3:23])[CH:18]=2)=[O:10])[CH:3]=1
Reactant: Cc1cc(N)ccc1C(C)C
Reactant: COC(=O)c1cc(Br)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)c2cc(Br)ccn2)ccc1C(C)C
Temperature: 25 °C
Yield: 79.2 %

Procedure:
To a solution of methyl 4-bromopicolinate (1.0 g, 5.0 mmol) in DCM (500 mL) and DMF (20 mL) was added 4-isopropyl-3-methylbenzenamine hydrochloride (1.08 g, 5.90 mmol), HATU (3.8 g, 10 mmol), DIPEA (4.9 mL, 30 mmol) and the mixture was stirred at reflux overnight. After cooling to room temperature and evaporation of the solvent, the residue was purified by combi-flash (ISCO, 40g silica, UV254, 3:1 pet ether/ethyl acetate) to afford 4-bromo-N-(4-isopropyl-3-methylphenyl)picolinamide (1.32 g, 80% yield) as a yellow oil: MS (ES) m/z 333 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Br-].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[Br:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:6]/[C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: BrCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: [Br-]
Product: Fc1ccc(/C=C/CCCBr)cc1

Procedure:
4-Fluorobenzaldehyde (1.0 g) and 4-bromobutyl-triphenylphosphonium bromide (4.62 g) were treated in the same manner as in Preparation Example 83 to obtain the title compound.
Reaction SMILES: N1C=CC([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:23][CH3:24])=[CH:12][CH:11]=2)=[O:9])=CC=1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[CH3:24][O:23][C:13]1[C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[C:18]=2[C:10]([C:8]([NH2:7]=[O:33])=[O:9])=[CH:11][CH:12]=1
Reactant: COc1ccc(C(=O)Nc2ccncc2)c2c1oc1ccccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)[NH2+][O-])c2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of N-(pyrid-4-yl)-4-methoxy dibenzo[b,d]furan-1-carboxamide (150 mg, 0.47 mmol) (example 3) and m-chloroperbenzoic acid (50-55%) (406 mg, 2.3 mmol) in chloroform (2.5 ml) was stirred at room temperature for 16 h. Chloroform was evaporated and the resulting solid was washed with saturated sodium bicarbonate solution, water, dried and then purified by column chromatography using 20% acetone-chloroform as the eluent to give 70 mg of N-pyrid-4-yl)-4-methoxy dibenzo[b,d]furan-1-carboxamide-N1-oxide as white solid; nip: 246-251° C.; IR (KBr): 3207, 3116, 3056, 2931, 2840, 2797, 1678, 1626, 1603, 1530, 1485, 1458, 1439, 1391, 1330, 1277, 1214, 1174, 1122, 1099, 1023, 851, 829, 791, 749 cm−1.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH2:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[O:22])=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([C:10]2[CH:11]=[CH:12][C:7]([CH2:5][CH3:6])=[CH:8][CH:9]=2)=[O:22])=[CH:16][CH:15]=1
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Reactant: CCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CCc1ccc(C(=O)Cc2ccc(Br)cc2)cc1
Yield: 68 %

Procedure:
To a 50 mL three-necked flask containing AlCl3 (7.305 g; 54.79 mmol) under N2, ethyl benzene (IVc) (8.40 mL; 68.48 mmol) was added in one portion at RT. To this suspension (4-bromo-phenyl)-acetyl chloride (IIIa) (10.66 g; 45.65 mmol) was added drop wise keeping temperature below 40° C. Protocol and work-up was then similar with those described above. Title compound was obtained as a white powder (m=9.923 g) in a 68% yield. Melting point: 146° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[O:19][C:18]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26]N=[CH:24][CH:23]=4)=[N:17][CH:16]=3)[CH:12]=[CH:11][CH:10]=2)[CH:3]=1.Cl[C:29]1[O:30][CH:31]=CN=1.COC1C=CC(CN)=CC=1>CC(O)C>[CH3:29][O:30][C:31]1[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:18]2[O:19][C:15]([C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([NH:8][C:4]4[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=4)[N:14]=3)=[CH:16][N:17]=2)=[CH:23][CH:24]=1
Reactant: Cc1ccnc(Nc2cccc(-c3cnc(NCc4ccncc4)o3)n2)c1
Reactant: Clc1ncco1
Agent: COc1ccc(CN)cc1
Solvent: CC(C)O
Product: COc1ccc(CNc2ncc(-c3cccc(Nc4cc(C)ccn4)n3)o2)cc1

