Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:17]2[C:5]([C:6]3[CH:29]=[CH:28][CH:27]=[CH:26][C:7]=3[C:8]3[C:16]=2[CH:15]=[C:14]2[C:9]=3[C:10]3[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=3[C:12]3[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=32)=[CH:4][CH:3]=[CH:2]1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:48]([O:50][C:51](=[O:70])[C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68]Br)=[CH:54][CH:53]=1)[CH3:49]>O1CCOCC1.C(OCC)C>[CH:18]1[C:13]2[C:12](=[C:11]3[CH:22]=[CH:23][CH:24]=[CH:25][C:10]3=[C:9]3[C:14]=2[CH:15]([CH2:68][CH2:67][CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][O:58][C:55]2[CH:56]=[CH:57][C:52]([C:51]([O:50][CH2:48][CH3:49])=[O:70])=[CH:53][CH:54]=2)[C:16]2[C:8]3=[C:7]3[CH:26]=[CH:27][CH:28]=[CH:29][C:6]3=[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:17]3=2)[CH:21]=[CH:20][CH:19]=1
Reactant: C1=CCc2c3c(c4ccccc4c2=C1)=c1c(c2ccccc2c2ccccc12)=C3
Reactant: CCOC(=O)c1ccc(OCCCCCCCCCCBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCOC(=O)c1ccc(OCCCCCCCCCCC2c3c(c4ccccc4c4ccccc34)-c3c2c2ccccc2c2ccccc32)cc1

Procedure:
1H-Tetrabenzo[a,c,g,i]fluorene (13) (2.08 g, 5.68 mmol) was suspended in degassed dioxane 80 mL) and heated to reflux under an atmosphere of nitrogen. Tetrabutylammonium hydroxide (40% w/w in H2O, 3.50 g, 5.41 mmol) was added as a solution in dioxane (20 mL) via syringe which was then washed with dioxane (2×5 mL). A yellow precipitate formed immediately which was filtered under nitrogen and washed with warm dioxane (100 mL) and diethyl ether (100 mL). The salt was resuspended in dioxane (100 mL) and to it added 4-(10-bromo-decyloxy)-benzoic acid ethyl ester (10) (2.08 g, 5.40 mmol). The reaction mixture was refluxed under an atmosphere of nitrogen after which time a dark solution had formed. Solvent was removed in vacuo to form a dark brown oil. This was dissolved in diethyl ether and the supernatant removed to leave a yellow slurry. This was washed with diethyl ether (2×30 mL) and all the diethyl ether extracts combined and concentrated. The resulting residue was purified by flash column chromatography using CH2Cl2 /hexane (1:1) as the eluting solvent. The product was isolated as a pale yellow airy solid which was washed with and concentrated from diethyl ether four times. The desired product was precipitated from diethyl ether as a pale yellow powder (2.46 g, 3.67 mmol, 68%).
Reaction SMILES: [Mg].C(I)C.II.Br[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=O)[CH3:23])=[CH:18][CH:17]=1.S(=O)(=O)(O)O>C1COCC1>[C:11]1([CH3:14])[CH:12]=[CH:13][C:8]([C:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=2)=[CH2:23])=[CH:9][CH:10]=1
Reactant: Cc1ccc(Br)cc1
Reactant: CC(=O)c1ccc(C)cc1
Agent: II
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCI
Solvent: C1CCOC1
Product: C=C(c1ccc(C)cc1)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
Into a 1-liter reaction flask were introduced in a nitrogen stream 15.6 g (0.65 mol) of magnesium and 20 ml of THF. Slight amounts of ethyl iodide and iodine were added thereto to initiate reaction. A solution of 111.15 g (0.65 mol) of p-bromotoluene in 500 ml of THF was then added dropwise at room temperature to 40° C. over a period of 2 hours to prepare a Grignard reagent. Thereto was added dropwise a solution of 83.75 g (0.625 mol) of p-methylacetophenone (10a) in 200 ml of THF at that temperature over a period of 3 hours. This mixture was stirred first at room temperature for 3 hours and then with refluxing for 4 hours. The resulting reaction mixture was cooled and poured into 1 liter of 5% aqueous sulfuric acid solution to conduct hydrolysis. This mixture was extracted with toluene, and the extract was washed with aqueous soda ash solution and then with water and concentrated. Thereto were added 300 ml of toluene and 0.5 g of PTSA. The resulting mixture was stirred with refluxing for 4 hours to conduct azeotropic dehydration, followed by washing with aqueous soda ash solution, washing with water, and concentration. The resulting crude 1,1-di(p-tolyl)ethylene (9b) was distilled with a Claisen flask equipped with a vigreux, giving 98.5 g of the desired compound.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Cl:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=[CH:10][CH:11]=1>O.C(O)(=O)C>[Cl:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][C:14](=[O:21])[C:15](=[N:1][OH:3])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)CC(=O)CCc1cccc(Cl)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=NO)C(=O)CCc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium nitrite (12.6 g) in water (25 ml) was added to a stirred solution of the product from step (i) (42.2 g) in acetic acid (50 ml) at <30° C. The reaction mixture was stirred at room temperature for 30 min. Water (75 ml) was added and the mixture was stirred for 2 hours and extracted with diethyl ether. The combined extracts were washed with water and saturated aqueous sodium bicarbonate solution. The organic layer was collected, dried (MgSO4) and solvent evaporated under reduced pressure to give the subtitle product.
Reaction SMILES: [N:1]#[N:2].[CH3:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([S:15]([NH:18][C@H:19]([C:27]([OH:29])=[O:28])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:26])[NH2:25])(=[O:17])=[O:16])=[CH:12]2)=[CH:7][CH:6]=1.[ClH:30].[CH3:31]O>>[N:1]#[N:2].[ClH:30].[CH3:31][O:28][C:27](=[O:29])[C@H:19]([CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:25])[NH2:26])[NH:18][S:15]([C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[CH:14][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[CH:12]=1)(=[O:16])=[O:17]
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cc2c1
Reactant: CO
Agent: Cl
Agent: N#N
Product: COC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2ccc(OC)cc2c1
Yield: 95 %

