Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=3)[O:11][CH:12]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>O.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)[O:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2nc(-c3ccc(Cl)cc3)co2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2nc(-c3ccc(Cl)cc3)co2)cc1
Yield: 63.5 %

Procedure:
A mixture of methyl 4-[4-(4-chlorophenyl)-2-oxazolyl]benzoate (450 mg), a 1N aqueous solution of sodium hydroxide (2.5 ml), tetrahydrofuran (10 ml) and methanol (5 ml) was stirred at 60 to 70° C. for 20 minutes. The reaction mixture was poured into water. To the mixture was added 1N hydrochloric acid, and precipitated 4-[4-(4-chlorophenyl)-2-oxazolyl]benzoic acid (273 mg, Yield: 64%) was collected by filtration and then washed with water. The product was recrystallized from acetone-isopropyl ether to obtain pale yellow prisms. Melting Point: 283 to 284° C. (decomposition).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[CH:23]=[CH:24][C:25]3[N:31]4[N:32]=[N:33][N:34]=[C:30]4[CH2:29][S:28][CH:27]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=4)[C:26]=3[CH:42]=2)=[O:21])=[CH:16][CH:15]=1.CCOC(C)=O>C(OCC)C.C1COCC1>[Cl:41][C:37]1[CH:36]=[C:35]([CH:27]2[C:26]3[CH:42]=[C:22]([C:20]([C:17]4[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=4)([C:7]4[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=4)[OH:21])[CH:23]=[CH:24][C:25]=3[N:31]3[N:32]=[N:33][N:34]=[C:30]3[CH2:29][S:28]2)[CH:40]=[CH:39][CH:38]=1
Reactant: Brc1cccnc1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCc1nnnn1-2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: OC(c1ccc(Cl)cc1)(c1cccnc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCc1nnnn1-2
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 6.3 %

Procedure:
nBuLi (0.009 mol) was added dropwise at −70° C. to a mixture of 3-bromo-pyridine (0.009 mol) in diethyl ether (10 ml) under N2 flow. The mixture was stirred at −70° C. for 15 minutes. A suspension of intermediate (31) (0.003 mol) in THF (30 ml) was added dropwise at −70° C. The mixture was stirred at −70° C. for 1 hour, then brought slowly to room temperature, stirred overnight and poured out into ice water. EtOAc was added. The mixture was extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 95/5/0.2; 15–40 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.12 g (7%). This fraction was taken up in diethyl ether. The precipitate was filtered off and dried in a vacuum, yielding 0.1 g (6%) of 6-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(3-pyridinyl)-4H,6H-tetrazolo[1,5-a][4,1]benzothiazepine-8-methanol, MS (MH+) m/e: 532, 534, 536.
Reaction SMILES: C(N1CCN(C2C=CC(N)=CC=2)CC1)CC(C)C.[CH:19]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)([CH3:21])[CH3:20].C(Cl)Cl>CCO.[Pd]>[CH:19]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)([CH3:21])[CH3:20]
Reactant: CC(C)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Agent: CC(C)CCN1CCN(c2ccc(N)cc2)CC1
Solvent: ClCCl
Solvent: CCO
Product: CC(C)N1CCN(c2ccc(N)cc2)CC1
Reaction time: 3 h
Yield: 86.4 %

Procedure:
Using the method described above for the synthesis of 4-(4-isopentylpiperazin-1-yl)aniline, treatment of 1-isopropyl-4-(4-nitrophenyl)piperazine (11.0 g, 40.1 mmol) with H2 and 10% Pd/C (1.0 g) at RT in EtOH (150 mL) for 24 h, followed by the addition of DCM (100 mL) to the reaction mixture and stirring for a further 3 h, provided crude 4-(4-isopropylpiperazin-1-yl)aniline (7.6 g, 86% recovery, 99% purity as determined by LC/MS analysis @ UV 254 nm detection). The crude product is used in the next step without further purification. LCMS-ESI (m/z): calcd for C13H21N3, 219; [M+H]+ found, 220.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:25][C:26]1[C:34]([OH:35])=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[C:29]([CH3:36])[NH:30]2>CN(C=O)C>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)[N:5]=[CH:4][CH:3]=[C:2]2[O:35][C:34]1[C:26]([F:25])=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29]([CH3:36])=[CH:28]2)#[N:13]
Reactant: CN1CCN(CCCOc2cc3nccc(Cl)c3cc2C#N)CC1
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Solvent: CN(C)C=O
Product: Cc1cc2c(F)c(Oc3ccnc4cc(OCCCN5CCN(C)CC5)c(C#N)cc34)ccc2[nH]1
Yield: 44.3 %

