Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([N:17]4[CH:22]=[CH:21][C:20]([Sn](C)(C)C)=[CH:19][C:18]4=[O:27])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][C:29]1[CH:30]=[CH:31][C:32]2[O:36][C:35](SC)=[N:34][C:33]=2[CH:39]=1.[ClH:40]>C1COCC1.C(Cl)Cl.CCOCC.[Cu](Br)Br>[ClH:40].[CH3:28][C:29]1[CH:30]=[CH:31][C:32]2[O:36][C:35]([C:20]3[CH:21]=[CH:22][N:17]([C:13]4[CH:12]=[C:11]5[C:16](=[CH:15][CH:14]=4)[N:8]([CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[N:9]=[CH:10]5)[C:18](=[O:27])[CH:19]=3)=[N:34][C:33]=2[CH:39]=1
Reactant: C[Sn](C)(C)c1ccn(-c2ccc3c(cnn3CCN3CCCC3)c2)c(=O)c1
Reactant: CSc1nc2cc(C)ccc2o1
Agent: Br[Cu]Br
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc2oc(-c3ccn(-c4ccc5c(cnn5CCN5CCCC5)c4)c(=O)c3)nc2c1
Temperature: 70 °C
Yield: 24 %

Procedure:
1-(1-(2-(Pyrrolidin-1-yl)ethyl)-1H-indazol-5-yl)-4-(trimethylstannyl)pyridin-2(1H)-one (prepared according to Example 30, step a) (250 mg, 0.530 mmol), 5-methyl-2-(methylthio)benzo[d]oxazole (198 mg, 1.11 mmol), copper(II) bromide (331 mg, 1.16 mmol) and palladium tetrakistriphenylphosphine (61 mg, 0.053 mmol) were stirred in dry THF (6 mL) under a nitrogen atmosphere. The mixture was heated to 70° C. for 20 h. Upon cooling, the mixture was diluted with THF, filtered through celite and rinsed with THF/methylene chloride. The organics were concentrated and purified by flash chromatography (40 g ISCO column eluting with methylene chloride and methanol/ammonia (10:1); 100% methylene chloride to 15% methanol/ammonia over 35 min at 40 mL/min) then further purified by Preparatory HPLC. The appropriate fractions were concentrated and partitioned between methylene chloride and Na2CO3. The organics were dried with Na2SO4, filtered, and concentrated to provide the free base. This was dissolved in methylene chloride (2 mL) and treated with 1 equivalent of 2 M HCl in Et2O, and the mixture was concentrated to provide the title compound (55.8 mg, 24%) as a yellow solid: mp 270-280° C.; 1H NMR (500 MHz, CD3OD) δ 8.27 (s, 1H), 7.94 (d, J=1.7 Hz, 1H), 7.88 (d, J=7.1 Hz, 1H), 7.83 (d, J=8.9 Hz, 1H), 7.64-7.61 (m, 2H), 7.58-7.55 (dd, J=8.9, 1.9 Hz, 1H), 7.44 (d, J=1.7 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.24-7.22 (dd, J=7.1, 1.9 Hz, 1H), 4.89 (t, J=5.7, 2H), 3.88 (t, J=5.7, 2H), 3.74-3.70 (m, 2H), 3.21-3.16 (m, 2H), 2.51 (s, 3H), 2.20-2.16 (m, 2H) 2.04-2.01 (m, 2H); ESI MS m/z 440 [M+H]+; HPLC (Method C) 98.7% (AUC), tR=13.1 min.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:36](=[O:37])[CH2:35][O:34][CH3:33])[CH2:31][CH2:32]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f18) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]2)=[C:6]([F:8])[CH:7]=1.N1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:25]([O:24][C:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]2)=[C:6]([F:8])[CH:7]=1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1cn(-c2ccc(N)cc2F)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cn(-c2ccc(NC(=O)OCc3ccccc3)cc2F)cn1
Reaction time: 16 h
Yield: 92.9 %