Procedure:
A suspension of 1.0 gram of N2 -(7-methoxy-2-naphthalenesulfonyl) -L-arginine in 15 ml of anhydrous methanol was saturated with dry hydrogen chloride for one hour. The reaction mixture was refluxed for an additional one hour. After cooling, the reaction mixture was concentrated in vacuo. The residue was triturated with cold ethyl ether to give a cyrstalline product. After crystallization from methanolethyl ether, N2 -(7-methoxy-2-naphthalenesulfonyl)-L-arginine methyl ester hydrochloride was obtained in 95% yield; mp. 115° - 118°C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.C(N(CC)CC)C.[NH2:20][C:21]1[CH:42]=[CH:41][C:24]([C:25]([N:27]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[CH2:31][N:30]3[CH:38]=[CH:39][CH:40]=[C:29]3[CH2:28]2)=[O:26])=[CH:23][CH:22]=1>C(Cl)Cl>[CH:40]1[CH:39]=[CH:38][N:30]2[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[N:27]([C:25]([C:24]3[CH:23]=[CH:22][C:21]([NH:20][C:6](=[O:7])[C:5]4[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=4[O:11][CH3:12])=[CH:42][CH:41]=3)=[O:26])[CH2:28][C:29]=12
Reactant: COc1cc(Cl)ccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Cl)ccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 0.05 h
Yield: 41.1 %