Procedure:
Using an analogous procedure to that described in Example 11, 4-chloro-6-cyano-7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline (500 mg, 1.45 mmol) was reacted with 4-fluoro-5-hydroxy-2-methylindole (287 mg, 1.74 mmol), (prepared as described for the starting material in Example 11), in DMF (1 ml) to give 6-cyano-4-(4-fluoro-2-methylindol-5-yloxy)-7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline (304 mg, 44%).
Reaction SMILES: C[NH:2]CCOCCNC.[CH3:10][N:11]([CH3:17])[C:12]([N:14]([CH3:16])[CH3:15])=[NH:13].NC(N)=[NH2+].NC(N)=N.[C:26](=[O:28])=[O:27]>>[C:26](=[O:28])([O-:27])[NH2:2].[CH3:10][N:11]([CH3:17])[C:12](=[NH:13])[N:14]([CH3:16])[CH3:15]
Reactant: CNCCOCCNC
Reactant: O=C=O
Agent: CN(C)C(=N)N(C)C
Agent: N=C(N)N
Agent: NC(N)=[NH2+]
Product: NC(=O)[O-]

Procedure:
A procedure similar to Examples 1 and 2 was carried out using a ˜1:˜2.1 mixture of 1,5-bis(methylamino)-3-oxapentane (BMAOP) with pKa ˜9.87 and 1,1,3,3-tetramethylguanidine (˜1:1.05 mixture on the basis of amine sites) for ˜2 hours. Only one product, a mixed dicarbamate (monocarbamate at each amine site), appeared to form. The 1H NMR spectrum after carboxylation showed movement of the guanidinium protons (in relatively fast equilibrium with any remaining guanidine protons) downfield to ˜9.92 ppm, plus movement of the amine —NCH2— backbone resonance from ˜2.6 to ˜3.2-3.4 ppm. That most of BMAOP molecules reacted was confirmed by the absence of free peaks. Based on integration of the product peak at ˜161.6 ppm compared to the sharp C—O peak of DMAOP at ˜69.89 ppm, ˜99.7 mol % of BMAOP molecules were calculated to have reacted with CO2 to form a mixed carbamate with tetramethylguanidine. The difunctional BMAOP molecules appeared to react with two pairs of tetramethylguanidine and CO2 to form two mixed carbamate moieties per molecule at room temperature (˜199.4 mol % of CO2 per DMAOP molecule).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([N:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[N:21][CH2:20]2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:18][CH2:17][CH:16]([N:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[N:21][CH2:20]1)[CH2:15][CH:12]1[CH2:14][CH2:13]1)=[O:6]
Reactant: O=C(O)c1c(F)cccc1Cl
Reactant: NCC(CC1CC1)N1C=CC(C(F)(F)F)=NC1
Product: O=C(NCC(CC1CC1)N1C=CC(C(F)(F)F)=NC1)c1c(F)cccc1Cl

Procedure:
From 2-chloro-6-fluorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propan-1-amine. LCMS (MH+): m/z=402.1, tR (minutes, Method D)=0.77
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(COC)OC.C([O-])(O)=O.[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1OCc1ccccc1
Reactant: Clc1cc(Cl)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Clc1cc(-c2ccccc2OCc2ccccc2)ncn1
Yield: 79.9 %