Procedure:
5-Amino-2-(4-methyl-imidazol-1-yl)fluorobenzene (50.6 g, 0.265 M) was dissolved in dry dichloromethane (800 ml) under nitrogen, and cooled to −5°. Pyridine (26.1 g, 0.33 M) was added, followed by benzyl chloroformate (49.9 g, 0.292 M) over 30 minutes. The mixture was stirred and the temperature allowed to rise to ambient over 16 hours. Aqueous sodium bicarbonate (5%, 350 ml) was added, the organic layer separated, and the aqueous layer re-extracted with dichloromethane (2×200 ml), and combined organics dried (magnesium sulfate). After filtration and evaporation, the residue was recrystallised from toluene (300 ml) to give title product (80 g).
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([F:25])([F:24])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])([O:6]CC)=[O:5])C.Br[Si](C)(C)C>ClCCl.CO>[P:4]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([F:24])([F:25])[C:14]([F:22])([F:23])[C:15]([F:20])([F:21])[C:16]([F:17])([F:18])[F:19])([OH:5])([OH:6])=[O:3]
Reactant: CCOP(=O)(CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CO
Product: O=P(O)(O)CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.2 %

Procedure:
To a solution of 11.54 g of 1-(diethylphosphono)-4-(nonafluorobutyl)butane in 50 mL of dichloromethane was added 10.7 g of bromotrimethylsilane. After 18 hr at room temperature, the solution was concentrated to a nearly colorless liquid, and the intermediate silylphosphonate ester was dissolved in 250 mL of methanol. The resultant solution was stirred at room temperature for 1 hr, and then concentrated to give a white solid. Dissolution in methanol and concentration were repeated two more times, and recrystallization of the crude product from acetonitrile gave 8.39 g of 1-phosphono-4-(nonafluorobutyl)butane (CF3(CF2)3(CH2)4PO3H2) as colorless needles, m.p. 123-124° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1([C:11]#[N:12])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[Na+].[I-].[NH2:15][OH:16].[C:17]([C:24]([O:26][CH2:27][CH3:28])=[O:25])#[C:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CCOC(C)=O>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][C:17]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[O:16][N:15]2[CH2:2][CH2:3][CH2:4][C:5]3([CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)[C:11]2=[N:12]1)[CH3:23]
Reactant: N#CC1(CCCCl)CCOCC1
Reactant: NO
Reactant: CCOC(=O)C#CC(=O)OCC
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(C(=O)OCC)N=C2N(CCCC23CCOCC3)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.1 %

Procedure:
A mixture of 4-(3-chloropropyl)-tetrahydro-2H-pyran-4-carbonitrile (1.83 g, 9.75 mmol) and NaI (3.0 g, 20 mmol) was stirred at ambient temperature for 1 h. To this reaction mixture was added 50% aqueous hydroxylamine (1 mL, 10.87 mmol) and stirred for three-days at ambient temperature. To this was added diethyl acetylenedicarboxylate (1.6 mL, 10 mmol) and stirred for 1 h. Then, the reaction mixture was diluted with EtOAc (100 mL) washed with water (50 mL), brine (10 mL), dried (Na2SO4), filtered and concentrated to give yellow oil. Flash chromatography using 10-50% EtOAc/Hexanes afforded the title compound as pale yellow oil (0.627 g, 18%). 1H NMR (500 MHz, CDCl3) δ: HRMS (M+H) calcd for C17H27N2O5; found. 1H NMR (500 MHz, CDCl3) δ: 4.32-4.20 (2H, m), 4.14 (2H, q, J=7.0 Hz), 3.86 (1H, td, J=11.0, 2.7 Hz), 3.79-3.70 (3H, m), 3.52-3.46 (1H, m), 3.38-3.34 (1H, m), 3.26 (1H, d, JAB=16.2 Hz), 2.97 (1H, d, JAB=16.2 Hz), 2.06-1.89 (4H, m), 1.66-1.66 (2H, m), 1.60-1.53 (2H, m), 1.30 (3H, t, J=7.0 Hz), 1.24 (3H, t, J=7.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[F:29][C:30]([F:44])([F:43])[C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:34]Br>O1CCCC1>[F:29][C:30]([F:44])([F:43])[C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:34][N:8]([CH3:9])[C:6](=[O:7])[C:5]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:11][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CNC(=O)c1cnc(Cl)cc1-c1ccccc1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cc(Cl)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
To a solution of 10.0 g (38.4 mmol) 6-chloro-N-methyl-4-o-tolyl-nicotinamide in 190 ml tetrahydrofuran 46 ml of a 1 M solution (46 mmol) of potassium hexamethyldisilazide in tetrahydrofuran were added at 0° C. After 30 min, 8.5 ml (46 mmol) 3,5-bis(trifluoromethyl)benzyl bromide were added dropwise to the resulting suspension. After completed addition the ice-water cooling bath was removed and the reaction mixture was allowed to warm to room temperature. After 2 h the reaction was quenched with water. The mixture was adjusted to pH 3 with 1 M aqueous hydrochloric acid solution and stirred for 10 min. Basification with 1 M aqueous sodium hydroxide solution to pH 8 was followed by concentration to remove tetrahydrofuran. The aqueous residue was extracted with four portions of dichloromethane. The combined organic extracts were dried with sodium sulfate and concentrated to give 21.4 g of crude product. Column chromatography afforded 18.4 g (98.5%) of the title compound as a white solid. MS m/e (%): 485 ([M−H]+, 2).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]([CH2:12][P:13]([O:17]Cl)([O:15]Cl)=[O:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4].[C:21]1([OH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.[C:35]1([SH:41])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CCOCC>[F:1][C:2]([F:20])([F:19])[C:3]([N:5]([CH:12]([O:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[P:13]([OH:17])([O:15][S:41][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Reactant: Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)CN(C(=O)C(F)(F)F)C(Oc1ccccc1)P(=O)(O)OSc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 64.6 %