Procedure:
Prepared as for 5-[6-(4-methylpyridin-2-ylamino)pyridin-2-yl]-N-(pyridin-4-ylmethyl)oxazol-2-amine above from the chlorooxazole and 4-methoxybenzylamine in iPrOH. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.18-8.00 (m, 2H), 7.75 (s, 1H), 7.63 (t, J=7.9 Hz, 1H), 7.45 (d, J=8.3 Hz, 1H), 7.38-7.24 (m, 3H), 6.95-6.86 (m, 3H), 6.73 (d, J=5.0 Hz, 1H), 4.37 (d, J=5.9 Hz, 2H), 3.72 (s, 3H), 2.30 (s, 3H). (ESI+) m/z 388 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:4]([NH:25][C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)[N:3]=1.[NH2:33][C@@H:34]1[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]1[NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44].CCN(CC)CC.C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[C:43]([O:42][C:41]([NH:40][C@H:35]1[CH2:36][CH2:37][CH2:38][CH2:39][C@H:34]1[NH:33][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:4]([NH:25][C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)[N:3]=1)=[O:47])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: CCOC(=O)c1c(CN2C(=O)c3ccccc3C2=O)nc(Cl)nc1Nc1cccc(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(CN2C(=O)c3ccccc3C2=O)nc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A mixture of ethyl 2-chloro-4-((1,3-dioxoisoindolin-2-yl)methyl)-6-(m-tolylamino)pyrimidine-5-carboxylate (96.3 mg, 0.214 mmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (58.14 mg, 0.271 mmol) and Et3N (0.030 mL, 0.214 mmol) in DMA (2 mL) was stirred at 80° C. for 3 h. Saturated aq NaHCO3 was added to the mixture, which was extracted with EtOAc. The combined organic layers were washed with aqueous NaHCO3, water, and brine, were dried over anhydrous Na2SO4, and then filtered through SiO2. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, hexanes/EtOAc=3/1) to give the title compound as a yellow oil (123.8 mg, 92%). 1H NMR (400 MHz, CDCl3) δ ppm 1.12-1.71 (m, 20H), 2.33 (s, 3H), 3.39-3.57 (m, 1H), 3.84-3.99 (m, 1H), 4.42 (q, J=7.2 Hz, 2H), 4.55-4.79 (m, 1H), 5.16 (s, 2H), 5.41 (br s, 1H), 6.87-6.89 (m, 1H), 7.16-7.49 (m, 3H), 7.74-7.75 (m, 2H), 7.90-7.91 (m, 2H), 10.68-10.81 (m, 1H). [M+H] calc'd for C34H41N6O6, 629. found, 629.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1.BrC1C=CC2OCCN3C(CN4CCCC4)=C(C(N)=O)N=C3C=2C=1.CN1CCNCC1.[CH3:58][C:59]([OH:63])([C:61]#[CH:62])[CH3:60]>>[OH:63][C:59]([CH3:60])([CH3:58])[C:61]#[C:62][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1
Reactant: C#CC(C)(C)O
Reactant: CN1CCN(Cc2c(C(N)=O)nc3n2CCOc2ccc(Br)cc2-3)CC1
Agent: CN1CCNCC1
Agent: NC(=O)c1nc2n(c1CN1CCCC1)CCOc1ccc(Br)cc1-2
Product: CN1CCN(Cc2c(C(N)=O)nc3n2CCOc2ccc(C#CC(C)(C)O)cc2-3)CC1
Yield: 23 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-3-((4-methylpiperazin-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (prepared similarly as described in the synthesis of 10-bromo-3-(pyrrolidin-1-ylmethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide replacing pyrrolidine with N-methylpiperazine) was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as a colorless solid (12 mg, 23%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][CH2:9][C:10]#[N:11])=[CH:3][CH:2]=1.CN(C)P(N(C)C)(N(C)C)=O.C([N-]C(C)C)(C)C.[Li+].Cl[CH:38]([C:40]1[CH:49]=[CH:48][CH:47]=[C:46]2[C:41]=1[CH:42]=[CH:43][CH:44]=[N:45]2)[CH3:39]>C1COCC1.CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C>[C:7](=[N:8][CH:9]([CH:38]([C:40]1[CH:49]=[CH:48][CH:47]=[C:46]2[C:41]=1[CH:42]=[CH:43][CH:44]=[N:45]2)[CH3:39])[C:10]#[N:11])([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#CCN=C(c1ccccc1)c1ccccc1
Reactant: CC(Cl)c1cccc2ncccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Product: CC(c1cccc2ncccc12)C(C#N)N=C(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
A solution of N-(diphenylmethylene)aminoacetonitrile (5.84 g, 26.0 mmol, commercially available from Aldrich) in THF (20 mL) and hexamethylphosphoramide (HMPA) (5.43 mL, 31 mmol) at −78° C. was reacted with lithium diisopropylamide (LDA) (15.4 mL of a 2M soln in heptane/THF/ethylbenzene) (commercially available from Aldrich). After 1 h, 5-(1-chloro-ethyl)-quinoline (Intermediate E1) (4.15 g, 21.7 mmol) in THF (15 mL) was introduced by dropwise addition. The mixture was kept at −78° C. for 5 m before removal of the cold bath. After 5 m, the mixture was quenched with cold water and extracted with ethyl acetate (3×). The organic solution was dried over MgSO4, filtered and concentrated to give 2-(benzhydrylidene-amino)-3-quinolin-5-yl-butyronitrile that was used in the next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:31])[CH2:4][C:5]([NH:7][CH:8]1[C:29](=[O:30])[N:10]2[C:11]([C:18]([O:20][CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:19])=[C:12]([CH2:15][O:16][CH3:17])[CH2:13][S:14][C@H:9]12)=[O:6].[N:32]([O-])=[O:33].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][CH2:2][C:3](=[O:31])[C:4](=[N:32][OH:33])[C:5]([NH:7][CH:8]1[C:29](=[O:30])[N:10]2[C:11]([C:18]([O:20][CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:26])([CH3:27])[CH3:25])=[O:19])=[C:12]([CH2:15][O:16][CH3:17])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: O=N[O-]
Reactant: COCC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)CC(=O)CCl)[C@H]2SC1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COCC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)C(=NO)C(=O)CCl)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
2.57 g of pivaloyloxymethyl 7-(4-chloro-3-oxobutyrylamino)-3-methoxymethyl-3-cephem-4-carboxylate were dissolved in 25 ml of acetic acid, and then 409 mg of sodium nitrite were added, little by little, at room temperature to the solution, after which the mixture was stirred for 30 minutes. The mixture was then diluted with 200 ml of ethyl acetate, washed three times with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulphate and then concentrated by evaporation under reduced pressure. The residue was twice subjected to azeotropic distillation using toluene and the resulting residue was dried, giving 2.7 g of the title compound as a foamy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN1CCCC1=O>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7]1)[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: CS(=O)(=O)c1c[nH]c2cc(Cl)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)Cn1cc(S(C)(=O)=O)c2ccc(Cl)cc21
Temperature: 0 °C
Yield: 78.8 %