Procedure:
To a stirred solution of 0.406 g of 4-chloro-2-methoxybenzoyl chloride in 5 ml of methylene chloride is added 0.346 g of triethylamine at 0° C. After stirring for 3 minutes, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 18 hours at room temperature. An additional 0.406 g of 4-chloro-2-methoxybenzoyl chloride and 0.346 g of triethylamine is added and stirring is continued for 2 hours. The reaction mixture is diluted with 45 ml of methylene chloride and washed with water, 2N citric acid, 1M NaHCO3, and brine. The reaction mixture is dried with Na2SO4 filtered and evaporated in vacuo to give a residue which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give a solid which is crystallized from ethyl acetate to give 0.320 g of the desired product as a white crystals, m.p. 222°-224 ° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:31]=[CH:32][C:33]=2[CH3:34])[CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:15]([NH:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[C:30]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:31]=[CH:32][C:33]=3[CH3:34])[CH2:24][CH2:23]2)=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Reactant: O=C(O)C1(c2ccc(F)cc2Cl)CCCCC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C2(c3ccc(F)cc3Cl)CCCCC2)CC1

Procedure:
Example 134 was prepared from 1-(2-chloro-4-fluorophenyl)cyclo hexanecarboxylic acid and N-{3-[1-(3-amino propyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.55 (dd, 1H, J=8.9, 6.3 Hz), 7.32 (s, 1H), 7.23–7.18 (m, 2H), 7.06 (dd, 1H, J=8.5, 3.0 Hz), 7.01–6.92 (m, 2H), 5.99–5.93 (m, 1H), 3.24 (q, 2H, J=5.9 Hz), 2.85–2.79 (m, 3H), 2.59–2.50 (m, 1H), 2.44 (septet, 1H, J=7.0 Hz), 2.41–2.37 (br, 1H), 2.26 (t, 2H, J=5.7 Hz), 2.19 (s, 3H), 2.07–2.01 (m, 2H), 1.81–1.69 (m, 4H), 1.61–1.37 (m, 10H), 1.17 (d, 6H, J=7.0 Hz); ESMS m/e: 556.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].CCCCCCC>C(OCC)(=O)C>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]1=[O:1])[CH3:16]
Reactant: COc1cccnc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCOC(=O)Cn1cccc(OC)c1=O
Yield: 92 %

Procedure:
As described for example 320a, 2-hydroxy-3-methoxy-pyridine was reacted with ethyl bromoacetate and potassium carbonate. Extractive workup followed by chromatography (SiO2, heptane:ethyl acetate=100:0 to 0: 100) afforded the title compound as a white solid (yield: 92%). MS: m/e=212.3[M+H]+.
Reaction SMILES: N[C:2]1[C:3](=[O:13])[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([CH3:12])[N:8]=[CH:7][CH:6]=2.[OH-:14].[Na+]>C(O)(=O)C>[OH:14][C:2]1[C:3](=[O:13])[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([CH3:12])[N:8]=[CH:7][CH:6]=2
Reactant: [OH-]
Reactant: Cc1nccc2[nH]c(=O)c(N)cc12
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nccc2[nH]c(=O)c(O)cc12
Temperature: 25 °C

Procedure:
This compound was prepared by heating 3-amino-5-methyl-1,6-naphthyridin-2(1H)-one following in part the procedure described in Example E-4 without purification of 3-amino-5-methyl-1,6-naphthyridin-2(1H)-one by reacting said unpurified 3-amino compound with aqueous sodium hydroxide solution or by similarly reacting said purified 3-amino compound with aqueous sodium hydroxide solution. These procedures are described as follows. Following the procedure described in Example E-4 using 27 g of 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carboxylic acid hydrazide, 60 ml of concentrated sulfuric acid, 200 ml of water and 9.1 g of sodium nitrite and after concentrating the reaction mixture to dryness on a rotary evaporator, the residue containing the corresponding said 3-amino compound was treated with 75 ml of 35% sodium hydroxide solution and 100 ml of water and the resulting aqueous mixture was heated on a steam bath for 30 hours and then acidified with acetic acid. The acidified mixture was allowed to stand at room temperature overnight and the resulting product that separated was collected, washed with water and air-dried. It was then recrystallized from 400 ml of boiling dimethylformamide, filtering off the insoluble material, concentrating the filtrate to a volume of about 200 ml and then allowing it to stand at room temperature for 3 hours. The yellow crystalline solid was collected, washed with methanol and dried at 100° C. to yield 7.6 g of 3-hydroxy-5-methyl-1,6-naphthyridin-2-(1H)-one, m.p. >320° C. The same compound was also prepared by heating a mixture containing 3-amino-5-methyl-1,6-naphthyridin-2(1H)-one with 25 ml of 10% aqueous sodium hydroxide solution on a steam bath for 7 hours and then cooled to room temperature. The reaction mixture was acidified with acetic acid and the resulting white crystalline precipitate was collected, washed with water and dried at 95° C. to yield 1.2 g of 3-hydroxy-5-methyl-1,6-naphthyridin-2(1H)-one, m.p. >320° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([NH:9]C(=O)OCC1C=CC=CC=1)([CH3:8])[CH3:7].[H][H]>C(O)C.[Pd]>[CH3:7][C:6]([CH3:8])([C:2]1[O:1][CH:5]=[CH:4][N:3]=1)[NH2:9]
Reactant: [H][H]
Reactant: CC(C)(NC(=O)OCc1ccccc1)c1ncco1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(N)c1ncco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.3 %