Procedure:
A solution of ethyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (8.25 g, 0.025 mole) in ether (150 ml.) was cooled to 0° C. and a solution of phenol (2.35 g, 0.025 mole) and triethylamine (3.49 ml, 0.025 mole) in 50 ml. of ether was added to it. The resulting mixture was stirred for three hours, then filtered. The filtrate was cooled to 0° C. and thiophenol (2.5 ml, 0.025 mole) and triethylamine (3.49 ml, 0.025 mole) in 50 ml. of ether was added. The resulting solution was stirred overnight at 25° C., filtered and concentrated in vacuo. The residue was chromatographed on silica eluting first with methylene chloride, then with ether to yield ethyl N-trifluoroacetyl-N-(phenoxy(phenylthio)phosphonomethyl)glycinate (7.97 g) as a white solid, m.p. 80°-82° C.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[N:12]=[C:11]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH2:26][CH3:27])[NH:15][C:16](=[O:17])[C:10]2=[CH:9][N:8]=1.ClC1C=C(C=CC=1)C(OO)=[O:33]>ClCCl>[CH3:1][S:2]([CH2:3][CH2:4][CH2:5][NH:6][C:7]1[N:12]=[C:11]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH2:26][CH3:27])[NH:15][C:16](=[O:17])[C:10]2=[CH:9][N:8]=1)=[O:33]
Reactant: CCCOc1ccccc1-c1nc2nc(NCCCSC)ncc2c(=O)[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCOc1ccccc1-c1nc2nc(NCCCS(C)=O)ncc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 240 h

Procedure:
A cool (0° C.) solution of 7-(3-methylthiopropylamino)-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (1.84 g) and m-chloroperoxybenzoic acid (0.97 g) in dichloromethane (180 ml) was allowed to warm to ambient temperature with stirring. The solution was then stirred for 18 hours at ambient temperature and allowed to stand for 10 days. The reaction mixture was evaporated under reduced pressure and the residue eluted from a silica column with chloroform:methanol (gradient elution). The combined fractions containing product were evaporated under reduced pressure and the residue was recrystallized from isopropanol to yield the title compound, 1.73 g, m.p. 188-9° C.
Reaction SMILES: [C:1]([O:5]C([NH:8][CH:9]1[C:39](=[O:40])[N:11]2[C:12]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[C:13]([C:16]3[C:19](=[O:20])[C:18](=[O:21])[C:17]=3[CH3:22])[CH2:14][S:15][C@H:10]12)=O)(C)([CH3:3])[CH3:2].O.[C:42]1([CH3:52])[CH:47]=CC(S(O)(=O)=O)=CC=1.O>C(#N)C.C(OCC)(=O)C>[NH2:8][CH:9]1[C:39](=[O:40])[N:11]2[C:12]([C:23]([O:25][CH:26]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])=[C:13]([C:16]3[C:19](=[O:20])[C:18](=[O:21])[C:17]=3[CH3:22])[CH2:14][S:15][C@H:10]12.[CH:1]([O:5][CH:42]([CH3:47])[CH3:52])([CH3:3])[CH3:2]
Reactant: Cc1c(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)[C@H]3SC2)c(=O)c1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CC(C)OC(C)C
Product: Cc1c(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3SC2)c(=O)c1=O
Reaction time: 0.5 h