Procedure:
4,6-dichloropyrimidine (6.0 g, 40 mmol) and 2-benzyloxyphenylboronic acid (6.61 g, 29 mmol) were added to a solution of dimethoxyethane (120 mL) and water (18 mL), followed by the addition of NaHCO3 (6.72 g, 80 mmol) and (PPh3)2PdCl2 (0.84 g). To this end the reaction mixture was allowed to reflux for 8 h, and the solvent removed under reduced pressure. The residue was taken up in CH2Cl2 (100 mL), and the resulting solution washed with water, dried over anhydrous K2CO3, filtered and the solvent removed under reduced pressure. The crude product was purified by flash chropatography on silica gel (eluent CH2Cl2) and recrystallized from hexanes yielding 4-chloro-6-(2-benzyloxyphenyl)-pyrimidine (6.88 g; 80%) as white powder.
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][C:10]([CH:13]3[CH2:16][N:15](C(OCC4C=CC=CC=4)=O)[CH2:14]3)=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[NH2:2]>[Pd].CO>[NH:15]1[CH2:14][CH:13]([C:10]2[O:11][C:12]3[C:4]([C:1]([NH2:2])=[O:3])=[CH:5][CH:6]=[CH:7][C:8]=3[N:9]=2)[CH2:16]1
Reactant: NC(=O)c1cccc2nc(C3CN(C(=O)OCc4ccccc4)C3)oc12
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1cccc2nc(C3CNC3)oc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.1 %

Procedure:
A mixture of benzyl 3-(7-carbamoylbenzo[d]oxazol-2-yl)azetidine-1-carboxylate (160 mg, 0.45 mmol), 10% Pd/C (20 mg) of methanol (30 ml) was stirred at room temperature for 2 h. Then the mixture was filtered and evaporated under reduced pressure. The residue was purified by pre-HPLC. 6 mg of 2-(azetidin-3-yl)benzo[d]oxazole-7-carboxamide was obtained. LC-MS (ESI) m/z: 218 (M+1)+. 1H-NMR (400 MHz, CDCl3): δ 1.84 (brs, 1H), 3.39 (t, 3H), 4.11 (t, 3H), 4.21 (m, 1H), 6.12 (brs, 1H), 6.96 (brs, 1H), 7.39 (t, J=8 Hz, 1H), 7.81 (d, J=8 Hz, 1H), 8.01 (d, J=8 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH:21]=[O:22])[C:3]=1[CH:4]=[CH:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:23].O[C@@:25]1(C)CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(C=O)C(=CC(=O)CC1)C=C3.O[C@@]1(C#CC)CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(C=O)C(=CC(=O)CC1)C=C3.C[C@]12CC[C@H]3[C@@H](C=CC4[C@]3(C=O)CCC(=O)C=4)[C@@H]1CCC2=O>>[CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][CH2:17][C@@:16]2([CH2:21][OH:22])[C:3]=1[CH2:4][C@@H:5]([CH3:25])[C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[OH:23]
Reactant: CC1=C2C=C[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C=O)CCC1=O
Reactant: C[C@]1(O)CC[C@H]2[C@@H]3C=CC4=CC(=O)CC[C@]4(C=O)[C@H]3CC[C@@]21C
Agent: CC#C[C@]1(O)CC[C@H]2[C@@H]3C=CC4=CC(=O)CC[C@]4(C=O)[C@H]3CC[C@@]21C
Agent: C[C@]12CC[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@]43C=O)[C@@H]1CCC2=O
Product: CC1=C2C[C@@H](C)[C@@H]3[C@H](CC[C@]4(C)[C@@H](O)CC[C@@H]34)[C@@]2(CO)CC[C@@H]1O