Procedure:
A mixture of benzyl 2-(oxazol-2-yl)propan-2-ylcarbamate (0.63 g, 24 mmol) and palladium 10% on carbon (0.06 g) in ethanol (20 mL) was charged with hydrogen balloon and stirred at room temperature for 2 h. TLC showed the reaction was completed; it was filtered and concentrated to give a yellow oil (0.1 g, 33%); MS: m/e 127.1 [M+H]+. 1H NMR (300 MHz, CDCl3): δ 7.58 (d, 1H, J=0.6 Hz), 7.02 (s, 1H), 2.56 (bs, 4H), 1.59 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O)#[N:2].[F:12][C:13]1([F:31])[CH2:18][CH2:17][C:16]([CH2:29][NH2:30])([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH:30][CH2:29][C:16]1([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=2)[CH2:17][CH2:18][C:13]([F:12])([F:31])[CH2:14][CH2:15]1)=[O:7])#[N:2]
Reactant: NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1
Reactant: N#Cc1ccccc1C(=O)O
Product: N#Cc1ccccc1C(=O)NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1

Procedure:
From 2-cyanobenzoic acid and C-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=424.2, tR (minutes, Method D)=0.66
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:13]=2)[O:3]1.[CH3:21][S:22]([CH:25]=[CH2:26])(=[O:24])=[O:23].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:21][S:22]([CH2:25][CH2:26][N:17]1[CH2:18][CH2:19][CH:14]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:20])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:15][CH2:16]1)(=[O:24])=[O:23]
Reactant: CC1(C)OB(c2cnn(C3CCNCC3)c2)OC1(C)C
Reactant: C=CS(C)(=O)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OB(c2cnn(C3CCN(CCS(C)(=O)=O)CC3)c2)OC1(C)C
Yield: 10.8 %

Procedure:
A solution of 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine (500 mg, 1.80 mmol), (methylsulfonyl)ethene (212 mg, 1.99 mmol), and DIPEA (500 mL, 2.87 mmol) in DMF (6 mL) was stirred at 25° C. for 30 min. The reaction mixture was then concentrated in vacuo to a solid and then purified by flash chromatography (0 to 5% MeOH:EtOAc) to yield 74.5 mg (11%) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 7.98 (s, 1H), 7.59 (s, 1H), 4.17 (tt, J=10.36, 5.05 Hz, 1H), 3.30 (s, 2H), 3.05 (s, 3H), 2.98 (d, J=11.62 Hz, 2H), 2.74 (t, J=6.57 Hz, 2H), 2.13 (td, J=11.37, 3.28 Hz, 2H), 1.88-2.00 (m, 4H), 1.25 (s, 12H).
Reaction SMILES: C([Mg]Cl)(C)C.[Li]Cl.Br[C:9]1[C:10]([Cl:33])=[C:11]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])=[CH:16][N:15]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:12]2=[N:13][CH:14]=1.[B:34]([O:43][CH:44]([CH3:46])[CH3:45])([O:39][CH:40]([CH3:42])[CH3:41])OC(C)C.OC(C(O)(C)C)(C)C>C1COCC1>[Cl:33][C:10]1[C:9]([B:34]2[O:39][C:40]([CH3:41])([CH3:42])[C:44]([CH3:45])([CH3:46])[O:43]2)=[CH:14][N:13]=[C:12]2[N:15]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:11]=12
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccccc2F)c2c(Cl)c(Br)cnc21
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)(O)C(C)(C)O
Agent: CC(C)[Mg]Cl
Agent: [Li]Cl
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnc3c(c(-c4ccccc4F)cn3COCC[Si](C)(C)C)c2Cl)OC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.8 %