Procedure:
6-Chloro-3-methanesulfonyl-1H-indole (1.35 g, 5.88 mmole) was dissolved in anhydrous N-methylpyrrolidin-2-one (15 ml), cooled to 0° C. and placed under a nitrogen atmosphere. Sodium hydride (60% in oil, 0.28 g, 7 mmole) was added all at once and the mixture was stirred until the evolution of gas ceased (ca. 20-30 minutes). Ethyl bromoacetate (1.08 g, 6.47 mmole) was added all at once and the mixture was stirred for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water, the organic layer was washed three times with water, dried over magnesium sulfate, filtered, and evaporated to dryness. The crude material thus obtained was purified by chromatography on silica gel, eluting with ethyl acetate-hexane (1:9) to (4:6) to afford 1.463 g of (6-chloro-3-methanesulfonyl-indol-1-yl)-acetic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:9]3[CH:14]=[C:13]([O:15][C:16]4[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=4)[C:19]([O:21]C)=[O:20])[N:12]=[CH:11][C:10]=3[N:26]=2)=[N:4][O:5][N:6]=1.[OH-].[Li+]>C1COCC1.O>[NH2:1][C:2]1[C:3]([C:7]2[N:8]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:9]3[CH:14]=[C:13]([O:15][C:16]4[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=4)[C:19]([OH:21])=[O:20])[N:12]=[CH:11][C:10]=3[N:26]=2)=[N:4][O:5][N:6]=1
Reactant: COC(=O)c1cccc(Oc2cc3c(cn2)nc(-c2nonc2N)n3-c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1nonc1-c1nc2cnc(Oc3cccc(C(=O)O)c3)cc2n1-c1ccccc1
Temperature: 65 °C
Yield: 93.9 %

Procedure:
The product from Step 8 (0.22 g, 0.514 mmol) in THF (10 mL) was treated with a solution of 1N lithium hydroxide in water (1.5 mL) and heated to 65° C. for 10 h. The reaction mixture was cooled and concentrated and the residue was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the organic layers were combined, washed with brine and dried over Na2SO4 and concentrated to give the title compound (0.20 g, 94%). MS (ES+) m/e 415 [M+H]+.