Procedure:
A solution of diphenylmethyl 7-(t-butoxycarbonylamino)-3-(3,4-dioxo-2-methyl-1-cyclobutenyl)-3-cephem-4-carboxylate (100 mg, 0.178 mmol) and p-toluenesulfonic acid monohydrate (pTSOH.H2O, 68 mg, 0.357 mmol) in acetonitrile (0.5 mL) was stirred for 1 hr at 22° C. when additional pTSOH.H2O (34 mg, 0.178 mmol) was added. Stirring was continued for an additional 0.5 hr when the mixture was diluted with ethyl acetate. The solution was sequentially washed with dilute aqueous NaHCO3, H2O, and saturated NaCl. The solution was dried (Na2SO4) and concentrated. The residue was chromatographed on SiO2 (6 g) with methylene chloride/2-propanol (97:3) to provide the title compound as a yellow solid after trituration with diisopropyl ether.
Reaction SMILES: O[CH2:2][C:3]1[NH:7][N:6]=[C:5]([O:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:4]=1.[F:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([NH:24][NH2:25])=O>C(Cl)(Cl)Cl.C1(C)C(C)=CC=CC=1.[O-2].[O-2].[Mn+4]>[F:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]1[N:7]2[N:6]=[C:5]([O:8][S:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)(=[O:11])=[O:10])[CH:4]=[C:3]2[CH:2]=[N:25][N:24]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(CO)[nH]n2)cc1
Reactant: NNC(=O)c1ccccc1F
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1C
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)Oc2cc3cnnc(-c4ccccc4F)n3n2)cc1
Temperature: 70 °C
Yield: 92.4 %

Procedure:
To a solution of toluene-4-sulfonic acid 5-hydroxymethyl-1H-pyrazol-3-yl ester (25 g, 93 mmol) in chloroform (800 ml) was added manganese dioxide (40.3 g, 465 mmol) and the suspension was heated at 70° C. for 14 h. The reaction mixture was filtered through sand/silica and the plug of silica was then washed several times with 10% methanol/dichloromethane. The combined filtrates were concentrated under vacuum to give crude aldehyde (25 g). Some of the crude aldehyde (2 g, 7.6 mmol) and 2-fluorobenzoic hydrazide (1.16 g, 7.6 mmol) were suspended in xylene (60 ml) and heated together at reflux for 3 h. After cooling, the solid formed was collected by filtration and dried under vacuum at 80° C. to afford 2.7 g (94%) of the condensation product as a light brown solid. Some of this condensation product, which existed in nmr solution as a mixture of isomers (1 g, 2.5 mmol), was dissolved in Dowtherm A (100 ml) and heated at 180° C. for 72 h. The whole reaction solution was cooled and eluted through a silica gel column using 0 to 15% ethyl acetate/dichloromethane to give the title compound as a light tan solid (0.614 g, 64%); 1H NMR (360 MHz, CDCl3) δ 2.46 (3H, s), 6.73 (1H, s), 7.18-7.35 (4H, m), 7.61 (1H, m), 7.71 (1H, m), 7.82 (2H, d, J 8.3 Hz), 9.33 (1H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(C)([O-])C.[K+]>CS(C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: Oc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Brc1ccc(Oc2ccccc2)nc1
Temperature: 160 °C
Reaction time: 4 h
Yield: 70.5 %