Procedure:
Isopropyl magnesium chloride/Li—Cl complex (10.7 ml, 10.9 mmol-14% in THF) was added dropwise to a solution of 5-bromo-4-chloro-3-(2-fluoro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo-[2,3-b]pyridine (2.5 g, 5.4 mmol) under nitrogen in THF at −20° C. The reaction was let to proceed at −20° C. for another 2 hours. Then triisopropyl borate (3.1 ml, 13.6 mmol) in THF was added dropwise and the reaction was continued at −20° C. for another hour. At this time pinacol (1.3 g, 10.9 mmol) was added. The reaction was stirred at room temperature overnight. The solvent was removed under vacuum. Silica chromatography of the crude using a gradient of ethyl acetate and hexane afforded 4-chloro-3-(2-fluoro-phenyl)-5-(4,4,5,5-tetramethyl[1,3,2]-dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (1.0 g, 63% yield). 1H NMR (500 MHz, DMSO-d6) δ 0.01 (s, 9H), 0.94 (t, 2H), 1.58 (s, 12H), 3.69 (t, 2H), 5.81 (s, 2H), 7.40 (m, 2H), 7.56 (m, 2H), 7.99 (s, 1H), 8.40 (m, 1H). MS: m/z 503.2 (M+H+).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:34](=[O:35])[N:14]2[CH:15]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[C:16](=[CH2:20])[CH2:17][S:18](=O)[C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]([O:39]C(=O)C)(=[O:38])[CH3:37]>C(Cl)(=O)C.C1C=CC=CC=1>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:34](=[O:35])[N:14]2[CH:15]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[C:16]([CH2:20][O:39][C:36](=[O:38])[CH3:37])=[CH:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: C=C1CS(=O)[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)Cl
Solvent: c1ccccc1
Product: CC(=O)OCC1=CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 85 °C

Procedure:
To 10 ml. of benzene were added 500 mg. (1 millimole) of p-nitrobenzyl 7-phenoxyacetamido-3-methylenecepham-4-carboxylate-1-oxide. To the resulting slurry were added 2 ml. of acetic anhydride and 2 drops of acetyl chloride. The resulting mixture was refluxed at 85° C. for about 15 hours. The resulting reaction mixture then was treated as in Example 1 to obtain p-nitrobenzyl 7-phenoxyacetamido-3-acetoxymethyl-2-cephem-4-carboxylate.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].C(N(CC)CC)C.Cl[C:19]([O:21][CH3:22])=[O:20].[Cl-].[Na+]>C(Cl)(Cl)Cl>[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:19](=[O:20])[O:21][CH3:22]
Reactant: COC(=O)Cl
Reactant: NCc1cccc(Br)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)NCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a suspension of 10.0 g of 3-bromobenzylamine hydrochloride in chloroform (100 ml), 9.55 g of triethylamine was added at room temperature. To this solution, 4.67 g of methyl chloroformate was dropwise added under cooling with ice, followed by stirring at room temperature for 2 hours. The reaction solution was poured into a sodium chloride aqueous solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 9.54 g of methyl N-(3-bromobenzyl)carbamate as white crystals.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)(=[O:13])=[O:12].S1C=CC=C1>C1COCC1.[Pd]>[NH2:26][C:23]1[CH:22]=[CH:21][C:20]([N:17]2[CH2:16][CH2:15][N:14]([S:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)(=[O:13])=[O:12])[CH2:19][CH2:18]2)=[CH:25][CH:24]=1
Reactant: O=[N+]([O-])c1ccc(N2CCN(S(=O)(=O)c3ccc4ccccc4c3)CC2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: c1ccsc1
Product: Nc1ccc(N2CCN(S(=O)(=O)c3ccc4ccccc4c3)CC2)cc1
Yield: 86.7 %