Procedure:
Substituting 4-methyl-4,6-androstadiene-3,17,19-trione, 17β-hydroxy-17α-methyl-4,6-androstadiene-3,19-dione and 17β-hydroxy-17α-propinyl-4,6-androstadiene-3,19-dione for the 4,6-androstadiene-3,17,19-trione above results in the formation of 4,7α-dimethyl-4-androstene-3β,17β,19-triol, 7α,17α-dimethyl-4-androstene-3β,17β,19-triol and 7α-methyl-17α-propinyl-4-androstene-3β,17β,19-triol, respectively.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:12]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15]>C1COCC1>[CH2:1]([O:8][C:12]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(F)c1F
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cccc(F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Benzyl alcohol (5.51 mL) was added dropwise over 20 min to a stirred suspension of sodium hydride (2.128 g of a 60% dispersion in mineral oil) and 2,3-difluorobenzonitrile (7.4 g) in THF (100 mL) with external ice bath cooling to maintain temperature around 25° C. After addition was complete, the reaction mixture was stirred at room temperature for 24 h, quenched with water (200 mL) and extracted into ethyl acetate (3×120 mL), combined organics were dried (MgSO4) and evaporated. The residual oil was purified (SiO2 chromatography eluting with 20% ether in isohexane) to give the subtitle compound as an oil (9.70 g).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.O[CH:13]1[C:26]2[CH:25]=[C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:23]=[CH:22][C:21]=2[O:20][C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2.[C:35]([NH-:52])([O:37][CH2:38][CH:39]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]2[C:40]1=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36]>C(O)(=O)C>[CH:41]1[C:40]2[CH:39]([CH2:38][O:37][C:35]([NH:52][CH:13]3[C:26]4[CH:25]=[C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:23]=[CH:22][C:21]=4[O:20][C:19]4[C:14]3=[CH:15][CH:16]=[CH:17][CH:18]=4)=[O:36])[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:45]=2[CH:44]=[CH:43][CH:42]=1
Reactant: [NH-]C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(O)CCCCOc1ccc2c(c1)C(O)c1ccccc1O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: O=C(O)CCCCOc1ccc2c(c1)C(NC(=O)OCC1c3ccccc3-c3ccccc31)c1ccccc1O2

Procedure:
A solution of p-toluenesulfonic acid (0.15 g, 0.8 mmol) in glacial acetic acid (3 mL) was added dropwise at 25° C. over 15 minutes to a well-stirred suspsension of 5-(9-hydroxy-xanthen-2-oxy)valeric acid (2.0 g, 6.4 mmol) prepared as described above and Fmoc-amide (1.84 g, 8.2 mmol) in glacial acetic acid (50 mL). This mixture was stirred continuously and then filtered after 3 hours to collect a white solid which was washed with water (3×20 mL) and ehtyl ether (3×20 mL). The solid was dried in vacuo over P2O5 at 25° C. Yield: 2.35 g(61%, m.p. 210-211° C., Rf : 0.53 EtOAc/MeOh 5:1. NMR data and elemental analysis in accordance with structure. ##STR12##
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:17]=1[C:18]([O:20]C)=[O:19]>>[Cl:26][C:23]1[CH:24]=[CH:25][C:16]([NH:15][C:12]([C:10]2[O:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)=[O:14])=[C:17]([CH:22]=1)[C:18]([OH:20])=[O:19]
Reactant: COC(=O)c1cc(Cl)ccc1N
Reactant: O=C(O)c1ccc(-c2ccccc2)o1
Product: O=C(Nc1ccc(Cl)cc1C(=O)O)c1ccc(-c2ccccc2)o1
Yield: 77 %

Procedure:
Using the same method as in Example 3-(i), methyl 5-chloro-2-{[(5-phenylfuran-2-yl)carbonyl]amino}benzoate was obtained using 5-phenylfuran-2-carboxylic acid and methyl 2-amino-5-chlorobenzoate. Thereafter, using the same method as in Example 3-(ii), the target 5-chloro-2-{[(5-phenylfuran-2-yl)carbonyl]amino}benzoic acid was obtained (yield: 77%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[N+:19]([O-])([OH:21])=[O:20]>[N+](C)([O-])=O>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1nccnc1Nc1ccc(Cl)cc1
Solvent: C[N+](=O)[O-]
Product: COC(=O)c1nccnc1Nc1ccc(Cl)cc1[N+](=O)[O-]
Reaction time: 0.75 h