Procedure:
A mixture of 2,5-dibromo pyridine (25 g, 106 mmol), phenol (10.5 g, 111 mmol), potassium tert-butoxide (12.5 g, 111 mmol) and dimethyl sulfoxide (250 mL) was stirred for 4 hours at 160° C. This mixture was cooled to room temperature, and partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried with anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=10:1) to obtain the title compound (18.7 g, 70%).
Reaction SMILES: [C:1]12([S:11][CH2:12][CH2:13][NH:14][C@H:15]([C:17]([OH:19])=[O:18])[CH3:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(O)(=O)C.[N:24]([O-])=[O:25].[Na+]>O>[C:1]12([S:11][CH2:12][CH2:13][N:14]([N:24]=[O:25])[C@H:15]([C:17]([OH:19])=[O:18])[CH3:16])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: C[C@H](NCCSC12CC3CC(CC(C3)C1)C2)C(=O)O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C[C@@H](C(=O)O)N(CCSC12CC3CC(CC(C3)C1)C2)N=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of 22.7 parts of N-[2-(1- adamantylthio)ethyl]alanine in 216 parts of acetic acid is cooled to 15°, then treated with a solution of 6.2 parts of sodium nitrite in 20 parts of water, added dropwise over a 15 minute period. Stirring is continued at low temperature for an additional 15 minutes, then at room temperature for another 15 minutes. The resultant clear yellow solution is added to 1000 parts of ice-water and stirring is continued. The resultant mixture is extracted with methylene chloride. The organic phase is separated, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to yield, as a gumlike material, N-[2-(1-adamantylthio)ethyl]-N-nitrosoalanine.
Reaction SMILES: CS(C)=O.[OH:5][CH:6]1[CH2:28][CH2:27][C:9]2([C:13](=[O:14])[N:12]([C:15]3[CH:16]=[N:17][C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:19][CH:20]=3)[CH2:11][CH2:10]2)[CH2:8][CH2:7]1.C(Cl)(=O)C(Cl)=O.Cl>ClCCl.C(N(CC)CC)C>[F:26][C:23]([F:24])([F:25])[CH2:22][O:21][C:18]1[N:17]=[CH:16][C:15]([N:12]2[CH2:11][CH2:10][C:9]3([CH2:8][CH2:7][C:6](=[O:5])[CH2:28][CH2:27]3)[C:13]2=[O:14])=[CH:20][CH:19]=1
Reactant: O=C1N(c2ccc(OCC(F)(F)F)nc2)CCC12CCC(O)CC2
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC2(CC1)CCN(c1ccc(OCC(F)(F)F)nc1)C2=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 65.3 %

Procedure:
DMSO (5.19 mL) was added dropwise over a period of 5 minutes to a solution of 8-hydroxy-2-[6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-2-aza-spiro[4.5]decan-1-one (9.53 g, obtained in example 108, step 3) in dichloromethane (100 mL) that was cooled down to −78° C. in a CO2/acetone-bath. After 5 minutes, oxalylchloride (3.04 mL) was added dropwise over a period of 10 minutes and stirring was continued for 30 minutes at −78° C. Then, triethylamine (17 mL) was added dropwise over a period of 10 minutes to the reaction mixture and after 5 minutes, the mixture was allowed to warm to 20° C. The reaction mixture was poured into ice/water and was acidified with 2M aqueous HCl solution (150 mL) to pH 3. The aqueous phase was extracted two times with dichloromethane and the combined organic layers were washed with brine, dried over Na2SO4 and filtered. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, gradient of dichloromethane in acetonitrile) to give the title compound as a light yellow solid (6.19 g, 80%). MS (m/e): 343.2 [MH+].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6]O.[H-].[Na+].[H][H].O1C2C=CC=CC=2N=C1SCCCCC[N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37]>CN(C)C=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:1][CH2:5][CH2:4][CH2:3][CH2:2][CH2:6][C:36]1[CH:35]=[CH:34][CH:33]=[C:30]2[C:31]([NH:27][C:28](=[O:37])[C:29]=12)=[O:32]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCSc1nc2ccccc2o1
Reactant: [H][H]
Reactant: OCc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2c(CCCCCSCc3cccs3)cccc21
Temperature: 0 °C
Yield: 159.9 %