Procedure:
A mixture of 1-(2-naphthalenylsulfonyl)-4-(4-nitrophenyl)-piperazine (7.5 mmol) in THF (150 ml) was hydrogenated at 50° C. with Pd/C 10% (1 g) as a catalyst in the presence of thiophene solution (0.5 ml). After uptake of H2 (3 equiv.), the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from 2-propanol. The formed precipitate was filtered off, washed with 2-propanol and dried (55° C., vacuum), yielding 2.39 g (87%) of 1-(4-aminophenyl)-4-(2-naphthalenylsulfonyl)-piperazine (interm. 7).
Reaction SMILES: C([Li])CCC.S1CCCSC1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([C:20]#[N:21])[CH:14]=1.[CH3:22][O:23][C:24]([CH3:26])=[CH2:25].[Br:27][C:28]1[CH:29]=[CH:30][C:31]2[O:36][C:35]([CH3:38])([CH3:37])[N:34]=[C:33]([CH:39]3[S:44][CH2:43][CH2:42][CH2:41][S:40]3)[C:32]=2[CH:45]=1>CCCCCC.O1CCCC1>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:25][CH:24]([O:23][CH3:22])[CH3:26])=[C:15]([CH:14]=1)[C:20]#[N:21].[Br:27][C:28]1[CH:29]=[CH:30][C:31]2[O:36][C:35]([CH3:37])([CH3:38])[N:34]=[C:33]([CH:39]3[S:40][CH2:41][CH2:42][CH2:43][S:44]3)[C:32]=2[CH:45]=1
Reactant: N#Cc1cc(Br)ccc1O
Reactant: C=C(C)OC
Agent: C1CSCSC1
Agent: CC1(C)N=C(C2SCCCS2)c2cc(Br)ccc2O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(C)COc1ccc(Br)cc1C#N
Reaction time: 0.5 h

Procedure:
A solution (13.8 ml) of 1.6M n-butyllithium in hexane was added dropwise to a solution of 1,3-dithian (1.5 g) in anhydrous tetrahydrofuran (35 ml) at -78° C. under an argon atmosphere over 10 minutes. After stirring for 30 minutes, a solution of 5-bromo-2-(2-methoxy-2-methylethoxy)benzonitrile, which was prepared from 4-bromo-2-cyanophenol (m.p. 148°-150° C., 2.48 g) and 2-methoxypropene (1.1 g) according to the same manner as described in Example 29, in anhydrous tetrahydrofuran (5 ml) was added to the mixture. The mixture was treated in the same manner as that in Example 29 to obtain 6-bromo-2,2-dimethyl-4-(1,3-dithian-2-yl)-2H-1,3-benzoxazine (0.90 g) (Compound 105).
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8](OC)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:19][NH2:20]>CCO>[C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([NH:19][NH2:20])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(c1ccccc1)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)C(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 97 %

Procedure:
To a stirred solution of methyl 2,2-diphenylacetate (0.5 g, 1 equiv) in anhydrous EtOH (150 mL) was added hydrazine hydrate (8 mL) and heated to reflux. Stirring was then continued for 1 hour. The reaction mixture was then cooled and the solvents removed under reduced pressure. The crude oil was diluted with EtOAc and washed with H2O and the organic phase dried over Na2SO4, filtered, and the solvents removed under reduced pressure to yield a yellow oil (0.97 g, 97%) that was used without further purification.