Procedure:
A suspension of 2.6 g 3-(4-chlorophenylamino)-pyrazine-2-carboxylic acid methyl ester in 100 ml nitromethane is stirred and treated dropwise at 0° C. with 24 ml nitric acid (99%). Stirring is continued at 0° C. for further 45 minutes. The solution is poured on ice and extracted with methylene chloride. The organic phase is washed with saturated sodium bicarbonate solution, dried over sodium sulphate and evaporated to give the heading compound, m.p. 191°-192°.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C@@H:10]1[C:33](=[O:34])[N:12]2[C:13]([C:20]([O:22]CC3C=CC([N+]([O-])=O)=CC=3)=[O:21])=[C:14]([N:17]=[N+:18]=[N-:19])[CH2:15][S:16][C@H:11]12)=[O:8].C1COCC1.Cl>[Zn].O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C@@H:10]1[C:33](=[O:34])[N:12]2[C:13]([C:20]([OH:22])=[O:21])=[C:14]([N:17]=[N+:18]=[N-:19])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: [N-]=[N+]=NC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: [N-]=[N+]=NC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 5 °C

Procedure:
A solution of 0.625 g. of p-nitrobenzyl 7β-(2-thienylacetamido)-3-azido-3-cephem-4-carboxylate in 24 ml. of THF was diluted with 10 ml. of cold water and cooled in an ice-water bath. To the cold solution were added portionwise over about two hours 1.58 g. of zinc dust and sufficient 0.1N to 1N hydrochloric acid to maintain the pH of the mixture at about 4.3. Throughout the addition of zinc and acid the temperature of the reaction mixture was maintained at about 5° C. After the zinc dust addition was completed, the pH was adjusted to 2.7 with 1N hydrochloric acid and the mixture filtered. The filtrate was mixed with ethyl acetate and extracted twice with aqueous sodium bicarbonate. The aqueous layer was separated, layered with ethyl acetate, acidified with cold 1N hydrochloric acid, the organic layer separated, washed with brine, dried, and evaporated to yield 0.116 g. of the title acid as a pale yellow solid. The product was triturated with diethyl ether, filtered, and air dried to provide 80 mg. of the product acid as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([O:19]C)[CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].B(Br)(Br)Br>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COc1ccc2nc(-c3ccc([N+](=O)[O-])cc3)sc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(-c2nc3ccc(O)cc3s2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.4 %

Procedure:
To a suspension of 2-(4′-nitrophenyl)-6-methoxy benzothiazole (400 mg, 1.5 mmol) in CH2Cl2 (10 mL) was added BBr3 (1M in CH2Cl2, 10 mL, 10 mmol). The reaction mixture was stirred at room temperature for 24 hr. The reaction was then quenched with water, and extracted with ethyl acetate (3×20 mL). The organic layers were combined and washed with water, dried over MgSO4, and evaporated. The residue was purified by flash chromatography (silica gel, hexanes:ethyl acetate=1:1) to give the product as a yellow solid (210 mg, 55%). 1HNMR (300 MHz, Acetone-d6) δ (Ppm): 9.02 (s, OH), 8.41 (d, J=9.1 Hz, 1H), 8.33 (d, J=9.1 Hz, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.53 (d, J=2.4 Hz, 1H), 7.15 (dd, J1=8.6 Hz, J2=2.4 Hz, 1H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:23])=[C:7]2[CH2:21][CH2:20][N:19]([CH3:22])[C:8]2=[N:9][C:10]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:3])[CH3:2]>C1C=CC=CC=1.[O-2].[O-2].[O-2].[Ni+3].[Ni+3]>[C:1]([O:4][C:5]1[C:6]([CH3:23])=[C:7]2[CH:21]=[CH:20][N:19]([CH3:22])[C:8]2=[N:9][C:10]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:3])[CH3:2]
Reactant: CCCCCCCCc1nc2c(c(C)c1OC(C)=O)CCN2C
Agent: [Ni+3]
Agent: [O-2]
Solvent: c1ccccc1
Product: CCCCCCCCc1nc2c(ccn2C)c(C)c1OC(C)=O