Procedure:
2 g (17.5 mM) of 2-thiophenemethanol was dissolved in 15 ml of dimethylformamide. Thereto was added 800 mg (20 mM) of 60% sodium hydride in a nitrogen stream with ice cooling, and the mixture was stirred. When hydrogen generation was over, thereto was dropwise added a solution of 6.5 g of N-{5-(2-benzoxazolylthio)pentyl}phthalimide in 30 ml of DMF. The resulting mixture was stirred for 3 hours with ice cooling and for 60 hours at room temperature to give rise to a reaction. After the completion of the reaction, the reaction mixture was placed in ice water. Extraction with benzene was conducted. The benzene layer was washed with water and a saturated aqueous sodium chloride solution in this order and dried over anhydrous sodium sulfate. The solvent was removed by distillation. The residue was purified by silica gel chromatography to obtain 4.84 g of N-{5-(2-thienylmethylthio)pentylphthalimide at a yield of 80%.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1.Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1>>[F:22][C:18]1[CH:17]=[C:16]([C:2]2[CH:14]=[CH:13][C:5]3[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=3[CH:3]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: Fc1cccc(Br)c1
Reactant: CC1(C)OC(=O)Nc2ccc(Br)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(F)c3)cc21

Procedure:
6-(3-Fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one was prepared, from 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and 1-bromo-3-fluorobenzene according to the procedure of Example 4, as a light yellow solid: mp 181-182° C.; 1H-NMR (DMSO-d6) δ10.4 (s, 1H), 7.62-7.44 (m, 5H), 7.16 (t, 1H, J=2.22 Hz), 6.97 (d, 1H, J=8.83), 1.67 (s, 6H); MS (EI) m/z 271 ([M+H]+, 40%); Anal. Calc. For C16H14FNO2: C, 69.91; H, 5.3; N, 5.1. Found: C, 70.0; H, 5.32; N, 4.92.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][C:14](=[O:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])(C)(C)C.[Cl:17][C:18]1[CH:23]=[C:22]([N:24]=C=O)[CH:21]=[C:20]([Cl:27])[CH:19]=1.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:33][NH2:34]>>[Cl:27][C:20]1[CH:21]=[C:22]([NH:24][C:6]([N:8]2[CH2:15][C:14](=[O:16])[CH2:13][C@H:9]2[C:10]([NH:34][CH2:33][C:32]2[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:30]([O:29][CH3:28])[CH:31]=2)=[O:12])=[O:7])[CH:23]=[C:18]([Cl:17])[CH:19]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Product: COc1ccc(CNC(=O)[C@@H]2CC(=O)CN2C(=O)Nc2cc(Cl)cc(Cl)c2)cc1OC

Procedure:
Following the general method as outlined in Example 22, starting from 1-(tert-butoxycarbonyl)-4-oxoproline, 1,3-dichloro-5-isocyanatobenzene, and 3,4-dimethoxybenzylamine the title compound was obtained in 48% purity by LC/MS. MS(ESI+): m/z=466.6.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=[O:8])=[CH:3][N:2]=1.OS(O)(=O)=O.[CH2:15](O)[CH3:16]>>[CH2:15]([O:8][C:7]([C:4]1[CH:5]=[CH:6][N:1]=[N:2][CH:3]=1)=[O:9])[CH3:16]
Reactant: CCO
Reactant: O=C(O)c1ccnnc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccnnc1
Yield: 79 %

Procedure:
To pyridazine-4-carboxylic acid (1.0 g, 8.1 mmol) in ethanol (10 mL) was added concentrated H2SO4 (4.2 mL) and then heated at reflux for 5 hours. The reaction mixture was cooled, concentrated in vacuo and basified with saturated Na2CO3. After filtration, the aqueous was extracted with ethyl acetate, dried over anhydrous Na2SO4, filtered and concentrated to give the title product as a dark yellow oil (970 mg, 79%).