Procedure:
To a solution containing 65 mg (0.20 mmol) of 1d in 5 mL of benzene was added 56 mg (0.61 mmol) of nickel peroxide. The reaction was stirred at reflux for 18 h. The reaction mixture was filtered through a silica gel plug and washed with three 25-mL portions of benzene, followed by two 25-mL portions of ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under diminished pressure. The residue was purified via flash chromatography on a silica gel column (25×1.7 cm). Step gradient elution with 1:10→1:4 ethyl acetate-hexanes as eluent gave 1,4-dimethyl-6-octyl-1H-pyrrolo[2,3-b]pyridin-5-yl acetate (2d) as a colorless oil: yield 50 mg (48%); silica gel TLC Rf 0.29 (3:7 ethyl acetate-hexanes); 1H NMR (CDCl3) δ 0.98 (t, 3H, J=7.2 Hz), 1.35-1.50 (m, 10H), 1.72 (quint, 2H, J=8.0 Hz), 2.11 (s, 3H), 2.38 (s, 3H), 2.52 (t, 2H, J=8.0 Hz), 3.34 (s, 3H), 6.21 (d, 1H, J=3.6 Hz), 6.88 (d, 1H, J=3.6 Hz).
Reaction SMILES: [F:1][CH:2]([F:33])[O:3][C:4]1[C:13]2[C:8](=[C:9]([F:20])[CH:10]=[CH:11][C:12]=2[O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:7]=[C:6]([CH2:21][CH3:22])[C:5]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.[CH:34]([C:37]1[NH:38][CH:39]=[CH:40][N:41]=1)([CH3:36])[CH3:35]>>[CH3:19][O:18][C:16](=[O:17])[CH2:15][O:14][C:12]1[CH:11]=[CH:10][C:9]([F:20])=[C:8]2[C:13]=1[C:4]([O:3][CH:2]([F:33])[F:1])=[C:5]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:38]3[CH:39]=[CH:40][N:41]=[C:37]3[CH:34]([CH3:36])[CH3:35])=[CH:26][CH:25]=1)[C:6]([CH2:21][CH3:22])=[N:7]2
Reactant: CC(C)c1ncc[nH]1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(B(O)O)cc1
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(-n2ccnc2C(C)C)cc1

Procedure:
The title compound was prepared by the method of Preparation 23b using (4-{[4-difluoromethoxy-2-ethyl-8-fluoro-5-(2-methoxy-2-oxoethoxy)quinolin-3-yl]methyl}phenyl)boronic acid and 2-isopropyl-1H-imidazole.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([CH3:13])=[CH2:12])[CH:8]=[C:7]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=1)=[N+]=[N-].[O:22](C(OC(C)(C)C)=O)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=O>CCOC(C)=O.[Pd]>[CH2:15]([O:14][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=1)[CH2:4][NH:1][C:23](=[O:22])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=C(C)c1cc(CN=[N+]=[N-])cc(OCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)c1cc(CNC(=O)OC(C)(C)C)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 11.5 h
Yield: 62 %

Procedure:
A mixture of 573 mg (1.97 mmol) of 1-(azidomethyl)-3-(benzyloxy)-5-(prop-1-en-2-yl)benzene, 0.5 mL of BOC2O, and 60.5 mg of 10% Pd/C in 10 mL of EtOAc was stirred at r.t. under H2 balloon for 11.5 h. The mixture was filtered through Celite and concentrated. Purification by flash silica gel chromatography (10% EtOAc/hexanes) provided 336 mg of tert-butyl 3-(benzyloxy)-5-isopropylbenzylcarbamate in 62% yield.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:14](N(CC)CC)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(O)(=O)C>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: CCN(CC)CC
Reactant: Brc1ccc(C2CCNC2)cc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCC(c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 135.3 %

Procedure:
To a mixture of 3-(4-bromophenyl)pyrrolidine hydrochloride (200 mg, 0.76 mmol) in methanol (6 mL) was added triethylamine (77 mg, 0.76 mmol) and several drops of acetic acid. The reaction mixture was stirred at room temperature for 5 min and treated with aqueous formaldehyde (37%, 0.2 mL) and sodium triacetoxyborohydride (322 mg, 1.52 mmol). The reaction mixture was stirred for 18 h at room temperature. The methanol was evaporated in vacuo and the residue was partitioned between water and EtOAc. The phases were separated and the aqueous phase was back-extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo to give 3-(4-bromophenyl)-1-methylpyrrolidine (0.247 g) as a solid, which was used in the next step without further purification. MS (ES+) 239.9 (M+H)+.